bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical, biochemical and molecular analysis in a cohort of individuals with gyrate atrophy
Authors: Palmer Eleanor , Stepien Karolina M. , Campbell Christopher , Barton Stephanie , Ghosh Arunabha , Broomfield Alexander , Woodall Alison , Wilcox Gisela , Sergouniotis Panagiotis I. , Black Graeme C.
Published: February 2023

Background

Gyrate atrophy of the choroid and retina is a rare autosomal recessive metabolic disorder caused by biallelic variants in theOATgene, encoding the enzyme ornithineƍ-aminotransferase. Impaired enzymatic activity leads to systemic hyperornithaemia, which in turn underlies progressive chorioretinal degeneration. In this study, we describe the clinical and molecular findings in a cohort of individuals with gyrate atrophy.

Methods

Study participants were recruited through a tertiary UK clinical ophthalmic genetic service. All cases had a biochemical and molecular diagnosis of gyrate atrophy. Retrospective phenotypic and biochemical data were collected using electronic healthcare records.

Results

18 affected individuals from 12 families (8 male, 12 female) met the study inclusion criteria. The median age at diagnosis was 8 years (range 10 months – 33 years) and all cases had hyperornithaemia (median: 800 micromoles/L; range: 458-1244 micromoles/L). Common features at presentation included high myopia (10/18) and nyctalopia (5/18). Ophthalmic findings were present in all study participants who were above the age of 6 years. One third of patients had co-existing macular oedema and two thirds developed pre-senile cataracts. Compliance with dietary modifications was suboptimal in most cases. A subset of participants had extraocular features including a trend towards reduced fat-free mass and developmental delay.

Conclusions

Our findings highlight the importance of multidisciplinary care in families with gyrate atrophy. Secondary ophthalmic complications such as macular oedema and cataract formation are common. Management of affected individuals remains challenging due to the highly restrictive nature of the recommended diet and the limited evidence-base for current strategies.
“I felt shamed and blamed”: An exploration of the parental lived experience of School Distress
Authors: Mullally Sinéad L. , Connolly Sophie E.
Published: February 2023

School Distress refers to a child or young person’s (CYP) difficulty attending school due to the extreme emotional distress they experience before/during/after school. Limited research exists on the impact of School Distress on the parents/carers supporting these CYP. Using a case–control, concurrent embedded mixed-method design, we explored this lived experience. 947 parents of CYP with School Distress completed a bespoke online questionnaire, alongside two control parent groups (n=149, n=25) and one professional group (n=19).

Findings revealed a devastating impact on the mental health of parents, with parents displaying significantly heightened daily anxiety and significantly lower mood during, but not before, their children’s school attendance difficulties. In addition, parents with children experiencing School Distress reported significantly more negative emotion states and significantly fewer positive emotion states. Parents also reported overwhelmingly negative treatment from professionals, including being disbelieved or blamed for their children’s difficulties, threatened with fines and court action, and disempowered by the actions of professionals surrounding their child. Significant, deleterious impacts were also evident across all aspects of their lives, including their careers, finances, and other children. Perhaps unsurprisingly, half of these parents reported developing a new mental health condition since their child’s difficulties began, with the experience itself rated as the second most threatening potential life event, superseded only by the death of a first-degree relative (including a child or spouse). On the other hand, professionals working with CYP with School Distress did not experience these deleterious mental health or wider life consequences. Despite understanding how threatening the experience is for parents, they were often quick to blame parents for their children’s difficulties. Professionals, like parents, expressed frustration with the lack of help available for these CYP and their families.

This study highlights a bleak, adversarial, and lonely picture for parents of CYP struggling to attend school. More specifically, the findings depict a system rife with parental blame; a system that appears to isolate parents through hostile, threatening, and punitive actions. A wider lack of societal understanding of the experience of School Distress further compounds this dearth of support for parents, placing parental mental health in further peril.
Genome-wide Association Study of Traumatic Brain Injury in U.S. Military Veterans Enrolled in the VA Million Veteran Program
Authors: Merritt Victoria C. , Maihofer Adam X. , Gasperi Marianna , Ketema Elizabeth , Chanfreau-Coffinier Catherine , Stein Murray B. , Panizzon Matthew S. , Hauger Richard L. , Logue Mark W. , Delano-Wood Lisa , Nievergelt Caroline M.
Published: February 2023

Large-scale genetic studies of traumatic brain injury (TBI) are lacking; thus, our understanding of the influence of genetic factors on TBI risk and recovery is incomplete. This study aimed to conduct a genome-wide association study (GWAS) of TBI in VA Million Veteran Program enrollees. Participants included a multi-ancestry cohort (European, African, and Hispanic ancestries; N=304,485; 111,494 TBI cases, 192,991 controls). TBI was assessed using MVP survey data and ICD codes from the Veterans Health Administration’s electronic health record. GWAS was performed using logistic regression in PLINK, and meta-analyzed in METAL. FUMA was used for post-GWAS analysis. Genomic structural equation modeling (gSEM) was conducted to investigate underlying genetic associations with TBI, and bivariate MiXeR was used to estimate phenotype specific and shared polygenicity. SNP-based heritability was 0.060 (SE=0.004,p=7.83×10−66). GWAS analysis identified 15 genome-wide significant (GWS) loci atp<5×10−8. Gene-based analyses revealed 14 gene-wide significant genes, includingNCAM1, APOE, FTO, andFOXP2. Gene tissue expression analysis identified the brain as significantly enriched, particularly in the frontal cortex, anterior cingulate cortex, and nucleus accumbens. Genetic correlations with TBI were significant for risk-taking behaviors and psychiatric disorders, but generally not significant for the neurocognitive variables investigated. gSEM analysis revealed stronger associations with risk-taking traits than with psychiatric traits. Finally, the genetic architecture of TBI was similar to polygenic psychiatric disorders. Neurodegenerative disorders including Alzheimer’s and Parkinson’s disease showed much less polygenicity, however, the proportion of shared variance with TBI was high. This first well-powered GWAS of TBI identified 15 loci including genes relevant to TBI biology, and showed that TBI is a heritable trait with comparable genetic architecture and high genetic correlation with psychiatric traits. Our findings set the stage for future TBI GWASs that focus on injury severity and diversity and chronicity of symptom sequelae.
Identifying characteristics and clinical conditions associated with hand grip strength in adults: the Baseline Health Study
Authors: Taylor Kenneth A. , Carroll Megan K. , Short Sarah , Goode Adam P.
Published: February 2023

Background

Low hand grip strength (HGS) predicts several conditions, but its value outside of the older adult population is unclear. We sought to identify the most salient factors associated with HGS using a rich list of candidate variables while stratifying by age and sex.

Methods

We used data from the initial visit from the Project Baseline Health Study (N=2502) which captured detailed demographic, occupational, social, lifestyle, and clinical data. We applied MI-LASSO using group methods to determine variables most associated with HGS out of 175 candidate variables. We performed analyses separately for sex and age (<65 vs. ≥65).

Results

Race was associated with HGS to varying degrees across groups. Osteoporosis and osteopenia were negatively associated with HGS in female study participants. Immune cell counts were negatively associated with HGS for male participants ≥65 (neutrophils) and female participants (≥65, monocytes; <65, lymphocytes). Most findings were age and/or sex group-specific; few were common across all groups.

Conclusions

Several of the variables associated with HGS in each group were novel, while others corroborate previous research. Our results support HGS as a useful indicator of a variety of clinical characteristics; however, its utility varies by age and sex.
TopNEXt: Automatic DDA Exclusion Framework for Multi-Sample Mass Spectrometry Experiments
Authors: McBride Ross , Wandy Joe , Weidt Stefan , Rogers Simon , Davies Vinny , Daly Rónán , Bryson Kevin
Published: February 2023

Motivation

Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) experiments aim to produce high quality fragmentation spectra which can be used to identify metabolites. However, current Data-Dependent Acquisition (DDA) approaches may fail to collect spectra of sufficient quality and quantity for experimental outcomes, and extend poorly across multiple samples by failing to share information across samples or by requiring manual expert input.

Results

We present TopNEXt, a real-time scan prioritisation framework that improves data acquisition in multi-sample LC-MS/MS metabolomics experiments. TopNEXt extends traditional DDA exclusion methods across multiple samples by using a Region of Interest (RoI) and intensity-based scoring system. Through both simulated and lab experiments we show that methods incorporating these novel concepts acquire fragmentation spectra for an additional 10% of our set of target peaks and with an additional 20% of acquisition intensity. By increasing the quality and quantity of fragmentation spectra, TopNEXt can help improve metabolite identification with a potential impact across a variety of experimental contexts.

Availability

TopNEXt is implemented as part of the ViMMS framework and the latest version can be found athttps://github.com/glasgowcompbio/vimms. A stable version used to produce our results can be found at10.5281/zenodo.7468914. Data can be found at10.5525/gla.researchdata.1382.

Contact

r.mcbride.1@research.gla.ac.ukorvinny.davies@glasgow.ac.uk

Supplementary information

Supplementary data are available atBioarxivonline.
The histone chaperone activity of SPT2 controls chromatin structure and function in Metazoa
Authors: Saredi Giulia , Carelli Francesco N. , Furlan Giulia , Rolland Stephane , Piquet Sandra , Appert Alex , Sanchez-Pulido Luis , Price Jonathan L. , Alcon Pablo , Lampersberger Lisa , Déclais Anne-Cécile , Ramakrishna Navin B. , Toth Rachel , Ponting Chris P. , Polo Sophie E. , Miska Eric A. , Ahringer Julie , Gartner Anton , Rouse John
Published: February 2023

Histone chaperones control nucleosome density and chromatin structure. In yeast, the H3-H4 chaperone Spt2 controls histone deposition at active genes but its roles in metazoan chromatin structure and organismal physiology are not known. Here we identify theCaenorhabditis elegansorthologue of SPT2 (CeSPT-2) and show that its ability to bind histones H3-H4 is important for germline development and transgenerational epigenetic gene silencing, and thatspt-2mutants display signatures of a global stress response. Genome-wide profiling showed that CeSPT-2 binds to a range of highly expressed genes, and we find thatspt-2 mutants have increased chromatin accessibility at these loci. We also show that human SPT2 controls the incorporation of new H3.3 into chromatin. Our work reveals roles for SPT2 in controlling chromatin structure and function in Metazoa.
3D Microcapsules for Human Bone Marrow Derived Mesenchymal Stem Cell Biomanufacturing in a Vertical-Wheel Bioreactor
Authors: Teryek Matthew , Jadhav Pankaj , Bento Raphaela , Parekkadan Biju
Published: February 2023

Microencapsulation of human mesenchymal stromal cells (MSCs) via electrospraying has been well documented in tissue engineering and regenerative medicine. Herein, we report the use of microencapsulation, via electrospraying, for MSC expansion using a commercially available hydrogel that is durable, optimized to MSC culture, and enzymatically degradable for cell recovery. Critical parameters of the electrospraying encapsulation process such as seeding density, correlation of microcapsule output with hydrogel volume, and applied voltage were characterized to consistently fabricate cell-laden microcapsules of uniform size. Upon encapsulation, we then verified ∼ 10x expansion of encapsulated MSCs within a vertical-wheel bioreactor and the preservation of critical quality attributes such as immunophenotype and multipotency after expansion and cell recovery. Finally, we highlight the genetic manipulation of encapsulated MSCs as an example of incorporating bioactive agents in the capsule material to create new compositions of MSCs with altered phenotypes.
Genetic manipulation of betta fish
Authors: Palmiotti Alec , Lichak Madison R , Shih Pei-Yin , Bendesky Andres
Published: February 2023

Betta splendens, also known as Siamese fighting fish or ‘betta’, are renowned for their astonishing morphological diversity and extreme aggressive behavior. Despite recent advances in our understanding of the genetics and neurobiology of betta, the lack of tools to manipulate their genome has hindered progress at functional and mechanistic levels. In this study, we outline the use of three genetic manipulation technologies, which we have optimized for use in betta: CRISPR/Cas9-mediated knockout, CRISPR/Cas9-mediated knockin, and Tol2-mediated transgenesis. We knocked out three genes:alkal2l, bco1l, andmitfa, and analyzed their effects on viability and pigmentation. Furthermore, we successfully knocked in a fluorescent protein into themitfalocus, a proof-of-principle experiment of this powerful technology in betta. Finally, we used Tol2-mediated transgenesis to create fish with ubiquitous expression of GFP, and then developed a bicistronic plasmid with heart-specific expression of a red fluorescent protein to serve as a visible marker of successful transgenesis. Our work highlights the potential for the genetic manipulation of betta, providing valuable resources for the effective use of genetic tools in this animal model.
Proteomic analyses of the Arabidopsis cap-binding complex define core set and TOR-dependent protein components
Authors: Matthes Annemarie , Ouibrahim Laurence , Lecampion Cécile , Caranta Carole , Davanture Marlène , Lebrun Régine , Couté Yohann , Baudet Mathieu , Meyer Christian , Robaglia Christophe
Published: February 2023

The eukaryotic cap-binding complex (CBC) is a hub for regulations affecting mRNA behaviour including translation, degradation and storage. Beside the core eukaryotic translation initiation factors, other proteins, many of which are yet unknown, are thought to interact stably or transiently with the CBC depending on cell status. The prototype of these regulators is the animal eIF4E binding protein (4E-BP), a direct target of the TOR (Target of Rapamycin) kinase that competes with the cap-binding protein eIF4E, thus repressing translation. In plants, no functional homologs of 4E-BP have so far been characterized. In this work we performed several deep proteomic analyses of the Arabidopsis CBC after cap-affinity purification from wild-type plants. We also investigated the CBC in eIF4E mutant plants, Arabidopsis lines with lower TOR activity, or during infection with eIF4E-dependent potyviruses, conditions which are all affecting translation at the initiation level. These analyses allowed us to define a limited core set of CBC components, which were detected in all samples. Interestingly, we identified proteins, like AGO1 or VCS, which were always detected in conditions where either TOR or mRNA translation were reduced. Meta-analysis of these data revealed several new plant interactors of the CBC, potentially defining pathways related to mRNA stability and degradation, metabolism and viral life cycle. A search for eIF4E binding motifs identified several new potential 4E-BP relatives in plants.
Endothelial Cells are Heterogeneous in Different Brain Regions and are Dramatically Altered in Alzheimer’s Disease
Authors: Bryant Annie , Li Zhaozhi , Jayakumar Rojashree , Serrano-Pozo Alberto , Woost Benjamin , Hu Miwei , Woodbury Maya E. , Wachter Astrid , Lin Gen , Kwon Taekyung , Talanian Robert V. , Biber Knut , Karran Eric H. , Hyman Bradley T. , Das Sudeshna , Bennett Rachel
Published: February 2023

Vascular endothelial cells play an important role in maintaining brain health, but their contribution to Alzheimer’s disease (AD) is obscured by limited understanding of the cellular heterogeneity in normal aged brain and in disease. To address this, we performed single nucleus RNAseq on tissue from 32 AD and non-AD donors each with five cortical regions: entorhinal cortex, inferior temporal gyrus, prefrontal cortex, visual association cortex and primary visual cortex. Analysis of 51,586 endothelial cells revealed unique gene expression patterns across the five regions in non-AD donors. Alzheimer’s brain endothelial cells were characterized by upregulated protein folding genes and distinct transcriptomic differences in response to amyloid beta plaques and cerebral amyloid angiopathy (CAA). This dataset demonstrates previously unrecognized regional heterogeneity in the endothelial cell transcriptome in both aged non-AD and AD brain.

Significance Statement

In this work, we show that vascular endothelial cells collected from five different brain regions display surprising variability in gene expression. In the presence of Alzheimer’s disease pathology, endothelial cell gene expression is dramatically altered with clear differences in regional and temporal changes. These findings help explain why certain brain regions appear to differ in susceptibility to disease-related vascular remodeling events that may impact blood flow.
The pseudokinase Trib1 regulates the transition of exhausted T cells to a KLR+CD8+effector state and its deletion improves checkpoint blockade
Authors: McClory Susan E. , Bardhan Oishi , Rome Kelly S. , Giles Josephine R. , Baxter Amy E. , Xu Lanwei , Gimotty Phyllis A. , Faryabi Robert B. , Wherry E. John , Pear Warren S. , Jordan Martha S.
Published: February 2023

T cell exhaustion (TEX) impairs the ability of T cells to clear chronic infection or cancer. While exhausted T cells are hypofunctional, some exhausted T cells retain effector gene signatures, a feature that is associated with expression of KLRs (killer lectin-like receptors). Although KLR+T cells may improve control of chronic antigen, the signaling molecules regulating this population are poorly understood. Using scRNA-seq, flow cytometry, RNA velocity, and scTCR-seq, we demonstrate that deleting the pseudokinase Trib1 shifts TEXtowards CX3CR1+intermediates (TINT) with robust enrichment of KLR+CD8+T cells (TKLR) via clonal T cell expansion. These changes are associated with globally increased KLR gene expression throughout the exhaustion program. Further, Trib1 loss augments anti-PD-L1 blockade to improve viral clearance by expanding the TKLRpopulation. Together, these data identify Trib1 as an important regulator of T cell exhaustion whose targeting enhances the KLR+effector state and improves the response to checkpoint inhibitor therapy.
Enhanced simulations of whole-brain dynamics using hybrid resting-state structural connectomes
Authors: Manos Thanos , Diaz-Pier Sandra , Fortel Igor , Driscoll Ira , Zhan Liang , Leow Alex
Published: February 2023

The human brain, composed of billions of neurons and synaptic connections, is an intricate network coordinating a sophisticated balance of excitatory and inhibitory activity between brain regions. The dynamical balance between excitation and inhibition is vital for adjusting neural input/output relationships in cortical networks and regulating the dynamic range of their responses to stimuli. To infer this balance using connectomics, we recently introduced a computational framework based on the Ising model, first developed to explain phase transitions in ferromagnets, and proposed a novel hybrid resting-state structural connectome (rsSC). Here, we show that a generative model based on the Kuramoto phase oscillator can be used to simulate static and dynamic functional connectomes (FC) with rsSC as the coupling weight coefficients, such that the simulated FC well aligns with the observed FC when compared to that simulated with traditional structural connectome. Simulations were performed using the open source framework The Virtual Brain on High Performance Computing infrastructure.
Exploring the Optimization of Autoencoder Design for Imputing Single-Cell RNA Sequencing Data
Authors: Xi Nan Miles , Li Jingyi Jessica
Published: February 2023

Autoencoders are the backbones of many imputation methods that aim to relieve the sparsity issue in single-cell RNA sequencing (scRNA-seq) data. The imputation performance of an autoencoder relies on both the neural network architecture and the hyperparameter choice. So far, literature in the single-cell field lacks a formal discussion on how to design the neural network and choose the hyperparameters. Here, we conducted an empirical study to answer this question. Our study used many real and simulated scRNA-seq datasets to examine the impacts of the neural network architecture, the activation function, and the regularization strategy on imputation accuracy and downstream analyses. Our results show that (i) deeper and narrower autoencoders generally lead to better imputation performance; (ii) the sigmoid and tanh activation functions consistently outperform other commonly used functions including ReLU; (iii) regularization improves the accuracy of imputation and downstream cell clustering and DE gene analyses. Notably, our results differ from common practices in the computer vision field regarding the activation function and the regularization strategy. Overall, our study offers practical guidance on how to optimize the autoencoder design for scRNA-seq data imputation.
Regulated assembly and neurosteroid modulation constrain GABAAreceptor pharmacologyin vivo
Authors: Sun Chang , Zhu Hongtao , Clark Sarah , Gouaux Eric
Published: February 2023

Type A GABA receptors (GABAARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anesthetics, sedatives, hypnotics, and antidepressants. However, our understanding of GABAAR pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from a total 19 different subunits and the lack of structural knowledge of clinically relevant receptors. Here, we isolate native murine GABAAR assemblies containing the widely expressed α1subunit, and elucidate their structures in complex with drugs used to treat insomnia (zolpidem and flurazepam) and postpartum depression (the neurosteroid allopregnanolone). Using cryo-EM analysis and single-molecule photobleaching experiments, we uncover only three structural populations in the brain: the canonical α1β2γ2receptor containing two α1subunits and two unanticipated assemblies containing one α1and either an α2, α3or α5subunit. Both of the noncanonical assemblies feature a more compact arrangement between the transmembrane and extracellular domains. Interestingly, allopregnanolone is bound at the transmembrane α/β subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABAARs. Together with structurally engaged lipids, neurosteroids produce global conformational changes throughout the receptor that modify both the pore diameter and binding environments for GABA and insomnia medications. Together, our data reveal that GABAAR assembly is a strictly regulated process that yields a small number of structurally distinct complexes, defining a structural landscape from which subtype-specific drugs can be developed.
Nine-residue low-complexity disordered peptide as a model system, an NMR/CD study
Authors: Vugmeyster Liliya , Rodgers Aryana , Gwin Kirsten , Ostrovsky Dmitry , Smirnov Serge L.
Published: February 2023

Disordered proteins and protein segments can be crucial for biological function. In this work we present a detailed biophysical characterization of the low-complexity nine-residue peptide with the sequence GGKGMGFGL. Based on proton solution NMR chemical shifts, circular dichroism measurements, as well as the analysis of concentration dependence of NMR linewidth, proton longitudinal relaxation times, hydrogen-deuterium exchange measurements, and15N rotating frame NMR relaxation measurements, we conclude that the peptide is fully disordered and monomeric in solution. The peptide will serve as a model system for future structural and dynamics studies of biologically relevant disordered peptides in solution and solid states.
Mechanistic insights into the UFM1 E3 ligase complex in ufmylation and ribosome-associated protein quality control
Authors: Ishimura Ryosuke , Ito Sota , Mao Gaoxin , Komatsu-Hirota Satoko , Inada Toshifumi , Noda Nobuo N , Komatsu Masaaki
Published: February 2023

Ubiquitin-fold modifier 1 (UFM1) is a ubiquitin-like protein covalently conjugated with intracellular proteins through ufmylation, similar to ubiquitylation. Ufmylation is involved in processes such as endoplasmic reticulum (ER)-associated protein degradation, ribosome-associated protein quality control (RQC) at the ER (ER-RQC), and ER-phagy. However, it remains unclear how ufmylation regulates such distinct ER-related functions. Herein, we provide insights into the mechanism of the UFM1 E3 complex in not only ufmylation but also ER-RQC. The E3 complex consisting of UFL1 and UFBP1 interacted with UFC1, UFM1 E2, and subsequently CDK5RAP3, the last of which is an adaptor for ufmylating ribosomal subunit RPL26. When CDK5RAP3 was absent from the E3 complex, UFBP1 ufmylation occurred, a process thought to drive ER-phagy. Further, upon treatment with anisomycin, an inducer of disome formation, the UFM1 E3 complex associated with ufmylated RPL26 on the 60S ribosomal subunit through the UFM1-interacting region of UFBP1. Loss of E3 components or disruption of the interaction between UFBP1 and ufmylated RPL26 attenuated ER-RQC. These results clarify the molecular mechanism of the UFM1 system and provide new insights into the role of ufmylation.
Generation of human cerebral organoids with a structured outer subventricular zone
Authors: Walsh Ryan , Giacomelli Elisa , Ciceri Gabriele , Rittenhouse Chelsea , Galimberti Maura , Wu Youjun , Muller James , Vezzoli Elena , Jungverdorben Johannes , Zhou Ting , Barker Roger A , Cattaneo Elena , Studer Lorenz , Baggiolini Arianna
Published: February 2023

Mammalian outer radial glia (oRG) emerge as cortical progenitor cells that directly support the development of an enlarged outer subventricular zone (oSVZ) and, in turn, the expansion of the neocortex. Thein vitrogeneration of oRG is essential to model and investigate the underlying mechanisms of human neocortical development and expansion. By activating the STAT3 pathway using LIF, which is not produced in guided cortical organoids, we developed a cerebral organoid differentiation method from human pluripotent stem cells (hPSCs) that recapitulates the expansion of a progenitor pool into the oSVZ. The structured oSVZ is composed of progenitor cells expressing specific oRG markers such asGFAP, LIFR, HOPX, which closely matches human oRGin vivo. In this microenvironment, cortical neurons showed faster maturation with enhanced metabolic and functional activity. Incorporation of hPSC-derived brain vascular LIF- producing pericytes in cerebral organoids mimicked the effects of LIF treatment. These data indicate that the cellular complexity of the cortical microenvironment, including cell-types of the brain vasculature, favors the appearance of oRG and provides a platform to routinely study oRG in hPSC-derived brain organoids.
An FGF timer for zygotic genome activation
Authors: Treen Nicholas , Chavarria Emily , Weaver Claire J. , Brangwynne Clifford P. , Levine Michael
Published: February 2023

Zygotic genome activation has been extensively studied in a variety of systems including flies, frogs, and mammals. However, there is comparatively little known about the precise timing of gene induction during the earliest phases of embryogenesis. Here we used high-resolution in situ detection methods, along with genetic and experimental manipulations, to study the timing of zygotic activation in the simple model chordateCionawith minute-scale temporal precision. We found that twoPrdm1homologs inCionaare the earliest genes that respond to FGF signaling. We present evidence for a FGF timing mechanism that is driven by ERK-mediated derepression of the ERF repressor. Depletion of ERF results in ectopic activation of FGF target genes throughout the embryo. A highlight of this timer is the sharp transition in FGF responsiveness between the eight- and 16-cell stages of development. We propose that this timer is an innovation of chordates that is also used by vertebrates.
Regulation of endogenous retrovirus–derived regulatory elements by GATA2/3 and MSX2 in human trophoblast stem cells
Authors: Du Cui , Jiang Jing , Li Yuzhuo , Yu Miao , Jin Jian , Chen Shuai , Fan Hairui , Macfarlan Todd S. , Cao Bin , Sun Ming-an
Published: February 2023

The placenta is an organ with extraordinary phenotypic diversity in eutherian mammals. Recent evidence suggests that numerous human placental enhancers are evolved from lineage-specific insertions of endogenous retroviruses (ERVs), yet the transcription factors (TFs) underlying their regulation remain largely elusive. Here, by first focusing on MER41, a primate-specific ERV family previously linked to placenta and innate immunity, we uncover the binding motifs of multiple crucial trophoblast TFs (GATA2/3, MSX2, GRHL2) in addition to innate immunity TFs STAT1 and IRF1. Integration of ChIP-seq data confirms the binding of GATA2/3, MSX2, and their related factors on the majority of MER41-derived enhancers in human trophoblast stem cells (TSCs). MER41-derived enhancers that are constitutively active in human TSCs are distinct from those activated upon interferon stimulation, which is determined by the binding of relevant TFs and their subfamily compositions. We further demonstrate that GATA2/3 and MSX2 have prevalent binding to numerous other ERV families — indicating their broad impact on ERV-derived enhancers. Functionally, the derepression of many syncytiotrophoblast genes after MSX2 knockdown is likely to be mediated by regulatory elements derived from ERVs — suggesting ERVs are also important for mediating transcriptional repression. Overall, this study characterizes the regulation of ERV-derived regulatory elements by GATA2/3, MSX2, and their cofactors in human TSCs, and provides mechanistic insights into the importance of ERVs in human trophoblast regulatory network.
‘Brave men’ and ‘pampered children’: Male bodies, labour and coming of age in Belgian Congo
Authors: Henriet Benoît
Published: February 2023

This article sheds light on male identities in interwar Belgian Congo by using the colony's largest palm oil concession as a case study. Based on colonial archives and oral testimonies, it shows how vernacular and colonial understandings of masculinity interplayed and keep on influencing ways to ‘be a man’ in the present. This article is divided into four parts. First, it highlights how vigorous male bodies supposedly constituted entry points in the colonial ‘civilizing mission’. Second, it addresses the convergences between coming‐of‐age rituals and of palm oil labour as markers of adulthood. Third, it nuances the association of dominant masculinity with brute force by showing how the ‘strongest’ palm oil workers were suspected to use witchcraft. Fourth, it addresses the apparent contradiction between recollection of colonial labour as an experience of hardships and paternalist ‘pampering’.
FRINGE FINANCIAL ECOLOGIES AND PLACE‐BASED EXCLUSION: A Tale of Two Cities
Authors: Dunham Ian , Foster Alec
Published: February 2023

Access to safe and affordable financial services is essential to the economic well‐being of individual households and entire urban neighborhoods. However, prior research raises concerns about spatial inequities in the distribution of brick‐and‐mortar financial services offerings—either mainstream financial institutions or alternative ‘fringe’ financial service providers—and the resulting implications for financial inclusion and social justice. This study uses a novel method to identify fringe financial ecologies that captures the recent tandem processes of abandonment by mainstream financial institutions and the proliferation of alternative financial service providers. We explore how fringe financial ecologies potentially overlap existing inequalities of race, class and subprime mortgage lending in two US metropolitan areas, Los Angeles, California, and Miami, Florida. Our results raise concerns that communities of color, low‐income neighborhoods and otherwise vulnerable segments of the population are disproportionately at risk of both financial exclusion and predatory targeting. We find that fringe financial ecologies are associated with a high prevalence of subprime mortgage lending. The results advance an understanding of financial ecologies that raises awareness about place‐based financial exclusion as a form of systemic racism in the broader context of the national reckoning with racial justice in the US.
Triage to electrocardiogram sign‐off time in patients with acute coronary syndrome at a metropolitan Sydney hospital
Authors: Turner Dane , Yu Jennifer , Murphy David , Chiew Angela
Published: February 2023

Objective

To compare the time from triage to ECG sign‐off in patients with acute coronary syndrome, before and after the introduction of an electronic medical record‐integrated ECG workflow system (Epiphany). Additionally, to assess for any correlation between patient characteristics and ECG sign‐off times.

Methods

A retrospective, single‐centre cohort study was performed at Prince of Wales Hospital, Sydney. Patients were included if they were over 18 years, presented to Prince of Wales Hospital ED during 2021, had an ED diagnosis code of ‘ACS’, ‘UA’, ‘NSTEMI’ or ‘STEMI’ and were subsequently admitted under the cardiology team. ECG sign‐off times and demographic data were compared between patients presenting prior to 29 June (pre‐Epiphany group) and those presenting after (post‐Epiphany group). Those without ECGs signed‐off were excluded.

Results

There were 200 patients (100 each group) included in the statistical analysis. There was a significant decrease in the median triage to ECG sign‐off time, from 35 min (IQR 18–69) pre‐Epiphany, to 21 min (IQR 13–37) post‐Epiphany. There were only 10 (5%) patients in the pre‐Epiphany group and 16 (8%) in the post‐Epiphany group, who had ECG sign‐off times less than the 10‐min. There was no correlation between gender, triage category, age or time of shift with triage to ECG sign‐off time.

Conclusions

The introduction of the Epiphany system has significantly reduced the triage to ECG sign‐off time in the ED. Despite this, there remains a large proportion of patients with acute coronary syndrome who do not have an ECG signed‐off within the guideline‐recommended 10 min.
CCR4‐NOT subunit CCF‐1/CNOT7 promotes transcriptional activation to multiple stress responses in Caenorhabditis elegans
Authors: Tabarraei Hadi , Waddell Brandon M. , Raymond Kelly , Murray Sydney M. , Wang Ying , Choe Keith P. , Wu Cheng‐Wei
Published: February 2023

CCR4‐NOT is a versatile eukaryotic protein complex that controls multiple steps in gene expression regulation from synthesis to decay. In yeast, CCR4‐NOT has been implicated in stress response regulation, though this function in other organisms remains unclear. In a genome‐wide RNAi screen, we identified a subunit of the CCR4‐NOT complex, ccf‐1, as a requirement for the C. elegans transcriptional response to cadmium and acrylamide stress. Using whole‐transcriptome RNA sequencing, we show that the knockdown of ccf‐1 attenuates the activation of a broad range of stress‐protective genes in response to cadmium and acrylamide, including those encoding heat shock proteins and xenobiotic detoxification. Consistently, survival assays show that the knockdown of ccf‐1 decreases C. elegans stress resistance and normal lifespan. A yeast 2‐hybrid screen using a CCF‐1 bait identified the homeobox transcription factor PAL‐1 as a physical interactor. Knockdown of pal‐1 inhibits the activation of ccf‐1 dependent stress genes and reduces C. elegans stress resistance. Gene expression analysis reveals that knockdown of ccf‐1 and pal‐1 attenuates the activation of elt‐2 and elt‐3 under stress that encode master transcriptional co‐regulators of stress response in the C. elegans, and that overexpression of ELT‐2 can suppress ccf‐1's requirement for gene transcription in a stress‐dependent manner. Our findings reveal a new role for CCR4‐NOT in the environmental stress response and define its role in stress resistance and longevity in C. elegans.
Indomethacin restores loss of hippocampal neurogenesis and cholinergic innervation and reduces innate immune expression and reversal learning deficits in adult male and female rats following adolescent ethanol exposure
Authors: Macht Victoria , Vetreno Ryan , Elchert Natalie , Fisher Rachael , Crews Fulton
Published: February 2023

Background

Adolescent intermittent ethanol (AIE) exposure causes long‐term changes in the brain and behavior of adult male rodents, including persistent induction of innate immune pathways, reductions in hippocampal neurogenic and forebrain cholinergic neuronal markers, and reversal learning deficits. The current study tests the hypothesis that proinflammatory induction mediates AIE‐induced (1) loss of adult neurogenesis (i.e., doublecortin (DCX) expressing immature neurons), (2) reductions in forebrain and hippocampal cholinergic markers, and (3) reversal learning deficits.

Methods

Male and female rats underwent AIE (5.0 g/kg/day ethanol or water, i.g., 2 day‐on/2 day‐off from postnatal day (PND) 25–54), followed by a 2‐week regimen of the anti‐inflammatory compound indomethacin (4.0 g/kg/day, PND 56–69) or vehicle, after which one cohort was euthanized for immunohistochemical markers (PND 70) and the second underwent the Morris water maze to assess reversal learning.

Results

AIE reduced adult (PND 70) DCX+ immunoreactivity (IR) and increased hippocampal expression of the innate immune signal's high‐mobility group box protein 1 (HMGB1 + IR) and cyclooxygenase‐2 (COX‐2 + IR) in adult male and female rats. AIE also reduced choline acetyltransferase (ChAT+IR) in the basal forebrain and co‐labeling of hippocampal vesicular acetylcholine transporter (VAChT+) cholinergic terminals on DCX + IR neurons. Indomethacin treatment after AIE restored molecular endpoints to control levels and rescued AIE‐induced reversal learning deficits in the Morris water maze in both sexes. Of note, indomethacin produced several adverse effects selectively in control conditions, highlighting the uniquely beneficial effect of indomethacin in AIE rats.

Conclusions

These data suggest that in males and females, (1) AIE persistent neuroimmune induction mediates both the loss of adult hippocampal DCX and loss of basal forebrain cholinergic neurons and their innervation to hippocampal targets, and (2) anti‐inflammatory indomethacin treatment following AIE that restores these persistent molecular pathologies also restores spatial reversal learning deficits.
Morphological tongue and palate characterizations in Trachemys adiutrix (Vanzolini, 1995) turtles
Authors: Ferraz Rafaella Sousa , Corrêa Lukas Allayn Diniz , Calvet Margareth Cavalcante Ribeiro , Santiago Paula Maria Mesquita , da Silva Teófilo Tiago , de Oliveira Radan Elvis Matias , Martins Adriano Luis , Barreto Larissa Nascimento , Silva Melaine Mont’Alverne Lawall
Published: February 2023

Morphological studies on the oropharyngeal cavity of turtles are an interesting tool in understanding evolutionary processes associated with feeding habits. There is paucity of morphological information on the oropharyngeal cavity of the Trachemys adiutrix turtle. Thus, the aim of this study was to describe the tongue and palate morphology of T. adiutrix to establish a standard model for the species, providing information that may improve knowledge on the species feeding habits. Gross dissection, light microscopy and scanning electron microscopy assessments of 11 specimens were carried out. The tongue of T. adiutrix is triangular with a slightly rounded apex and broad base and lingual papillae widely distributed throughout the entire dorsal surface. The palate is composed of bony structures, displaying a triangular apex with one pair of choanae and palatine raphe that begin in the middle region, dividing the two openings. The body was elongated and smooth. The root was wrinkled and opened into the oesophagus. The tongue was lined by non‐keratinized stratified squamous epithelium, rich in mucous cells and a large number of different‐shaped papillae and taste buds. The palate was mainly lined by a pseudostratified cylindrical ciliated epithelium rich in mucous cells. In conclusion, the tongue and palate characteristics of T. adiutrix include evidence that these animals are semiaquatic, displaying morphological characteristics associated with aquatic and terrestrial trophic ecology, similar to that observed in other semiaquatic and terrestrial chelonian species.
Pregnancy complications and later life women's health
Authors: McNestry Catherine , Killeen Sarah L. , Crowley Rachel K. , McAuliffe Fionnuala M.
Published: February 2023

There has been increasing recognition of the association between various pregnancy complications and development of chronic disease in later life. Pregnancy has come to be regarded as a physiological stress test, as the strain it places on a woman's body may reveal underlying predispositions to disease that would otherwise remain hidden for many years. Despite the increasing body of data, there is a lack of awareness among healthcare providers surrounding these risks. We performed a narrative literature review and have summarized the associations between the common pregnancy complications including gestational hypertension, pre‐eclampsia, gestational diabetes, placental abruption, spontaneous preterm birth, stillbirth and miscarriage and subsequent development of chronic disease. Hypertensive disorders of pregnancy, spontaneous preterm birth, gestational diabetes, pregnancy loss and placental abruption are all associated with increased risk of various forms of cardiovascular disease. Gestational diabetes, pre‐eclampsia, early miscarriage and recurrent miscarriage are associated with increased risk of diabetes mellitus. Pre‐eclampsia, stillbirth and recurrent miscarriage are associated with increased risk of venous thromboembolism. Pre‐eclampsia, gestational diabetes and stillbirth are associated with increased risk of chronic kidney disease. Gestational diabetes is associated with postnatal depression, and also with increased risk of thyroid and stomach cancers. Stillbirth, miscarriage and recurrent miscarriage are associated with increased risk of mental health disorders including depression, anxiety and post‐traumatic stress disorders. Counseling in the postnatal period following a complicated pregnancy, and advice regarding risk reduction should be available for all women. Further studies are required to establish optimal screening intervals for cardiovascular disease and diabetes following complicated pregnancy.
Differences in the location of bleeding with direct oral anticoagulants vs. vitamin K antagonists: A study in the World Health Organization's pharmacovigilance database
Authors: Montastruc Jean‐Louis , Tessier Samuel , Bura‐Riviere Alessandra
Published: February 2023

Aims

Clinical trials have found differences in bleeding locations between direct oral anticoagulants (DOAC) and vitamin K antagonists (VKA). The present study was performed to investigate these differences in real life using reports of adverse drug reactions registered in the World Health Organization's pharmacovigilance database, VigiBase®.

Methods

All bleeding registered between 1 January 2008 and 31 December 2021 in adults were included. The main objective was to compare bleeding locations reported with DOAC with those with VKA. As a secondary objective, we performed the same comparison with Xa vs. thrombin inhibitors. Results were presented as reporting odds ratios (RORs) adjusted on age, gender, origin of reports and co‐medications with their 95% confidence interval.

Results

During this 14‐year period, 142 228 instances of bleeding were registered with oral anticoagulants, including 39 570 with VKA and 102 658 with DOAC. Mean time to event was lower with DOAC (7.6 months) than with VKA (29.9 months) (P < .001). Significant differences in bleeding locations were found in the reports with less cerebral, urologic and nasal bleeding, more gynaecologic bleeding with DOAC than with VKA, without any significant differences in digestive and cutaneous locations. A higher risk of bleeding reports was found with Xa inhibitors vs. dabigatran whatever the locations (except digestive bleeding).

Conclusion

This real‐life study shows that the differences in bleeding locations between DOAC and VKA are not limited to the brain or gastrointestinal tracts. Significant differences were also found between Xa and thrombin inhibitors.
Nonlinear Function-on-Scalar Regression via Functional Universal Approximation
Authors: Luo Ruiyan , Qi Xin
Published: February 2023

We consider general nonlinear function-on-scalar (FOS) regression models, where the functional response depends on multiple scalar predictors in a general unknown nonlinear form. Existing methods either assume specific model forms (e.g., additive models) or directly estimate the nonlinear function in a space with dimension equal to the number of scalar predictors, which can only be applied to models with a few scalar predictors. To overcome these shortcomings, motivated by the classic universal approximation theorem used in neural networks, we develop a functional universal approximation theorem which can be used to approximate general nonlinear FOS maps and can be easily adopted into the framework of functional data analysis. With this theorem and utilizing smoothness regularity, we develop a novel method to fit the general nonlinear FOS regression model and make predictions. Our new method does not make any specific assumption on the model forms, and it avoids the direct estimation of nonlinear functions in a space with dimension equal to the number of scalar predictors. By estimating a sequence of bivariate functions, our method can be applied to models with a relatively large number of scalar predictors. The good performance of the proposed method is demonstrated by empirical studies on various simulated and real datasets.