bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXPLORING THE EFFECTS OF METABOLISM-DISRUPTING CHEMICALS ON PANCREATIC α-CELL BIOLOGY: A SCREENING TESTING APPROACH
Authors: Al-Abdulla Ruba , Ferrero Hilda , Boronat-Belda Talía , Soriano Sergi , Quesada Iván , Alonso-Magdalena Paloma 
Published: November 2022

AbstractHumans are constantly exposed to many environmental pollutants, some of which have been largely acknowledged as key factors in the development of metabolic disorders such as diabetes and obesity. These chemicals have been classified as endocrine-disrupting chemicals (EDCs) and, more recently, since they can interfere with metabolic functions, they have been renamed as metabolism-disrupting chemicals (MDCs). MDCs are present in many consumer products, including food packaging, personal care products, plastic bottles and containers, and detergents. The scientific literature has ever-increasingly focused on insulin-releasing pancreatic β-cells as one of the main targets for MDCs. Evidence highlights that these substances may disrupt glucose homeostasis, altering pancreatic β-cell physiology. However, their potential impact on glucagon-secreting pancreatic α-cells remains poorly known despite the essential role that this cellular type plays in controlling glucose metabolism. In the present study, we have selected seven paradigmatic EDCs representing major toxic classes, including bisphenols, phthalates, perfluorinated compounds, metals, and pesticides. By using an in vitro cell-based model, the pancreatic α-cell line αTC1-9, we have explored the effects of these compounds on pancreatic α-cell viability, gene expression, and secretion. Our results indicated that most of the selected chemicals studied caused functional alterations in pancreatic α-cells. Moreover, we revealed, for the first time, their direct effects on key molecular aspects of pancreatic α-cell biology.
Landscape-scale exposure to multiazole-resistantAspergillus fumigatusbioaerosols
Authors: Shelton Jennifer M. G. , Rhodes Johanna , Uzzell Christopher B. , Hemmings Samuel , Brackin Amelie P. , Sewell Thomas R. , Alghamdi Asmaa , Dyer Paul S. , Fraser Mark , Borman Andrew M. , Johnson Elizabeth M. , Piel Frédéric B. , Singer Andrew C. , Fisher Matthew C. 
Published: November 2022

AbstractWe demonstrate country-wide exposures to aerosolized spores of a human fungal pathogen,Aspergillus fumigatus, that has acquired resistance to first line azole clinical antifungal drugs. Assisted by a network of citizen scientists across the United Kingdom, we show that 1 in 20 viable aerosolized spores of this mold are resistant to the agricultural fungicide tebuconazole and 1 in 140 spores are resistant to the four most used azoles for treating clinical aspergillosis infections. Season and proximity to industrial composters were associated with growth ofA. fumigatusfrom air samples, but not with the presence of azole resistance, and hotspots were not stable between sampling periods suggesting a high degree of atmospheric mixing. Genomic analysis shows no distinction between those resistant genotypes found in the environment and in patients, indicating that ~40% (58/150 sequenced genomes) of azole-resistantA. fumigatusinfections are acquired from environmental exposures. Due to the ubiquity of this measured exposure, it is crucial that we determine source(s) of azole-resistantA. fumigatus, who is at greatest risk of exposure and how to mitigate these exposures, in order to minimize treatment failure in patients with aspergillosis.One sentence summaryUK-wide citizen science surveillance finds a ubiquitous exposure to aerosolized spores of a human fungal pathogen that have evolved in the environment cross-resistance to essential clinical antifungal drugs
Allosteric activation of cell wall synthesis during bacterial growth
Authors: Shlosman Irina , Fivenson Elayne M. , Gilman Morgan S.A. , Sisley Tyler A. , Walker Suzanne , Bernhardt Thomas G. , Kruse Andrew C. , Loparo Joseph J. 
Published: November 2022

SummaryThe peptidoglycan (PG) cell wall protects bacteria against osmotic lysis and determines cell shape, making this structure a key antibiotic target. Peptidoglycan is a polymer of glycan chains connected by peptide crosslinks, and its synthesis requires precise spatiotemporal coordination between glycan polymerization and crosslinking. However, the molecular mechanism by which these reactions are initiated and coupled is unclear. Here we use single-molecule FRET and cryo-EM to show that an essential PG synthase (RodA-PBP2) responsible for bacterial elongation undergoes dynamic exchange between closed and open states. Structural opening couples the activation of polymerization and crosslinking and is essentialin vivo.Given the high conservation of this family of synthases, the opening motion that we uncovered likely represents a conserved regulatory mechanism that controls activation of PG synthesis during other cellular processes, including cell division.
Bias in group-level EEG microstate analysis
Authors: Murphy M , Wang J , Jiang C , Wang L , Kozhemiako N , Wang Y ,   the GRINS consortium, Pan JQ , Purcell SM 
Published: November 2022

AbstractMicrostate analysis is a promising technique for analyzing high-density electroencephalographic data, but there are multiple questions about methodological best practices. Between and within individuals, microstates can differ both in terms of characteristic topographies and temporal dynamics, which leads to analytic challenges as the measurement of microstate dynamics is dependent on assumptions about their topographies. Here we focus on the analysis of group differences, using simulations seeded on real data from healthy control subjects to compare approaches that derive separate sets of maps within subgroups versus a single set of maps applied uniformly to the entire dataset. In the absence of true group differences in either microstate maps or temporal metrics, we found that using separate subgroup maps resulted in substantially inflated type I error rates. On the other hand, when groups truly differed in their microstate maps, analyses based on a single set of maps confounded topographic effects with differences in other derived metrics. We propose an approach to alleviate both classes of bias, based on a paired analysis of all subgroup maps. We illustrate the qualitative and quantitative impact of these issues in real data by comparing waking versus non-rapid eye movement sleep microstates. Overall, our results suggest that even subtle chance differences in microstate topography can have profound effects on derived microstate metrics and that future studies using microstate analysis should take steps to mitigate this large source of error.
The genetic structure within a single tree is determined by the behavior of the stem cells in the meristem
Authors: Iwasa Yoh , Tomimoto Sou , Satake Akiko 
Published: November 2022

AbstractGenomic sequencing revealed that somatic mutations cause a genetic differentiation of the cells in a single tree. In this study, we consider a mathematical model for stem cell proliferation in the shoot apical meristem (abbrev. SAM), which results in genetic diversification between the cells differing in the distance along the shoot and the angle around a shoot axis. The assumptions are as follows. Stem cells in the SAM normally undergo asymmetric cell division and produce successor stem cells and differentiated cells. The differentiated cells proliferate and contribute to shoot elongation.Occasionally, a stem cell is replaced by a copy of an adjacent stem cell. We discuss the “coalescent length” between cells indicating their genetic difference with respect to neutral mutations. A mathematical analysis revealed the following. The genetic diversity of cells sampled at the same position along the shoot increases with the distance from the bottom of the shoot. Stem cells hold a larger variation if they are replaced only by the nearest neighbors than if they are replaced by any cells. The coalescent length between two cells increases not only with the difference in the position along the shoot but also in the angle around the shoot axis. The dynamics of stem cells at the SAM determine the genetic pattern of the entire shoot.
Kinesin-12 KLP-18 contributes to the kinetochore-microtubule poleward flux during the metaphase ofC. elegansone-cell embryo
Authors: Soler Nina , Da Silva Mathis , Tascon Christophe , Chesneau Laurent , Foliard Pauline , Bouvrais Hélène , Pastezeur Sylvain , Le Marrec Loïc , Pecreaux Jacques 
Published: November 2022

AbstractThe mitotic spindle, a key structure to partition chromosomes during cell division, connects its poles to the chromosomes through microtubules. Their plus-ends, oriented towards the chromosomes, exhibit dynamic instability crucial for kinetochores’ correct attachment. Involved in this process, the poleward flux implicates the displacement of microtubules towards the spindle poles, coordinated with polymerisation at the plus ends. The mechanisms behind this are diverse. It includes treadmilling powered by microtubule depolymerisation at the spindle poles, sliding of spindle microtubules by molecular motors like Kinesin-5, and pushing microtubules away from the chromosomes by chromokinesins. Interestingly, no such flux was reported in theCaenorhabditis eleganszygote, although all proteins contributing to flux in mammals have homologous in the nematode.To explore this, we fluorescently labelled microtubules and conducted photobleaching. We found no global poleward flow; the bleached zone’s edges moved inward. The centrosome-side front motion was caused by dynamic instability, while the chromosome-side front exhibited faster recovery, suggesting an additional mechanism. This extra velocity was localised near chromosomes, indicating that only kinetochore microtubules may undergo flux. Consistently, this flux depended on proteins ensuring the chromosome attachment and growth of the kinetochore microtubules, notably NDC-80, CLS-2CLASP, and ZYG-9XMAP215. Furthermore, this flux decreased as metaphase progressed and attachments transitioned from side- to end-on; it was reduced by SKA-1 recruitment. Traditional treadmilling was unlikely as many kinetochore microtubules do not reach spindle poles in the zygote spindle. Conversely, the depletion of kinesin-12 KLP-18KIF15, which cross-links and focuses microtubules at meiosis, reduced the front rate. Ultimately, we propose that the sole kinetochore microtubules slide along spindle microtubules likely powered by KLP-18, contrasting with solid displacement in other systems, aligning with observations in human cells of decreasing flux with increasing chromosome distance.
High Coverage Mitogenomes and Y-Chromosomal Typing Reveal Ancient Lineages in the Modern-day Székely Population in Romania
Authors: Borbély Noémi , Székely Orsolya , Szeifert Bea , Gerber Dániel , Máthé István , Benkő Elek , Gusztáv Mende Balázs , Egyed Balázs , Pamjav Horolma , Szécsényi-Nagy Anna 
Published: November 2022

AbstractHere we present 115 whole mitogenomes and 92 Y-chromosomal STR and SNP profiles from a Hungarian ethnic group, the Székelys (in Romanian: Secuii, in German: Sekler) living in southeast Transylvania (Romania). The Székelys can be traced back to the 12th century in the region, and numerous scientific theories exist as to their origin. We carefully selected sample providers that had local ancestors inhabiting small villages in the area of Odorheiu Secuiesc/Székelyudvarhely in Romania. The results of our research and the reported data signify a qualitative leap compared to previous studies, since complete mitochondrial DNA sequences and Y-chromosomal data containing 23 STRs have not been available from the region until now. We evaluated the results with population genetic and phylogenetic methods, in the context of the modern and ancient populations that are either geographically or historically related to the Székelys. Our results demonstrate a predominantly local uniparental make-up of the population that also indicates limited admixture with neighbouring populations. Phylogenetic analyses confirmed the presumed eastern origin of certain maternal (A, C, D) and paternal (Q, R1a) lineages and, in some cases, they could also be linked to ancient DNA data from Migration Period (5th-9thcenturies AD) and Hungarian Conquest Period (10th century AD) populations.
Adaptive variation in avian eggshell structure and gas conductance across elevational gradients?
Authors: Ocampo David , Cadena Carlos Daniel , Londoño Gustavo A. 
Published: November 2022

AbstractMany tropical species have restricted elevational distributions, which are potentially bounded by constraints imposed by physical conditions on physiological processes. Although some studies have examined variation in the physiology of adult birds with respect to elevation, little attention has been paid to the structure and function of eggshells, which mediate gas exchange between the embryo and the environment. At high elevations, dry air is expected to increase water loss from the egg; selection to avoid desiccation might therefore be expected to favor reduced gas conductance by means of increased eggshell thickness or reduced pore size. We used gas diffusion experiments and scanning electron microscopy to examine water vapor conductance rates and eggshell structures in 197 bird species distributed along an elevational gradient in the Andes. As predicted, water vapor conductance across the eggshell declined in a narrow range with elevation among all species and among species within families, but not among individuals within species. Variation among species in eggshell conductance was lower at high-elevation sites, potentially indicating greater constraints at such sites. Structural changes in eggshells with respect to elevation varied among taxonomic families of birds, suggesting potentially different adaptive responses to common selective pressures in terms of eggshell thickness and pore density, and size. We suggest that considering functional and structural traits of eggshells, which influence embryo development, may help one to better understand the elevational distributions of species and to forecast their responses to global climate change.
Live Imaging of Cutaneous Wound Healing in Zebrafish
Authors: Greenspan Leah J. , Ameyaw Keith , Castranova Daniel , Mertus Caleb A. , Weinstein Brant M. 
Published: November 2022

AbstractCutaneous wounds are common afflictions that follow a stereotypical healing process involving hemostasis, inflammation, proliferation, and remodeling phases. In the elderly or those suffering from vascular or metabolic diseases, poor healing following cutaneous injuries can lead to open chronic wounds susceptible to infection. The discovery of new therapeutic strategies to improve this defective wound healing requires a better understanding of the cellular behaviors and molecular mechanisms that drive the different phases of wound healing and how these are altered with age or disease. The zebrafish provides an ideal model for visualization and experimental manipulation of the cellular and molecular events during wound healing in the context of an intact, living animal. To facilitate studies of cutaneous wound healing in the zebrafish, we have developed an inexpensive, simple, and effective method for generating reproducible cutaneous injuries in adult zebrafish using a rotary tool. Using our injury system in combination with live imaging, we can monitor skin re-epithelialization, immune cell recruitment, and vessel regrowth and remodeling in the same animal over time. This injury system provides a valuable new experimental platform to study key cellular and molecular events during wound healingin vivowith unprecedented resolution.
Folding stabilities of ribosome-bound nascent polypeptides probed by mass spectrometry
Authors: Tan Ruiyue , Hoare Margaret , Welle Kevin A. , Swovick Kyle , Hryhorenko Jennifer R. , Ghaemmaghami Sina 
Published: November 2022

AbstractThe folding of most proteins occurs during the course of their translation while their tRNA-bound C-termini are embedded in the ribosome. How the close proximity of nascent proteins to the ribosome influences their folding thermodynamics remains poorly understood. Here, we have developed a mass spectrometry-based approach for determining the stabilities of nascent polypeptide chains using methionine oxidation as a folding probe. This approach enables quantitative measurements sub-global folding stabilities of ribosome nascent chains (RNCs) within complex protein mixtures and extracts. To validate the methodology, we analyzed the folding thermodynamics of three model proteins (DHFR, CheY and DinB) in soluble and ribosome-bound states. The data indicated that the ribosome can significantly alter the stability of nascent polypeptides. Ribosome-induced stability modulations were highly variable among different folding domains and were dependent on localized charge distributions within nascent polypeptides. The results implicated electrostatic interactions between the ribosome surface and nascent polypeptides as the cause of ribosome-induced stability modulations. The study establishes a robust proteomic methodology for analyzing localized stabilities within ribosome-bound nascent polypeptides and sheds light on how the ribosome influences the thermodynamics of protein folding.
On why we lack confidence in signal-detection-based analyses of confidence
Authors: Arnold Derek H. , Johnston Alan , Adie Joshua , Yarrow Kielan 
Published: November 2022

Signal-detection theory (SDT) is one of the most popular frameworks for analyzing data from studies of human behavior – including investigations of confidence. SDT-based analyses of confidence deliver both standard estimates of sensitivity (d’), and a second estimate based only on high-confidence decisions – meta d’. The extent to which meta d’ estimates fall short of d’ estimates is regarded as a measure of metacognitive inefficiency, quantifying the contamination of confidence by additional noise. These analyses rely on a key but questionable assumption – that repeated exposures to an input will evoke a normally-shaped distribution of perceptual experiences (the normality assumption). Here we show, via analyses inspired by an experiment and modelling, that when distributions of experiences do not conform with the normality assumption, meta d’ can be systematically underestimated relative to d’. Our data therefore highlight that SDT-based analyses of confidence do not provide a ground truth measure of human metacognitive inefficiency.Public Significance StatementSignal-detection theory is one of the most popular frameworks for analysing data from experiments of human behaviour – including investigations of confidence. The authors show that the results of these analyses cannot be regarded as ground truth. If a key assumption of the framework is inadvertently violated, analyses can encourage conceptually flawed conclusions.
Deep-learning and transfer learning identify new breast cancer survival subtypes from single-cell imaging data
Authors: Yadav Shashank , Zhou Shu , He Bing , Du Yuheng , Garmire Lana X 
Published: November 2022

ABSTRACTQuantitative models that explicitly capture single-cell resolution cell-cell interaction features to predict patient survival at population scale are currently missing. Here, we computationally extracted hundreds of features describing single-cell based cell-cell interactions and cellular phenotypes from a large, published cohort of cyto-images of breast cancer patients. We applied these features to a neural-network based Cox-nnet survival model and obtained high accuracy in predicting patient survival in test data (Concordance Index > 0.8). We identified seven survival subtypes using the top survival features, which present distinct profiles of epithelial, immune, fibroblast cells, and their interactions. We identified atypical subpopulations of TNBC patients with moderate prognosis (marked by GATA3 over-expression) and Luminal A patients with poor prognosis (marked by KRT6 and ACTA2 over-expression and CDH1 under-expression). These atypical subpopulations are validated in TCGA-BRCA and METABRIC datasets. This work provides important guidelines on bridging single-cell level information towards population-level survival prediction.STATEMENT OF TRANSLATIONAL RELEVANCEOur findings from a breast cancer population cohort demonstrate the clinical utility of using the single-cell level imaging mass cytometry (IMC) data as a new type of patient prognosis prediction marker. Not only did the prognosis prediction achieve high accuracy with a Concordance index score greater than 0.8, it also enabled the discovery of seven survival subtypes that are more distinguishable than the molecular subtypes. These new subtypes present distinct profiles of epithelial, immune, fibroblast cells, and their interactions. Most importantly, this study identified and validated atypical subpopulations of TNBC patients with moderate prognosis (GATA3 over-expression) and Luminal A patients with poor prognosis (KRT6 and ACTA2 over-expression and CDH1 under-expression), using multiple large breast cancer cohorts.
NPC1variants are not associated with Parkinson’s Disease, REM-sleep behaviour disorder or Dementia with Lewy bodies in European cohorts
Authors: Somerville Emma N. , Krohn Lynne , Yu Eric , Rudakou Uladzislau , Senkevich Konstantin , Ruskey Jennifer A. , Asayesh Farnaz , Ahmad Jamil , Spiegelman Dan , Dauvilliers Yves , Arnulf Isabelle , Hu Michele T.M. , Montplaisir Jacques Y. , Gagnon Jean-François , Desautels Alex , Ibrahim Abubaker , Stefani Ambra , Hogl Birgit , Gigli Gian Luigi , Valente Mariarosaria , Janes Francesco , Bernardini Andrea , Dusek Petr , Sonka Karel , Kemlink David , Plazzi Giuseppe , Antelmi Elena , Biscarini Francesco , Mollenhauer Brit , Trenkwalder Claudia , Sixel-Doring Friederike , Figorilli Michela , Puligheddu Monica , De Cock Valerie Cochen , Ferini-Strambi Luigi , Heibreder Anna , Monaca Christelle Charley , Abril Beatriz , Dijkstra Femke , Viaene Mineke , Boeve Bradley F. , Postuma Ronald B. , Rouleau Guy A. , Gan-Or Ziv 
Published: November 2022

AbstractNPC1encodes a lysosomal protein involved in cholesterol transport. Biallelic mutations in this gene may lead to Nieman-Pick disease type C, a lysosomal storage disorder. The role ofNPC1in alpha synucleinopathies is still unclear, as different genetic, clinical, and pathological studies have reported contradictory results. This study aimed to evaluate the association ofNPC1variants with the synucleinopathies Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and rapid eye movement (REM)-sleep behavior disorder (RBD). We analyzed common and rare variants from three cohorts of European descent: 1,084 RBD cases and 2,945 controls, 2,852 PD cases and 1,686 controls, and 2,610 DLB cases and 1,920 controls. Logistic regression models were used to assess common variants while optimal sequence Kernel association tests (SKAT-O) were used to assess rare variants, both adjusted for sex, age, and principal components. No variants were associated with any of the synucleinopathies, supporting that common and rareNPC1variants do not play an important role in alpha synucleinopathies.