bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Machine Learning Framework to Identify the Correlates of Disease Severity in Acute Arbovirus Infection
Authors: Herder Vanessa , Caporale Marco , MacLean Oscar A , Pintus Davide , Huang Xinyi , Nomikou Kyriaki , Palmalux Natasha , Nichols Jenna , Scivoli Rosario , Boutell Chris , Taggart Aislynn , Allan Jay , Malik Haris , Ilia Georgios , Gu Quan , Ronchi Gaetano Federico , Furnon Wilhelm , Zientara Stephan , Bréard Emmanuel , Antonucci Daniela , Capista Sara , Giansante Daniele , Cocco Antonio , Mercante Maria Teresa , Di Ventura Mauro , Filipe Ana Da Silva , Puggioni Giantonella , Sevilla Noemi , Stewart Meredith E. , Ligios Ciriaco , Palmarini Massimo 
Published: February 2024

AbstractMost viral diseases display a variable clinical outcome due to differences in virus strain virulence and/or individual host susceptibility to infection. Understanding the biological mechanisms differentiating a viral infection displaying severe clinical manifestations from its milder forms can provide the intellectual framework toward therapies and early prognostic markers. This is especially true in arbovirus infections, where most clinical cases are present as mild febrile illness. Here, we used a naturally occurring vector-borne viral disease of ruminants, bluetongue, as an experimental system to uncover the fundamental mechanisms of virus-host interactions resulting in distinct clinical outcomes. As with most viral diseases, clinical symptoms in bluetongue can vary dramatically. We reproduced experimentally distinct clinical forms of bluetongue infection in sheep using three bluetongue virus (BTV) strains (BTV-1IT2006, BTV-1IT2013and BTV-8FRA2017). Infected animals displayed clinical signs varying from clinically unapparent, to mild and severe disease. We collected and integrated clinical, haematological, virological, and histopathological data resulting in the analyses of 332 individual parameters from each infected and uninfected control animal. We subsequently used machine learning to identify the key viral and host processes associated with disease pathogenesis. We identified five different fundamental processes affecting the severity of bluetongue: (i) virus load and replication in target organs, (ii) modulation of the host type-I IFN response, (iii) pro-inflammatory responses, (iv) vascular damage, and (v) immunosuppression. Overall, our study using an agnostic machine learning approach, can be used to prioritise the different pathogenetic mechanisms affecting the disease outcome of an arbovirus infection.
Canonical AREs are tumor suppressive regulatory elements in the prostate
Authors: Augello Michael A. , Chen Xuanrong , Liu Deli , Lin Kevin , Hakansson Alex , Sjöström Martin , Khani Francesca , Deonarine Lesa D. , Liu Yang , Travascio-Green Jaida , Wu Jiansheng , Loda Massimo , Feng Felix Y. , Robinson Brian D. , Davicioni Elai , Sboner Andrea , Barbieri Christopher E. 
Published: February 2024

AbstractThe androgen receptor (AR) is the central determinant of prostate tissue identity and differentiation, controlling normal, growth-suppressive prostate-specific gene expression1. It is also a key driver of prostate tumorigenesis, becoming “hijacked” to drive oncogenic transcription2-5. However, the regulatory elements determining the execution of the growth suppressive AR transcriptional program, and whether this can be reactivated in prostate cancer (PCa) cells remains unclear. Canonical androgen response element (ARE) motifs are the classic DNA binding element for AR6. Here, we used a genome-wide strategy to modulate regulatory elements containing AREs to define distinct AR transcriptional programs. We find that activation of these AREs is specifically associated with differentiation and growth suppressive transcription, and this can be reactivated to cause death in AR+PCa cells. In contrast, repression of AREs is well tolerated by PCa cells, but deleterious to normal prostate cells. Finally, gene expression signatures driven by ARE activity are associated with improved prognosis and luminal phenotypes in human PCa patients. This study demonstrates that canonical AREs are responsible for a normal, growth-suppressive, lineage-specific transcriptional program, that this can be reengaged in PCa cells for potential therapeutic benefit, and genes controlled by this mechanism are clinically relevant in human PCa patients.
Miniature linear and split-belt treadmills reveal mechanisms of adaptive motor control in walkingDrosophila
Authors: Pratt Brandon G. , Lee Su-Yee J. , Chou Grant M. , Tuthill John C. 
Published: February 2024

AbstractTo navigate complex environments, walking animals must detect and overcome unexpected perturbations. One technical challenge when investigating adaptive locomotion is measuring behavioral responses to precise perturbations during naturalistic walking; another is that manipulating neural activity in sensorimotor circuits often reduces spontaneous locomotion. To overcome these obstacles, we introduce miniature treadmill systems for coercing locomotion and tracking 3D kinematics of walkingDrosophila. By systematically comparing walking in three experimental setups, we show that flies compelled to walk on the linear treadmill have similar stepping kinematics to freely walking flies, while kinematics of tethered walking flies are subtly different. Genetically silencing mechanosensory neurons alters step kinematics of flies walking on the linear treadmill across all speeds, while inter-leg coordination remains intact. We also found that flies can maintain a forward heading on a split-belt treadmill by adapting the step distance of their middle legs. Overall, these new insights demonstrate the utility of miniature treadmills for studying insect locomotion.
RinRK1 Promotes Accumulation of Nod Factor Receptors in Nanodomain-like structures at the tip of infected root hairs
Authors: Zhou Ning , Li Xiaolin , Zheng Zhiqiong , Liu Jing , Downie J. Allan , Xie Fang 
Published: February 2024

ABSTRACTLegume-rhizobia root-nodule symbioses involve the recognition of rhizobial Nod factor (NF) signals by NF receptors, triggering both nodule organogenesis and rhizobial infection.RinRK1is induced by NF signaling and is essential for infection thread (IT) formation inLotus japonicus. However, the precise mechanism underlying this process remains unknown. Here, we show that RinRK1 interacts with the extracellular domains of NF receptors NFR1 and NFR5 to promote their accumulation at root hair tips in response to rhizobia or NFs. Furthermore, Flotillin 1 (Flot1), a nanodomain-organizing protein, associates with the kinase domains of NFR1, NFR5 and RinRK1. RinRK1 promotes the interactions between Flot1 and NFR1 or NFR5 and both RinRK1 and Flot1 are necessary for the accumulation of NFR1 and NFR5 at root hair tips upon NF stimulation. Our study show that RinRK1 and Flot1 play a crucial role in NF receptor complex assembly within localized plasma membrane signaling centers to promote symbiotic infection.
High-confidence calling of normal epithelial cells allows identification of a novel stem-like cell state in the colorectal cancer microenvironment
Authors: Wei Tzu-Ting , Blanc Eric , Peidli Stefan , Bischoff Philip , Trinks Alexandra , Horst David , Sers Christine , Blüthgen Nils , Beule Dieter , Morkel Markus , Obermayer Benedikt 
Published: February 2024

AbstractSingle-cell analyses can be confounded by assigning unrelated groups of cells to common developmental trajectories. For instance, cancer cells and admixed normal epithelial cells could potentially adopt similar cell states thus complicating analyses of their developmental potential. Here, we develop and benchmark CCISM (for Cancer Cell Identification using Somatic Mutations) to exploit genomic single nucleotide variants for the disambiguation of cancer cells from genomically normal non-cancer epithelial cells in single-cell data. In colorectal cancer datasets, we find that our method and others based on gene expression or allelic imbalances identify overlapping sets of cancer versus normal epithelial cells, depending on molecular characteristics of individual cancers. Further, we define consensus cell identities of normal and cancer epithelial cells with higher transcriptome cluster homogeneity than those derived using existing tools. Using the consensus identities, we identify significant shifts of cell state distributions in genomically normal epithelial cells developing in the cancer microenvironment, with immature states increased at the expense of terminal differentiation throughout the colon, and a novel stem-like cell state arising in the left colon. Trajectory analyses show that the new cell state extends the pseudo-time range of normal colon stem-like cells in a cancer context. We identify cancer-associated fibroblasts as sources of WNT and BMP ligands potentially contributing to increased plasticity of stem cells in the cancer microenvironment. Our analyses advocate careful interpretation of cell heterogeneity and plasticity in the cancer context and the consideration of genomic information in addition to gene expression data when possible.Novelty and ImpactSingle-cell analyses have become standard to assess cell heterogeneity and developmental hierarchies in cancer tissues. However, these datasets are complex and contain cancer and non-cancer lineage cells. Here, we develop and systematically benchmark tools to distinguish between cancer and non-cancer single-cell transcriptomes, based on gene expression or different levels of genomic information. We provide strategies to combine results of different tools into consensus calls tailored to the biology and genetic characteristics of the individual cancer.
Role of PLK1 in the epigenetic maintenance of centromeres
Authors: Conti Duccio , Verza Arianna Esposito , Pesenti Marion E. , Cmentowski Verena , Vetter Ingrid R. , Pan Dongqing , Musacchio Andrea 
Published: February 2024

AbstractThe centromere, a chromosome locus defined by the histone H3-like protein CENP-A, seeds the kinetochore to bind microtubules during cell division. Centromere maintenance requires CENP-A to be actively replenished by dedicated protein machinery in the early G1 cell-cycle phase, compensating for its two-fold dilution following DNA replication. Cyclin-dependent kinases (CDKs) limit CENP-A deposition to once per cell cycle and function as negative regulators outside early G1. Antithetically, Polo-like kinase 1 (PLK1) promotes CENP-A deposition in early G1, but the molecular details are still unknown. We reveal a phosphorylation network that recruits PLK1 to the deposition machinery to control a conformational switch required for licensing the CENP-A deposition reaction. Our findings solve the long-standing question of how PLK1 contributes to the epigenetic maintenance of centromeres.One-Sentence SummaryPLK1 licenses epigenetic maintenance of centromeres by regulating a conformational switch on the MIS18α protein.
Memory load influences our preparedness to act on visual representations in working memory without affecting their accessibility
Authors: Nasrawi Rose , Mautner-Rohde Mika , van Ede Freek 
Published: February 2024

ABSTRACTIt is well established that when we hold more content in working memory, we are slower to act upon specific content when it becomes relevant for behavior. Here, we asked whether slower responses with higher working-memory load can be accounted for by slower access to sensory representations held in working memory (according to a serial internal search), or by a lower preparedness to act upon them. To address this, we designed a visual-motor working-memory task in which participants memorized the orientation of two or four colored bars, of which one was cued for reproduction. We independently tracked the selection of visual (cued item location) and motor (relevant manual action) information from the EEG time-frequency signal, and compared their latencies between our memory-load conditions. We confirm slower memory-guided behavior with higher working-memory load and show that this is associated with delayed motor selection, but find no evidence for a concomitant delay in the latency of visual selection. Moreover, we show that variability in decision times within each memory-load condition is associated with corresponding changes in the latency of motor, but not visual selection. These results reveal how memory load affects our preparedness to act on, without necessarily changing the ability to access, sensory representations in working memory. This posits action readiness is a key factor that shapes the speed of memory-guided behavior and that underlies delayed responses with higher working-memory load.
Impacts of a prolonged marine heatwave and chronic local human disturbance on juvenile coral assemblages
Authors: Tietjen Kristina L. , Perks Nelson F. , O’Brien Niallan C. , Baum Julia K. 
Published: February 2024

AbstractCoral reefs are threatened by climate change and chronic local human disturbances. Although some laboratory studies have investigated the effects of combined stressors, such as nutrient enrichment and heat stress, on growth and survival of early life stage corals,in situstudies remain limited. To assess the influence of multiple stressors on juvenile corals, we quantified densities of corals ≤5 cm at 18 forereef sites with different exposure levels to underlying chronic local human disturbance before, during, and after the 2015-2016 El Niño. This marine heatwave caused prolonged heat stress and devastating losses of coral cover at our study site, Kiritimati, in the central equatorial Pacific Ocean. In total, we enumerated 7732 juvenile corals from 13 different families. Over 80% of corals were from four families: 70% from Agariciidae, Merulinidae, or Poritidae, which all have stress-tolerant life history strategies, and 11% from Acroporidae which has a competitive life-history strategy. Both local disturbance and heat stress were significantly negatively related to juvenile coral densities. Prior to the heatwave, juvenile densities were on average 72% lower at the most disturbed sites (7.2 ± 1.9 m2) compared to the least disturbed ones (15.3 ± 3.8 m2). Overall, juvenile corals had a lower bleaching prevalence and lower mortality during the heatwave when compared to their adult counterparts. Still, the heatwave resulted in the loss of half (50%) of all juvenile corals, with competitive and weedy life history strategy corals undergoing greater declines than stress-tolerant ones. Although juvenile coral densities increased slightly in the year following the heatwave, the effect was statistically non-significant. Our results highlight the influence of local chronic anthropogenic and climate change-driven marine heatwaves on juvenile coral densities.
Mammalian Cell Models of the Distal Convoluted Tubule: A Systematic Review of Cell Lines, Culture Condition and Gene Expression
Authors: Zhong Chutong , Sun Zhen , Grillo Alessandra , Walsh Stephen B , Siew Keith 
Published: February 2024

ABSTRACTThis review examines the crucial role of human cellular models in renal physiology research, with a specific focus on the distal convoluted tubule (DCT). It aims to provide a comprehensive summary of the origins, culture practices, and genetic studies associated with commonly employed DCT cell models. To achieve this, a systematic literature review was performed on Europe PMC, employing a Boolean search strategy. A total of 6,559 articles were initially screened, resulting in 301 articles on human-origin cell models, 69 on murine models, and 29 on canine models being included in the final analysis. Notably, the review identified two studies that introduced novel immortalised human DCT cell lines developed from primary DCT cells. This paper provides a detailed account of the lineage of each cell model, their prevalent culture conditions, and the frequency and nature of gene transfections—both wild type and mutant—conducted in these models. A significant observation from the analysis was the inconsistent reporting of methodological details across studies, which compromises the reproducibility of the research. Additionally, there was a considerable variation in culture conditions and transfection methods used across different studies. The review also highlights that HEK293 family and murine DCT cell lines do not serve as accurate models for DCT cells, pointing out the frequent need for transfecting DCT-specific genes to simulate DCT functionality adequately.NEW & NOTEWORTHYThis review is the first review to detail the current state of play with cell models of the distal convoluted tubule, including endogenous protein expression, culture conditions etc. We expect this review to be of great utility to established and early career researchers who are interested in nephrological or hypertensive patho/physiology. We have highlighted some important gaps in reporting the established cell models, we think that this kind of review is important for open science.
Evaluation of Bayesian Linear Regression Derived Gene Set Test Methods
Authors: Bai Zhonghao , Gholipourshahraki Tahereh , Shrestha Merina , Hjelholt Astrid , Kjølby Mads , Rohde Palle Duun , Sørensen Peter 
Published: February 2024

AbstractGene set tests can pinpoint genes and biological pathways that exert small to moderate effects on complex diseases like Type 2 Diabetes (T2D). By aggregating genetic markers based on biological information, these tests can enhance the statistical power needed to detect genetic associations. Our goal was to develop a gene set test utilizing Bayesian Linear Regression (BLR) models, which account for both linkage disequilibrium (LD) and the complex genetic architectures intrinsic to diseases, thereby increasing the detection power of genetic associations. Through a series of simulation studies, we demonstrated how the efficacy of BLR derived gene set tests is influenced by several factors, including the proportion of causal markers, the size of gene sets, the percentage of genetic variance explained by the gene set, and the genetic architecture of the traits. Comparing our method with other approaches, such as the gold standard MAGMA (Multi-marker Analysis of Genomic Annotation) approach, our BLR gene set test showed superior performance. This suggests that our BLR-based approach could more accurately identify genes and biological pathways underlying complex diseases.
Structural Determinants for Activity of the Antidepressant Vortioxetine at Human and Rodent 5-HT3receptors
Authors: López-Sánchez Uriel , Munro Lachlan Jake , Ladefoged Lucy Kate , Pedersen Anders Juel , Nielsen Christian C. , Lyngby Signe M. , Baud Delphine , Lummis Sarah C. R. , Bang-Andersen Benny , Schiøtt Birgit , Chipot Christophe , Schoehn Guy , Neyton Jacques , Dehez Francois , Nury Hugues , Kristensen Anders S. 
Published: February 2024

SummaryVortioxetine (VTX) is a recent antidepressant that targets a variety of serotonin receptors. We investigate the drug’s molecular mechanism of operation at serotonin 5-HT3receptors (5-HT3R), which features two mysterious properties: VTX acts differently on rodent and human 5-HT3R; VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT3R and an agonist bound-like state of the human 5-HT3R, in line with the functional profile of the drug. We report four human 5-HT3R structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism.
Design, optimization, and inference of biphasic decay of infectious virus particles
Authors: Seurat Jérémy , Gerbino Krista R. , Meyer Justin R. , Borin Joshua M. , Weitz Joshua S. 
Published: February 2024

AbstractVirus population dynamics are driven by counter-balancing forces of production and loss. Whereas viral production arises from complex interactions with susceptible hosts, the loss of infectious virus particles is often approximated as a first-order kinetic process. As such, experimental protocols to measure infectious virus loss are not typically designed to identify non-exponential decay processes. Here, we propose methods to evaluate if an experimental design is adequate to identify multiphasic virus particle decay and to optimize the sampling times of decay experiments, accounting for uncertainties in viral kinetics. First, we evaluate synthetic scenarios of biphasic decays, with varying decay rates and initial proportions of subpopulations. We show that robust inference of multiphasic decay is more likely when the faster decaying subpopulation predominates insofar as early samples are taken to resolve the faster decay rate. Moreover, design optimization involving non-equal spacing between observations increases the precision of estimation while reducing the number of samples. We then apply these methods to infer multiple decay rates associated with the decay of bacteriophage (‘phage’) ΦD9, an evolved isolate derived from phage Φ21. A pilot experiment confirmed that ΦD9 decay is multiphasic, but was unable to resolve the rate or proportion of the fast decaying subpopulation(s). We then applied a Fisher information matrix-based design optimization method to propose nonequally spaced sampling times. Using this strategy, we were able to robustly estimate multiple decay rates and the size of the respective subpopulations. Notably, we conclude that the vast majority (94%) of the phage ΦD9 population decays at a rate 16-fold higher than the slow decaying population. Altogether, these results provide both a rationale and a practical approach to quantitatively estimate heterogeneity in viral decay.
C. elegansdisplay antipathy behavior towards food after contemporaneous integration of nutritional needs and dietary lipid availability
Authors: Stuhr Nicole L. , Ramos Carmen M. , Turner Chris D. , Soukas Alexander A. , Curran Sean P. 
Published: February 2024

SUMMARYOrganisms utilize sophisticated neurocircuitry to select optimal food sources within their environment.Methylobacteriumis a lifespan-promoting bacterial diet forC. elegansthat drives faster development and longevity, however after ingestion,C. elegansconsistently choose any other food option available. A screen for genetic regulators of the avoidance behavior towardMethylobacteriumidentified the AWB and AWC sensory neurons and theodr-1guanylate cyclase expressed exclusively in those four ciliated neurons as mediators of the antipathy response. Metabolic profiling of theMethylobacteriumdiet reveals a macromolecular profile enriched in saturated fats and here we show thatC. eleganssense and integrate signals related to the type of ingested lipids that subsequently cues food-related behaviors. Moreover, disruption of endogenous lipid metabolism modifies the intensity of antipathy towardMethylobacteriumwhich suggests that the current state of lipid homeostasis influences food preference. Enhanced expression of the sphingolipid degradation enzyme Saposin/spp-9enhances antipathy behaviors and activation of the sphingosine rheostat and more specifically modulation of the bioactive lipid mediator sphingosine-1-phosphate (S1P) acts as a signal to promote avoidance ofMethylobacterium. Taken together, our work reveals thatC. elegansmodify food choices contemporaneously based on the availability of dietary lipids and the ability to metabolize dietary lipids.HIGHLIGHTSUncover new molecular mechanisms underlying the decision matrix an animal uses to choose what foods to eat.Define the molecular mechanisms underlying an antipathy behavioral response toward foods after initial ingestion that contemporaneously integrates dietary needs with nutritional profile.ODR-1 signaling from AWB and AWC ciliated neurons of theC. elegansnervous system mediate the antipathy response to diet.Manipulation of sphingosine-1-phosphate (S1P) of the sphingosine rheostat controls the intensity of the antipathy behavioral response.Modulating antipathy behaviors can impact the magnitude of the lifespan-promoting effects of longevity diets.