bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Association between the JAK-STAT Pathway and Hypertension among Kenyan Women Diagnosed with Breast Cancer
Authors: Gitau John , Kinyori Godfrey , Sayed Shahin , Saleem Mohammad , Makokha Francis W , Kirabo Annet 
Published: June 2024

AbstractBackgroundBreast cancer is the most common malignant tumor in women worldwide, and disproportionately affects Sub-Saharan Africa compared to high income countries. The global disease burden is growing, with Sub-Saharan Africa reporting majority of the cases. In Kenya, breast cancer is the most commonly diagnosed cancer, with an annual incidence of 7,243 new cases in 2022, representing 25.5% of all reported cancers in women. Evidence suggests that women receiving breast cancer treatment are at a greater risk of developing hypertension than women without breast cancer. Hypertension prevalence has been on the rise in SSA, with poor detection, treatment and control. The JAK-STAT signaling is activated in hormone receptor-positive breast tumors, leading to inflammation, cell proliferation, and treatment resistance in cancer cells. We sought to understand the association between the expression of JAK-STAT Pathway genes and hypertension among Kenyan women diagnosed with breast cancer.MethodsBreast tumor and non-tumor tissues were acquired from patients with a pathologic diagnosis of invasive breast carcinoma. RNA was extracted from fresh frozen tumor and adjacent normal tissue samples of 23 participants who had at least 50% tumor after pathological examination, as well as their corresponding adjacent normal samples. Differentially expressed JAK-STAT genes between tumor and normal breast tissues were assessed using the DESEq2 R package. Pearson correlation was used to assess the correlation between differentially expressed JAK-STAT genes and participants’ blood pressure, heart rate, and body mass index (BMI).Results11,868 genes were differentially expressed between breast tumor and non-tumor tissues. Eight JAK-STAT genes were significantly dysregulated (Log2FC ≥ 1.0 and an Padj ≤ 0.05), with two genes (CISH and SCNN1A) being upregulated. Six genes (TGFBR2, STAT5A, STAT5B, TGFRB3, SMAD9, and SOCS2) were downregulated. We identified STAT5A and SOCS2 genes to be significantly correlated with elevated systolic pressure and heart rate, respectively.ConclusionsOur study provides insights underlying the molecular mechanisms of hypertension among Kenyan women diagnosed with breast cancer. Understanding these mechanisms may help develop targeted treatments that may improve health outcomes of Kenyan women diagnosed with breast cancer. Longitudinal studies with larger cohorts will be needed to validate our results.
Optimization of systemic AAV9 gene therapy in Niemann-Pick disease type C1 mice
Authors: Mylvara Avani V. , Gibson Alana L. , Gu Tansy , Davidson Cristin D. , Incao Art A. , Melnyk Katerina , Pierre-Jacques Dominick , Cologna Stephanie M. , Venditti Charles P. , Porter Forbes D. , Pavan William J. 
Published: June 2024

AbstractNiemann-Pick disease, type C1 (NPC1) is a rare, fatal neurodegenerative disorder caused by pathological variants inNPC1, which encodes a lysosomal cholesterol transport protein. There are no FDA approved treatments for this disorder. Both systemic and central nervous system delivery of AAV9-hNPC1have shown significant disease amelioration in NPC1 murine models. To assess the impact of dose and window of therapeutic efficacy inNpc1m1Nmice, we systemically administered three different doses of AAV9-hNPC1at 4 weeks old and the medium dose at pre-, early, and post-symptomatic timepoints. Higher vector doses and treatment earlier in life were associated with enhanced transduction in the nervous system and resulted in significantly increased lifespan. Similar beneficial effects were noted after gene therapy inNpc1I1061Tmice, a model that recapitulates a common human hypomorphic variant. Our findings help define dose ranges, treatment ages, and efficacy in severe and hypomorphic models of NPC1 deficiency and suggest that earlier delivery of AAV9-hNPC1in a pre-symptomatic disease state is likely to yield optimal outcomes in individuals with NPC1.Summary BlurbSystemic AAV9-hNPC1gene therapy in nullNpc1m1Nmice at higher doses or with earlier administration and treatment of hypomorphicNpc1I1061Tmice delays disease progression and increases lifespan.
Multimodal framework to resolve variants of uncertain significance inTSC2
Authors: Biar Carina G , Pfeifer Cole , Carvill Gemma L , Calhoun Jeffrey D 
Published: June 2024

AbstractEfforts to resolve the functional impact of variants of uncertain significance (VUS) have lagged behind the identification of new VUS; as such, there is a critical need for scalable VUS resolution technologies. Computational variant effect predictors (VEPs), once trained, can predict pathogenicity for all missense variants in a gene, set of genes, or the exome. Existing tools have employed information on known pathogenic and benign variants throughout the genome to predict pathogenicity of VUS. We hypothesize that taking a gene-specific approach will improve pathogenicity prediction over globally-trained VEPs. We tested this hypothesis using the geneTSC2, whose loss of function results in tuberous sclerosis, a multisystem mTORopathy affecting about 1 in 6,000 individuals born in the United States.TSC2has been identified as a high-priority target for VUS resolution, with (1) well-characterized molecular and patient phenotypes associated with loss-of-function variants, and (2) more than 2,700 VUS already documented in ClinVar. We developedTuberous sclerosis classifier toResolve variants ofUncertainSignificance inTSC2(TRUST), a machine learning model to predict pathogenicity ofTSC2missense VUS. To test whether these predictions are accurate, we further introduce curated loci prime editing (cliPE) as an accessible strategy for performing scalable multiplexed assays of variant effect (MAVEs). Using cliPE, we tested the effects of more than 200TSC2variants, including 106 VUS. It is highly likely this functional data alone would be sufficient to reclassify 92 VUS with most being reclassified as likely benign. We found that TRUST’s classifications were correlated with the functional data, providing additional validation for thein silicopredictions. We provide our pathogenicity predictions and MAVE data to aid with VUS resolution. In the near future, we plan to host these data on a public website and deposit into relevant databases such as MAVEdb as a community resource. Ultimately, this study provides a framework to complete variant effect maps ofTSC1andTSC2and adapt this approach to other mTORopathy genes.
Combining supervised and unsupervised analyses to quantify behavioral phenotypes and validate therapeutic efficacy in a triple transgenic mouse model of Alzheimer’s disease
Authors: Del Rosario Hernandez Thais , Joshi Narendra R. , Gore Sayali V. , Kreiling Jill A. , Creton Robbert 
Published: June 2024

AbstractBehavioral testing is an essential tool for evaluating cognitive function and dysfunction in preclinical research models. This is of special importance in the study of neurological disorders such as Alzheimer’s disease. However, the reproducibility of classic behavioral assays is frequently compromised by interstudy variation, leading to ambiguous conclusions about the behavioral markers characterizing the disease. Here, we identify age- and genotype-driven differences between 3xTg-AD and non-transgenic control mice using a low-cost, highly customizable behavioral assay that requires little human intervention. Through behavioral phenotyping combining both supervised and unsupervised behavioral classification methods, we are able to validate the preventative effects of the immunosuppressant cyclosporine A in a rodent model of Alzheimer’s disease, as well as the partially ameliorating effects of candidate drugs nebivolol and cabozantinib.Abstract Figure
The transient and dynamic nature of splitter cells derive from behavior
Authors: Chaix-Eichel Naomi , Dagar Snigdha , Alexandre Fréderic , Boraud Thomas , Rougier Nicolas P. 
Published: June 2024

AbstractOver the past decades, the hippocampal formation has undergone extensive studies leading researchers to identify a vast collection of cells with functional properties. The origin of such cells has been the topic of several investigations complemented with carefully crafted models whose latest hypothesized the role of temporal sequences to be the probable cause of observed spatial properties. We aim at investigating whether a random recurrent structure is sufficient to allow for such latent sequence to appear. To do so, we simulated an agent with egocentric sensory inputs that must navigate and alternate choices at intersections. We were subsequently able to identify several splitter cells inside the model. Lesioning those cells induce the incapacity for the agent to solve the task unless some hyper-parameters are tuned. In such case, new splitter cells appear even though the initial structure of the networks has been conserved. These results tend to show that splitter cells activity may appear spontaneously inside a random reccurrent network as long as the agent is performing the alternating task. These results may also modify our view regarding the origin on splitter cells. They are not the cause nor the consequence of learning and behavior.
Activation of three targets by a TAL effector confers susceptibility to bacterial blight of cotton
Authors: Mormile Brendan , Bauer Taran , Wang Li , Rivero Rachel , Carpenter Sara C.D. , Danmaigona-Clement Catherine , Cox Kevin , Zhang Lin , Ma Xiyu , Wheeler Terry A. , Dever Jane K. , He Ping , Bogdanove Adam J. , Shan Libo 
Published: June 2024

ABSTRACTXanthomonasspp. employ transcription activator-like effectors (TALEs) to promote pathogenicity by activating host susceptibility (S) genes. CottonGhSWEET10is anSgene targeted by a TALE in an early isolate ofXanthomonas citripv.malvacearum(Xcm), but not by recent fieldXcmisolates. To understand the pathogenicity shift inXcmand its adaptation to cotton, we assembled the whole genome and the TALE repertoire of three recentXcmTexas field isolates. A newly evolved TALE, Tal7b, activated differentGhSWEETgenes,GhSWEET14aandGhSWEET14b. Simultaneous activation ofGhSWEET14aandGhSWEET14bresulted in pronounced water-soaked lesions. Transcriptome profiling coupled with TALE-binding element prediction identified a pectin lyase as an additional Tal7b target, quantitatively contributing toXcmvirulence alongsideGhSWEET14a/b. CRISPR-Cas9-based gene editing supported the function ofGhSWEETsasSgenes in cotton bacterial blight and the promise of disrupting the TALE-binding site in these genes to control the disease. Collectively, our findings elucidate the rapid evolution of TALEs inXanthomonasfield isolates and highlight the virulence mechanism wherein TALEs induce multipleSgenes simultaneously to promote pathogenicity.
A cognitive process model captures near-optimal confidence-guided waiting in rats
Authors: Boyd-Meredith J Tyler , Piet Alex T , Kopec Chuck D , Brody Carlos D 
Published: June 2024

AbstractRational decision-makers invest more time pursuing rewards they are more confident they will eventually receive. A series of studies have therefore used willingness to wait for delayed rewards as a proxy for decision confidence. However, interpretation of waiting behavior is limited because it is unclear how environmental statistics influence optimal waiting, and how sources of internal variability influence subjects’ behavior. We trained rats to perform a confidence-guided waiting task, and derived expressions for optimal waiting that make relevant environmental statistics explicit, including travel time incurred traveling from one reward opportunity to another. We found that rats waited longer than fully optimal agents, but that their behavior was closely matched by optimal agents with travel times constrained to match their own. We developed a process model describing the decision to stop waiting as an accumulation to bound process, which allowed us to compare the effects of multiple sources of internal variability on waiting. Surprisingly, although mean wait times grew with confidence, variability did not, inconsistent with scalar invariant timing, and best explained by variability in the stopping bound. Our results describe a tractable process model that can capture the influence of environmental statistics and internal sources of variability on subjects’ decision process during confidence-guided waiting.
Novel Behavioral Assays Reveal Sex Specific Behavioral Syndromes in Anemonefish
Authors: Graham Gabriel J. , Wilton Isabella M. , Panczyk Emily K. , Rhodes Justin S. 
Published: June 2024

AbstractSexually dimorphic behaviors are common across taxa, particularly in the contexts of parental care and territorial aggression. The false clown anemonefishAmphiprion ocellarisis unique among animals for its combination of female behavioral dominance and territoriality, protandrous sex change, and mutualistic symbiosis with sea anemones. Several laboratory studies have begun characterizing sex differences in parental care and aggression in this species, but aggression assays have mostly focused on intra-specific aggression where individual differences are large. The goals of this study were to expand the repertoire of behavioral assays available forA. ocellaris, establish repeatability of individual differences, identify assays that produce the most robust sex differences, and explore whether individual differences in correlated behaviors can be detected consistently across experimental contexts (i.e., whether behavioral syndromes can be detected). To this end, we measured 39 behaviors across 7 behavioral assays (parental care, large intruder aggression, small intruder aggression, male-oriented aggression, female-oriented aggression, immediate reaction to a threat, and nest maintenance) in 9 reproductively activeA. ocellarispairs under 3 different contexts (without eggs in the nest, with their own eggs, and with surrogate eggs). Behaviors were repeatedly measured three separate times (rounds) over repeated spawning cycles. We found 34 out of 39 behaviors were significantly individually repeatable across egg contexts and rounds, with an average intra-class correlation of 0.33. We found parental care, large intruder aggression, and female-oriented aggression assays produced the largest sex differences. Males performed 7-fold more egg care behaviors than females, while females performed 3.5-fold more aggressive behaviors toward a large interspecific intruder. Further, females bit, chased and struck the female intruder 6.5, 4.1, and 3.2 times as many times as males did. Five different behavioral syndromes were observed in males but only one was observed in females. These results expand our understanding of sex differences in behavior and the division of labor in the iconic anemonefish. Future studies can use these assays to measure the behavioral sex of fish in the middle of sex change, in the study of behavioral plasticity, or in the study of the neuroendocrine bases of aggression and parental care in this unique species.
Ribosome-Associated Vesicles promote activity-dependent local translation
Authors: Martin-Solana Eva , Carter Stephen D. , Donahue Eric K.F. , Ning Jiying , Glausier Jill R. , Preisegger Matias A. , Eisenman Leanna , Joseph Paul N. , Bouchet-Marquis Cedric , Wu Ken , Mobini Catherina L. , Frantz Amber N. , Puig Stephanie , Hampton Cheri M. , Kabbani Nadine , Jensen Grant J. , Watkins Simon C. , Deisseroth Karl , Fenno Lief E. , Gold Michael S. , Wills Zachary P. , Burkewitz Kristopher , Das Sulagna , Freyberg Zachary 
Published: June 2024

AbstractLocal protein synthesis in axons and dendrites underpins synaptic plasticity. However, the composition of the protein synthesis machinery in distal neuronal processes and the mechanisms for its activity-driven deployment to local translation sites remain unclear. Here, we employed cryo-electron tomography, volume electron microscopy, and live-cell imaging to identify Ribosome-Associated Vesicles (RAVs) as a dynamic platform for moving ribosomes to distal processes. Stimulation via chemically-induced long-term potentiation causes RAV accumulation in distal sites to drive local translation. We also demonstrate activity-driven changes in RAV generation and dynamicsin vivo, identifying tubular ER shaping proteins in RAV biogenesis. Together, our work identifies a mechanism for ribosomal delivery to distal sites in neurons to promote activity-dependent local translation.
The Pangenome ofEscherichia coli
Authors: Chauhan Siddharth M. , Ardalani Omid , Hyun Jason C. , Monk Jonathan M. , Phaneuf Patrick V. , Palsson Bernhard O. 
Published: June 2024

AbstractThousands of complete genome sequences for strains of a species that are now available enable the advancement of pangenome analytics to a new level of sophistication. We collected 2,377 publicly-available complete genomes ofEscherichia colifor detailed pangenome analysis. The core genome and accessory genomes consisted of 2,398 and 5,182 genes, respectively. We developed a machine learning approach to define the accessory genes characterizing the major phylogroups ofE. coliplus Shigella: A, B1, B2, C, D, E, F, G, and Shigella. The analysis resulted in a detailed structure of the genetic basis of the phylogroups’ differential traits. This pangenome structure was largely consistent with a housekeeping-gene-based MLST distribution, sequence-based Mash distance, and the Clermont quadruplex classification. The rare genome consisted of 163,619 genes, about 79% of which represented variations of 315 underlying transposon elements. This analysis generated a mathematical definition of the genetic basis for a species.
Menstrual cycle phase modulates causal connectivity in the resting-state brain of healthy females
Authors: Mcleod J. , Sattari S. , Chavan A. , Galea L. A.M. , Babul S. , Virji-Babul N. 
Published: June 2024

AbstractBackgroundOvarian hormones exert direct and indirect influences on the brain; however, little is known about how these hormones impact causal brain connectivity. Studying the female brain at a single time point may be confounded by distinct hormone phases. Despite this, the menstrual cycle is often overlooked. The primary objective of this pilot study was to evaluate resting-state causal connectivity during the early follicular and mid-luteal menstrual phases corresponding to lowvshigh estradiol and progesterone, respectively.MethodsFourteen healthy control females (M= 20.36 years,SD =2.02) participated in this study. Participants were scheduled for two resting-state electroencephalography (EEG) scans during their monthly menstrual cycle. A saliva sample was also collected at each EEG session for hormone analyses. Causal connectivity was quantified using information flow rate of EEG source data. Demographic information, emotional empathy, and sleep quality were obtained from self-report questionnaires.ResultsProgesterone levels were significantly higher in the mid-luteal phase compared to the early follicular phase (p= .041). We observed distinct patterns of causal connectivity along the menstrual cycle. Connectivity in the early follicular phase was centralized and shifted posteriorly during the mid-luteal phase. During the early follicular phase, the primary regions driving activity were the right central and left/right parietal regions, with the left central region being the predominant receiver of activity. During the mid-luteal phase, connections were primarily transmitted from the right side and the main receiver region was the left occipital region. Network topology during the mid-luteal phase was found to be significantly more assortative compared to the early follicular phase.ConclusionsThe observed difference in causal connectivity demonstrates how network dynamics reorganize as a function of menstrual phase and level of progesterone. In the mid-luteal phase, there was a strong shift for information flow to be directed at visual spatial processing and visual attention areas, whereas in the follicular phase, there was strong information flow primarily within the sensory-motor regions. The mid-luteal phase was significantly more assortative, suggesting greater network efficiency and resilience. These results contribute to the emerging literature on brain-hormone interactions.
MITOCHONDRIAL ANTIVIRAL PATHWAYS CONTROL ANTI-HIV RESPONSES AND ISCHEMIC STROKE OUTCOMES VIA THE RIG-1 SIGNALING AND INNATE IMMUNITY MECHANISMS
Authors: Torices Silvia , Moreno Thaidy , Ramaswamy Sita , Naranjo Oandy , Teglas Timea , Osborne Olivia M. , Park Minseon , Sun Enze , Toborek Michal 
Published: June 2024

SUMMARYOccludin (ocln) is one of the main regulatory cells of the blood-brain barrier (BBB). Ocln silencing resulted in alterations of the gene expression signatures of a variety of genes of the innate immunity system, including IFN-stimulated genes (ISGs) and the antiviral retinoic acid-inducible gene-1 (RIG-1) signaling pathway, which functions as a regulator of the cytoplasmic sensors upstream of the mitochondrial antiviral signaling protein (MAVS). Indeed, we observed dysfunctional mitochondrial bioenergetics, dynamics, and autophagy in our system. Alterations of mitochondrial bioenergetics and innate immune protection translated into worsened ischemic stroke outcomes in EcoHIV-infected ocln deficient mice. Overall, these results allow for a better understanding of the molecular mechanisms of viral infection in the brain and describe a previously unrecognized role of ocln as a key factor in the control of innate immune responses and mitochondrial dynamics, which affect cerebral vascular diseases such as ischemic stroke.
Social valence dictates sex differences in identity recognition
Authors: Larosa Amanda , Xu Qi Wei , Wong Alice S. , Lee J. Quinn , Brandon Mark P. , Wong Tak Pan 
Published: June 2024

AbstractSocial valence is the directional emotional significance affiliated with social experiences. Maladaptive processing of negative social valence (NSV) has been linked to mood disorder susceptibility, which is more prevalent in women. To determine whether there are sex differences in NSV processing, we developed social valence tasks where the identity recognition of conspecifics with distinct valences served as the readout. Male mice demonstrated identity recognition regardless of social valence. Conversely, female mice did not show identity recognition following the NSV task.In vivocalcium imaging of the dorsal CA1 further revealed sex differences in NSV processing with reduced hippocampal representation of social information in female mice. These results suggest the imprecise encoding of NSV may contribute to the heightened vulnerability to social stress-related mood disorders in women.