bluuebunny/crossref_metadata_2025_split huggingface dataset:
Key role of down-regulated in adenoma (SLC26A3) chloride/bicarbonate exchanger in linaclotide-stimulated intestinal bicarbonate secretion upon loss of CFTR function
Authors: Sarthi Jessica B. , Trumbull Annie M. , Abazari Shayda M. , van Unen Vincent , Chan Joshua E. , Jiang Yanfen , Gammons Jesse , Anderson Marc O. , Cil Onur , Kuo Calvin J. , Sellers Zachary M. 
Published: May 2023

ABSTRACTDuodenal bicarbonate secretion is critical to epithelial protection, nutrient digestion/absorption and is impaired in cystic fibrosis (CF). We examined if linaclotide, typically used to treat constipation, may also stimulate duodenal bicarbonate secretion. Bicarbonate secretion was measured in vivo and in vitro using mouse and human duodenum (biopsies and enteroids). Ion transporter localization was identified with confocal microscopy and de novo analysis of human duodenal single cell RNA sequencing (sc-RNAseq) datasets was performed. Linaclotide increased bicarbonate secretion in mouse and human duodenum in the absence of CFTR expression (Cftrknockout mice) or function (CFTRinh-172). NHE3 inhibition contributed to a portion of this response. Linaclotide-stimulated bicarbonate secretion was eliminated by down-regulated in adenoma (DRA, SLC26A3) inhibition during loss of CFTR activity. Sc-RNAseq identified that 70% of villus cells expressedSLC26A3, but notCFTR, mRNA. Loss of CFTR activity and linaclotide increased apical brush border expression of DRA in non-CF and CF differentiated enteroids. These data provide further insights into the action of linaclotide and how DRA may compensate for loss of CFTR in regulating luminal pH. Linaclotide may be a useful therapy for CF individuals with impaired bicarbonate secretion.
Soluble antigen arrays improve the efficacy and safety of peptide-based tolerogenic immunotherapy
Authors: Firdessa-Fite Rebuma , Johnson Stephanie N. , Leon Martin A. , Sestak Joshua O. , Berkland Cory , Creusot Remi J. 
Published: May 2023

ABSTRACTAutoantigen-specific immunotherapy using peptides offers a more targeted approach to treat autoimmune diseases, but the limitedin vivostability and uptake of peptides impedes clinical implementation. We previously showed that multivalent delivery of peptides as soluble antigen arrays (SAgAs) efficiently protects against spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse model. Here, we compared the efficacy, safety, and mechanisms of action of SAgAs versus free peptides. SAgAs, but not their corresponding free peptides at equivalent doses, efficiently prevented the development of diabetes. SAgAs increased the frequency of regulatory T cells among peptide-specific T cells or induce their anergy/exhaustion or deletion, depending on the type of SAgA (hydrolysable (hSAgA) and non-hydrolysable ‘click’ SAgA (cSAgA)) and duration of treatment, whereas their corresponding free peptides induced a more effector phenotype following delayed clonal expansion. Moreover, the N-terminal modification of peptides with aminooxy or alkyne linkers, which was needed for grafting onto hyaluronic acid to make hSAgA or cSAgA variants, respectively, influenced their stimulatory potency and safety, with alkyne-functionalized peptides being more potent and less anaphylactogenic than aminooxy-functionalized peptides. Both SAgA variants significantly delayed anaphylaxis compared to their respective free peptides. The anaphylaxis, which occurred in NOD mice but not in C57BL/6 mice, was dose-dependent but did not correlate with the production of IgG1 or IgE against the peptides. We provide evidence that SAgAs significantly improve the efficacy and safety of peptide-based immunotherapy.SIGNIFICANCE STATEMENTPeptide-based immunotherapy has several advantages over using full antigen as they are easy to synthetize, chemically modify and customize for precision medicine. However, their use in the clinic has been limited by issues of membrane impermeability, poor stability and potencyin vivo, and in some cases, hypersensitivity reactions. Here, we provide evidence that soluble antigen arrays and alkyne-functionalization of peptides could be used as strategies to improve the safety and efficacy of peptide-based immunotherapy for autoimmune diseases by influencing the nature and dynamics of immune responses induced by the peptides.
Risk and Loss Aversion and Attitude to COVID and Vaccines in Anxious Individuals
Authors: Ferrari Filippo , Alexander Jesse , Seriès Peggy 
Published: May 2023

AbstractAnxious individuals are known to show impaired decision-making in economic gambling task and in everyday life decisions. This impairment can be due to aversion to uncertainty about outcomes (risk aversion) and/or aversion to negative outcomes (loss aversion). We investigate how non-clinical individuals with high levels of Generalised Anxiety Disorder (GAD) (N = 54) behave compared to less anxious subjects (N = 61) in a gambling decision-making task delivered online and designed to separate the distinct influences of risk and loss aversion on decision-making. By modelling subjects’ choices using computational models derived from Prospect Theory and fitted using Hierarchical Bayesian methods, we estimate individual levels of risk and loss aversion. Moreover we analyse the reaction times and choice data using Hierarchical Drift Diffusion Models (HDDMs). We also link estimates of these parameters to individual propensity to risk averse behaviours during the COVID pandemic, like wearing safer types of face masks, or completing a COVID vaccination course. We report increased loss aversion in individuals with increased level of GAD compared to less anxious individuals and no differences in risk aversion. The HDDM analysis suggests that high anxiety subjects have a reduced bias towards gambling in trials where there is a risk to loose points, also consistent with them being loss averse. We also report no links between risk and loss aversion and attitudes towards COVID and vaccines. These results shed new light on the interplay of anxiety and risk and loss aversion and they can provide useful directions for clinical intervention.
A longitudinal single-cell therapeutic atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease
Authors: Thomas Tom , Rich-Griffin Charlotte , Pohin Mathilde , Friedrich Matthias , Aschenbrenner Dominik , Pakpoor Julia , Jainarayanan Ashwin , Voda Alexandru , Sanches-Peres Raphael , Nee Eloise , Sathananthan Dharshan , Kotliar Dylan , Turner Jason , Nayar Saba ,   IBD Cohort Investigators,   AMP RA investigators, Zhang Fan , Jonsson Anna , Brenner Michael , Raychaudhuri Soumya , Kulicke Ruth , Ramsdell Danielle , Stransky Nicolas , Pagliarini Ray , Bielecki Piotr , Spies Noah , Wagner Allon , Walsh Alissa , Coles Mark , Jostins-Dean Luke , Powrie Fiona M. , Filer Andrew , Travis Simon , Uhlig Holm H. , Dendrou Calliope A , Buckley Christopher D 
Published: May 2023

AbstractPrecision medicine in immune-mediated inflammatory diseases (IMIDs) requires an understanding of how cellular networks change following therapy. We describe a therapeutic atlas for Crohn’s disease (CD) and ulcerative colitis (UC) following anti-tumour necrosis factor (TNF) therapy. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies from 38 patients and three controls, revealing disease- and therapy-specific differences. A systems-biology analysis identified distinct spatially-resolved cellular microenvironments: granuloma signatures in CD and interferon (IFN)-response signatures localising to T-cell aggregates and epithelial damage in CD and UC. Longitudinal comparisons demonstrated that disease progression in non-responders associated with myeloid and stromal cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas informs drug positioning across IMIDs, and suggests a rationale for the use of janus kinase (JAK) inhibition following anti-TNF resistance.
Lactate and Immunomagnetic-purified iPSC-derived Cardiomyocytes Generate Comparable Engineered Cardiac Tissue Constructs
Authors: Rossler Kalina J. , de Lange Willem J. , Mann Morgan W. , Aballo Timothy J. , Melby Jake A. , Zhang Jianhua , Kim Gina , Bayne Elizabeth F. , Zhu Yanlong , Farrell Emily T. , Kamp Timothy J. , Ralphe J. Carter , Ge Ying 
Published: May 2023

AbstractThree-dimensional engineered cardiac tissue (ECT) using purified human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) has emerged as an appealing model system for the study of human cardiac biology and disease. A recent study reported widely-used metabolic (lactate) purification of monolayer hiPSC-CM cultures results in an ischemic cardiomyopathy-like phenotype compared to magnetic antibody-based cell sorting (MACS) purification, complicating the interpretation of studies using lactate-purified hiPSC-CMs. Herein, our objective was to determine if use of lactate relative to MACs-purified hiPSC-CMs impacts the properties of resulting hiPSC-ECTs. Therefore, hiPSC-CMs were differentiated and purified using either lactate-based media or MACS. After purification, hiPSC-CMs were combined with hiPSC-cardiac fibroblasts to create 3D hiPSC-ECT constructs maintained in culture for four weeks. There were no structural differences observed, and there was no significant difference in sarcomere length between lactate and MACS hiPSC-ECTs. Assessment of isometric twitch force, Ca2+transients, and β-adrenergic response revealed similar functional performance between purification methods. High-resolution mass spectrometry (MS)-based quantitative proteomics showed no significant difference in any protein pathway expression or myofilament proteoforms. Taken together, this study demonstrates lactate- and MACS-purified hiPSC-CMs generate ECTs with comparable molecular and functional properties, and suggests lactate purification does not result in an irreversible change in hiPSC-CM phenotype.Graphical Abstract
ZymePackNet: rotamer-sampling free graph neural network method for protein sidechain prediction
Authors: Mukhopadhyay Abhishek , Kadan Amit , McMaster Benjamin , McWhirter J. Liam , Dixit Surjit B. 
Published: May 2023

AbstractProtein sidechain conformation prediction, or packing, is a key step in many in silico protein modeling and design tasks. Popular protein packing methods typically rely on approximated energy functions and complex algorithms to search dense rotamer libraries. Inspired by the recent success of deep learning in protein modeling tasks, we present ZymePackNet, a graph neural network based protein packing tool that does not require a rotamer library, scoring functions or a search algorithm. We train regression models using protein crystal structures represented as graphs, which are employed sequentially to “germinate” the sidechain starting from atoms anchoring the protein backbone to the sidechains’ termini, followed by an iterative refinement stage. ZymePackNet is fast and accurate compared to state-of-the-art protein packing methods. We validate our model on three native backbone datasets achieving a mean average error of 16.6°, 24.1°, 42.1°, and 53.0° for sidechain dihedral angles (χ1toχ4). ZymePackNet captures complex physical interactions such asπstacking without explicitly accounting for it in the model; such effects are currently lacking in the energy terms used in traditional packing tools.Contactabmukho@vt.eduSupplementary informationSupplementary data are available atBioinformaticsonline.
Human macroH2A1 drives nucleosome dephasing and genome instability in histone-humanized yeast
Authors: Haase Max A. B. , Lazar-Stefanita Luciana , Ólafsson Guðjón , Wudzinska Aleksandra , Shen Michael J. , Truong David M. , Boeke Jef D. 
Published: May 2023

SummaryIn addition to replicative histones, eukaryotic genomes encode a repertoire of non-replicative variant histones providing additional layers of structural and epigenetic regulation. Here, we systematically replaced individual replicative human histones with non-replicative human variant histones using a histone replacement system in yeast. Variants H2A.J, TsH2B, and H3.5 complemented for their respective replicative counterparts. However, macroH2A1 failed to complement and its expression was toxic in yeast, negatively interacting with native yeast histones and kinetochore genes. To isolate yeast with “macroH2A1 chromatin” we decoupled the effects of its macro and histone fold domains, which revealed that both domains sufficed to override native yeast nucleosome positioning. Furthermore, both modified constructs of macroH2A1 exhibited lower nucleosome occupancy that correlated with decreased short-range chromatin interactions (<20 Kb), disrupted centromeric clustering, and increased chromosome instability. While supporting viability, macroH2A1 dramatically alters chromatin organization in yeast, leading to genome instability and massive fitness defects.
Linked CD4+/CD8+T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression
Authors: Dolina Joseph S. , Lee Joey , Brightman Spencer E. , McArdle Sara , Hall Samantha M. , Thota Rukman R. , Lanka Manasa , Premlal Ashmitaa Logandha Ramamoorthy , Greenbaum Jason A. , Cohen Ezra E.W. , Peters Bjoern , Schoenberger Stephen P. 
Published: May 2023

AbstractTherapeutic benefit to immune checkpoint blockade (ICB) is currently limited to the subset of cancers thought to possess a sufficient tumor mutational burden (TMB) to allow for the spontaneous recognition of neoantigens (NeoAg) by autologous T cells. We explored whether the response of an aggressive low TMB squamous cell tumor to ICB could be improved through combination immunotherapy using functionally defined NeoAg as targets for endogenous CD4+and CD8+T cells. We found that, whereas vaccination with CD4+or CD8+NeoAg alone did not offer prophylactic or therapeutic immunity, vaccines containing NeoAg recognized by both subsets overcame ICB resistance and led to the eradication of large established tumors that contained a subset of PD-L1+tumor-initiating cancer stem cells (tCSC), provided the relevant epitopes were physically linked. Therapeutic CD4+/CD8+T cell NeoAg vaccination produced a modified tumor microenvironment (TME) with increased numbers of NeoAg-specific CD8+T cells existing in progenitor and intermediate exhausted states enabled by combination ICB-mediated intermolecular epitope spreading. The concepts explored herein should be exploited for the development of more potent personalized cancer vaccines that can expand the range of tumors treatable with ICB.
Apoptotic signaling clears engineeredSalmonellain an organ-specific manner
Authors: Abele Taylor J. , Billman Zachary P. , Li Lupeng , Harvest Carissa K. , Bryan Alexia K. , Magalski Gabrielle R , Lopez Joseph P , Larson Heather N. , Yin Xiao-Ming , Miao Edward A. 
Published: May 2023

AbstractPyroptosis and apoptosis are two forms of regulated cell death that can defend against intracellular infection. Although pyroptosis and apoptosis have distinct signaling pathways, when a cell fails to complete pyroptosis, backup pathways will initiate apoptosis. Here, we investigated the utility of apoptosis compared to pyroptosis in defense against an intracellular bacterial infection. We previously engineeredSalmonella entericaserovar Typhimurium to persistently express flagellin, and thereby activate NLRC4 during systemic infection in mice. The resulting pyroptosis clears this flagellin-engineered strain. We now show that infection of caspase-1 or gasdermin D deficient macrophages by this flagellin-engineeredS. Typhimurium induces apoptosis in vitro. Additionally, we also now engineerS. Typhimurium to translocate the pro-apoptotic BH3 domain of BID, which also triggers apoptosis in macrophages in vitro. In both engineered strains, apoptosis occurred somewhat slower than pyroptosis. During mouse infection, the apoptotic pathway successfully cleared these engineeredS.Typhimurium from the intestinal niche, but failed to clear the bacteria from the myeloid niche in the spleen or lymph nodes. In contrast, the pyroptotic pathway was beneficial in defense of both niches. In order to clear an infection, distinct cell types may have specific tasks that they must complete before they die. In some cells, either apoptotic or pyroptotic signaling may initiate the same tasks, whereas in other cell types these modes of cell death may lead to different tasks that may not be identical in defense against infection. We recently suggested that such diverse tasks can be considered as different cellular “bucket lists” to be accomplished before a cell dies.
DNA methylation, combined with RNA sequencing, provide novel insight into molecular classification of chordomas and their microenvironment
Authors: Baluszek Szymon , Kober Paulina , Rusetska Natalia , Wągrodzki Michał , Mandat Tomasz , Kunicki Jacek , Bujko Mateusz 
Published: May 2023

ABSTRACTChordomas are rare tumors of notochord remnants, occurring mainly in the sacrum and skull base. In spite of slow growth, they are highly invasive what makes the treatment challenging. Because of low incidence the molecular background of chordomas is poorly recognized.Our study aims to determine role of DNA methylation abnormalities in skull base chordomas including its role in deregulation of gene expression. We subjected 32 tumor and 4 normal nucleus pulposus (NP) samples to profiling of DNA methylation with EPIC microarrays and gene expression with RNAseq.Genome-wide DNA methylation analysis showed two distinct chordoma clusters (subtypes C and I) with different patterns of aberrant DNA methylation. C Chordomas are characterized by general hypomethylation with hypermethylation of CpG islands, while I chordomas are generally hypermethylated. These differences were reflected by distinct distribution of differentially methylated probes (DMPs). Differentially methylated regions were determined in each chordoma subtype indicating aberrant methylation in known tumor-related genes and regions encoding small RNAs in C chordomas. Correlation between methylation and expression was observed in minority of these genes. Upregulation ofTBXTin chordomas appeared related to lower methylation at tumor-specific DMR in gene promoter.Gene expression-based clusters of tumor samples did not overlap with DNA methylation subtypes. Nevertheless, the subtypes substantially differ in transcriptomic profile that shows immune activation in I chordomas and enhanced proliferation in C chordomas. Immune enrichment in chordomas I was confirmed with deconvolution methods (cohesively based on methylation and transcriptomic data). Copy number analysis showed higher chromosomal instability in C chordomas. All but one have 9p deletion (CDKN2A/B) and downregulation of genes encoded in related chromosomal band. No significant difference in patients’ survival was observed between tumor subtypes, however, shorter survival was observed in patients with higher number of copy number alterations.
Health aspects of vegan diets among children and adolescents: a systematic review and meta-analyses
Authors: Koller Alina , Rohrmann Sabine , Wakolbinger Maria , Gojda Jan , Selinger Eliska , Cahova Monika , Svetnicka Martin , Haider Sandra , Schlesinger Sabrina , Kuhn Tilman , Keller Jeffrey 
Published: May 2023

AbstractHealth effects of vegan diets among children are a controversial public health topic. Thus, we evaluated a broad range of health outcomes among vegan children and adolescents aged 0 to 18 years by a systematic review and meta-analyses. 17 studies met the inclusion criteria (16 cross-sectional studies, one randomized trial). Meta-analyzes showed lower intakes of protein (%E MD[95%CI]: −3.54 [−5.08, −2.00]) and higher intakes of fiber (g/1000kcal MD[95%CI]: 8.01 [6.96, 9.06]) in vegans compared to omnivores. Non-meta-analyzable studies showed lower calorie, vitamin B12 (when not using supplements) and selenium intakes, as well as lower blood levels of ferritin and vitamin B12. By contrast, vegans had significantly higher intakes of folate, vitamin C and iron. Levels of several cardiometabolic biomarkers (cholesterol, LDL) and indicators of bone health (vitamin D and calcium intake, vitamin D blood levels, bone mineral density) were lower in vegans. Risk of Bias was rated as high or very high in seven out of 17 primary studies. The Certainty of the Evidence was low or very low in all meta-analyses. Vegan children and adolescents following a vegan diet may have a beneficial cardiovascular risk profile but may be at risk for impaired bone health.
Diffusion-limited O2release in human kidneys perfused with stored blood
Authors: Dumbill Richard , Rabcuka Julija , Knight Simon , Hunter James , Fallon John , Voyce Daniel , Barrett Jacob , Ellen Matt , Weissenbacher Annemarie , Kurniawan Tetuko , Blonski Slawomir , Korczyk Piotr , Ploeg Rutger , Coussios Constantin , Friend Peter , Swietach Pawel 
Published: May 2023

ABSTRACTA central dogma in physiology is that oxygen release at tissues is not diffusion-limited because gas exchange at capillaries is rapid. This assertion has influenced clinical care, which focuses on optimising oxygen delivery through improving blood flow and oxygen content, rather than oxygen unloading from red blood cells (RBCs). Since storage of blood causes profound changes that slow oxygen release from RBCs, transfusions could compromise tissue respiration. We investigated this in transplant human kidneys normothermically perfused with stored blood. During perfusions, renal respiration was measured from blood gases and RBCs were analysed for oxygen-unloading kinetics. Respiratory rate did not correlate significantly with the standard definition of oxygen delivery based on blood flow and oxygen content. However, a strong correlation was obtained after introducing a factor describing oxygen release from RBCs. Oxygen release to tissues can become diffusion-limited with transfused blood, and therefore the kinetic quality of RBCs should be considered.