bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adenomyosis and fibrosis define the morphological memory of the postpartum uterus of dairy cows previously exposed to metritis
Authors: Sellmer Ramos I , Caldeira MO , Poock SE , Moraes JGN , Lucy MC , Patterson AL 
Published: June 2024

AbstractOptimal reproductive success following parturition in lactating dairy cows is dependent upon adequate completion of uterine involution. Failure to resolve pathogenic bacterial contamination within the first week postpartum can lead to uterine disease (metritis). Metritis is associated with decreased fertility and a failure or delay to establish pregnancy. We hypothesized that the inflammation resulting from early postpartum metritis would be associated with long-term changes in uterine morphology due to impaired uterine involution within the first 30 days postpartum (dpp). First parity Holstein cows were diagnosed with or without metritis at 7-10 dpp and uterine tissue were analyzed at 30 (Exp. 1), or 80 and 165 (Exp. 2) dpp for the presence of abnormal morphology, including abnormal invasion of endometrial glands and stroma into the myometrium (adenomyosis) using immunohistochemistry for FOXA2 (uterine gland specific marker) and presence of late postpartum endometrial fibrosis using mason’s trichrome stain (MTS). Severity of adenomyosis was determined by the number and size of adenomyotic foci, distance of foci from the endometrium-myometrium interface (EMI), and degree of fibrosis (MTS stain intensity). The presence, size, and distance from the EMI of adenomyotic foci were greater later postpartum and in cows with early postpartum diagnosis of metritis. Endometrial fibrosis was greater at the stratum basalis (at EMI) compared to the stratum compactum endometrium (near lumen) for all Exp. 2 cows, but greater endometrial fibrosis (regardless of endometrial region) was observed in cows that were diagnosed with metritis. Taken together, these data indicate that early postpartum metritis is associated with long-term modifications to the postpartum uterine morphology, including aberrant endometrial invasion into the myometrium (adenomyosis) and increased pathological fibrogenesis, leading to the presence of late postpartum endometrial fibrosis (scar tissue). Additionally, increased collagen fiber at the EMI suggests a correlation between the development of adenomyosis and fibrosis, which could possibly result from sustained endometrial inflammation caused by uterine disease.
Circulating miR-126-3p is a mechanistic biomarker for knee osteoarthritis
Authors: Wilson Thomas G. , Baghel Madhu , Kaur Navdeep , Datta Indrani , Loveless Ian , Potla Pratibha , Mendez Devin , Hansen Logan , Baker Kevin , Lynch T. Sean , Moutzouros Vasilios , Davis Jason , Ali Shabana Amanda 
Published: June 2024

AbstractAs a chronic joint disease, osteoarthritis (OA) is a major contributor to pain and disability worldwide, and yet there are currently no validated soluble biomarkers or disease-modifying treatments. Since microRNAs are promising mechanistic biomarkers that can be therapeutically targeted, we aimed to prioritize reproducible circulating microRNAs in knee OA. We performed secondary analysis on two microRNA-sequencing datasets and found circulating miR-126-3p to be elevated in radiographic knee OA compared to non-OA individuals. This finding was validated in an independent cohort (N=145), where miR-126-3p showed an area under the receiver operating characteristic curve of 0.91 for distinguishing knee OA. Measuring miR-126-3p in six primary human knee OA tissues, subchondral bone, fat pad and synovium exhibited the highest levels, and cartilage the lowest. Following systemic miR-126-3p mimic treatment in a surgical mouse model of knee OA, we found reduced disease severity. Following miR-126-3p mimic treatment in human knee OA tissue explants, we found direct inhibition of genes associated with angiogenesis and indirect inhibition of genes associated with osteogenesis, adipogenesis, and synovitis. These findings suggest miR-126-3p becomes elevated during knee OA and mitigates disease processes to attenuate severity.
Personalizing computational models to construct medical digital twins
Authors: Knapp Adam C. , Cruz Daniel A. , Mehrad Borna , Laubenbacher Reinhard C. 
Published: June 2024

Digital twin technology, pioneered for engineering applications, is being adapted to biomedicine and healthcare; however, several problems need to be solved in the process. One major problem is that of dynamically calibrating a computational model to an individual patient, using data collected from that patient over time. This kind of calibration is crucial for improving model-based forecasts and realizing personalized medicine. The underlying computational model often focuses on a particular part of human biology, combines different modeling paradigms at different scales, and is both stochastic and spatially heterogeneous. A commonly used modeling framework is that of an agent-based model, a computational model for simulating autonomous agents such as cells, which captures how system-level properties are affected by local interactions. There are no standard personalization methods that can be readily applied to such models. The key challenge for any such algorithm is to bridge the gap between the clinically measurable quantities (the macrostate) and the fine-grained data at different physiological scales which are required to run the model (the microstate). In this paper we develop an algorithm which applies a classic data assimilation technique, the ensemble Kalman filter, at the macrostate level. We then link the Kalman update at the macrostate level to an update at the microstate level that produces microstates which are not only compatible with desired macrostates but also highly likely with respect to model dynamics.Significance StatementTo realize the promise of personalized medicine, we need to be able to integrate different types of data collected from a given patient into a computational framework that enables decision making about optimal interventions to help this patient to either maintain or regain health. Digital twins represent such a framework, once the technology is sufficiently developed. A fundamental problem that currently does not have a widely applicable solution is how to calibrate a generic computational model of human biology to a given patient at a given time. This paper presents a solution to this problem for the agent-based model framework, commonly used to capture stochastic and spatially heterogeneous biological processes, such as tumor growth or immune system dynamics.
Collaboration between IL-7 and IL-15 enables adaptation of tissue-resident and circulating memory CD8+T cells
Authors: Jarjour Nicholas N. , Dalzell Talia S. , Maurice Nicholas J. , Wanhainen Kelsey M. , Peng Changwei , DePauw Taylor A. , Block Katharine E. , Valente William J. , Ashby K. Maude , Masopust David , Jameson Stephen C. 
Published: June 2024

SUMMARYInterleukin-7 (IL-7) is considered a critical regulator of memory CD8+T cell homeostasis, but this is primarily based on analysis of circulating and not tissue-resident memory (TRM) subsets. Furthermore, the cell-intrinsic requirement for IL-7 signaling during memory homeostasis has not been directly tested. Using inducible deletion, we found thatIl7raloss had only a modest effect on persistence of circulating memory and TRMsubsets and that IL-7Rα was primarily required for normal basal proliferation. Loss of IL-15 signaling imposed heightened IL-7Rα dependence on memory CD8+T cells, including TRMpopulations previously described as IL-15-independent. In the absence of IL-15 signaling, IL-7Rα was upregulated, and loss of IL-7Rα signaling reduced proliferation in response to IL-15, suggesting cross-regulation in memory CD8+T cells. Thus, across subsets and tissues, IL-7 and IL-15 act in concert to support memory CD8+T cells, conferring resilience to altered availability of either cytokine.HighlightsTissue-resident and circulating memory CD8+T cells modestly decline after loss of IL-7Rα IL-7Rα is required for normal self-renewal of memory CD8+T cellsCombined loss of IL-7 and IL-15 causes a profound defect across memory CD8+T cell subsets Cross-regulation of IL-7 and IL-15 signaling occurs in memory CD8+T cellsAbstract Figure
High-Resolution In Silico Painting with Generative Models
Authors: Le Trang , Lundberg Emma 
Published: June 2024

AbstractLabel-free organelle prediction presents a longstanding challenge in cellular imaging, given the promise to to circumvent the numerous drawbacks associated with fluorescent microscopy, including its high costs, cytotoxicity, and time-consuming nature. Recent advancements in deep learning have introduced numerous effective algorithms, primarily deterministic, for predicting fluorescent patterns from transmitted light microscopy images. However, existing models frequently suffer from poor performance or are limited to specific datasets, image modalities, and magnifications, thus lacking a universal solution. In this paper, we present a simplified VQGAN training scheme that is easily adapted with different input/output channels for image-to-image translation tasks. We applied the algorithm to generate multi-channel organelle staining outputs from bright field inputs, equivalent to the popular Cell Painting assay. The same algorithm also participated and placed first in the ISBI 2024 Light My Cell challenge.
Developing and Benchmarking Sulfate and Sulfamate Force Field Parameters for Glycosaminoglycans via Ab Initio Molecular Dynamics Simulations
Authors: Riopedre-Fernandez Miguel , Kostal Vojtech , Martinek Tomas , Martinez-Seara Hector , Biriukov Denys 
Published: June 2024

AbstractGlycosaminoglycans (GAGs) are negatively charged polysaccharides found on cell surfaces, where they regulate transport pathways of foreign molecules toward the cell. The structural and functional diversity of GAGs is largely attributed to varied sulfa-tion patterns along the polymer chains, which makes understanding their molecular recognition mechanisms crucial. Molecular dynamics (MD) simulations, with their un-matched microscopic perspective, have the potential to be a reference tool for exploring the patterns responsible for biologically relevant interactions. However, the capability of molecular dynamics models (i.e., force fields) used in biosimulations to accurately capture sulfation-specific interactions is not well established. In this work, we evalu-ate the performance of molecular dynamics force fields for sulfated GAGs by studying ion pairing of Ca2+to sulfated moieties — N-methylsulfamate and methylsulfate — that resemble N- and O-sulfation found in GAGs, respectively. We tested nonpolariz-able (CHARMM36 and GLYCAM06), explicitly polarizable (Drude and AMOEBA), and implicitly polarizable through charge scaling (prosECCo75 and GLYCAM-ECC75) force fields. The Ca–sulfamate/sulfate interaction free energy profiles obtained with the tested force fields were compared against reference ab initio molecular dynamics (AIMD) simulations. AIMD reveals that the preferential Ca2+binding mode to sul-fated GAG groups is solvent-shared pairing, and only the charge-scaled models agree satisfactorily with the AIMD data. All other force fields exhibit poorer performance, sometimes even qualitatively. Surprisingly, even explicitly polarizable force fields dis-play a notable shortfall in their performance, attributed to difficulties in their optimiza-tion and possible inherent limitations in depicting high-charge-density ion interactions accurately. Finally, the underperforming force fields lead to unrealistic aggregation of sulfated saccharides, qualitatively distorting our understanding of the soft glycocalyx environment. Our results highlight the importance of accurately treating electronic polarization in MD simulations of sulfated GAGs and caution against over-reliance on currently available models without thorough validation and optimization.
Thermal acclimation of spreading depolarization in the CNS ofDrosophila melanogaster
Authors: Andersen Mads Kuhlmann , Robertson R. Meldrum , MacMillan Heath A. 
Published: June 2024

AbstractDuring exposure to extreme stress, the CNS of mammals and insects fails through a phenomenon known as spreading depolarization (SD). SD is characterized by an abrupt disruption of ion gradients across neural and glial membranes that spreads through the CNS, silencing neural activity. In humans, SD is associated with neuropathological conditions like migraine and stroke. In insects, it is coincident with critical thermal limits for activity and can be conveniently monitored by observing the transperineurial potential (TPP). We used the TPP to explore the temperature-dependence and plasticity of SD thresholds and SD-induced changes to the TPP in fruit flies (Drosophila melanogaster) acclimated to different temperatures. Specifically, we characterized the effects of thermal acclimation on the TPP characteristics of cold-induced SD, after which we induced SDviaanoxia at different temperatures in both acclimation groups to examine the interactive effects of temperature and acclimation status. Lastly, we investigated these effects on the rate of SD propagation across the fruit fly CNS. Cold acclimation enhanced resistance to both cold- and anoxic SD and our TPP measurements revealed independent and interactive effects of temperature and acclimation on the TPP and SD propagation. This suggests thermodynamic processes and physiological mechanisms interact to modulate the threshold for activity through SD and its electrophysiological phenomenology. These findings are discussed in relation to conceptual models for SD and established mechanisms for variation in the thermal threshold for SD.
CAMSAP3 Forms Dimers via its α-helix Domain that Directly Stabilize Non-centrosomal Microtubule Minus Ends
Authors: Li Yuejia , Zhang Rui , Ren Jinqi , Chen Wei , Zhou Zhengrong , Xu Honglin , Li Dong , Cheng Haisu , Xie Qi , Ji Wei , Feng Wei , Liang Xin , Meng Wenxiang 
Published: June 2024

AbstractMicrotubules are vital components of the cytoskeleton. Their plus ends are dynamic and respond to changes in cell morphology, while the minus ends are stable and serve a crucial role in microtubule seeding and maintaining spatial organization. In mammalian cells, the calmodulin-regulated spectrin-associated proteins (CAMSAPs), play a key role in directly regulating the dynamics of non-centrosomal microtubules minus ends. However, the molecular mechanisms are not yet fully understood. Our study reveals that CAMSAP3 forms dimers through its C-terminal α-helix; this dimerization not only enhances the microtubule-binding affinity of the CKK domain but also enables the CKK domain to regulate the dynamics of microtubules. Furthermore, CAMSAP3 also specializes in decorating at the minus end of microtubules through the combined action of the microtubule-binding domain (MBD) and the C-terminal α-helix, thereby achieving dynamic regulation of the minus ends of microtubules. These findings are crucial for advancing our understanding and treatment of diseases associated with non-centrosomal microtubules.SignificanceOur study reveals the molecular mechanism of how CAMSAP3, a key regulator of non-centrosomal microtubule dynamics, directly regulates the dynamics of non-centrosomal microtubule minus ends through CKK domain. CAMSAP3 forms dimers through its C-terminal α-helix, which enhances the CKK domain of CAMSAP3 binding to microtubule minus ends and confers stability of them. This finding is not limited to CAMSAP3, but can also be applied to the understanding of the regulation of non-centrosomal microtubule minus end stability by CAMSAP family proteins. Our findings deepen our comprehension of cellular structure and function, offering insights into the role of microtubules in cellular integrity and disease. This study fills a significant knowledge gap and lays the foundation for future research into the complex balance of microtubule dynamics required for cellular health and disease prevention.
Food webs can deliver win-win strategies for tropical agroforestry and biodiversity conservation
Authors: Jarrett Crinan , Powell Luke L. , Claire Tabe Tiku Regine , Kowo Cyril , Ferreira Diogo F. , Quiñones Alma L.S. , Welch Andreanna J. , Haydon Daniel T. , Matthiopoulos Jason 
Published: June 2024

AbstractBalancing biodiversity conservation and agricultural productivity is commonly regarded as a trade-off, but such analyses overlook ecosystem services that functional biodiverse communities provide in agroecosystems, and the possibility that win-win strategies may exist. We developed a dynamic mechanistic community model of the bird-insect food web associated with African cocoa agroforestry, structurally informed by metabarcoding data on bird diets, and fitted to trapping data on species abundances. We used the model to predict equilibrium community composition under varying intensities of shade management and pesticide use. Our results indicate that low-intensity farming favours forest bird species, and potential pollinator abundance, with no increase in pest biomass. Furthermore, using simulations of pesticide application, we found that pesticides do not effectively reduce pest biomass, and result in forest bird extinction. Our mechanistic framework combines the influence of management and the direct and indirect effects of species’ interactions, and demonstrates that low intensity agriculture may provide a win-win for biodiversity and ecosystem services.
Early life adversity promotes gastrointestinal dysfunction through a sex-dependent phenotypic switch in enteric glia
Authors: Gonzales Jacques , Dharshika Christine , Mazhar Khadijah , Morales-Soto Wilmarie , McClain Jonathon L. , Moeser Adam J. , Nault Rance , Price Theodore J. , Gulbransen Brian D. 
Published: June 2024

AbstractIrritable bowel syndrome and related disorders of gut-brain interaction (DGBI) are common and exhibit a complex, poorly understood etiology that manifests as abnormal gut motility and pain. Risk factors such as biological sex, stressors during critical periods, and inflammation are thought to influence DGBI vulnerability by reprogramming gut-brain circuits, but the specific cells affected are unclear. Here, we used a model of early life stress to understand cellular mechanisms in the gut that produce DGBIs. Our findings identify enteric glia as a key cellular substrate in which stress and biological sex converge to dictate DGBI susceptibility. Enteric glia exhibit sexual dimorphism in genes and functions related to cellular communication, inflammation, and disease susceptibility. Experiencing early life stress has sex-specific effects on enteric glia that cause a phenotypic switch in male glia toward a phenotype normally observed in females. This phenotypic transformation is followed by physiological changes in the gut, mirroring those observed in DGBI in humans. These effects are mediated, in part, by alterations to glial prostaglandin and endocannabinoid signaling. Together, these data identify enteric glia as a cellular integration site through which DGBI risk factors produce changes in gut physiology and suggest that manipulating glial signaling may represent an attractive target for sex-specific therapeutic strategies in DGBIs.
Homologous Recombination Shapes the Architecture and Evolution of Bacterial Genomes
Authors: Torrance Ellis L. , Diop Awa , Bobay Louis-Marie 
Published: June 2024

AbstractHomologous recombination is a key evolutionary force that varies considerably across bacterial species. However, how the landscape of homologous recombination varies across genes and within individual genomes has only been studied in a few species. Here, we used Approximate Bayesian Computation to estimate the recombination rate along the genomes of 145 bacterial species. Our results show that homologous recombination varies greatly along bacterial genomes and shapes many aspects of genome architecture and evolution. The genomic landscape of recombination presents several key signatures: rates are highest near the origin of replication in most species, patterns of recombination generally appear symmetrical in both replichores (i.e.replicational halves of circular chromosomes) and most species have genomic hotpots of recombination. Furthermore, many closely related species share conserved landscapes of recombination across orthologs indicating that recombination landscapes are conserved over significant evolutionary distances. We show evidence that recombination drives the evolution of GC-content through increasing the effectiveness of selection and not through biased gene conversion, thereby contributing to an ongoing debate. Finally, we demonstrate that the rate of recombination varies across gene function and that many hotspots of recombination are associated with adaptive and mobile regions often encoding genes involved in pathogenicity.
Characterizing population structure and documenting rapid loss of genetic diversity in Chiricahua Leopard Frogs (Lithobates chiricahuensis) with high throughput microsatellite genotyping
Authors: Beimfohr Caleb , Moreno Linet Rivas , Anderson Regan , Cardwell Raina , Seeman Zach , Spry Ryan , Holding Matthew L , Owens Audrey , Denton Robert 
Published: June 2024

AbstractThe use of molecular markers to assess genetic diversity has become a common component of recovery action plans for threatened and endangered species. In this study, we use an unusually large number of microsatellite markers (N=91) to characterize the genetic variation of Chiricahua Leopard Frogs (Lithobates chiricahuensis) across their range in order to understand their distribution of genetic variation, identify genetic bottlenecks, and measure genetic changes over time in a single, highly-managed population. Populations were best divided into three genetically distinct clusters, with the southeastern Arizona and New Mexico populations forming distinct genetic clusters. While there is moderate genetic variation distributed across the sampled populations, each population on its own shows relatively low allelic diversity. Most populations displayed strong genetic signals of recent genetic bottlenecks or a deficiency of heterozygous genotypes that is typically associated with frequent inbreeding. Populations that have a history of no management through translocations harbored the greatest number of unique alleles and overall allelic richness, especially in a subset of the Mexican populations. Finally, long-term cohort sampling at one specific site (the Southwestern Research Station in Portal, Arizona) allowed us to demonstrate how rapidly genetic diversity can decrease across a matter of years in a population with few founders. This work shows how microsatellite markers can provide important context for conservation agencies, but even a large suite of markers beyond what is typical may not be enough for populations that are extremely bottlenecked and have low levels of standing genetic diversity.