bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating intra-subject and inter-subject oxygen consumption in outdoor human gait using multiple neural network approaches
Authors: Müller Philipp , Pham-Dinh Khoa , Trinh Huy , Rauhameri Anton , Cronin Neil J. 
Published: April 2024

AbstractOxygen consumptionis an important parameter for exercise test, such as walking and running, that can be measured using portable spirometers or metabolic analyzers. However, these devices are not feasible for regular use by consumers as they intervene with the user’s physical integrity, and are expensive and difficult to operate. To circumvent these drawbacks, indirect estimation ofusing neural networks combined with motion parameters and heart rate measurements collected with consumer-grade sensors has been shown to yield reasonably accuratefor intra-subject estimation. However, estimatingwith neural networks trained with data from other individuals than the user, known as inter-subject estimation, remains an open problem. In this paper, five types of neural network were tested in various configurations for inter-subjectestimation. To analyse predictive performance, data from 16 participants walking and running at speeds between 1.0 m/s and 3.3 m/s were used. The most promising approach was XceptionNet, which in most configurations even yielded a lower average estimation error than the LSTM neural network from an earlier study for intra-subject estimation. This suggests that XceptionNet could be embedded in portable devices for real-time estimation of oxygen consumption during walking and running.
Productivity and resilience of Chinook salmon compromised by ‘Mixed-Maturation’ fisheries in marine waters
Authors: Gayeski Nick , Swanson Devin , MacDuffee Misty , Rosenberger Andrew 
Published: April 2024

AbstractMost Chinook salmon (Oncorhynchus tshawytscha) in the northeast Pacific Ocean are harvested in mixed-stock marine fisheries. Here, multiple populations with varying abundance and productivities are encountered. In addition, many of these fisheries generally encounter both mature and immature Chinook. Hence, these fisheries are better described as mixed-stock and “mixed-maturation” (MM) fisheries. Harvest of immature fish can skew the age composition of Chinook populations towards younger, and hence smaller, individuals. Older Chinook are generally larger and contribute disproportionately to the productivity of their populations. We developed an individual-based demographic-genetic model of ocean-type Chinook to evaluate the effects of fisheries that harvest immature Chinook. We then compared those effects to terminal fisheries that harvest only mature fish. Our model provides the ability to assess the benefits of terminal Chinook fisheries to both landed catch and Chinook rebuilding. Recovered populations show a more archetypal age– and sex-structure than contemporary ocean-type Chinook subject to marine mixed-maturation fisheries. In our modeled scenarios of mixed-maturation fisheries, we found that immature Chinook can comprise up to 59% of the total numbers of fish caught, and 47% of the total weight of the catch. If instead, these Chinook were not harvested until they mature and reach terminal fisheries, they would contribute greater biomass to landed catches. These terminal fisheries allow a higher percentage of larger, older Chinook to escape, and would increase the fecundity and productivities of their populations. The benefits of terminal fisheries would accrue to fishers, sustainable wild harvesting, wildlife, and the rebuilding of depleted Chinook runs.
Tumor-expressed SPPL3 supports innate anti-tumor immune responses
Authors: Verkerk Tamara , de Waard Antonius A. , Koomen Sofie J.I. , Sanders Jasper , Jorritsma Tineke , Pappot Anouk T. , Zandhuis Nordin D. , Zhang Tao , Wuhrer Manfred , Stockinger Hannes S.J. , van Gisbergen Klaas P.J.M. , Spaapen Robbert M. , van Ham S. Marieke 
Published: April 2024

AbstractThe development of an effective anti-tumor response relies on the synergistic actions of various immune cells that recognize tumor cells via distinct receptors. Tumors, however, often manipulate receptor-ligand interactions to evade recognition by the immune system. Recently, we highlighted the role of neolacto-series glycosphingolipids (nsGSLs), produced by the enzyme β1,3-N-acetylglucosaminyltransferase 5 (B3GNT5), in tumor immune escape. We previously demonstrated that loss of signal peptidase like 3 (SPPL3), an inhibitor of B3GNT5, results in elevated levels of nsGSLs and impairs CD8 T cell activation. The impact of loss of SPPL3 and an elevated nsGSL profile in tumor cells on innate immune recognition remains to be elucidated. This study investigates the anti-tumor efficacy of neutrophils, NK cells, and γδ T cells on tumor cells lacking SPPL3. Our findings demonstrate that SPPL3-deficient target cells are less susceptible to trogocytosis by neutrophils and killing by NK cells and γδ T cells. Mechanistically, SPPL3 influences trogocytosis and γδ T cell instigated killing through modulation of nsGSL expression while SPPL3-mediated reduced killing by NK cells is nsGSL-independent. The nsGSL-dependent SPPL3 sensitivity depends on the proximity of surface receptor domains to the cell membrane and the affinity of receptor-ligand interactions as shown with various sets of defined antibodies.Thus, SPPL3 expression by tumor cells alters crosstalk with immune cells through the receptor-ligand interactome thereby driving escape not only from adaptive but also from innate immunity. These data underline the importance of investigating a potential synergism of GSL synthesis inhibitors with current immune cell activating immunotherapies.
Standardizing protein corona characterization in nanomedicine: a multi-center study to enhance reproducibility and data homogeneity
Authors: Ashkarran Ali Akbar , Gharibi Hassan , Modaresi Seyed Majed , Saei Amir Ata , Mahmoudi Morteza 
Published: April 2024

AbstractOur recent findings reveal substantial variability in the characterization of identical protein corona across different proteomics facilities, demonstrating that protein corona datasets are not easily comparable between independent studies. We have shown that heterogeneity in the final composition of the identical protein corona mainly originates from variations in sample preparation protocols, liquid chromatography mass spectrometry (LC-MS) workflows, and raw data processing. Here, to address this issue, we developed standardized protocols and unified sample preparation workflows, and distributed identical protein corona digests to several proteomics centers that performed better in our previous study. Additionally, we examined the influence of using similar mass spectrometry instruments on data homogeneity. Furthermore, we evaluated whether standardizing database search parameters and data processing workflows could enhance data uniformity. More specifically, our new findings reveal a remarkable, stepwise improvement in protein corona data consistency across various proteomics facilities. Streamlining the whole workflow results in a dramatic increase in protein ID overlaps from 11% for good centers to 40% across core facilities that utilized similar instruments and were subjected to a uniform database search. This comprehensive analysis identifies key factors contributing to data heterogeneity in mass spectrometry-based proteomics of protein corona and plasma-related samples. By streamlining these processes, our findings significantly advance the potential for consistent and reliable nanomedicine-based diagnostics and therapeutics across different studies.
Identifying key regulatory genes in drug resistance acquisition: Modeling pseudotime trajectories of single-cell transcriptome
Authors: Iida Keita , Okada Mariko 
Published: April 2024

AbstractSingle-cell RNA-sequencing (scRNA-seq) technology has provided significant insights into cancer drug resistance at the single-cell level. However, understanding dynamic cell transitions at the molecular systems level remains limited, requiring a systems biology approach. We present an approach that combines mathematical modeling with pseudotime analysis using time-series scRNA-seq data obtained from the breast cancer cell line MCF-7 treated with tamoxifen. Our single-cell analysis identified five distinct subpopulations, including tamoxifen-sensitive and -resistant groups. Using a single-gene mathematical model, we discovered approximately 560–680 genes out of 6,000 exhibiting multistable expression states in each subpopulation, including key estrogen receptor-positive breast cancer cell survival genes, such asRPS6KB1. Bifurcation analysis elucidated their regulatory mechanisms, and we mapped these genes into a molecular network associated with cell survival and metastasis-related pathways. Our modeling approach comprehensively identifies key regulatory genes for drug resistance acquisition, enhancing our understanding of potential drug targets in breast cancer.SummaryDespite recent advancements in experimental technology for genome-wide molecular profiling, our understanding of the dynamic mechanism underlying cancer drug resistance remains limited. In this study, we present an approach that combines mathematical modeling with the pseudotime analysis of single-cell time-series transcriptome data of drug-treated breast cancer cells. Our method identifies approximately 600 genes out of 6,000 exhibiting multistable expression states, includingRPS6KB1, a predictor of poor prognosis, cell survival, and growth in estrogen receptor-positive breast cancers. The bifurcation analysis elucidates the regulatory mechanisms of the key regulatory genes, which can also be mapped into a molecular network based on cell survival and metastasis-related pathways, providing a comprehensive understanding of the interplay between signaling pathways and regulatory genes. Our method serves as a powerful tool for deciphering the complexities of drug resistance mechanisms in human diseases.
Working memory as a representational template for reinforcement learning
Authors: Shibata Kengo , Klar Verena , Fallon Sean J , Husain Masud , Manohar Sanjay G 
Published: April 2024

AbstractWorking memory (WM) and reinforcement learning (RL) both influence decision-making, but how they interact to affect behaviour remains unclear. We assessed whether RL is influenced by the format of visual stimuli in WM, either feature-based or unified, object-based representations. In a pre-registered paradigm, participants learned stimulus-action combinations, mapping four stimuli onto two feature dimensions to one of two actions through probabilistic feedback. In parallel, participants retained the RL stimulus in WM and were asked to recall this stimulus after each trial. Crucially, the format of representation probed in WM was manipulated, with blocks encouraging either separate features or bound objects to be remembered. Incentivising a feature-based WM representation facilitated feature-based learning, shown by an improved choice strategy. This reveals a role of WM in providing sustained internal representations that are harnessed by RL, providing a framework by which these two cognitive processes cooperate.
The adhesion GPCR ADGRV1 controls glutamate homeostasis in hippocampal astrocytes supporting neuron development: first insights into to pathophysiology ofADGRV1-associated epilepsy
Authors: Güler Baran E. , Zorin Mark , Linnert Joshua , Nagel-Wolfrum Kerstin , Wolfrum Uwe 
Published: April 2024

AbstractADGRV1 is the largest member of adhesion G protein-coupled receptor (aGPCR) family. In the cell, aGPCRs have dual roles in cell adhesion and signal transduction. Mutations inADGRV1have been linked not only to Usher syndrome (USH), which causes deaf-blindness, but recently also to various forms of epilepsy. While the USH defects are attributed to the loss of fiber links between membranes formed by the extracellular domain of ADGRV1, the pathomechanisms leading to epilepsy remain elusive to date.Here, we study the specific functions of ADGRV1 in astrocytes where it is highest expressed in the nervous system. Affinity proteomics showed the interaction of ADRGV1 with proteins enriched in astrocytes. Dysregulations of cellular processes important in astrocyte function were indicated by the different transcriptomes of patient-derived cells and Adgrv1-deficent mouse hippocampi compared to appropriate controls. Alteration in morphology and reduced numbers of astrocytes in the hippocampus of Adgrv1-deficent mice. Monitoring the glutamate uptake in colorimetric assay and by live cell imaging of a genetic glutamate reporter consistently showed that glutamate uptake from the extracellular environment is significantly reduced in Adgrv1-deficent astrocytes. Expression analyses of key enzymes of the glutamate-glutamine cycle in astrocytes and the glutamate metabolism indicated imbalanced glutamate homeostasis in Adgrv1-deficient astrocytes. Finally, we provide evidence that the supportive function of astrocytes in neuronal development also relies on ADGRV1 expression in astrocytes. Our data collectively provides first insights into the molecular pathophysiology underlying the development of epilepsy associated with mutations inADGRV1.HighlightsADGRV1 deficiency reduces the number of astrocytes in CA1 and changes the morphology of astrocytes in the hippocampus.ADGRV1 interacts with numerous proteins enriched in astrocytes.Differential transcriptomes revealed differential expression of genes related to glutamate homeostasis and epilepsy in ADGRV1 deficient models.ADGRV1 controls glutamate uptake and regulates homeostasis in astrocytes.ADGRV1 in astrocytes is vital for neuron morphogenesis.First insights into the molecular pathophysiology underlying the development of epilepsy associated with mutations in ADGRV1.Graphical Abstract
Cell Painting and chemical structure read-across can complement each other for rat acute oral toxicity prediction in chemical early de-risking
Authors: Camilleri Fabrice , Wenda Joanna M. , Pecoraro-Mercier Claire , Comet Jean-Paul , Rouquié David 
Published: April 2024

ABSTRACTEarly de-risking decisions in the development of new chemical compounds, enable the identification of novel chemical candidates with improved safety profiles. In vivo studies are traditionally conducted in the early assessment of acute oral toxicity of crop protection products to avoid compounds which are considered “very acutely toxic”, with an in vivo Lethal Dose of 50% (LD50) ≤ 60 mg/kg bodyweight. Those studies are lengthy, costly, and raise ethical concerns, catalyzing the use of non-animal alternatives. The objective of our analysis was to assess the predictive efficacy of read-across approaches for acute oral toxicity in rats, comparing the use of chemical structure information, in vitro biological data derived from the Cell Painting profiling assay on U2OS cells or the combination of both. Our findings indicate that the classification of compounds as very acute oral toxic (LD50 ≤ 60 mg/kg) or not is possible using a read-across approach, with chemical structure information, morphological profiles, or a combination of both. When classifying compounds structurally similar to those in the training set, chemical structure was more predictive (balanced accuracy of 0.82). Conversely, when the compounds to be classified were structurally different from those in the training set, the morphological profiles were more predictive (balanced accuracy of 0.72). Combining the two models allowed for the classification of compounds structurally similar to those in the training set, to slightly improve the predictions (balanced accuracy of 0.85).Abstract FigureFor Table of Contents Only
Sex-Specific Deflection of Age-Related DNA Methylation and Gene Expression in Mouse Heart by Perinatal Toxicant Exposures
Authors: Wang Kai , Sartor Maureen A. , Colacino Justin A. , Dolinoy Dana C. , Svoboda Laurie K. 
Published: April 2024

AbstractBackgroundGlobal and site-specific changes in DNA methylation and gene expression are associated with cardiovascular aging and disease, but how toxicant exposures during early development influence the normal trajectory of these age-related molecular changes, and whether there are sex differences, has not yet been investigated.ObjectivesWe used an established mouse model of developmental exposures to investigate the effects of perinatal exposure to either lead (Pb) or diethylhexyl phthalate (DEHP), two ubiquitous environmental contaminants strongly associated with CVD, on age-related cardiac DNA methylation and gene expression.MethodsDams were randomly assigned to receive human physiologically relevant levels of Pb (32 ppm in water), DEHP (25 mg/kg chow), or control water and chow. Exposures started two weeks prior to mating and continued until weaning at postnatal day 21 (3 weeks of age). Approximately one male and one female offspring per litter were followed to 3 weeks, 5 months, or 10 months of age, at which time whole hearts were collected (n ≥ 5 per sex per exposure). Enhanced reduced representation bisulfite sequencing (ERRBS) was used to assess the cardiac DNA methylome at 3 weeks and 10 months, and RNA-seq was conducted at all 3 time points. MethylSig and edgeR were used to identify age-related differentially methylated regions (DMRs) and differentially expressed genes (DEGs), respectively, within each sex and exposure group. Cell type deconvolution of bulk RNA-seq data was conducted using the MuSiC algorithm and publicly available single cell RNA-seq data.ResultsThousands of DMRs and hundreds of DEGs were identified in control, DEHP, and Pb-exposed hearts across time between 3 weeks and 10 months of age. A closer look at the genes and pathways showing differential DNA methylation revealed that the majority were unique to each sex and exposure group. Overall, pathways governing development and differentiation were most frequently altered with age in all conditions. A small number of genes in each group showed significant changes in DNA methylation and gene expression with age, including several that were altered by both toxicants but were unchanged in control. We also observed subtle, but significant changes in the proportion of several cell types due to age, sex, and developmental exposure.DiscussionTogether these data show that perinatal Pb or DEHP exposures deflect normal age-related gene expression, DNA methylation programs, and cellular composition across the life course, long after cessation of exposure, and highlight potential biomarkers of developmental toxicant exposures. Further studies are needed to investigate how these epigenetic and transcriptional changes impact cardiovascular health across the life course.
Caspar specifies primordial germ cell count and identity inDrosophila melanogaster
Authors: Das Subhradip , Hegde Sushmitha , Wagh Neel , Sudhakaran Jyothish , Roy Adheena Elsa , Deshpande Girish , Ratnaparkhi Girish S 
Published: April 2024

AbstractRepurposing of pleiotropic factors during execution of diverse cellular processes has emerged as a regulatory paradigm. Embryonic development in metazoans is controlled by maternal factors deposited in the egg during oogenesis. Here, we explore maternal role(s) of Caspar (Casp), theDrosophilaorthologue of human Fas-associated factor-1 (FAF1) originally implicated in host-defense as a negative regulator of NF-κB signaling. Maternal loss of either Casp or it’s protein partner, Transitional endoplasmic reticulum 94 (TER94) leads to partial embryonic lethality correlated with aberrant centrosome behavior, cytoskeletal abnormalities, and defective gastrulation. Although ubiquitously distributed, both proteins are enriched in the primordial germ cells (PGCs), and in keeping with the centrosome problems, mutant embryos display a significant reduction in the PGC count. Moreover, the total number of pole buds is directly proportional to the level of Casp. Consistently, it’s ‘loss’ and ‘gain’ results in respective reduction and increase in the Oskar protein levels, the master determinant of PGC fate. To elucidate this regulatory loop, we analyzed several known components of mid-blastula transition and identify the translational repressor Smaug, a zygotic regulator of germ cell specification, as a potential critical target. We present a detailed structure-function analysis of Casp aimed at understanding its novel involvement during PGC development.
APOE3-R136Smutation confers resilience against tau pathology via cGAS-STING-IFN inhibition
Authors: Naguib Sarah , Lopez-Lee Chloe , Torres Eileen Ruth , Lee Se-In , Zhu Jingjie , Zhu Daphne , Ye Pearly , Norman Kendra , Zhao Mingrui , Wong Man Ying , Ambaw Yohannes A. , Castaneda Rodrigo , Wang Wei , Patel Tark , Bhagwat Maitreyee , Norinsky Rada , Mok Sue-Ann , Walther Tobias C. , Farese Robert V. , Luo Wenjie , Sinha Subhash , Wu Zhuhao , Fan Li , Gong Shiaoching , Gan Li 
Published: April 2024

SummaryThe Christchurch mutation (R136S) on theAPOE3(E3S/S) gene is associated with attenuation of tau load and cognitive decline despite the presence of a causalPSEN1mutation and high levels of amyloid beta pathology in the carrier1. However, the specific molecular mechanisms enabling theE3S/Smutation to mitigate tau-induced neurodegeneration remain unclear. Here, we replaced mouseApoEwith wild-type humanE3orE3S/Son a tauopathy background. TheR136Smutation markedly decreased tau load and protected against tau-induced synaptic loss, myelin loss, and reduction in theta and gamma powers. Additionally, theR136Smutation reduced interferon response to tau pathology in both mouse and human microglia, suppressing cGAS-STING activation. Treating tauopathy mice carrying wild-typeE3with a cGAS inhibitor protected against tau-induced synaptic loss and induced similar transcriptomic alterations to those induced by theR136Smutation across brain cell types. Thus, suppression of microglial cGAS-STING-IFN pathway plays a central role in mediating the protective effects ofR136Sagainst tauopathy.One-sentence summaryThe R136S mutation on APOE3 enhances resistance to tau-related pathology and toxicity by downregulating the cGAS-STING-IFN signaling pathway.
The Role of Similarity of Stimuli and Responses in Learning by Nectar-Foraging Bumble Bees: A Test of Osgood’s Model
Authors: Baek Minjung , Papaj Daniel R. 
Published: April 2024

AbstractLearning stimulus – response associations helps animals to adjust to changing environments. Sequentially learned associations may interact with each other, either reinforcing memory, a process referred to as ‘transfer’, or hindering memory, a process referred to as ‘interference.’ According to Osgood’s (1949) model, close similarity between new and previously learned stimuli can enhance the transfer of memory through a process of stimulus generalization. In contrast, the model proposes that if responses are different from those previously learned, generalizing stimuli may lead to confusion, resulting in the interference of memory. Except for some work in humans, the interaction between stimulus similarity and response similarity is poorly documented. Here, we tested Osgood’s model using bumble bees (Bombus impatiens) foraging for sucrose on artificial flowers with varied colours (= stimuli) that required either legitimate visitation or nectar robbing (= responses). Bees were first allowed to forage on one type of flower, were then switched to another, and finally were returned to the initial flower type. We measured learning performance via flower handling time and the number of failed visits. Consistent with Osgood’s model, bees made more failed visits when they switched between similarly coloured flowers requiring different foraging techniques but made fewer failed visits when switching between similarly coloured flowers with the same technique. Regardless of similarities in stimuli or responses, however, experienced bees were faster in handling flowers than were naïve bees. Results taken together thus provided mixed support for Osgood’s model. Possible explanations for the mixed results are discussed.