bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stochasticity in genetics and gene regulation
Authors: van Heyningen Veronica 
Published: March 2024

Development from fertilized egg to functioning multi-cellular organism requires precision. There is no precision, and often no survival, without plasticity. Plasticity is conferred partly by stochastic variation, present inherently in all biological systems. Gene expression levels fluctuate ubiquitously through transcription, alternative splicing, translation and turnover. Small differences in gene expression are exploited to trigger early differentiation, conferring distinct function on selected individual cells and setting in motion regulatory interactions. Non-selected cells then acquire new functions along the spatio-temporal developmental trajectory. The differentiation process has many stochastic components. Meiotic segregation, mitochondrial partitioning, X-inactivation and the dynamic DNA binding of transcription factor assemblies—all exhibit randomness. Non-random X-inactivation generally signals deleterious X-linked mutations. Correct neural wiring, such as retina to brain, arises through repeated confirmatory activity of connections made randomly. In immune system development, both B-cell antibody generation and the emergence of balanced T-cell categories begin through stochastic trial and error followed by functional selection. Aberrant selection processes lead to immune dysfunction. DNA sequence variants also arise through stochastic events: some involving environmental fluctuation (radiation or presence of pollutants), or genetic repair system malfunction. The phenotypic outcome of mutations is also fluid. Mutations may be advantageous in some circumstances, deleterious in others.
This article is part of a discussion meeting issue ‘Causes and consequences of stochastic processes in development and disease’.
Prevalence of hepatitis A virus among migrant workers in Qatar: A national study
Authors: Younes Nadin , Chemaitelly Hiam , Nizamuddin Parveen Banu , Al-Hamad Tasneem , Abdallah Marah , Yassine Hadi M , Abu-Raddad Laith J , Nasrallah Gheyath K. 
Published: March 2024

ABSTRACTBackgroundHepatitis A virus (HAV) is the predominant cause of acute viral hepatitis worldwide; however, data on HAV antibody prevalence (seroprevalence) among migrant populations are limited. This study aimed to investigate HAV seroprevalence among Qatar’s migrant craft and manual workers (CMWs), constituting approximately 60% of the country’s population.MethodsHAV antibody testing was conducted on stored serum specimens obtained from CMWs during a nationwide severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) population- based cross-sectional survey between July 26 and September 9, 2020. Associations with HAV infection were investigated through regression analyses.ResultsOf the 2,607 specimens with HAV antibody test results, 2,393 were positive, and 214 were negative. The estimated HAV seroprevalence among CMWs was 92.0% (95% CI: 90.9- 93.1%). HAV seroprevalence was generally high but exhibited some variation, ranging from 70.9% (95% CI: 62.4-78.2%) among Sri Lankans to 99.8% (95% CI: 98.2-99.9%) among Pakistanis. The multivariable regression analysis identified age, nationality, and educational attainment as statistically significant factors associated with HAV infection. Relative to CMWs aged ≤29 years, the adjusted relative risk (ARR) was 1.06 (95% CI: 1.03-1.10) in CMWs aged 30- 39 years and reached 1.15 (95% CI: 1.10-1.19) in those aged ≥50 years. In comparison to Indians, the ARR was lower among Sri Lankans, assessed at 0.81 (95% CI: 0.72-0.91), but higher among Nepalese at 1.07 (95% CI: 1.04-1.11), Bangladeshis at 1.10 (95% CI: 1.07-1.13), Pakistanis at 1.12 (95% CI: 1.09-1.15), and Egyptians at 1.15 (95% CI: 1.08-1.23). No evidence for differences was found by geographic location or occupation.ConclusionsHAV seroprevalence among Qatar’s CMW population is very high, with over nine out of every ten individuals having been exposed to this infection, likely during childhood.
IMPACT OF GEOSPATIAL FOOD ACCESS ON ACUTE PANCREATITIS OUTCOMES
Authors: Chhoda Ankit , Noriega Marco , Kahan Tamara , Cartelle Anabel Liyen , Anderson Kelsey , Zuberi Shaharyar A. , Olivares Miriam , Kelly Jill , Freedman Steven D. , Rabinowitz Loren G. , Sheth Sunil G. 
Published: March 2024

ABSTRACTBACKGROUND AND AIMFood access is an important social determinant of health and refers to geographical and infrastructural aspects of food availability. Using publicly available data on food access from the United States Department of Agriculture (USDA), geospatial analyses can identify regions with variable food access, which may impact acute pancreatitis (AP), an acute inflammatory condition characterized by unpredictable outcomes and substantial mortality. This study aimed to investigate the association of clinical outcomes in patients with AP with geospatial food access.METHODSWe examined AP-related hospitalizations at a tertiary center from January 2008 to December 2018. The physical addresses were geocoded through ArcGIS Pro2.7.0 (ESRI, Redlands, CA). USDA Food Access Research Atlas defined low food access as urban areas with 33% or more of the population residing over one mile from the nearest food source. Regression analyses enabled assessment of the association between AP outcomes and food access.RESULTSThe study included 772 unique patients with AP residing in Massachusetts with 931 AP-related hospitalizations. One hundred and ninety-eight (25.6%) patients resided in census tracts withnormalurban food access and 574 (74.4%) patients resided in tracts withlowfood access. AP severity per revised Atlanta classification [OR: 1.88 (95%CI: 1.21-2.92);p=0.005], and 30-day AP-related readmission [OR: 1.78(95%CI: 1.11-2.86);p=0.02] had significant association with food access, despite adjustment for demographics, healthcare behaviors, and comorbidities (Charlson Comorbidity Index). However, food access lacked significant association with AP-related mortality (p=0.40) and length of stay (LOS:p=0.99).CONCLUSIONLow food access had a significant association with 30-day AP-related readmissions and AP severity. However, mortality and LOS lacked significant association with food access. The association between nutrition, lifestyle, and AP outcomes warrants further prospective investigation.
Thymidine Phosphorylase Promotes the Formation of Abdominal Aortic Aneurysm in Mice Fed a Western Diet
Authors: Hong Liang , Yue Hong , Cai Dunpeng , DeHart Autumn , Toloza-Alvarez Gretel , Du Lili , Zhou Xianwu , Fan Xiaoping , Huang Huanlei , Chen Shiyou , Rahaman Shaik O. , Zhuang Jian , Li Wei 
Published: March 2024

AbstractAimsThe precise molecular drivers of abdominal aortic aneurysm (AAA) remain unclear. Thymidine phosphorylase (TYMP) contributes to increased platelet activation, thrombosis, and inflammation, all of which are key factors in AAA development. Additionally, TYMP suppresses the proliferation of vascular smooth muscle cells (VSMCs), which are central to the development and progression of AAA. We hypothesize that TYMP plays a key role in AAA development.Methods and ResultsWe conducted a histological study using human AAA samples and normal abdominal aortas, revealing heightened levels of TYMP in human AAA vessel walls. To validate this observation, we utilized an Ang II perfusion-induced AAA model in wild-type C57BL/6J (WT) andTymp−/−mice, feeding them a Western diet (TD.88137) starting from 4 weeks of age. We found thatTymp−/−mice were protected from Ang II perfusion-induced AAA formation. Furthermore, by using TYMP-expressing VSMCs as well as primarily cultured VSMCs from WT andTymp−/−mice, we elucidated the essential role of TYMP in regulating MMP2 expression and activation. TYMP deficiency or inhibition by tipiracil, a selective TYMP inhibitor, led to reduced MMP2 production, release, and activation in VSMCs. Additionally, TYMP was found to promote pro-inflammatory cytokine expression systemically, and its absence attenuates TNF-α-stimulated activation of MMP2 and AKT. By co-culturing VSMCs and platelets, we observed that TYMP-deficient platelets had a reduced inhibitory effect on VSMC proliferation compared to WT platelets. Moreover, TYMP appeared to enhance the expression of activated TGFβ1 in cultured VSMCs in vitro and in human AAA vessel walls in vivo. TYMP also boosted the activation of thrombospondin-1 type 1 repeat domain-enhanced TGFβ1 signaling, resulting in increased connective tissue growth factor production.ConclusionOur findings collectively demonstrated that TYMP serves as a novel regulatory force in vascular biology, exerting influence over VSMC functionality and inflammatory responses that promote the development of AAA.Translational PerspectiveThymidine phosphorylase (TYMP) is increased in the vessel walls of patients with abdominal aortic aneurysm (AAA), and TYMP deficiency in mice reduces the incidence of AAA, suggesting that TYMP plays a crucial role in AAA development. This could be attributed to TYMP’s role in enhancing systemic inflammation and thrombosis, inhibiting vascular smooth muscle cell function, increasing the activation of matrix metalloproteinase and AKT, as well as enhancing the expression of TGFβ1 and connective tissue growth factor. Tipiracil is an FDA-approved drug known to inhibit TYMP-enhanced thrombosis. Targeting TYMP with tipiracil could represent a promising new therapeutic strategy for AAA development.
The trade-off between grain weight and grain number in wheat is explained by the overlapping of the key phases determining these major yield components
Authors: Vicentin Lucas , Canales Javier , Calderini Daniel F. 
Published: March 2024

AbstractEnhancing grain yield is a primary goal in the cultivation of major staple crops, including wheat. Recent research has focused on identifying the physiological and molecular factors that influence grain weight, a critical determinant of crop yield. However, a bottleneck has arisen due to the trade-off between grain weight and grain number, whose underlying causes remain elusive. In a novel approach, a wheat expansin gene, TaExpA6, known for its expression in root tissues, was engineered to express in the grains of the spring wheat cultivar Fielder. This modification led to increases in both grain weight and yield without adversely affecting grain number. Conversely, a triple mutant line targeting the gene TaGW2, a known negative regulator of grain weight, resulted in increased grain weight but decreased grain number, potentially offsetting yield gains. This study aimed to evaluate four wheat genotypes: (i) a transgenic line expressing TaExpA6, (ii) its wild-type counterpart (Fielder), (iii) a TaGW2 triple mutant line, and (iv) its wild-type. Conducted in southern Chile, the study employed a Complete Randomized Block Design with four replications, under well-managed field conditions including fertilization, irrigation, and pest control. The primary metrics assessed were grain yield, grain number, and average grain weight per spike, along with detailed measurements of grain weight and dimensions across the spike, and ovary weight at pollination (Waddington’s scale 10). The expression levels of TaExpA6 and TaGW2 were also monitored post-anthesis. Results indicated that both the TaExpA6 line and the triple mutant line achieved significantly higher average grain weights compared to their respective wild types. Notably, the TaExpA6 line did not exhibit a reduction in grain number, thereby enhancing grain yield per spike. In contrast, the triple mutant line showed a reduced grain number per spike, with no significant change in overall yield. Analysis of ovary size, grain weight dynamics, and gene expression patterns suggests that the trade-off between grain weight and number could be attributed to the overlapping of the critical periods for the determination of these traits.
MMCCI: multimodal integrative analysis of single-cell and spatial cell-type communications to uncover overarching and condition-specific ligand-receptor interaction pathways
Authors: Hockey Levi , Mulay Onkar , Xiong Zherui , Tan Samuel X. , Khosrotehrani Kiarash , Nefzger Christian M. , Nguyen Quan 
Published: March 2024

AbstractCell-cell interaction (CCI) analyses are an indispensable tool for harnessing the detail and depth of spatial and single-cell transcriptomics datasets by inferring inter-cellular communications, but no methods to integrate CCI results across samples exist currently. To address this, we have developed a computational pipeline, Multimodal CCI (MMCCI), to statistically integrate and analyze CCI results from existing popular CCI tools. We benchmarked MMCCI’s integration on single-cell spatial datasets and found it to be highly accurate compared to simpler methods. We utilized MMCCI’s integration and downstream biological analyses to uncover global and differential interaction patterns in multimodal aging brain and melanoma spatial datasets.
HY5 and COP1 function antagonistically in the light-dependent regulation of nicotine biosynthesis in tobacco
Authors: Singh Deeksha , Dwivedi Shambhavi , Singh Nivedita , Trivedi Prabodh Kumar 
Published: March 2024

ABSTRACTNicotine constitutes approximately 90% of the total alkaloid content within theNicotianaspecies, rendering it the most prevalent alkaloid. While the majority of genes responsible for nicotine biosynthesis express in root tissue, the influence of light on this process through shoot-to-root mobile ELONGATED HYPOCOTYL 5 (HY5) has been recognized. CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1), a key regulator of light-associated responses, known for its role in modulating HY5 accumulation, remains largely unexplored in its relationship to light-dependent nicotine accumulation. Here, we identified NtCOP1, a COP1 homolog inNicotiana tabacum, and demonstrated its ability to complement thecop1mutant inArabidopsis thalianaat molecular, morphological, and biochemical levels. Through the development of NtCOP1 overexpression (NtCOP1OX) plants, we observed a significant reduction in nicotine and flavonol content, inversely correlated with the down-regulation of nicotine and phenylpropanoid pathway. Conversely, CRISPR/Cas9-based knockout mutant plants (NtCOP1CR) exhibited an increase in nicotine levels. Further investigations, including yeast-two hybrid assays, grafting experiments, and western blot analyses, revealed that NtCOP1 modulates nicotine biosynthesis by targeting NtHY5, thereby impeding its transport from shoot-to-root. We conclude that the interplay between HY5 and COP1 functions antagonistically in the light-dependent regulation of nicotine biosynthesis in tobacco.HighlightCharacterization of CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1) overexpressing and CRISPR/Cas9-based mutant plants suggests the intricate role of COP1 in modulating nicotine biosynthesis in tobacco.
Functional Specialization and Distributed Processing across Marmoset Lateral Prefrontal Subregions
Authors: Wong Raymond Ka , Selvanayagam Janahan , Johnston Kevin D , Everling Stefan 
Published: March 2024

AbstractA prominent aspect of the organization of primate lateral prefrontal cortex (lPFC) is its division into a number of cytoarchitecturally distinct subregions. Investigations in macaque lPFC using neurophysiological approaches have provided much insight into the functions associated with these subregions; however, our understanding is based largely on a patchwork of findings from many studies and across many animals, rarely covering the entire lPFC in individual subjects. Here, we leveraged the small size and lissencephalic cortex of the common marmoset (Callithrix jacchus) to characterize the responses of large numbers of single lPFC neurons to a diverse collection of test stimuli recorded across sets of lPFC subregions using high-density microelectrode arrays. Untethered extracellular electrophysiological recordings were obtained from two adult marmosets with 4 x 4 mm 96-channel Utah arrays implanted in lPFC, covering areas 8aD, 8aV, 9, 10, 46D, 46V and 47. We employed a test battery comprised of a variety of visual stimuli including faces and body parts, auditory stimuli including marmoset calls, and a spatial working memory task. Task-modulated units and units responsive to different stimulus modalities were distributed throughout the lPFC. Visual, auditory and call-selective units were distributed across all lPFC subregions. Neurons with contralateral visual receptive fields were found in 8aV and 8aD. Neurons responsive to faces and saccade-related units were found in 8aV, 8aD, 10, 46V and 47. These findings demonstrate that responses to some stimuli are relatively restricted within specific lPFC subregions, while others are more distributed throughout the marmoset lPFC.
Comparing cellular response to two radiation treatments based on key features visualization
Authors: Arsenteva Polina , Guipaud Olivier , Paget Vincent , Santos Morgane Dos , Tarlet Georges , Milliat Fabien , Cardot Hervé , Benadjaoud Mohamed Amine 
Published: March 2024

AbstractMotivationIn modern treatment by radiotherapy, different irradiation modalities can be used, potentially producing different amounts of adverse effects. The differences between these modalities are often studied via two-sample time course in vitro experiments. The resulting data may be of high complexity, in which case simple methods are unadapted for extracting all the relevant information.MethodsIn this article we introduce network-based tools for the visualization of the key statistical features, extracted from the data. For the key features extraction we utilize a statistical framework performing estimation, clustering with alignment of temporal omic fold changes originating from two-sample time course data.ResultsThe approach was applied to real transcriptomic data obtained with two different types of irradiation. The results were analyzed using biological literature and enrichment analysis, thus validating the robustness of the proposed tools as well as achieving better understanding of the differences in the impact of the treatments in question.Availability and implementationPython package freely available here:https://github.com/parsenteva/scanofc.Contactpolina.arsenteva@u-bourgogne.fr
Assessing the Effects of Various Physiological Signal Modalities on Predicting Different Human Cognitive States
Authors: Aygun Ayca , Nguyen Thuan , Scheutz Matthias 
Published: March 2024

AbstractRobust estimation of systemic human cognitive states is critical for a variety of applications, from simply detecting inefficiencies in task assignments, to the adaptation of artificial agents’ behaviors to improve team performance in mixed-initiative human-machine teams. This study showed that human eye gaze, in particular, the percentage change in pupil size (PCPS), is the most reliable biomarker for assessing three human cognitive states including workload, sense of urgency, and mind wandering compared to electroencephalogram (EEG), functional near-infrared spectroscopy (fNIRS), respiration, and skin conductance. We used comprehensive multi-modal driving dataset to examine the accuracy of signals to assess these cognitive states. We performed comprehensive statistical tests to validate the performance of several physiological signals to determine human cognitive states and demonstrated that PCPS shows noticeably superior performance. We also characterized the link between workload and sense of urgency with eye gaze and observed that consecutive occurrences of higher sense of urgency were prone to increase overall workload. Finally, we trained five machine learning (ML) models and showed that four of them had similar accuracy in cognitive state classification (with one, random forest, showing inferior performance). The results provided evidence that the PCPS is a reliable physiological marker for cognitive state estimation.
Noise leads to the perceived increase in evolutionary rates over short time scales
Authors: O’Meara Brian C. , Beaulieu Jeremy M. 
Published: March 2024

AbstractAcross a variety of biological datasets, from genomes to conservation to the fossil record, evolutionary rates appear to increase toward the present or over short time scales. This has long been seen as an indication of processes operating differently at different time scales, even potentially as an indicator of a need for new theory connecting macroevolution and microevolution. Here we introduce a set of models that assess the relationship between rate and time and demonstrate that these patterns are statistical artifacts of time-independent errors present across ecological and evolutionary datasets, which produce hyperbolic patterns of rates through time. We show that plotting a noisy numerator divided by time versus time leads to the observed hyperbolic pattern; in fact, randomizing the amount of change over time generates patterns functionally identical to observed patterns. Ignoring errors can not only obscure true patterns but create novel patterns that have long misled scientists.
Alpha-synuclein regulates the repair of genomic DNA double-strand breaks in a DNA-PKcs-dependent manner
Authors: Rose Elizabeth P. , Osterberg Valerie R. , Banga Jovin S. , Gorbunova Vera , Unni Vivek K. 
Published: March 2024

Abstractα-synuclein (αSyn) is a presynaptic and nuclear protein that aggregates in important neurodegenerative diseases such as Parkinson’s Disease (PD), Parkinson’s Disease Dementia (PDD) and Lewy Body Dementia (LBD). Our past work suggests that nuclear αSyn may regulate forms of DNA double-strand break (DSB) repair in HAP1 cells after DNA damage induction with the chemotherapeutic agent bleomycin1. Here, we report that genetic deletion of αSyn specifically impairs the non-homologous end-joining (NHEJ) pathway of DSB repair using an extrachromosomal plasmid-based repair assay in HAP1 cells. Importantly, induction of a single DSB at a precise genomic location using a CRISPR/Cas9 lentiviral approach also showed the importance of αSyn in regulating NHEJ in HAP1 cells and primary mouse cortical neuron cultures. This modulation of DSB repair is dependent on the activity of the DNA damage response signaling kinase DNA-PKcs, since the effect of αSyn loss-of-function is reversed by DNA-PKcsinhibition. Usingin vivomultiphoton imaging in mouse cortex after induction of αSyn pathology, we find an increase in longitudinal cell survival of inclusion-bearing neurons after Polo-like kinase (PLK) inhibition, which is associated with an increase in the amount of aggregated αSyn within inclusions. Together, these findings suggest that αSyn plays an important physiologic role in regulating DSB repair in both a transformed cell line and in primary cortical neurons. Loss of this nuclear function may contribute to the neuronal genomic instability detected in PD, PDD and DLB and points to DNA-PKcsand PLK as potential therapeutic targets.
Prioritizing replay when future goals are unknown
Authors: Sagiv Yotam , Akam Thomas , Witten Ilana B. , Daw Nathaniel D. 
Published: March 2024

AbstractAlthough hippocampal place cells replay nonlocal trajectories, the computational function of these events remains controversial. One hypothesis, formalized in a prominent reinforcement learning account, holds that replay plans routes to current goals. However, recent puzzling data appear to contradict this perspective by showing that replayed destinations lag current goals. These results may support an alternative hypothesis that replay updates route information to build a “cognitive map.” Yet no similar theory exists to formalize this view, and it is unclear how such a map is represented or what role replay plays in computing it. We address these gaps by introducing a theory of replay that learns a map of routes to candidate goals, before reward is available or when its location may change. Our work extends the planning account to capture a general map-building function for replay, reconciling it with data, and revealing an unexpected relationship between the seemingly distinct hypotheses.