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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: 2020-10-11

Pan L, Dumoncel J, Mazurier A, et al (2020)

Hominin diversity in East Asia during the Middle Pleistocene: A premolar endostructural perspective.

Journal of human evolution, 148:102888 pii:S0047-2484(20)30149-4 [Epub ahead of print].

Following the recent studies of East Asian mid-Middle to early Late Pleistocene hominin material, a large spectrum of morphological diversity has been recognized and the coexistence of archaic ('Homo erectus-like') and derived ('modern-like') dental morphological patterns has been highlighted. In fact, for most of these Chinese fossils, generally categorized as 'archaic Homo sapiens' or 'post-H. erectus Homo', the taxonomic attribution is a matter of contention. With the help of μCT techniques and a deformation-based 3D geometric morphometric approach, we focused on the morphological variation in the enamel-dentine junction (EDJ) of 18 upper and lower premolars from Chinese Middle Pleistocene hominins. We then compared our results with a number of fossil and modern human groups, including Early Pleistocene H. erectus from Sangiran; late Early Pleistocene hominins from Tighenif, Algeria; classic Neanderthals; and modern humans. Our results highlight an evolutionary/chronological trend of crown base reduction, elevation of EDJ topography, and EDJ surface simplification in the hominin groups studied here. Moreover, this study brings insights to the taxonomy/phylogeny of 6 late Middle Pleistocene specimens whose evolutionary placement has been debated for decades. Among these specimens, Changyang premolars show features that can be aligned with the Asian H. erectus hypodigm, whereas Panxian Dadong and Tongzi premolars are more similar to Late Pleistocene Homo. Compared with early to mid-Middle Pleistocene hominins in East Asia, late Middle Pleistocene hominins evince an enlarged morphological variation. A persistence of archaic morphotypes and possible admixture among populations during the late Middle Pleistocene are discussed.

RevDate: 2020-09-25

Petr M, Hajdinjak M, Fu Q, et al (2020)

The evolutionary history of Neanderthal and Denisovan Y chromosomes.

Science (New York, N.Y.), 369(6511):1653-1656.

Ancient DNA has provided new insights into many aspects of human history. However, we lack comprehensive studies of the Y chromosomes of Denisovans and Neanderthals because the majority of specimens that have been sequenced to sufficient coverage are female. Sequencing Y chromosomes from two Denisovans and three Neanderthals shows that the Y chromosomes of Denisovans split around 700 thousand years ago from a lineage shared by Neanderthals and modern human Y chromosomes, which diverged from each other around 370 thousand years ago. The phylogenetic relationships of archaic and modern human Y chromosomes differ from the population relationships inferred from the autosomal genomes and mirror mitochondrial DNA phylogenies, indicating replacement of both the mitochondrial and Y chromosomal gene pools in late Neanderthals. This replacement is plausible if the low effective population size of Neanderthals resulted in an increased genetic load in Neanderthals relative to modern humans.

RevDate: 2020-09-21

Merisaari J, Denisova OV, Doroszko M, et al (2020)

Monotherapy efficacy of blood-brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma.

Brain communications, 2(1):fcaa002 pii:fcaa002.

Glioblastoma is a fatal disease in which most targeted therapies have clinically failed. However, pharmacological reactivation of tumour suppressors has not been thoroughly studied as yet as a glioblastoma therapeutic strategy. Tumour suppressor protein phosphatase 2A is inhibited by non-genetic mechanisms in glioblastoma, and thus, it would be potentially amendable for therapeutic reactivation. Here, we demonstrate that small molecule activators of protein phosphatase 2A, NZ-8-061 and DBK-1154, effectively cross the in vitro model of blood-brain barrier, and in vivo partition to mouse brain tissue after oral dosing. In vitro, small molecule activators of protein phosphatase 2A exhibit robust cell-killing activity against five established glioblastoma cell lines, and nine patient-derived primary glioma cell lines. Collectively, these cell lines have heterogeneous genetic background, kinase inhibitor resistance profile and stemness properties; and they represent different clinical glioblastoma subtypes. Moreover, small molecule activators of protein phosphatase 2A were found to be superior to a range of kinase inhibitors in their capacity to kill patient-derived primary glioma cells. Oral dosing of either of the small molecule activators of protein phosphatase 2A significantly reduced growth of infiltrative intracranial glioblastoma tumours. DBK-1154, with both higher degree of brain/blood distribution, and more potent in vitro activity against all tested glioblastoma cell lines, also significantly increased survival of mice bearing orthotopic glioblastoma xenografts. In summary, this report presents a proof-of-principle data for blood-brain barrier-permeable tumour suppressor reactivation therapy for glioblastoma cells of heterogenous molecular background. These results also provide the first indications that protein phosphatase 2A reactivation might be able to challenge the current paradigm in glioblastoma therapies which has been strongly focused on targeting specific genetically altered cancer drivers with highly specific inhibitors. Based on demonstrated role for protein phosphatase 2A inhibition in glioblastoma cell drug resistance, small molecule activators of protein phosphatase 2A may prove to be beneficial in future glioblastoma combination therapies.

RevDate: 2020-09-03

Eremin D, Boiko D, Kostyukovich A, et al (2020)

Mechanistic study of Pd/NHC-catalyzed Sonogashira reaction: discovery of NHC-ethynyl coupling process.

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

The product of a revealed transformation - NHC-ethynyl coupling - was observed as a catalyst transformation pathway in the Sonogashira cross-coupling, catalyzed by Pd/NHC complexes. The 2-ethynylated azolium salt was isolated in individual from and fully characterized, including the X-Ray analysis. A number of possible intermediates of this transformation with common formulae (NHC)xPd(C2Ph) (x = 1,2) were observed and subjected to collision-induced dissociation (CID) and infrared multiphoton dissociation (IRMPD) experiments studies to elucidate their structure. Measured bond dissociation energies (BDEs) and IRMPD spectra were in an excellent agreement with quantum calculations for coupling product π-complexes with Pd(0). Molecular dynamics simulations confirmed multiple observed CID fragmentation pathways. Performed study of catalyst evolution suggests the reported transformation to be considered in the development of new catalytic systems for alkyne functionalization reactions.

RevDate: 2020-08-25

Telis N, Aguilar R, K Harris (2020)

Selection against archaic hominin genetic variation in regulatory regions.

Nature ecology & evolution pii:10.1038/s41559-020-01284-0 [Epub ahead of print].

Traces of Neandertal and Denisovan DNA persist in the modern human gene pool, but have been systematically purged by natural selection from genes and other functionally important regions. This implies that many archaic alleles harmed the fitness of hybrid individuals, but the nature of this harm is poorly understood. Here, we show that enhancers contain less Neandertal and Denisovan variation than expected given the background selection they experience, suggesting that selection acted to purge these regions of archaic alleles that disrupted their gene regulatory functions. We infer that selection acted mainly on young archaic variation that arose in Neandertals or Denisovans shortly before their contact with humans; enhancers are not depleted of older variants found in both archaic species. Some types of enhancer appear to have tolerated introgression better than others; compared with tissue-specific enhancers, pleiotropic enhancers show stronger depletion of archaic single-nucleotide polymorphisms. To some extent, evolutionary constraint is predictive of introgression depletion, but certain tissues' enhancers are more depleted of Neandertal and Denisovan alleles than expected given their comparative tolerance to new mutations. Foetal brain and muscle are the tissues whose enhancers show the strongest depletion of archaic alleles, but only brain enhancers show evidence of unusually stringent purifying selection. We conclude that epistatic incompatibilities between human and archaic alleles are needed to explain the degree of archaic variant depletion from foetal muscle enhancers, perhaps due to divergent selection for higher muscle mass in archaic hominins compared with humans.

RevDate: 2020-08-12

Quartier P, Alexeeva E, Tamàs C, et al (2020)

Tapering Canakinumab Monotherapy in Patients with Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results from an Open-label, Randomized Phase IIIb/IV Study.

Arthritis & rheumatology (Hoboken, N.J.) [Epub ahead of print].

OBJECTIVE: To evaluate the efficacy and safety of two canakinumab monotherapy tapering regimens to maintain complete clinical remission (CR) in children with systemic juvenile idiopathic arthritis (sJIA).

METHODS: Two-part open-label study. In Part I, patients received 4 mg/kg canakinumab subcutaneously every 4 weeks (q4w) and discontinued glucocorticoids and/or methotrexate as appropriate. Patients who achieved CR (inactive disease for at least 24 weeks) on canakinumab monotherapy entered Part II and were randomized (1:1) to Arm 1 (dose reduction from 4 to 2 to 1 mg/kg and then discontinuation) or Arm 2 (dose interval prolongation from q4w to q8w to q12w and then discontinuation). In both arms, canakinumab exposure could be reduced provided that patients remained in CR for 24 weeks with each step. The primary objective was to assess whether more than 40% of randomized patients in either arm remained in CR for 24 weeks in the first step.

RESULTS: 182 patients entered Part I of the study and 75 were randomized and entered Part II. Of the 75 patients, 27/38 (71%) in Arm 1 (2 mg/kg q4w) and 31/37 (84%) in Arm 2 (4 mg/kg q8w) maintained CR for 24 weeks in the first step (P ≤ 0.0001 for each arm vs 40%). Overall, 25/75 (33%) patients discontinued canakinumab and remained in CR for at least 24 weeks. No new safety signals were identified.

CONCLUSION: Reduction of exposure to canakinumab may be feasible in patients with sJIA who achieved CR, but consistent IL-1 inhibition seems necessary to maintain this response.

RevDate: 2020-08-09

Agrawal R, Testi I, Bodaghi B, et al (2020)

Collaborative Ocular Tuberculosis Study Consensus Guidelines on the Management of Tubercular Uveitis-Report 2: Guidelines for Initiating Antitubercular Therapy in Anterior Uveitis, Intermediate Uveitis, Panuveitis, and Retinal Vasculitis.

Ophthalmology pii:S0161-6420(20)30598-4 [Epub ahead of print].

TOPIC: The Collaborative Ocular Tuberculosis Study (COTS), supported by the International Ocular Inflammation Society, International Uveitis Study Group, and Foster Ocular Immunological Society, set up an international, expert-led consensus project to develop evidence- and experience-based guidelines for the management of tubercular uveitis (TBU).

CLINICAL RELEVANCE: The absence of international agreement on the use of antitubercular therapy (ATT) in patients with TBU contributes to a significant heterogeneity in the approach to the management of this condition.

METHODS: Consensus statements for the initiation of ATT in TBU were generated using a 2-step modified Delphi technique. In Delphi step 1, a smart web-based survey based on background evidence from published literature was prepared to collect the opinion of 81 international experts on the use of ATT in different clinical scenarios. The survey included 324 questions related to tubercular anterior uveitis (TAU), tubercular intermediate uveitis (TIU), tubercular panuveitis (TPU), and tubercular retinal vasculitis (TRV) administered by the experts, after which the COTS group met in November 2019 for a systematic and critical discussion of the statements in accordance with the second round of the modified Delphi process.

RESULTS: Forty-four consensus statements on the initiation of ATT in TAU, TIU, TPU, and TRV were obtained, based on ocular phenotypes suggestive of TBU and corroborative evidence of tuberculosis, provided by several combinations of immunologic and radiologic test results. Experts agreed on initiating ATT in recurrent TAU, TIU, TPU, and active TRV depending on the TB endemicity. In the presence of positive results for any 1 of the immunologic tests along with radiologic features suggestive of past evidence of tuberculosis infection. In patients with a first episode of TAU, consensus to initiate ATT was reached only if both immunologic and radiologic test results were positive.

DISCUSSION: The COTS consensus guidelines were generated based on the evidence from published literature, specialists' opinions, and logic construction to address the initiation of ATT in TBU. The guidelines also should inform public policy by adding specific types of TBU to the list of conditions that should be treated as tuberculosis.

RevDate: 2020-08-07

Hubisz MJ, Williams AL, A Siepel (2020)

Mapping gene flow between ancient hominins through demography-aware inference of the ancestral recombination graph.

PLoS genetics, 16(8):e1008895 pii:PGENETICS-D-19-01657.

The sequencing of Neanderthal and Denisovan genomes has yielded many new insights about interbreeding events between extinct hominins and the ancestors of modern humans. While much attention has been paid to the relatively recent gene flow from Neanderthals and Denisovans into modern humans, other instances of introgression leave more subtle genomic evidence and have received less attention. Here, we present a major extension of the ARGweaver algorithm, called ARGweaver-D, which can infer local genetic relationships under a user-defined demographic model that includes population splits and migration events. This Bayesian algorithm probabilistically samples ancestral recombination graphs (ARGs) that specify not only tree topologies and branch lengths along the genome, but also indicate migrant lineages. The sampled ARGs can therefore be parsed to produce probabilities of introgression along the genome. We show that this method is well powered to detect the archaic migration into modern humans, even with only a few samples. We then show that the method can also detect introgressed regions stemming from older migration events, or from unsampled populations. We apply it to human, Neanderthal, and Denisovan genomes, looking for signatures of older proposed migration events, including ancient humans into Neanderthal, and unknown archaic hominins into Denisovans. We identify 3% of the Neanderthal genome that is putatively introgressed from ancient humans, and estimate that the gene flow occurred between 200-300kya. We find no convincing evidence that negative selection acted against these regions. Finally, we predict that 1% of the Denisovan genome was introgressed from an unsequenced, but highly diverged, archaic hominin ancestor. About 15% of these "super-archaic" regions-comprising at least about 4Mb-were, in turn, introgressed into modern humans and continue to exist in the genomes of people alive today.

RevDate: 2020-08-04

Course MM, Gudsnuk K, Smukowski SN, et al (2020)

Evolution of a Human-Specific Tandem Repeat Associated with ALS.

American journal of human genetics pii:S0002-9297(20)30234-2 [Epub ahead of print].

Tandem repeats are proposed to contribute to human-specific traits, and more than 40 tandem repeat expansions are known to cause neurological disease. Here, we characterize a human-specific 69 bp variable number tandem repeat (VNTR) in the last intron of WDR7, which exhibits striking variability in both copy number and nucleotide composition, as revealed by long-read sequencing. In addition, greater repeat copy number is significantly enriched in three independent cohorts of individuals with sporadic amyotrophic lateral sclerosis (ALS). Each unit of the repeat forms a stem-loop structure with the potential to produce microRNAs, and the repeat RNA can aggregate when expressed in cells. We leveraged its remarkable sequence variability to align the repeat in 288 samples and uncover its mechanism of expansion. We found that the repeat expands in the 3'-5' direction, in groups of repeat units divisible by two. The expansion patterns we observed were consistent with duplication events, and a replication error called template switching. We also observed that the VNTR is expanded in both Denisovan and Neanderthal genomes but is fixed at one copy or fewer in non-human primates. Evaluating the repeat in 1000 Genomes Project samples reveals that some repeat segments are solely present or absent in certain geographic populations. The large size of the repeat unit in this VNTR, along with our multiplexed sequencing strategy, provides an unprecedented opportunity to study mechanisms of repeat expansion, and a framework for evaluating the roles of VNTRs in human evolution and disease.

RevDate: 2020-08-03

Örd T, Puurand T, Örd D, et al (2020)

A human-specific VNTR in the TRIB3 promoter causes gene expression variation between individuals.

PLoS genetics, 16(8):e1008981 pii:PGENETICS-D-20-00244 [Epub ahead of print].

Tribbles homolog 3 (TRIB3) is pseudokinase involved in intracellular regulatory processes and has been implicated in several diseases. In this article, we report that human TRIB3 promoter contains a 33-bp variable number tandem repeat (VNTR) and characterize the heterogeneity and function of this genetic element. Analysis of human populations around the world uncovered the existence of alleles ranging from 1 to 5 copies of the repeat, with 2-, 3- and 5-copy alleles being the most common but displaying considerable geographical differences in frequency. The repeated sequence overlaps a C/EBP-ATF transcriptional regulatory element and is highly conserved, but not repeated, in various mammalian species, including great apes. The repeat is however evident in Neanderthal and Denisovan genomes. Reporter plasmid experiments in human cell culture reveal that an increased copy number of the TRIB3 promoter 33-bp repeat results in increased transcriptional activity. In line with this, analysis of whole genome sequencing and RNA-Seq data from human cohorts demonstrates that the copy number of TRIB3 promoter 33-bp repeats is positively correlated with TRIB3 mRNA expression level in many tissues throughout the body. Moreover, the copy number of the TRIB3 33-bp repeat appears to be linked to known TRIB3 eQTL SNPs as well as TRIB3 SNPs reported in genetic association studies. Taken together, the results indicate that the promoter 33-bp VNTR constitutes a causal variant for TRIB3 expression variation between individuals and could underlie the results of SNP-based genetic studies.

RevDate: 2020-06-29

Mustafina SV, Ovsyannikova AK, Voevoda MI, et al (2018)

[The prevalence of components of metabolic syndrome in the patients with diabetes melitus type 2 and mody diabetes in young people of Novosibirsk].

Terapevticheskii arkhiv, 90(10):55-59.

AIM: To estimate the prevalence of type 2 diabetes mellitus (DM2) and MODY diabetes as well as the prevalence of metabolic syndrome (MS) components for these types of diabetes in the young population of the city of Novosibirsk.

MATERIALS AND METHODS: In 2013-2017 years a population survey was conducted of a random representative sample of the population of 25-45 years of both sexes, residents of one of the typical districts of Novosibirsk. WHO criteria (1999-2013) were used for the diagnosis of diabetes: fasting blood glucose ≥7.0 mmol / l after an 8-hour fasting. Also group with DM2 included persons with a fasting blood glucose level.

RevDate: 2020-06-25

Filippenkov IB, Stavchansky VV, Denisova AE, et al (2020)

Novel Insights into the Protective Properties of ACTH(4-7)PGP (Semax) Peptide at the Transcriptome Level Following Cerebral Ischaemia-Reperfusion in Rats.

Genes, 11(6): pii:genes11060681.

Cerebral ischaemia is the most common cause of impaired brain function. Biologically active peptides represent potential drugs for reducing the damage that occurs after ischaemia. The synthetic melanocortin derivative, ACTH(4-7)PGP (Semax), has been used successfully in the treatment of patients with severe impairment of cerebral blood circulation. However, its molecular mechanisms of action within the brain are not yet fully understood. Previously, we used the transient middle cerebral artery occlusion (tMCAO) model to study the damaging effects of ischaemia-reperfusion on the brain transcriptome in rats. Here, using RNA-Seq analysis, we investigated the protective properties of the Semax peptide at the transcriptome level under tMCAO conditions. We have identified 394 differentially expressed genes (DEGs) (>1.5-fold change) in the brains of rats at 24 h after tMCAO treated with Semax relative to saline. Following tMCAO, we found that Semax suppressed the expression of genes related to inflammatory processes and activated the expression of genes related to neurotransmission. In contrast, ischaemia-reperfusion alone activated the expression of inflammation-related genes and suppressed the expression of neurotransmission-related genes. Therefore, the neuroprotective action of Semax may be associated with a compensation of mRNA expression patterns that are disrupted during ischaemia-reperfusion conditions.

RevDate: 2020-06-23

Mathov Y, Batyrev D, Meshorer E, et al (2020)

Harnessing epigenetics to study human evolution.

Current opinion in genetics & development, 62:23-29 pii:S0959-437X(20)30074-5 [Epub ahead of print].

Recent advances in ancient DNA extraction and high-throughput sequencing technologies enabled the high-quality sequencing of archaic genomes, including the Neanderthal and the Denisovan. While comparisons with modern humans revealed both archaic-specific and human-specific sequence changes, in the absence of gene expression information, understanding the functional implications of such genetic variations remains a major challenge. To study gene regulation in archaic humans, epigenetic research comes to our aid. DNA methylation, which is highly correlated with transcription, can be directly measured in modern samples, as well as reconstructed in ancient samples. This puts DNA methylation as a natural basis for comparative epigenetics between modern humans, archaic humans and nonhuman primates.

RevDate: 2020-06-23

Kim J, Perkins GB, PT Coates (2020)

Evolutionary immunology: how your ancestry can affect your kidney transplant.

Kidney international, 98(1):45-47.

RevDate: 2020-06-19

Khan N, de Manuel M, Peyregne S, et al (2020)

Multiple Genomic Events Altering Hominin SIGLEC Biology and Innate Immunity Predated the Common Ancestor of Humans and Archaic Hominins.

Genome biology and evolution pii:5859627 [Epub ahead of print].

Human-specific pseudogenization of the CMAH gene eliminated the mammalian sialic acid (Sia) Neu5Gc (generating an excess of its precursor Neu5Ac), thus changing ubiquitous cell surface "self-associated molecular patterns" (SAMPs) that modulate innate immunity via engagement of CD33-related-Siglec receptors. The Alu-fusion-mediated loss-of-function of CMAH fixed ∼2-3 million years ago (Mya), possibly contributing to the origins of the genus Homo. The mutation likely altered human SAMPs, triggering multiple events, including emergence of human-adapted pathogens with strong preference for Neu5Ac recognition and/or presenting Neu5Ac-containing molecular mimics of human glycans, which can suppress immune responses via CD33-related-Siglec engagement. Human-specific alterations reported in some genes encoding Sia-sensing proteins suggested a "hotspot" in hominin evolution. The availability of more hominid genomes including those of two extinct hominins now allows full reanalysis and evolutionary timing. Functional changes occur in 8/13 members of the human genomic cluster encoding CD33-related-Siglecs, all predating the human common ancestor. Comparisons with great ape genomes indicate that these changes are unique to hominins. We found no evidence for strong selection after the Human-Neanderthal/Denisovan common ancestor, and these extinct hominin genomes include almost all major changes found in humans, indicating that these changes in hominin sialobiology predate the Neanderthal-human divergence ∼0.6Mya. Multiple changes in this genomic cluster may also explain human-specific expression of CD33rSiglecs in unexpected locations such as amnion, placental trophoblast, pancreatic islets, ovarian fibroblasts, microglia, NK cells and epithelia. Taken together, our data suggest that innate immune interactions with pathogens markedly altered hominin Siglec biology between 0.6-2 Mya, potentially affecting human evolution.

RevDate: 2020-06-17

Mafessoni F, Grote S, de Filippo C, et al (2020)

A high-coverage Neandertal genome from Chagyrskaya Cave.

Proceedings of the National Academy of Sciences of the United States of America pii:2004944117 [Epub ahead of print].

We sequenced the genome of a Neandertal from Chagyrskaya Cave in the Altai Mountains, Russia, to 27-fold genomic coverage. We show that this Neandertal was a female and that she was more related to Neandertals in western Eurasia [Prüfer et al., Science 358, 655-658 (2017); Hajdinjak et al., Nature 555, 652-656 (2018)] than to Neandertals who lived earlier in Denisova Cave [Prüfer et al., Nature 505, 43-49 (2014)], which is located about 100 km away. About 12.9% of the Chagyrskaya genome is spanned by homozygous regions that are between 2.5 and 10 centiMorgans (cM) long. This is consistent with the fact that Siberian Neandertals lived in relatively isolated populations of less than 60 individuals. In contrast, a Neandertal from Europe, a Denisovan from the Altai Mountains, and ancient modern humans seem to have lived in populations of larger sizes. The availability of three Neandertal genomes of high quality allows a view of genetic features that were unique to Neandertals and that are likely to have been at high frequency among them. We find that genes highly expressed in the striatum in the basal ganglia of the brain carry more amino-acid-changing substitutions than genes expressed elsewhere in the brain, suggesting that the striatum may have evolved unique functions in Neandertals.

RevDate: 2020-06-12

Almarri MA, Bergström A, Prado-Martinez J, et al (2020)

Population Structure, Stratification, and Introgression of Human Structural Variation.

Cell pii:S0092-8674(20)30619-X [Epub ahead of print].

Structural variants contribute substantially to genetic diversity and are important evolutionarily and medically, but they are still understudied. Here we present a comprehensive analysis of structural variation in the Human Genome Diversity panel, a high-coverage dataset of 911 samples from 54 diverse worldwide populations. We identify, in total, 126,018 variants, 78% of which were not identified in previous global sequencing projects. Some reach high frequency and are private to continental groups or even individual populations, including regionally restricted runaway duplications and putatively introgressed variants from archaic hominins. By de novo assembly of 25 genomes using linked-read sequencing, we discover 1,643 breakpoint-resolved unique insertions, in aggregate accounting for 1.9 Mb of sequence absent from the GRCh38 reference. Our results illustrate the limitation of a single human reference and the need for high-quality genomes from diverse populations to fully discover and understand human genetic variation.

RevDate: 2020-06-04

Skov L, Coll Macià M, Sveinbjörnsson G, et al (2020)

The nature of Neanderthal introgression revealed by 27,566 Icelandic genomes.

Nature, 582(7810):78-83.

Human evolutionary history is rich with the interbreeding of divergent populations. Most humans outside of Africa trace about 2% of their genomes to admixture from Neanderthals, which occurred 50-60 thousand years ago1. Here we examine the effect of this event using 14.4 million putative archaic chromosome fragments that were detected in fully phased whole-genome sequences from 27,566 Icelanders, corresponding to a range of 56,388-112,709 unique archaic fragments that cover 38.0-48.2% of the callable genome. On the basis of the similarity with known archaic genomes, we assign 84.5% of fragments to an Altai or Vindija Neanderthal origin and 3.3% to Denisovan origin; 12.2% of fragments are of unknown origin. We find that Icelanders have more Denisovan-like fragments than expected through incomplete lineage sorting. This is best explained by Denisovan gene flow, either into ancestors of the introgressing Neanderthals or directly into humans. A within-individual, paired comparison of archaic fragments with syntenic non-archaic fragments revealed that, although the overall rate of mutation was similar in humans and Neanderthals during the 500 thousand years that their lineages were separate, there were differences in the relative frequencies of mutation types-perhaps due to different generation intervals for males and females. Finally, we assessed 271 phenotypes, report 5 associations driven by variants in archaic fragments and show that the majority of previously reported associations are better explained by non-archaic variants.

RevDate: 2020-06-03

Denisova K, A Barmettler (2020)

Oculoplastic considerations for refractive procedures.

Current opinion in ophthalmology [Epub ahead of print].

PURPOSE OF REVIEW: Refractive surgery is one of the most popular elective procedures performed in the world. Given that dry eye is a common complaint following keratorefractive surgery, evaluation, and treatment of periocular conditions that further predispose the patient to dry eye symptoms is an important part of the presurgical assessment. Periocular conditions and surgeries can also affect the ocular surface and keratometry, and should be addressed. For example, ptosis, orbital fat herniation, ectropion, and eyelid masses have been shown to induce corneal topography changes and astigmatism. The oculoplastic considerations for refractive surgery include both the contribution of eyelid position on dry eye, ocular surface damage, refractive error, and outcomes, as well as the timing of oculoplastic surgery in relation to the refractive surgery. In this review, the recently published literature on eyelid and orbital surgery in relation to keratorefractive surgery is reviewed to elucidate the relationship of periocular factors with refractive surgery outcomes and complications. To improve keratorefractive surgery outcomes, a literature review is presented, discussing evaluation, management, and timing of management of oculoplastics conditions.

RECENT FINDINGS: Dry eye syndrome is a well known complication of keratorefractive procedures. This is exacerbated with concurrent eyelid or orbital disorders, such as ectropion, lagophthalmos, and thyroid eye disease. In addition to impacting dry eye and ocular surface damage, eyelid surgeries can also affect corneal topography and refraction. Studies have found that patients with ptosis have topographic corneal aberrations from the eyelid exerting pressure on the cornea, while ptosis repair and blepharoplasty patients may undergo an astigmatic change postoperatively. Finally, the corneal flap created in laser-assisted in situ keratomileusis may be at risk for displacement or damage postoperatively with this risk changing, depending on method of flap creation, and time elapsed since keratorefractive surgery.

SUMMARY: Eyelid and orbital conditions that predispose to dry eye syndrome and refractive changes should be evaluated and optimized prior to keratorefractive surgery. Patients electing to have oculoplastic surgery, like ptosis repair, should be fully healed prior to any refractive surgery to allow both refractive changes and eyelid positions to stabilize prior to the refractive surgery.

RevDate: 2020-05-07

Larina VN, Akhmatova FD, Arakelov SE, et al (2020)

[Modern strategies for cardiac rehabilitation after myocardial infarction and percutaneous coronary intervention].

Kardiologiia, 60(3):111-118.

Modern cardiac rehabilitation represents a structured, multicomponent program, which includes physical activity, education of the patient, modification of the health behavior, and psychological and social support. In EU countries, only 44.8% of patients with ischemic heart disease receive a recommendation to participate in any form of rehabilitation, and only 36.5% of all patients presently have an access to any rehabilitation program. Systematic analysis of programs for prevention of cardiovascular diseases and for rehabilitation in patients with myocardial infarction (MI) and percutaneous coronary intervention showed that complex programs can still reduce all-cause and cardiovascular mortality and frequency of recurrent MI and stroke. These programs include key components of cardiac rehabilitation, reduction of six or more risk factors, and effective control by drug therapy.

RevDate: 2020-05-05

Denisova SA, SV Shchenkov (2020)

Fine structure of the nervous system of Cercaria parvicaudata Stunkard & Shaw, 1931 (Digenea, Renicolidae).

Journal of morphology [Epub ahead of print].

The biology of free-living and parasitic Platyhelminthes is diverse. Taking into account the widespread prevalence of parasitic flatworms, Digenea is the least studied group regarding the fine structure of nervous system especially of the cercarial life stage. Here, we present a description of the fine structure of central nervous system (CNS) and two types of uniciliate sensory papillae of xiphidiocercaria Cercaria parvicaudata (Microphalloidea, Renicolidae). The present study documents that C. parvicaudata has a complex nervous system that includes a well-developed ganglion with a cortex of perikarya and glia-like sheaths, myelin-like structures within one of the dorsal nerve cords and four types of polarized synapses between neurites. Different types of neurons in the CNS could not be distinguished on ultrastructural level due to high similarity in their fine structure. Shared polarized synapses with high electron density of presynaptic components are numerous in the neuropile and nerve cords of this larva. Within the larval body, we detected specialized "support" processes that relate to different tissues. Some "support" processes are also closely related to the nervous system of C. parvicaudata, where they are considered as glia-like structures. In this case, the fine structure of glia-like "support" cells of C. parvicaudata differs from those described as glia-like cells in adult flatworms. We suggest a wide prevalence of glia-like cells among cercariae, as well as the fact that glia-like structures in digenean nervous systems can develop from various nonneuronal tissues.

RevDate: 2020-05-05

Hammill JA, Kwiecien JM, Dvorkin-Gheva A, et al (2020)

A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity.

Molecular therapy oncolytics, 17:278-292 pii:S2372-7705(20)30051-6.

Tumor-targeted chimeric antigen receptor (CAR)-engineered T lymphocytes (CAR-T cells) have demonstrated striking clinical success, but their use has been associated with a constellation of toxicities. A better understanding of the pathogenesis of these toxicities is required to improve the safety profile of CAR-T cells. Herein, we describe a xenograft model of off-tumor CAR-T cell-associated toxicity. Human CAR-T cells targeted against HER2 using a small-protein binding domain induced acute, dose-dependent toxicities in mice. The inclusion of a CD28 or 4-1BB co-stimulatory domain in the CAR was required to produce toxicity; however, co-stimulation through CD28 was most toxic on a per-cell basis. CAR-T cell activation in the lungs and heart was associated with a systemic cytokine storm. The severity of observed toxicities was dependent upon the peripheral blood mononuclear cell (PBMC) donor used as a T cell source and paralleled the CD4+-to-CD8+ T cell ratio in the adoptive transfer product. CD4+ CAR-T cells were determined to be the primary contributors to CAR-T cell-associated toxicity. However, donor-specific differences persisted after infusion of a purified CD4+ CAR-T cell product, indicating a role for additional variables. This work highlights the contributions of CAR-T cell-intrinsic variables to the pathogenesis of off-tumor toxicity.

RevDate: 2020-04-24

Lodewijk GA, Fernandes DP, Vretzakis I, et al (2020)

Evolution of human brain-size associated NOTCH2NL genes proceeds towards reduced protein levels.

Molecular biology and evolution pii:5824797 [Epub ahead of print].

Ever since the availability of genomes from Neanderthals, Denisovans and ancient humans, the field of evolutionary genomics has been searching for protein coding variants that may hold clues to how our species evolved over the last ∼ 400,000 years. In this study, we identify such variants in the human-specific NOTCH2NL gene family, which were recently identified as possible contributors to the evolutionary expansion of the human brain. We find evidence for the existence of unique protein-coding NOTCH2NL variants in Neanderthals and Denisovans which could affect their ability to activate Notch signaling. Furthermore, in the Neanderthal and Denisovan genomes, we find unusual NOTCH2NL configurations, not found in any of the modern human genomes analyzed. Finally, genetic analysis of archaic and modern humans reveals ongoing adaptive evolution of modern human NOTCH2NL genes, identifying three structural variants acting complementary to drive our genome to produce a lower dosage of NOTCH2NL protein. Because copy-number variations of the 1q21.1 locus, encompassing NOTCH2NL genes, are associated with severe neurological disorders, this seemingly contradicting drive towards low levels of NOTCH2NL protein indicates that the optimal dosage of NOTCH2NL may have not yet been settled in the human population.

RevDate: 2020-04-24

Gouy A, L Excoffier (2020)

Polygenic Patterns of Adaptive Introgression in Modern Humans Are Mainly Shaped by Response to Pathogens.

Molecular biology and evolution, 37(5):1420-1433.

Anatomically modern humans carry many introgressed variants from other hominins in their genomes. Some of them affect their phenotype and can thus be negatively or positively selected. Several individual genes have been proposed to be the subject of adaptive introgression, but the possibility of polygenic adaptive introgression has not been extensively investigated yet. In this study, we analyze archaic introgression maps with refined functional enrichment methods to find signals of polygenic adaptation of introgressed variants. We first apply a method to detect sets of connected genes (subnetworks) within biological pathways that present higher-than-expected levels of archaic introgression. We then introduce and apply a new statistical test to distinguish between epistatic and independent selection in gene sets of present-day humans. We identify several known targets of adaptive introgression, and we show that they belong to larger networks of introgressed genes. After correction for genetic linkage, we find that signals of polygenic adaptation are mostly explained by independent and potentially sequential selection episodes. However, we also find some gene sets where introgressed variants present significant signals of epistatic selection. Our results confirm that archaic introgression has facilitated local adaptation, especially in immunity related and metabolic functions and highlight its involvement in a coordinated response to pathogens out of Africa.

RevDate: 2020-04-08

Kurmukov A, Mussabaeva A, Denisova Y, et al (2020)

Optimizing Connectivity-Driven Brain Parcellation using Ensemble Clustering.

Brain connectivity [Epub ahead of print].

This work addresses the problem of constructing a unified, topologically optimal connectivity-based brain atlas. The proposed approach aggregates an ensemble partition from individual parcellations without label agreement, providing a balance between sufficiently flexible individual parcellations and intuitive representation of the average topological structure of the connectome. The methods exploit a previously proposed dense connectivity representation, first performing graph-based hierarchical parcellation of individual brains, and subsequently aggregating the individual parcellations into a consensus parcellation. The search for consensus - based on the Hard Ensemble algorithm - approximately minimizes the sum of cluster membership distances, effectively estimating a pseudo-Karcher mean of individual parcellations. Computational stability, graph structure preservation and biological relevance of the simplified representation resulting from the proposed parcellation are assessed on the Human Connectome Project dataset. These aspects are assessed using (1) edge weight distribution divergence with respect to the dense connectome representation, (2) inter-hemispheric symmetry, (3) network characteristics' stability and agreement with respect to individually and anatomically parcellated networks, and (4) performance of the simplified connectome in a biological sex classification task. Ensemble parcellation was found to be highly stable with respect to subject sampling, outperforming anatomical atlases and other connectome-based parcellations in classification as well as preserving global connectome properties. The Hard Ensemble-based parcellation also showed a degree symmetry comparable to anatomical atlases and a high degree of spatial contiguity without using explicit priors.

RevDate: 2020-04-06

Agrawal R, Testi I, Mahajan S, et al (2020)

The Collaborative Ocular Tuberculosis Study (COTS) Consensus (CON) Group Meeting Proceedings.

Ocular immunology and inflammation [Epub ahead of print].

An international, expert led consensus initiative was set up by the Collaborative Ocular Tuberculosis Study (COTS) group to develop systematic, evidence, and experience-based recommendations for the treatment of ocular TB using a modified Delphi technique process. In the first round of Delphi, the group identified clinical scenarios pertinent to ocular TB based on five clinical phenotypes (anterior uveitis, intermediate uveitis, choroiditis, retinal vasculitis, and panuveitis). Using an interactive online questionnaires, guided by background knowledge from published literature, 486 consensus statements for initiating ATT were generated and deliberated amongst 81 global uveitis experts. The median score of five was considered reaching consensus for initiating ATT. The median score of four was tabled for deliberation through Delphi round 2 in a face-to-face meeting. This report describes the methodology adopted and followed through the consensus process, which help elucidate the guidelines for initiating ATT in patients with choroidal TB.

RevDate: 2020-03-23

Mitoudi Vagourdi E, Zhang W, Denisova K, et al (2020)

Synthesis and Characterization of Two New Second Harmonic Generation Active Iodates: K3Sc(IO3)6 and KSc(IO3)3Cl.

ACS omega, 5(10):5235-5240.

Transparent single crystals of two new iodates K3Sc(IO3)6 and KSc(IO3)3Cl have been synthesized hydrothermally. Single-crystal X-ray diffraction was used to determine their crystal structures. Both compounds crystallize in non-centrosymmetric space groups. The compound K3Sc(IO3)6 crystallizes in the orthorhombic space group Fdd2. The crystal structure is made up of [ScO6] octahedra, [IO3] trigonal pyramids, and [KO8] distorted cubes. The compound KSc(IO3)3Cl crystallizes in the trigonal space group R3. The building blocks are [ScO6] octahedra, [KO12] polyhedra, and [IO3] trigonal pyramids. The Cl- ions act as counter ions and reside in tunnels in the crystal structure. The second harmonic generation (SHG) measurements at room temperature, using 1064 nm radiation, on polycrystalline samples show that the SHG intensities of K3Sc(IO3)6 and KSc(IO3)3Cl are around 2.8 and 2.5 times that of KH2PO4 (KDP), respectively. In addition, K3Sc(IO3)6 and KSc(IO3)3Cl are phase-matchable at the fundamental wavelength of 1064 nm. The large anharmonicity in the optical response of both compounds is further supported by an anomalous temperature dependence of optical phonon frequencies as well as their enlarged intensities in Raman scattering. The latter corresponds to a very large electronic polarizability.

RevDate: 2020-03-20

Bergström A, McCarthy SA, Hui R, et al (2020)

Insights into human genetic variation and population history from 929 diverse genomes.

Science (New York, N.Y.), 367(6484):.

Genome sequences from diverse human groups are needed to understand the structure of genetic variation in our species and the history of, and relationships between, different populations. We present 929 high-coverage genome sequences from 54 diverse human populations, 26 of which are physically phased using linked-read sequencing. Analyses of these genomes reveal an excess of previously undocumented common genetic variation private to southern Africa, central Africa, Oceania, and the Americas, but an absence of such variants fixed between major geographical regions. We also find deep and gradual population separations within Africa, contrasting population size histories between hunter-gatherer and agriculturalist groups in the past 10,000 years, and a contrast between single Neanderthal but multiple Denisovan source populations contributing to present-day human populations.

RevDate: 2020-03-10

Stark MS, Denisova E, Kays TA, et al (2020)

Mutation signatures in melanocytic nevi reveal characteristics of defective DNA repair.

The Journal of investigative dermatology pii:S0022-202X(20)30243-8 [Epub ahead of print].

RevDate: 2020-03-04

Rogers AR, Harris NS, AA Achenbach (2020)

Neanderthal-Denisovan ancestors interbred with a distantly related hominin.

Science advances, 6(8):eaay5483 pii:aay5483.

Previous research has shown that modern Eurasians interbred with their Neanderthal and Denisovan predecessors. We show here that hundreds of thousands of years earlier, the ancestors of Neanderthals and Denisovans interbred with their own Eurasian predecessors-members of a "superarchaic" population that separated from other humans about 2 million years ago. The superarchaic population was large, with an effective size between 20 and 50 thousand individuals. We confirm previous findings that (i) Denisovans also interbred with superarchaics, (ii) Neanderthals and Denisovans separated early in the middle Pleistocene, (iii) their ancestors endured a bottleneck of population size, and (iv) the Neanderthal population was large at first but then declined in size. We provide qualified support for the view that (v) Neanderthals interbred with the ancestors of modern humans.

RevDate: 2020-03-02

Denisova OA, Gudina TV, Bukina IA, et al (2020)

[The medical pedagogical prevention of deviant behavior in adolescents from disadvantaged family in conditions of rural school].

Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsiny, 28(1):74-82.

The article considers medical and pedagogical prevention of deviant behavior of adolescents from dysfunctional families in conditions of rural school, related to the need of strengthening targeted joint interaction of medical and pedagogical institutions. The description and results of testing of diagnostic tools used to establish severity of deviant behavior of children in a selected group is discussed. The interaction of medical and educational institutions in preventing deviant behavior of adolescents from dysfunctional families in rural school is of key importance for combating prevalence of drug addiction, tobacco smoking, alcohol abuse and psychoactive substances consumption, and contributing to physical and mental health promotion of younger generation, development of healthy lifestyle. The study was organized to cover cognitive, behavioral, affective and value-motivational components. The qualitative characteristics of levels of severity of deviant behavior of adolescents from dysfunctional families were developed and proposed for practice application.

RevDate: 2020-03-02

Agrawal R, Testi I, Mahajan S, et al (2020)

Collaborative Ocular Tuberculosis Study Consensus Guidelines on the Management of Tubercular Uveitis-Report 1: Guidelines for Initiating Antitubercular Therapy in Tubercular Choroiditis.

Ophthalmology pii:S0161-6420(20)30013-0 [Epub ahead of print].

TOPIC: An international, expert-led consensus initiative organized by the Collaborative Ocular Tuberculosis Study (COTS), along with the International Ocular Inflammation Society and the International Uveitis Study Group, systematically developed evidence- and experience-based recommendations for the treatment of tubercular choroiditis.

CLINICAL RELEVANCE: The diagnosis and management of tubercular uveitis (TBU) pose a significant challenge. Current guidelines and literature are insufficient to guide physicians regarding the initiation of antitubercular therapy (ATT) in patients with TBU.

METHODS: An international expert steering subcommittee of the COTS group identified clinical questions and conducted a systematic review of the published literature on the use of ATT for tubercular choroiditis. Using an interactive online questionnaire, guided by background knowledge from published literature, 81 global experts (including ophthalmologists, pulmonologists, and infectious disease physicians) generated preliminary consensus statements for initiating ATT in tubercular choroiditis, using Oxford levels of medical evidence. In total, 162 statements were identified regarding when to initiate ATT in patients with tubercular serpiginous-like choroiditis, tuberculoma, and tubercular focal or multifocal choroiditis. The COTS group members met in November 2018 to refine these statements by a 2-step modified Delphi process.

RESULTS: Seventy consensus statements addressed the initiation of ATT in the 3 subtypes of tubercular choroiditis, and in addition, 10 consensus statements were developed regarding the use of adjunctive therapy in tubercular choroiditis. Experts agreed on initiating ATT in tubercular choroiditis in the presence of positive results for any 1 of the positive immunologic tests along with radiologic features suggestive of tuberculosis. For tubercular serpiginous-like choroiditis and tuberculoma, positive results from even 1 positive immunologic test were considered sufficient to recommend ATT, even if there were no radiologic features suggestive of tuberculosis.

DISCUSSION: Consensus guidelines were developed to guide the initiation of ATT in patients with tubercular choroiditis, based on the published literature, expert opinion, and practical experience, to bridge the gap between clinical need and available medical evidence.

RevDate: 2020-02-18

Shlyakhtina AV, Avdeev M, Lyskov NV, et al (2020)

Structure, conductivity and magnetism of orthorhombic and fluorite polymorphs in MoO3-Ln2O3 (Ln = Gd, Dy, Ho) systems.

Dalton transactions (Cambridge, England : 2003) [Epub ahead of print].

Phase-pure orthorhombic compositions at a Ln/Mo ratio ∼ 5.2-5.7 (Ln = Gd, Dy, Ho) have been obtained for the first time by prolonged (40-160 h) heat treatment of mechanically activated 5Ln2O3 + 2MoO3 (Ln = Gd, Dy, Ho) oxide mixtures at 1200 °C. Although the starting Ln : Mo ratio was 5 : 1 (Ln10Mo2O21 (Ln = Dy, Ho)), it changed slightly in the final product due to the volatility of molybdenum oxide at 1200 °C (40-160 h) (ICP-MS analysis). Brief high-temperature firing (1600 °C, 3 h) of 5Ln2O3 + 2MoO3 (Ln = Gd, Dy, Ho) oxide mixtures leads to the formation of phase-pure fluorites with compositions close to Ln10Mo2O21 (Ln = Gd, Dy, Ho). Gd10Mo2O21 molybdate seems to undergo an order-disorder (orthorhombic-fluorite) phase transition in the range of 1200-1600 °C. For the first time, using the neutron diffraction method, it was shown that low-temperature phases with a Ln/Mo ratio ∼ 5.2-5.7 (Ln = Gd, Dy, Ho) have an orthorhombic structure rather than a tetragonal structure. Proton contribution to the total conductivity of Ln10Mo2O21 (Ln = Gd, Dy, Ho) fluorites and gadolinium and dysprosium orthorhombic phases in a wet atmosphere was observed for the first time. In both orthorhombic and fluorite phases, the total conductivity in wet air decreases with decreasing lanthanide ionic radii. In a wide temperature range, the compounds under study exhibit paramagnetic behaviour. However, the orthorhombic phases of Dy and Ho compounds reach the antiferromagnetic state at 2.4 K and 2.6 K, respectively.

RevDate: 2020-02-07

Gokhman D, Mishol N, de Manuel M, et al (2020)

Reconstructing Denisovan Anatomy Using DNA Methylation Maps.

Cell, 180(3):601.

RevDate: 2020-01-28

Rudnev S, Burns JS, Williams PL, et al (2020)

Comparison of bioimpedance body composition in young adults in the Russian Children's Study.

Clinical nutrition ESPEN, 35:153-161.

BACKGROUND & AIMS: Body mass index is a simple anthropometric measure (kg/m2) used as an indirect estimate of body fat in individuals, and in assessments of population health and comparisons between populations. Bioelectrical impedance analysis (BIA) is often used to provide additional information on body fat and fat-free mass, and has been used to generate body composition reference data in national health surveys. However, BIA measurements are known to be device-specific and there are few published studies comparing results from different BIA instruments. Therefore, we compared the performance of two BIA instruments in the Russian Children's Study (RCS) of male growth, pubertal development and maturation.

METHODS: Paired BIA measurements were obtained using the Tanita BC-418MA (Tanita Corp., Tokyo, Japan) and ABC-01 'Medas' (Medas Ltd, Moscow, Russia) BIA instruments. Cross-sectional data on 236 RCS subjects aged 18-22 years were used for the BIA comparison and the development of a conversion formula between measured resistances; follow-up data (n = 96) were used for validation of the conversion formula.

RESULTS: Whole-body resistances were highly correlated (Spearman rho = 0.95), but fat mass (FM) estimates were significantly higher with the Medas than the Tanita device (median difference 3.3 kg, 95% CI: 2.9, 3.6 kg) with large limits of agreement (LoA) for the FM difference (-2.0, 8.6 kg). A conversion formula between the resistances (Res) was obtained: Medas Res = 0.882 × Tanita Res+26.2 (r2 = 0.91, SEE = 17.6 Ohm). After applying the conversion formula to Tanita data and application of the Medas assessment algorithm, the 'converted' Tanita FM estimates closely matched the Medas original estimates (median difference -0.1 kg, 95% CI: -0.3, 0.2 kg), with relatively small LoA for the FM difference (-2.3 to 2.1 kg), suggesting potential interchangeability of the ABC-01 'Medas' and Tanita BC-418MA data at the group level.

CONCLUSIONS: Our results support the importance of cross-calibration of BIA instruments for population comparisons and proper data interpretation in clinical and epidemiological studies.

RevDate: 2019-12-27

Bücking R, Cox MP, Hudjashov G, et al (2019)

Archaic mitochondrial DNA inserts in modern day nuclear genomes.

BMC genomics, 20(1):1017 pii:10.1186/s12864-019-6392-8.

BACKGROUND: Traces of interbreeding of Neanderthals and Denisovans with modern humans in the form of archaic DNA have been detected in the genomes of present-day human populations outside sub-Saharan Africa. Up to now, only nuclear archaic DNA has been detected in modern humans; we therefore attempted to identify archaic mitochondrial DNA (mtDNA) residing in modern human nuclear genomes as nuclear inserts of mitochondrial DNA (NUMTs).

RESULTS: We analysed 221 high-coverage genomes from Oceania and Indonesia using an approach which identifies reads that map both to the nuclear and mitochondrial DNA. We then classified reads according to the source of the mtDNA, and found one NUMT of Denisovan mtDNA origin, present in 15 analysed genomes; analysis of the flanking region suggests that this insertion is more likely to have happened in a Denisovan individual and introgressed into modern humans with the Denisovan nuclear DNA, rather than in a descendant of a Denisovan female and a modern human male.

CONCLUSIONS: Here we present our pipeline for detecting introgressed NUMTs in next generation sequencing data that can be used on genomes sequenced in the future. Further discovery of such archaic NUMTs in modern humans can be used to detect interbreeding between archaic and modern humans and can reveal new insights into the nature of such interbreeding events.

RevDate: 2019-12-18

Scott GR, Irish JD, M Martinón-Torres (2019)

A more comprehensive view of the Denisovan 3-rooted lower second molar from Xiahe.

RevDate: 2019-12-10

Agrawal R, Agarwal A, Jabs DA, et al (2019)

Standardization of Nomenclature for Ocular Tuberculosis - Results of Collaborative Ocular Tuberculosis Study (COTS) Workshop.

Ocular immunology and inflammation [Epub ahead of print].

Purpose: To standardize a nomenclature system for defining clinical phenotypes, and outcome measures for reporting clinical and research data in patients with ocular tuberculosis (OTB).Methods: Uveitis experts initially administered and further deliberated the survey in an open meeting to determine and propose the preferred nomenclature for terms related to the OTB, terms describing the clinical phenotypes and treatment and reporting outcomes.Results: The group of experts reached a consensus on terming uveitis attributable to tuberculosis (TB) as tubercular uveitis. The working group introduced a SUN-compatible nomenclature that also defines disease "remission" and "cure", both of which are relevant for reporting treatment outcomes.Conclusion: A consensus nomenclature system has been adopted by a large group of international uveitis experts for OTB. The working group recommends the use of standardized nomenclature to prevent ambiguity in communication and to achieve the goal of spreading awareness of this blinding uveitis entity.

RevDate: 2019-12-06

Wall JD, Ratan A, Stawiski E, et al (2019)

Identification of African-Specific Admixture between Modern and Archaic Humans.

American journal of human genetics, 105(6):1254-1261.

Recent work has demonstrated that two archaic human groups (Neanderthals and Denisovans) interbred with modern humans and contributed to the contemporary human gene pool. These findings relied on the availability of high-coverage genomes from both Neanderthals and Denisovans. Here we search for evidence of archaic admixture from a worldwide panel of 1,667 individuals using an approach that does not require the presence of an archaic human reference genome. We find no evidence for archaic admixture in the Andaman Islands, as previously claimed, or on the island of Flores, where Homo floresiensis fossils have been found. However, we do find evidence for at least one archaic admixture event in sub-Saharan Africa, with the strongest signal in Khoesan and Pygmy individuals from Southern and Central Africa. The locations of these putative archaic admixture tracts are weighted against functional regions of the genome, consistent with the long-term effects of purifying selection against introgressed genetic material.

RevDate: 2019-12-03

Buzlukov AL, Arapova IY, Baklanova YV, et al (2019)

Coexistence of three types of sodium motion in double molybdate Na9Sc(MoO4)6: 23Na and 45Sc NMR data and ab initio calculations.

Physical chemistry chemical physics : PCCP [Epub ahead of print].

The rechargeable Na-ion batteries attract much attention as an alternative to the widely used but expensive Li-ion batteries. The search for materials with high sodium diffusion is important for the development of solid state electrolytes. We present the results of experimental and ab initio studies of the Na-ion diffusion mechanism in Na9Sc(MoO4)6. The ion conductivity reaches the value of 3.6 × 10-2 S cm-1 at T ∼ 850 K. The 23Na and 45Sc NMR data reveal the coexistence of three different types of Na-ion motion in the temperature range from 300 to 750 K. They are activated at different temperatures and are characterized by substantially different dynamics parameters. These features are confirmed by ab initio calculations of activation barriers for sodium diffusion along various paths.

RevDate: 2019-12-03

Bulynko SA, Denisova OA, Kovalets ES, et al (2019)

[Two cases of bilateral lymphangiomatous palatine tonsil polyps in children].

Vestnik otorinolaringologii, 84(5):73-75.

Lymphangiomatous polyps of palatine tonsils are a rare condition, which is diagnosed with patomorphological study. About cases in total are reported in the literature, mostly with one-sided lesions. We managed to find only two reports of lymphangiomatous polyps of palatine tonsils in the available literature. The patients were children in both cases. We report our two cases of children with lymphangiomatous polyps of palatine tonsils.

RevDate: 2019-12-04

Evseeva NV, Tkachenko OV, Denisova AY, et al (2019)

Functioning of plant-bacterial associations under osmotic stress in vitro.

World journal of microbiology & biotechnology, 35(12):195.

The search for effective plant-growth-promoting strains of rhizospheric bacteria that would ensure the resistance of plant-microbial associations to environmental stressors is essential for the design of environmentally friendly agrobiotechnologies. We investigated the interaction of potato (cv. Nevsky) microplants with the plant-growth-promoting bacteria Azospirillum brasilense Sp245 and Ochrobactrum cytisi IPA7.2 under osmotic stress in vitro. The bacteria improved the physiological and biochemical variables of the microplants, significantly increasing shoot length and root number (1.3-fold, on average). Inoculation also led a more effective recovery of the plants after stress. During repair, inoculation contributed to a decreased leaf content of malonic dialdehyde. With A. brasilense Sp245, the decrease was 1.75-fold; with O. cytisi IPA7.2, it was 1.4-fold. During repair, the shoot length, node number, and root number of the inoculated plants were greater than the control values by an average of 1.3-fold with A. brasilense Sp245 and by an average of 1.6-fold with O. cytisi IPA7.2. O. cytisi IPA7.2, previously isolated from the potato rhizosphere, protected the physiological and biochemical processes in the plants under stress and repair better than did A. brasilense Sp245. Specifically, root weight increased fivefold during repair, as compared to the noninoculated plants, while chlorophyll a content remained at the level found in the nonstressed controls. The results indicate that these bacteria can be used as components of biofertilizers. A. brasilense Sp245 has favorable prospects for use in temperate latitudes, whereas O. cytisi IPA7.2 can be successfully used in saline and drought-stressed environments.

RevDate: 2019-11-30

Bazhan N, Jakovleva T, Feofanova N, et al (2019)

Sex Differences in Liver, Adipose Tissue, and Muscle Transcriptional Response to Fasting and Refeeding in Mice.

Cells, 8(12): pii:cells8121529.

Fasting is often used for obesity correction but the "refeeding syndrome" limits its efficiency, and molecular mechanisms underlying metabolic response to different food availability are under investigation. Sex was shown to affect hormonal and metabolic reactions to fasting/refeeding. The aim of this study was to evaluate hormonal and transcriptional responses to fasting and refeeding in male and female C57Bl/6J mice. Sex asymmetry was observed both at the hormonal and transcriptional levels. Fasting (24 h) induced increase in hepatic Fgf21 gene expression, which was associated with elevation of plasma FGF21 and adiponectin levels, and the upregulation of expression of hepatic (Pparα, Cpt1α) and muscle (Cpt1β, Ucp3) genes involved in fatty acid oxidation. These changes were more pronounced in females. Refeeding (6 h) evoked hyperinsulinemia and increased hepatic expression of gene related to lipogenesis (Fasn) only in males and hyperleptinemia and increase in Fgf21 gene expression in muscles and adipose tissues only in females. The results suggest that in mice, one of the molecular mechanisms underlying sex asymmetry in hepatic Pparα, Cpt1α, muscle Cpt1β, and Ucp3 expression during fasting is hepatic Fgf21 expression, and the reason for sex asymmetry in hepatic Fasn expression during refeeding is male-specific hyperinsulinemia.

RevDate: 2019-11-14

Eremin DB, Denisova EA, Yu 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].

Invited for the cover of this issue is Valentine P. Ananikkov and co-workers. The image depicts the dynamic behaviour of a Pd/NHC catalytic system with easy transition from molecular to ionic complex. Read the full text of the article at 10.1002/chem.201903221.

RevDate: 2019-11-25

Denisova EI, Kozhevnikova VV, Bazhan NM, et al (2019)

Sex-specific effects of leptin administration to pregnant mice on the placentae and the metabolic phenotypes of offspring.

FEBS open bio [Epub ahead of print].

Obesity during pregnancy has been shown to increase the risk of metabolic diseases in the offspring. However, the factors within the maternal milieu which affect offspring phenotypes and the underlying mechanisms remain unknown. The adipocyte hormone leptin plays a key role in regulating energy homeostasis and is known to participate in sex-specific developmental programming. To examine the action of leptin on fetal growth, placental gene expression and postnatal offspring metabolism, we injected C57BL mice with leptin or saline on gestational day 12 and then measured body weights (BWs) of offspring fed on a standard or obesogenic diet, as well as mRNA expression levels of insulin-like growth factors and glucose and amino acid transporters. Male and female offspring born to leptin-treated mothers exhibited growth retardation before and a growth surge after weaning. Mature male offspring, but not female offspring, exhibited increased BWs on a standard diet. Leptin administration prevented the development of hyperglycaemia in the obese offspring of both sexes. The placentas of the male and female foetuses differed in size and gene expression, and leptin injection decreased the fetal weights of both sexes, the placental weights of the male foetuses and placental gene expression of the GLUT1 glucose transporter in female foetuses. The data suggest that mid-pregnancy is an ontogenetic window for the sex-specific programming effects of leptin, and these effects may be exerted via fetal sex-specific placental responses to leptin administration.

RevDate: 2019-11-08

Gokcumen O (2019)

Archaic hominin introgression into modern human genomes.

American journal of physical anthropology [Epub ahead of print].

Ancient genomes from multiple Neanderthal and the Denisovan individuals, along with DNA sequence data from diverse contemporary human populations strongly support the prevalence of gene flow among different hominins. Recent studies now provide evidence for multiple gene flow events that leave genetic signatures in extant and ancient human populations. These events include older gene flow from an unknown hominin in Africa predating out-of-Africa migrations, and in the last 50,000-100,000 years, multiple gene flow events from Neanderthals into ancestral Eurasian human populations, and at least three distinct introgression events from a lineage close to Denisovans into ancestors of extant Southeast Asian and Oceanic populations. Some of these introgression events may have happened as late as 20,000 years before present and reshaped the way in which we think about human evolution. In this review, I aim to answer anthropologically relevant questions with regard to recent research on ancient hominin introgression in the human lineage. How have genomic data from archaic hominins changed our view of human evolution? Is there any doubt about whether introgression from ancient hominins to the ancestors of present-day humans occurred? What is the current view of human evolutionary history from the genomics perspective? What is the impact of introgression on human phenotypes?

RevDate: 2019-11-05

Denisova O, Chernogoryuk G, Baranovskaya N, et al (2019)

Trace Elements in the Lung Tissue Affected by Sarcoidosis.

Biological trace element research pii:10.1007/s12011-019-01915-z [Epub ahead of print].

In the lungs of 76 patients with verified sarcoidosis, 28 chemical elements were identified with neutron activation analysis. High levels of Ca, Fe, Cr, Co, Cs, Eu, Lu, Th, Hf, Au, and U and low level of Na compared to the control samples were determined in sarcoidosis. There were no significant differences in the content of Zn, Rb, La, Sm, Sr, Nd, As, Br, Ag, Tb, Sc, Ta, Sb, Ba, and Yb. Spearman correlation analysis shows multiple positive associations, with the maximum being in pairs as follows: Fe-Cr, Eu-La, Ce-Lu, Hf-Cr, Sc-Zn, Fe-Hf, Ce-Co, and Sb-Cr. These studies support the hypothesis that sarcoidosis is a response of the organism in the form of granulomatous inflammation when exposed to heavy metals and rare earth elements in the environment. We assume that the role of calcium and iron is to separate granulomas from the tissues of the body.

RevDate: 2019-11-15

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

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

Nature ecology & evolution, 3(11):1598-1606.

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: 2019-10-25

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, 94:e94 pii:S0022149X19000853.

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: 2019-11-29

Mata X, Renaud G, C Mollereau (2019)

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

Peptides, 122:170154 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: 2019-10-23

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.

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: 2019-09-20

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

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

Nature immunology, 20(10):1299-1310.

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: 2019-09-15

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: 2019-11-19
CmpDate: 2019-11-19

Callaway E (2019)

Lost Denisovan bone reveals surprisingly human-like finger.

Nature, 573(7773):175-176.

RevDate: 2019-11-11

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: 2019-10-31

Eremin DB, Denisova EA, Yu 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 (NHC) ligands 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 ion 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 through either Ph-NHC coupling or reversible H-NHC coupling. The present study formulates novel ideas for M/NHC catalyst design.

RevDate: 2019-09-27
CmpDate: 2019-09-27

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, 58(18):12218-12227.

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: 2019-11-11
CmpDate: 2019-11-11

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, 294(6):1547-1559.

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: 2019-11-15

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, 20(3):321-332.

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: 2019-11-20

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: 2019-11-01
CmpDate: 2019-11-01

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: 2019-11-29
CmpDate: 2019-11-29

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: 2019-12-06

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.

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: 2019-10-21

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, 94:e52 pii:S0022149X1900035X.

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: 2019-12-03

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: 2019-11-20

Warren M (2019)

Biggest Denisovan fossil yet spills ancient human's secrets.

Nature, 569(7754):16-17.

RevDate: 2019-11-20

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: 2019-11-20

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: 2019-11-20

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: 2019-10-08

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, 60(5):549-555.

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: 2019-11-20

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: 2019-09-13
CmpDate: 2019-09-13

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: 2019-11-20

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: 2019-11-20

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.


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.


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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 )