bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell Chirality of Micropatterned Endometrial Microvascular Endothelial Cells
Authors: Zambuto Samantha G. , Jain Ishita , Theriault Hannah S. , Underhill Gregory H. , Harley Brendan A.C. 
Published: October 2023

ABSTRACTChirality is an intrinsic cellular property that describes cell polarization biases along the left-right axis, apicobasal axis, or front-rear axes. Cell chirality plays a significant role in the arrangement of organs in the body as well as the orientation of organelles, cytoskeletons, and cells. Vascular networks within the endometrium, the mucosal inner lining of the uterus, commonly display spiral architectures that rapidly form across the menstrual cycle. Herein, we systematically examine the role of endometrial-relevant extracellular matrix stiffness, composition, and soluble signals on endometrial endothelial cell chirality using a high-throughput microarray. Endometrial endothelial cells display marked patterns of chirality as individual cells and as cohorts in response to substrate stiffness and environmental cues. Vascular networks formed from endometrial endothelial cells also display shifts in chirality as a function of exogenous hormones. Changes in cellular-scale chirality correlate with changes in vascular network parameters, suggesting a critical role for cellular chirality in directing endometrial vessel network organization.
Meta-Analysis Reveals That Explore-Exploit Decisions are Dissociable by Activation in the Dorsal Lateral Prefrontal Cortex, Anterior Insula, and the Anterior Cingulate Cortex
Authors: Sazhin Daniel , Dachs Abraham , Smith David V. 
Published: October 2023

AbstractExplore-exploit research faces challenges in generalizability due to a limited theoretical basis for exploration and exploitation. Neuroimaging can help identify whether explore-exploit decisions involve an opponent processing system to address this issue. Thus, we conducted a coordinate-based meta-analysis (N=23 studies) finding activation in the dorsal lateral prefrontal cortex, anterior insula, and anterior cingulate cortex during exploration versus exploitation, which provides some evidence for opponent processing. However, the conjunction of explore-exploit decisions was associated with activation in the dorsal anterior cingulate cortex and dorsal medial prefrontal cortex, suggesting that these brain regions do not engage in opponent processing. Furthermore, exploratory analyses revealed heterogeneity in brain responses between task types during exploration and exploitation respectively. Coupled with results suggesting that activation during exploration and exploitation decisions is generally more similar than it is different suggests, there remain significant challenges in characterizing explore-exploit decision making. Nonetheless, dlPFC, AI, and ACC activation differentiate explore and exploit decisions and identifying these responses can aid in targeted interventions aimed at manipulating these decisions.
CONE: COntext-specific Network Embedding via Contextualized Graph Attention
Authors: Liu Renming , Yuan Hao , Johnson Kayla A , Krishnan Arjun 
Published: October 2023

AbstractHuman gene interaction networks, commonly known as interactomes, encode genes’ functional relationships, which are invaluable knowledge for translational medical research and the mechanistic understanding of complex human diseases. Meanwhile, the advancement of network embedding techniques has inspired recent efforts to identify novel human disease-associated genes using canonical interac-tome embeddings. However, one pivotal challenge that persists stems from the fact that many complex diseases manifest in specific biological contexts, such as tissues or cell types, and many existing interactomes do not encapsulate such information. Here, we propose CONE3, a versatile approach to generate context-specific embeddings from a context-free interactome. The core component of CONE consists of a graph attention network with contextual conditioning, and it is trained in a noise contrastive fashion using contextualized interactome random walks localized around contextual genes. We demonstrate the strong performance of CONE embeddings in identifying disease-associated genes when using known associated biological contexts to the diseases. Furthermore, our approach offers insights into understanding the biological contexts associated with human diseases.
Evaluation of the cross reactivity of neutralising antibody response in vaccinated human and convalescent hamster sera against SARS-CoV-2 variants up to and including JN.1 using an authentic virus neutralisation assay
Authors: Coombes Naomi S. , Bewley Kevin R. , Le Duff Yann , Alami-Rahmouni Nassim , Ryan Kathryn A. , Kempster Sarah , Ferguson Deborah , Davies Elizabeth R. , Weldon Thomas M. , Cross Eleanor S. , Smith Lauren , Norris Conner , Rogers-Broadway Karly Rai , Lewandowski Kuiama , Treagus Samantha , Everall Isobel , Pullan Steven T. , Hallis Bassam , Charlton Sue , Hall Yper , Funnell Simon G. P. 
Published: October 2023

AbstractNew vaccines, therapeutics and immunity elicited by natural infection create evolutionary pressure on SARS-CoV-2 to evolve and adapt to evade vaccine-induced and infection-elicited immunity. Vaccine and therapeutics developers thus find themselves in an “arms race” with the virus. The ongoing assessment of emerging SARS-CoV-2 variants remains essential as the global community transitions from an emergency response to a long-term management plan. Here, we describe how an authentic virus neutralisation assay using low passage clinical virus isolates has been employed to monitor resistance of emerging virus variants to neutralising antibodies from humans and experimentally infected hamsters. Sera and plasma from people who received three doses of a vaccine as well as those who received a bivalent booster were assessed against SARS-CoV-2 variants, up to and including JN.1. Contemporary or recent virus variants showed substantial resistance to neutralisation by antibodies from those who had received three doses of an ancestral vaccine but were still effectively neutralised by antibodies from individuals who had received a bivalent booster (ancestral/BA.1). In our recent studies, however, the JN.1 VOI was found to be significantly more resistant to neutralisation by antibodies from those who had received the ancestral/BA.1 bivalent boost. Convalescent sera from hamsters that had been experimentally infected with one of seven virus variants (ancestral, BA.1, BA.4, BA.5.2.1, XBB.1.5, XBB.1.16, XBB.2.3) were also tested here. The recent contemporary variant, BA.2.86, was effectively neutralised by sera from hamsters infected with XBB.1.5 and XBB.1.16 but it was not neutralised by sera from those infected with BA.5.2.1. These data support the recommendations given by the WHO that a new vaccine was required and should consist of an XBB sub-lineage antigen.
Parietal stimulation reverses age-related decline in exploration, learning, and decision-making
Authors: Hwang Eun Jung , Korde Sayli , Han Ying , Sambangi Jaydeep , Lian Bowen , Owusu-Ofori Ama , Diasamidze Megi , Wong Lea M. , Pickering Nadine , Begin Sam 
Published: October 2023

ABSTRACTAging can compromise decision-making and learning, potentially due to reduced exploratory behaviors crucial for novel problem-solving. We posit that invigorating exploration could mitigate these declines. Supporting this hypothesis, we found that older mice mirrored human aging, displaying less exploration and learning during decision-making, but optogenetic stimulation of their posterior parietal cortex boosted initial exploration, subsequently improving learning. Thus, enhancing exploration-driven learning could be a key to countering cognitive aging.
Molecular dynamic investigation for ROCO-4 kinase inhibitor as treatment options for parkinsonism
Authors: Datta Kankana , Ravi Lokesh 
Published: October 2023

AbstractParkinson’s disease (PD) is a neurodegenerative condition that degenerates dopaminergic neurons and is characterized by motor disabilities like rigidity, bradykinesia, postural instability, and resting tremors. Although the etiology of PD remains uncertain, familial and sporadic forms of PD are known to be predominately caused by the G2019S mutation present in the kinase domain of LRRK2. Therefore, it might be possible to treat Parkinson’s by inhibiting the kinase action of the mutated LRRK2 protein. In order to find possible inhibitors, 3069 phytochemicals were examined for their ability to bind ROCO4 kinase, which has structural and functional similarities to the LRRK2 protein. Open-source bioinformatics tools were used to determine the binding affinities of phytochemicals to the native and mutant variants of the protein. Mongolicain-A exhibited high specificity and selectivity towards the G2019S mutation of the ROCO4 protein with -12.3 Kcal/mol binding affinity, whereas Bacoside-A displayed high affinity (11.4 Kcal/mol) for the target protein, but lacked specificity towards the mutant form of the protein. Based on molecular simulation studies., RMSD, RMSF, SASA, potential energy, and hydrogen bond analysis, it was suggested that Mongolicain-A may be an effective inhibitor of the G2019S mutation and a promising drug molecule to address PD.
Microfluidic antibody profiling after repeated SARS-CoV-2 vaccination links antibody affinity and concentration to impaired immunity and variant escape in patients on anti-CD-20 therapy
Authors: Priddey Ashley , Chen-Xu Michael Xin Hua , Cooper Daniel James , MacMillan Serena , Meisl Georg , Xu Catherine K , Hosmillo Myra , Goodfellow Ian G. , Kollyfas Rafael , Doffinger Rainer , Bradley John R , Mohorianu Irina I , Jones Rachel , Knowles Tuomas P.J. , Smith Rona , Kosmoliaptsis V 
Published: October 2023

AbstractBackgroundPatients with autoimmune/inflammatory conditions on anti-CD20 therapies, such as Rituximab, have suboptimal humoral responses to vaccination and are vulnerable to poorer clinical outcomes following SARS-CoV-2 infection. We aimed to examine how the fundamental parameters of antibody responses, namely affinity and concentration, shape the quality of humoral immunity after vaccination in these patients.MethodsWe performed in depth antibody characterisation in sera collected four to six weeks after each of three vaccine doses to wild-type (WT) SARS-CoV-2 in Rituximab-treated primary vasculitis patients (n=14) using Luminex and pseudovirus neutralisation assays, whereas a novel microfluidic-based immunoassay was used to quantify polyclonal antibody affinity and concentration against both WT and Omicron (B.1.1.529) variants. Comparative antibody profiling was performed at equivalent time points in healthy individuals after three antigenic exposures to WT SARS-CoV-2 (one infection and two vaccinations; n=15) and in convalescent patients after WT SARS-CoV-2 infection (n=30).ResultsRituximab-treated patients had lower antibody levels and neutralisation titres against both WT and Omicron SARS-CoV-2 variants compared to healthy individuals. Neutralisation capacity was weaker against Omicron versus WT both in Rituximab-treated patients and in healthy individuals. In the Rituximab cohort, this was driven by lower antibody affinity against Omicron versus WT (median [range] KD: 21.6 [9.7-38.8] nM vs 4.6 [2.3-44.8] nM, p=0.0004). By contrast, healthy individuals with hybrid immunity produced a broader antibody response, a subset of which recognised Omicron with higher affinity than antibodies in Rituximab-treated patients (median [range] KD: 1.05 [0.45-1.84] nM vs 20.25 [13.2-38.8] nM, p=0.0002), underpinning the stronger serum neutralisation capacity against Omicron in the former group. Rituximab-treated patients had similar anti-WT antibody levels and neutralisation titres to unvaccinated convalescent individuals, despite two more exposures to SARS-CoV-2 antigen. Temporal profiling of the antibody response showed evidence of affinity maturation in healthy convalescent patients after a single SARS-CoV-2 infection which was not observed in Rituximab-treated patients, despite repeated vaccination.DiscussionOur results enrich previous observations of impaired humoral immune responses to SARS-CoV-2 in Rituximab-treated patients and highlight the significance of quantitative assessment of serum antibody affinity and concentration in monitoring anti-viral immunity, viral escape, and the evolution of the humoral response.
Missense mutations in Myc Box I influence MYC cellular localization, mRNA partitioning and turnover to promote leukemogenesis
Authors: Arthur Nancy BJ , Christensen Keegan A , Mannino Kathleen , Ruzinova Marianna B. , Kumar Ashutosh , Gruszczynska Agata , Day Ryan B. , Erdmann-Gilmore Petra , Mi Yiling , Sprung Robert , York Conner R. , Reid Townsend R , Spencer David H. , Sykes Stephen M. , Ferraro Francesca 
Published: October 2023

ABSTRACTSomatic missense mutations in the phosphodegron domain of theMYCgene (MYC Box I) are detected in the dominant clones of a subset of acute myeloid leukemia (AML) patients, but the mechanisms by which they contribute to AML are unknown. To unveil unique proprieties of MBI MYC mutant proteins, we systematically compared the cellular and molecular consequences of expressing similar oncogenic levels of wild type and MBI mutant MYC. We found that MBI MYC mutants can accelerate leukemia by driving unique transcriptional signatures in highly selected, myeloid progenitor subpopulations. Although these mutations increase MYC stability, they overall dampen MYC chromatin localization and lead to a cytoplasmic accumulation of the mutant proteins. This phenotype is coupled with increased translation of RNA binding proteins and nuclear export machinery, which results in altered RNA partitioning and accelerated decay of select transcripts encoding proapoptotic and proinflammatory genes. Heterozygous knockin mice harboring the germline MBI mutationMyc p.T73Nexhibit cytoplasmic MYC localization, myeloid progenitors’ expansion with similar transcriptional signatures to the overexpression model, and eventually develop hematological malignancies. This study uncovers that MBIMYCmutations alter MYC localization and disrupt mRNA subcellular distribution and turnover of select transcripts to accelerate tumor initiation and growth.
Hypothalamic control of noradrenergic neurons stabilizes sleep
Authors: Broglia Gianandrea , Corsi Giorgio , Bouvier Pierre-Hugues Prouvot , Vassalli Anne , Tafti Mehdi , Bandarabadi Mojtaba 
Published: October 2023

AbstractHypocretin/orexin neurons are essential to stabilize sleep, but the underlying mechanisms remain elusive. We report that hypocretin neurons of the perifornical hypothalamus are highly active during rapid eye movement sleep and show state-specific correlation with noradrenergic neurons. Deletion of hypocretin gene significantly increased periodic reactivations of locus coeruleus noradrenergic neurons during sleep and dysregulated their activity across transitions, suggesting a role for hypocretin neurons in mediating neuromodulation to stabilize sleep.
Body composition and blood pressure relationship among western-Kenya school children and adolescents
Authors: Magutah Karani , Mbuthia Grace Wambura , Meiring Rebecca M. 
Published: October 2023

AbstractKenyan studies relating body composition (BC) and blood pressure (BP) have focused on adults. Insight into this relationship among children and adolescents provides evidence for reduction of adulthood cardiovascular disease-risk development. We describe BC and BP correlation among Kenyan children and adolescents.This cross-sectional study randomly sampled 389 school-going participants. Weight, height, BP, waist circumference (WC) and hip circumference were measured. Waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and body-mass-index (BMI) were calculated. Relationships between BP and WC, WHR, WHtR and BMI were determined.Males and females were 14.7±2.9 and 14.4±2.5 years old, respectively. Secondary and primary schools’ males had SBP 119.1±10.3 mmHg and 107.4±13.7 mmHg; females 111.2±11.8 mmHg and 106.7±11.7 mmHg respectively. The DBP in secondary and primary schools’ males was 69.2±7.8 mmHg and 65.7±8.6mmHg, and, 69.6±7.9 mmHg and 68.1±7.4 mmHg for females. Higher BMI, WC, and WHtR correlated with higher SBP in both sexes (Pearson’s “R” +0.3 to +0.5; p<0.05). In females, DBP correlated with BMI, WC and WHtR, and only with WC for males. In all schools, only WC correlated with SBP in both sexes, BMI, WHR and WHtR correlating only among females. For males, BMI in primary and WHtR and WHR in secondary schools additionally correlated with SBP. For females, BMI and WHtR had correlations across school levels. For private and public schools, BMI, WC and WHtR had +0.2 to +0.6 correlations with SBP. The DBP correlated with WC and WHtR among private schools’ males, and, with WHtR and BMI in both school sets for females.For both sexes, WC had strongest and WHR weakest correlation with SBP. Only in secondary school females did DBP correlate some BC variables. In both sexes, BMI, WC and WHtR all fairly correlated with SBP in private and public schools, WHR appearing least applicable in predicting Kenyan children and adolescents’ BP.
Synaptic plasticity in the medial preoptic area of male mice encodes social experiences with female and regulates behavior toward young
Authors: Ito Kazuki , Sato Keiichiro , Tsuneoka Yousuke , Maejima Takashi , Okuno Hiroyuki , Hamasaki Yumi , Murakawa Shunsaku , Takabayashi Yuzu , Yoshihara Chihiro , Shindo Sayaka , Uki Haruka , Herlitze Stefan , Seki Masahide , Suzuki Yutaka , Sakurai Takeshi , Kuroda Kumi O , Minami Masabumi , Amano Taiju 
Published: October 2023

SummaryA dramatic shift from aggressive infanticidal to paternal behaviors is an essential event for male mice after mating. While the central part of the medial preoptic area (cMPOA) has been shown to critically mediate the paternal behaviors in mice, how this brain region becomes activated by mating and subsequent interaction with pups has not been investigated. Here, we demonstrate that the reduction in inhibitory synaptic strength towards the cMPOA provided by posterior-dorsal medial amygdala (MePD) neurons is a key event for the post-mating behavioral shift in males. Consistent with this, we found optogenetic disinhibition of MeCartptto the cMPOA synapses reduces male aggression towards pups. The cMPOA of paternal mice mediated pup-induced neural plastic changes in the bed nucleus of the stria terminalis. These findings provide possible functions of cMPOA neural circuits required for the reception to young in male mice.
Heterogeneous dual-metal control ofSalmonellainfection
Authors: Roche Béatrice , Cunrath Olivier , Bleck Christopher , Claudi Beatrice , Antelo Varela Minia , Li Jiagui , Bumann Dirk 
Published: October 2023

AbstractIron controls bacterial infections through diverse pathogen and host mechanisms that remain challenging to disentangle. Here, we determined how individualSalmonellacells access iron in infected mice. Our results showed that the iron transporter SLC11A1 restricted iron availability. However, manySalmonellabypassed this restriction by targeting macrophage endosomes that contained remnants of iron-rich red blood cells. These iron-replete bacteria dominated overallSalmonellagrowth and masked the relieve of iron-starved bacteria under iron overload. These data, combined with our previous discovery of magnesium deprivation as a primary mechanism for controllingSalmonella, reveal a heterogeneous dual-metal mechanism of nutritional immunity, and highlight the power of single-cell analyses under physiological in-vivo conditions to unravel complex anti-bacterial host mechanisms.One sentence summaryIron and magnesium limitations control distinctSalmonellasubsets during infection.
MUSE-XAE: MUtational Signature Extraction with eXplainable AutoEncoder enhances tumour type classification
Authors: Pancotti Corrado , Rollo Cesare , Birolo Giovanni , Fariselli Piero , Sanavia Tiziana 
Published: October 2023

AbstractMutational signatures are a critical component in deciphering the genetic alterations that underlie cancer development and have become a valuable resource for understanding the genomic changes that occur during tumorigenesis. In this paper, we present MUSE-XAE, a novel method for mutational signature extraction from cancer genomes using an explainable Auto-Encoder. Our approach employs a hybrid architecture consisting of a nonlinear encoder that can capture nonlinear interactions and a linear decoder, ensuring the interpretability of the active signatures in cancer genomes. We evaluated and compared MUSE-XAE with other available tools on synthetic and experimental cancer datasets and demonstrated that it achieves very accurate extraction capabilities while enhancing tumour-type classification. Our findings indicate that the use of Auto-Encoders is feasible and effective. This approach could facilitate further research in this area, with neural network-based models playing a critical role in advancing our understanding of cancer genomics
Leukemic cell-secreted interleukin-9 suppresses cytotoxic T cell-mediated killing in chronic lymphocytic leukemia
Authors: Boncompagni Gioia , Tatangelo Vanessa , Lopresti Ludovica , Ulivieri Cristina , Capitani Nagaja , Tangredi Carmela , Finetti Francesca , Marotta Giuseppe , Frezzato Federica , Visentin Andrea , Ciofini Sara , Gozzetti Alessandro , Bocchia Monica , Calzada-Fraile Diego , Cofreces Noa B. Martin , Trentin Livio , Patrussi Laura , Baldari Cosima T. 
Published: October 2023

ABSTRACTThe tumor microenvironment (TME) plays a central role in the pathogenesis of chronic lymphocytic leukemia (CLL), contributing to disease progression and chemoresistance. Leukemic cells shape the TME into a pro-survival and immunosuppressive niche through contact-dependent and contact-independent interactions with the cellular components of the TME. Immune synapse (IS) formation is defective in CLL. Here we asked whether soluble factors released by CLL cells contribute to their protection from cytotoxic T cell (CTL)-mediated killing by interfering with this process. We found that healthy CTLs cultured in media conditioned by leukemic cells from CLL patients or Eμ-TCL1 mice upregulate the exhaustion marker PD-1 and become unable to form functional ISs and kill target cells. These defects were more pronounced when media were conditioned by leukemic cells lacking p66Shc, a proapoptotic adaptor whose deficiency has been implicated in disease aggressiveness both in CLL and in the Eμ-TCL1 mouse model. Multiplex ELISA assays showed that leukemic cells from Eμ-TCL1 mice secrete abnormally elevated amounts of CCL22, CCL24, IL-9 and IL-10, which are further upregulated in the absence of p66Shc. Among these, IL-9 and IL-10 were also overexpressed in leukemic cells from CLL patients, where they inversely correlated with residual p66Shc. Using neutralizing antibodies or the recombinant cytokines we show that IL-9, but not IL-10, mediates both the enhancement in PD-1 expression and the suppression of effector functions in healthy CTLs. Our results demonstrate that IL-9 secreted by leukemic cells negatively modulates the anti-tumor immune abilities of CTLs, highlighting a new suppressive mechanism and a novel potential therapeutical target in CLL.