bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Association Studies in Transgender Cohorts: A Systematic Review and Meta-Analysis
Authors: Ashley Blake , Harley Vincent 
Published: March 2023

AbstractAccording to twin studies, there is a heritable contribution to gender incongruence, but the genetic mechanisms of this are unknown. Recent efforts to identify an aetiology of gender incongruence have focused on the hypothesis that sex hormones establish gender identity through influencing the development of neuroanatomy. Candidate gene studies that have sought to elucidate whether polymorphisms in sex steroidogenesis genes are overrepresented in transgender populations have been equivocal. A systematic search for case-control genetic association studies in transgender populations was conducted. Mean (+SD) or allele frequencies were extracted and combined quantitatively in random effects meta-analysis, summarised as standardised mean difference for continuous alleles or odds ratios for allele frequencies. Eight studies were included in the analysis. These studies spanned polymorphisms in five genes; the CAG repeat in androgen receptor (AR), the TA repeat in estrogen receptor 1 (ESR1), the CA repeat in estrogen receptor 2 (ESR2), the TTTA repeat in cytochrome P450 family 19 subfamily A member 1 (CYP19), and the T>C SNP in cytochrome P450 family 17 subfamily A member 1 (CYP17). Pooled estimates indicated that transgender women have a significant overrepresentation of shortESR1alleles compared to cisgender men (OR = 1.23, 95% CI: 1.06, 1.44, p = 0.0089). This may contribute an increased likelihood of developing gender incongruence amongst natal males. Future investigations into gender incongruence should use genome-wide methods.
Noise-induced synaptopathy impacts the long and short sensory hair cells differently in the mammalian cochlea
Authors: Lu Yan , Liu Jing , Li Bei , Wang Haoyu , Wang Shengxiong , Wang Fangfang , Wu Hao , Han Hua , Hua Yunfeng 
Published: March 2023

SummaryIn the mammalian cochlea, moderate acoustic overexposure leads to irreversible loss of ribbon-type synapse between sensory inner hair cell (IHC) and its postsynaptic auditory nerve fiber (ANF), causing a reduced dynamic range of hearing but not a permanently-elevated threshold. A prevailing view is that such ribbon loss (known as synaptopathy) selectively impacts those low-spontaneous-rate and high-threshold ANFs contacting predominantly the modiolar face of IHCs. However, the spatial pattern of synaptopathy remains scarce in the most sensitive mid-cochlear region, where long and short IHCs with distinct ribbon size gradients coexist. Here, we used volume electron microscopy to investigate noise exposure-related changes in the mouse IHCs with and without ribbon loss. Our quantifications reveal that the worst-hit areas of synaptopathy are the modiolar face of long IHCs and the pillar face of short IHCs. Moreover, we show relative enrichment of mitochondrial content in the survived ANF terminals, providing key experimental evidence for the long-proposed role of postsynaptic mitochondria in selective ribbon synapse degeneration following noise insult.
Methodological challenges and recommendations for identifying childhood immunisations using routine electronic health records in the United Kingdom
Authors: Suffel Anne M , Walker Jemma L , Campbell Colin , Carreira Helena , Warren-Gash Charlotte , McDonald Helen I 
Published: March 2023

AbstractRoutinely collected electronic health records (EHR) offer a valuable opportunity to carry out research on immunisation uptake, effectiveness and safety, using large and representative samples of the population. However, using EHR presents challenges for identifying vaccinated and unvaccinated cohorts. Some vaccinations are delivered in different care settings, so may not be fully recorded in primary care EHR. In contrast to other drugs, they do not require electronic prescription in many settings, which may lead to ambiguous coding of vaccination status and timing. Additionally, for childhood vaccination, there may be other challenges of identifying the study population eligible for vaccination due to changes in immunisation schedules over time, different vaccine indications depending on the context (e.g., tetanus vaccination after exposure) and the lack of full dates of birth in many databases of data confidentiality restrictions.In this paper, we described our approach to tackling methodological issues related to identifying childhood immunisations in the Clinical Practice Research Datalink (CPRD) Aurum, a UK primary care dataset of EHR, as an example, and we introduce a comprehensive algorithm to support high-quality studies of childhood vaccination. We showed that a broad variety of considerations is important to identify vaccines in EHR and offer guidance on decisions to ascertain the vaccination status, such as considering data source and delivery systems (e.g., primary or secondary care), using a wide range of medical codes in combination to identify vaccination events, and using appropriate wash-out periods and quality checks to deal with issues of over-recording and back dating in EHR.Our algorithm reproduced estimates of vaccination coverage which are comparable to official national estimates in England. This paper aims to improve transparency, quality, comparability and reproducibility of studies on immunisations.
A scalable, GMP-compatible, autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa
Authors: Neumayer Gernot , Torkelson Jessica L. , Li Shengdi , McCarthy Kelly , Zhen Hanson H. , Vangipuram Madhuri , Jackow Joanna , Rami Avina , Hansen Corey , Guo Zongyou , Gaddam Sadhana , Pappalardo Alberto , Li Lingjie , Cramer Amber , Roy Kevin R. , Nguyen Thuylinh Michelle , Tanabe Koji , McGrath Patrick S. , Bruckner Anna , Bilousova Ganna , Roop Dennis , Bailey Irene , Tang Jean Y. , Christiano Angela , Steinmetz Lars M. , Wernig Marius , Oro Anthony E. 
Published: March 2023

SummaryBackgroundGene editing in induced pluripotent stem (iPS) cells has been hailed to enable new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa (DEB). However, manufacturing, efficacy and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies.MethodsWe developed Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a new generation GMP-compatible (cGMP), reproducible, and scalable platform to produce autologous clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts to treat incurable wounds of patients lacking type VII collagen (C7). DEBCT uses a combined high-efficiency reprogramming and CRISPR-based genetic correction single step to generate genome scar- free,COL7A1corrected clonal iPS cells from primary patient fibroblasts. Validated iPS cells are converted into epidermal, dermal and melanocyte progenitors with a novel 2D organoid differentiation protocol, followed by CD49f enrichment and expansion to minimize maturation heterogeneity. iSC product characterization by single cell transcriptomics was followed by mouse xenografting for disease correcting activity at 1 month and toxicology analysis at 1-6 months. Culture-acquired mutations, potential CRISPR-off targets, and cancer-driver variants were evaluated by targeted and whole genome sequencing.FindingsiPS cell-derived iSC grafts were reproducibly generated from four recessive DEB patients with different pathogenic mutations. Organotypic iSC grafts onto immune-compromised mice developed into stable stratified skin with functional C7 restoration. Single cell transcriptomic characterization of iSCs revealed prominent holoclone stem cell signatures in keratinocytes and the recently described Gibbin-dependent signature in dermal fibroblasts. The latter correlated with enhanced graftability. Multiple orthogonal sequencing and subsequent computational approaches identified random and non-oncogenic mutations introduced by the manufacturing process. Toxicology revealed no detectable tumors after 3-6 months in DEBCT- treated mice.InterpretationDEBCT successfully overcomes previous roadblocks and represents a robust, scalable, and safe cGMP manufacturing platform for production of a CRISPR-corrected autologous organotypic skin graft to heal DEB patient wounds.
Unraveling Neuronal Identities Using SIMS: A Deep Learning Label Transfer Tool for Single-Cell RNA Sequencing Analysis
Authors: Gonzalez-Ferrer Jesus , Lehrer Julian , O’Farrell Ash , Paten Benedict , Teodorescu Mircea , Haussler David , Jonsson Vanessa D. , Mostajo-Radji Mohammed A. 
Published: March 2023

AbstractLarge single-cell RNA datasets have contributed to unprecedented biological insight. Often, these take the form of cell atlases and serve as a reference for automating cell labeling of newly sequenced samples. Yet, classification algorithms have lacked the capacity to accurately annotate cells, particularly in complex datasets. Here we present SIMS (Scalable, Interpretable Ma-chine Learning for Single-Cell), an end-to-end data-efficient machine learning pipeline for discrete classification of single-cell data that can be applied to new datasets with minimal coding. We benchmarked SIMS against common single-cell label transfer tools and demonstrated that it performs as well or better than state of the art algorithms. We then use SIMS to classify cells in one of the most complex tissues: the brain. We show that SIMS classifies cells of the adult cerebral cortex and hippocampus at a remarkably high accuracy. This accuracy is maintained in trans-sample label transfers of the adult hu-man cerebral cortex. We then apply SIMS to classify cells in the developing brain and demonstrate a high level of accuracy at predicting neuronal sub-types, even in periods of fate refinement, shedding light on genetic changes affecting specific cell types across development. Finally, we apply SIMS to single cell datasets of cortical organoids to predict cell identities and unveil genetic variations between cell lines. SIMS identifies cell-line differences and misannotated cell lineages in human cortical organoids derived from different pluripotent stem cell lines. When cell types are obscured by stress signals, label transfer from primary tissue improves the accuracy of cortical organoid annotations, serving as a reliable ground truth. Altogether, we show that SIMS is a versatile and robust tool for cell-type classification from single-cell datasets.
Lipofuscin-like autofluorescence within microglia and its impact on studying microglial engulfment
Authors: Stillman Jacob M. , Lopes Francisco M. , Lin Jing-Ping , Hu Kevin , Reich Daniel S. , Schafer Dorothy P. 
Published: March 2023

AbstractEngulfment of cellular material and proteins is a key function for microglia, a resident macrophage of the central nervous system (CNS). Among the techniques used to measure microglial engulfment, confocal light microscopy has been used the most extensively. Here, we show that autofluorescence (AF), likely due to lipofuscin and typically associated with aging, can also be detected within microglial lysosomes in the young mouse brain by light microscopy. This lipofuscin-AF signal accumulates first within microglia and increases with age, but it is not exacerbated by amyloid beta-related neurodegeneration. We further show that this lipofuscin-AF signal within microglia can confound the interpretation of antibody-labeled synaptic material within microglia in young adult mice. Finally, we implement a robust strategy to quench AF in mouse, marmoset, and human brain tissue.
Olfactory and neuropeptide inputs to appetite neurons in the arcuate nucleus
Authors: Kuang Donghui , Hanchate Naresh K. , Lee Chia-Ying , Heck Ashley , Ye Xiaolan , Erdenebileg Michidsaran , Buck Linda B. 
Published: March 2023

AbstractThe sense of smell has potent effects on appetite, but the underlying neural mechanisms are largely a mystery. The hypothalamic arcuate nucleus contains two subsets of neurons linked to appetite: AgRP (agouti-related peptide) neurons, which enhance appetite, and POMC (pro-opiomelanocortin) neurons, which suppress appetite. Here, we find that AgRP and POMC neurons receive indirect inputs from partially overlapping areas of the olfactory cortex, thus identifying their sources of odor signals. We also find neurons directly upstream of AgRP or POMC neurons in numerous other areas, identifying potential relays between the olfactory cortex and AgRP or POMC neurons. Transcriptome profiling of individual AgRP neurons reveals differential expression of receptors for multiple neuromodulators. Notably, known ligands of the receptors define subsets of neurons directly upstream of AgRP neurons in specific brain areas. Together, these findings indicate that higher olfactory areas can differentially influence AgRP and POMC appetite neurons, that subsets of AgRP neurons can be regulated by different neuromodulators, and that subsets of neurons upstream of AgRP neurons in specific brain areas use different neuromodulators, together or in distinct combinations to modulate AgRP neurons and thus appetite.
Mesenchymal stromal cells affect CD8 naïve to memory subsets polarization by down-modulating IL12Rβ1 and IL2Rα signaling pathways
Authors: Papait Andrea , Vertua Elsa , Signoroni Patrizia Bonassi , Cargnoni Anna , Magatti Marta , Stefani Francesca Romana , Romoli Jacopo , Silini Antonietta Rosa , Parolini Ornella 
Published: March 2023

AbstractAdaptive immunity is typified by specificity and memory. Immune memory protects from subsequent infection and relies on functional, fully activated, T lymphocytes. Mesenchymal stromal cells (MSC) have been investigated for their potential therapeutic applications in a variety of diseases in which a dysregulated immune response plays a central role in pathogenesis or progression. Notably, for adaptive immunity, MSC can reduce the activation and cytotoxic activity of CD8+T lymphocytes as well as the polarization of CD4+T lymphocytes toward inflammatory subsets while favoring polarization toward the T regulatory subset. Although MSC have been widely reported to impact CD4 T cell proliferation and polarization, how MSC affect T-cell commitment toward memory subsets is still not known. Here, we report for the first time that MSC isolated from the amniotic membrane of human term placenta (hAMSC) determine T cell fate. We show that hAMSC influence naïve CD8+T cell activation and differentiation by downregulating mTOR pathway activation and modulating the expression of Tbet and Eomes, master regulators of the commitment of naïve CD8+T cells toward memory precursor effector cells (MPECs). This effect can be partly attribute to the ability of hAMSC to reduce the phosphorylation of STAT4 and STAT5, two transcriptional factors downstream IL-12Rβ1 and IL-2Rα receptors. Our results unravel a novel feature of MSC, offering new mechanistic insights into the effects of MSC in the treatment of diseases characterized by an altered activation of memory subsets, such as autoimmune diseases and graft versus host disease.
Triggering blood-lipid-profile by immunomodulatory and antimicrobial molecules for cross-evaluation of early detection of cancer
Authors: Prakash Om , Khan Feroz 
Published: March 2023

ABSTRACTBackgroundAl-guided mapping establishes relationship between gene-signature and phenotype. Since, Immunomodulatory & antimicrobial molecules, both show anticancer as well as their relation with lipid; therefore, can be further used for cross-validation or enrichment analysis for early detection of cancer. Considering the information, a study was performed on the influence of Immunomodulatory and antimicrobial molecules on blood lipid profile at the early stage of cancer.Materials and MethodPresent study established a relationship between small molecule-vs-genotype to phenotype. Genotypic features extracted through RNAseq analysis for stomach adenocarcinoma, which was further mapped with blood lipid profile. RNA-seq expression, from a population, was collected as gene expression profile of transcriptome. Gene signature was identified through in-house processing. Blood lipid profile was as: Total Cholesterol, LDL Cholesterol, HDL Cholesterol, Triglycerides, Non-HDL-C, and TG to HDL ratio.ResultsTo evaluate the Immunomodulatory and antimicrobial molecules for anticancer activity in terms of their influence on blood lipid-profile, computational models were established for developing relationships between small molecules-vs-genotype. Immunomodulatory and antimicrobial activity showed significant impact on genotypic expression at cancerous conditions.ConclusionIt was concluded that usage of Immunomodulatory small molecules & antibiotics showed their impact on blood lipid profile. These results may support cross-checking the possibility of cancer during the early detection of cancer. Furthermore, suggested the use of immunomodulatory and antimicrobial small molecules for cross evaluation of early disease prediction of different cancer types.
Are 150 km of open sea enough? Gene flow and population differentiation in a bat-pollinated columnar cactus
Authors: Arenas Sebastián , Búrquez Alberto , Bustamante Enriquena , Scheinvar Enrique , Eguiarte Luis E. 
Published: March 2023

AbstractGenetic differentiations and phylogeographical patterns are controlled by the interplay between spatial isolation and gene flow. To test the extent of gene flow across an oceanic barrier, we explored the effect of the separation of the peninsula of Baja California on the evolution of mainland and peninsular populations of the long-lived columnar cactusStenocereus thurberi. We analyzed twelve populations throughout the OPC distribution range to assess genetic diversity and structure using chloroplast DNA sequences. Genetic diversity was higher (Hd=0.81), and genetic structure was lower (GST=0.143) in mainland populations vs peninsular populations (Hd=0.71,GST=0.358 respectively). Genetic diversity was negatively associated with elevation but positively with rainfall. Two mainland and one peninsular ancestral haplotypes were reconstructed. Peninsular populations were as isolated among them as with mainland populations. Peninsular haplotypes formed a group with one mainland coastal population, and populations across the gulf shared common haplotypes giving support to regular gene flow across the Gulf. Gene flow is likely mediated by bats, the main pollinators and seed dispersers. Niche modeling suggests that during the Last Glacial Maximum (c. 130 ka), OPC populations shrank to southern locations. Currently, Stenocereus thurberi populations are expanding, and the species is under population divergence despite ongoing gene flow. Ancestral populations are located on the mainland and although vicariant peninsular populations cannot be ruled out, they are likely the result of gene flow across the seemingly formidable barrier of the Gulf of California. Still, unique haplotypes occur in the peninsula and the mainland, and peninsular populations are more structured than these on the mainland.
CellBin: a highly accurate single-cell gene expression processing pipeline for high-resolution spatial transcriptomics
Authors: Li Mei , Liu Huanlin , Kang Qiang , Fang Shuangsang , Li Min , Zhang Jiajun , Teng Fei , Wang Dan , Cen Weixuan , Li Zepeng , Feng Ning , Guo Jing , He Qiqi , Wang Leying , Zheng Tiantong , Li Shengkang , Bai Yinqi , Xie Min , Bai Yong , Liao Sha , Chen Ao , Zhang Yong , Brix Susanne , Xu Xun , Li Yuxiang 
Published: March 2023

AbstractBackgroundOwing to recent advances in resolution and field-of-view, spatially resolved transcriptomics sequencing, such as Stereo-seq, has emerged as a cutting-edge technology for the interpretation of large tissues at the single-cell level. To generate accurate single-cell spatial gene expression profiles from high-resolution spatial omics data, a powerful computational tool is required.FindingsWe present CellBin, an image-facilitated one-stop pipeline for high-resolution and large field-of-view spatial transcriptomic data of Stereo-seq. CellBin provides a comprehensive and systematic platform for generating high-confidence single-cell spatial gene expression profiles, which specifically includes image stitching, image registration, tissue segmentation, nuclei segmentation and molecule labeling. CellBin is user-friendly and does not require a specific level of omics and image analysis expertise.ConclusionsDuring image stitching and molecule labeling, CellBin delivers better-performing algorithms to reduce stitching error and time, in addition to improving the signal-to-noise ratio of single-cell gene expression data, in comparison with existing methods. Additionally, CellBin has been shown to obtain highly accurate single-cell spatial data using mouse brain tissue, which facilitated clustering and annotation.
Cell-autonomous metabolic reprogramming and oxidative stress underlie endothelial dysfunction in acute myocardial infarction
Authors: Zodda Erika , Tura-Ceide Olga , Mills Nicholas L. , Tarragó-Celada Josep , Carini Marina , Thomson Timothy M , Cascante Marta 
Published: March 2023

AbstractCompelling evidence has accumulated for the role of oxidative stress on the endothelial cell (EC) dysfunction underlying acute coronary syndromes. However, understanding the metabolic determinants of EC dysfunction has been hampered by the scarcity of appropriate cell models. Here, we have generated and phenotypically characterized EC derived from thrombectomy specimens in patients with acute myocardial infarction (AMI). We have found that AMI-derived endothelial cells (AMIECs), but not control EC from health coronary arteries, display impaired growth, migration and tubulogenesis. These phenotypic abnormalities were accompanied with metabolic abnormalities including augmentation of reactive oxygen species (ROS) and glutathione intracellular content, along with diminished glucose consumption coupled to increased lactate production. In AMIECs, the protein levels of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase type 3, PFKFB3, were downregulated, while those of PFKFB4 were upregulated, suggesting a shunting of glycolysis towards the pentose phosphate pathway (PPP) in the pathological ECs. PPP overactivation was further supported by upregulation of G6PD in AMIECs, the key enzyme in the oxidative branch of the PPP, which supplies the bulk of NADPH reducing equivalents necessary for the reduction/turnover and lipid synthesis.. Further, the glutaminolytic enzyme glutaminase (GLS) was upregulated in AMIECs, providing a mechanistic explanation for the observed increase in glutathione content. Finally, AMIECs had higher mitochondrial membrane potential than control ECs, which, together with high ROS levels, suggest a highly coupled mitochondrial activity in patient ECs. We suggest that high proton coupling underlies the abnormally high production of ROS, balanced by PPP-driven glutathione turnover, as a primary, cell-autonomous abnormality driving EC dysfunction in AMI.