bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study design and the sampling of deleterious rare variants in biobank-scale datasets
Authors: Steiner Margaret C. , Rice Daniel P. , Biddanda Arjun , Ianni-Ravn Mariadaria K. , Porras Christian , Novembre John 
Published: December 2024

AbstractOne key component of study design in population genetics is the “geographic breadth” of a sample (i.e., how broad a region across which individuals are sampled). How the geographic breadth of a sample impacts observations of rare, deleterious variants is unclear, even though such variants are of particular interest for biomedical and evolutionary applications. Here, in order to gain insight into the effects of sample design on ascertained genetic variants, we formulate a stochastic model of dispersal, genetic drift, selection, mutation, and geographically concentrated sampling. We use this model to understand the effects of the geographic breadth of sampling effort on the discovery of negatively selected variants. We find that samples which are more geographically broad will discover a greater number variants as compared geographically narrow samples (an effect we label “discovery”); though the variants will be detected at lower average frequency than in narrow samples (e.g. as singletons, an effect we label “dilution”). Importantly, these effects are amplified for larger sample sizes and moderated by the magnitude of fitness effects. We validate these results using both population genetic simulations and empirical analyses in the UK Biobank. Our results are particularly important in two contexts: the association of large-effect rare variants with particular phenotypes and the inference of negative selection from allele frequency data. Overall, our findings emphasize the importance of considering geographic breadth when designing and carrying out genetic studies, especially at biobank scale.SignificanceAs genetic studies grow, researchers are increasingly seeking to identify rare genetic variants with large impacts on traits. In this paper, we combine theoretical methods and data analysis to show how differences in sampling with respect to geographic location can influence the number and frequency of genetic variants that are found. Our results suggest that geographically broad samples will include more distinct genetic variants, though each variant will be found at a lower frequency, as compared to geographically narrow samples. Our results can help researchers to consider the implications of study design on expected results when constructing new genetic samples.
Early-life adversity alters adult nucleus incertus neurons: implications for neuronal mechanisms of increased stress and compulsive behavior vulnerability
Authors: Gugula Anna , Sambak Patryk , Trenk Aleksandra , Drabik Sylwia , Nogaj Aleksandra , Soltys Zbigniew , Gundlach Andrew L. , Blasiak Anna 
Published: December 2024

ABSTRACTBACKGROUNDEarly-life stress (ELS) arising from physical and emotional abuse disrupts normal brain development and impairs hypothalamic-pituitary-adrenal axis function, increasing the risk of psychopathological disorders and compulsive behaviors in adulthood. However, the underlying neural mechanisms remain unclear. The brainstem nucleus incertus (NI) is a highly stress-sensitive locus, involved in behavioral activation and stress-induced reward (food/alcohol) seeking, but its sensitivity to ELS remains unexplored.METHODSWe used neonatal maternal separation stress in rats as a model for ELS and examined its impact on stress-related mRNA and neuropeptide expression in the NI, using fluorescentin situhybridization and immunohistochemistry, respectively. Using whole-cell, patch-clamp recordings we determined the influence of ELS on the synaptic activity, excitability, and electrophysiological properties of NI neurons. Using c-Fos protein expression we also assessed the impact of ELS on the sensitivity of NI neurons to acute restraint stress in adulthood.RESULTSELS weakened the acute stress responsiveness of NI neurons, and caused dendritic shrinkage, impaired synaptic transmission and altered electrophysiological properties of NI neurons in a cell-type-specific manner. Additionally, ELS increased the expression of mRNA encoding corticotropin-releasing hormone receptor type 1 and the nerve-growth factor receptor, TrkA in adult NI.CONCLUSIONSThe multiple, cell-type specific changes in the expression of neuropeptides and molecules associated with stress and substance abuse in the NI, as well as impairments in NI neuron morphology and electrophysiology caused by early-life stress and observed in the adult brain, may contribute to the increased susceptibility to stress and compulsive behaviors observed in individuals with a history of ELS.
Effect of network structure and adaptive foraging on pollination services of species-rich plant-pollinator communities
Authors: Valdovinos Fernanda S. 
Published: December 2024

AbstractNetwork science has had a great impact on ecology by providing tools to characterize the structure of species interactions in communities and evaluate the effect of such network structure on community dynamics. This has been particularly the case for the study of plant-pollinator communities, which has experienced a tremendous growth with the adoption of network analyses. Here, I build on such body of research to evaluate how network structure and adaptive foraging of pollinators affect ecosystem services of plant-pollinator communities. Specifically, I quantify — using model simulations — pollen deposition in networks that exhibit structures like the ones of empirical networks (hereafter empirically connected networks) and those with higher connectance and lower nestedness than empirical networks, for scenarios where pollinators are fixed foragers and scenarios where they are adaptive foragers. I found that empirically connected networks with adaptive foraging exhibit the highest pollen deposition rate. Increased network connectance reduces pollen deposition as increased number of interactions lead to greater conspecific pollen dilution in the absence of other mechanisms such as pollinator floral constancy. High nestedness in moderately connected networks increases the proportion of pollinators visiting only one or two plant species, which are associated with the highest quality visits. Adaptive foraging allows pollinators to quantitatively specialize on specialist plant species which increases conspecific pollen deposition. This research advances pollination biology by elucidating how population dynamics, consumer-resource interactions, adaptive foraging, and network structure affects pollen deposition in a network context.
Anapc5andAnapc7as genetic modifiers of KIF18A function in fertility and mitotic progression
Authors: Nesbit Carleigh , Martin Whitney , Czechanski Anne , Byers Candice , Raghupathy Narayanan , Ferraj Ardian , Stumpff Jason , Reinholdt Laura 
Published: December 2024

ABSTRACTThe kinesin family member 18A (KIF18A) is an essential regulator of microtubule dynamics and chromosome alignment during mitosis. Functional dependency on KIF18A varies by cell type and genetic context but the heritable factors that influence this dependency remain unknown. To address this, we took advantage of the variable penetrance observed in different mouse strain backgrounds to screen for loci that modulate germ cell depletion in the absence of KIF18A. We found a significant association at a Chr5 locus where anaphase promoting complex subunits 5 (Anapc5) and 7 (Anapc7) were the top candidate genes. We found that both genes were differentially expressed in a sensitive strain background when compared to resistant strain background at key timepoints in gonadal development. We also identified a novel retroviral insertion inAnapc7that may in part explain the observed expression differences. In cell line models, we found that depletion of KIF18A induced mitotic arrest, which was partially rescued by co-depletion of ANAPC7 (APC7) and exacerbated by co-depletion of ANAPC5 (APC5). These findings suggest that differential expression and activity ofAnapc5andAnapc7may influence sensitivity to KIF18A depletion in germ cells and CIN cells, with potential implications for optimizing antineoplastic therapies.
Pirin does not bind to p65 or regulate NFκB-dependent gene expression but does modulate cellular quercetin levels
Authors: Meschkewitz Melissa , Lisabeth Erika M , Cab-Gomez A. Denaly , Leipprandt Jeffrey , Neubig Richard R 
Published: December 2024

AbstractPirin is a non-heme iron binding protein with a variety of proposed functions including serving as a co-activator of p65 NFκB and quercetinase activity. We report here, failure to confirm pirin’s primary proposed mechanism, binding of Fe(III)-pirin and p65. Analytical size exclusion chromatography (SEC) and fluorescence polarization (FP) studies did not detect an interaction. We also found no effects of pirin on TNFα-activated p65-regulated gene transcription using mouse embryonic fibroblasts (MEFs) from a pirin knockout mouse and a pirin knockdown NIH3T3 fibroblast cell line. TNFα - activated p65 response gene mRNA was neither increased nor decreased in cells with loss of pirin compared to wildtype cells. Furthermore, pirin immunofluorescence in NIH3T3 fibroblasts showed primarily a cytoplasmic localization, not nuclear as in most previous studies. This was confirmed by cell fractionation analysis. Pirin did show colocalization with the endoplasmic reticulum (ER) marker protein disulfide-isomerase (PDI) as well as cyotoplasmic labeling. We confirmed pirin’s quercetinase activity in biochemical assays and demonstrated competitive inhibition by the pirin inhibitor CCG-257081. Cellular quercetin levels in cells exposed to quercetinin vitrowere increased by knockdown of pirin or by treatment with pirin inhibitors. Since pirin is localized to ER and flavanols are protective of ER stress, we investigated whether pirin knockdown altered ER stress signaling but did not find any effect of pirin knockdown on ER stress response genes. Our results challenge the dominant model of pirin’s function (NFκB regulation) but confirm its quercetinase activity with implications for the mechanisms of pirin binding small molecules.Significance StatementPirin has multiple proposed functions and plays an important role in cancer (melanoma, colon, and breast) and inflammatory diseases. Small molecule pirin-binding compounds have been identified but pirin’s functional mechanism remains poorly understood. We raise doubts about the primary description of pirin as a nuclear regulator of p65 NFκB function but validate pirin’s role as a quercetinase. We show that pirin-binding compounds can raise cellular quercetin levels. Further studies will be required to fully understand pirin’s biological mechanisms.
Regulated resource reallocation is transcriptionally hard wired into the yeast stress response
Authors: Kocik Rachel A. , Gasch Audrey P. 
Published: December 2024

ABSTRACTMany organisms maintain generalized stress responses activated by adverse conditions. Although details vary, a common theme is the redirection of transcriptional and translational capacity away from growth-promoting genes and toward defense genes. Yet the precise roles of these coupled programs are difficult to dissect. Here we investigatedSaccharomyces cerevisiaeresponding to salt as a model stressor. We used molecular, genomic, and single-cell microfluidic methods to examine the interplay between transcription factors Msn2 and Msn4 that induce stress-defense genes and Dot6 and Tod6 that transiently repress growth-promoting genes during stress. Surprisingly, loss of Dot6/Tod6 led to slower acclimation to salt, whereas loss of Msn2/4 produced faster growth during stress. This supports a model where transient repression of growth-promoting genes accelerates the Msn2/4 response, which is essential for acquisition of subsequent peroxide tolerance. Remarkably, we find that Msn2/4 regulateDOT6mRNA production, influence Dot6 activation dynamics, and are required for full repression of growth-promoting genes. Thus, Msn2/4 directly regulate resource reallocation needed to mount their own response. We discuss broader implications for common stress responses across organisms.SYNOPSISThis study investigates how genes induced and repressed in the yeast Environmental Stress Response contribute to stress tolerance, growth rate, and resource allocation. The work uses molecular, genomic, and systems biology approaches to present new insights into eukaryotic responses to acute stress.HIGHLIGHTSCells lacking stress-activated transcription factors have a faster post-stress growth rateCells lacking repressors of growth-promoting genes have a slower post-stress growth rateStress-defense factors control the induction of growth-promoting gene repressors, thereby coordinating the resource re-allocation needed for the response
Chemically Induced Nuclear Pore Complex Protein Degradation via E3 Ligase TRIM21
Authors: Li Xiaomei , Wang Qingyang , Guo Anping , Qiu Yaping , Chen Qiuxia , Li You , Zhang Lanjun , Guo Yaxin , Meng Xiaoyun , Li Shiqian , Liu Guizhi , Zhang Liyun , Liu Jian , Li Xianyang , Cai Longying , Cheng Xuemin , Liu Chuan , Wang Xiaotao , Wood Andrew , Murray James , Liu Guansai , Li Jin , Huang Xiaodong , Dou Dengfeng 
Published: December 2024

AbstractDespite the exciting progress of the bifunctional degrader molecules, also known as proteolysis-targeting chimeras (PROTACs), the rapidly expanding field is still significantly hampered by the lacking of available E3 ligase ligands. Our research bridges this gap by uncovering a series of small-molecule ligands to the E3 ligase TRIM21 through DNA-Encoded Library (DEL) technology. We confirmed their interaction with TRIM21 using crystallography and demonstrated their anti-proliferative effects across various cancer cell types. Furthermore, proteomic studies identified that the mRNA Export Factor GLE1, and the Nuclear Pore Complex Protein NUP155, were significantly down-regulated upon TRIM21 ligand treatment. This degradation required TRIM21 and was ubiquitin-proteasome-dependent. More specifically, NUP155 was the primary target for the TRIM21 ligands, while GLE1 was considered a passenger target upon the initial degradation of NUP155. Using immunofluorescence techniques, we further demonstrated that the degradation of GLE1 and NUP155 proteins impaired the integrity of the nuclear envelope, leading to cell death. Highlighted by this research, a novel mode of action has been discovered for the TRIM21 E3 ligase ligand, acting as a monovalent degrader that triggers de novo interaction with functional complex proteins and induces their degradation.
Individual differences in probabilistic learning and updating predictive representations in individuals with obsessive-compulsive tendencies
Authors: Brezóczki Bianka , Farkas Bence Csaba , Hann Flóra , Pesthy Orsolya , Tóth-Fáber Eszter , Farkas Kinga , Csigó Katalin , Németh Dezső , Vékony Teodóra 
Published: December 2024

AbstractObsessive-compulsive (OC) tendencies involve intrusive thoughts and rigid, repetitive behaviours that also manifest at the subclinical level in the general population. The neurocognitive factors driving the development and persistence of the excessive presence of these tendencies remain highly elusive, though emerging theories emphasize the role of implicit information processing. Despite various empirical studies on distinct neurocognitive processes, the incidental retrieval of environmental structures in dynamic and noisy environments, such as probabilistic learning, has received relatively little attention. In this study, we aimed to unravel potential individual differences in implicit probabilistic learning and the updating of predictive representations related to OC tendencies in the general population. We conducted two independent online experiments (NStudy1= 164, NStudy2= 257) with young adults. Probabilistic learning was assessed using a reliable implicit visuomotor probabilistic learning task, which involved sequences with second-order non-adjacent dependencies. Our findings revealed that even among individuals displaying a broad spectrum of OC tendencies within a non-clinical population, implicit probabilistic learning remained remarkably robust. Furthermore, the results highlighted effective updating capabilities of predictive representations, which were not influenced by OC tendencies. These results offer new insights into individual differences in probabilistic learning and updating in relation to OC tendencies, contributing to theoretical, methodological, and practical approaches for understanding the maladaptive behavioural manifestations of OC disorder and subclinical tendencies.
A fast-track, high-throughput screening platform for biological nitrification inhibitors discovery based on soil relevant ammonia oxidizing strains
Authors: Kanellopoulos Alexandros E. , Malits Andrea , Ribeiro Hugo , Kerou Melina , Ghatak Arindam , Chaturvedi Palak , Weckwerth Wolfram , Karpouzas Dimitrios G. , Schleper Christa , Papadopoulou Evangelia S. 
Published: December 2024

AbstractNitrogen cycling is critical for ecosystem functioning, with nitrification playing a central role. Excessive nitrification, triggered by heavy nitrogen fertilisation, contributes to reduced nitrogen use efficiency, nitrate leaching, and nitrous oxide emissions. While synthetic nitrification inhibitors (SNIs) help reduce these impacts, their erratic performance and environmental risks have shifted focus to biological nitrification inhibitors (BNIs) as sustainable alternatives.In vitrobioassays with ammonia-oxidising microorganisms (AOM) are valuable for BNI discovery and research, but often have low throughput and rely on a limited number of mostly non-soil-relevant or genetically modified ammonia-oxidizing bacteria (AOB) strains, lacking validation with established BNIs. We present a refined fast-track, high-throughput assay for BNI screening, utilizing soil-relevant, ecophysiologically and phylogenetically diverse AOB (Nitrosospira multiformis, Nitrosomonas ureae, Nitrosomonas communis) and ammonia-oxidizing archaea (AOA) strains (Nitrososphaera viennensis,“Ca. Nitrosocosmicus franklandianus”), achieving consistent cellular activity and density. The assay was validated with established SNIs and BNIs, showing differences in inhibition efficacy and strain sensitivity, consistent with literature. As a proof of concept, root exudates from diverse wheat genotypes were screened, demonstrating distinct inhibition profiles. The proposed system advances previously available screening systems and, when integrated with realistic soil tests, will facilitate the discovery of novel BNIs and BNI-producing plant genotypes.
Improving AlphaFold 3 structural modeling by incorporating explicit crosslinks
Authors: Kosinski Jan 
Published: December 2024

AbstractAlphaFold 3 has significantly advanced the modeling of macromolecular structures, including proteins, DNA, RNA, and their interactions with small molecules or post-translational modifications. However, challenges remain when modeling specific structural conformations or complexes with limited evolutionary data, such as protein-antibody complexes. Previous studies with AlphaFold2 demonstrated that adding distance restraints from crosslinking mass spectrometry (XL-MS) can improve predictions for such cases. In this study, we investigate whether XL-MS restraints can be incorporated into AlphaFold 3 by explicitly modeling crosslinks as covalently-bound ligands. Our results show that this approach is able to increase the accuracy of AlphaFold 3 models. We explore the opportunities and limitations of this method, which has been implemented as a proof-of-concept pipeline named AlphaFold 3x, available athttps://github.com/KosinskiLab/alphafold3x.
CBAM-ResNet34-based classification and evaluation method for developmental processes of greenhouse strawberries
Authors: Wang Jianxu , Liang Zhongyue , Jiang Fengan , Feng Jian , Xiao Yuyang , Yang Ming , Wang Deguang 
Published: December 2024

AbstractStrawberries, known for their economic significance and rich nutritional value, are cultivated extensively worldwide. However, a host of workers need to be employed every year to identify and categorize the developmental stages of the strawberries in the greenhouses, which is not only time-consuming, inefficient, increasing the cultivation cost, but also difficult to guarantee the classification accuracy. Meanwhile, affected by the complicated background, occlusions, and color interference, the features of strawberries are proven challenging to be extracted via the traditional neural networks due to serious gradient disappearance. Therefore, an improved CBAM-ResNet34- based classification evaluation method for developmental processes of greenhouse strawberries is investigated. The procedure of this method is as follows: firstly, the developmental stages of greenhouse strawberries are classified by experts into four stages: Stage I (initial stage), Stage II (green and white fruit stage), Stage III (early ripening stage), and Stage IV (fully ripe stage). The 627, 640, 604, and 340 strawberry images for these four stages are captured. Subsequently, the images are divided into training, validation, as well as testing sets and then undergo image pre- processing, expansion, and augmentation. Whereafter, the 7×7 convolution kernel in the first layer of the network is replaced by three consecutive 3×3 convolution cores to eliminate the redundant weights and unnecessary model parameters, and the BasicBlocks configuration is adjusted. Finally, the CBAM attention mechanism is added to each BasicBlock so as to pinpoint the spatial position of the strawberries and extract their major features such as shape, size, and color. Comparison experiments with the conventional deep neural networks LeNet5, AlexNet, VGG16, ResNet18, ResNet34, and every improved part of CBAM-ResNet34 demonstrated that when the learning rate is 0.001, the Dropout rate is 0.3, and the Adam’s weight decay parameter is 0.001, the accuracies for validation and testing sets can reach to 92.36% and 87.56% with F1 scores of 0.92, 0.87, 0.85 and 0.88.
Microglia undergoes chemokine receptor, CX3CR1-mediated internalization of extracellular Tau
Authors: Chidambaram Hariharakrishnan , Desale Smita Eknath , Suri Kapali , Murugan N Arul , Chinnathambi Subashchandrabose 
Published: December 2024

AbstractIn Alzheimer’s disease, the microtubule-associated protein, Tau misfolds to form aggregates and filaments in the intra- and extracellular region of neuronal cells. CX3CR1 receptor is involved in monomeric Tau internalization by directly binding to the receptor. In our study, we are interested in understanding the interaction of different pathological structures of Tau with microglial chemokine receptor, CX3CR1 and its role in CX3CR1-mediated Tau internalization by immunofluorescence assay. Co-immunoprecipitation further confirmed the receptor interaction with Tau oligomers and even aggregated filaments. We next determined the role of Tau as a chemoattractant in regulating the migration of microglia by wound healing assay. Further, immunolocalization studies of CX3CR1 with β-arrestin proved the desensitization of CX3CR1 receptor upon Tau binding. Upon ligand interaction, GPCRs undergoes desensitization and encytosed to the cytosol. We have quantified the CX3CR1 internalization by measuring the membrane to cytosol intensity ratio of CX3CR1 receptor upon extracellular Tau exposure. In addition to experimental assays, a comprehensive analysis of the interaction between the CX3CR1 receptor, the Tau protein, and the AZD8797 ligand has been derived from the combined molecular docking, molecular dynamics and free energy calculations using molecular mechanics-generalized Born approach. In particular, two different molecular dynamics simulations were carried out for CX3CR1-Tau protein and AZD8797-bound CX3CR1-Tau protein interaction. The molecular modeling study establishes that AZD8797 binds to CX3CR1 receptor and modulates the Tau interaction with the receptor.