bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Diabetes Mellitus in Pregnancy and Perinatal Depression
Authors: Björvang Richelle D. , Liakea Iliana , Carpentsier Beatrice , Kozinszky Zoltan , Skalkidou Alkistis , Fransson Emma 
Published: November 2023

ABSTRACT

Objective
Diabetes is frequently linked with depression, and both conditions are common complications during pregnancy. However, research findings exploring the relationship between diabetes mellitus in pregnancy (DMP) and perinatal depression (PND) have been inconsistent. Thus, this study seeks to examine the association between DMP and PND in a prospective population-based cohort.

Methods
Women aged 18 to 48 years (n = 4459) were identified from the Biology, Affect, Stress, Imaging and Cognition study. The diagnosis of DMP was based on International Classification of Diseases code O24 from medical records and was classified as pregestational, gestational, or unspecified diabetes. PND was assessed using psychometric instruments, clinical interviews, and/or register data and categorized into antepartum or postpartum depression. Multivariable logistic regressions were used to study the associations of DMP with antepartum and postpartum depression. The association between DMP and continuous depression scores, antepartum and postpartum, was investigated with multivariable linear regressions.

Results
Of 4459 pregnancies, 949 women had antepartum depression (21.2%) and 1123 had postpartum depression (25%). DMP had a prevalence of 1.2%. Women with DMP had twofold higher odds for postpartum depression compared with women without DMP. Although no association was observed between DMP and antepartum depression, DMP was associated with higher antepartum depression scores.

Conclusions
Our study shows an association between DMP and PND, which might be considered a risk factor when screening for high-risk groups.
SARS-CoV-2 monoclonal antibody treatment followed by vaccination shifts human memory B cell epitope recognition suggesting antibody feedback
Authors: Coelho Camila H. , Bloom Nathaniel , Ramirez Sydney I. , Parikh Urvi M. , Heaps Amy , Sieg Scott F. , Greninger Alex , Ritz Justin , Moser Carlee , Eron Joseph J. , Currier Judith S. , Klekotka Paul , Wohl David A. , Daar Eric S. , Li Jonathan , Hughes Michael D. , Chew Kara W. , Smith Davey M. , Crotty Shane ,   the Accelerating COVID-19 Therapeutic Interventions and Vaccines–2/A5401 (ACTIV-2/A5401) Study Team
Published: November 2023

ABSTRACTTherapeutic anti-SARS-CoV-2 monoclonal antibodies (mAbs) have been extensively studied in humans, but the impact on immune memory of mAb treatment during an ongoing immune response has remained unclear. Here, we evaluated the effect of infusion of the anti-SARS-CoV-2 spike receptor binding domain (RBD) mAb bamlanivimab on memory B cells (MBCs) in SARS-CoV-2–infected individuals. Bamlanivimab treatment skewed the repertoire of memory B cells targeting Spike towards non-RBD epitopes. Furthermore, the relative affinity of RBD memory B cells was weaker in mAb-treated individuals compared to placebo-treated individuals over time. Subsequently, after mRNA COVID-19 vaccination, memory B cell differences persisted and mapped to a specific defect in recognition of the class II RBD site, the same RBD epitope recognized by bamlanivimab. These findings indicate a substantial role of antibody feedback in regulating human memory B cell responses, both to infection and vaccination. These data indicate that mAb administration can promote alterations in the epitopes recognized by the B cell repertoire, and the single administration of mAb can continue to determine the fate of B cells in response to additional antigen exposures months later.SIGNIFICANCE STATEMENTEvaluating the therapeutic use of monoclonal antibodies during SARS-CoV-2 infection requires a comprehensive understanding of their impact on B cell responses at the cellular level and how these responses are shaped after vaccination. We report for the first time the effect of bamlanivimab on SARS-CoV-2 specific human memory B cells of COVID-19 infected humans receiving, or not, mRNA immunization.
A nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth
Authors: Zuazo-Gaztelu Iratxe , Lawrence David , Oikonomidi Ioanna , Marsters Scot , Pechuan-Jorge Ximo , Gaspar Catarina J , Kan David , Segal Ehud , Clark Kevin , Beresini Maureen , Braun Marie-Gabrielle , Rudolph Joachim , Modrusan Zora , Choi Meena , Sandoval Wendy , Reichelt Mike , Kujala Pekka , van Dijk Suzanne , Klumperman Judith , Ashkenazi Avi 
Published: November 2023

ABSTRACTEndoplasmic-reticulum resident inositol-requiring enzyme 1α (IRE1) supports protein homeostasis via a cytoplasmic kinase-RNase module. Known cancer dependency on IRE1 entails its enzymatic activation of the transcription factor XBP1s and of RNA decay. We discovered that some cancer cells require IRE1 but not its enzymatic activity. IRE1 knockdown, but not enzymatic inhibition or XBP1 disruption, increased DNA damage and chromosome instability while engaging the TP53 pathway and cyclin-dependent kinase inhibitors and attenuating cell cycle progression. IRE1 depletion downregulated factors involved in chromosome replication and segregation and in chromatin remodeling. Immunoelectron microscopy indicated that endogenous IRE1 can localize to the nuclear envelope. Thus, cancer cells can require IRE1 either enzymatically or nonenzymatically, with significant implications for IRE1’s biological role and therapeutic targeting.
The doublecortin-family kinase ZYG-8DCLK1regulates motor activity to achieve proper force balance inC. elegansacentrosomal spindles
Authors: Czajkowski Emily R. , Divekar Nikita S. , Wignall Sarah M. 
Published: November 2023

ABSTRACTAlthough centrosomes help organize spindles in most cell types, oocytes of most species lack these structures. During acentrosomal spindle assembly inC. elegansoocytes, microtubule minus ends are sorted outwards away from the chromosomes where they form poles, but then these outward forces must be balanced to form a stable bipolar structure. How proper force balance is achieved in these spindles is not known. Here, we have gained insight into this question through studies of ZYG-8, a conserved doublecortin-family kinase; the mammalian homolog of this microtubule-associated protein is upregulated in many cancers and has been implicated in cell division, but the mechanisms by which it functions are poorly understood. Interestingly, we found that ZYG-8 depletion from oocytes resulted in spindles that were over-elongated, suggesting that there was excess outward force following ZYG-8 removal. Experiments with monopolar spindles confirmed this hypothesis and revealed a role for ZYG-8 in regulating the force-generating motor BMK-1/kinesin-5. Importantly, further investigation revealed that kinase activity is required for the function of ZYG-8 in both meiosis and mitosis. Altogether, our results support a model in which ZYG-8 regulates motor-driven forces within the oocyte spindle, thus identifying a new function for a doublecortin-family protein in cell division.
Adherent reformed islets: a long-term primary cell-based platform for exploring mouse and human islet biology
Authors: Haq N. , Toczyska K.W. , Wilson M.E. , Jacobs M. , Zhao Min , Lei Y. , Pearson J. , Persaud S.J. , Pullen T.J. , Bewick G.A. 
Published: November 2023

AbstractPancreatic islets are 3-dimensional micro-organs that maintain β-cell functionality via cell-cell and cell-matrix communication. Isolated primary islets are the gold standard for in vitro models. However, native islets present experimental challenges for long-term mechanistic studies owing to their short culture life (approximately 1 week). We developed a novel long-term protocol to study the function of primary islets. The protocol employed reformed islets following dispersion and a fine-tuned culture environment. Reformed islets are highly similar to their primary counterparts across various physiological characteristics. Long-term culture of reformed islets enables high-resolution imaging, repeated functional assessment, and the study of cell-cell communication. Unlike other platforms such as stem cell-derived organoids, reformed islets retain their resident immune populations, making them ideal for studying both resident and infiltrating immune cells and their interactions with hormone-producing islet cells.Qualitative and quantitative analyses revealed that the composition and cytoarchitecture of the reformed islets mimicked those found in primary islets, including the presence of macrophages and CD4+and CD8+T cells, which are the key resident immune cell types. Reformed islets secrete insulin and are glucose-responsive, and their β-cells can be stimulated to proliferate using GLP-1 receptor agonism. Furthermore, a comparison of the transcriptomic landscape of isolated human islets and reformed islets generated from the same donor demonstrated a high degree of similarity.Our reformed islets provide an ideal platform to study diabetes pathology. We recapitulated both the T1DM and T2DM disease milieu and validated our model for studying islet immune trafficking and invasion using activated macrophages and T cells.Our data illustrates that reformed islets are an anatomical and functional alternative to native human and mouse islets. Moreover, reformed islets have an advantage over mouse and human β-cell lines, including MIN6 and EndoC-βH1cells, that lack the signalling input of non-β-endocrine cells and immune cell crosstalk. In this study, we showed that reformed islets are a durable paradigm (cell-based model) for islet-based exploration and a means of target discovery/validation for diabetes research.Graphical Abstract
Expanding the GPCR-RAMP interactome
Authors: Kotliar Ilana B. , Bendes Annika , Dahl Leo , Chen Yuanhuang , Saarinen Marcus , Ceraudo Emilie , Dodig-Crnković Tea , Uhlén Mathias , Svenningsson Per , Schwenk Jochen M. , Sakmar Thomas P. 
Published: November 2023

ABSTRACTReceptor activity-modifying proteins (RAMPs) can form complexes with G protein-coupled receptors (GPCRs) and regulate their cellular trafficking and pharmacology. RAMP interactions have been identified for about 50 GPCRs, but only a few GPCR-RAMP complexes have been studied in detail. To elucidate a complete interactome between GPCRs and the three RAMPs, we developed a customized library of 215 Dual Epitope-Tagged (DuET) GPCRs representing all GPCR subfamilies. Using a multiplexed suspension bead array (SBA) assay, we identified 122 GPCRs that showed strong evidence for interaction with at least one RAMP. We screened for native interactions in three cell lines and found 23 GPCRs that formed complexes with RAMPs. Mapping the GPCR-RAMP interactome expands the current system-wide functional characterization of RAMP-interacting GPCRs to inform the design of selective GPCR-targeted therapeutics.One-Sentence SummaryNovel complexes between G protein-coupled receptors and interacting proteins point to a system-wide regulation of GPCR function.
Mono-methylated histones control PARP-1 in chromatin and transcription
Authors: Bamgbose Gbolahan , Bordet Guillaume , Lodhi Niraj , Tulin Alexei 
Published: November 2023

ABSTRACTPARP-1 is central to transcriptional regulation under both normal and stress conditions, with the governing mechanisms yet to be fully understood. Our biochemical and ChIP-seq-based analyses showed that PARP-1 binds specifically to active histone marks, particularly H4K20me1. We found that H4K20me1 plays a critical role in facilitating PARP-1 binding and the regulation of PARP-1-depenednt loci during both development and heat shock stress. Here we report that the sole H4K20 mono-methylase,pr-set7, andparp-1 Drosophilamutants undergo developmental arrest. RNA-seq analysis showed an absolute correlation between PR-SET7- and PARP-1-dependent loci expression, confirming co-regulation during developmental phases. PARP-1 and PR-SET7 are both essential for activatinghsp70and other heat shock genes during heat stress, with a notable increase of H4K20me1 at their gene body. Mutatingpr-set7disrupts monometylation of H4K20 along heat shock loci and abolish PARP-1 binding there. These data strongly suggest that H4 monometylation is a key triggering point in PARP-1 dependent processes in chromatin.
Methionine availability influences essential H3K36me3 dynamics during cell differentiation
Authors: Sun Yudong , Ramesh Vijyendra , Wei Fangchao , Locasale Jason W. 
Published: November 2023

AbstractHistone modifications are integral to epigenetics through their influence on gene expression and cellular status. While it’s established that metabolism, including methionine metabolism, can impact histone methylation, the direct influence of methionine availability on crucial histone marks that determine the epigenomic process remains poorly understood. In this study, we demonstrate that methionine, through its metabolic product, S-adenosylmethionine (SAM), dynamically regulates H3K36me3, a cancer-associated histone modification known to influence cellular status, and myogenic differentiation of mouse myoblast cells. We further demonstrate that the methionine-dependent effects on differentiation are mediated in part through the histone methyltransferase SETD2. Methionine restriction leads to preferential decreases in H3K36me3 abundance and genome accessibility of genes involved in myogenic differentiation. Importantly, the effects of methionine restriction on differentiation and chromatin accessibility can be phenocopied by the deletion of Setd2. Collectively, this study demonstrates that methionine metabolism through its ability to be sensed by chromatin modifying enzymes can have a direct role in influencing cell fate determination.
Engineering luminopsins with improved coupling efficiencies
Authors: Slaviero Ashley , Gorantla Nipun , Simkins Jacob , Crespo Emmanuel L , Ikefuama Ebenezer C , Tree Maya O , Prakash Mansi , Björefeldt Andreas , Barnett Lauren M , Lambert Gerard G , Lipscombe Diane , Moore Christopher I , Shaner Nathan C , Hochgeschwender Ute 
Published: November 2023

ABSTRACTSignificanceLuminopsins (LMOs) are bioluminescent-optogenetic tools with a luciferase fused to an opsin that allow bimodal control of neurons by providing both optogenetic and chemogenetic access. Determining which design features contribute to the efficacy of LMOs will be beneficial for further improving LMOs for use in research.AimWe investigated the relative impact of luciferase brightness, opsin sensitivity, pairing of emission and absorption wavelength, and arrangement of moieties on the function of LMOs.ApproachWe quantified efficacy of LMOs through whole cell patch clamp recordings in HEK293 cells by determining coupling efficiency, the percentage of maximum LED induced photocurrent achieved with bioluminescent activation of an opsin. We confirmed key results by multielectrode array (MEAs) recordings in primary neurons.ResultsLuciferase brightness and opsin sensitivity had the most impact on the efficacy of LMOs, and N-terminal fusions of luciferases to opsins performed better than C-terminal and multi-terminal fusions. Precise paring of luciferase emission and opsin absorption spectra appeared to be less critical.ConclusionsWhole cell patch clamp recordings allowed us to quantify the impact of different characteristics of LMOs on their function. Our results suggest that coupling brighter bioluminescent sources to more sensitive opsins will improve LMO function. As bioluminescent activation of opsins is most likely based on Förster resonance energy transfer (FRET), the most effective strategy for improving LMOs further will be molecular evolution of luciferase-fluorescent protein-opsin fusions.
SCC3 is an axial element essential for homologous chromosome pairing and synapsis
Authors: Zhao Yangzi , Ren Lijun , Zhao Tingting , You Hanli , Miao Yongjie , Liu Huixin , Cao Lei , Wang Bingxin , Shen Yi , Li Yafei , Tang Ding , Cheng Zhukuan 
Published: November 2023

AbstractCohesin is a multi-subunit protein that plays a pivotal role in holding sister chromatids together during cell division. Sister chromatid cohesion 3 (SCC3), constituents of cohesin complex, is highly conserved from yeast to mammals. Since the deletion of individual cohesin subunit always causes lethality, it is difficult to dissect its biological function in both mitosis and meiosis. Here, we obtainedscc3weak mutants using CRISPR-Cas9 system to explore its function during rice mitosis and meiosis. Thescc3weak mutants displayed obvious vegetative defects and complete sterility, underscoring the essential roles of SCC3 in both mitosis and meiosis. SCC3 is localized on chromatin from interphase to prometaphase in mitosis. However, in meiosis, SCC3 acts as an axial element during early prophase I and subsequently situates onto centromeric regions following the disassembly of the synaptonemal complex. The loading of SCC3 onto meiotic chromosomes depends on REC8.scc3shows severe defects in homologous pairing and synapsis. Consequently, SCC3 functions as an axial element that is essential for maintaining homologous chromosome pairing and synapsis during meiosis.
Feasibility of improving manufacturability based on protein engineering
Authors: Capito Florian , Wong Ting Hin , Faust Christine , Brand Kilian , Dittrich Werner , Sommerfeld Mark , Langer Thomas 
Published: November 2023

AbstractWhile bioactivity and a favorable safety profile for biotherapeutics is of utmost importance, manufacturability is also worth of consideration to ease the manufacturing process. Many biotherapeutics are typically expressed in mammalian cells. Process-related impurities or biological impurities like viruses and host cell proteins (HCP) are present in the harvest which have mostly acid isoelectric points and need to be removed to ensure safety for the patients. Therefore, during molecule design, an isoelectric point of the target molecule should preferably differ sufficiently from the isoelectric points of the impurities to enable an efficient and straightforward purification strategy. In this feasibility study we have evaluated the possibility to improve manufacturability by increasing the isoelectric point of the target protein. We have generated several variants of a GLP1-receptor-agonist-Fc-domain -FGF21 fusion protein and demonstrate that the critical anion exchange chromatography step can be run at high pH values with maximal product recovery theoretically allowing removal of HCP and viruses. Addressing the isoelectric point can be useful for an efficient process for removing HCP and viruses and this topic should be considered early in the research phase to ensure that other important molecule properties, e.g. safety, efficacy and expression yield are not impacted.
Facilitated introgression from domestic goat into Alpine ibex at immune loci
Authors: Münger Xenia , Robin Mathieu , Dalén Love , Grossen Christine 
Published: November 2023

AbstractIntrogression is expected to be adaptive at loci under balancing selection, for instance at loci relevant for the immune response, but these loci generally also contain ancient polymorphisms. Ancient genomics is a promising tool to detect recent introgression and disentangle it from ancient polymorphisms. Alpine ibex (Capra ibex), a wild goat species native to the European Alps, faced near-extinction two centuries ago, but has recovered thanks to successful restoration programs. Previously, signals of introgression from the domestic goat (Capra aegagrus hircus) into the Alpine ibex genome were found at the major histocompatibility complex. This introgression was suggested to potentially be adaptive since it introduced new diversity at a gene locus important for immunity. But no genome-wide analyses of introgression have been performed to confirm the potential relevance of immune loci.Here we take advantage of two ancient whole genomes of Alpine ibex combined with 29 modern Alpine ibex genomes and 31 genomes representing six related Capra species to investigate genome-wide patterns of introgression. Our complementary analysis of putatively introgressed haplotypes and demographic modelling suggests 2.3% recent domestic goat ancestry among wild Alpine ibex. The introgression was estimated to have happened during the last 300 years coinciding with the time when the species had very small population size. Further analysis suggested an enrichment of immune-related genes, where the adaptive value of alternative alleles may give individuals with otherwise depleted genetic diversity a selective advantage.
Unstructured Domains in Assembly Factors Promote the Hierarchy of Ribosome Maturation via Their Structural Plasticity
Authors: Blomqvist Ebba K. , Yang Yoon-Mo , Huang Haina , Karbstein Katrin 
Published: November 2023

AbstractRibosomes are assembled with the help of a large machinery of assembly factors (AFs), whose roles remain incompletely characterized. Recent structural studies of assembly intermediates have provided tremendous context for such studies and helped reveal novel roles, including as RNA chaperones. These structures have also revealed that a subset of the AFs have entirely non-globular structures, or large non-globular extensions, which extend across the assembling ribosomal subdomains, contacting many rRNA regions, ribosomal proteins (RPs) and other AFs. How these unusual structures could help promote assembly has remained unclear although it has been suggested that their potential for making multiple interactions helps constrain early assembly steps. By studying the roles of the AF Ltv1, an entirely non-globular protein, during late maturation steps of the 40S subunit’s head, we show here how the structural plasticity that derives from the non-globular structure is used to communicate maturation steps across the nascent subunit, thereby establishing the previously described hierarchy in head assembly. Our data indicate that while this structural plasticity enables integration of distinct folding and assembly steps, it also creates the potential for mutations that allow for bypass of these QC steps. These mutations are pathogenic in humans, further demonstrating the importance of proper 40S subunit assembly for protein homeostasis.
Genetic architecture of inbreeding depression may explain its persistence in a population of wild red deer
Authors: Hewett Anna M. , Johnston Susan E. , Pemberton Josephine M. 
Published: November 2023

AbstractInbreeding depression is of major concern in declining populations, but relatively little is known about its genetic architecture in wild populations, such as the degree to which it is composed of large or small effect loci and their distribution throughout the genome. We combine fitness and genomic data from a wild population of red deer to investigate the genomic distribution of inbreeding effects. Inspired by the runs of homozygosity (ROH)-based inbreeding coefficient, FROH, we use chromosome-specific inbreeding coefficients (FROHChr) to explore whether the effect of inbreeding varies between chromosomes. Under the assumption that within an individual the probability of being identical-by-descent is equal across all chromosomes, we used a multi-membership model to estimate the deviation of FROHChrfrom the average inbreeding effect. This novel approach ensures effect sizes are not overestimated whilst maximising the power of our available dataset containing >35,000 autosomal SNPs. We find that most chromosomes confer a minor reduction in fitness-related traits, which when these effects are summed, results in the observed inbreeding depression in birth weight, survival and lifetime breeding success. However, no chromosomes had a significantly detrimental effect compared to the overall effect of inbreeding. We conclude that in this population, inbreeding depression is the result of multiple mild or moderately deleterious mutations spread across all chromosomes. As predicted by genetic theory these mutations will be inefficiently purged, explaining the persistence of inbreeding depression in this population.