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Bibliography on: The Denisovans, Another Human Ancestor

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The Denisovans, Another Human Ancestor

Wikipedia: The Denisovans are an extinct species or subspecies of human in the genus Homo. In March 2010, scientists announced the discovery of a finger bone fragment of a juvenile female who lived about 41,000 years ago, found in the remote Denisova Cave in the Altai Mountains in Siberia, a cave that has also been inhabited by Neanderthals and modern humans. Two teeth belonging to different members of the same population have since been reported. In November 2015, a tooth fossil containing DNA was reported to have been found and studied. A bone needle dated to 50,000 years ago was discovered at the archaeological site in 2016 and is described as the most ancient needle known. Analysis of the mitochondrial DNA (mtDNA) of the finger bone showed it to be genetically distinct from the mtDNAs of Neanderthals and modern humans. Subsequent study of the nuclear genome from this specimen suggests that Denisovans shared a common origin with Neanderthals, that they ranged from Siberia to Southeast Asia, and that they lived among and interbred with the ancestors of some modern humans. A comparison with the genome of a Neanderthal from the same cave revealed significant local interbreeding with local Neanderthal DNA representing 17% of the Denisovan genome, while evidence was also detected of interbreeding with an as yet unidentified ancient human lineage.

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Citations The Papers (from PubMed®)

RevDate: 2019-10-08

Colbran LL, Gamazon ER, Zhou D, et al (2019)

Inferred divergent gene regulation in archaic hominins reveals potential phenotypic differences.

Nature ecology & evolution pii:10.1038/s41559-019-0996-x [Epub ahead of print].

Sequencing DNA derived from archaic bones has enabled genetic comparison of Neanderthals and anatomically modern humans (AMHs), and revealed that they interbred. However, interpreting what genetic differences imply about their phenotypic differences remains challenging. Here, we introduce an approach for identifying divergent gene regulation between archaic hominins, such as Neanderthals, and AMH sequences, and find 766 genes that are likely to have been divergently regulated (DR) by Neanderthal haplotypes that do not remain in AMHs. DR genes include many involved in phenotypes known to differ between Neanderthals and AMHs, such as the structure of the rib cage and supraorbital ridge development. They are also enriched for genes associated with spontaneous abortion, polycystic ovary syndrome, myocardial infarction and melanoma. Phenotypes associated with modern human variation in these genes' regulation in ~23,000 biobank patients further support their involvement in immune and cardiovascular phenotypes. Comparing DR genes between two Neanderthals and a Denisovan revealed divergence in the immune system and in genes associated with skeletal and dental morphology that are consistent with the archaeological record. These results establish differences in gene regulatory architecture between AMHs and archaic hominins, and provide an avenue for exploring phenotypic differences between archaic groups from genomic information alone.

RevDate: 2019-09-30

Shchenkov SV, Denisova SA, Kremnev GA, et al (2019)

Five new morphological types of virgulate and microcotylous xiphidiocercariae based on morphological and molecular phylogenetic analyses.

Journal of helminthology pii:S0022149X19000853 [Epub ahead of print].

The phylogenetic position of most xiphidiocercariae from subgroups Cercariae virgulae and Cercariae microcotylae remains unknown or unclear, even at the family level. In this paper, we studied the morphology and molecular phylogeny of 15 microcotylous and virgulate cercariae (11 new and four previously described ones). Based on morphological and molecular data, we suggested five distinct morphological types of xiphidiocercariae, which are a practical alternative to Cercariae virgulae and Cercariae microcotylae subgroups. Four of these types correspond to actual digenean taxa (Microphallidae, Lecithodendriidae, Pleurogenidae and Prosthogonimidae), while the fifth is represented by Cercaria nigrospora Wergun, 1957, which we classified on the basis of molecular data for the first time. We reassessed the relative importance of morphological characters used for the classification of virgulate and microcotylous cercariae, and discussed the main evolutionary trends within xiphidiocercariae. Now stylet cercariae can be reliably placed into several sub-taxa of Microphalloidea on the basis of their morphological features.

RevDate: 2019-09-27

Mata X, Renaud G, C Mollereau (2019)

The repertoire of family A-peptide GPCRs in archaic hominins.

Peptides pii:S0196-9781(19)30132-9 [Epub ahead of print].

Given the importance of G-protein coupled receptors in the regulation of many physiological functions, deciphering the relationships between genotype and phenotype in past and present hominin GPCRs is of main interest to understand the evolutionary process that contributed to the present-day variability in human traits and health. Here, we carefully examined the publicly available genomic and protein sequence databases of the archaic hominins (Neanderthal and Denisova) to draw up the catalog of coding variations in GPCRs for peptide ligands, in comparison with living humans. We then searched in the literature the functional changes, phenotypes and risk of disease possibly associated with the detected variants. Our survey suggests that Neanderthal and Denisovan hominins were likely prone to lower risk of obesity, to enhanced platelet aggregation in response to thrombin, to better response to infection, to less anxiety and aggressiveness and to favorable sociability. While some archaic variants were likely advantageous in the past, they might be responsible for maladaptive disorders today in the context of modern life and/or specific regional distribution. For example, an archaic haplotype in the neuromedin receptor 2 is susceptible to confer risk of diabetic nephropathy in type 1 diabetes in present-day Europeans. Paying attention to the pharmacological properties of some of the archaic variants described in this study may be helpful to understand the variability of therapeutic efficacy between individuals or ethnic groups.

RevDate: 2019-09-27

Morley MW, Goldberg P, Uliyanov VA, et al (2019)

Hominin and animal activities in the microstratigraphic record from Denisova Cave (Altai Mountains, Russia).

Scientific reports, 9(1):13785 pii:10.1038/s41598-019-49930-3.

Denisova Cave in southern Siberia uniquely contains evidence of occupation by a recently discovered group of archaic hominins, the Denisovans, starting from the middle of the Middle Pleistocene. Artefacts, ancient DNA and a range of animal and plant remains have been recovered from the sedimentary deposits, along with a few fragmentary fossils of Denisovans, Neanderthals and a first-generation Neanderthal-Denisovan offspring. The deposits also contain microscopic traces of hominin and animal activities that can provide insights into the use of the cave over the last 300,000 years. Here we report the results of a micromorphological study of intact sediment blocks collected from the Pleistocene deposits in the Main and East Chambers of Denisova Cave. The presence of charcoal attests to the use of fire by hominins, but other evidence of their activities preserved in the microstratigraphic record are few. The ubiquitous occurrence of coprolites, which we attribute primarily to hyenas, indicates that the site was visited for much of its depositional history by cave-dwelling carnivores. Microscopic traces of post-depositional diagenesis, bioturbation and incipient cryoturbation are observed in only a few regions of the deposit examined here. Micromorphology can help identify areas of sedimentary deposit that are most conducive to ancient DNA preservation and could be usefully integrated with DNA analyses of sediments at archaeological sites to illuminate features of their human and environmental history that are invisible to the naked eye.

RevDate: 2019-09-20

Gokhman D, Mishol N, de Manuel M, et al (2019)

Reconstructing Denisovan Anatomy Using DNA Methylation Maps.

Cell, 179(1):180-192.e10.

Denisovans are an extinct group of humans whose morphology remains unknown. Here, we present a method for reconstructing skeletal morphology using DNA methylation patterns. Our method is based on linking unidirectional methylation changes to loss-of-function phenotypes. We tested performance by reconstructing Neanderthal and chimpanzee skeletal morphologies and obtained >85% precision in identifying divergent traits. We then applied this method to the Denisovan and offer a putative morphological profile. We suggest that Denisovans likely shared with Neanderthals traits such as an elongated face and a wide pelvis. We also identify Denisovan-derived changes, such as an increased dental arch and lateral cranial expansion. Our predictions match the only morphologically informative Denisovan bone to date, as well as the Xuchang skull, which was suggested by some to be a Denisovan. We conclude that DNA methylation can be used to reconstruct anatomical features, including some that do not survive in the fossil record.

RevDate: 2019-09-19

Zammit NW, Siggs OM, Gray PE, et al (2019)

Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity.

Nature immunology pii:10.1038/s41590-019-0492-0 [Epub ahead of print].

Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A;I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.

RevDate: 2019-09-13

Bennett EA, Crevecoeur I, Viola B, et al (2019)

Morphology of the Denisovan phalanx closer to modern humans than to Neanderthals.

Science advances, 5(9):eaaw3950 pii:aaw3950.

A fully sequenced high-quality genome has revealed in 2010 the existence of a human population in Asia, the Denisovans, related to and contemporaneous with Neanderthals. Only five skeletal remains are known from Denisovans, mostly molars; the proximal fragment of a fifth finger phalanx used to generate the genome, however, was too incomplete to yield useful morphological information. Here, we demonstrate through ancient DNA analysis that a distal fragment of a fifth finger phalanx from the Denisova Cave is the larger, missing part of this phalanx. Our morphometric analysis shows that its dimensions and shape are within the variability of Homo sapiens and distinct from the Neanderthal fifth finger phalanges. Thus, unlike Denisovan molars, which display archaic characteristics not found in modern humans, the only morphologically informative Denisovan postcranial bone identified to date is suggested here to be plesiomorphic and shared between Denisovans and modern humans.

RevDate: 2019-09-11

Callaway E (2019)

Lost Denisovan bone reveals surprisingly human-like finger.

Nature, 573(7773):175-176.

RevDate: 2019-09-02

Garduño-Alanís A, Malyutina S, Pajak A, et al (2019)

Association between soft drink, fruit juice consumption and obesity in Eastern Europe: cross-sectional and longitudinal analysis of the HAPIEE study.

Journal of human nutrition and dietetics : the official journal of the British Dietetic Association [Epub ahead of print].

BACKGROUND: Fruit juice and soft drink consumption have been shown to be related to obesity. However, this relationship has not been explored in Eastern Europe. The present study aimed to assess the cross-sectional and longitudinal relationships between fruit juice, soft drink consumption and body mass index (BMI) in Eastern European cohorts.

METHODS: Data from the Health, Alcohol and Psychosocial factors in Eastern Europe population-based prospective cohort study, based in Russia, Poland and the Czech Republic, were used. Intakes of sugar-sweetened beverage (SSB), artificially-sweetened beverage (ASB) and fruit juice were estimated from a food frequency questionnaire. Participant BMI values were assessed at baseline (n = 26 634) and after a 3-year follow-up (data available only for Russia, n = 5205).

RESULTS: Soft drink consumption was generally low, particularly in Russia. Compared to never drinkers of SSB, participants who drank SSB every day had a significantly higher BMI in the Czech [β-coefficient = 0.28; 95% confidence interval (CI) = 0.02-0.54], Russian (β-coefficient = 1.38; 95% CI = 0.62-2.15) and Polish (β-coefficient = 0.83; 95% CI = 0.29-1.37) cohorts. Occasional or daily ASB consumption was also positively associated with BMI in all three cohorts. Results for daily fruit juice intake were inconsistent, with a positive association amongst Russians (β-coefficient = 0.75; 95% CI = 0.28-1.21) but a negative trend in the Czech Republic (β-coefficient = -0.42; 95% CI = -0.86 to 0.02). Russians participants who drank SSB or ASB had an increased BMI after follow-up.

CONCLUSIONS: Our findings support previous studies suggesting that soft drink consumption (including SSBs and ASBs) is positively related to BMI, whereas our results for fruit juice were less consistent. Policies regarding these beverages should be considered in Eastern Europe to lower the risk of obesity.

RevDate: 2019-08-28

Eremin D, Denisova E, Kostyukovich A, et al (2019)

Ionic Pd/NHC Catalytic System Enables Recoverable Homogeneous Catalysis. Mechanistic Study and Application in the Mizoroki-Heck Reaction.

Chemistry (Weinheim an der Bergstrasse, Germany) [Epub ahead of print].

N-Heterocyclic carbene ligands (NHC) are ubiquitously utilized in catalysis. A common catalyst design model assumes strong M-NHC binding in this metal-ligand framework. In contrast to this common assumption, we demonstrate here that lability and controlled cleavage of the M-NHC bond (rather than its stabilization) could be more important for high-performance catalysis at low catalyst concentrations. The present study reveals a dynamic stabilization mechanism with labile metal-NHC binding and [PdX3]-[NHC-R]+ ion pair formation. Access to reactive anionic palladium intermediates formed by dissociation of the NHC ligands and plausible stabilization of the molecular catalyst in solution by interaction with the [NHC-R]+ azolium cation is of particular importance for an efficient and recyclable catalyst. These ionic Pd/NHC complexes allowed for the first time the recycling of the complex in a well-defined form with isolation at each cycle. Computational investigation of the reaction mechanism confirms a facile formation of NHC-free anionic Pd in polar media via either Ph-NHC coupling or reversible H-NHC coupling. The present study formulates novel ideas for M/NHC catalyst design.

RevDate: 2019-08-26

Denisova EA, Eremin DB, Gordeev EG, et al (2019)

Addressing Reversibility of R-NHC Coupling on Palladium: Is Nano-to-Molecular Transition Possible for the Pd/NHC System?.

Inorganic chemistry [Epub ahead of print].

It has recently been shown that palladium-catalyzed reactions with N-heterocyclic carbene (NHC) ligands involve R-NHC coupling accompanied by transformation of the molecular catalytic system into the nanoscale catalytic system. An important question appeared in this regard is whether such a change in the catalytic system is irreversible. More specifically, is the reverse nano-to-molecular transformation possible? In view of the paramount significance of this question to the area of catalyst design, we studied the capability of 2-substituted azolium salts to undergo the breakage of C-C bond and exchange substituents on the carbene carbon with corresponding aryl halides in the presence of Pd nanoparticles. The study provides important experimental evidence of possibility of the reversible R-NHC coupling. The observed behavior indicates that the nanosized metal species are capable of reverse transition to molecular species. Such an option, known for phosphine ligands, was previously unexplored for NHC ligands. The present study for the first time demonstrates bidirectional dynamic transitions between the molecular and nanostructured states in Pd/NHC systems. As a unique feature, surprisingly small activation barriers (<18 kcal/mol) and noticeable thermodynamic driving force (-5 to -7 kcal/mol) were calculated for C-C bond oxidative addition to Pd(0) centers in the studied system. The first example of NHC-mediated Pd leaching from metal nanoparticles to solution was observed and formation of Pd/NHC complex in solution was detected by ESI-MS.

RevDate: 2019-08-22

Mikaeeli S, Susan-Resiga D, Girard E, et al (2019)

Functional analysis of natural PCSK9 mutants in modern and archaic humans.

The FEBS journal [Epub ahead of print].

PCSK9 is the last member of the proprotein convertases (PCs) family and its gene is mutated in ~ 2% to 3% of individuals with familial hypercholesterolemia (FH). This protein enhances the degradation of the low-density lipoprotein receptor (LDLR) and hence increases the levels of circulating LDL-cholesterol (LDLc). Studies of the underlying mechanism(s) regulating the activity of different mutations in the PCSK9 gene are ongoing as they enhance our understanding of the biology and clinical relevance of PCSK9 and its partners. In an attempt to unravel the regulation of PCSK9 transcription and possibly identify mutation 'hot spot' regions with alterations in CpG methylation, we present for the first time the complete methylome profile of the PCSK9 gene in modern and archaic humanoids. Our data showed that the genomes of modern humans and archaic PCSK9 exhibit a similar methylation pattern. Next, we defined the mechanistic consequences of three PCSK9 natural mutations (PCSK9-R96L, -R105W, and -P174S) and one archaic Denisovan mutation (PCSK9-H449L) using various complementary cellular and in vitro binding assays. Our results showed that the PCSK9-H449L is a loss-of-function (LOF) mutation, likely due to its lower binding affinity to the LDLR. Similarly, PCSK9-R96L and -R105W are LOF mutations, even though they have been identified in FH patients. The PCSK9-R105W mutation leads to a significantly lower autocatalytic processing of proPCSK9. PCSK9-P174S resulted in a LOF in both extracellular and intracellular pathways. In conclusion, our extensive analyses revealed that all studied mutations result in PCSK9 LOF, via various mechanisms, leading to lower levels of LDLc.

RevDate: 2019-08-02

Derenko M, Denisova G, Malyarchuk B, et al (2019)

Insights into matrilineal genetic structure, differentiation and ancestry of Armenians based on complete mitogenome data.

Molecular genetics and genomics : MGG pii:10.1007/s00438-019-01596-2 [Epub ahead of print].

Distinctive peculiarities of Armenians such as their millennia-long genetic isolation and strong national identity attract a keen interest while studying the demographic history of the West Asia. Here, to examine their fine-scale matrilineal genetic structure, ancestry and relationships with neighboring populations, we analyzed 536 complete mitogenomes (141 of which are novel) from 8 geographically different Armenian populations, covering the whole stretch of historical Armenia. The observed patterns highlight a remarkable degree of matrilineal genetic heterogeneity and weak population structuring of Armenians. Moreover, our phylogeographic analysis reveals common ancestries for some mtDNA lineages shared by West Asians, Transcaucasians, Europeans, Central Asians and Armenians. About third of the mtDNA subhaplogroups found in Armenian gene pool might be considered as Armenian-specific, as these are virtually absent elsewhere in Europe, West Asia and Transcaucasia. Coalescence ages of most of these lineages do not exceed 3.1 kya and coincide well with the population size growth started around 1.8-2.8 kya detectable only in the Bayesian Skyline Plots based on the Armenian-specific mtDNA haplotypes.

RevDate: 2019-08-04

Bailey SE, Hublin JJ, SC Antón (2019)

Rare dental trait provides morphological evidence of archaic introgression in Asian fossil record.

Proceedings of the National Academy of Sciences of the United States of America, 116(30):14806-14807.

The recently described Denisovan hemimandible from Xiahe, China [F. Chen et al., (2019) Nature 569, 409-412], possesses an unusual dental feature: a 3-rooted lower second molar. A survey of the clinical and bioarchaeological literature demonstrates that the 3-rooted lower molar is rare (less than 3.5% occurrence) in non-Asian Homo sapiens In contrast, its presence in Asian-derived populations can exceed 40% in China and the New World. It has long been thought that the prevalence of 3-rooted lower molars in Asia is a relatively late acquisition occurring well after the origin and dispersal of H. sapiens However, the presence of a 3-rooted lower second molar in this 160,000-y-old fossil hominin suggests greater antiquity for the trait. Importantly, it also provides morphological evidence of a strong link between archaic and recent Asian H. sapiens populations. This link provides compelling evidence that modern Asian lineages acquired the 3-rooted lower molar via introgression from Denisovans.

RevDate: 2019-07-06

Brzozowska MM, Havula E, Allen RB, et al (2019)

Genetics, adaptation to environmental changes and archaic admixture in the pathogenesis of diabetes mellitus in Indigenous Australians.

Reviews in endocrine & metabolic disorders pii:10.1007/s11154-019-09505-z [Epub ahead of print].

Indigenous Australians are particularly affected by type 2 diabetes mellitus (T2D) due to both their genetic susceptibility and a range of environmental and lifestyle risk factors. Recent genetic studies link predisposition to some diseases, including T2D, to alleles acquired from archaic hominins, such as Neanderthals and Denisovans, which persist in the genomes of modern humans today. Indo-Pacific human populations, including Indigenous Australians, remain extremely underrepresented in genomic research with a paucity of data examining the impact of Denisovan or Neanderthal lineages on human phenotypes in Oceania. The few genetic studies undertaken emphasize the uniqueness and antiquity of Indigenous Australian genomes, with possibly the largest proportion of Denisovan ancestry of any population in the world. In this review, we focus on the potential contributions of ancient genes/pathways to modern human phenotypes, while also highlighting the evolutionary roles of genetic adaptation to dietary and environmental changes associated with an adopted Western lifestyle. We discuss the role of genetic and epigenetic factors in the pathogenesis of T2D in understudied Indigenous Australians, including the potential impact of archaic gene lineages on this disease. Finally, we propose that greater understanding of the underlying genetic predisposition may contribute to the clinical efficacy of diabetes management in Indigenous Australians. We suggest that improved identification of T2D risk variants in Oceania is needed. Such studies promise to clarify how genetic and phenotypic differences vary between populations and, crucially, provide novel targets for personalised medical therapies in currently marginalized groups.

RevDate: 2019-07-10

Kobelkova IV, Martinchik AN, Keshabyants EE, et al (2019)

[An analysis of the diet of members of the Russian national men's water polo team during the sports training camps].

Voprosy pitaniia, 88(2):50-57.

Increasing the adaptive capacity of professional athletes depends on proper nutrition, especially in training and competitions' period. In this regard, it is relevant to study the actual nutrition and assess its compliance with the energy expenditure of athletes. The aim - to study the actual nutrition and energy expenditure of athletes from male water polo national team of the Russian Federation in the competitive period. Material and methods. In March 2018, 15 highly skilled sportsmen-men engaged in water polo were examined; qualification - 11 masters of sports, 4 candidates for the master of sports; Slavic ethnos. The average age was 23.1±0.6 years. The actual nutrition was studied by a 24-hour food record method and by the frequency method. The anthropometric examination was carried out according to a unified method using standard medical scales, a medical height meter and a rubberized measuring tape. Measurement of energy expenditure and heart rate at rest and under load was performed on a bicycle ergometer using an wireless ergospirometer and a chest pulse meter. Results and discussion. The determination of daily energy expenditure in athletes of the men's Russian national water polo team showed that the average value was 4350±129 kcal. А peculiar feature of the diet of water polo players is its high caloric value (5165±539 kcal/day), caused by energy expenditure during physical exertion and additional thermogenesis in conditions of long training in water. Excessive (1.5 times in comparison with the recommended values) consumption of fats, including saturated fatty acids by 1.3 times, added sugar and added salt is a risk factor of cardiovascular diseases, diseases of digestive organs, endocrine system, including type 2 diabetes. Low values of consumption of vegetables and fruits, dairy products, fish products and high levels of sugar and confectionery have been established. Conclusion. The imbalance of diets on two basic nutrients (fats, carbohydrates) has been revealed. The data obtained were the basis for the formation of individual recommendations on nutrition for each athlete, taking into account athletes' metabolic parameters and the level of physical activity. It is necessary to continue studies of anthropometric indices in dynamics for the most adequate assessment of the compliance of actual nutrition with energy consumption, and further correction of the diet in order to improve athletes' performance.

RevDate: 2019-08-28
CmpDate: 2019-08-28

Denisova OA, Livzan MA, Denisov AP, et al (2019)

[Clinical aspect of diagnostics of gastroesophageal reflux disease in elderly patients.].

Advances in gerontology = Uspekhi gerontologii, 32(1-2):108-111.

Insufficient knowledge age peculiarities of gastroesophageal reflux disease (GERD) in the elderly against the background of its prevalence determine the high demand for studies on the topic. In an open study cohort by cross-sectional analysis was conducted clinical features GERD patients older age groups. By continuous sampling of 90 patients taken away: the main group - 45 persons 60-86, comparison group - 45 persons 25-59 years. Found that for GERD in patients older than 60 years has its own characteristics. Maximum observed incidence of GERD in the range of 60-69 years (57%) with a further reduction. More typical is a decrease in the frequency of heartburn (p<0,05) with increasing retrosternal pain (p<0,001) and dysphagia (p<0,05) and coughing (p<0,001) with simultaneous increase in the number of complaints from various organs and systems. In this case, deterioration of health associated with a statistically significant reduction in quality of life parameters when compared with the young. When survey by questionnaire SF-36 in elderly patients reported a more marked reduction of scales that characterize the physical and psychological health of the component against high polymorbidity. Identified features of the flow of GERD in the elderly, may be useful for streamlining diagnosis and therapy.

RevDate: 2019-06-27

Zotova TY, Lapaev NN, Azova MM, et al (2019)

Distribution of Polymorphisms of the Renin-Angiotensin System Genes (ACE, AGT, and AGTR1), ITGB3, and FTO in Pregnant Patients with Hypertensive Disorders.

Bulletin of experimental biology and medicine, 167(1):74-78.

The study included pregnant women aged 23-41 years with preeclampsia and gestation-associated arterial hypertension at weeks 27-40 and patients with essential arterial hypertension developing under conditions of the metabolic syndrome and without it. Frequency analysis of polymorphisms of the renin-angiotensin system genes (ACE, AGT, and AGTR1), ITGB3, FTO and their associations confirmed the syndrome nature of hypertensive disorders in pregnancy. The presence allele T of AGT gene and/or allele C of AGTR1 gene in the genotype of patients with preeclampsia was associated with higher BP and pressure load over 24 h. Allele D of ACE gene was also essential for BP parameters (pressure load) in patients with preeclampsia and gestation-associated arterial hypertension. Due to high genetic heterogeneity of the preeclampsia syndrome and genetic differences in the incidence of the studied gene polymorphisms in preeclampsia and gestation-associated arterial hypertension, no direct associations between these gestation disorders and polymorphic markers of the renin-angiotensin system genes can be established. However, polymorphisms of the renin-angiotensin system genes are essential for the 24-h dynamics of BP and pressure load under conditions of hypertensive disorders in pregnancy.

RevDate: 2019-08-06

Shebanits K, Günther T, Johansson ACV, et al (2019)

Copy number determination of the gene for the human pancreatic polypeptide receptor NPY4R using read depth analysis and droplet digital PCR.

BMC biotechnology, 19(1):31 pii:10.1186/s12896-019-0523-9.

BACKGROUND: Copy number variation (CNV) plays an important role in human genetic diversity and has been associated with multiple complex disorders. Here we investigate a CNV on chromosome 10q11.22 that spans NPY4R, the gene for the appetite-regulating pancreatic polypeptide receptor Y4. This genomic region has been challenging to map due to multiple repeated elements and its precise organization has not yet been resolved. Previous studies using microarrays were interpreted to show that the most common copy number was 2 per genome.

RESULTS: We have investigated 18 individuals from the 1000 Genomes project using the well-established method of read depth analysis and the new droplet digital PCR (ddPCR) method. We find that the most common copy number for NPY4R is 4. The estimated number of copies ranged from three to seven based on read depth analyses with Control-FREEC and CNVnator, and from four to seven based on ddPCR. We suggest that the difference between our results and those published previously can be explained by methodological differences such as reference gene choice, data normalization and method reliability. Three high-quality archaic human genomes (two Neanderthal and one Denisova) display four copies of the NPY4R gene indicating that a duplication occurred prior to the human-Neanderthal/Denisova split.

CONCLUSIONS: We conclude that ddPCR is a sensitive and reliable method for CNV determination, that it can be used for read depth calibration in CNV studies based on already available whole-genome sequencing data, and that further investigation of NPY4R copy number variation and its consequences are necessary due to the role of Y4 receptor in food intake regulation.

RevDate: 2019-07-15

Santander C, Montinaro F, C Capelli (2019)

Searching for archaic contribution in Africa.

Annals of human biology, 46(2):129-139.

Context: Africa's role in the narrative of human evolution is indisputably emphasised in the emergence of Homo sapiens. However, once humans dispersed beyond Africa, the history of those who stayed remains vastly under-studied, lacking the proper attention the birthplace of both modern and archaic humans deserves. The sequencing of Neanderthal and Denisovan genomes has elucidated evidence of admixture between archaic and modern humans outside of Africa, but has not aided efforts in answering whether archaic admixture happened within Africa. Objectives: This article reviews the state of research for archaic introgression in African populations and discusses recent insights into this topic. Methods: Gathering published sources and recently released preprints, this review reports on the different methods developed for detecting archaic introgression. Particularly it discusses how relevant these are when implemented on African populations and what findings these studies have shown so far. Results: Methods for detecting archaic introgression have been predominantly developed and implemented on non-African populations. Recent preprints present new methods considering African populations. While a number of studies using these methods suggest archaic introgression in Africa, without an African archaic genome to validate these results, such findings remain as putative archaic introgression. Conclusion: In light of the caveats with implementing current archaic introgression detection methods in Africa, we recommend future studies to concentrate on unravelling the complicated demographic history of Africa through means of ancient DNA where possible and through more focused efforts to sequence modern DNA from more representative populations across the African continent.

RevDate: 2019-08-27

Denisova K (2019)

Failure to attune to language predicts autism in high risk infants.

Brain and language, 194:109-120.

Young humans are typically sensitive to evolutionarily important aspects of information in the surrounding environment in a way that makes us thrive. Seeking to probe the putative disruptions of this process in infancy, I examined the statistical character of head movements in 52 9-10 mo-old infants, half at high familial risk (HR) for Autism Spectrum Disorders (ASD), who underwent an fMRI scan while listening to words spoken with alternating stress patterns on syllables. Relative to low risk (LR) infants, HR infants, in particular those showing the least rapid receptive language progress, had significantly lower noise-to-signal levels and increased symmetry. A comparison of patterns during a native language and a sleep scan revealed the most atypical ordering of signatures on the 3 tasks in a subset of HR infants, suggesting that the biological mechanism of language development is least acquisitive in those HR infants who go on to develop ASD in toddlerhood.

RevDate: 2019-08-30

Denisova K (2019)

Age attenuates noise and increases symmetry of head movements during sleep resting-state fMRI in healthy neonates, infants, and toddlers.

Infant behavior & development, 57:101317 pii:S0163-6383(19)30009-8 [Epub ahead of print].

Newborns produce spontaneous movements during sleep that are functionally important for their future development. This nuance has been previously studied using animal models and more recently using movement data from sleep resting-state fMRI (rs-fMRI) scans. Age-related trajectory of statistical features of spontaneous movements of the head is under-examined. This study quantitatively mapped a developmental trajectory of spontaneous head movements during an rs-fMRI scan acquired during natural sleep in 91 datasets from healthy children from ∼birth to 3 years old, using the Open Science Infancy Research upcycling protocol. The youngest participants studied, 2-3 week-old neonates, showed increased noise-to-signal levels as well as lower symmetry features of their movements; noise-to-signal levels were attenuated and symmetry was increased in the older infants and toddlers (all Spearman's rank-order correlations, P < 0.05). Thus, statistical features of spontaneous head movements become more symmetrical and less noisy from birth to ∼3 years in children. Because spontaneous movements during sleep in early life may trigger new neuronal activity in the cortex, the key outstanding question for in vivo, non-invasive neuroimaging studies in young children is not "How can we correct head movement better?" but rather: How can we represent all important sources of neuronal activity that shape functional connections in the still-developing human central nervous system?

RevDate: 2019-06-25
CmpDate: 2019-06-25

Kovalkova NA, Ragino YI, Scherbakova LV, et al (2019)

Relationships of arterial hypertension and reduced renal function in a population 25-45 years.

Terapevticheskii arkhiv, 91(1):64-70.

AIM: To study relationships of reduced renal function with hypertension and other cardiometabolic risk factors in persons aged 25-45 years.

MATERIALS AND METHODS: A cross-sectional population study of one of the typical district of Novosibirsk (Russia) was performed during 2013-2016 years. The study included 468 men and 606 women aged 25-45 years. Blood pressure (BP), waist circumference (WC), blood lipids, glucose, creatinine were measured. Glomerular filtration rate (GFR) was calculated with the formula CKD-EPI. Hypertension was registered if blood pressure (BP) was ≥140/90 mm Hg, reduced kidney function - at GFR<90 ml/min/1.73 cm2.

RESULTS: Prevalence of hypertension among men was 28%, among women - 9%. The proportion of people with GFR<90 ml/min/1.73 cm2 among men was 9.8%, among women - 34%. Among all examined people GFRs <60 ml/min/1.73 cm2 was revealed in 0.3% only. The association of hypertension with reduced renal function was determined only in men. Based on results of multivariate linear regression analysis, a significant negative association of GFR with age was determined, there was no association of GFR with systolic BP (SBP) in either men or women. In men, inverse relationships of GFR with low-density lipoprotein cholesterol (LDL-С), triglycerides (TG), direct - with WC were determined. Significant inverse association of GFR with diastolic BP (DBP) was revealed only after exception of TG from the regression model. In women, GFR's inverse relationship with LDL-С and DBP was observed, and the direct - with WC. In stepwise analysis the validity of all associations was confirmed after exception of the association of GFR with WC in men.

CONCLUSION: In a population of 25-45 years a reduced GFR was associated with increased DBP; levels of LDL-С, TG showed negative association with GFR; in men increased TG levels were more important in reducing GFR than elevated DBP.

RevDate: 2019-05-15

Denisova SA, SV Shchenkov (2019)

New data on the nervous system of Cercaria parvicaudata Stunkard & Shaw, 1931 (Trematoda: Renicolidae): revisiting old hypotheses.

Journal of helminthology pii:S0022149X1900035X [Epub ahead of print].

Data on the interposition of the immunoreactive nerve cords in Cercaria parvicaudata Stunkard & Shaw, 1931 (Trematoda: Renicolidae) and its chaetotaxy were obtained. The nervous system of C. parvicaudata was described using immunostaining of 5-hydroxytryptamine and FMRFamide immunoreactive nerve elements. The morphology and distribution of sensory receptors were analysed using scanning electron microscopy and the silver nitrate impregnation technique. Our integrated approach to the study of the nervous system revealed a clear colocalization of surface papillae with nerve cords and commissures in C. parvicaudata. The structure of the nervous system in C. parvicaudata differs partly from the classical model that defines the entire nomenclature of chaetotaxy.

RevDate: 2019-05-16

Chen F, Welker F, Shen CC, et al (2019)

A late Middle Pleistocene Denisovan mandible from the Tibetan Plateau.

Nature, 569(7756):409-412.

Denisovans are members of a hominin group who are currently only known directly from fragmentary fossils, the genomes of which have been studied from a single site, Denisova Cave1-3 in Siberia. They are also known indirectly from their genetic legacy through gene flow into several low-altitude East Asian populations4,5 and high-altitude modern Tibetans6. The lack of morphologically informative Denisovan fossils hinders our ability to connect geographically and temporally dispersed fossil hominins from Asia and to understand in a coherent manner their relation to recent Asian populations. This includes understanding the genetic adaptation of humans to the high-altitude Tibetan Plateau7,8, which was inherited from the Denisovans. Here we report a Denisovan mandible, identified by ancient protein analysis9,10, found on the Tibetan Plateau in Baishiya Karst Cave, Xiahe, Gansu, China. We determine the mandible to be at least 160 thousand years old through U-series dating of an adhering carbonate matrix. The Xiahe specimen provides direct evidence of the Denisovans outside the Altai Mountains and its analysis unique insights into Denisovan mandibular and dental morphology. Our results indicate that archaic hominins occupied the Tibetan Plateau in the Middle Pleistocene epoch and successfully adapted to high-altitude hypoxic environments long before the regional arrival of modern Homo sapiens.

RevDate: 2019-06-17

Warren M (2019)

Biggest Denisovan fossil yet spills ancient human's secrets.

Nature, 569(7754):16-17.

RevDate: 2019-05-09

Jones M, Denisova A, Mitchell S, et al (2019)

Acceptability of a Plasticity-Focused Serious Game Intervention for Posttraumatic Stress Disorder: User Requirements Analysis.

JMIR serious games, 7(2):e11909 pii:v7i2e11909.

BACKGROUND: Trauma-focused cognitive behavioral therapy (TF-CBT) is a first-line treatment for posttraumatic stress disorder (PTSD). Despite a solid evidence base, TF-CBT response and attrition rates vary considerably. Plasticity-focused interventions, including the use of serious games, have the potential to improve TF-CBT response and treatment retention.

OBJECTIVE: The aim of this study was to assess the acceptability of a mobile phone-delivered plasticity-focused serious game to improve response to TF-CBT for PTSD, and carry out a user requirements analysis should the development of a prototype be warranted.

METHODS: We conducted 2 one-to-one interviews (n=2), one focus group involving service users who had received a diagnosis of PTSD (n=3) and one focus group involving psychological trauma service clinicians (n=4).

RESULTS: We found that the concept of a plasticity-focused mobile phone intervention for PTSD is acceptable to patients and clinicians. Service users and clinicians both believed that the usage should be guided by a therapist, and both contributed useful inputs regarding the audiovisual aspects of the proposed serious game. It was accepted that the game would not be suitable for all patients and that clinicians would need to appropriately prescribe the usage of the game.

CONCLUSIONS: The findings highlight the acceptability of the proposed serious game and clarify the user requirements for such an intervention. It is the intention of the authors to carry out a user experience evaluation using a prototype serious game in a clinical population.

RevDate: 2019-05-23
CmpDate: 2019-05-23

Ragino YI, Shcherbakova LV, Denisova DV, et al (2019)

[Blood lipids and angina pectoris (by epidemiological cardiological Rose questionnaire) in the population of 25-45 years of Novosibirsk].

Kardiologiia, 59(3S):30-35.

The aim of the study was to investigate the prevalence of angina pectoris (AP) according to the standardized epidemiological questionnaire of Rose in the population of 25-45 years of Novosibirsk and to identify its association with some lipid and non-lipid risk factors for coronary heart disease (CHD).

MATERIAL AND METHODS: Cross-sectional survey of the population aged 25-45 in Novosibirsk was carried out. The study included 1439 people (656 men and 783 women). Within the framework of the complex survey program, the standardized epidemiological questionnaire of Rose (WHO, 1984) was used. Blood levels of total cholesterol (total C), triglycerides (TG), low and high density lipoprotein cholesterol (LDL-C, HDL-C) were determinate by biochemical methods.

RESULTS: For all lipid indicators, significant differences were found between men and women. The levels of total C, TG and LDL-C were significantly higher, and the level of HDL-C was lower in men, than in women. According to the Rose questionnaire, out of 1439 people included in the study, 12 patients (0.8%) had AP (75% women). In persons with AP, blood levels of TG were 1.8 times higher, and the levels of HDL-C in blood was 1.2 times lower compared to persons without AP. Univariate analysis of associations of AP with CHD risk factors showed that the chance of developing angina pectoris in the population of 25-45 years was significantly increased in individuals with high blood TG levels (OR 3,515, DI 1,106-11,168, p = 0.039) and low HDL-C (OR 1,203, DI 1,054-1,372, p = 0.006). A natural, although statistically not significant (OR 3,165, p=0,055, due to the small number of groups with AP) increasing in the chance of developing AP in hypertension was detected.

CONCLUSION: In the young population of 25-45 years in Novosibirsk, elevated blood levels of TG, reduced levels of HDL-C, and hypertension were associated with AP, according to Rosecardiological questionnaire, which underlines the importance of conducting screening surveys of the young population to improve effective prevention and treatment of diseases.

RevDate: 2019-05-21
CmpDate: 2019-05-21

Kuznetsov AA, Tsvetkova EE, Denisova DV, et al (2019)

[Central Aortic Pressure: Reference and Diagnostic Values].

Kardiologiia, 59(3):11-17.

OBJECTIVE: Practical application of central aortic pressure (CAP) parameters is limited by the absence of generally recognized reference and threshold diagnostic indices. The purpose of this work is to establish their values in the general population of Novosibirsk. Materials and Methods. A total of 327 people were examined: 155 men and 172 women aged 25-44 years from a representative sample from the general population of Novosibirsk. Applanation tonometry of the radial artery was performed by the SphygmoCor system. The reference values of CAP parameters were obtained by a nonparametric method according to the Clinical and Laboratory Standards Institute (CLSI) recommendations (95 % percentile interval with 2.5 % and 97.5 % cut-off points and their 90 % confidence intervals). Diagnostic thresholds and categories of CAP were determined as mean values depending on the categories of brachial arterial pressure (BP) and on the basis of risk estimates, as well as sensitivity and specificity values for left ventricular hypertrophy similar to risk and sensitivity and specificity values of threshold levels (categories) of brachial BP.

RESULTS: The reference values of the parameters of the CAP were: 18-43 mm Hg for pulse pressure; 5-24 mm Hg for the amplification of pulse pressure; - 8.8-40 % for the augmentation index. Diagnostic categories of CAP were determined to be: optimal - less than 110 / 80, normal - 110 / 80-114 / 84, high normal - 115 / 85-124 / 89, hypertension - more than 125 / 90 mm Hg.

CONCLUSION: The reference values, diagnostic thresholds and categories of parameters of CAP in the general population of Novosibirsk aged 25-44 years have been determined. It is expedient to further study them.

RevDate: 2019-05-03

Jacobs GS, Hudjashov G, Saag L, et al (2019)

Multiple Deeply Divergent Denisovan Ancestries in Papuans.

Cell, 177(4):1010-1021.e32.

Genome sequences are known for two archaic hominins-Neanderthals and Denisovans-which interbred with anatomically modern humans as they dispersed out of Africa. We identified high-confidence archaic haplotypes in 161 new genomes spanning 14 island groups in Island Southeast Asia and New Guinea and found large stretches of DNA that are inconsistent with a single introgressing Denisovan origin. Instead, modern Papuans carry hundreds of gene variants from two deeply divergent Denisovan lineages that separated over 350 thousand years ago. Spatial and temporal structure among these lineages suggest that introgression from one of these Denisovan groups predominantly took place east of the Wallace line and continued until near the end of the Pleistocene. A third Denisovan lineage occurs in modern East Asians. This regional mosaic suggests considerable complexity in archaic contact, with modern humans interbreeding with multiple Denisovan groups that were geographically isolated from each other over deep evolutionary time.

RevDate: 2019-08-29
CmpDate: 2019-08-29

Harris DN, Ruczinski I, Yanek LR, et al (2019)

Evolution of Hominin Polyunsaturated Fatty Acid Metabolism: From Africa to the New World.

Genome biology and evolution, 11(5):1417-1430.

The metabolic conversion of dietary omega-3 and omega-6 18 carbon (18C) to long chain (>20 carbon) polyunsaturated fatty acids (LC-PUFAs) is vital for human life. The rate-limiting steps of this process are catalyzed by fatty acid desaturase (FADS) 1 and 2. Therefore, understanding the evolutionary history of the FADS genes is essential to our understanding of hominin evolution. The FADS genes have two haplogroups, ancestral and derived, with the derived haplogroup being associated with more efficient LC-PUFA biosynthesis than the ancestral haplogroup. In addition, there is a complex global distribution of these haplogroups that is suggestive of Neanderthal introgression. We confirm that Native American ancestry is nearly fixed for the ancestral haplogroup, and replicate a positive selection signal in Native Americans. This positive selection potentially continued after the founding of the Americas, although simulations suggest that the timing is dependent on the allele frequency of the ancestral Beringian population. We also find that the Neanderthal FADS haplotype is more closely related to the derived haplogroup and the Denisovan clusters closer to the ancestral haplogroup. Furthermore, the derived haplogroup has a time to the most recent common ancestor of 688,474 years before present. These results support an ancient polymorphism, as opposed to Neanderthal introgression, forming in the FADS region during the Pleistocene with possibly differential selection pressures on both haplogroups. The near fixation of the ancestral haplogroup in Native American ancestry calls for future studies to explore the potential health risk of associated low LC-PUFA levels in these populations.

RevDate: 2019-05-10

Vyas DN, CJ Mulligan (2019)

Analyses of Neanderthal introgression suggest that Levantine and southern Arabian populations have a shared population history.

American journal of physical anthropology, 169(2):227-239.

OBJECTIVES: Modern humans are thought to have interbred with Neanderthals in the Near East soon after modern humans dispersed out of Africa. This introgression event likely took place in either the Levant or southern Arabia depending on the dispersal route out of Africa that was followed. In this study, we compare Neanderthal introgression in contemporary Levantine and southern Arabian populations to investigate Neanderthal introgression and to study Near Eastern population history.

MATERIALS AND METHODS: We analyzed genotyping data on >400,000 autosomal SNPs from seven Levantine and five southern Arabian populations and compared these data to those from populations from around the world including Neanderthal and Denisovan genomes. We used f4 and D statistics to estimate and compare levels of Neanderthal introgression between Levantine, southern Arabian, and comparative global populations. We also identified 1,581 putative Neanderthal-introgressed SNPs within our dataset and analyzed their allele frequencies as a means to compare introgression patterns in Levantine and southern Arabian genomes.

RESULTS: We find that Levantine and southern Arabian populations have similar levels of Neanderthal introgression to each other but lower levels than other non-Africans. Furthermore, we find that introgressed SNPs have very similar allele frequencies in the Levant and southern Arabia, which indicates that Neanderthal introgression is similarly distributed in Levantine and southern Arabian genomes.

DISCUSSION: We infer that the ancestors of contemporary Levantine and southern Arabian populations received Neanderthal introgression prior to separating from each other and that there has been extensive gene flow between these populations.

RevDate: 2019-03-19

Alexeeva E, Dvoryakovskaya T, Denisova R, et al (2019)

Dynamics of concomitant therapy in children with juvenile idiopathic arthritis treated with etanercept and methotrexate.

Pediatrics and neonatology pii:S1875-9572(18)30396-6 [Epub ahead of print].

BACKGROUND: Both the steroid- and NSAID-sparing effects of biologics in juvenile idiopathic arthritis (JIA) treatment are key aspects of the dynamics of patient's condition. The proper selection of biologics enables maximum treatment effectiveness and reduction of the dosage of concomitant therapy. Our aim was to study the dynamics of concomitant therapy during etanercept (ETA) and methotrexate (MTX) treatment in patients with JIA.

METHODS: This analysis included 215 JIA patients (63.3% females) showing sufficient response to main therapy. One hundred patients received MTX as main therapy, 24 received ETA monotherapy, and 91 received ETA þ MTX combination therapy. The dynamics of concomitant therapy were analyzed after 1 month, every 3 months during the first year, and every 6 months during the long-term follow-up (up to 5 years).

RESULTS: At the baseline, 24 (11.2%) patients received concomitant oral glucocorticoids (orGCs) and NSAIDs; the remaining 191 (88.8%) patients were treated with concomitant NSAIDs only. Within 1-year treatment, NSAIDs were discontinued in 162 (75.3%) patients. There were no significant differences in the dynamics of withdrawal of NSAIDs in patients who received and did not receive concomitant MTX. However, the percentage of treatment discontinuation in the MTX group was significantly lower compared to the other two groups (p < 0.001). Oral GCs were discontinued completely in 4 children (16.7%), and the dose of oral GCs was reduced in another 4 patients (16.7%). By the end of the follow-up period, 44 of 115 patients (38.3%) treated with ETA in combination with any concomitant therapy could switch to ETA monotherapy.

CONCLUSION: Therapy with ETA makes it possible to reduce the dosage or completely discontinue most concomitant medications (orGCs, NSAIDs, MTX) in a significant percentage of patients. This reduces the risk of development of NSAID- and GC-induced pathological conditions, while the effectiveness of therapy of the underlying condition remains high.

RevDate: 2019-05-21
CmpDate: 2019-05-21

Kovalkova NA, Ragino YI, Hudyakovа AD, et al (2019)


Kardiologiia, 59(2):32-37.

PURPOSE: to study blood pressure levels and the prevalence of hypertension in persons aged 25-45 years in Novosibirsk.

MATERIALS AND METHODS: A cross-sectional population study in one of typical areas of Novosibirsk was performed in 2013-2016. The study included 479 men and 612 women aged 25-45 years. Arterial hypertension was defined as blood pressure (BP) ≥140 / 90 mmHg according to Russian recommendations (2004). For analysis two age groups were distinguished: 25-34 years and 35-45 years.

RESULTS: Mean values of systolic and diastolic BP were significantly lower in women than in men in age groups. In men and women, the analyzed indicators were significantly higher in the older than in the younger age group. Mean values of pulse pressure in men were significantly higher than in women in both age groups, there were no differences in the analyzed index between age groups in either men or women. Optimal BP was more often recorded among women than among men in both age groups. The proportion of persons with normal BP among men was grate than among women in both age groups. In the age group 35-45 years compared with the younger group, in men there was a decrease in incidence of category with BP<140 / 90 mmHg, an increase of the proportion of persons with hypertension grades 1 and 2, the appearance of persons with grade 3 hypertension; in women - an increase of the proportion of individuals with normal, high-normal BP, and with grade 1 hypertension, appearance of individuals with grades 2 and 3 hypertension. Frequency of BP categories ≥140 / 90 mmHg in age group 25-34 years among men was 17.6 %, among women 3.1 % (p<0.0001); in age group 35-45 years among men - 34.7 %, among women - 12.5 % (p<0.0001).

CONCLUSIONS: Prevalence of hypertension in men was 28 %, in women - 9 %. Favorable tendencies of BP indicators in both sexes were revealed over a 30-year period, while gender differences did not change.

RevDate: 2019-06-25
CmpDate: 2019-06-25

Buttura RV, Ramalho J, Lima THA, et al (2019)

HLA-F displays highly divergent and frequent haplotype lineages associated with different mRNA expression levels.

Human immunology, 80(2):112-119.

HLA-F is one of the most conserved loci among the HLA gene family. The exact function of HLA-F is still under investigation. HLA-F might present tolerogenic features, participate in the stabilization of HLA molecules in open conformation, and also participate in the recycling of HLA molecules. Here we evaluate the variability and haplotype structure of the HLA-F distal promoter segment (from -1893 to -943) and how this segment is correlated with the coding region. Variability at the promoter segment was surveyed in 196 Brazilian samples using second-generation sequencing. The HLA-F promoter region presents two major haplotype lineages. Most of the variable sites are in perfect linkage and associated with a single promoter haplotype, here named F∗distal-C. This haplotype is associated with F∗01:01:02 alleles, while alleles from the F∗01:01:01 or F∗01:03 groups present closely related promoter sequences. F∗distal-C is quite frequent in Brazil and in worldwide populations, with frequencies ranging from 8.41% at the Iberian Population in Spain to 34.34% in Vietnam. F∗distal-C is also present in Neanderthal and Denisovan samples. In silico analyses demonstrated that F∗distal-C presents a different transcription factor binding profile compared with other HLA-F promoters. Moreover, individuals carrying this haplotype present higher HLA-F mRNA expression levels. Functional studies are required to define the exact mechanism underlying this higher HLA-F mRNA expression level associated with F∗distal-C and F∗01:01:02 alleles.

RevDate: 2019-05-02

James WPT, Johnson RJ, Speakman JR, et al (2019)

Nutrition and its role in human evolution.

Journal of internal medicine, 285(5):533-549.

Our understanding of human evolution has improved rapidly over recent decades, facilitated by large-scale cataloguing of genomic variability amongst both modern and archaic humans. It seems clear that the evolution of the ancestors of chimpanzees and hominins separated 7-9 million years ago with some migration out of Africa by the earlier hominins; Homo sapiens slowly emerged as climate change resulted in drier, less forested African conditions. The African populations expanded and evolved in many different conditions with slow mutation and selection rates in the human genome, but with much more rapid mutation occurring in mitochondrial DNA. We now have evidence stretching back 300 000 years of humans in their current form, but there are clearly four very different large African language groups that correlate with population DNA differences. Then, about 50 000-100 000 years ago a small subset of modern humans also migrated out of Africa resulting in a persistent signature of more limited genetic diversity amongst non-African populations. Hybridization with archaic hominins occurred around this time such that all non-African modern humans possess some Neanderthal ancestry and Melanesian populations additionally possess some Denisovan ancestry. Human populations both within and outside Africa also adapted to diverse aspects of their local environment including altitude, climate, UV exposure, diet and pathogens, in some cases leaving clear signatures of patterns of genetic variation. Notable examples include haemoglobin changes conferring resistance to malaria, other immune changes and the skin adaptations favouring the synthesis of vitamin D. As humans migrated across Eurasia, further major mitochondrial changes occurred with some interbreeding with ancient hominins and the development of alcohol intolerance. More recently, an ability to retain lactase persistence into adulthood has evolved rapidly under the environmental stimulus of pastoralism with the ability to husband lactating ruminants. Increased amylase copy numbers seem to relate to the availability of starchy foods, whereas the capacity to desaturase and elongate monounsaturated fatty acids in different societies seems to be influenced by whether there is a lack of supply of readily available dietary sources of long-chain polyunsaturated fatty acids. The process of human evolution includes genetic drift and adaptation to local environments, in part through changes in mitochondrial and nuclear DNA. These genetic changes may underlie susceptibilities to some modern human pathologies including folate-responsive neural tube defects, diabetes, other age-related pathologies and mental health disorders.

RevDate: 2019-06-07

Denisova EI, Korolev AA, Nikitenko EI, et al (2018)

[Hygienic assessment of indoles in the diet of medical students].

Voprosy pitaniia, 87(6):22-27.

A number of studies have shown the relationship between the regular consumption of cruciferous vegetables and the risk of malignant tumors in certain localizations, the activation of mechanisms of alimentary adaptation of the organism under conditions of alien loads, by inducing enzymes of the biotransformation system of xenobiotics. The cruciferous vegetables are distinguished by the presence of minor components, such as indole-3-carbinol, formed during the hydrolysis of glucosinolates. The aim of the investigation was a retrospective study of the content of indoles in students' diet with subsequent quantitative analysis in different comparison groups. The study involved 250 students from a medical university aged 21 to 27 years. To assess the actual nutrition, the developed questionnaires were used, which included the most common products in the Moscow region, sources of indole glucosinolates. It was found that 44% of the respondents didn't include cruciferous vegetables in the diet, and of those who consumed sources of indoles (56% of respondents), only about half received them in the recommended amount. It should also be noted that as in men, in women the most commonly used in the diet product as a source of indoles was cabbage, it was included in the diet of 68% of the respondents who used cruciferous vegetables, rarely pekin cabbage was used (16.3%) and broccoli (16.3%). Cauliflower, radishes, Kale and horseradish was included in the diet of 7.8-14.9% of the students. Less often turnip was consumed - only by 2.1% of the students. No significant differences in the consumption of indoles in the student with deficient, normal or overweight was revealed. Also, there was no correlation between excess weight and the consumption of various indoles sources. The obtained results testify to the extremely low level of alimentary intake of indole-3-carbinol.

RevDate: 2019-02-14

Gringolts ML, Denisova YI, Finkelshtein ES, et al (2019)

Olefin metathesis in multiblock copolymer synthesis.

Beilstein journal of organic chemistry, 15:218-235.

Multiblock copolymers constitute a basis for an emerging class of nanomaterials that combine various functional properties with durability and enhanced mechanical characteristics. Our mini-review addresses synthetic approaches to the design of multiblock copolymers from unsaturated monomers and polymers using olefin metathesis reactions and other ways of chemical modification across double C=C bonds. The main techniques, actively developed during the last decade and discussed here, are the coupling of end-functionalized blocks, sequential ring-opening metathesis polymerization, and cross metathesis between unsaturated polymers, or macromolecular cross metathesis. The last topic attracts special interest due to its relative simplicity and broad opportunities to tailor the structure and hence the properties of the copolymer products. Whenever possible, we analyze the structure-property relations for multiblock copolymers and point to their possible practical applications.

RevDate: 2019-06-17
CmpDate: 2019-06-17

Bulynko SA, Denisova OA, Soldatsky YL, et al (2018)

[The observation of two cases of isolated parapharyngeal abscess in a single child].

Vestnik otorinolaringologii, 83(6):44-45.

This article reports a rare observation of the simultaneous appearance of two isolated parapharyngeal abscesses in a 3 year-old child.

RevDate: 2019-02-15
CmpDate: 2019-02-12

Dennell R (2019)

Dating of hominin discoveries at Denisova.

Nature, 565(7741):571-572.

RevDate: 2019-06-19
CmpDate: 2019-06-19

Douka K, Slon V, Jacobs Z, et al (2019)

Age estimates for hominin fossils and the onset of the Upper Palaeolithic at Denisova Cave.

Nature, 565(7741):640-644.

Denisova Cave in the Siberian Altai (Russia) is a key site for understanding the complex relationships between hominin groups that inhabited Eurasia in the Middle and Late Pleistocene epoch. DNA sequenced from human remains found at this site has revealed the presence of a hitherto unknown hominin group, the Denisovans1,2, and high-coverage genomes from both Neanderthal and Denisovan fossils provide evidence for admixture between these two populations3. Determining the age of these fossils is important if we are to understand the nature of hominin interaction, and aspects of their cultural and subsistence adaptations. Here we present 50 radiocarbon determinations from the late Middle and Upper Palaeolithic layers of the site. We also report three direct dates for hominin fragments and obtain a mitochondrial DNA sequence for one of them. We apply a Bayesian age modelling approach that combines chronometric (radiocarbon, uranium series and optical ages), stratigraphic and genetic data to calculate probabilistically the age of the human fossils at the site. Our modelled estimate for the age of the oldest Denisovan fossil suggests that this group was present at the site as early as 195,000 years ago (at 95.4% probability). All Neanderthal fossils-as well as Denisova 11, the daughter of a Neanderthal and a Denisovan4-date to between 80,000 and 140,000 years ago. The youngest Denisovan dates to 52,000-76,000 years ago. Direct radiocarbon dating of Upper Palaeolithic tooth pendants and bone points yielded the earliest evidence for the production of these artefacts in northern Eurasia, between 43,000 and 49,000 calibrated years before present (taken as AD 1950). On the basis of current archaeological evidence, it may be assumed that these artefacts are associated with the Denisovan population. It is not currently possible to determine whether anatomically modern humans were involved in their production, as modern-human fossil and genetic evidence of such antiquity has not yet been identified in the Altai region.

RevDate: 2019-06-19
CmpDate: 2019-06-19

Jacobs Z, Li B, Shunkov MV, et al (2019)

Timing of archaic hominin occupation of Denisova Cave in southern Siberia.

Nature, 565(7741):594-599.

The Altai region of Siberia was inhabited for parts of the Pleistocene by at least two groups of archaic hominins-Denisovans and Neanderthals. Denisova Cave, uniquely, contains stratified deposits that preserve skeletal and genetic evidence of both hominins, artefacts made from stone and other materials, and a range of animal and plant remains. The previous site chronology is based largely on radiocarbon ages for fragments of bone and charcoal that are up to 50,000 years old; older ages of equivocal reliability have been estimated from thermoluminescence and palaeomagnetic analyses of sediments, and genetic analyses of hominin DNA. Here we describe the stratigraphic sequences in Denisova Cave, establish a chronology for the Pleistocene deposits and associated remains from optical dating of the cave sediments, and reconstruct the environmental context of hominin occupation of the site from around 300,000 to 20,000 years ago.

RevDate: 2019-05-13
CmpDate: 2019-05-13

Henry JP (2019)

[Genetics and origin of Homo sapiens].

Medecine sciences : M/S, 35(1):39-45.

Usually, paleoanthropology studies remains and artefacts. However, more recently, genetics offer new avenues. Information on humanisation mechanisms has been obtained from comparison with primate or archaic Homo DNA sequences. Likewise, the 1 000 Genomes Project has characterized the geographic spectrum of human genetic variation offering a basis for a genomic study of Homo sapiens phylogeny. From these studies, a model, Out of Africa, was derived. His origin is Africa, where he lived 200 000 years ago. A small fraction of the population left Africa between 50 and 100 000 years ago that have populated the rest of the world, to Europe, coastal Asia to Australia and mainland Asia to Behring Land Bridge and America. The model is supported by the decrease of genetic diversity with the distance to Eastern Africa (serial founder effect). In Europe and Asia, Homo sapiens met archaic Homo neanderthalis and H denisova. The presence of 1-3% neanderthalis sequences in modern Homo ADN indicates admixtures between these groups. Some archaic sequences are on positive selection pressure, thus suggesting that the extinct hominins might have facilitated the adaptation of H sapiens to new environments.

RevDate: 2019-02-15
CmpDate: 2019-02-01

Mondal M, Bertranpetit J, O Lao (2019)

Approximate Bayesian computation with deep learning supports a third archaic introgression in Asia and Oceania.

Nature communications, 10(1):246 pii:10.1038/s41467-018-08089-7.

Since anatomically modern humans dispersed Out of Africa, the evolutionary history of Eurasian populations has been marked by introgressions from presently extinct hominins. Some of these introgressions have been identified using sequenced ancient genomes (Neanderthal and Denisova). Other introgressions have been proposed for still unidentified groups using the genetic diversity present in current human populations. We built a demographic model based on deep learning in an Approximate Bayesian Computation framework to infer the evolutionary history of Eurasian populations including past introgression events in Out of Africa populations fitting the current genetic evidence. In addition to the reported Neanderthal and Denisovan introgressions, our results support a third introgression in all Asian and Oceanian populations from an archaic population. This population is either related to the Neanderthal-Denisova clade or diverged early from the Denisova lineage. We propose the use of deep learning methods for clarifying situations with high complexity in evolutionary genomics.

RevDate: 2019-04-18
CmpDate: 2019-04-18

Kirpichenkova EV, Korolev AA, Onishchenko GG, et al (2018)

[Study of lutein and zeaxanthin content in the diet with the assessment of the relationship between the level of alimentary intake of non-vitamin carotenoids and the density of the macular region of the retina at a young age].

Voprosy pitaniia, 87(5):20-26.

Lutein and zeaxanthin are carotenoid pigments that affect the function of the visual analyzer. They selectively accumulate in the yellow spot of the retina, form macular pigment and determine the density of the retina macula. Lutein and zeaxanthin slow down the progression of age-related macular degeneration, a leading cause of senior-age blindness. The main food sources of non-vitamin carotenoids are green leafy vegetables, zucchini, pumpkin, green peas, broccoli. The aim of the study is a retrospective assessment of the levels and sources of alimentary intake of lutein and zeaxanthin in young people and research of the effect of lutein and zeaxanthin in the diet on macula density. A specially designed questionnaire was used to quantify the content of lutein and zeaxanthin in the diet, reflecting the amount of consumption of the main sources of these carotenoids on the day preceding the survey. A non-invasive non-contact method of optical coherence tomography of the retina was used to determine the density of the macula. The study involved 96 students of Sechenov University at the age of 21-27 years. The study found that only 6.25% of the respondents had daily intake of lutein and zeaxanthin of 6 mg or more, 8.33% had 4.6-5.9 mg, 8.33% had 3.0-4.5 mg, in 18.75% - 1.5-2.9 mg, in 45.83% <1.4 mg. 12.5% of respondents didn't include sources of lutein and zeaxanthin in the diet. The more common sources of lutein and zeaxanthin in the diet were eggs and fresh tomatoes. Retinal density indices corresponded to the age standards in the majority of the examined. In 8.3% surveyed the thickness of the retina was decreased, and 4.2% had higher thickness of the retina in comparison with the standards. Significant differences in the Central subfield thickness in men and women were revealed. There was no dependence of the levels of lutein and zeaxanthin coming from food sources on the retina thickness indicators.

RevDate: 2019-04-18
CmpDate: 2019-04-18

Martinchik AN, Baeva VS, Peskova EV, et al (2018)

[Actual liquid consumption by highly qualified athletes in the mode of the training process].

Voprosy pitaniia, 87(3):36-44.

The purpose of the study was to evaluate the actual intake of fluids by athletes of various sports during the day with one and two training sessions before, during and after workout. The dietary intake, including consumption of various types of liquid foods and beverages, was evaluated by the method of 24-hour recall in 280 athletes of high qualification (candidates for masters and masters of sports) of both gender of various sports during the training period. It has been established that the main drink of rehydration was drinking bottled water. Bottled water was consumed on average by 86% of athletes. It was consumed by 95-96% of sportsmen from the group of single combats and power kinds, whereas in other groups the share of water consumers was less - 67-79%. In second place in terms of percentage of consuming was tea. Consumption of sports drinks was observed only during training by athletes from the group of cyclic sports (31%) and single combat (11%). Calculating the per capita fluid intake of athletes who had 2 workouts a day showed that athletes from the martial arts group consumed the largest volumes of fluid in the mode of both training sessions as compared to representatives of other sports. Athletes of other sports consumed on average less liquid in the 2nd training mode compared to the 1st one. The total fluid intake during two training sessions was maximum in the group of martial arts and was minimum in the group of complex coordination sports. It should be specially noted a small proportion of athletes who consumed specialized sports drinks - only 17% of athletes and more than half of them - cyclical sportsmen. Consumption of liquid food outside training has been observed in 76% of athletes. The mean volume of consumed liquid products varied by the user from 382 and 437 ml in complex coordination and game sports up to 504-553 ml in other sports. The daily fluid intake was maximum (2326 ml) in athletes engaged in martial arts, minimum (1009 ml) - in athletes of complex coordination sports.

RevDate: 2019-04-12
CmpDate: 2019-04-12

Reher D, Key FM, Andrés AM, et al (2019)

Immune Gene Diversity in Archaic and Present-day Humans.

Genome biology and evolution, 11(1):232-241 pii:5253179.

Genome-wide analyses of two Neandertals and a Denisovan have shown that these archaic humans had lower genetic heterozygosity than present-day people. A similar reduction in genetic diversity of protein-coding genes (gene diversity) was found in exome sequences of three Neandertals. Reduced gene diversity, particularly in genes involved in immunity, may have important functional consequences. In fact, it has been suggested that reduced diversity in immune genes may have contributed to Neandertal extinction. We therefore explored gene diversity in different human groups, and at different time points on the Neandertal lineage, with a particular focus on the diversity of genes involved in innate immunity and genes of the Major Histocompatibility Complex (MHC).We find that the two Neandertals and a Denisovan have similar gene diversity, all significantly lower than any present-day human. This is true across gene categories, with no gene set showing an excess decrease in diversity compared with the genome-wide average. Innate immune-related genes show a similar reduction in diversity to other genes, both in present-day and archaic humans. There is also no observable decrease in gene diversity over time in Neandertals, suggesting that there may have been no ongoing reduction in gene diversity in later Neandertals, although this needs confirmation with a larger sample size. In both archaic and present-day humans, genes with the highest levels of diversity are enriched for MHC-related functions. In fact, in archaic humans the MHC genes show evidence of having retained more diversity than genes involved only in the innate immune system.

RevDate: 2019-08-30
CmpDate: 2019-08-30

Starshinova A, Zinchenko Y, Filatov M, et al (2018)

Specific features of immune complexes in patients with sarcoidosis and pulmonary tuberculosis.

Immunologic research, 66(6):737-743.

Clinical and radiological features of tuberculosis and sarcoidosis are quite overlapping, and therefore, a diagnostic dilemma often persists. There are no commonly accepted criteria for the diagnosis of sarcoidosis due to the lack of data on the etiology of the disease. The exclusion of tuberculosis in every patient with suspected sarcoidosis is a mandatory stage of diagnosis, especially in countries with a high burden of tuberculosis. A prospective study was conducted with two groups of patients: group I (n = 50)-patients with pulmonary sarcoidosis established according to standard criteria; group II (n = 28)-patients with pulmonary tuberculosis with bacterial excretion. The control group (n = 24) was presented by healthy subjects. The examination complex included x-ray, bacteriological, immunological (Mantoux test with 2 TE, TB.SPOT test), and histological methods. All patients and healthy subjects were assessed for immune complexes with the use of the dynamic light scattering (DLS) method and adding of "healthy lung tissue extract" antigens and specific tuberculosis antigens ESAT-6 and SFP-10 in vitro. Significant differences were found in determining specific immune complexes in patients with pulmonary sarcoidosis and pulmonary tuberculosis. Registration of specific immune complex formation with "healthy lung tissue extract" in 100% cases may indicate the autoimmune nature of sarcoidosis. The absence of the immune complex formation in response to ESAT-6/SFP-10 antigens can be used for the differential diagnosis of two diseases. The diagnostic significance of the DLS method was 100% for sarcoidosis and 92.2% for tuberculosis. The data obtained in the study allows not only understanding the etiology of sarcoidosis, but also obtaining new criteria for the differential diagnosis of tuberculosis and pulmonary sarcoidosis.

RevDate: 2018-12-17

Pol JG, Acuna SA, Yadollahi B, et al (2019)

Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials.

Oncoimmunology, 8(1):e1512329.

Multiple immunotherapeutics have been approved for cancer patients, however advanced solid tumors are frequently refractory to treatment. We evaluated the safety and immunogenicity of a vaccination approach with multimodal oncolytic potential in non-human primates (NHP) (Macaca fascicularis). Primates received a replication-deficient adenoviral prime, boosted by the oncolytic Maraba MG1 rhabdovirus. Both vectors expressed the human MAGE-A3. No severe adverse events were observed. Boosting with MG1-MAGEA3 induced an expansion of hMAGE-A3-specific CD4+ and CD8+ T-cells with the latter peaking at remarkable levels and persisting for several months. T-cells reacting against epitopes fully conserved between simian and human MAGE-A3 were identified. Humoral immunity was demonstrated by the detection of circulating MAGE-A3 antibodies. These preclinical data establish the capacity for the Ad:MG1 vaccination to engage multiple effector immune cell populations without causing significant toxicity in outbred NHPs. Clinical investigations utilizing this program for the treatment of MAGE-A3-positive solid malignancies are underway (NCT02285816, NCT02879760).

RevDate: 2019-04-03
CmpDate: 2019-04-03

Denisova TG, Gerasimova LI, Pakhmutova NL, et al (2018)

Individualized Homeopathic Therapy in a Case of Obesity, Dysfunctional Uterine Bleeding, and Autonomic Dystonia.

The American journal of case reports, 19:1474-1479 pii:913328.

BACKGROUND Obesity is one of the leading causes of morbidity and mortality globally and challenging to treat because of the multifactorial etiology and presentation. Individualized homeopathy takes into account factors that led to a patient's health condition and hence may have a role in the treatment of obesity and related co-morbidities; co-morbidities that may arising from the same etiology may respond as a whole to homeopathy treatment. CASE REPORT A 39-year-old Russian female who developed multiple problems after severe emotional stress was treated with individualized classical homeopathic therapy. Obesity, dysfunctional uterine bleeding, and dysautonomia were pathologies that showed improvement. CONCLUSIONS The response in this patient's case, supports the need for further investigation on the relevance of individualized homeopathy in these related conditions.

RevDate: 2019-07-10
CmpDate: 2019-07-10

Safronova EI, Dydykin SS, Grigorevskiy ED, et al (2019)

Experimental animal model for assessment of tracheal epithelium regeneration.

The Laryngoscope, 129(6):E213-E219.

OBJECTIVES/HYPOTHESIS: To develop an experimental model in rabbits for assessment of tracheal epithelium regeneration through application of either natural or artificial polymer scaffolds.

STUDY DESIGN: First, we identified the size of full-thickness mucosal defect, which does not allow self-healing (a "critical defect"), thus representing an adequate experimental model for regenerative therapy of tracheal epithelium damage. Then, two methods of polymer scaffold fixation at the site of the epithelium defect were compared: suturing and fixation with a stent. This was done through: 1) formation of a full-thickness anterolateral mucosal defect by tracheal mucosa excision; and 2) fixation of the scaffold at the site of the tracheal epithelium defect using sutures (through a tracheal wall "window") or a vascular stent (through a small tracheal incision).

RESULTS: The dimension of a critical anterolateral mucosal defect of the trachea for rabbits was found to be 1.5 cm in length and more than 50% of the tracheal circumference. Fixation of the scaffold with a stent proved to be more efficient due to a uniform distribution of the pressure over the entire surface of the scaffold, whereas the suturing of the scaffold provided unsatisfactory results. In addition, fixation of the scaffold by suturing required formation of a large "window" in the tracheal wall. Thus, using the stent appeared to be technically less complicated and much less traumatic as compared to suturing.

CONCLUSION: We present an experimental in vivo animal model of tracheal epithelium injury and recovery. It can be effectively used with certain further modifications as a basis for routine testing of bioengineered constructs.

LEVEL OF EVIDENCE: NA Laryngoscope, 129:E213-E219, 2019.

RevDate: 2019-03-07
CmpDate: 2019-03-07

Malinova LI, Furman NV, Dolotovskaya PV, et al (2018)

[ADP-Induced Recalcified Blood Clotting Time as a Marker of Rethrombosis Risk and Effectiveness of Antiplatelet Therapy in Acute Coronary Syndrome].

Kardiologiia, 58(6):5-12.

PURPOSE: to assess the possibility of the use of ADP induced blood-clotting time measurement in clinical practice prognostication of the course of acute coronary syndrome (ACS) and assessment of effectiveness of antiplatelet therapy (APT).

MATERIALS AND METHODS: We enrolled in the study 163 male patients admitted to the coronary unit for acute coronary syndrome (ACS) and 38 male practically healthy volunteers (PHV). ADP induced blood-clotting time (ADP BCT) was measured as time (sec) between addition of ADP (10 μcmol) to recalcificated sample of citrate blood and clot formation. In healthy volunteers ADP BCT was determined before and 45 minutes after oral administration of acetylsalicylic acid (ASA, 250 mg). Risk of cardiovascular death was calculated using the GRACE score. Platelet function tests were performed by optical aggregometry. Follow-up period for patients with ACS was 24 months. The primary end point (PEP) was the composite of cardiovascular death and rehospitalization.

RESULTS: In ACS patients ADP BCT was significantly lower than in PHV: 134.8 (109.9; 161.3) vs 85.7 (60.5; 108.7) sec, p=0.015. In PHV ASA increased ADP BCT - 103.2 (95.1; 130.7) vs 133.1 (102.8; 154.3) sec, p=0.041. ADP BCT correlated with age in both PHV and patients (R= -0.431, p.

RevDate: 2019-05-21
CmpDate: 2019-05-21

Johannessen TC, Hasan-Olive MM, Zhu H, et al (2019)

Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide.

International journal of cancer, 144(7):1735-1745.

Glioblastoma multiforme (GBM) has a poor prognosis with an overall survival of 14-15 months after surgery, radiation and chemotherapy using temozolomide (TMZ). A major problem is that the tumors acquire resistance to therapy. In an effort to improve the therapeutic efficacy of TMZ, we performed a genome-wide RNA interference (RNAi) synthetic lethality screen to establish a functional gene signature for TMZ sensitivity in human GBM cells. We then queried the Connectivity Map database to search for drugs that would induce corresponding changes in gene expression. By this approach we identified several potential pharmacological sensitizers to TMZ, where the most potent drug was the established antipsychotic agent Thioridazine, which significantly improved TMZ sensitivity while not demonstrating any significant toxicity alone. Mechanistically, we show that the specific chemosensitizing effect of Thioridazine is mediated by impairing autophagy, thereby preventing adaptive metabolic alterations associated with TMZ resistance. Moreover, we demonstrate that Thioridazine inhibits late-stage autophagy by impairing fusion between autophagosomes and lysosomes. Finally, Thioridazine in combination with TMZ significantly inhibits brain tumor growth in vivo, demonstrating the potential clinical benefits of compounds targeting the autophagy-lysosome pathway. Our study emphasizes the feasibility of exploiting drug repurposing for the design of novel therapeutic strategies for GBM.

RevDate: 2019-03-14
CmpDate: 2019-03-14

Hoover KC (2018)

Intragenus (Homo) variation in a chemokine receptor gene (CCR5).

PloS one, 13(10):e0204989.

Humans have a comparatively higher rate of more polymorphisms in regulatory regions of the primate CCR5 gene, an immune system gene with both general and specific functions. This has been interpreted as allowing flexibility and diversity of gene expression in response to varying disease loads. A broad expression repertoire is useful to humans-the only globally distributed primate-due to our unique adaptive pattern that increased pathogen exposure and disease loads (e.g., sedentism, subsistence practices). The main objective of the study was to determine if the previously observed human pattern of increased variation extended to other members of our genus, Homo. The data for this study are mined from the published genomes of extinct hominins (four Neandertals and two Denisovans), an ancient human (Ust'-Ishim), and modern humans (1000 Genomes). An average of 15 polymorphisms per individual were found in human populations (with a total of 262 polymorphisms). There were 94 polymorphisms identified across extinct Homo (an average of 13 per individual) with 41 previously observed in modern humans and 53 novel polymorphisms (32 in Denisova and 21 in Neandertal). Neither the frequency nor distribution of polymorphisms across gene regions exhibit significant differences within the genus Homo. Thus, humans are not unique with regards to the increased frequency of regulatory polymorphisms and the evolution of variation patterns across CCR5 gene appears to have originated within the genus. A broader evolutionary perspective on regulatory flexibility may be that it provided an advantage during the transition to confrontational foraging (and later hunting) that altered human-environment interaction as well as during migration to Eurasia and encounters with novel pathogens.

RevDate: 2019-01-16
CmpDate: 2019-01-16

Skov L, Hui R, Shchur V, et al (2018)

Detecting archaic introgression using an unadmixed outgroup.

PLoS genetics, 14(9):e1007641.

Human populations outside of Africa have experienced at least two bouts of introgression from archaic humans, from Neanderthals and Denisovans. In Papuans there is prior evidence of both these introgressions. Here we present a new approach to detect segments of individual genomes of archaic origin without using an archaic reference genome. The approach is based on a hidden Markov model that identifies genomic regions with a high density of single nucleotide variants (SNVs) not seen in unadmixed populations. We show using simulations that this provides a powerful approach to identifying segments of archaic introgression with a low rate of false detection, given data from a suitable outgroup population is available, without the archaic introgression but containing a majority of the variation that arose since initial separation from the archaic lineage. Furthermore our approach is able to infer admixture proportions and the times both of admixture and of initial divergence between the human and archaic populations. We apply the model to detect archaic introgression in 89 Papuans and show how the identified segments can be assigned to likely Neanderthal or Denisovan origin. We report more Denisovan admixture than previous studies and find a shift in size distribution of fragments of Neanderthal and Denisovan origin that is compatible with a difference in admixture time. Furthermore, we identify small amounts of Denisova ancestry in South East Asians and South Asians.

RevDate: 2019-07-12
CmpDate: 2019-07-12

Clyde D (2018)

The girl with Neanderthal and Denisovan parents.

Nature reviews. Genetics, 19(11):668-669.

RevDate: 2018-11-14
CmpDate: 2018-11-12

Dergunova LV, Filippenkov IB, Stavchansky VV, et al (2018)

Genome-wide transcriptome analysis using RNA-Seq reveals a large number of differentially expressed genes in a transient MCAO rat model.

BMC genomics, 19(1):655.

BACKGROUND: The transient middle cerebral artery occlusion (tMCAO) model is used for studying the molecular mechanisms of ischemic damage and neuroprotection. Numerous studies have demonstrated the role of individual genes and associated signaling pathways in the pathogenesis of ischemic stroke. Here, the tMCAO model was used to investigate the genome-wide response of the transcriptome of rat brain tissues to the damaging effect of ischemia and subsequent reperfusion.

RESULTS: Magnetic resonance imaging and histological examination showed that the model of focal ischemia based on endovascular occlusion of the right middle cerebral artery for 90 min using a monofilament, followed by restoration of the blood flow, led to reproducible localization of ischemic damage in the subcortical structures of the brain. High-throughput RNA sequencing (RNA-Seq) revealed the presence of differentially expressed genes (DEGs) in subcortical structures of rat brains resulting from hemisphere damage by ischemia after tMCAO, as well as in the corresponding parts of the brains of sham-operated animals. Real-time reverse transcription polymerase chain reaction expression analysis of 20 genes confirmed the RNA-Seq results. We identified 469 and 1939 genes that exhibited changes in expression of > 1.5-fold at 4.5 and 24 h after tMCAO, respectively. Interestingly, we found 2741 and 752 DEGs under ischemia-reperfusion and sham-operation conditions at 24 h vs. 4.5 h after tMCAO, respectively. The activation of a large number of genes involved in inflammatory, immune and stress responses, apoptosis, ribosome function, DNA replication and other processes was observed in ischemia-reperfusion conditions. Simultaneously, massive down-regulation of the mRNA levels of genes involved in the functioning of neurotransmitter systems was recorded. A Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that dozens of signaling pathways were associated with DEGs in ischemia-reperfusion conditions.

CONCLUSIONS: The data obtained revealed a global profile of gene expression in the rat brain sub-cortex under tMCAO conditions that can be used to identify potential therapeutic targets in the development of new strategies for the prevention and treatment of ischemic stroke.

RevDate: 2018-08-28

Alexeeva E, Dvoryakovskaya T, Denisova R, et al (2018)

Comparative Analysis of the Etanercept Efficacy in Children with Juvenile Idiopathic Arthritis Under the Age of 4 Years and Children of Older Age Groups Using the Propensity Score Matching Method.

Modern rheumatology [Epub ahead of print].

OBJECTIVE: The study aim was to analyze the efficacy and safety of etanercept (ETA) in children with juvenile idiopathic arthritis (JIA) under the age of 4 years and to compare the data with those for older age groups.

METHODS: Three groups comprising 34 patients each (the total number, 102 patients) were selected using the PSM method. The study group (patients under the age of 4 years; the Junior group (JNR)) were compared with patients of the older age groups adjusted for gender, JIA category, JIA severity, and either age at disease onset (the RAO group) or disease duration (the RDD group).

RESULTS: All three groups showed good response to ETA therapy. During the follow-up period, only 4 (3.9%) patients failed to reach ACR50. In the JNR group, 82.4% of patients achieved ACR90 within median time 3 months (IQR, 3 - 6 months), which was a better result compared to the other two groups: 61.8% (RAO group) and 58.8% (RDD group) of patients achieved ACR90 within 6 (IQR, 3 - 9) months (p = 0.028). Three (9%) patients in the JNR group and none of the RDD and RAO groups discontinued treatment because of clinical remission (p = 0.045).

CONCLUSION: An analysis of the ETA efficacy in different age groups comparable in terms of the diagnosis and disease severity demonstrated a higher efficacy of earlier ETA therapy in children of the same age at disease onset. In children at the early stage of arthritis (≤ 2.5 years long), ETA was more efficient in those with an earlier disease onset.

RevDate: 2019-03-05
CmpDate: 2019-02-26

Slon V, Mafessoni F, Vernot B, et al (2018)

The genome of the offspring of a Neanderthal mother and a Denisovan father.

Nature, 561(7721):113-116.

Neanderthals and Denisovans are extinct groups of hominins that separated from each other more than 390,000 years ago1,2. Here we present the genome of 'Denisova 11', a bone fragment from Denisova Cave (Russia)3 and show that it comes from an individual who had a Neanderthal mother and a Denisovan father. The father, whose genome bears traces of Neanderthal ancestry, came from a population related to a later Denisovan found in the cave4-6. The mother came from a population more closely related to Neanderthals who lived later in Europe2,7 than to an earlier Neanderthal found in Denisova Cave8, suggesting that migrations of Neanderthals between eastern and western Eurasia occurred sometime after 120,000 years ago. The finding of a first-generation Neanderthal-Denisovan offspring among the small number of archaic specimens sequenced to date suggests that mixing between Late Pleistocene hominin groups was common when they met.

RevDate: 2019-02-15
CmpDate: 2019-02-13

Warren M (2018)

Mum's a Neanderthal, Dad's a Denisovan: First discovery of an ancient-human hybrid.

Nature, 560(7719):417-418.

RevDate: 2018-11-19
CmpDate: 2018-11-19

Zotova TY, Blagonravov ML, Lapaev NN, et al (2018)

Hemodynamic Allostasis of Pregnant Women against the Background of Preeclampsia.

Bulletin of experimental biology and medicine, 165(4):440-444.

We analyzed diurnal hemodynamic parameters (HR, systolic BP, and diastolic BP) recorded from two groups of edematous and preeclamptic pregnant women. The unidirectional character of changes in the control over the functional state of cardiovascular system was revealed except for the indices, which mark a pathological process: elevated diurnal BP in preeclampsia and diminished percentage of oscillation power in edematous patients. Uniformity of the regulatory changes in patients with and without arterial hypertension can be viewed as manifestation of allostasis developed by the cardiovascular system during pregnancy. In preeclampsia, the greater allostatic load was reflected by the changes in diurnal, daytime, and nighttime BP and in the circadian index calculated for HR, systolic BP, and diastolic BP. In edematous patients, elevation of allostatic load was indicated by the percentage of ultradian rhythms.

RevDate: 2019-08-03
CmpDate: 2019-01-15

Helsen CW, Hammill JA, Lau VWC, et al (2018)

The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity.

Nature communications, 9(1):3049.

Engineering T cells with chimeric antigen receptors (CARs) is an effective method for directing T cells to attack tumors, but may cause adverse side effects such as the potentially lethal cytokine release syndrome. Here the authors show that the T cell antigen coupler (TAC), a chimeric receptor that co-opts the endogenous TCR, induces more efficient anti-tumor responses and reduced toxicity when compared with past-generation CARs. TAC-engineered T cells induce robust and antigen-specific cytokine production and cytotoxicity in vitro, and strong anti-tumor activity in a variety of xenograft models including solid and liquid tumors. In a solid tumor model, TAC-T cells outperform CD28-based CAR-T cells with increased anti-tumor efficacy, reduced toxicity, and faster tumor infiltration. Intratumoral TAC-T cells are enriched for Ki-67+ CD8+ T cells, demonstrating local expansion. These results indicate that TAC-T cells may have a superior therapeutic index relative to CAR-T cells.

RevDate: 2018-08-01

Morgunov LY, Denisova IA, Rozhkova TI, et al (2018)

Hypogonadism and its treatment following ischaemic stroke in men with type 2 diabetes mellitus.

The aging male : the official journal of the International Society for the Study of the Aging Male [Epub ahead of print].

Premature mortality in Russia is a major socio-economic problem, especially from acute cerebrovascular diseases which constitute 21.4% of the total mortality and is a considerable contributor to chronic disability. Risk of vascular catastrophe is higher in males than females, thought, in part, due to anti-atherosclerotic effects of oestrogens in females whilst an associated age-related deficiency of testosterone is observed in men. Clinical symptoms such as high blood pressure, changes in lipid profile, insulin resistance, obesity, and blood coagulation factors often accompany declining testosterone in males and reduced total testosterone is considered a cardiovascular risk factor. In the present study, the prevalence of hypogonadism in men who had suffered ischaemic stroke was evaluated along with the efficacy of testosterone undecanoate injections (TU) in patients with testosterone deficiency and type-2 diabetes (T2DM) in the acute phase of hemispheric ischaemic stroke. Hypogonadism was present in 66.3% of patients with ischaemic stroke, 50% with T2DM, and 26.3% without T2DM, respectively. TU treatment, at both the 2 and 5-year observation points, demonstrated significant improvements in biochemical, physical, and mental parameters. This supports that testosterone deficiency is a contributing factor in ischaemic events and that long-term testosterone therapy could play an important role in patient recovery.

RevDate: 2018-11-14

Dolgova O, O Lao (2018)

Evolutionary and Medical Consequences of Archaic Introgression into Modern Human Genomes.

Genes, 9(7):.

The demographic history of anatomically modern humans (AMH) involves multiple migration events, population extinctions and genetic adaptations. As genome-wide data from complete genome sequencing becomes increasingly abundant and available even from extinct hominins, new insights of the evolutionary history of our species are discovered. It is currently known that AMH interbred with archaic hominins once they left the African continent. Current non-African human genomes carry fragments of archaic origin. This review focuses on the fitness consequences of archaic interbreeding in current human populations. We discuss new insights and challenges that researchers face when interpreting the potential impact of introgression on fitness and testing hypotheses about the role of selection within the context of health and disease.

RevDate: 2019-03-07
CmpDate: 2019-03-07

Denisova K (2019)

Neurobiology, not artifacts: Challenges and guidelines for imaging the high risk infant.

NeuroImage, 185:624-640.

The search for the brain-basis of atypical development in human infants is challenging because the process of imaging and the generation of the MR signal itself relies on assumptions that reflect biophysical properties of the brain tissue. These assumptions are not inviolate, have been questioned by recent empirical evidence from high risk infant-sibling studies, and to date remain largely underexamined at the between-group level. In particular, I consider recent work showing that infants at High vs. Low familial risk (HR vs. LR, respectively) for developing Autism Spectrum Disorders (ASD) have atypical patterns of head movements during an MR scan that are functionally important-they are linked to future learning trajectories in toddlerhood. Addressing head movement issues in neuroimaging analyses in infant research as well as understanding the causes of these movements from a developmental perspective requires acknowledging the complexity of this endeavor. For example, head movement signatures in infants can interact with experimental task conditions (such as listening to language compared to sleeping), autism risk, and age. How can new knowledge about newborns' individual, subject-specific behavioral differences which may impact MR signal acquisition and statistical inference ignite critical thinking for the field of infant brain imaging across the spectrum of typical and atypical development? Early behavioral differences between HR and LR infant cohorts that are often examples of "artifactual" confounds in MR work provide insight into nascent neurobiological differences, including biophysical tissue properties and hemodynamic response variability, in these and related populations at risk for atypical development. Are these neurobiological drivers of atypical development? This work identifies important knowledge gaps and suggests guidelines at the leading edge of baby imaging science to transform our understanding of atypical brain development in humans. The precise study of the neurobiological underpinnings of atypical development in humans calls for approaches including quantitative MRI (qMRI) pulse sequences, multi-modal imaging (including DTI, MRS, as well as MEG), and infant-specific HRF shapes when modeling BOLD signal.

RevDate: 2018-07-13

Raevis JJ, Denisova K, Mechel E, et al (2018)


Retinal cases & brief reports [Epub ahead of print].

BACKGROUND/PURPOSE: Report a case of markedly asymmetric retinal tessellations and propose mosaicism as a mechanism.

METHODS AND RESULTS: A 59-year-old pseudophakic woman presented with uncorrected 20/20 vision and was found to have markedly different retinal tessellation appearances in both eyes. The axial lengths were 25.66 mm and 25.88 mm in the right and left eyes, respectively, and no significant asymmetrical choroidal thinning was seen on optical coherence tomography or optical coherence tomography angiography. Fluorescein angiogram showed significant hyperfluorescence, representing the underlying choroid, which correlated with the tessellation patterns in the left eye. She had no other ocular or systemic findings such as stripes or whorled skin.

CONCLUSION: This is the first reported case of markedly asymmetric retinal tessellation patterns that are not due to asymmetric axial myopia or choroidal thinning. We propose that mosaicism is a possible mechanism causing this finding.

RevDate: 2018-12-27
CmpDate: 2018-12-27

Zhao G, Walsh K, Long J, et al (2018)

Reduced structural complexity of the right cerebellar cortex in male children with autism spectrum disorder.

PloS one, 13(7):e0196964.

The cerebellum contains 80% of all neurons in the human brain and contributes prominently to implicit learning and predictive processing across motor, sensory, and cognitive domains. As morphological features of the cerebellum in atypically developing individuals remain unexplored in-vivo, this is the first study to use high-resolution 3D fractal analysis to estimate fractal dimension (FD), a measure of structural complexity of an object, of the left and right cerebellar cortex (automatically segmented from Magnetic Resonance Images using FreeSurfer), in male children with Autism Spectrum Disorders (ASD) (N = 20; mean age: 8.8 years old, range: 7.13-10.27) and sex, age, verbal-IQ, and cerebellar volume-matched typically developing (TD) boys (N = 18; mean age: 8.9 years old, range: 6.47-10.52). We focus on an age range within the 'middle and late childhood' period of brain development, between 6 and 12 years. A Mann-Whitney U test revealed a significant reduction in the FD of the right cerebellar cortex in ASD relative to TD boys (P = 0.0063, Bonferroni-corrected), indicating flatter and less regular surface protrusions in ASD relative to TD males. Consistent with the prediction that the cerebellum participates in implicit learning, those ASD boys with a higher (vs. lower) PIQ>VIQ difference showed higher, more normative complexity values, closer to TD children, providing new insight on our understanding of the neurological basis of differences in verbal and performance cognitive abilities that often characterize individuals with ASD.

RevDate: 2018-11-14
CmpDate: 2018-10-22

Malyarchuk B, Derenko M, Denisova G, et al (2018)

Whole mitochondrial genome diversity in two Hungarian populations.

Molecular genetics and genomics : MGG, 293(5):1255-1263.

Complete mitochondrial genomics is an effective tool for studying the demographic history of human populations, but there is still a deficit of mitogenomic data in European populations. In this paper, we present results of study of variability of 80 complete mitochondrial genomes in two Hungarian populations from eastern part of Hungary (Szeged and Debrecen areas). The genetic diversity of Hungarian mitogenomes is remarkably high, reaching 99.9% in a combined sample. According to the analysis of molecular variance (AMOVA), European populations showed a low, but statistically significant level of between-population differentiation (Fst = 0.61%, p = 0), and two Hungarian populations demonstrate lack of between-population differences. Phylogeographic analysis allowed us to identify 71 different mtDNA sub-clades in Hungarians, sixteen of which are novel. Analysis of ancestry-informative mtDNA sub-clades revealed a complex genetic structure associated with the genetic impact of populations from different parts of Eurasia, though the contribution from European populations is the most pronounced. At least 8% of ancestry-informative haplotypes found in Hungarians demonstrate similarity with East and West Slavic populations (sub-clades H1c23a, H2a1c1, J2b1a6, T2b25a1, U4a2e, K1c1j, and I1a1c), while the influence of Siberian populations is not so noticeable (sub-clades A12a, C4a1a, and probably U4b1a4).

RevDate: 2019-05-16
CmpDate: 2019-05-16

Rzaev DA, Denisova NP, Moisak GI, et al (2018)

[Experience of the use of gasserian ganglion balloon compression in patients with trigeminal neuralgia associated with multiple sclerosis].

Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 118(5):30-35.

AIM: To evaluate the efficacy of gasserian ganglion balloon compression in patients with trigeminal neuralgia associated with multiple sclerosis (MS).

MATERIAL AND METHODS: Eight patients (3 men, 5 women), aged from 46 to 66 years (mean age 55 years), with trigeminal neuralgia associated with MS underwent surgery. An average duration of the pain syndrome was 8,4 years. Six patients had previous surgeries due to facial pain. Percutaneous balloon compression of gasserian ganglion was performed to all patients. Follow up period was from 2 to 24 months.

RESULTS: Six patients (75%) reported 100% of pain relief right after the surgery, 2 patients (25%) reported a significant decrease of pain (2-3 points on VAS). Pain recurrence occurred in 3 patients: in 4 months, in 12 months and in 6 months. All of them were operated repeatedly. After the surgery, hypoesthesia on the side of surgery was observed in all patients with a trend towards regression. There was no keratopathy or any complications.

CONCLUSION: Percutaneous balloon compression of gasserian ganglion is an effective and minimally invasive method which can be performed repeatedly in patients with trigeminal neuralgia associated with MS.

RevDate: 2019-01-16
CmpDate: 2019-01-16

Cserhati MF, Mooter ME, Peterson L, et al (2018)

Motifome comparison between modern human, Neanderthal and Denisovan.

BMC genomics, 19(1):472.

BACKGROUND: The availability of the genomes of two archaic humans, Neanderthal and Denisovan, and that of modern humans provides researchers an opportunity to investigate genetic differences between these three subspecies on a genome-wide scale. Here we describe an algorithm that predicts statistically significant motifs based on the difference between a given motif's actual and expected distributions. The algorithm was previously applied to plants but was modified for this work.

RESULTS: The result of applying the algorithm to the human, Neanderthal, and Denisovan genomes is a catalog of potential regulatory motifs in these three human subspecies. We examined the distributions of these motifs in genetic elements including human retroviruses, human accelerated regions, and human accelerated conserved noncoding sequences regions. Differences in these distributions could be the origin of differences in phenotype between the three subspecies. Twenty significant motifs common to all three genomes were found; thirty-three were found in endogenous retroviruses in Neanderthal and Denisovan. Ten of these motifs mapped to the 22 bp core of MiR-1304. The core of this genetic element regulates the ENAM and AMTN genes, which take part in odontogenesis and whose 3' UTRs contained significant motifs. The introns of 20 genes were found to contain a large number of significant motifs, which were also overrepresented in 49 human accelerated regions. These genes include NAV2, SorCS2, TRAPPC9, GRID1, PRDM16, CAMTA1, and ASIC which are all involved in neuroregulation. Further analysis of these genes using the GO database indicates that many are associated with neurodevelopment. Also, varying numbers of significant motifs were found to occur in regions of the Neanderthal and Denisovan genomes that are missing from the human genome, suggesting further functional differences between modern and archaic humans.

CONCLUSION: Although Neanderthal and Denisovan are now extinct, detailed examination of elements from their genomes can shed light on possible phenotypic and cognitive differences between these two archaic human subspecies and modern humans. Genetic similarities and differences between these three subspecies and other fossil hominids would also be of interest.

RevDate: 2018-11-14
CmpDate: 2018-10-15

Banerjee N, Polushina T, Bettella F, et al (2018)

Recently evolved human-specific methylated regions are enriched in schizophrenia signals.

BMC evolutionary biology, 18(1):63.

BACKGROUND: One explanation for the persistence of schizophrenia despite the reduced fertility of patients is that it is a by-product of recent human evolution. This hypothesis is supported by evidence suggesting that recently-evolved genomic regions in humans are involved in the genetic risk for schizophrenia. Using summary statistics from genome-wide association studies (GWAS) of schizophrenia and 11 other phenotypes, we tested for enrichment of association with GWAS traits in regions that have undergone methylation changes in the human lineage compared to Neanderthals and Denisovans, i.e. human-specific differentially methylated regions (DMRs). We used analytical tools that evaluate polygenic enrichment of a subset of genomic variants against all variants.

RESULTS: Schizophrenia was the only trait in which DMR SNPs showed clear enrichment of association that passed the genome-wide significance threshold. The enrichment was not observed for Neanderthal or Denisovan DMRs. The enrichment seen in human DMRs is comparable to that for genomic regions tagged by Neanderthal Selective Sweep markers, and stronger than that for Human Accelerated Regions. The enrichment survives multiple testing performed through permutation (n = 10,000) and bootstrapping (n = 5000) in INRICH (p < 0.01). Some enrichment of association with height was observed at the gene level.

CONCLUSIONS: Regions where DNA methylation modifications have changed during recent human evolution show enrichment of association with schizophrenia and possibly with height. Our study further supports the hypothesis that genetic variants conferring risk of schizophrenia co-occur in genomic regions that have changed as the human species evolved. Since methylation is an epigenetic mark, potentially mediated by environmental changes, our results also suggest that interaction with the environment might have contributed to that association.

RevDate: 2019-07-26
CmpDate: 2019-07-26

Akkuratov EE, Gelfand MS, EE Khrameeva (2018)

Neanderthal and Denisovan ancestry in Papuans: A functional study.

Journal of bioinformatics and computational biology, 16(2):1840011.

Sequencing of complete nuclear genomes of Neanderthal and Denisovan stimulated studies about their relationship with modern humans demonstrating, in particular, that DNA alleles from both Neanderthal and Denisovan genomes are present in genomes of modern humans. The Papuan genome is a unique object because it contains both Neanderthal and Denisovan alleles. Here, we have shown that the Papuan genomes contain different gene functional groups inherited from each of the ancient people. The Papuan genomes demonstrate a relative prevalence of Neanderthal alleles in genes responsible for the regulation of transcription and neurogenesis. The enrichment of specific functional groups with Denisovan alleles is less pronounced; these groups are responsible for bone and tissue remodeling. This analysis shows that introgression of alleles from Neanderthals and Denisovans to Papuans occurred independently and retention of these alleles may carry specific adaptive advantages.

RevDate: 2018-06-05
CmpDate: 2018-06-05

Shkliaev AE, Denisova NI, IV Kulikov (2018)

[Splenic artery aneurysm masked by postcholecystectomy syndrome].

Angiologiia i sosudistaia khirurgiia = Angiology and vascular surgery, 24(1):175-178.

Visceral artery aneurysms appear to belong to uncommon and potentially lethal vascular diseases. They are usually revealed accidentally during an ultrasonographic examination, magnetic resonance imaging, or computed tomography. Described in the article is a clinical case report concerning a sacciform aneurysm of the splenic artery, detected in a 53-year-old woman presenting with postcholecystectomy syndrome and followed up for abdominalgia by therapeutists and gastroenterologists. Timely performed radiodiagnosis (including multispiral computed tomography and angiography of the abdominal vessels) made it possible not only to detect the aneurysm, having thus verified the volumetric formation previously found on ultrasonographic examination, but to take adequate measures aimed at preventing rupture of the aneurysm and consisting in endovascular occlusion of the aneurysmatic cavity with metal spirals. Lack of complete clarity in the understanding of the mechanisms of the origin of and no distinctly defined therapeutic-and-diagnostic algorithm for visceral artery aneurysms dictate the necessity to continue collecting and generalizing clinical case reports regarding this rarely encountered vascular pathology.

RevDate: 2018-09-11
CmpDate: 2018-09-11

Bogomolov DV, Fetisov VA, Denisova OP, et al (2018)

[The principal and auxiliary immunohistochemical markers of intravital mechanical strangulation asphyxia].

Sudebno-meditsinskaia ekspertiza, 61(2):11-13.

The objective of the present study was the evaluation of the auxiliary methods for the diagnostics of the intravital formation of the constriction marks; the secondary objective was to determine the pace at which the death and asphyxia occur.

MATERIAL AND METHODS: The materials on which the study was based included 17 cases of mechanical strangulation asphyxia involving 13 men and 4 women at the age from 8 to 28 years. All cases of hanging were associated with different blood alcohol levels. Their characteristic feature was the formation of the obliquely ascending constriction marks. The group of comparison was comprised of three cases of death by drowning and one case of manual strangulation. The control group consisted of 10 patients who died from the acute form of coronary heart disease and 5 cases of death from traumatic shock. All the corpses were examined with the use of the traditional methods within the first 24 hours after death. The special laboratory studies were performed by means of the standard histological and immunohistochemical methods with the use of the polyclonal antibodies against total cytokeratin, fibrinogen, immunoglobulin-lambda, fibronectin, and CD-117 antigen. The histological preparations were stained by the method of Spielmeyer and with toluidine blue.

RESULTS: The results of the study give evidence of the possibility of diagnostics of mechanical strangulation asphyxia making use of the reaction with anti-fibrinogen antibodies in the stromal tissue of the constriction mark even in the absence of other intravital signs of death. Such diagnostics is also possible with the use of the CD-117 antigen in the pulmonary tissue. The expression of this antigen is characteristic of the cases of alveolar hypoxia. The possibility of application of other markers for the differential diagnostics of mechanical strangulation asphyxia from other causes of death is discussed.

RevDate: 2018-11-14

Khabarova EA, Denisova NP, Dmitriev AB, et al (2018)

Deep Brain Stimulation of the Subthalamic Nucleus in Patients with Parkinson Disease with Prior Pallidotomy or Thalamotomy.

Brain sciences, 8(4):.

Objective. To evaluate the efficacy of deep brain stimulation of the subthalamic nucleus (STN DBS) in patients with Parkinson disease (PD) who previously underwent lesioning of the basal ganglia. Material and methods. The study included 22 patients who underwent STN DBS. Eleven patients had undergone prior unilateral pallidotomy (n = 6) or VL/VIM thalamotomy (n = 5) while the other 11 patients had not. The primary outcome was the change from baseline in the motor subscore of the Unified Parkinson Disease Rating Scale (UPDRS-III) 12 months after STN DBS. Secondary outcomes included change in motor response complications (UPDRS-IV) and change in levodopa equivalent daily dose (LEDD). Results. In the group with prior lesioning UPDRS-III improved by 45%, from 51.5 &plusmn; 9.0% (range, 35&ndash;65) to 26.5 &plusmn; 8.4 (range, 21&ndash;50) (p < 0.01) and UPDRS-IV by 75%, from 8.0 &plusmn; 2.01 (range, 5&ndash;11) to 2.1 &plusmn; 0.74 (range, 1&ndash;3) (p < 0.01). In the group without prior lesioning UPDRS-III improved by 61%, from 74.2% &plusmn; 7.32 (range, 63&ndash;82) to 29.3 &plusmn; 5.99 (range, 20&ndash;42) (p < 0.01) and UPDRS-IV by 77%, from 9.1 &plusmn; 2.46 (range, 5&ndash;12) to 2.0 &plusmn; 1.1 (range, 1&ndash;4) (p < 0.01). Comparing the two groups (with and without lesioning) no significant differences were found either in UPDRS-III (p > 0.05) or UPDRS-IV scores (p > 0.05) at 12 months post-DBS. The LEDD was reduced by 51.4%, from 1008.2 &plusmn; 346.4 to 490.0 &plusmn; 194.3 in those with prior surgery (p < 0.01) and by 55.0%, from 963.4 &plusmn; 96.2 to 433.3 &plusmn; 160.2 in those without (p < 0.01).UPDRS-III improved by 51.8%, from 53.7 &plusmn; 4.6 (range, 50&ndash;62) to 25.0 &plusmn; 3.8 (range, 21&ndash;31) in those with prior pallidotomy (p < 0.01), and by 37.5%, from 48.8 &plusmn; 12.6 (range, 35&ndash;65) to 29.8 &plusmn; 13.6 (range, 22&ndash;50) in those with prior thalamotomy (p < 0.01). This numerical difference in improvement was not statistically significant (p > 0.05). Conclusion. Our comparative study indicates that bilateral STN DBS is effective and can be used in patients with Parkinson disease with prior unilateral stereotactic destructive operations on subcortical structures. The results in our patient cohort are generally consistent with previously published reports of smaller series from multiple centers worldwide.

RevDate: 2018-11-14

Viscardi LH, Paixão-Côrtes VR, Comas D, et al (2018)

Searching for ancient balanced polymorphisms shared between Neanderthals and Modern Humans.

Genetics and molecular biology, 41(1):67-81.

Hominin evolution is characterized by adaptive solutions often rooted in behavioral and cognitive changes. If balancing selection had an important and long-lasting impact on the evolution of these traits, it can be hypothesized that genes associated with them should carry an excess of shared polymorphisms (trans- SNPs) across recent Homo species. In this study, we investigate the role of balancing selection in human evolution using available exomes from modern (Homo sapiens) and archaic humans (H. neanderthalensis and Denisovan) for an excess of trans-SNP in two gene sets: one associated with the immune system (IMMS) and another one with behavioral system (BEHS). We identified a significant excess of trans-SNPs in IMMS (N=547), of which six of these located within genes previously associated with schizophrenia. No excess of trans-SNPs was found in BEHS, but five genes in this system harbor potential signals for balancing selection and are associated with psychiatric or neurodevelopmental disorders. Our approach evidenced recent Homo trans-SNPs that have been previously implicated in psychiatric diseases such as schizophrenia, suggesting that a genetic repertoire common to the immune and behavioral systems could have been maintained by balancing selection starting before the split between archaic and modern humans.

RevDate: 2018-11-14
CmpDate: 2018-10-02

Zehra R, AA Abbasi (2018)

Homo sapiens-Specific Binding Site Variants within Brain Exclusive Enhancers Are Subject to Accelerated Divergence across Human Population.

Genome biology and evolution, 10(3):956-966.

Empirical assessments of human accelerated noncoding DNA frgaments have delineated presence of many cis-regulatory elements. Enhancers make up an important category of such accelerated cis-regulatory elements that efficiently control the spatiotemporal expression of many developmental genes. Establishing plausible reasons for accelerated enhancer sequence divergence in Homo sapiens has been termed significant in various previously published studies. This acceleration by including closely related primates and archaic human data has the potential to open up evolutionary avenues for deducing present-day brain structure. This study relied on empirically confirmed brain exclusive enhancers to avoid any misjudgments about their regulatory status and categorized among them a subset of enhancers with an exceptionally accelerated rate of lineage specific divergence in humans. In this assorted set, 13 distinct transcription factor binding sites were located that possessed unique existence in humans. Three of 13 such sites belonging to transcription factors SOX2, RUNX1/3, and FOS/JUND possessed single nucleotide variants that made them unique to H. sapiens upon comparisons with Neandertal and Denisovan orthologous sequences. These variants modifying the binding sites in modern human lineage were further substantiated as single nucleotide polymorphisms via exploiting 1000 Genomes Project Phase3 data. Long range haplotype based tests laid out evidence of positive selection to be governing in African population on two of the modern human motif modifying alleles with strongest results for SOX2 binding site. In sum, our study acknowledges acceleration in noncoding regulatory landscape of the genome and highlights functional parts within it to have undergone accelerated divergence in present-day human population.

RevDate: 2019-01-21
CmpDate: 2019-01-21

Vernot B, S Pääbo (2018)

The Predecessors Within . . .

Cell, 173(1):6-7.

By examining the genomes of present-day people from Asia, researchers show that modern humans met and interbred with Denisovans, distant relatives to Neanderthals, on at least two occasions. As a result, people today carry DNA from two different Denisovan populations.

RevDate: 2019-03-29
CmpDate: 2019-01-31

Browning SR, Browning BL, Zhou Y, et al (2018)

Analysis of Human Sequence Data Reveals Two Pulses of Archaic Denisovan Admixture.

Cell, 173(1):53-61.e9.

Anatomically modern humans interbred with Neanderthals and with a related archaic population known as Denisovans. Genomes of several Neanderthals and one Denisovan have been sequenced, and these reference genomes have been used to detect introgressed genetic material in present-day human genomes. Segments of introgression also can be detected without use of reference genomes, and doing so can be advantageous for finding introgressed segments that are less closely related to the sequenced archaic genomes. We apply a new reference-free method for detecting archaic introgression to 5,639 whole-genome sequences from Eurasia and Oceania. We find Denisovan ancestry in populations from East and South Asia and Papuans. Denisovan ancestry comprises two components with differing similarity to the sequenced Altai Denisovan individual. This indicates that at least two distinct instances of Denisovan admixture into modern humans occurred, involving Denisovan populations that had different levels of relatedness to the sequenced Altai Denisovan. VIDEO ABSTRACT.

RevDate: 2019-08-20

Warren KA, Ritzman TB, Humphreys RA, et al (2018)

Craniomandibular form and body size variation of first generation mouse hybrids: A model for hominin hybridization.

Journal of human evolution, 116:57-74.

Hybridization occurs in a number of mammalian lineages, including among primate taxa. Analyses of ancient genomes have shown that hybridization between our lineage and other archaic hominins in Eurasia occurred numerous times in the past. However, we still have limited empirical data on what a hybrid skeleton looks like, or how to spot patterns of hybridization among fossils for which there are no genetic data. Here we use experimental mouse models to supplement previous studies of primates. We characterize size and shape variation in the cranium and mandible of three wild-derived inbred mouse strains and their first generation (F1) hybrids. The three parent taxa in our analysis represent lineages that diverged over approximately the same period as the human/Neanderthal/Denisovan lineages and their hybrids are variably successful in the wild. Comparisons of body size, as quantified by long bone measurements, are also presented to determine whether the identified phenotypic effects of hybridization are localized to the cranium or represent overall body size changes. The results indicate that hybrid cranial and mandibular sizes, as well as limb length, exceed that of the parent taxa in all cases. All three F1 hybrid crosses display similar patterns of size and form variation. These results are generally consistent with earlier studies on primates and other mammals, suggesting that the effects of hybridization may be similar across very different scenarios of hybridization, including different levels of hybrid fitness. This paper serves to supplement previous studies aimed at identifying F1 hybrids in the fossil record and to introduce further research that will explore hybrid morphologies using mice as a proxy for better understanding hybridization in the hominin fossil record.

RevDate: 2018-11-13

Leacock S, Syed P, James VM, et al (2018)

Structure/Function Studies of the α4 Subunit Reveal Evolutionary Loss of a GlyR Subtype Involved in Startle and Escape Responses.

Frontiers in molecular neuroscience, 11:23.

Inhibitory glycine receptors (GlyRs) are pentameric ligand-gated anion channels with major roles in startle disease/hyperekplexia (GlyR α1), cortical neuronal migration/autism spectrum disorder (GlyR α2), and inflammatory pain sensitization/rhythmic breathing (GlyR α3). However, the role of the GlyR α4 subunit has remained enigmatic, because the corresponding human gene (GLRA4) is thought to be a pseudogene due to an in-frame stop codon at position 390 within the fourth membrane-spanning domain (M4). Despite this, a recent genetic study has implicated GLRA4 in intellectual disability, behavioral problems and craniofacial anomalies. Analyzing data from sequenced genomes, we found that GlyR α4 subunit genes are predicted to be intact and functional in the majority of vertebrate species-with the exception of humans. Cloning of human GlyR α4 cDNAs excluded alternative splicing and RNA editing as mechanisms for restoring a full-length GlyR α4 subunit. Moreover, artificial restoration of the missing conserved arginine (R390) in the human cDNA was not sufficient to restore GlyR α4 function. Further bioinformatic and mutagenesis analysis revealed an additional damaging substitution at K59 that ablates human GlyR α4 function, which is not present in other vertebrate GlyR α4 sequences. The substitutions K59 and X390 were also present in the genome of an ancient Denisovan individual, indicating that GLRA4 has been a pseudogene for at least 30,000-50,000 years. In artificial synapses, we found that both mouse and gorilla α4β GlyRs mediate synaptic currents with unusually slow decay kinetics. Lastly, to gain insights into the biological role of GlyR α4 function, we studied the duplicated genes glra4a and glra4b in zebrafish. While glra4b expression is restricted to the retina, using a novel tol2-GAL4FF gene trap line (SAIGFF16B), we found that the zebrafish GlyR α4a subunit gene (glra4a) is strongly expressed in spinal cord and hindbrain commissural neurones. Using gene knockdown and a dominant-negative GlyR α4aR278Q mutant, we found that GlyR α4a contributes to touch-evoked escape behaviors in zebrafish. Thus, although GlyR α4 is unlikely to be involved in human startle responses or disease states, this subtype may contribute to escape behaviors in other organisms.

RevDate: 2018-12-02
CmpDate: 2018-10-31

Jiang L, Peng J, Huang M, et al (2018)

Differentiation analysis for estimating individual ancestry from the Tibetan Plateau by an archaic altitude adaptation EPAS1 haplotype among East Asian populations.

International journal of legal medicine, 132(6):1527-1535.

Tibetans have adapted to the extreme environment of high altitude for hundreds of generations. A highly differentiated 5-SNP (Single Nucleotide Polymorphism) haplotype motif (AGGAA) on a hypoxic pathway gene, EPAS1, is observed in Tibetans and lowlanders. To evaluate the potential usage of the 5-SNP haplotype in ancestry inference for Tibetan or Tibetan-related populations, we analyzed this haplotype in 1053 individuals of 12 Chinese populations residing on the Tibetan Plateau, peripheral regions of Tibet, and plain regions. These data were integrated with the genotypes from the 1000 Genome populations and populations in a previously reported paper for population structure analyses. We found that populations representing highland and lowland groups have different dominant ancestry components. The core Denisovan haplotype (AGGAA) was observed at a frequency of 72.32% in the Tibetan Plateau, with a frequency range from 9.48 to 21.05% in the peripheral regions and < 2.5% in the plains area. From the individual perspective, 87.57% of the individuals from the Tibetan Plateau carried the archaic haplotype, while < 5% of the Chinese Han people carried the haplotype. Our findings indicate that the 5-SNP haplotype has a special distribution pattern in populations of Tibet and peripheral regions and could be integrated into AISNP (Ancestry Informative Single Nucleotide Polymorphism) panels to enhance ancestry resolution.

RevDate: 2019-02-08
CmpDate: 2018-03-13

Rodríguez-Paredes M, Bormann F, Raddatz G, et al (2018)

Methylation profiling identifies two subclasses of squamous cell carcinoma related to distinct cells of origin.

Nature communications, 9(1):577.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and usually progresses from a UV-induced precancerous lesion termed actinic keratosis (AK). Despite various efforts to characterize these lesions molecularly, the etiology of AK and its progression to cSCC remain partially understood. Here, we use Infinium MethylationEPIC BeadChips to interrogate the DNA methylation status in healthy, AK and cSCC epidermis samples. Importantly, we show that AK methylation patterns already display classical features of cancer methylomes and are highly similar to cSCC profiles. Further analysis identifies typical features of stem cell methylomes, such as reduced DNA methylation age, non-CpG methylation, and stem cell-related keratin and enhancer methylation patterns. Interestingly, this signature is detected only in half of the samples, while the other half shows patterns more closely related to healthy epidermis. These findings suggest the existence of two subclasses of AK and cSCC emerging from distinct keratinocyte differentiation stages.

RevDate: 2019-03-26
CmpDate: 2019-03-26

Yew CW, Lu D, Deng L, et al (2018)

Genomic structure of the native inhabitants of Peninsular Malaysia and North Borneo suggests complex human population history in Southeast Asia.

Human genetics, 137(2):161-173.

Southeast Asia (SEA) is enriched with a complex history of peopling. Malaysia, which is located at the crossroads of SEA, has been recognized as one of the hubs for early human migration. To unravel the genomic complexity of the native inhabitants of Malaysia, we sequenced 12 samples from 3 indigenous populations from Peninsular Malaysia and 4 native populations from North Borneo to a high coverage of 28-37×. We showed that the Negritos from Peninsular Malaysia shared a common ancestor with the East Asians, but exhibited some level of gene flow from South Asia, while the North Borneo populations exhibited closer genetic affinity towards East Asians than the Malays. The analysis of time of divergence suggested that ancestors of Negrito were the earliest settlers in the Malay Peninsula, whom first separated from the Papuans ~ 50-33 thousand years ago (kya), followed by East Asian (~ 40-15 kya), while the divergence time frame between North Borneo and East Asia populations predates the Austronesian expansion period implies a possible pre-Neolithic colonization. Substantial Neanderthal ancestry was confirmed in our genomes, as was observed in other East Asians. However, no significant difference was observed, in terms of the proportion of Denisovan gene flow into these native inhabitants from Malaysia. Judging from the similar amount of introgression in the Southeast Asians and East Asians, our findings suggest that the Denisovan gene flow may have occurred before the divergence of these populations and that the shared similarities are likely an ancestral component.

RevDate: 2018-06-27
CmpDate: 2018-06-27

Shipilovskikh SA, Vaganov VY, Denisova EI, et al (2018)

Dehydration of Amides to Nitriles under Conditions of a Catalytic Appel Reaction.

Organic letters, 20(3):728-731.

A highly expedient protocol for a catalytic Appel-type dehydration of amides to nitriles has been developed that employs oxalyl chloride and triethylamine along with triphenylphosphine oxide as a catalyst. The reactions are usually complete in less than 10 min with only a 1 mol % catalyst loading. The reaction scope includes aromatic, heteroaromatic, and aliphatic amides, including derivatives of α-hydroxy and α-amino acids.

RevDate: 2019-04-08
CmpDate: 2018-12-11

Belousov AB, Nishimune H, Denisova JV, et al (2018)

A potential role for neuronal connexin 36 in the pathogenesis of amyotrophic lateral sclerosis.

Neuroscience letters, 666:1-4.

Neuronal gap junctional protein connexin 36 (Cx36) contributes to neuronal death following a range of acute brain insults such as ischemia, traumatic brain injury and epilepsy. Whether Cx36 contributes to neuronal death and pathological outcomes in chronic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), is not known. We show here that the expression of Cx36 is significantly decreased in lumbar segments of the spinal cord of both human ALS subjects and SOD1G93A mice as compared to healthy human and wild-type mouse controls, respectively. In purified neuronal cultures prepared from the spinal cord of wild-type mice, knockdown of Cx36 reduces neuronal death caused by overexpression of the mutant human SOD1-G93A protein. Taken together, these data suggest a possible contribution of Cx36 to ALS pathogenesis. A perspective for the use of blockers of Cx36 gap junction channels for ALS therapy is discussed.

RevDate: 2018-11-13
CmpDate: 2018-07-26

Derenko M, Denisova G, Malyarchuk B, et al (2018)

Mitogenomic diversity and differentiation of the Buryats.

Journal of human genetics, 63(1):71-81.

In this paper we present a results of first comprehensive study of the complete mitogenomes in the Buryats with regard to their belonging to the main regional (eastern and western Buryats); tribal (Khori, Ekhirid, Bulagad, and Khongodor), and ethno-territorial (Aginsk, Alar, Balagansk, Barguzin, Ida, Khorinsk, Kuda, Selenga, Verkholensk, Olkhon, Tunka, and Shenehen Buryats) groups. The analysis of molecular variation performed using regional, tribal, and ethno-territorial divisions of the Buryats showed lack of genetic differentiation at all levels. Nonetheless, the complete mitogenome analysis revealed a very high level of genetic diversity in the Buryats which is the highest among Siberian populations and comparable to that in populations of eastern and western Asia. The AMOVA and MDS analyses results imply to a strong genetic similarity between the Buryats and eastern Asian populations of Chinese and Japanese, suggesting their origin on the basis of common maternal ancestry components. Several new Buryat-specific branches of haplogroup G (G2a2a, G2a1i, G2a5a) display signals of dispersals dating to 2.6-6.6 kya with a possible origin in eastern Asia, thus testifying Bronze Age and Neolithic arrival of ancestral eastern Asian component to the South Siberia region.

RevDate: 2019-01-16
CmpDate: 2018-07-23

Walter Costa MB, Höner Zu Siederdissen C, Tulpan D, et al (2018)

Temporal ordering of substitutions in RNA evolution: Uncovering the structural evolution of the Human Accelerated Region 1.

Journal of theoretical biology, 438:143-150.

The Human Accelerated Region 1 (HAR1) is the most rapidly evolving region in the human genome. It is part of two overlapping long non-coding RNAs, has a length of only 118 nucleotides and features 18 human specific changes compared to an ancestral sequence that is extremely well conserved across non-human primates. The human HAR1 forms a stable secondary structure that is strikingly different from the one in chimpanzee as well as other closely related species, again emphasizing its human-specific evolutionary history. This suggests that positive selection has acted to stabilize human-specific features in the ensemble of HAR1 secondary structures. To investigate the evolutionary history of the human HAR1 structure, we developed a computational model that evaluates the relative likelihood of evolutionary trajectories as a probabilistic version of a Hamiltonian path problem. The model predicts that the most likely last step in turning the ancestral primate HAR1 into the human HAR1 was exactly the substitution that distinguishes the modern human HAR1 sequence from that of Denisovan, an archaic human, providing independent support for our model. The MutationOrder software is available for download and can be applied to other instances of RNA structure evolution.

RevDate: 2018-03-27
CmpDate: 2018-03-27

Kovalkova NA, Ragino YI, Travnikova NY, et al (2017)

[Associations between metabolic syndrome and reduced lung function in young people].

Terapevticheskii arkhiv, 89(10):54-61.

AIM: To reveal possible associations between metabolic syndrome (MS) and reduced lung function.

SUBJECTS AND METHODS: In 2013-016, a cross-sectional survey was conducted in 908 Novosibirsk dwellers, which included spirometry to evaluate external respiratory function (ERF). For the detection of MS, the investigators used the 2009 All-Russian Research Society of Cardiologists criteria: waist circumference (WC) > 80 cm for women and >94 cm for men in combination with two of the following criteria: blood pressure (BP) ≥130/85 mm Hg, triglycerides (TG) ≥1.7 mmol/l, high-density lipoproteins (HDL) cholesterol <1.0 mmol/l for men and <1.2 mmol/l for women, low-density lipoprotein (LDL) cholesterol >3.0 mmol/l, and glucose ≥6.1 mmol/l.

RESULTS: The mean values of WC were significantly greater with a forced expiratory volume in one second (FEV1) <80% than those with a FEV1 of ≥80% in both men (p=0.002) and women (p=0.050); in women, the mean values of WS were higher than those with a FEV1/forced vital capacity (FVC) <70% than those with a FEV1/FVC of ≥70% (p=0.047); the mean systolic and diastolic BP levels were significantly more with reductions in FEV1 and FVC, and the level of HDL cholesterol was significantly lower than that with a FEV1 of < 80% in men only. Significant correlations were found between FEV1 and all components of MS in men, between the majority of components of MS and FVC in men, between WC, BP, and FEV1/FVC in men and women, between plasma glucose levels and FEV1/FVC in women. Linear regression analysis revealed significant inverse correlations of FEV1 with TG, glucose, BP; those of FVC with TG, glucose; at the same time a positive association with HDL cholesterol in men, and only a negative correlation of FEV1/FVC with WC.

CONCLUSION: The revealed associations between MS and reduced lung function can most likely be explained by the greater prevalence of both MS and its components (hypertension, hypertriglyceridemia, hyperglycemia, LDL hypercholesterolemia) among Novosibirsk men. This is consistent with the assertion that the decline in ERF, particularly FEV1, may be a marker of future cardiovascular disease morbidity and mortality.

RevDate: 2018-03-15
CmpDate: 2018-03-15

Soldatsky YL, Denisova OA, SA Bulynko (2017)

[The specific features of the past medical history and etiology of pharyngeal abscess in the children].

Vestnik otorinolaringologii, 82(5):12-14.

The present study was undertaken for the purpose of elucidating the specific features of the past medical history and the etiological factors responsible for the development of tonsillogenic pharyngeal abscesses in the children. We performed the retrospective analysis of the medical histories of 291 children presenting with this condition who had been admitted for the treatment to the ENT Department of the Morozovskzya City Children's Clinical Hospital during the period from January till December 2015. The study has demonstrated the following most common shortcomings of the outpatient treatment of the patients suffering from chronic tonsillitis at the stage preceding formation of paratonsillar abscess: inadequate antibacterial therapy of acute chronic tonsillitis or its exacerbation and limited indications for tonsillectomy at the level of the outpatient treatment. The leading role in the etiology of tonsillogenic pharyngeal abscesses in the children is played by beta-hemolytic Streptococcus of group A. It is concluded that the medical history suggesting past paratonsillar abscess is the absolute indication for the subsequent tonsillectomy in the children of any age.

RevDate: 2018-04-18
CmpDate: 2018-04-18

Yazdanyar A, Rizzuti AE, Mechel E, et al (2018)

Gout Keratitis: A Case of Peripheral Ulcerative Keratitis Secondary to Gout With a Review of the Literature.

Cornea, 37(3):379-381.

PURPOSE: To report a case of peripheral ulcerative keratitis secondary to gout.

METHODS: A 41-year-old man with a history of severe gout disease presented with pain and redness of the right eye. Physical examination revealed 2 areas of peripheral corneal thinning with overlying epithelial defects. Adjacent to these areas, reflective crystals were identified in the corneal stroma. Anterior segment optical coherence tomography demonstrated stromal corneal deposits.

RESULTS: Systemic workup was negative aside from an elevated serum uric acid level. The patient was administered oral prednisone, allopurinol, and colchicine. At his 2-month follow-up visit, the patient was asymptomatic and his corneal thinning had significantly improved.

CONCLUSIONS: Gout is the most common type of inflammatory arthritis in adults with rising incidence and prevalence. Ocular findings in gout are common, but patients are usually asymptomatic. Monosodium urate crystal deposition has been reported to occur in various parts of the eye, with and without ocular inflammation. Crystal deposition in the cornea is extremely rare and may be a cause of peripheral ulcerative keratitis.

RevDate: 2019-01-22

Vashee S, Stockwell TB, Alperovich N, et al (2017)

Cloning, Assembly, and Modification of the Primary Human Cytomegalovirus Isolate Toledo by Yeast-Based Transformation-Associated Recombination.

mSphere, 2(5):.

Genetic engineering of cytomegalovirus (CMV) currently relies on generating a bacterial artificial chromosome (BAC) by introducing a bacterial origin of replication into the viral genome using in vivo recombination in virally infected tissue culture cells. However, this process is inefficient, results in adaptive mutations, and involves deletion of viral genes to avoid oversized genomes when inserting the BAC cassette. Moreover, BAC technology does not permit the simultaneous manipulation of multiple genome loci and cannot be used to construct synthetic genomes. To overcome these limitations, we adapted synthetic biology tools to clone CMV genomes in Saccharomyces cerevisiae. Using an early passage of the human CMV isolate Toledo, we first applied transformation-associated recombination (TAR) to clone 16 overlapping fragments covering the entire Toledo genome in Saccharomyces cerevisiae. Then, we assembled these fragments by TAR in a stepwise process until the entire genome was reconstituted in yeast. Since next-generation sequence analysis revealed that the low-passage-number isolate represented a mixture of parental and fibroblast-adapted genomes, we selectively modified individual DNA fragments of fibroblast-adapted Toledo (Toledo-F) and again used TAR assembly to recreate parental Toledo (Toledo-P). Linear, full-length HCMV genomes were transfected into human fibroblasts to recover virus. Unlike Toledo-F, Toledo-P displayed characteristics of primary isolates, including broad cellular tropism in vitro and the ability to establish latency and reactivation in humanized mice. Our novel strategy thus enables de novo cloning of CMV genomes, more-efficient genome-wide engineering, and the generation of viral genomes that are partially or completely derived from synthetic DNA. IMPORTANCE The genomes of large DNA viruses, such as human cytomegalovirus (HCMV), are difficult to manipulate using current genetic tools, and at this time, it is not possible to obtain, molecular clones of CMV without extensive tissue culture. To overcome these limitations, we used synthetic biology tools to capture genomic fragments from viral DNA and assemble full-length genomes in yeast. Using an early passage of the HCMV isolate Toledo containing a mixture of wild-type and tissue culture-adapted virus. we directly cloned the majority sequence and recreated the minority sequence by simultaneous modification of multiple genomic regions. Thus, our novel approach provides a paradigm to not only efficiently engineer HCMV and other large DNA viruses on a genome-wide scale but also facilitates the cloning and genetic manipulation of primary isolates and provides a pathway to generating entirely synthetic genomes.

RevDate: 2018-04-17
CmpDate: 2018-04-17

Saakyan SV, Katargina LA, Krichevskaya GI, et al (2017)

[Specific immunoglobulins G and M in blood serum in retinoblastoma and 'pseudoretinoblastoma'].

Vestnik oftalmologii, 133(4):12-16.

Perinatal inflammatory retinal diseases and intrauterine retinal maldevelopments are mistaken for retinoblastoma as often as in 8-16% of cases.

AIM: To analyze the infectious status in children with retinoblastoma and pseudoretinoblastoma at different ages.

MATERIAL AND METHODS: A total of 47 retinoblastoma suspects aged 4-69 months were enrolled. Pseudoretinoblastoma (inflammatory retinal diseases and intrauterine maldevelopments of the retina) was detected in 14 children (group 1), retinoblastoma - in 33 children (group 2). In each group, two subgroups were identified: 'a' - children under 12 months of age (1a - 5 patients, 2a - 10 patients) and 'b'- children over 12 months of age (1b - 9 patients, 2b - 23 patients). Their blood sera were examined for antibodies to herpes simplex virus types 1 and 2, cytomegalovirus, Epstein-Barr virus, toxoplasma, toxocara, chlamydia, and mycoplasma (enzyme-linked immunosorbent assay).

RESULTS: According to serological screening, all patients from group 1a (children under 12 months of age with pseudoretinoblastoma), in contrast to other groups, were infected perinatally with cytomegalovirus infection. All 47 patients were seronegative to toxoplasma. Toxocara infection was identified in children over 12 months of age: in 3 out of 9 patients with pseudoretinoblastoma and in 2 out of 23 patients with retinoblastoma (p>0.05). Markers of Epstein-Barr viral activity were detected only in 3 retinoblastoma children over 12 months of age.

CONCLUSION: The results suggest that cytomegalovirus infection plays the leading role in the development of perinatal eye pathology, which, in infants, is clinically similar to retinoblastoma. In children over 12 months of age we found no serological signs that could be regarded as specific of either retinoblastoma, or pseudoretinoblastoma. The only thing worth paying attention to is the activation of Epstein-Barr virus infection in children over 12 months of age with retinoblastoma.

RevDate: 2019-01-16
CmpDate: 2018-01-08

Xu D, Jaber Y, Pavlidis P, et al (2017)

VCFtoTree: a user-friendly tool to construct locus-specific alignments and phylogenies from thousands of anthropologically relevant genome sequences.

BMC bioinformatics, 18(1):426.

BACKGROUND: Constructing alignments and phylogenies for a given locus from large genome sequencing studies with relevant outgroups allow novel evolutionary and anthropological insights. However, no user-friendly tool has been developed to integrate thousands of recently available and anthropologically relevant genome sequences to construct complete sequence alignments and phylogenies.

RESULTS: Here, we provide VCFtoTree, a user friendly tool with a graphical user interface that directly accesses online databases to download, parse and analyze genome variation data for regions of interest. Our pipeline combines popular sequence datasets and tree building algorithms with custom data parsing to generate accurate alignments and phylogenies using all the individuals from the 1000 Genomes Project, Neanderthal and Denisovan genomes, as well as reference genomes of Chimpanzee and Rhesus Macaque. It can also be applied to other phased human genomes, as well as genomes from other species. The output of our pipeline includes an alignment in FASTA format and a tree file in newick format.

CONCLUSION: VCFtoTree fulfills the increasing demand for constructing alignments and phylogenies for a given loci from thousands of available genomes. Our software provides a user friendly interface for a wider audience without prerequisite knowledge in programming. VCFtoTree can be accessed from .

RevDate: 2018-11-13
CmpDate: 2017-10-31

Zanolli C, Hourset M, Esclassan R, et al (2017)

Neanderthal and Denisova tooth protein variants in present-day humans.

PloS one, 12(9):e0183802.

Environment parameters, diet and genetic factors interact to shape tooth morphostructure. In the human lineage, archaic and modern hominins show differences in dental traits, including enamel thickness, but variability also exists among living populations. Several polymorphisms, in particular in the non-collagenous extracellular matrix proteins of the tooth hard tissues, like enamelin, are involved in dental structure variation and defects and may be associated with dental disorders or susceptibility to caries. To gain insights into the relationships between tooth protein polymorphisms and dental structural morphology and defects, we searched for non-synonymous polymorphisms in tooth proteins from Neanderthal and Denisova hominins. The objective was to identify archaic-specific missense variants that may explain the dental morphostructural variability between extinct and modern humans, and to explore their putative impact on present-day dental phenotypes. Thirteen non-collagenous extracellular matrix proteins specific to hard dental tissues have been selected, searched in the publicly available sequence databases of Neanderthal and Denisova individuals and compared with modern human genome data. A total of 16 non-synonymous polymorphisms were identified in 6 proteins (ameloblastin, amelotin, cementum protein 1, dentin matrix acidic phosphoprotein 1, enamelin and matrix Gla protein). Most of them are encoded by dentin and enamel genes located on chromosome 4, previously reported to show signs of archaic introgression within Africa. Among the variants shared with modern humans, two are ancestral (common with apes) and one is the derived enamelin major variant, T648I (rs7671281), associated with a thinner enamel and specific to the Homo lineage. All the others are specific to Neanderthals and Denisova, and are found at a very low frequency in modern Africans or East and South Asians, suggesting that they may be related to particular dental traits or disease susceptibility in these populations. This modern regional distribution of archaic dental polymorphisms may reflect persistence of archaic variants in some populations and may contribute in part to the geographic dental variations described in modern humans.

RevDate: 2019-06-21
CmpDate: 2019-06-21

Denisova K, G Zhao (2017)

Inflexible neurobiological signatures precede atypical development in infants at high risk for autism.

Scientific reports, 7(1):11285.

Variability in neurobiological signatures is ubiquitous in early life but the link to adverse developmental milestones in humans is unknown. We examined how levels of signal and noise in movement signatures during the 1st year of life constrain early development in 71 healthy typically developing infants, either at High or Low familial Risk (HR or LR, respectively) for developing Autism Spectrum Disorders (ASD). Delays in early learning developmental trajectories in HR infants (validated in an analysis of 1,445 infants from representative infant-sibling studies) were predicted by worse stochastic patterns in their spontaneous head movements as early as 1-2 months after birth, relative to HR infants who showed more rapid developmental progress, as well as relative to all LR infants. While LR 1-2 mo-old infants' movements were significantly different during a language listening task compared to during sleep, HR infants' movements were more similar during both conditions, a striking lack of diversity that reveals context-inflexible experience of ambient information. Contrary to expectation, it is not the level of variability per se that is particularly detrimental in early life. Rather, inflexible sensorimotor systems and/or atypical transition between behavioral states may interfere with the establishment of capacity to extract structure and important cues from sensory input at birth, preceding and contributing to an atypical brain developmental trajectory in toddlerhood.

RevDate: 2019-04-27
CmpDate: 2018-06-12

Gardner EJ, Lam VK, Harris DN, et al (2017)

The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology.

Genome research, 27(11):1916-1929.

Mobile element insertions (MEIs) represent ∼25% of all structural variants in human genomes. Moreover, when they disrupt genes, MEIs can influence human traits and diseases. Therefore, MEIs should be fully discovered along with other forms of genetic variation in whole genome sequencing (WGS) projects involving population genetics, human diseases, and clinical genomics. Here, we describe the Mobile Element Locator Tool (MELT), which was developed as part of the 1000 Genomes Project to perform MEI discovery on a population scale. Using both Illumina WGS data and simulations, we demonstrate that MELT outperforms existing MEI discovery tools in terms of speed, scalability, specificity, and sensitivity, while also detecting a broader spectrum of MEI-associated features. Several run modes were developed to perform MEI discovery on local and cloud systems. In addition to using MELT to discover MEIs in modern humans as part of the 1000 Genomes Project, we also used it to discover MEIs in chimpanzees and ancient (Neanderthal and Denisovan) hominids. We detected diverse patterns of MEI stratification across these populations that likely were caused by (1) diverse rates of MEI production from source elements, (2) diverse patterns of MEI inheritance, and (3) the introgression of ancient MEIs into modern human genomes. Overall, our study provides the most comprehensive map of MEIs to date spanning chimpanzees, ancient hominids, and modern humans and reveals new aspects of MEI biology in these lineages. We also demonstrate that MELT is a robust platform for MEI discovery and analysis in a variety of experimental settings.

RevDate: 2018-11-13
CmpDate: 2018-05-15

Jinam TA, Phipps ME, Aghakhanian F, et al (2017)

Discerning the Origins of the Negritos, First Sundaland People: Deep Divergence and Archaic Admixture.

Genome biology and evolution, 9(8):2013-2022.

Human presence in Southeast Asia dates back to at least 40,000 years ago, when the current islands formed a continental shelf called Sundaland. In the Philippine Islands, Peninsular Malaysia, and Andaman Islands, there exist indigenous groups collectively called Negritos whose ancestry can be traced to the "First Sundaland People." To understand the relationship between these Negrito groups and their demographic histories, we generated genome-wide single nucleotide polymorphism data in the Philippine Negritos and compared them with existing data from other populations. Phylogenetic tree analyses show that Negritos are basal to other East and Southeast Asians, and that they diverged from West Eurasians at least 38,000 years ago. We also found relatively high traces of Denisovan admixture in the Philippine Negritos, but not in the Malaysian and Andamanese groups, suggesting independent introgression and/or parallel losses involving Denisovan introgressed regions. Shared genetic loci between all three Negrito groups could be related to skin pigmentation, height, facial morphology and malarial resistance. These results show the unique status of Negrito groups as descended from the First Sundaland People.

RevDate: 2019-01-15
CmpDate: 2018-04-27

Sharbrough J, Havird JC, Noe GR, et al (2017)

The Mitonuclear Dimension of Neanderthal and Denisovan Ancestry in Modern Human Genomes.

Genome biology and evolution, 9(6):1567-1581.

Some human populations interbred with Neanderthals and Denisovans, resulting in substantial contributions to modern-human genomes. Therefore, it is now possible to use genomic data to investigate mechanisms that shaped historical gene flow between humans and our closest hominin relatives. More generally, in eukaryotes, mitonuclear interactions have been argued to play a disproportionate role in generating reproductive isolation. There is no evidence of mtDNA introgression into modern human populations, which means that all introgressed nuclear alleles from archaic hominins must function on a modern-human mitochondrial background. Therefore, mitonuclear interactions are also potentially relevant to hominin evolution. We performed a detailed accounting of mtDNA divergence among hominin lineages and used population-genomic data to test the hypothesis that mitonuclear incompatibilities have preferentially restricted the introgression of nuclear genes with mitochondrial functions. We found a small but significant underrepresentation of introgressed Neanderthal alleles at such nuclear loci. Structural analyses of mitochondrial enzyme complexes revealed that these effects are unlikely to be mediated by physically interacting sites in mitochondrial and nuclear gene products. We did not detect any underrepresentation of introgressed Denisovan alleles at mitochondrial-targeted loci, but this may reflect reduced power because locus-specific estimates of Denisovan introgression are more conservative. Overall, we conclude that genes involved in mitochondrial function may have been subject to distinct selection pressures during the history of introgression from archaic hominins but that mitonuclear incompatibilities have had, at most, a small role in shaping genome-wide introgression patterns, perhaps because of limited functional divergence in mtDNA and interacting nuclear genes.

RevDate: 2018-11-13
CmpDate: 2018-05-31

Rogers AR, Bohlender RJ, CD Huff (2017)

Early history of Neanderthals and Denisovans.

Proceedings of the National Academy of Sciences of the United States of America, 114(37):9859-9863.

Extensive DNA sequence data have made it possible to reconstruct human evolutionary history in unprecedented detail. We introduce a method to study the past several hundred thousand years. Our results show that (i) the Neanderthal-Denisovan lineage declined to a small size just after separating from the modern lineage, (ii) Neanderthals and Denisovans separated soon thereafter, and (iii) the subsequent Neanderthal population was large and deeply subdivided. They also (iv) support previous estimates of gene flow from Neanderthals into modern Eurasians. These results suggest an archaic human diaspora early in the Middle Pleistocene.


ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.


Order from Amazon

One of the most intriguing, and philosophically suggestive, recent scientific findings has been the discovery that the human lineage included several branches at the species level in which each species had developed culture (tool making, mastery of fire, burial of the dead). Before the Chicxulub impact that ended the realm of the dinosaurs, sentience and culture had not occurred in any lineage, despite several hundred million years of evolution. However, in the mammalian radiation that occurred afterwards, several primate lineages occurred. In just the last few million years, one of those lineages diverged into several sentient, culture-developing species. This book explores how only one of those species (ours) survived, while the others went extinct. Recommended. R. Robbins

Electronic Scholarly Publishing
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Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).


ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.


Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )