bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early real world evidence on the relative SARS-COV-2 vaccine effectiveness of bivalent COVID-19 booster doses: a rapid review
Authors: Schepisi M. Sane 
Published: March 2023

AbstractThe objective of this review is to give an overall view of COVID-19 bivalent vaccines knowledge and to explore their early available real world effectiveness evidence in the Omicron era.Presently, bivalent vaccines are generally offered to all groups eligible for their next booster, as defined by the national vaccination campaign, with varying policies between countries.The use of bivalent vaccines is supported by immunogenity studies, which, nevetheless, have led to contradictory conclusions, and are not generally designed to measure clinical impact.In order to critically appraise the available research on real world effectiveness, a systematic literature search was performed: out of 876 references examined, 14 studies were finally included and extracted. The findings of this review demonstrate modest to moderate additional protection of vaccination with bivalent BA.4-5 or BA.1 mRNA-booster vaccines against COVID-19 associated illness and hospitalization, -if compared with having received a monovalent dose as booster-, during a period when BA.5 and other Omicron sublineage viruses predominated globally,Considering the complexity of the current immunity situation at global level, and the high level of heterogeneity both at study and at review level, these findings must be taken with caution. Further research on SARS-CoV-2 vaccine effectiveness against emerging SARS-CoV-2 variants is encouraged.
Multi-omic characterization reveals a distinct molecular landscape in young-onset pancreatic cancer
Authors: Ogobuiro Ifeanyichukwu , Baca Yasmine , Ribeiro Jennifer R , Walker Phillip , Wilson Gregory C , Gulhati Prateek , Marshall John L , Shroff Rachna T , Spetzler David , Oberley Matthew J , Abbott Daniel E , Kim Hong Jin , Kooby David A , Maithel Shishir K , Ahmad Syed A , Merchant Nipun B. , Xiu Joanne , Hosein Peter J. , Datta Jashodeep 
Published: March 2023

ABSTRACTPurposeUsing a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between young-onset pancreatic cancer (YOPC; <50-yrs.) and average-onset pancreatic cancer (AOPC; ≥70-yrs.) patients.MethodsWe analyzed matched whole-transcriptome and DNA sequencing data from 2430 patient samples (YOPC, n=292; AOPC, n=2138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data was obtained from insurance claims (n=4928); Kaplan-Meier estimates were calculated for age-and molecularly-defined cohorts. Significance was determined as FDR-correctedP-values (Q)<0.05.ResultsYOPC patients had higher proportions of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H),BRCA2-mutant, andPALB2-mutant tumors compared with AOPC patients, but fewerSMAD4-, RNF43-, CDKN2A-, andSF3B1-mutant tumors. Notably, YOPC patients demonstrated significantly lower incidence ofKRASmutations compared with AOPC patients (81.3% vs. 90.9%;Q=0.004). In theKRAS-wildtype subset (n=227), YOPC tumors demonstrated fewerTP53mutations and were more likely driven byNRG1andMETfusions, whileBRAFfusions were exclusively observed in AOPC patients. Immune deconvolution revealed significant enrichment of natural killer (NK) cells, CD8+T cells, monocytes, and M2 macrophages in YOPC patients relative to AOPC patients, which corresponded with lower rates ofHLA-DPA1homozygosity. There was an association with improved OS in YOPC patients compared with AOPC patients withKRAS-wildtype tumors (median 16.2 [YOPC-KRASWT] vs. 10.6 [AOPC-KRASWT] months;P=0.008) but notKRAS-mutant tumors (P=0.084).ConclusionIn this large, real-world multi-omic characterization of age-stratified molecular differences in PDAC, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.
BRCA1-BARD1 combines multiple chromatin recognition modules to bridge nascent nucleosomes
Authors: Burdett Hayden , Foglizzo Martina , Musgrove Laura J. , Kumar Dhananjay , Clifford Gillian , Campbell Lisa J. , Heath George R. , Zeqiraj Elton , Wilson Marcus D. 
Published: March 2023

ABSTRACTChromatin association of the BRCA1-BARD1 heterodimer is critical to promote homologous recombination repair of DNA double-strand breaks (DSBs) in S/G2. How the BRCA1-BARD1 complex interacts with chromatin that contains both damage induced histone H2A ubiquitin and inhibitory H4AK20 methylation is not fully understood. We characterised BRCA1-BARD1 binding and enzymatic activity to an array of mono- and di-nucleosome substrates using biochemical, structural, and single molecule imaging approaches. We find that the BRCA1-BARD1 complex preferentially interacts and modifies di-nucleosomes over mono-nucleosomes, allowing integration of H2A Lys-15 ubiquitylation signals with other chromatin modifications and features. Using high speed-AFM to provide real-time visualization of BRCA1-BARD1 complex recognising chromatin, we show a highly dynamic complex that bridges two nucleosomes and associates with the DNA linker region. Bridging is aided by multivalent cross-nucleosome interactions that enhance BRCA1-BARD1 E3 ubiqiutin ligase catalytic activity. Multivalent interactions across nucleosomes explains how BRCA1-BARD1 can recognize chromatin that retains partial di-methylation at H4 Lys-20 (H4K20me2), a parental histone mark that blocks BRCA1-BARD1 interaction with nucleosomes, to promote its enzymatic and DNA repair activities.
Single-cell multi-scale footprinting reveals the modular organization of DNA regulatory elements
Authors: Hu Yan , Ma Sai , Kartha Vinay K. , Duarte Fabiana M. , Horlbeck Max , Zhang Ruochi , Shrestha Rojesh , Labade Ajay , Kletzien Heidi , Meliki Alia , Castillo Andrew , Durand Neva , Mattei Eugenio , Anderson Lauren J. , Tay Tristan , Earl Andrew S. , Shoresh Noam , Epstein Charles B. , Wagers Amy , Buenrostro Jason D. 
Published: March 2023

AbstractCis-regulatory elements control gene expression and are dynamic in their structure, reflecting changes to the composition of diverse effector proteins over time1–3. Here we sought to connect the structural changes atcis-regulatory elements to alterations in cellular fate and function. To do this we developed PRINT, a computational method that uses deep learning to correct sequence bias in chromatin accessibility data and identifies multi-scale footprints of DNA-protein interactions. We find that multi-scale footprints enable more accurate inference of TF and nucleosome binding. Using PRINT with single-cell multi-omics, we discover wide-spread changes to the structure and function of candidatecis-regulatory elements (cCREs) across hematopoiesis, wherein nucleosomes slide, expose DNA for TF binding, and promote gene expression. Activity segmentation using the co-variance across cell states identifies “sub-cCREs” as modular cCRE subunits of regulatory DNA. We apply this single-cell and PRINT approach to characterize the age-associated alterations to cCREs within hematopoietic stem cells (HSCs). Remarkably, we find a spectrum of aging alterations among HSCs corresponding to a global gain of sub-cCRE activity while preserving cCRE accessibility. Collectively, we reveal the functional importance of cCRE structure across cell states, highlighting changes to gene regulation at single-cell and single-base-pair resolution.
Gamma-Mobile-Trio systems define a new class of mobile elements rich in bacterial defensive and offensive tools
Authors: Mahata Tridib , Kanarek Katarzyna , Goren Moran G. , Rameshkumar Marimuthu Ragavan , Bosis Eran , Qimron Udi , Salomon Dor 
Published: March 2023

AbstractConflicts between bacteria and their rivals led to an evolutionary arms race and the development of bacterial immune systems. Although diverse immunity mechanisms were recently identified, many remain unknown, and their dissemination within bacteria is poorly understood. Here, we describe a widespread genetic element, defined by the presence of the Gamma-Mobile-Trio (GMT) proteins, that serves as a bacterial survival kit. We show that GMT-containing genomic islands are active mobile elements with cargo comprising various anti-phage defense systems, in addition to antibacterial type VI secretion system (T6SS) effectors and antibiotic resistance genes. We identify four new anti-phage defense systems encoded within GMT islands. A thorough investigation of one system reveals that it is triggered by a phage capsid protein to induce cell dormancy. Our findings underscore the need to broaden the concept of ‘defense islands’ to include also antibacterial offensive tools, such as T6SS effectors, as they share the same mobile elements as defensive tools for dissemination.
Self-eating while being eaten: Elucidating the relationship between aphid feeding and the plant autophagy machinery in Arabidopsis leaves
Authors: Hao Let Kho , Dangol Anuma , Shavit Reut , Pitt William Jacob , Nalam Vamsi , Brotman Yariv , Michaeli Simon , Peled-Zehavi Hadas , Tzin Vered 
Published: March 2023

AbstractAutophagy, an intracellular process that facilitates the degradation of cytoplasmic materials, plays a dominant role in plant fitness and immunity. While autophagy was shown to be involved in plant response to fungi, bacteria, and viruses, its role in response to insect herbivory is as yet unknown. In this study, we demonstrate a role of autophagy in plant defense against herbivory usingArabidopsis thalianaand the green peach aphid,Myzus persicae. Following six hours of aphid infestation of wildtype plants, we observed high expression of the autophagy-related genesATG8aandATG8f, as well asNBR1(Next to BRCA1 gene 1), a selective autophagy receptor. Moreover, the number of autophagosomes detected by the overexpression of GFP-fused ATG8f in Arabidopsis increased upon aphid infestation. Following this,atg5.1andatg7.2mutants were used to study the effect of autophagy on aphid reproduction and feeding behavior. While aphid reproduction on both mutants was lower than on wildtype, feeding behavior was only affected byatg7.2mutants. Moreover, upon aphid feeding, thePhytoalexin-deficient 4(PAD4) defense gene was upregulated in wildtype plants but not affected in the mutants. By contrast, the hydrogen peroxide content was much higher in the mutants relative to wildtype, which might have disturbed aphid reproduction and interfered with their feeding. Additionally, an analysis of the phloem sap metabolite profile revealed thatatg7.2mutant plants have lower levels of amino acids and sugars. These findings, together with the high hydrogen peroxide levels, suggest that aphids might exploit the plant autophagy mechanism for their survival.
ChoruMM: a versatile multi-components mixed model for bacterial-GWAS
Authors: Frouin Arthur , Laporte Fabien , Hafner Lukas , Maury Mylene , McCaw Zachary R. , Julienne Hanna , Henches Léo , Chikhi Rayan , Lecuit Marc , Aschard Hugues 
Published: March 2023

AbstractGenome-wide Association Studies (GWAS) have been central to studying the genetics of complex human outcomes, and there is now tremendous interest in implementing GWAS-like approaches to study pathogenic bacteria. A variety of methods have been proposed to address the complex linkage structure of bacterial genomes, however, some questions remain about to optimize the genetic modelling of bacteria to decipher causal variations from correlated ones. Here we examined the genetic structure underlying whole-genome sequencing data from 3,824Listeria monocytogenesstrains, and demonstrate that the standard human genetics model, commonly assumed by existing bacterial GWAS methods, is inadequate for studying such highly structured organisms. We leverage these results to developChoruMM, a robust and powerful approach that consists of a multi-component linear mixed model, where components are inferred from a hierarchical clustering of the bacteria genetic relatedness matrix. OurChoruMMapproach also includes post-processing and visualization tools that address the pervasive long-range correlation observed in bacteria genome and allow to assess the type I error rate calibration.
GRAPHENE OXIDE AS A NOVEL IMMUNOTHERAPY TOOL FOR THE MODULATION OF MYELOID-DERIVED SUPPRESSOR CELL ACTIVITY IN THE CONTEXT OF MULTIPLE SCLEROSIS
Authors: Camacho-Toledano Celia , Machín-Díaz Isabel , Lebrón-Galán Rafael , González-Mayorga Ankor , Palomares Francisco J. , Serrano María C. , Clemente Diego 
Published: March 2023

ABSTRACTMultiple Sclerosis (MS) is a chronic, inflammatory disease of the central nervous system. Despite the pharmacological arsenal approved for MS, there are treatment-reluctant patients for whom cell therapy appears as the only therapeutic alternative. Myeloid-derived suppressor cells (MDSCs) are immature cells of the innate immune response able to immunosuppress T lymphocytes and to promote oligodendroglial differentiation in experimental autoimmune encephalomyelitis (EAE), a preclinical model for MS. Culture devices need to be designed so that MDSCs maintain a state of immaturity and immunosuppressive function similar to that exerted in the donor organism. Graphene oxide (GO) has been described as a biocompatible material with the capacity to biologically modulate different cell types, including immune cells. In the present work, we show how MDSCs isolated from immune organs of EAE mice maintain an immature phenotype and highly immunosuppressive activity on T lymphocytes after being cultured on 2D reduced GO films (rGO200) compared to those grown on glass. This activity is depleted when MDSCs are exposed to slightly rougher and more oxidized GO substrates (rGO90). The greater reduction in cell size of cells exposed to rGO90compared to rGO200is associated with the activation of apoptosis processes. Taken together, the exposure of MDSCs to GO substrates with different redox state and roughness appears as a good strategy to control MDSC activityin vitro. This versatility of GO nanomaterials and the impact of their physico-chemical properties in immunomodulation open the door to its possible selective therapeutic use for pathologies where MDSCs need to be enhanced or inhibited.
Reduced histone gene copy number disruptsDrosophilaPolycomb function
Authors: McPherson Jeanne-Marie E. , Grossmann Lucy C. , Armstrong Robin L. , Kwon Esther , Salzler Harmony R. , Matera A. Gregory , McKay Daniel J. , Duronio Robert J. 
Published: March 2023

AbstractThe chromatin of animal cells contains two types of histones: canonical histones that are expressed during S phase of the cell cycle to package the newly replicated genome, and variant histones with specialized functions that are expressed throughout the cell cycle and in non-proliferating cells. Determining whether and how canonical and variant histones cooperate to regulate genome function is integral to understanding how chromatin-based processes affect normal and pathological development. Here, we demonstrate that variant histone H3.3 is essential forDrosophiladevelopment only when canonical histone gene copy number is reduced, suggesting that coordination between canonicalH3.2and variantH3.3expression is necessary to provide sufficient H3 protein for normal genome function. To identify genes that depend upon, or are involved in, this coordinate regulation we screened for heterozygous chromosome 3 deficiencies that impair development of flies bearing reducedH3.2andH3.3gene copy number. We identified two regions of chromosome 3 that conferred this phenotype, one of which contains thePolycombgene, which is necessary for establishing domains of facultative chromatin that repress master regulator genes during development. We further found that reduction inPolycombdosage decreases viability of animals with noH3.3gene copies. Moreover, heterozygousPolycombmutations result in de-repression of the Polycomb target geneUbxand cause ectopic sex combs when either canonical or variantH3gene copy number is also reduced. We conclude that Polycomb-mediated facultative heterochromatin function is compromised when canonical and variantH3gene copy number falls below a critical threshold.
Steroid Receptor Coactivator-3 is a Key Modulator of Regulatory T Cell-Mediated Tumor Evasion
Authors: Han Sang Jun , Jain Prashi , Gilad Yosef , Xia Yan , Sung Nuri , Park Mi Jin , Dean Adam M. , Lanz Rainer B. , Xu Jianming , Dacso Clifford C. , Lonard David M. , O’Malley Bert W. 
Published: March 2023

AbstractsSteroid receptor coactivator 3 (SRC-3) is most strongly expressed in regulatory T cells (Tregs) and B cells, suggesting that it plays an important role in the regulation of Treg function. Using an aggressive E0771 mouse breast cell line syngeneic immune-intact murine model, we observed that breast tumors were ‘permanently eradicated’ in a genetically engineered tamoxifen-inducible Treg-cell specific SRC-3 knockout (KO) female mouse that does not possess a systemic autoimmune pathological phenotype. A similar eradication of tumor was noted in a syngeneic model of prostate cancer. A subsequent injection of additional E0771 cancer cells into these mice showed continued resistance to tumor development without the need for tamoxifen induction to produce additional SRC-3 KO Tregs. SRC-3 KO Tregs were highly proliferative and preferentially infiltrated into breast tumors by activating the Chemokine (C-C motif) ligand (Ccl) 19/Ccl21/ Chemokine (C-C motif) Receptor (Ccr)7 signaling axis, generating antitumor immunity by enhancing the interferon-γ/C-X-C Motif Chemokine Ligand (Cxcl) 9 signaling axis to facilitate the entrance and function of effector T cells and Natural Killer cells. SRC-3 KO Tregs also show a dominant effect by blocking the immune suppressive function of WT Tregs. Importantly, a single adoptive transfer of SRC-3 KO Tregs into wild-type E0771 tumor-bearing mice can completely abolish pre-established breast tumors by generating potent antitumor immunity with a durable effect that prevents tumor reoccurrence. Therefore, treatment with SRC-3 deleted Tregs represents a novel approach to completely block tumor growth and recurrence without the autoimmune side-effects that typically accompany immune checkpoint modulators.Significance statementTregs are essential in restraining immune responses for immune homeostasis. SRC-3 is a pleiotropic coactivator, the second-most highly expressed transcriptional coactivator in Tregs, and a suspect in Treg function. The disruption of SRC-3 expression in Tregs leads to a ‘complete lifetime eradication’ of tumors in aggressive syngeneic breast cancer mouse models because deletion of SRC-3 alters the expression of a wide range of key genes involved in efferent and afferent Treg signaling. SRC-3KO Tregs confer this long-lasting protection against cancer recurrence in mice without an apparent systemic autoimmune pathological phenotype. Therefore, treatment with SRC-3 deleted Tregs could represent a novel and efficient future target for eliminating tumor growth and recurrence without the autoimmune side-effects that typically accompany immune checkpoint modulators.
A Conserved Switch Controls Virulence, Sporulation, and Motility inC. difficile
Authors: DiCandia Michael A. , Edwards Adrianne N. , Lee Cheyenne D. , Monteiro Marcos P. , Cuebas Germán Vargas , Bagchi Pritha , McBride Shonna M. 
Published: March 2023

SUMMARYSpore formation is required for environmental survival and transmission of the human enteropathogenicClostridioides difficile. In all bacterial spore formers, sporulation is regulated through activation of the master response regulator, Spo0A. However, the factors and mechanisms that directly regulateC. difficileSpo0A activity are not defined. In the well-studiedBacillusspecies, Spo0A is directly inactivated by Spo0E, a small phosphatase. To understand Spo0E function inC. difficile, we created a null mutation of thespo0Eortholog and assessed sporulation and physiology. Thespo0Emutant produced significantly more spores, demonstrating Spo0E repressesC. difficilesporulation. Unexpectedly, thespo0Emutant also exhibited increased motility and toxin production, and enhanced virulence in animal infections. We uncovered that Spo0E interacts with both Spo0A and the toxin and motility regulator, RstA. Direct interactions between Spo0A, Spo0E, and RstA constitute a previously unknown molecular switch that coordinates sporulation with motility and toxin production. Reinvestigation of Spo0E function inB. subtilisrevealed that Spo0E induced motility, demonstrating Spo0E regulation of motility and sporulation among divergent species. Further, we found that Spo0E orthologs are widespread among prokaryotes, suggesting that Spo0E performs conserved regulatory functions in diverse bacteria.
Ribosomal protein mutation suppresses gonadal leader cell migration defects inmig-17/ADAMTSmutants inCaenorhabditis elegans
Authors: Kim Hon-Song , Mitsuzumi Kaito , Kondo Shohei , Yamaoka Rie , Ihara Shinji , Otsuka Hiroshi , Kubota Yukihiko , Fujiwara Toshinobu , Shibata Yukimasa , Nishiwaki Kiyoji 
Published: March 2023

AbstractThe migration of the gonadal distal tip cells (DTCs) inCaenorhabditis elegansprovides an excellent model for studying the migration of epithelial tubes during organogenesis. Mutations in themig-17/ADAMTSgene cause misdirected migration of DTCs during gonad formation, resulting in deformed gonad arms. An amino-acid substitution in RPL- 20 corresponding to the mammalian RPL18a/eL20, a component of the 60S ribosomal large subunit, showed a slow growth phenotype and strongly suppressed themig-17gonadal defects. Slow-growing mutantsclk-1andclk-2also suppressedmig-17, although weaker thanrlp-20mutants. MIG-17 recruits FBL-1C/fibulin-1C to the gonadal basement membrane to regulate DTC migration. Reducing the gene dosage offbl-1by half partially compromised the suppressor activity of the mutantrpl-20gene onmig-17. Analysis using the mNeonGreen-FBL-1 reporter revealed that its localization to the gonadal basement membrane was significantly reduced inmig-17, whereas it was recovered to the wild-type levels inmig-17; rpl-20double mutants. These results indicate that therpl-20mutation suppressesmig-17gonadal defects through dual mechanisms: deceleration of growth rate and enhancement of FBL-1C recruitment to the gonadal basement membrane.