bluuebunny/crossref_metadata_2025_split huggingface dataset:
Waist circumference thresholds predicting incident dysglycemia and type 2 diabetes in Black African men and women
Authors: Goedecke Julia H. , Nguyen Kim , Kufe Clement , Masemola Maphoko , Chikowore Tinashe , Mendham Amy E. , Norris Shane A. , Crowther Nigel J. , Karpe Fredrik , Olsson Tommy , Kengne Andre Pascal , Micklesfield Lisa K 
Published: October 2021

ABSTRACTObjectiveTo determine the waist circumference (WC) thresholds for the prediction of incident dysglycemia and type 2 diabetes in Black South African (SA) men and women and compare these to advocated International Diabetes Federation (IDF) Europid thresholds.Research design and methodIn this prospective study, Black SA men (n=502) and women (n=527) from the Middle Aged Sowetan Cohort (MASC) study who had normal or impaired fasting glucose at baseline (2011-2015) were followed up through 2017-2018. Baseline measurements included anthropometry, blood pressure and fasting glucose, HDL-cholesterol and triglyceride concentrations. At follow-up, glucose tolerance was assessed using an oral glucose tolerance test. The Youden index was used to determine the optimal threshold of WC to predict incident dysglycemia and type 2 diabetes.ResultsIn men, the optimal WC threshold was 96.8 cm for both dysglycemia and type 2 diabetes (sensitivity 56 and 70%, specificity 74 and 70%, respectively), which performed similarly to the IDF threshold of 94 cm. In women, the optimal WC threshold for incident dysglycemia was 91.8 cm (sensitivity 86%, specificity 37%) and for type 2 diabetes was 95.8 cm (sensitivity 85%, specificity 45%). In comparison, the IDF threshold of 80 cm in women had higher sensitivity (97 and 100%), but lower specificity (12 and 11%) to predict incident dysglycemia and type 2 diabetes, respectively.ConclusionsIn this first prospective study of incident type 2 diabetes in Africa, we show that African-specific WC thresholds perform better than the IDF WC thresholds to predict incident dysglycemia and type 2 diabetes.
Gene losses in the common vampire bat illuminate molecular adaptations to blood feeding
Authors: Blumer Moritz , Brown Tom , Freitas Mariella Bontempo , Destro Ana Luiza , Oliveira Juraci A. , Morales Ariadna , Schell Tilman , Greve Carola , Pippel Martin , Jebb David , Hecker Nikolai , Ahmed Alexis-Walid , Kirilenko Bogdan , Foote Maddy , Janke Axel , Lim Burton K. , Hiller Michael 
Published: October 2021

AbstractFeeding exclusively on blood, vampire bats represent the only obligate sanguivorous lineage among mammals. To uncover genomic changes associated with adaptations to this unique dietary specialization, we generated a new haplotype-resolved reference-quality genome of the common vampire bat (Desmodus rotundus) and screened 26 bat species for genes that were specifically lost in the vampire bat lineage. We discovered previously-unknown gene losses that relate to metabolic and physiological changes, such as reduced insulin secretion (FFAR1,SLC30A8), limited glycogen stores (PPP1R3E), and a distinct gastric physiology (CTSE). Other gene losses likely reflect the biased nutrient composition (ERN2,CTRL) and distinct pathogen diversity of blood (RNASE7). Interestingly, the loss ofREP15likely helped vampire bats to adapt to high dietary iron levels by enhancing iron excretion and the loss of the 24S-hydroxycholesterol metabolizing enzymeCYP39A1could contribute to their exceptional cognitive abilities. Finally, losses of key cone phototransduction genes (PDE6H,PDE6C) suggest that these strictly-nocturnal bats completely lack cone-based vision. These findings enhance our understanding of vampire bat biology and the genomic underpinnings of adaptations to sanguivory.
Lactate Increases Stemness of CD8+ T Cells to Augment Anti-Tumor Immunity
Authors: Feng Qiang , Liu Zhida , Yu Xuexin , Huang Tongyi , Chen Jiahui , Wang Jian , Wilhelm Jonathan , Li Suxin , Song Jiwon , Li Wei , Sun Zhichen , Sumer Baran , Li Bo , Fu Yang-Xin , Gao Jinming 
Published: October 2021

AbstractNutrients and metabolites play important roles in immune functions. Recent studies show lactate instead of glucose can serve as a primary carbon fuel source for most tissues. The role of lactate in tumor immunity is not well understood with immune suppressive functions reported for lactic acid, the conjugate acid form of lactate. In this study, we report lactate increases the stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of lactate but not glucose shows CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis revealed lactate treatment increased a subpopulation of stem-like TCF-1-expressing CD8+ T cells, which is further validated by ex vivo culture of CD8+ T cells from mouse splenocytes and human peripheral blood mononuclear cells. The inhibition of histone deacetylase activity by lactate increased acetylation in the histone H3K27 site at the Tcf7 super enhancer locus and increased the gene expression of Tcf7. Adoptive transfer of CD8+ T cells pretreated with lactate in vitro showed potent tumor growth inhibition in vivo. Our results elucidate the immune protective role of lactate in anti-tumor immunity without the masking effect of acid. These results may have broad implications for T cell therapy and the understanding of lactate in immune metabolism.
nQMaker: estimating time non-reversible amino acid substitution models
Authors: Dang Cuong Cao , Minh Bui Quang , McShea Hanon , Masel Joanna , James Jennifer Eleanor , Vinh Le Sy , Lanfear Robert 
Published: October 2021

AbstractAmino acid substitution models are a key component in phylogenetic analyses of protein sequences. All amino acid models available to date are time-reversible, an assumption designed for computational convenience but not for biological reality. Another significant downside to time-reversible models is that they do not allow inference of rooted trees without outgroups. In this paper, we introduce a maximum likelihood approach nQMaker, an extension of the recently published QMaker method, that allows the estimation of time non-reversible amino acid substitution models and rooted phylogenetic trees from a set of protein sequence alignments. We show that the non-reversible models estimated with nQMaker are a much better fit to empirical alignments than pre-existing reversible models, across a wide range of datasets including mammals, birds, plants, fungi, and other taxa, and that the improvements in model fit scale with the size of the dataset. Notably, for the recently published plant and bird trees, these non-reversible models correctly recovered the commonly known root placements with very high statistical support without the need to use an outgroup. We provide nQMaker as an easy-to-use feature in the IQ-TREE software (http://www.iqtree.org), allowing users to estimate non-reversible models and rooted phylogenies from their own protein datasets.
Systems-level analysis of transcriptome reorganization during liver regeneration
Authors: Porukala Manisri , Vinod P K 
Published: October 2021

AbstractTissue homeostasis and regeneration depend on the reversible transitions between quiescence (G0) and proliferation. The liver has a remarkable capacity to regenerate after injury or resection by cell growth and division. During regeneration, the liver needs to maintain the essential metabolic tasks and meet the metabolic requirements for hepatocyte growth and division. Understanding the regulatory mechanisms involved in balancing the liver function and proliferation demand after injury or resection is crucial. In this study, we analyzed high-resolution temporal RNA sequencing data of liver regeneration after two-thirds partial hepatectomy (PHx) using network inference and mathematical modeling approaches. The reconstruction of the dynamic regulatory network of liver regeneration reveals the trajectories of different metabolic pathways, protein processing in the endoplasmic reticulum (ER), ribosome biogenesis, RNA transport, spliceosome, immune response, and cell cycle. We further developed a mathematical model of the integrated circuit of liver regeneration that accounts for underlying features of compensatory metabolism, proliferation, and epithelial-to-mesenchymal transition during liver regeneration. We show that a mutually exclusive behavior emerges due to the bistable inactivation of HNF4A, which controls the initiation and termination of liver regeneration and different population-level expressions observed in single-cell RNA sequencing data of liver regeneration.
A common neural currency account for social and non-social decisions
Authors: Arabadzhiyska Desislava H. , Garrod Oliver G. B. , Fouragnan Elsa , De Luca Emanuele , Schyns Philippe G. , Philiastides Marios G. 
Published: October 2021

ABSTRACTTo date, social and non-social decisions have been studied in isolation. Consequently, the extent to which social and non-social forms of decision uncertainty are integrated using shared neurocomputational resources remains elusive. Here, we address this question using simultaneous EEG-fMRI and a task in which decision evidence in social and non-social contexts varies along comparable scales. First, we identify comparable time-resolved build-up of activity in the EEG, akin to a process of evidence accumulation. We then use the endogenous trial-by-trial variability in the slopes of these accumulating signals to construct parametric fMRI predictors. We show that a region of the posterior-medial frontal cortex (pMFC) uniquely explains trial-wise variability in the process of evidence accumulation in both the social and non-social contexts. We further demonstrate a task-dependent coupling between the pMFC and regions of the human valuation system in dorso- and ventro-medial prefrontal cortex (dmPFC/vmPFC) across both contexts. Finally, we report domain-specific representations in regions known to encode the early decision evidence for each context. These results are suggestive of a domain-general decision-making architecture, whereupon domain-specific information is likely converted into a “common currency” in the dmPFC/vmPFC and accumulated for the decision in the pMFC.
Pathogen-derived 9-methyl sphingoid base is perceived by a lectin receptor kinase in Arabidopsis
Authors: Kato H. , Nemoto K. , Shimizu M. , Abe A , Asai S. , Ishihama N. , Daimon T. , Ojika M. , Kawakita K. , Onai K. , Shirasu K. , Ishiura M. , Takemoto D. , Takano Y. , Terauchi R. 
Published: October 2021

AbstractIn plants, many invading microbial pathogens are recognized by cell-surface pattern recognition receptors (PRRs), inducing defense responses; yet how PRRs perceive pathogen sphingolipids remains unclear. Here, we show that the ceramide Pi-Cer D from a plant pathogenic oomycetePhytophthora infestanstriggers defense responses in Arabidopsis. Pi-Cer D is cleaved by an Arabidopsis apoplastic ceramidase, NCER2, and the resulting 9-methyl-branched sphingoid base is recognized by a plasma membrane lectin receptor-like kinase, RDA2. Importantly, 9-methyl-branched sphingoid base, which is unique to microbes, induces plant immune responses by interacting with RDA2. Loss ofRDA2orNCER2function compromised Arabidopsis resistance against an oomycete pathogen, indicating that these are crucial for defense. We provide new insights that help elucidate the recognition mechanisms of pathogen-derived lipid molecules in plants.One Sentence SummaryOomycete-derived ceramide is cleaved into sphingoid base by ceramidase and recognized by an Arabidopsis receptor kinase.
Different brain systems support the aversive and appetitive sides of human pain-avoidance learning
Authors: Jepma Marieke , Roy Mathieu , Ramlakhan Kiran , van Velzen Monique , Dahan Albert 
Published: October 2021

AbstractBoth unexpected pain and unexpected pain absence can drive avoidance learning, but whether they do so via shared or separate neural and neurochemical systems is largely unknown. To address this issue, we combined an instrumental pain-avoidance learning task with computational modeling, functional magnetic resonance imaging (fMRI) and pharmacological manipulations of the dopaminergic (100 mg levodopa) and opioidergic (50 mg naltrexone) systems (N=83). Computational modeling provided evidence that untreated participants learned more from received than avoided pain. Our dopamine and opioid manipulations negated this learning asymmetry by selectively increasing learning rates for avoided pain. Furthermore, our fMRI analyses revealed that pain prediction errors were encoded in subcortical and limbic brain regions, whereas no-pain prediction errors were encoded in frontal and parietal cortical regions. However, we found no effects of our pharmacological manipulations on the neural encoding of prediction errors. Together, our results suggest that human pain-avoidance learning is supported by separate threat- and safety-learning systems, and that dopamine and endogenous opioids specifically regulate learning from successfully avoided pain.
Investigating the interaction between inter-locus and intra-locus sexual conflict using hemiclonal analysis in Drosophila melanogaster
Authors: Arun Manas Geeta , Chechi Tejinder Singh , Meena Rakesh , Bhosle Shradha Dattaraya , Srishti  , Prasad Nagaraj Guru 
Published: October 2021

AbstractDivergence in the evolutionary interests of males and females leads to sexual conflict. Traditionally, sexual conflict has been classified into two types: inter-locus sexual conflict (IeSC) and intra-locus sexual conflict (IaSC). IeSC is modeled as a conflict over outcomes of intersexual reproductive interactions mediated by loci that are sex-limited in their effects. IaSC is thought to be a product of selection acting in opposite directions in males and females on traits with a common underlying genetic basis. While in their canonical formalisms IaSC and IeSC are mutually exclusive, there is growing support for the idea that the two may interact. Empirical evidence for such interactions, however, is limited. Here, we investigated the interaction between IeSC and IaSC in Drosophila melanogaster. Using hemiclonal analysis, we sampled 39 hemigenomes from a laboratory-adapted population of D. melanogaster. We measured the contribution of each hemigenome to adult male and female fitness at three different intensities of IeSC, obtained by varying the operational sex-ratio. Subsequently, we estimated the intensity of IaSC at each sex-ratio by calculating the intersexual genetic correlation for fitness and the proportion of sexually antagonistic fitness-variation. Our results indicate a statistically non-significant trend suggesting that increasing the strength of IeSC ameliorates IaSC in the population.
Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity
Authors: Pogacar Ziva , Johnson Jackie L. , Krenning Lenno , De Conti Giulia , Lieftink Cor , Velds Arno , Wardak Leyma , Jochems Fleur , Groot Kelvin , Schepers Arnout , Wang Liqin , Song Ji-Ying , van de Ven Marieke , van Tellingen Olaf , Medema Rene H. , Beijersbergen Roderick L. , Bernards Rene , de Oliveira Rodrigo Leite 
Published: October 2021

ABSTRACTInducing senescence in cancer cells is emerging as a new therapeutic strategy. In order to find ways to enhance senescence induction by palbociclib, a CDK4/6 inhibitor approved for treatment of metastatic breast cancer, we performed functional genetic screens in palbociclib-resistant cells. Using this approach, we found that loss of CDK2 results in strong senescence induction in palbociclib-treated cells. Treatment with the CDK2 inhibitor indisulam, which phenocopies genetic CDK2 inactivation, led to sustained senescence induction when combined with palbociclib in various cell lines and lung cancer xenografts. Treating cells with indisulam led to downregulation of cyclin H, which prevented CDK2 activation. Combined treatment with palbociclib and indisulam induced a senescence program and sensitized cells to senolytic therapy. Our data indicate that inhibition of CDK2 through indisulam treatment can enhance senescence induction by CDK4/6 inhibition.
Analysis of vascular architecture and parenchymal damage generated by reduced blood perfusion in decellularized porcine kidneys using a gray level co-occurrence matrix
Authors: Pantić Igor V. , Sharkeel Adeeba , Petroianu Georg A. , Corridon Peter R. 
Published: October 2021

AbstractThere is no cure for kidney failure, but a bioartificial kidney may help address this global problem. Decellularization provides a promising platform to generate transplantable organs. However, maintaining a viable vasculature is a significant challenge to this technology. Even though angiography offers a valuable way to assess scaffold structure/function, subtle changes are overlooked by specialists. In recent years, innovative image analysis methods in radiology have been suggested to detect and identify subtle changes in tissue architecture. The aim of our research was to apply one of these methods based on a gray level co-occurrence matrix (GLCM) computational algorithm in the analysis of vascular architecture and parenchymal damage generated by hypoperfusion in decellularized porcine. Perfusion decellularization of the whole porcine kidneys was performed using previously established protocols. We analyzed and compared angiograms of kidneys subjected to pathophysiological arterial perfusion of whole blood. For regions of interest (ROIs) covering kidney medulla and the main elements of the vascular network, five major GLCM features were calculated: angular second moment as an indicator of textural uniformity, inverse difference moment as an indicator of textural homogeneity, GLCM contrast, GLCM correlation, and sum variance of the co-occurrence matrix. In addition to GLCM, we also performed discrete wavelet transform analysis of angiogram ROIs by calculating the respective wavelet coefficient energies using high and low-pass filtering. We report statistically significant changes in GLCM and wavelet features, including the reduction of the angular second moment and inverse difference moment, indicating a substantial rise in angiogram textural heterogeneity. Our findings suggest that the GLCM method can be successfully used as an addition to conventional fluoroscopic angiography analyses of micro/macrovascular integrity following in vitro blood perfusion to investigate scaffold integrity. This approach is the first step toward developing an automated network that can detect changes in the decellularized vasculature.
Topological analysis of a bacterial DedA protein associated with alkaline tolerance and antimicrobial resistance
Authors: Scarsbrook Hollie L , Urban Roman , Streather Bree R. , Moores Alexandra , Mulligan Christopher 
Published: October 2021

AbstractMaintaining membrane integrity is of paramount importance to the survival of bacteria as the membrane is the site of multiple crucial cellular processes including energy generation, nutrient uptake, and antimicrobial efflux. The DedA family of integral membrane proteins are widespread in bacteria and are associated with maintaining the integrity of the membrane. In addition, DedA proteins have been linked to resistance to multiple classes of antimicrobials in various microorganisms. Therefore, the DedA family are attractive targets for the development of new antibiotics. Despite DedA family members playing a key physiological role in many bacteria, their structure, function and physiological role remain unclear. To help illuminate the structure of the bacterial DedA proteins, we have performed substituted cysteine accessibility method (SCAM) analysis on the most comprehensively characterized bacterial DedA protein, YqjA from Escherichia coli. By probing the accessibility of 15 cysteine residues across the length of YqjA using thiol reactive reagents, we have mapped the topology of the protein. Using these data, we have experimentally validated a structural model of YqjA generated using evolutionary co-variance, which consists of an α-helical bundle with two re-entrant hairpin loops reminiscent of several secondary active transporters. In addition, our cysteine accessibility data suggests that YqjA forms an oligomer wherein the protomers are arranged in a parallel fashion. This experimentally verified model of YqjA lays the foundation for future work in understanding the function and mechanism of this interesting and important family.
Structural basis for activation and gating of IP3 receptors
Authors: Schmitz Emily A. , Takahashi Hirohide , Karakas Erkan 
Published: October 2021

AbstractCalcium (Ca2+) is a universal and versatile cellular messenger used to regulate numerous cellular processes in response to external or internal stimuli. A pivotal component of the Ca2+ signaling toolbox in cells is the inositol 1,4,5-triphosphate (IP3) receptors (IP3Rs), which mediate Ca2+ release from the endoplasmic reticulum (ER), controlling cytoplasmic and organellar Ca2+ concentrations1-3. IP3Rs are activated by IP3 and Ca2+, inhibited by Ca2+ at high concentrations, and potentiated by ATP1-3. However, the underlying molecular mechanisms are unclear due to the lack of structures in the active conformation. Here we report cryo-electron microscopy (cryo-EM) structures of human type-3 IP3R in multiple gating conformations; IP3-ATP bound pre-active states with closed channels, IP3-ATP-Ca2+ bound active state with an open channel, and IP3-ATP-Ca2+ bound inactive state with a closed channel. The structures demonstrate how IP3-induced conformational changes prime the receptor for activation by Ca2+, how Ca2+ binding leads to channel opening, and how ATP modulates the activity, providing insights into the long-sought questions regarding the molecular mechanism of the receptor activation and gating.
Degradation of ribosome and chaperone proteins is attenuated during the Differentiation of Replicatively Aged C2C12 Myoblasts
Authors: Brown Alexander D. , Stewart Claire E. , Burniston Jatin G. 
Published: October 2021

AbstractAge-related impairments in myoblast differentiation may contribute to reductions in muscle function in older adults, however, the underlying proteostasis processes are not well understood. Young (P6-10) and replicatively aged (P48-50) C2C12 myoblast cultures were investigated during early (0h-24h) and late (72h-96h) stages of differentiation using deuterium oxide (D2O) labelling and mass spectrometry. The absolute dynamic profiling technique for proteomics (Proteo-ADPT) was applied to quantify the absolute rates of abundance change, synthesis and degradation of individual proteins. Proteo-ADPT encompassed 116 proteins and 74 proteins exhibited significantly (P<0.05, FDR <5 %) different changes in abundance between young and aged cells at early and later periods of differentiation. Young cells exhibited a steady pattern of growth, protein accretion and fusion, whereas aged cells failed to gain protein mass or undergo fusion during later differentiation. Maturation of the proteome was retarded in aged myoblasts at the onset of differentiation, but their proteome appeared to ‘catch up’ with the young cells during the early phase of the differentiation period. However, this ‘catch up’ process in aged cells was not accomplished by higher levels of protein synthesis. Instead, a lower level of protein degradation in aged cells was responsible for the elevated gains in protein abundance. Our novel data point to a loss of proteome quality as a precursor to the lack of fusion of aged myoblasts and highlights dysregulation of protein degradation, particularly of ribosomal and chaperone proteins, as a key mechanism that may contribute to age-related declines in the capacity of myoblasts to undergo differentiation.