bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dysfunctional β-cell longevity in diabetes relies on energy conservation and positive epistasis
Authors: Raval Kavit , Jamshidi Neema , Seyran Berfin , Salwinski Lukasz , Pillai Raju , Yang Lixin , Ma Feiyang , Pellegrini Matteo , Shin Juliana , Yang Xia , Tudzarova Slavica 
Published: March 2024

AbstractLong-lived PFKFB3 expressing β-cells are dysfunctional cells because of prevailing glycolysis that compromises metabolic coupling of insulin secretion. Their accumulation in type-2 diabetes (T2D) appears to be related to the loss of apoptotic competency of cell fitness competition (CFC) that maintains tissue function by favoring constant selection of healthy “winner” cells. To investigate how PFKFB3 can disguise the competitive traits of dysfunctional “loser” β-cells, we analyzed the overlap between human β-cells with bona-fide “loser signature” across diabetes pathologies utilizing the HPAP scRNA-seq and spatial transcriptomics of PFKFB3 positive β-cells from nPOD T2D pancreata. The overlapping transcriptional profile of “loser” β-cells was represented by downregulated ribosomal biogenesis- and genes encoding for mitochondrial respiration. PFKFB3 positive “loser” β-cells had reduced expression of HLA Class I and II genes. Gene-gene interaction analysis revealed that PFKFB3rs1983890can interact with anti-apoptotic geneMAIP1implicating positive epistasis as a mechanism for prolonged survival of “loser” β-cells in T2D. Inhibition of PFKFB3 resulted in the clearance of dysfunctional “loser” β-cells leading to restored glucose tolerance in mouse model of T2D.
A novel nabelschnur protein regulates segregation of the kinetoplast DNA inTrypanosoma brucei
Authors: Cadena Lawrence Rudy , Hammond Michael , Tesařová Martina , Chmelová Ľubomíra , Svobodová Michaela , Durante Ignacio M. , Yurchenko Vyacheslav , Lukeš Julius 
Published: March 2024

ABSTRACTThe kinetoplast DNA (kDNA), a distinctive arrangement of mitochondrial DNA found in trypanosomatid protists, comprises a concatenated network of minicircles and maxicircles that undergo division and segregation once during each cell cycle. Despite the identification and characterization of numerous proteins involved in kDNA maintenance and replication, its segregation and the formation of the nabelschnur remain poorly understood on a molecular level. This enigmatic filamentous structure, transiently appearing inTrypanosoma brucei,connects the daughter kDNA networks prior to their complete segregation. Here, we characterize TbNAB70, a high mobility group box-like protein localized exclusively to the nabelschnur and the kDNA disc. Our findings demonstrate that TbNAB70 is critical for the segregation, but not replication, of kDNA, a so far unprecedented phenotype. Furthermore, structural predictions suggest that this protein holds the capacity to bind to kDNA illuminating the exact molecular mechanisms of segregation involved. Thus, we propose that TbNAB70 plays a pivotal role in the faithful and efficient segregation of the daughter kDNA networks.
A salmon fish model reveals genetic signals in brain associated with early maturation
Authors: Pashay Ahi Ehsan , Verta Jukka-Pekka , Kurko Johanna , Ruokolainen Annukka , Singh Pooja , Debes Paul Vincent , Erkinaro Jaakko , Primmer Craig R. 
Published: March 2024

AbstractEmerging evidence suggests a link between adiposity and early maturation, potentially impacting hormonal signaling pathways governing puberty timing. Fish models have proven invaluable in studying these processes, given their genetic and physiological similarities to humans. In Atlantic salmon, in addition to being linked with environmental shifts and lipid reserves, the timing of sexual maturation also has a strong genetic basis. A gene encoding a co-factor of Hippo pathway,vgll3, is a major determinant of maturation timing in salmon, and the same gene was found to be associated with maturation timing in humans. Intriguingly,vgll3also inhibits adipogenesis in mice. Recent studies in salmon revealed correlations betweenvgll3genotypes and reproductive axis gene expression, possibly modulated through the Hippo signaling pathway. The Hippo pathway is known for its role in sexual maturation and adipogenesis and responds to environmental cues such as dietary fat and temperature. In this study, we employed a custom gene expression panel in male Atlantic salmon with differentvgll3 early(E) andlate(L) maturation genotypes testing components of this pathway in brain at immature and mature stages. We found increased brain expression of a major Hippo pathway kinase (lats1b) and melanocortin receptor encoding genes (mc4raandmc4rc) in individuals withearly(E) maturation genotypes ofvgll3before maturation development of testes. Moreover, we found components and interacting partners of Hippo pathway showing differential expression in brain of individuals withearly(E) andlate(L)vgll3genotypes prior to maturation. This could indicate extensive and complex roles of Hippo pathway in brain processes required for preparing for [the onset of] maturation at upstream of reproductive axis. This study elucidates molecular mechanisms underpinning early maturation, and for the first time in fish, offering insights into detecting it at molecular level in brain before visible gonadal changes occur.
Genome-Wide Transcription Response ofStaphylococcus epidermidisto Heat Shock and Medically Relevant Glucose Levels
Authors: Benjamin Kaisha N , Goyal Aditi , Nair Ramesh , Endy Drew 
Published: March 2024

ABSTRACTSkin serves as both barrier and interface between body and environment. Skin microbes are intermediaries evolved to respond, transduce, or act in response to changing environmental or physiological conditions. Here, we quantify genome-wide changes in gene expression levels for one abundant skin commensal,Staphylococcus epidermidis, in response to an internal physiological signal, glucose levels, and an external environmental signal, temperature. We find 85 of 2354 genes change up to∼34-fold in response to medically relevant changes in glucose concentration (0 mM to 17 mM; adjPvalue ≤ 0.05). We observed carbon catabolite repression in response to a range of glucose spikes, as well as upregulation of genes involved in glucose utilization in response to persistent glucose. We observed 366 differentially expressed genes in response to a physiologically relevant change in temperature (37°C to 45°C; adjPvalue ≤ 0.05) and anS. epidermidisheat-shock response that mostly resembles the heat-shock response of related staphylococcal species. DNA motif analysis also revealed CtsR and CIRCE operator sequences arranged in tandem upstream ofdnaKandgroESLoperons. We further identified 38 glucose-responsive genes as candidate ON or OFF switches for use in controlling synthetic genetic systems. Such systems might be used to instrument the in-situ skin microbiome or help control microbes bioengineered to serve as embedded diagnostics, monitoring, or treatment platforms.
Natural variation in neuraminidase activity influences the evolutionary potential of the seasonal H1N1 lineage hemagglutinin
Authors: Liu Tongyu , Reiser William K. , Tan Timothy J C , Lv Huibin , Rivera-Cardona Joel , Heimburger Kyle , Wu Nicholas C , Brooke Christopher B. 
Published: March 2024

ABSTRACTThe antigenic evolution of the influenza A virus hemagglutinin (HA) gene poses a major challenge for the development of vaccines capable of eliciting long-term protection. Prior efforts to understand the mechanisms that govern viral antigenic evolution mainly focus on HA in isolation, ignoring the fact that HA must act in concert with the viral neuraminidase (NA) during replication and spread. Numerous studies have demonstrated that the degree to which the receptor binding avidity of HA and receptor cleaving activity of NA are balanced with each other influences overall viral fitness. We recently showed that changes in NA activity can significantly alter the mutational fitness landscape of HA in the context of a lab-adapted virus strain. Here, we test whether natural variation in relative NA activity can influence the evolutionary potential of HA in the context of the seasonal H1N1 lineage (pdmH1N1) that has circulated in humans since the 2009 pandemic. We observed substantial variation in the relative activities of NA proteins encoded by a panel of H1N1 vaccine strains isolated between 2009 and 2019. We comprehensively assessed the effect of NA background on the HA mutational fitness landscape in the circulating pdmH1N1 lineage using deep mutational scanning and observed pronounced epistasis between NA and residues in or near the receptor binding site of HA. To determine whether NA variation could influence the antigenic evolution of HA, we performed neutralizing antibody selection experiments using a panel of monoclonal antibodies targeting different HA epitopes. We found that the specific antibody escape profiles of HA were highly contingent upon NA background. Overall, our results indicate that natural variation in NA activity plays a significant role in governing the evolutionary potential of HA in the currently circulating pdmH1N1 lineage.
Single-cell sequencing of rodent ventral pallidum reveals diverse neuronal subtypes with non-canonical interregional continuity
Authors: Ottenheimer David J. , Simon Rhiana C. , Burke Cassidy T. , Bowen Anna J. , Ferguson Susan M. , Stuber Garret D. 
Published: March 2024

AbstractThe ventral pallidum (VP) was defined as a basal ganglia nucleus with dense input from ventral striatum. To further investigate a VP regional identity, we conducted a cross-species transcriptional characterization of VP cell types. We performed single nucleus RNA-sequencing of VP tissue from mice and rats and identified 16 VP neuronal subclasses with striking cross-species conservation. VP GABAergic neurons were surprisingly heterogeneous, consisting of 14 sub-classes from 3 developmental classes. Combining our sequencing data with a spatial atlas revealed that all VP subclasses extended beyond the traditional borders of VP. Integrating our VP data with prior sequencing data from striatal, hypothalamic, and extended amygdalar tissue confirmed that cell types are shared among these regions. Due to the role of VP in feeding behavior, we also assessed the transcriptional impact of high-fat diet consumption, which induced altered expression of genes involved in oxidative phosphorylation and inhibitory signaling. Overall, our results demonstrate that VP is not a transcriptionally discrete nucleus; rather, VP contains cell types with diverse expression patterns that overlap with regions beyond the basal ganglia.
Metric Ion Classification (MIC): A deep learning tool for assigning ions and waters in cryo-EM and x-ray crystallography structures
Authors: Shub Laura , Liu Wenjin , Skiniotis Georgios , Keiser Michael J. , Robertson Michael J. 
Published: March 2024

AbstractAt sufficiently high resolution, x-ray crystallography and cryogenic electron microscopy are capable of resolving small spherical map features corresponding to either water or ions. Correct classification of these sites provides crucial insight for understanding structure and function as well as guiding downstream design tasks, including structure-based drug discovery and de novo biomolecule design. However, direct identification of these sites from experimental data can prove extremely challenging, and existing empirical approaches leveraging the local environment can only characterize limited ion types. We present a novel representation of chemical environments using interaction fingerprints and develop a machine-learning model to predict the identity of input water and ion sites. We validate the method, named Metric Ion Classification (MIC), on a wide variety of biomolecular examples to demonstrate its utility, identifying many probable mismodeled ions deposited in the PDB. Finally, we collect all steps of this approach into an easy-to-use open-source package that can integrate with existing structure determination pipelines.
Characterizing the temporal dynamics and maturation of brain activity during sleep: an EEG microstate study in preterm and full-term infants
Authors: Adibpour Parvaneh , Nasser Hala , Pedoux Amandine , Devisscher Laurie , Elbaz Nicolas , Ghozland Chloé , Hinnekens Elodie , Neumane Sara , Kabdebon Claire , Lefebvre Aline , Kaminska Anna , Hertz-Pannier Lucie , Heneau Alice , Sibony Olivier , Alison Marianne , Delanoë Catherine , Delorme Richard , Barbu-Roth Marianne , Biran Valérie , Dubois Jessica 
Published: March 2024

AbstractBy interfering with the normal sequence of mechanisms serving the brain maturation, premature birth and related stress can alter perinatal experiences, with potential long-term consequences on a child’s neurodevelopment. The early characterization of brain functioning and maturational changes is thus of critical interest in premature infants who are at high risk of atypical outcomes and could benefit from early diagnosis and dedicated interventions. Using high-density electroencephalography (HD-EEG), we recorded brain activity in extreme and very preterm infants at the equivalent age of pregnancy term (n=43), and longitudinally 2-months later (n=33), compared with full-term born infants (n=14). We characterized the maturation of brain activity by using a dedicated microstate analysis to quantify the spatio-temporal dynamics of the spontaneous transient network activity while controlling for vigilance states. The comparison of premature and full-term infants first showed slower dynamics as well as altered spatio-temporal properties of brain activity in preterm infants. Maturation of functional networks between term-equivalent age and 2 months later in preterms was linked to the emergence of faster dynamics, manifested in part by shorter duration of microstates, as well as an evolution in the spatial organization of the dominant microstates. The inter-individual differences in the temporal dynamics of brain activity at term-equivalent age were further impacted by sex (with slower microstate dynamics in boys) and by gestational age at birth for some microstate dynamics but not by other considered risk factors. This study highlights the potential of the microstate approach to reveal maturational properties of the emerging brain network activity in premature infants.
Efficient test for deviation from Hardy Weinberg Equilibrium with known or ambiguous typing in highly polymorphic loci
Authors: Shkuri Or , Israeli Sapir , Tshuva Yuli , Maiers Martin , Louzoun Yoram 
Published: March 2024

AbstractThe Hardy-Weinberg Equilibrium (HWE) assumption is essential to many population genetics models. Multiple tests were developed to test its applicability in observed genotypes. Current methods are divided into exact tests applicable to small populations and a small number of alleles, and approximate goodness of fit tests. Existing tests cannot handle ambiguous typing in multi-allelic loci. We here present a novel exact test (UMAT - Unambiguous Multi Allelic Test) practically not limited in the number of alleles and population size, based on a perturbative approach around the current observations. We show its accuracy in the detection of deviation from HWE. We then propose an additional model to handle ambiguous typing using either sampling into UMAT or a goodness of fit test with a variance estimate taking ambiguity into account, named ASTA (Asymptotic Statistical Test with Ambiguity). We show the accuracy of ASTA and the possibility to detect of the source of deviation from HWE. We apply these tests to the HLA loci to recover multiple previously reported deviations from HWE, and a large number of new ones.
Expression dynamics of long non-coding RNAs during imaginal disc development and regeneration inDrosophila
Authors: Camilleri-Robles Carlos , Amador Raziel , Tiebe Marcel , Teleman Aurelio A , Serras Florenci , Guigó Roderic , Corominas Montserrat 
Published: March 2024

AbstractThe discovery of functional long non-coding RNAs (lncRNAs) changed their initial concept as transcriptional noise. LncRNAs have been found to participate in the regulation of multiple biological processes, including chromatin structure, gene expression, splicing, and mRNA degradation and translation. However, functional studies of lncRNAs are hindered by the usual lack of phenotypes upon deletion or inhibition. Here, we usedDrosophilaimaginal discs as a model system to identify lncRNAs involved in development and regeneration. We examined a subset of lncRNAs expressed in the wing, leg, and eye disc development. Additionally, we analyzed transcriptomic data from regenerating wing discs to profile the expression pattern of lncRNAs during tissue repair. We focused on the lncRNACR40469, which is upregulated during regeneration. We generatedCR40469mutant flies that developed normally but showed impaired wing regeneration upon the induction of cell death. The ability of these mutants to regenerate was restored by the ectopic expression ofCR40469. Furthermore, we found that the lncRNACR34335has a high degree of sequence similarity withCR40469and can partially compensate for its function during regeneration in the absence ofCR40469. Our findings point to a potential role of the lncRNACR40469intransduring the response to damage in the wing imaginal disc.
Loss of intermicrovillar adhesion impairs basolateral junctional complexes in transporting epithelia
Authors: Cencer Caroline S. , Robinson Kianna L. , Tyska Matthew J. 
Published: March 2024

ABSTRACTTransporting epithelial cells in the gut and kidney rely on protocadherin-based apical adhesion complexes to organize microvilli that extend into the luminal space. In these systems, CDHR2 and CDHR5 localize to the distal ends of microvilli, where they form an intermicrovillar adhesion complex (IMAC) that links the tips of these structures, promotes the formation of a well-ordered array of protrusions, and in turn maximizes apical membrane surface area. Recently, we discovered that IMACs can also form between microvilli that extend from neighboring cells, across cell-cell junctions. As an additional point of physical contact between cells, transjunctional IMACs are well positioned to impact the integrity of canonical tight and adherens junctions that form more basolaterally. Here, we sought to test this idea using cell culture and mouse models that lacked CDHR2 expression and were unable to form IMACs. CDHR2 knockout perturbed cell and junction morphology, led to loss of key components from tight and adherens junctions, and impaired barrier function and wound healing. These results indicate that, in addition to organizing apical microvilli, IMACs provide a layer of cell-cell contact that functions in parallel with canonical tight and adherens junctions to support the physiological functions of transporting epithelia.
Intestinal tuft cells assemble a cytoskeletal superstructure composed of co-aligned actin bundles and microtubules
Authors: Silverman Jennifer B. , Krystofiak Evan E. , Caplan Leah R. , Lau Ken S. , Tyska Matthew J. 
Published: March 2024

ABSTRACTBackground & AimsAll tissues consist of a distinct set of cell types, which collectively support organ function and homeostasis. Tuft cells are a rare epithelial cell type found in diverse epithelia, where they play important roles in sensing antigens and stimulating downstream immune responses. Exhibiting a unique polarized morphology, tuft cells are defined by an array of giant actin filament bundles that support ∼2 μm of apical membrane protrusion and extend over 7 μm towards the cell’s perinuclear region. Despite their established roles in maintaining intestinal epithelial homeostasis, tuft cells remain understudied due to their rarity (e.g. ∼ 1% in the small intestinal epithelium). Details regarding the ultrastructural organization of the tuft cell cytoskeleton, the molecular components involved in building the array of giant actin bundles, and how these cytoskeletal structures support tuft cell biology remain unclear.MethodsTo begin to answer these questions, we used advanced light and electron microscopy to perform quantitative morphometry of the small intestinal tuft cell cytoskeleton.ResultsWe found that tuft cell core bundles consist of actin filaments that are crosslinked in a parallel “barbed-end out” configuration. These polarized structures are also supported by a unique group of tuft cell enriched actin-binding proteins that are differentially localized along the giant core bundles. Furthermore, we found that tuft cell actin bundles are co-aligned with a highly ordered network of microtubules.ConclusionsTuft cells assemble a cytoskeletal superstructure that is well positioned to serve as a track for subcellular transport along the apical-basolateral axis and in turn, support the dynamic sensing functions that are critical for intestinal epithelial homeostasis.SYNOPSISThis research leveraged advanced light and electron microscopy to perform quantitative morphometry of the intestinal tuft cell cytoskeleton. Three-dimensional reconstructions of segmented image data revealed a co-aligned actin-microtubule superstructure that may play a fundamental role in tuft cell function.
Problems and promises of postmodernism in (re)liberating disaster studies
Authors: Cadag Jake Rom 
Published: March 2024

PurposeThis paper is a critique of Western modernity and the problems and promises of postmodernism in (re)liberating disaster studies. It criticizes metanarratives and grand theories of Western discourses to advance postmodern discourses in disaster studies.Design/methodology/approachThis paper outlines a conceptual domain through which approaches of postmodernism can be employed to (re)liberate disaster studies.FindingsMetanarratives and grand theories frame the scope and focus of disaster studies. But the increasing number and the aggravated impacts of disasters and environmental challenges in the late 20th and early 21st centuries are proofs that our current “frames” do not capture the complexities of disasters. Postmodernism, in its diversity and various meanings, offers critical and complementary perspectives and approaches to capture the previously neglected dimensions of disasters.Research limitations/implicationsPostmodernism offers ways forward to (re)liberate disaster studies through ontological pluralism, epistemological diversity and hybridity of knowledge.Originality/valueThe agenda of postmodernism in disaster studies is proposed in terms of the focus of inquiry, ontological and epistemological positionalities, research paradigm, methodologies and societal goals.