bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell-cycle dependent inhibition of BRCA1 signaling by the lysine methyltransferase SET8
Authors: Perez Yannick , Alhourani Fatima , Patouillard Julie , Ribeyre Cyril , Larroque Marion , Baldin Véronique , Lleres David , Grimaud Charlotte , Julien Eric 
Published: November 2023

SUMMARYAlthough the inverse affinities of 53BP1 and BRCA1-BARD1 complexes for distinct methylation states of lysine (K) 20 at histone H4 have underscored a role of this epigenetic mark in the regulation of DNA-repair pathways choice, how the different H4K20 methyltransferases are involved remained unclear. Here, we show that the replication-coupled degradation of the lysine methyltransferase SET8 responsible for H4K20 mono-methylation (H4K20me1) is required for the onset of the recombinogenic functions of BRCA1 during unperturbed DNA replication. Indeed, we demonstrate that SET8 can work as a primary inhibitor of homologous recombination by tipping the balance from BRCA1-BARD1 to 53BP1 complexes in a manner depending on the single switch from un-methyl to mono-methyl H4K20 and the recruitment of the ubiquitin ligase RNF168 on post-replicated chromatin. Conversely, the lack of SET8 and K20 mono-methylation on newly assembly chromatin after DNA replication led to the untimely chromatin accumulation of BRCA1 at the exit of mitosis, which contributes to the improper progression from G1 to S-phase in daughter cells. Altogether, these results establish thede novoactivity of SET8 on chromatin as a primordial epigenetic lock of BRCA1-mediated HR pathway during the cell cycle.
Pervasive RNA Binding Protein Enrichment on TAD Boundaries Regulates TAD Organization
Authors: Sun Qiang , Zhou Qin , Qiao Yulong , Sun Hao , Wang Huating 
Published: November 2023

AbstractMammalian genome is hierarchically organized by CTCF and cohesin through loop extrusion mechanism to facilitate the organization of topologically associating domains (TADs). Mounting evidence suggests additional factors/mechanisms exist to orchestrate TAD formation and maintenance. In this study, we investigate the potential role of RNA binding proteins (RBPs) in TAD organization. By integrated analyses of global RBP binding and 3D genome mapping profiles from both K562 and HepG2 cells, our study unveils the prevalent enrichment of RBPs on TAD boundaries and define boundary associated RBPs (baRBPs). We also characterize chromatin features of baRBP binding and uncover clustering among baRBPs and with transcription factors (TFs). Moreover, we found that baRBP binding is correlated with enhanced TAD insulation strength and in a CTCF independent manner. Further analyses revealed that baRBP binding is associated with nascent promoter transcription thus RBP/transcription may synergistically demarcate TADs. Additional experimental testing was performed using RBFox2 as a paradigm. Knockdown ofRBFox2in K562 cells causes remarkable TAD reorganization and boundary loss. Moreover, we found RBFox2 enrichment on TAD boundaries is a conserved phenomenon in C2C12 myoblast (MB) cells. RBFox2 is down-regulated and its bound boundaries are remodeled during MB differentiation into myotubes (MTs). Knockout ofRbfox2in MBs also causes significant boundary reorganization. Finally, transcriptional inhibition in C2C12 cells indeed decreases RBFox2 binding and disrupts TAD boundary insulation. Altogether, our findings demonstrate that RBPs can play active role in modulating TAD organization through co-transcriptional association and synergistic action with nascent promoter transcripts.
Helicobacter pylori cancer associated CagA protein drives intestinal metaplastic transition in human gastric organoids
Authors: Reines Mar , Soerensen Meike , Berger Hilmar , Patel Mihir , Schlärmann Philipp , Meyer Thomas F. 
Published: November 2023

AbstractGastric intestinal metaplasia (GIM) constitutes a pre-neoplastic stage in the development of stomach cancer. While strong evidence points to a role of infection with CagA positiveHelicobacter pyloriin the development of GIM, currently available experimental models have not provided mechanistic clues on this association. Here, we ectopically expressed theH. pyloriCagA protein in human gastric organoids derived from normal, primary epithelial cells. Native CagA protein was produced and rapidly processed to yield a tyrosine-phosphorylated C-terminal fragment of ∼35 kDa. It led to an activation of the STAT3 pathway and aberrant elevation of CDX2 expression, a marker of intestinal type of cells, as well as other intestinal markers. Thus, CagA drives re-programming of gastric cells towards an intestinal-like phenotype, towards GIM. In summary, we describe a cooperative mechanism of CagA-induced STAT3 signaling and intestinal-like trans-differentiation, promoting a pre-neoplastic state. Our model provides mechanistic evidence for a direct role of CagA in driving premalignancy in gastric pathogenesis.
Successful gall induction byDiplolepis rosaeandD. mayrion the sweet briar (Rosa rubiginosa) under laboratory conditions
Authors: László Zoltán , Biró Mátyás , Iordache Constantin-Teodor , Macalik Borbála , Nicula Marco , Szilágyi Bálint , Podar Dorina 
Published: November 2023

AbstractPlant galls are unique outgrowths caused by various organisms, including insects, serving as nourishment for the inducer’s larvae. Despite the taxonomists and ecologists attempts to elucidate the mechanisms behind plant gall formation, its understanding is still incomplete. Modern genetic techniques allow in depth analysis of the molecular processes, but variations across species entangle the analysis. Establishing laboratory-friendly plant-gall inducer communities is crucial, yet past attempts have faced challenges.Our study aimed to create a sustainable laboratory community involving wild roses (Rosasp.) and as gall-inducing insects rose gall wasps belonging to the genusDiplolepis. Controlled indoor conditions were optimized for plant growth. Wild roses were transplanted, then exposed to gall inducers, and monitored.Successfully initialized gall growth was measures and analysed, revealing insights into the impact of plant vigour on gall size.Our study successfully established a novel laboratory community for further research on gall formation mechanisms.
Unraveling the Power of NAP-CNB’s Machine Learning-enhanced Tumor Neoantigen Prediction
Authors: Méndez-Pérez Almudena , Acosta-Moreno Andrés M. , Wert-Carvajal Carlos , Ballesteros-Cuartero Pilar , Sánchez-García Rubén , Macías José R , Sanz-Pamplona Rebeca , Alemany Ramon , Sorzano Carlos Óscar S. , Muñoz-Barrutia Arrate , Veiga Esteban 
Published: November 2023

AbstractIn this study, we present a proof-of-concept classical vaccination experiment that validates thein silicoidentification of tumor neoantigens (TNAs) using a machine learning-based platform called NAP-CNB. Unlike other TNA predictors, NAP-CNB leverages RNAseq data to consider the relative expression of neoantigens in tumors. Our experiments show the efficacy of NAP-CNB. Predicted TNAs elicited potent antitumor responsesin vivofollowing classical vaccination protocols. Notably, optimal antitumor activity was observed when targeting the antigen with higher expression in the tumor, which was not the most immunogenic. Additionally, the vaccination combining different neoantigens resulted in vastly improved responses compared to each one individually, showing the worth of multiantigen-based approaches. These findings validate NAP-CNB as an innovative TNA-identification platform and make a substantial contribution to advancing the next generation of personalized immunotherapies
Age-related differences in electrophysiological correlates of visuospatial reorientation
Authors: Naveilhan Clément , Delaux Alexandre , Durteste Marion , Lebrun Jerome , Zory Raphaël , Arleo Angelo , Ramanoël Stephen 
Published: November 2023

AbstractSpatial navigation abilities decline with age. Recent studies revealed a specific impairment in landmark-based reorientation, linked to changes in scene-selective brain regions activity. While fMRI studies suggest that these cortical modulations might be compensatory, a more precise investigation of the brain dynamics associated with visuospatial processing is warranted. We analyzed Event-Related Potentials and Event-Related Spectral Perturbations recorded from electrodes over scene-selective regions. 28 young adults and 28 older adults completed a desktop-based reorientation task using landmarks. Our findings show poorer reorientation performance among older adults. Signatures of age-related modulation of EEG activity imputable to scene-selective regions were predominantly observed within the right hemisphere. EEG analysis disclosed a tripartite worsening of scene processing accounting for older adults’ difficulties. Firstly, a delayed and reduced P1 component likely reflects a slower and less efficient stimulus discrimination. Secondly, an increased N1 amplitude and theta-band activity suggest a higher demand on cognitive resources associated with more effortful processing of visuospatial information. Thirdly, a decreased P2 amplitude may imply deficient attentional mechanisms to select task-relevant stimuli.
Efficient Analysis of Annotation Colocalization Accounting for Genomic Contexts
Authors: Gafurov Askar , Vinař Tomáš , Medvedev Paul , Brejová Broňa 
Published: November 2023

AbstractAn annotation is a set of genomic intervals sharing a particular function or property. Examples include genes or their exons, evolutionarily conserved elements, and regions with a particular epigenetic state. A common task is to compare two annotations to determine if one is enriched or depleted in the regions covered by the other. We study the problem of assigning statistical significance to such a comparison based on a null model representing two random unrelated annotations. To incorporate more background information into such analyses, we propose a new null model based on a Markov chain which differentiates among several genomic contexts. These contexts can capture various confounding factors, such as GC content or assembly gaps. We then develop a new algorithm for estimating p-values by computing the exact expectation and variance of the test statistics and then estimating the p-value using a normal approximation. Compared to the previous algorithm by Gafurov et al., the new algorithm provides three advances: (1) the running time is improved from quadratic to linear or quasi-linear, (2) the algorithm can handle two different test statistics, and (3) the algorithm can handle both simple and context-dependent Markov chain null models.We demonstrate the efficiency and accuracy of our algorithm on synthetic and real data sets, including the recent human telomere-to-telomere assembly. In particular, our algorithm computed p-values for 450 pairs of human genome annotations using 24 threads in under three hours. Moreover, the use of genomic contexts to correct for GC bias resulted in the reversal of some previously published findings.AvailabilityThe software is freely available athttps://github.com/fmfi-compbio/mcdp2under the MIT licence. All data for reproducibility are available athttps://github.com/fmfi-compbio/mcdp2-reproducibility
Impaired oxytocin signaling in the central amygdala in rats with chronic heart failure
Authors: Althammer Ferdinand , Roy Ranjan K. , Kirchner Matthew K. , Lira Elba Campos , Schimmer Stephanie , Charlet Alexandre , Grinevich Valery , Stern Javier E. 
Published: November 2023

AbstractAimsHeart failure (HF) patients often suffer from cognitive decline, depression, and mood impairments, but the molecular signals and brain circuits underlying these effects remain elusive. The hypothalamic neuropeptide oxytocin (OT) is critically involved in the regulation of mood, and OTergic signaling in the central amygdala (CeA) is a key mechanism controlling emotional responses including anxiety-like behaviors. Based on this, we used in this study a well-established ischemic rat HF model and aimed to study alterations in the hypothalamus-to-CeA OTergic circuit.Methods and ResultsTo study potential HF-induced changes in the hypothalamus-to-CeA OTertic circuit, we combined patch-clamp electrophysiology, immunohistochemical analysis, RNAScope assessment of OTR mRNA, brain region-specific stereotaxic injections of viral vectors and retrograde tracing, optogenetic stimulation and OT biosensors in the ischemic HF model. We found that most of OTergic innervation of the central amygdala (CeA) originated from the hypothalamic supraoptic nucleus (SON). While no differences in the numbers of SON➜CeA OTertic neurons (or their OT content) was observed between sham and HF rats, we did observe a blunted content and release of OT from axonal terminals within the CeA. Moreover, we report downregulation of neuronal and astrocytic OT receptors, and impaired OTR-driven GABAergic synaptic activity within the CeA microcircuit of rats with HF.ConclusionsOur study provides first evidence that HF rats display various perturbations in the hypothalamus-to-amygdala OTergic circuit, and lays the foundation for future translational studies targeting either the OT system or GABAergic amygdala GABA microcircuit to ameliorate depression or mood impairments in rats or patients with chronic HF.
Transmission dynamics of MERS-CoV in a transgenic human DPP4 mouse model
Authors: Doremalen Neeltje van , Bushmaker Trenton , Fischer Robert J. , Okumura Atsushi , Figueroa Dania , McMinn Rebekah J. , Letko Michael , Saturday Greg , Munster Vincent J. 
Published: November 2023

AbstractSince 2002, three novel coronavirus outbreaks have occurred: severe acute respiratory syndrome coronavirus (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2. A better understanding of the transmission potential of coronaviruses will result in adequate infection control precautions and an early halt of transmission within the human population. Experiments on the stability of coronaviruses in the environment, as well as transmission models, are thus pertinent. Here, we show that transgenic mice expressing human DPP4 can be infected with MERS-CoV via the aerosol route. Exposure to 5×106TCID50and 5×104TCID50MERS-CoV per cage via fomites resulted in transmission in 15 out of 20 and 11 out of 18 animals, respectively. Exposure of sentinel mice to donor mice one day post inoculation with 105TCID50MERS-CoV resulted in transmission in 1 out of 38 mice via direct contact and 4 out of 54 mice via airborne contact. Exposure to donor mice inoculated with 104TCID50MERS-CoV resulted in transmission in 0 out of 20 pairs via direct contact and 0 out of 5 pairs via the airborne route. Our model shows limited transmission of MERS-CoV via the fomite, direct contact, and airborne routes. The hDPP4 mouse model will allow assessment of the ongoing evolution of MERS-CoV in the context of acquiring enhanced human-to-human transmission kinetics and will inform the development of other transmission models.
Collection of Non Timber Forest Products (NTFPs) and their contribution to sustainable rural livelihoods in selected areas around Ayubia National Park, Pakistan
Authors: Zaman Mehwish , Jabeen Asma , Shabbir Rabia 
Published: November 2023

AbstractThis study shows the Collection of Non Timber Forest Products (NTFPs) and their contribution to sustainable rural livelihoods in selected areas around Ayubia National Park, Pakistan. Forests are an important component for daily life of rural residents living near forested areas. A protected area is a geographically designated area for the purpose of biological conservation. Ayubia National Park (ANP) is a protected area in KPK, Pakistan that was designated with the purpose of management and preservation of nature. Non Timber Forest Products (NTFPs) have been defined as “All biological materials, excluding timber, which are extracted from forests for human use”. NTFPs play an important role in income generation for indigenous people. Malaach Village, Pasala Village and Khanuspur Town present around ANP were selected study areas. Purposive sampling was used for selection of study areas. Quantitative research was done. Field visits were done for Questionnaire survey. 50 questionnaires were filled from each selected village/town and results were analysed using SPSS. Cross tabulation was done and Chi Square test was applied. It was found that Wild Vegetables, Wild Fruits, Medicinal Plants and Mushrooms are collected from forests in and around ANP by indigenous people. Chi square results showed significant relationship between gender and collection of NTFPs. Poverty is found to be the main reason for collecting NTFPs. Contribution of NTFPs to annual income of people is mostly less than 20% but this contribution is also 21%-40% and even 41%-60% for few people. ANP should be managed properly to inhibit the collection of NTFPs within the park. Indigenous people should cooperate in sustainable collection and use of NTFPs. The role of NTFPs to livelihoods in and around ANP are clearly understood by study and will be useful in the awareness and implementation of the conservation practices in the Ayubia National Park.
Contribution of B-1 cells in the cytotoxicity of CD8 T lymphocytes in encephalitozoonosis
Authors: de Oliveira Cristina Gabriela Nascimento , Perez Elizabeth Cristina , Alvares-Saraiva Anuska Marcelino , Lallo Maria Anete 
Published: November 2023

AbstractEncephalitozoon cuniculiis an opportunistic intracellular pathogen that establishes a balanced relationship with immunocompetent individuals depending on the activity of their CD8+T cells lymphocytes. However, lower resistance to experimental infection withE. cuniculiwas found in B-1 deficient mice (Xid), besides increased the number of CD8 T lymphocytes. Here, we evaluated the cytotoxic activity of CD8+T lymphocytes from Balb/c wild-type (WT) or Balb/c Xid mice (with B-1 cell deficiency) on the microbicidal activity of macrophages challenged withE. cuniculi. CD8 T lymphocytes from WT or Xid mice previously infected or not withE cuniculiwere co-cultured with macrophages challenged withE. cuniculi. We evaluated macrophages viability and microbicidal activity, and proliferation, viability, and presence of activating molecules (CD62L, CD69, and CD107a) in CD8 T lymphocytes. Macrophages co-cultured with CD8 T lymphocytes from WT demonstrated high microbicidal activity. CD8 T lymphocytes obtained from uninfected WT mice had a higher proliferative capacity and a higher expression of CD69 and LAMP-1-activating molecules compared to Xid CD8+T lymphocytes. CD8 T lymphocytes from infected Xid mice proliferated more than those from WT mice, however, when the expression of the activating molecule CD69 associated with the expression of CD62L was kept low. In conclusion, the absence of B-1 cells in Xid mice might be associated with the lower expression of activating molecules in CD8+T lymphocytes and their cytotoxic activity. However, after a previous infection withE. cuniculi, CD8 T lymphocytes were more effective in killing macrophages infected withE. cuniculi.
METTL3 alters capping enzyme expression and its activity on ribosomal proteins
Authors: del Valle-Morales Daniel , Romano Giulia , Le Patricia , Saviana Michela , Brown Rachel , Micalo Lavender , Li Howard , Ferlita Alessandro La , Nigita Giovanni , Nana-Sinkam Patrick , Acunzo Mario 
Published: November 2023

AbstractThe 5’ cap, catalyzed by RNA guanylyltransferase and 5’-phosphatase (RNGTT), is a vital mRNA modification for the functionality of mRNAs. mRNA capping occurs in the nucleus for the maturation of the functional mRNA and in the cytoplasm for fine-tuning gene expression. Given the fundamental importance of RNGTT in mRNA maturation and expression there is a need to further investigate the regulation of RNGTT. N6-methyladenosine (m6A) is one of the most abundant RNA modifications involved in the regulation of protein translation, mRNA stability, splicing, and export. We sought to investigate whether m6A could regulate the expression and activity of RNGTT. A motif for the m6A writer methyltransferase 3 (METTL3) in the 3’UTR of RNGTT mRNA was identified. Knockdown of METTL3 resulted in destabilizing RNGTT mRNA, and reduced protein expression. Sequencing of capped mRNAs identified an underrepresentation of ribosomal protein mRNA overlapping with 5’ terminal oligopyrimidine (TOP) mRNAs and genes are dysregulated when cytoplasmic capping is inhibited. Pathway analysis identified disruptions in the mTOR and p70S6K pathways. A reduction in RPS6 mRNA capping, protein expression, and phosphorylation was detected with METTL3 knockdown.
SHC-3: a previously unidentifiedC. elegansShc family member functions in the insulin-like signaling pathway to enhance survival during L1 arrest
Authors: Guerrero Victoria L. León , Di Bernardo Mercedes , Hardy W. Rod , Sutoski Jacob C. , MacNeil Lesley T. 
Published: November 2023

AbstractShc proteins function in many different signaling pathways where they mediate phosphorylation-dependent protein-protein interactions. These proteins are characterized by the presence of two phosphotyrosine-binding domains, an N-terminal PTB and a C-terminal SH2. We describe a previously unrecognizedC. elegansShc gene,shc-3and characterize its role of in stress response. Bothshc-3andshc-1are required for long-term survival in L1 arrest, however, they do not act redundantly but rather play distinct roles in this process. SHC-3 function in survival during L1 arrest is DAF-16-dependent, demonstrating that like SHC-1, SHC-3 functions in the Insulin-like signaling pathway. In the absence of SHC-3, nuclear entry and exit are slowed suggesting that SHC-3 is required for rapid changes in DAF-16 signaling.
LDER-GE estimates phenotypic variance component of gene-environment interactions in human complex traits accurately with GE interaction summary statistics and full LD information
Authors: Dong Zihan , Jiang Wei , Li Hongyu , DeWan Andrew T. , Zhao Hongyu 
Published: November 2023

AbstractGene-environment (GE) interactions are essential in understanding human complex traits. Identifying these interactions is necessary for deciphering the biological basis of such traits. In this study, we introduce a statistical method Linkage-Disequilibrium Eigenvalue Regression for Gene-Environment interactions (LDER-GE). LDER-GE improves the accuracy of estimating the phenotypic variance component explained by genome-wide GE interactions using large-scale biobank association summary statistics. LDER-GE leverages the complete Linkage Disequilibrium (LD) matrix, as opposed to only the diagonal squared LD matrix utilized by LDSC (Linkage Disequilibrium Score)-based methods. Our extensive simulation studies demonstrate that LDER-GE performs better than LDSC-based approaches by enhancing statistical efficiency by approximately 23%. This improvement is equivalent to a sample size increase of around 51%. Additionally, LDER-GE effectively controls type-I error rate and produces unbiased results. We conducted an analysis using UK Biobank data, comprising 307,259 unrelated European-Ancestry subjects and 966,766 variants, across 151 environmental covariate-phenotype (E-Y) pairs. LDER-GE identified 35 significant E-Y pairs while LDSC-based method only identified 25 significant E-Y pairs with 23 overlapped with LDER-GE. Furthermore, we employed LDER-GE to estimate the aggregated variance component attributed to multiple GE interactions, leading to an increase in the explained phenotypic variance with GE interactions compared to considering main genetic effects only. Our results suggest the importance of impacts of GE interactions on human complex traits.