bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety of RSV Vaccine among Pregnant Individuals: A Real-World Pharmacovigilance Study Using Vaccine Adverse Event Reporting System
Authors: Alami Abdallah , Perez-Lloret Santiago , Mattison Donald R. 
Published: April 2024

ABSTRACTObjectivesTo describe the post-marketing safety of RSVPreF among pregnant individuals.DesignThis case series study analyzed adverse event (AE) reports submitted to the U.S. Food and Drug Administration’s Vaccine Adverse Event Reporting System (VAERS) database following RSVPreF immunization from September 1, 2023, to February 23, 2024.SettingVAERS, as a national spontaneous vaccine safety surveillance system, provides insights into the safety profile of the RSVPreF vaccine in a real-world setting.ParticipantsSurveillance data included all AE reports submitted to VAERS for pregnant individuals following vaccination.ExposureReceipt of RSVPreF vaccine among pregnant individuals in the U.S.Primary and secondary outcome measuresDescriptive statistics assessed all AE reports with RSVPreF, including frequency, gestational age at vaccination, time to AE onset, and serious report proportions. The Bayesian Confidence Propagation Neural Network (BCPNN) was utilized, estimating the information component (IC) to identify disproportionate reporting of RSVPreF–event pairs.ResultsVAERS received 77 reports pertained to RSVPreF vaccination in pregnant individuals, with 42 (54.55%) classified as serious. The most reported non-pregnancy-specific AEs were headache, injection site erythema, and injection site pain. Preterm birth was the most frequently reported pregnancy-specific AE, followed by preterm premature rupture of membranes, cesarean section, cervical dilatation, and hemorrhage during pregnancy. The median time from immunization to reported preterm birth was 3 days, with two-thirds of cases within a week. Disproportionality analysis indicated a significant signal for various AEs, particularly highlighting preterm birth with an IC of 2.18 (95%CI, 1.54-2.63), suggesting that reports of preterm birth associated with RSVPreF vaccination occurred more frequently than statistically expected.ConclusionsWhile reported AEs were generally consistent with the safety profile observed in prelicensure studies, this study highlights ongoing concern about preterm birth among pregnant individuals following RSVPreF vaccination. Comprehensive longitudinal follow-up, including prospective pregnancy registries and infant follow-up studies is urgently required.
Exploring the Potential of Structure-Based Deep Learning Approaches for T cell Receptor Design
Authors: Ribeiro-Filho Helder V. , Jara Gabriel E. , Guerra João V. S. , Cheung Melyssa , Felbinger Nathaniel R. , Pereira José G. C. , Pierce Brian G. , Lopes-de-Oliveira Paulo S. 
Published: April 2024

AbstractDeep learning methods, trained on the increasing set of available protein 3D structures and sequences, have substantially impacted the protein modeling and design field. These advancements have facilitated the creation of novel proteins, or the optimization of existing ones designed for specific functions, such as binding a target protein. Despite the demonstrated potential of such approaches in designing general protein binders, their application in designing immunotherapeutics remains relatively unexplored. A relevant application is the design of T cell receptors (TCRs). Given the crucial role of T cells in mediating immune responses, redirecting these cells to tumor or infected target cells through the engineering of TCRs has shown promising results in treating diseases, especially cancer. However, the computational design of TCR interactions presents challenges for current physics-based methods, particularly due to the unique natural characteristics of these interfaces, such as low affinity and cross-reactivity. For this reason, in this study, we explored the potential of two structure-based deep learning protein design methods, ProteinMPNN and ESM-IF, in designing fixed-backbone TCRs for binding target antigenic peptides presented by the MHC through different design scenarios. To evaluate TCR designs, we employed a comprehensive set of sequence- and structure-based metrics, highlighting the benefits of these methods in comparison to classical physics-based design methods and identifying deficiencies for improvement.
Combined thermodynamic and time-resolved structural analysis of interactions between AP2 and biomimetic plasma membranes provides insights into clathrin-mediated endocytosis
Authors: Maestro Armando , Zaccai Nathan R. , Gonzalez-Martinez J.F. , Sanchez-Puga P. , Tajuelo J. , Rubio M. A. , Santamaria Andreas , Carrascosa-Tejedor J. , Pereira D. , Marín-Montesinos I. , Gutfreund P. , Campbell Richard , Kotar J. , Kelly Bernard T. , Cicuta Pietro , Owen David J. 
Published: April 2024

AbstractClathrin mediated endocytosis (CME) is the main mechanism for swift and selective uptake of proteins into eukaryotic cells. CME is initiated by recruitment to the plasma membrane (PM) of the adaptor protein AP2, which recognizes the PM-associated lipid PtdIns(4,5)P2, as well as the protein cargo to be internalized. Nonetheless, many aspects of this process remain unclear due to their in vivo complexity. Here, a thermodynamic and time-resolved structural analysis of AP2 binding to different biomimetic PM was undertaken under physiological conditions using a combination of neutron reflectometry, interfacial tensiometry and rheology, and atomic force microscopy. The resultant in vitro data replicated previous in vivo observations, as well as yielded biophysical insights into normal and aborted CME. The presence of cargo may not be pivotal for the “activating” conformational change of AP2. However, the presence of cargo extends AP2’s residence time on the membrane surface, due to slower on- and off-rates, thereby tentatively giving sufficient time for CME to proceed fully. Moreover, upon interaction with AP2, phospholipid lateral diffusion decreases markedly, inducing a gel phase attributed to creating a percolated network involving AP2 on the membrane, which could potentially serve as a mechanism for modulating subsequent clathrin binding.
Varying phylogenetic signal in susceptibility to four bacterial pathogens across species of Drosophilidae
Authors: Sun Hongbo , Hanson Mark A. , Walsh Sarah K. , Imrie Ryan M. , Raymond Ben , Longdon Ben 
Published: April 2024

AbstractBacterial infections are one of the major sources threatening public health. Pathogen host shifts – where a pathogen jumps from one host species to another – are important sources of emerging infectious diseases. However, compared to viruses, we know relatively little about the factors that determine whether a bacteria can infect a novel host, such as how host phylogenetics constrains variation in pathogen-host range and the link between host phylogeny and the infectivity and virulence of a pathogen. Here, we experimentally examined susceptibility to bacterial infections using a panel of 36 Drosophilidae species and four pathogens (Providencia rettgeri,Pseudomonas entomophila,Enterococcus faecalis,Staphylococcus aureus). The outcomes of infection differed greatly among pathogens and across host species. The host phylogeny explains a considerable amount of variation in susceptibility, with the greatest phylogenetic signal forP. rettgeriinfection, explaining 94% of the variation in mortality. Positive correlations were observed between mortality and bacterial load for three out of the four pathogens. Correlations in susceptibility between the four pathogens were positive but largely non-significant, suggesting susceptibility is mostly pathogen-specific. These results suggest that susceptibility to bacterial pathogens may be predicted by the host phylogeny, but the effect may vary in magnitude between different bacteria.
Spatiotemporal dynamics revealed the dark water community of giant virus from a deep freshwater lake
Authors: Zhang Liwen , Meng Lingjie , Fang Yue , Ogata Hiroyuki , Okazaki Yusuke 
Published: April 2024

AbstractGiant viruses significantly regulate the ecological dynamics of diverse ecosystems. Although metagenomics has expanded our understanding of their diversity and ecological roles played in marine environments, little is known about giant viruses of freshwater ecosystems. Most previous studies have employed short-read sequencing and therefore resulted in fragmented genomes, hampering accurate assessment of genetic diversity. We sought to bridge this knowledge gap and overcome previous technical limitations. We subjected spatiotemporal (2 depths × 12 months) samples from Lake Biwa to metagenome-assembled genome reconstruction enhanced by long-read metagenomics. This yielded 294 giant virus metagenome-assembled genomes. Of these, 285 included previously unknown species in five orders of nucleocytoviruses and the first representatives of freshwater mirusviruses, which exhibited marked divergence between freshwater- and marine-derived lineages. Notably, 42 (14.3%) genomes were composed of single contigs with completeness values >90%, demonstrating the good performance of our long-read metagenomic assembly. Giant viruses were partitioned across water depths, with most species specific to either the sunlit epilimnion or the dark hypolimnion. Epilimnion-specific members tended to be opportunistic and to exhibit short and intense abundance peaks, in line with the fact that they regulate the surface algal blooms. During the spring bloom, mirusviruses and members of three nucleocytovirus families were among the most abundant giant viruses. In contrast, hypolimnion-specific ones including algaviruses and mirusviruses were typically more persistent in the hypolimnion throughout the water-stratified period, suggesting that they infect hosts specific to the hypolimnion and play previously unexplored ecological roles in dark water-specific microbial ecosystems.
It is hard to be small: Inbreeding depression depends on the body size in a threatened songbird
Authors: Kubacka Justyna , Arantes Larissa S. , Herdegen-Radwan Magdalena , Osiejuk Tomasz S. , Sparmann Sarah , Mazzoni Camila J. 
Published: April 2024

AbstractWhile inbreeding is known to affect individual fitness and thus population extinction risk, studies have under-represented non-model species of conservation concern, and rarely sought conditionality of inbreeding depression. Here, using SNPs identified with RAD-seq, we determined inbreeding depression in a threatened bird, the aquatic warblerAcrocephalus paludicola, and whether its magnitude depends on phenotypic and environmental factors. We found that the inbreeding coefficient (F) of adults with small tarsi was negatively associated with the seasonal breeding success (in males) and clutch size (in females), with the respective decrease in fitness in the most inbred relative to the least inbred individuals of ~89% and ~12%. In contrast, in adult males, for the average tarsus, wing and mass, support was low forFto be related to the long-term return rate to breeding grounds. For mean phenotypic covariates and male density, we also found low evidence thatFis associated with the annual breeding success. Likewise, there was little support that motherFis related to egg hatch success and nestling survival, and – for average phenotypic traits, rainfall, temperature and nest density, and accounting for breeding peak – to clutch and fledged brood sizes. For nestlings, animal models showed that F is more negatively related to tarsus under higher temperatures and its effect varies by study year. However, for average brood size, temperature, rainfall and prey abundance, and when controlling for nestling sex, breeding peak and motherF, evidence for nestling F and tarsus association was weak. We conclude that (1) inbreeding depression on fitness components is stronger in smaller-bodied individuals, (2) considering interaction with phenotypic and environmental variables enables more accurate estimation of inbreeding depression, and (3) the inbreeding depression estimates will inform extinction risk analysis and conservation actions for the aquatic warbler.
The newSH3_Tdomain increases the structural and functional variability among SH3b-like CBDs from staphylococcal phage endolysins
Authors: Vázquez Roberto , Gutiérrez Diana , Grimon Dennis , Fernández Lucía , García Pilar , Rodríguez Ana , Briers Yves 
Published: April 2024

ABSTRACTEndolysins, proteins encoded by phages to lyse their hosts and release their progeny, have evolved to adapt to the structural features of each host. The endolysins fromStaphylococcus-infecting phages typically feature complex architectures with two enzymatically active domains (EADs) and one cell wall-binding domain (CBD) belonging to the bacterial SH3 (SH3b) superfamily. This study focuses on three SH3b-like CBDs from exemplary staphylococcal phage endolysins (LysRODI, LysC1C, and LysIPLA5) that were structurally and functionally characterized. While RODI_CBD and C1C_CBD were assigned to the well-knownSH3_5family, a new family,SH3b_T, was identified using the CBD from LysIPLA5 as a model. GFP-fused CBDs were created to assess their differential binding to a collection of staphylococcal strains. IPLA5_CBD showed enhanced binding toStaphylococcus epidermidis, while RODI_CBD and C1C_CBD exhibited distinct binding profiles, with RODI_CBD targetingStaphylococcus aureusspecifically and C1C_CBD displaying broad binding. Sequence comparisons suggested that a few differences in key amino acids could be responsible for the latter binding difference. The CBDs modulated the activity spectrum of synthetic EAD-CBD combinations in accordance with the previous binding profiles, but in a manner that was also dependent on the EAD present in the fusion protein. These results serve as a context for the diversity and versatility of SH3b domains in staphylococcal endolysins, providing insights on how (i) the CBDs from this superfamily have diverged to adapt to diverse bacterial ligands in spite of sharing a common fold; and (ii) the evolution of specificity relies on the EAD-CBD combination rather than solely the CBD.IMPORTANCEClinical management of bacterial infections is nowadays compromised by the rise in antimicrobial resistance. The development of new antimicrobial therapies with diverse modes of action is therefore of pivotal importance to complement the current standard of care. Phage endolysins are a new class of antibacterial agents based on rapid peptidoglycan degradation. The natural reservoir of phage endolysins offers a practically infinite diversity. This works reveals a broadly spread but still unknown phage endolysin domain targeting staphylococci while providing structural-functional insights that are paramount to understand the evolution of endolysins and how they can be applied as an antimicrobial.
Nonlinear progression during the occult transition establishes cancer lethality
Authors: Ginzel Joshua D. , Chapman Henry , Sills Joelle E. , Allen Edwin J. , Barak Lawrence S. , Cardiff Robert D. , Borowsky Alexander D. , Lyerly H. Kim , Rogers Bruce W. , Snyder Joshua C. 
Published: April 2024

SummaryCancer screening is based upon a linear model of neoplastic growth and malignant progression. Yet, historical observations suggest that malignant progression is uncoupled from growth which may explain the paradoxical increase in early-stage breast cancer detection without a dramatic reduction in metastatic burden. Here we lineage trace millions of genetically transformed field cells and thousands of screen detectable and symptomatic tumors using a cancer rainbow mouse model of HER2+ breast cancer. Transition rates from field cell to screen detectable tumor and then to symptomatic tumors were estimated from a dynamical model of tumor development. Field cells are orders of magnitude less likely to transition to a screen detectable tumor than the subsequent transition of a screen detectable tumor to a symptomatic tumor. Our model supports a critical occult transition in tumor development during which time a transformed cell becomes abona fideneoplasm. Lineage tracing and test-by-transplantation reveals that nonlinear progression during or prior to the occult transition gives rise to nascent lethal cancers at screen detection. Simulations illustrate how occult transition rates are a critical determinant of tumor growth and malignancy in the lifetime of a host. Our data provides direct experimental evidence that cancers can deviate from the predictable linear progression model foundational to current screening paradigms
TheChlamydiaeffector IncE employs two short linear motifs to reprogram host vesicle trafficking
Authors: Pha Khavong , Mirrashidi Katherine , Sherry Jessica , Tran Cuong Joseph , Herrera Clara M. , McMahon Eleanor , Elwell Cherilyn A. , Engel Joanne N. 
Published: April 2024

SummaryChlamydia trachomatis,a leading cause of bacteria sexually transmitted infections, creates a specialized intracellular replicative niche by translocation and insertion of a diverse array of effectors (Incs) into the inclusion membrane. Here, we characterize IncE, a multi-functional Inc that encodes two non-overlapping short linear motifs (SLiMs) within its short cytosolic C-terminus. The proximal SLiM mimics an R-SNARE motif to recruit syntaxin (STX) 7 and 12-containing vesicles to the inclusion. The distal SLiM mimics the Sorting Nexin (SNX) 5 and 6 cargo binding site to recruit SNX6-containing vesicles to the inclusion. By simultaneously binding to two distinct vesicle classes, IncE reprograms host cell trafficking to promote the formation of a class of hybrid vesicles at the inclusion that are required forC. trachomatisintracellular development. Our work suggests that Incs may have evolved SLiMs to facilitate rapid evolution in a limited protein space to disrupt host cell processes.
A novel micronemal protein, Scot1, is essential for apicoplast biogenesis and liver stage development inPlasmodium berghei
Authors: Ghosh Ankit , Mishra Akancha , Devi Raksha , Narwal Sunil Kumar , Nirdosh  , Srivastava Pratik Narain , Mishra Satish 
Published: April 2024

AbstractPlasmodiumsporozoites invade hepatocytes, transform into liver stages, and replicate into thousands of merozoites that infect erythrocytes and cause malaria. Proteins secreted from micronemes play an essential role in hepatocyte invasion, and unneeded micronemes are subsequently discarded for replication. The liver-stage parasites are potent immunogens that prevent malarial infection. Late liver stage-arresting genetically attenuated parasites (GAPs) exhibit greater protective efficacy than early GAP. However, the number of late liver-stage GAPs for generating GAPs with multiple gene deletions is limited. Here, we identified Scot1 (Sporozoite Conserved Orthologous Transcript 1), which was previously shown to be upregulated in sporozoites, and by endogenous tagging with mCherry, we demonstrated that it is expressed in the sporozoite and liver stages in micronemes. Using targeted gene deletion inPlasmodium berghei, we showed that Scot1 is essential for late liver-stage development.Scot1KO sporozoites grew normally into liver stages but failed to initiate blood-stage infection in mice due to impaired apicoplast biogenesis and merozoite formation. Bioinformatic studies suggested that Scot1 is a metal/small molecule carrier protein. Remarkably, supplementation with metals in the culture of infectedScot1KO cells did not rescue their phenotype. Immunization withScot1KO sporozoites in C57BL/6 mice confers protection against a malaria challenge via infection. These proof-of-concept studies will enable the generation ofP. falciparum Scot1mutants that could be exploited to generate GAP malaria vaccines.ImportanceMalaria parasites experience significant bottlenecks as transmitted to the mammalian host during a mosquito bite. Sporozoites invade liver cells, reproducing into thousands of merozoites, which are released after liver cell ruptures. The specific arrest of sporozoites during liver stage development acts as a powerful immunogen and provides sterile protection against sporozoite infection. GAP leading to an arrest in late liver stage development offers superior protection. Here, we report that a micronemal protein, Scot1, is essential for parasite maturation in the liver. Deletion of Scot1 resulted in impaired apicoplast biogenesis and merozoite formation. Vaccination withScot1KO sporozoites protects against malaria challenge. We have identified a late arresting GAP that will aid in developing new as well as safeguarding existing whole parasite vaccines.
Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder
Authors: Zillich Eric , Belschner Hanna , Avetyan Diana , Andrade-Brito Diego , Martínez-Magaña José Jaime , Frank Josef , Mechawar Naguib , Turecki Gustavo , Cabana-Domínguez Judit , Fernàndez-Castillo Noèlia , Cormand Bru , Montalvo-Ortiz Janitza L. , Nöthen Markus M. , Hansson Anita C. , Rietschel Marcella , Spanagel Rainer , Witt Stephanie H. , Zillich Lea 
Published: April 2024

AbstractStructural and functional changes of the brain are assumed to contribute to excessive cocaine intake, craving, and relapse in cocaine use disorder (CUD). Epigenetic and transcriptional changes were hypothesized as a molecular basis for CUD-associated brain alterations. Here we performed a multi-omics study of CUD by integrating epigenome-wide methylomic (N=42) and transcriptomic (N=25) data from the same individuals using postmortem brain tissue of Brodmann Area 9 (BA9). Of the N=1,057 differentially expressed genes (p<0.05), one gene,ZFAND2A, was significantly upregulated in CUD at transcriptome-wide significance (q<0.05). Differential alternative splicing (AS) analysis revealed N=98 alternatively spliced transcripts enriched in axon and dendrite extension pathways. Strong convergent overlap in CUD-associated expression deregulation was found between our BA9 cohort and independent replication datasets. Epigenomic, transcriptomic, and AS changes in BA9 converged at two genes,ZBTB4andINPP5E.In pathway analyses, synaptic signaling, neuron morphogenesis, and fatty acid metabolism emerged as the most prominently deregulated biological processes. Drug repositioning analysis revealed glucocorticoid receptor targeting drugs as most potent in reversing the CUD expression profile. Our study highlights the value of multi-omics approaches for an in-depth molecular characterization and provides insights into the relationship between CUD-associated epigenomic and transcriptomic signatures in the human prefrontal cortex.
Circadian regulation of stereotypic chromatin conformations at enhancers
Authors: Nie Xinyu Y. , Menet Jerome S. 
Published: April 2024

SummaryCooperation between the circadian transcription factor (TF) CLOCK:BMAL1 and other TFs atcis-regulatory elements (CREs) is critical to daily rhythms of transcription. Yet, the modalities of this cooperation are unclear. Here, we analyzed the co-binding of multiple TFs on single DNA molecules in mouse liver using single molecule footprinting (SMF). We found that SMF reads clustered in stereotypic chromatin states that reflect distinguishable organization of TFs and nucleosomes, and that were remarkably conserved between all samples. DNA protection at CLOCK:BMAL1 binding motif (E-box) varied between CREs, from E-boxes being solely bound by CLOCK:BMAL1 to situations where other TFs competed with CLOCK:BMAL1 for E-box binding. SMF also uncovered CLOCK:BMAL1 cooperative binding at E-boxes separated by 250 bp, which structurally altered the CLOCK:BMAL1-DNA interface. Importantly, we discovered multiple nucleosomes with E-boxes at entry/exit sites that were removed upon CLOCK:BMAL1 DNA binding, thereby promoting the formation of open chromatin states that facilitate DNA binding of other TFs and that were associated with rhythmic transcription. These results demonstrate the utility of SMF for studying how CLOCK:BMAL1 and other TFs regulate stereotypical chromatin states at CREs to promote transcription.