bluuebunny/crossref_metadata_2025_split huggingface dataset:
An oomycete effector co-opts a host RabGAP protein to remodel pathogen interface and subvert defense-related secretion
Authors: Yuen Enoch Lok Him , Tumtas Yasin , Chan Lok I , Ibrahim Tarhan , Evangelisti Edouard , Tulin Frej , Skłenar Jan , Menke Frank , Kamoun Sophien , Bubeck Doryen , Schornack Sebastian , Bozkurt Tolga O. 
Published: January 2024

AbstractPathogens have evolved sophisticated mechanisms to manipulate host cell membrane dynamics, a crucial adaptation to survive in hostile environments shaped by innate immune responses. Plant- derived membrane interfaces, engulfing invasive hyphal projections of fungal and oomycete pathogens, are prominent junctures dictating infection outcomes. Understanding how pathogens transform these host-pathogen interfaces to their advantage remains a key biological question. Here, we identified a conserved effector, secreted by plant pathogenic oomycetes, that co-opts a host Rab GTPase-activating protein (RabGAP), TBC1D15L, to remodel the host-pathogen interface. The effector, PiE354, hijacks TBC1D15L as a susceptibility factor to usurp its GAP activity on Rab8a—a key Rab GTPase crucial for defense-related secretion. By hijacking TBC1D15L, PiE354 purges Rab8a from the plasma membrane, diverting Rab8a-mediated immune trafficking away from the pathogen interface. This mechanism signifies an uncanny evolutionary adaptation of a pathogen effector in co- opting a host regulatory component to subvert defense-related secretion, thereby providing unprecedented mechanistic insights into the reprogramming of host membrane dynamics by pathogens.
Logic-based modeling of biological networks with Netflux
Authors: Clark Alexander P. , Chowkwale Mukti , Paap Alexander , Dang Stephen , Saucerman Jeffrey J. 
Published: January 2024

AbstractMolecular signaling networks drive a diverse range of cellular decisions, including whether to proliferate, how and when to die, and many processes in between. Such networks often connect hundreds of proteins, genes, and processes. Understanding these complex networks is aided by computational modeling, but these tools require extensive programming knowledge. In this article, we describe a user-friendly, programming-free network simulation tool called Netflux (https://github.com/saucermanlab/Netflux). Over the last decade, Netflux has been used to construct numerous predictive network models that have deepened our understanding of how complex biological networks make cell decisions. Here, we provide a Netflux tutorial that covers how to construct a network model and then simulate network responses to perturbations. Upon completion of this tutorial, you will be able to construct your own model in Netflux and simulate how perturbations to proteins and genes propagate through signaling and gene-regulatory networks.
A novel classification framework for genome-wide association study of whole brain MRI images using deep learning
Authors: Yu Shaojun , Wu Junjie , Shao Yumeng , Qiu Deqiang , Qin Zhaohui S. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2024

AbstractGenome-wide association studies (GWASs) have been widely applied in the neuroimaging field to discover genetic variants associated with brain-related traits. So far, almost all GWASs conducted in neuroimaging genetics are performed on univariate quantitative features summarized from brain images. On the other hand, powerful deep learning technologies have dramatically improved our ability to classify images. In this study, we proposed and implemented a novel machine learning strategy for systematically identifying genetic variants that lead to detectable nuances on Magnetic Resonance Images (MRI). For a specific single nucleotide polymorphism (SNP), if MRI images labeled by genotypes of this SNP can be reliably distinguished using machine learning, we then hypothesized that this SNP is likely to be associated with brain anatomy or function which is manifested in MRI brain images. We applied this strategy to a catalog of MRI image and genotype data collected by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) consortium. From the results, we identified novel variants that show strong association to brain phenotypes.
Heritable intraspecific variation among prey in size and movement interact to shape predation risk and potential natural selection
Authors: Coblentz Kyle E. , Yang Liuqingqing , Dalal Arpita , Incarnato Miyauna M. N. , Thilakarathne Dinelka D. , Shaw Cameron , Wilson Ryan , Biagioli Francis , Montooth Kristi L. , DeLong John P. 
Published: January 2024

AbstractPredator and prey traits are important determinants of the outcomes of trophic interactions. In turn, the outcomes of trophic interactions shape the evolution of predator and prey traits. How species’ traits are likely to respond to selection from trophic interactions depends crucially on whether and how heritable species’ traits are and their genetic correlations. Of the many traits potentially influencing the outcomes of trophic interactions, body size and movement traits have emerged as universally key traits. Yet, how these traits shape and are shaped by trophic interactions is generally unclear, as few studies have simultaneously measured the impacts of these traits on the outcomes of trophic interactions, their heritability, and their correlations within the same system.We used outcrossed and then clonally propagated lines of the ciliate protistParamecium caudatumfrom natural populations to examine variation in morphology and movement behavior, the extent to which this variation was heritable, and how intraspecific differences among lines alteredParameciumsusceptibility to predation by the copepodMacrocyclops albidus.We found that theParameciumlines exhibited heritable variation in body size and movement traits. In contrast to expectations from interspecific allometric relationships, body size and movement speed showed little covariance among clonal lines. The proportion ofParameciumconsumed by copepods was positively associated withParameciumbody size and velocity, however, we also found evidence of an interaction such that greater velocities led to greater predation risk for large body-sized paramecia but did not alter predation risk for smaller body-sized paramecia. The proportion of paramecia consumed was not related to copepod body size. These patterns of predation risk and heritable trait variation in paramecia suggest that copepod predation may act as a selective force operating independently on movement and body size and generating the strongest selection against large, high-velocity paramecia.Our results illustrate how the interactions between ecology and genetics can shape the potential natural selection on prey traits through the outcomes of trophic interactions. Further simultaneous measures of predation outcomes, traits, and their quantitative genetic characteristics will provide insights into the evolutionary ecology of species interactions and their eco-evolutionary consequences.
Aphid resistance segregates independently of cardiac glycoside and glucosinolate content in anErysimum cheiranthoides(wormseed wallflower) F2 population
Authors: Mirzaei Mahdieh , Younkin Gordon C. , Powell Adrian F. , Alani Martin L. , Strickler Susan R. , Jander Georg 
Published: January 2024

AbstractPlants in the genusErysimumproduce both glucosinolates and cardiac glycosides as defense against herbivory. Two natural isolates ofErysimum cheiranthoides(wormseed wallflower) differed in their glucosinolate content, cardiac glycoside content, and resistance toMyzus persicae(green peach aphid), a broad generalist herbivore. Both classes of defensive metabolites were produced constitutively and were not induced further by aphid feeding. To investigate the relative importance of glucosinolates and cardiac glycosides inE. cheiranthoidesdefense, we generated an improved genome assembly, genetic map, and segregating F2 population. Genotypic and phenotypic analysis of the F2 plants identified quantitative trait loci affecting glucosinolates and cardiac glycosides, but not aphid resistance. The abundance of most glucosinolates and cardiac glycosides was positively correlated in the F2 population, indicating that similar processes regulate their biosynthesis and accumulation. Aphid reproduction was positively correlated with glucosinolate content. Although overall cardiac glycoside content had little effect on aphid growth and survival, there was a negative correlation between aphid reproduction and helveticoside abundance. However, this variation in defensive metabolites could not explain the differences in aphid growth on the two parental lines, suggesting that processes other than the abundance of glucosinolates and cardiac glycosides have a predominant effect on aphid resistance inE. cheiranthoides.
Concordance of whole-genome amplified embryonic DNA with the subsequently born child
Authors: Li Shenglai , Giardina Thomas , Katz Maria , Chandramohan Dhruva , Slotnick Nathan , Behr Barry , Siddiqui Noor , Xia Yuntao , Podgursky Benjamin 
Published: January 2024

AbstractBefore implantation subsequent to in vitro fertilization (IVF), the current options for Preimplantation Genetic Testing (PGT) are PGT for Aneuploidy (PGT-A) and, if clinically indicated, PGT for monogenic conditions (PGT-M). A more comprehensive approach involves PGT whole genome sequencing (PGT-WGS). PGT-WGS incorporates PGT-A, screens for hundreds of monogenic conditions, and can evaluate polygenic risk. Here we compare PGT-WGS results against the genome of the subsequently born child. We demonstrated high levels of concordance (both in sensitivity and precision) in exome variant calls between amplified embryonic DNA and sequenced fetal cord blood. This concordance was higher when filtering against 1300 targeted monogenic conditions implicated in birth defects, neurodevelopmental disorders, and hereditary cancer. To evaluate PGT-WGS’s ability to identify de novo variants we compared the child’s genome to parental genomes and demonstrated that PGT-WGS successfully identified 5/5 confirmed de-novo variants. We further demonstrated concordance in polygenic risk scores calculated for both the embryo and the subsequently born child. This agreement extended to both traditional polygenic scores and oligogenic scores (Type 1 diabetes, Celiac disease, and Alzheimer’s Disease), which heavily rely on accurate genotyping of HLA and APOE sites. To our knowledge, this is the first direct concordance study between a whole-genome sequencing of a trophectoderm biopsy and the DNA of the subsequently born child. By demonstrating a high degree of whole-exome concordance and adept detection of de novo variants, this approach showcases PGT-WGS’s capability to identify genetic variants not explicitly targeted for monogenic screening.
Normalized level set model for segmentation of low-contrast objects in 2- and 3- dimensional images
Authors: Baig Mirza M. Junaid , Wang Yao L. , Chung Samuel H. , Stepanyants Armen 
Published: January 2024

ABSTRACTAnalyses of biomedical images often rely on accurate segmentation of structures of interest. Traditional segmentation methods based on thresholding, watershed, fast marching, and level set perform well in high-contrast images containing structures of similar intensities. However, such methods can under-segment or miss entirely low-intensity objects on noisy backgrounds. Machine learning segmentation methods promise superior performance but require large training datasets of labeled images which are difficult to create, particularly in 3D. Here, we propose an algorithm based on the Local Binary Fitting (LBF) level set method, specifically designed to improve the segmentation of low-contrast structures.
Connectivity and functional diversity of different temporo-occipital nodes for action perception
Authors: Li Baichen , Poyo Solanas Marta , Marrazzo Giuseppe , de Gelder Beatrice 
Published: January 2024

AbstractThe temporo-occipital cortex (TOC) plays a key role in body and action perception, but current understanding of its functions is still limited. TOC body regions are heterogeneous and their role in action perception is poorly understood. This study adopted data-driven approaches to region selectivity and investigated the connectivity of TOC nodes and the functional network sensitivity for different whole body action videos. In two human 7T fMRI experiments using independent component analysis, four adjacent body selective nodes were detected within the TOC network with distinct connectivity profiles and functional roles. Action type independent connectivity was observed for the posterior-ventral node to the visual cortex, the posterior-dorsal node to the precuneus and the anterior nodes to the frontal cortex. Action specific connectivity modulations were found in middle frontal gyrus for the aggressive condition with increased connectivity to the anterior node and decreased connectivity to the posterior-dorsal node. But for the defensive condition, node-nonspecific enhancement was found for the TOC-cingulate connectivity. By addressing the issue of multiple nodes in the temporo-occipital network we show a functional dissociation of different body selective centres related to the action type and a potential hierarchy within the TOC body network.
Dbp1 is a low performance paralog of RNA helicase Ded1 that drives impaired translation and heat stress response
Authors: Powers Emily N , Kuwayama Naohiro , Sousa Camila , Reynaud Kendra , Jovanovic Marko , Ingolia Nicholas T , Brar Gloria A 
Published: January 2024

AbstractDed1 and Dbp1 are paralogous conserved RNA helicases that enable translation initiation in yeast. Ded1 has been heavily studied but the role of Dbp1 is poorly understood. We find that the expression of these two helicases is controlled in an inverse and condition-specific manner. In meiosis and other long-term starvation states, Dbp1 expression is upregulated and Ded1 is downregulated, whereas in mitotic cells, Dbp1 expression is extremely low. Inserting theDBP1ORF in place of theDED1ORF cannot replace the function of Ded1 in supporting translation, partly due to inefficient mitotic translation of theDBP1mRNA, dependent on features of its ORF sequence but independent of codon optimality. Global measurements of translation rates and 5’ leader translation, activity of mRNA-tethered helicases, ribosome association, and low temperature growth assays show that—even at matched protein levels—Ded1 is more effective than Dbp1 at activating translation, especially for mRNAs with structured 5’ leaders. Ded1 supports halting of translation and cell growth in response to heat stress, but Dbp1 lacks this function, as well. These functional differences in the ability to efficiently mediate translation activation and braking can be ascribed to the divergent, disordered N- and C-terminal regions of these two helicases. Altogether, our data show that Dbp1 is a “low performance” version of Ded1 that cells employ in place of Ded1 under long-term conditions of nutrient deficiency.
Gadolinium-based nanoparticles AGuIX and their combination with ionizing radiation trigger AMPK-dependent proinflammatory reprogramming of tumor-associated macrophages
Authors: Muradova Zeinaf , Tannous Désirée , Mostefa-Kara Ali , Cao-Pham Thanh Trang , Lamy Constance , Broutin Sophie , Paci Angelo , Dufort Sandrine , Doussineau Tristan , Lux François , Tillement Olivier , Le Duc Géraldine , Allouch Awatef , Perfettini Jean-Luc 
Published: January 2024

AbstractBackgroundTumor-associated macrophages (TAMs) are essential components of the inflammatory microenvironment of tumors and are associated with poor clinical outcomes in the majority of cancers. TAMs mainly exhibit anti-inflammatory functions that promote and support the tissue remodeling, the immune suppression and the tumor growth. Regarding their plasticity, the functional reprogramming of anti-inflammatory TAMs into proinflammatory phenotype recently emerged as a therapeutic opportunity to improve the effectiveness of anticancer treatments such as radiotherapy.ResultsHere we show that gadolinium-based nanoparticles AGuIX alone and in combination with ionizing radiation (IR) induce in a dose-dependent manner, the accumulation of DNA double strand breaks, an Ataxia telangiectasia mutated (ATM)-dependent DNA-damage response, an increased expression of the Interferon regulatory factor 5 (IRF5) and the release of proinflammatory cytokines from targeted macrophages, thus directing their proinflammatory reprogramming. This process is associated with the activating phosphorylation of the Adenosine Monophosphate (AMP) activated protein kinase on threonine 172 (AMPKT172*) and the fragmentation of mitochondria. Furthermore, we demonstrate that the inactivation of AMPK reduces the mitochondrial fragmentation and the proinflammatory reprogramming of macrophages detected in response to AGuIX and their combination with IR. These results reveal that the AMPK-dependent regulation of mitochondrial fragmentation plays a central role during the proinflammatory reprogramming of macrophages. Accordingly, a positive correlation between AMPKT172* and proinflammatory activation of TAMs is detected following IR+AGuIX combination in syngeneic mouse model of colorectal cancer.ConclusionsAltogether, our results identify a novel signaling pathway elicited by AGuIX and their combined treatment with IR, that targets macrophage polarization, skews macrophage functions toward the proinflammatory phenotype and may enhance the effectiveness of radiotherapy.
Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer
Authors: Ewing Ailith , Meynert Alison , Silk Ryan , Aitken Stuart , Bendixsen Devin P. , Churchman Michael , Brown Stuart L. , Hamdan Alhafidz , Mattocks Joanne , Grimes Graeme R. , Ballinger Tracy , Hollis Robert L. , Herrington C. Simon , Thomson John P. , Sherwood Kitty , Parry Thomas , Esiri-Bloom Edward , Bartos Clare , Croy Ian , Ferguson Michelle , Lennie Mairi , McGoldrick Trevor , McPhail Neil , Siddiqui Nadeem , Glasspool Rosalind , Mackean Melanie , Nussey Fiona , McDade Brian , Ennis Darren ,   The Scottish Genomes Partnership, McMahon Lynn , Matakidou Athena , Dougherty Brian , March Ruth , Barrett J. Carl , McNeish Iain A. , Biankin Andrew V. , Roxburgh Patricia , Gourley Charlie , Semple Colin A. 
Published: January 2024

AbstractDeciphering the structural variation across tumour genomes is crucial to determine the events driving tumour progression and better understand tumour adaptation and evolution. High grade serous ovarian cancer (HGSOC) is an exemplar tumour type showing extreme, but poorly characterised structural diversity. We comprehensively describe the mutational landscape driving HGSOC, exploiting a large (N=324), deeply whole genome sequenced dataset. We reveal two divergent evolutionary trajectories, affecting patient survival and involving differing genomic environments. One involves homologous recombination repair deficiency (HRD) while the other is dominated by whole genome duplication (WGD) with frequent chromothripsis, breakage-fusion-bridges and extra-chromosomal DNA. These trajectories contribute to structural variation hotspots, containing novel candidate driver genes with significantly altered expression. While structural variation predominantly drives tumorigenesis, we also find high mtDNA mutation loads associated with shorter patient survival, and acting in combination with alterations in the nuclear genome to impact prognosis and suggesting new strategies for patient stratification.
Reproductive innovation enabled radiation in the deep sea during an ecological crisis
Authors: Brownstein Chase D. , Zapfe Katerina L. , Lott Spencer , Harrington Richard , Ghezelayagh Ava , Dornburg Alex , Near Thomas J. 
Published: January 2024

AbstractMajor ecological transitions are thought to fuel evolutionary radiations, but whether they are contingent on the evolution of certain traits is unclear. We show that the rapid ecological transition of anglerfishes into pelagic habitats during a period of major global warming coincided with the origins of sexual parasitism, in which male anglerfishes temporarily attach or permanently fuse to females to mate. A phylogenomic reconstruction of the evolutionary history of anglerfishes provides a strong inference for the convergent evolution of permanently-fusing deep-sea anglerfishes and their degenerate immune genes. Our results support that sexual parasitism was enabled by the degeneration of adaptive immunity and ancestral sexual size dimorphism. The combination of these traits facilitated the transition of pelagic anglerfishes into novel ecologies available in the deep open oceans after evolving from benthic ancestors. These results show how seemingly unrelated physiological and reproductive traits interact synergistically to drive evolutionary radiation in novel environments.
Loss of calpain 3 dysregulates store-operated calcium entry and its exercise response in mice
Authors: Villani Katelyn R. , Zhong Renjia , Spencer Henley-Beasley C. , Rastelli Giorgia , Boncompagni Simona , Barton Elisabeth R. , Wei-LaPierre Lan 
Published: January 2024

ABSTRACTLimb-Girdle Muscular Dystrophy 2A (LGMD2A) is caused by mutations in theCAPN3gene encoding Calpain 3, a skeletal-muscle specific, Ca2+-dependent protease. Localization of Calpain 3 within the triad suggests it contributes to Ca2+homeostasis. Through live-cell Ca2+measurements, muscle mechanics, immunofluorescence, and electron microscopy (EM) inCapn3deficient (C3KO) and wildtype (WT) mice, we determined if loss of Calpain 3 altered Store-Operated Calcium Entry (SOCE) activity. Direct Ca2+influx measurements revealed loss ofCapn3elicits elevated resting SOCE and increased resting cytosolic Ca2+, supported by high incidence of calcium entry units (CEUs) observed by EM. C3KO and WT mice were subjected to a single bout of treadmill running to elicit SOCE. Within 1HR post-treadmill running, C3KO mice exhibited diminished force production inextensor digitorum longusmuscles and a greater decay of Ca2+transients inflexor digitorum brevismuscle fibers during repetitive stimulation. Striking evidence for impaired exercise-induced SOCE activation in C3KO mice included poor colocalization of key SOCE proteins, stromal-interacting molecule 1 (STIM1) and ORAI1, combined with disappearance of CEUs in C3KO muscles. These results demonstrate that Calpain 3 is a key regulator of SOCE in skeletal muscle and identify SOCE dysregulation as a contributing factor to LGMD2A pathology.