bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selection shapes the genomic landscape of introgressed ancestry in a pair of sympatric sea urchin species
Authors: Glasenapp Matthew R. , Pogson Grant H. 
Published: December 2023

AbstractA growing number of recent studies have demonstrated that introgression is common across the tree of life. However, we still have a limited understanding of the fate and fitness consequence of introgressed variation at the whole-genome scale across diverse taxonomic groups. Here, we implemented a phylogenetic hidden Markov model to identify and characterize introgressed genomic regions in a pair of well-diverged, non-sister sea urchin species:Strongylocentrotus pallidusandS. droebachiensis. Despite the old age of introgression, a sizable fraction of the genome (1% - 5%) exhibited introgressed ancestry, including numerous genes showing signals of historical positive selection that may represent cases of adaptive introgression. One striking result was the overrepresentation of hyalin genes in the identified introgressed regions despite observing considerable overall evidence of selection against introgression. There was a negative correlation between introgression and chromosome gene density, and two chromosomes were observed with considerably reduced introgression. Relative to the non-introgressed genome-wide background, introgressed regions had significantly reduced nucleotide divergence (dXY) and overlapped fewer protein-coding genes, coding bases, and genes with a history of positive selection. Additionally, genes residing within introgressed regions showed slower rates of evolution (dN,dS,dN/dS) than random samples of genes without introgressed ancestry. Overall, our findings are consistent with widespread selection against introgressed ancestry across the genome and suggest that slowly evolving, low-divergence genomic regions are more likely to move between species and avoid negative selection following hybridization and introgression.
Molecular dynamics simulations provide insights into ULK-101 potency and selectivity toward autophagic kinases ULK1/2
Authors: Vaughan Robert M. , Dickson Bradley M. , Martin Katie R. , MacKeigan Jeffrey P. 
Published: December 2023

AbstractKinase domains are highly conserved within protein kinases in both sequence and structure. Many factors, including phosphorylation, amino acid substitutions or mutations, and small molecule inhibitor binding, influence conformations of the kinase domain and enzymatic activity. The serine/threonine kinases ULK1 and ULK2 are highly conserved with N- and C-terminal domains, phosphate-binding P-loops, -αC-helix, regulatory and catalytic spines, and activation loop DFG and APE motifs. Here, we performed molecular dynamics (MD) simulations to understand better the potency and selectivity of the ULK1/2 small molecule inhibitor, ULK-101. We observed stable bound states for ULK-101 to the adenosine triphosphate (ATP)-binding site of ULK2, coordinated by hydrogen bonding with the hinge backbone and the catalytic lysine sidechain. Notably, ULK-101 occupies a hydrophobic pocket associated with the N-terminus of the -αC-helix. Large movements in the P-loop are also associated with ULK-101 inhibitor binding and exit from ULK2. Our data further suggests that ULK-101 could induce a folded P-loop conformation and hydrophobic pocket reflected in its nanomolar potency and kinome selectivity.
Epistemic uncertainty challenges aging clock reliability in predicting rejuvenation effects
Authors: Kriukov Dmitrii , Kuzmina Ekaterina , Efimov Evgeniy , Dylov Dmitry V. , Khrameeva Ekaterina E. 
Published: December 2023

AbstractEpigenetic aging clocks have been widely used to validate rejuvenation effects during cellular reprogramming. However, these predictions are unverifiable because the true biological age of reprogrammed cells remains unknown. We present an analytical framework to consider rejuvenation predictions from the uncertainty perspective. Our analysis reveals that the DNA methylation profiles across reprogramming are poorly represented in the aging data used to train clock models, thus introducing high epistemic uncertainty in age estimations. Moreover, predictions of different published clocks are inconsistent, with some even suggesting zero or negative rejuvenation. While not questioning the possibility of age reversal, we show that the high clock uncertainty challenges the reliability of rejuvenation effects observed during in vitro reprogramming before pluripotency and throughout embryogenesis. Conversely, our method reveals a significant age increase after in vivo reprogramming. We recommend including uncertainty estimation in future aging clock models to avoid the risk of misinterpreting the results of biological age prediction.
Breathing in sync: how a social behavior structures respiratory epidemic risk in bottlenose dolphins
Authors: Collier Melissa A. , Jacoby Ann-Marie , Foroughirad Vivienne , Patterson Eric M. , Krzyszczyk Ewa , Wallen Megan , Miketa Madison , Karniski Caitlin , Wilkin Sarah , Mann Janet , Bansal Shweta 
Published: December 2023

AbstractDolphin morbillivirus has caused mass mortalities in dolphin populations globally. Given their role as ecosystem sentinels, mass mortalities among these populations can be detrimental. Morbillivirus is transmitted through respiratory droplets and occurs when dolphins breathe synchronously, a variable social behavior. To assess the role of variable social behavior on disease risk empirically, we collected behavioral data from two wild bottlenose dolphins populations (Tursiopsspp.), developed network models that synthesize transmission contacts, and used an epidemiological model to predict disease consequences. We find that juveniles have more contacts than adults, adult males have more contacts than adult females, and that individuals preferentially contact others in their own demographic group. These patterns translate to higher infection risk for juveniles and adult males, which we support using data from a morbillivirus outbreak. Our work characterizes the impact of bottlenose dolphin social dynamics on infectious disease risk and informs the structure of vulnerability for future epizootics.
Functional network collapse in neurodegenerative disease
Authors: Brown Jesse A. , Lee Alex J. , Fernhoff Kristen , Pistone Taylor , Pasquini Lorenzo , Wise Amy B. , Staffaroni Adam M. , Mandelli Maria Luisa , Lee Suzee E. , Boxer Adam L. , Rankin Katherine P. , Rabinovici Gil D. , Tempini Maria Luisa Gorno , Rosen Howard J. , Kramer Joel H. , Miller Bruce L. , Seeley William W. ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: December 2023

AbstractCognitive and behavioral deficits in Alzheimer’s disease (AD) and frontotemporal dementia (FTD) result from brain atrophy and altered functional connectivity. However, it is unclear how atrophy relates to functional connectivity disruptions across dementia subtypes and stages. We addressed this question using structural and functional MRI from 221 patients with AD (n=82), behavioral variant FTD (n=41), corticobasal syndrome (n=27), nonfluent (n=34) and semantic (n=37) variant primary progressive aphasia, and 100 cognitively normal individuals. Using partial least squares regression, we identified three principal structure-function components. The first component showed overall atrophy correlating with primary cortical hypo-connectivity and subcortical/association cortical hyper-connectivity. Components two and three linked focal syndrome-specific atrophy to peri-lesional hypo-connectivity and distal hyper-connectivity. Structural and functional component scores predicted global and domain-specific cognitive deficits. Anatomically, functional connectivity changes reflected alterations in specific brain activity gradients. Eigenmode analysis identified temporal phase and amplitude collapse as an explanation for atrophy-driven functional connectivity changes.
Optimizing PCR using mtDNA Universal Primers for Detecting Indigenous Domestic Animal Species from Pakistan
Authors: Saeed Hafiza Iqra , Suhail Mashmoom , Gill Sehreem , Saif Rashid 
Published: December 2023

AbstractThe prevalence of specific animal meat consumption is integral to human nutrition but is jeopardized by the widespread issue of meat adulteration, posing threats to both the industry and consumer health. Escalating demand has led to fraudulent practices, necessitating reliable techniques for authentic source identification, aligning with ethical and religious principles. PCR has proven effective in addressing this concern by examining twelve domestic animal species in Pakistan, differentiating between halal and haram species. The method employs universal primers for 16S rRNA gene amplification, generating species-specific DNA fragments. This sophisticated approach, producing distinct fragments for cow, camel, goat, sheep, chicken, cat, dog, donkey, duck, rabbit, horse, and human with 507, 385, 787, 763, 470, 700, 370, 600, 500, 750, 800 and 300bp holds promise for identifying and tracing these species in commercial meat products. By ensuring robust food traceability, this methodology combats contemporary challenges in adulteration, preserving the integrity of the food supply chain.
Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics
Authors: Dulyayangkul Punyawee , Beavis Thomas , Lee Winnie WY , Ardagh Robbie , Edwards Frances , Hamilton Fergus , Head Ian , Heesom Kate J. , Mounsey Oliver , Murarik Marek , Reding Carlos , Satapoomin Naphat , Shaw John M. , Takebayashi Yuiko , Tooke Catherine L. , Spencer James , Williams Philip B. , Avison Matthew B. 
Published: December 2023

AbstractAmikacin and piperacillin/tazobactam are frequent antibiotic choices to treat bloodstream infection, which is commonly fatal and most often caused by bacteria from the familyEnterobacterales. Here we show that two gene cassettes located side-by-side in and ancestral integron similar to In37have been “harvested” by insertion sequence IS26as a transposon that is already globally disseminated among theEnterobacterales. This transposon encodes the enzymes AAC(6’)-Ib-cr and OXA-1, reported, respectively, as amikacin and piperacillin/tazobactam resistance mechanisms. However, by studying bloodstream infection isolates from 769 patients from, three hospitals serving a population of 1.5 million people in South West England, we show that increased enzyme production due to mutation in an IS26/In37-derived hybrid promoter or, more commonly, transposon copy number amplification is required to simultaneously remove these two key therapeutic options; in many cases leaving only the last-resort antibiotic, meropenem. These findings may help improve the accuracy of predicting piperacillin/tazobactam treatment failure, allowing stratification of patients to receive meropenem or piperacillin/tazobactam, which may improve outcome and slow the emergence of meropenem resistance.
Deep Learning-based structural and functional annotation of Pandoravirus hypothetical proteins
Authors: Horder Joseph L. , Connor Abbie J. , Duggan Amy L. , Hale Joshua J. , McDermott Frederick J. , Norris Luke E. , Whinney Sophie J.D. , Mesdaghi Shahram , Murphy David L. , Simpkin Adam J. , Mello Luciane V. , Rigden Daniel J. 
Published: December 2023

AbstractGiant viruses, including Pandoraviruses, contain large amounts of genomic ‘dark matter’ - genes encoding proteins of unknown function. New generation, deep learning-based protein structure modelling offers new opportunities to apply structure-based function inference to these sequences, often labelled as hypothetical proteins. However, the AlphaFold Protein Structure Database, a convenient resource covering the majority of UniProt, currently lacks models for most viral proteins. Here, we apply a panoply of predictive methods to protein structure predictions representative of large clusters of hypothetical proteins shared among four Pandoraviruses. In several cases, strong functional predictions can be made. Thus, we identify a likely nucleotidyltransferase putatively involved in viral tRNA maturation that has a BTB domain presumably involved in protein-protein interactions. We further identify a cluster of membrane channel sequences presenting three paralogous families which may, as seen in other giant viruses, induce host cell membrane depolarization. And we identify homologues of calcium-activated potassium channel beta subunits and pinpoint their likely Acanthamoeba cellular alpha subunit counterparts. Despite these successes, many other clusters remain cryptic, having folds that are either too functionally promiscuous or too novel to provide strong clues as to their role. These results suggest that significant structural and functional novelty remains to be uncovered in the giant virus proteomes.
Tracer-based metabolomics for profiling nitric oxide metabolites in a 3D microvessel-on-a-chip model
Authors: Pandian Kanchana , Huang Luojiao , Junaid Abidemi , Harms Amy , van Zonneveld Anton Jan , Hankemeier Thomas 
Published: December 2023

AbstractEndothelial dysfunction is a common denominator in cardiovascular diseases (CVDs) associated with diabetes, hypertension, obesity, renal failure or hypercholesterolemia. In these disease states, circulating adverse metabolic or hemostatic risk factors drive the progression of inflammation, thrombosis, platelet activation and atherosclerosis. A hallmark of endothelial dysfunction is the reduced bioavailability of nitric oxide (NO), a signaling molecule essential for vascular homeostasis. Numerous studies have focused on NO synthesis by endothelial cells (ECs) usingin vitrocultures to understand the pathophysiology of endothelial dysfunction. A limitation of these studies is that the expression of the NO-generating enzyme, endothelial nitric oxide synthase (eNOS), in physiological conditions is modulated by the exposure of the ECs to laminar shear stress, a stimulus that is clearly lacking in most two-dimensional (2D) cultures.Here we developed a tracer-based metabolomics approach to measure NO-specific metabolites with mass spectrometry (MS) and show the impact of unidirectional fluid flow on metabolic parameters associated with NO synthesis using 2D and three-dimensional (3D) platforms. Specifically, we tracked the conversion of stable-isotope labeled NO substrate L-Arginine to L-Citrulline and L-Ornithine to determine eNOS activity. We demonstrated that when human coronary artery endothelial cells (HCAECs) cultured in media containing13C6,15N4-L-Arginine treated with eNOS stimulator – vascular endothelial growth factor (VEGF), eNOS inhibitor – L-NAME and arginase inhibitor - S-(2- boronoethyl)-L-cysteine (BEC), their downstream metabolites -13C6,15N3L-Citrulline and13C5,15N2L- Ornithine showed clear responses as measured using Ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). In this study, we also assessed the NO metabolic status of a static 2D culture, a 3D microvessel model with bidirectional flow, and our 3D model with unidirectional fluid flow generated by a microfluidic pump. Compared to 2D culture, our 3D model showed significant effects in the control and microvessels exposed to VEGF when Citrulline/Ornithine ratio was analyzed. The obtained result indicates that the 2D static culture mimics more endothelial dysfunction status. Our detection method and 3D model with a unidirectional fluid flow provides a more representative physiological environment that exhibits perfect model to study endothelial dysfunction.
Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma
Authors: Wasko Urszula N. , Jiang Jingjing , Curiel-Garcia Alvaro , Wang Yingyun , Lee Bianca , Orlen Margo , Drizyte-Miller Kristina , Menard Marie , Dilly Julien , Sastra Stephen A. , Palermo Carmine F. , Dalton Tanner , Hasselluhn Marie C. , Decker-Farrell Amanda R. , Chang Stephanie , Jiang Lingyan , Wei Xing , Yang Yu C. , Helland Ciara , Courtney Haley , Gindin Yevgeniy , Zhao Ruiping , Kemp Samantha B. , Clendenin Cynthia , Sor Rina , Vostrejs Will , Amparo Amber A. , Hibshman Priya S. , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Bakir Basil , Badgley Michael A. , Chabot John A. , Kluger Michael D. , Manji Gulam A. , Quintana Elsa , Wang Zhengping , Smith Jacqueline A. M. , Holderfield Matthew , Wildes David , Aguirre Andrew J. , Der Channing J. , Vonderheide Robert H. , Stanger Ben Z. , Singh Mallika , Olive Kenneth P. 
Published: December 2023

SummaryBroad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations inKRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-toleratedin vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.
Democratizing computational pathology: optimized Whole Slide Image representations for The Cancer Genome Atlas
Authors: Lazard Tristan , Lerousseau Marvin , Gardrat Sophie , Vincent-Salomon Anne , Stern Marc-Henri , Rodrigues Manuel , Decencière Etienne , Walter Thomas 
Published: December 2023

AbstractAutomatic analysis of hematoxylin and eosin (H&E) stained Whole Slide Images (WSI) bears great promise for computer assisted diagnosis and biomarker discovery. However, scarcity of annotated datasets leads to underperforming models. Furthermore, the size and complexity of the image data limit their integration into bioinformatic workflows and thus their adoption by the bioinformatics community. Here, we present Giga-SSL, a self-supervised method for learning WSI representations without any annotation. We show that applying a simple linear classifier on the Giga-SSL representations improves classification performance over the fully supervised alternative on five benchmarked tasks and across different datasets. Moreover, we observe a substantial performance increase for small datasets (average gain of 7 AUC point) and a doubling of the number of mutations predictable from WSIs in a pan-cancer setting (from 45 to 93). We make the WSI representations available, compressing the TCGA-FFPE images from 12TB to 23MB and enabling fast analysis on a laptop CPU. We hope this resource will facilitate multimodal data integration in order to analyze WSI in their genomic and transcriptomic context.
The picturesque roots of impression management: framing, Claude glass and “rose”-tinted lens?
Authors: McBride Karen , Atkins Jill Frances , Atkins Barry Colin 
Published: December 2023

PurposeThis paper explores the way in which industrial pollution has been expressed in the narrative accounts of nature, landscape and industry by William Gilpin in his 18th-century picturesque travel writings. A positive description of pollution is generally outdated and unacceptable in the current society. The authors contrast his “picturesque” view with the contemporary perception of industrial pollution, reflect on these early accounts of industrial impacts as representing the roots of impression management and use the analysis to inform current accounting.Design/methodology/approachThe research uses an interpretive content analysis of the text to draw out themes and features of impression management. Goffman's impression management is the theoretical lens through which Gilpin's travel accounts are interpreted, considering this microhistory through a thematic research approach. The picturesque accounts are explored with reference to the context of impression management.FindingsGilpin's travel writings and the “Picturesque” aesthetic movement, it appears, constructed a social reality around negative industrial externalities such as air pollution and indeed around humans' impact on nature, through a lens which described pollution as adding aesthetically to the natural landscape. The lens through which the picturesque tourist viewed and expressed negative externalities involved quite literally the tourists' tricks of the trade, Claude glass, called also Gray's glass, a tinted lens to frame the view.Originality/valueThe paper adds to the wealth of literature in accounting and business pertaining to the ways in which companies socially construct reality through their accounts and links closely to the impression management literature in accounting. There is also a body of literature relating to the use of images and photographs in published corporate reports, which again is linked to impression management as well as to a growing literature exploring the potential for the aesthetic influence in accounting and corporate communication. Further, this paper contributes to the growing body of research into the historical roots of environmental reporting.
A framework for consumers' assessments of location-based advertising (LBA) and selective exposure to privacy-related online information
Authors: Ryu Sann 
Published: December 2023

PurposeThe purpose of the current research is to present an explanatory framework for how people selectively attend to privacy-related news information about LBA depending on the extent to which they know about LBA already as well as their appraisals of privacy threats and efficacy.Design/methodology/approachThe proposed model was tested using structural equation modeling based on a total of 522 useable responses obtained from an online survey.FindingsThe results revealed two different approaches to information exposure: (1) people choose to seek out privacy-related news articles when their persuasion knowledge and perceived threat level are high, whereas (2) they tend to avoid such information when perceived threats accompany fear as well as psychological discomfort, or when they believe that they are knowledgeable about LBA practices and highly capable of protecting their privacy.Originality/valueWith the development of real-time location-tracking technologies, the practice of LBA is becoming increasingly popular. As such, however, concerns about data collection and privacy are also on the rise, garnering a great deal of media attention. Despite the importance and constant stream of news reports on the subject, a comprehensive understanding of consumers' privacy assessments and information consumption remains underexamined. By incorporating the persuasion knowledge model and extended parallel process model, the current research presents an explanatory framework for consumers' privacy perceptions and information choice.