bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4+T cell-derived IL21 regulates stem cell fate in acute myeloid leukemia by activation of p38-MAPK signaling
Authors: Rubino Viviana , Hüppi Michelle , Höpner Sabine , Tortola Luigi , Taylor Lea , Keller Irene , Bruggman Remy , Kronig Marie-Noëlle , Bacher Ulrike , Kopf Manfred , Ochsenbein Adrian F. , Riether Carsten 
Published: September 2023

SummarySelf-renewal programs in leukemia stem cells (LSCs) predict poor prognosis in acute myeloid leukemia (AML) patients. We identified CD4+T cell-derived interleukin (IL) 21 as an important negative regulator of self-renewal of murine and human LSCs, but not hematopoietic stem cells. IL21/IL21R signaling favored asymmetric cell division and differentiation in LSCs through accumulation of reactive oxygen species (ROS) and activation of p38-MAPK signaling, resulting in reduced LSCs number and significantly prolonged survival in murine AML models. In human AML, serum IL21 at diagnosis was identified as an independent positive prognostic biomarker for outcome and correlated with better survival and higher complete remission rate in patients that underwent high-dose chemotherapy. IL21 inhibited primary AML LSCs function in vitro by activating ROS and p38-MAPK signaling and this effect was enhanced by cytarabine treatment. Consequently, promoting IL21/IL21R signaling on LSCs may be a novel approach to decrease stemness and increase differentiation in AML.
Prot-SCL: State of the art Prediction of Protein Subcellular Localization from Primary Sequence Using Contrastive Learning
Authors: Giannakoulias Sam , Ferrie John J. , Apicello Andrew , Mitchell Carter 
Published: September 2023

ABSTRACTProtein subcellular localization is a critically important parameter to consider when designing expression constructs and production strategies for industry scale protein production. In this study, we present Prot-SCL an innovative self-supervised machine learning approach to predict protein subcellular localization exclusively from primary sequence. The models herein were learned from a dataset of subcellular localizations derived by exhaustively analyzing the Uniprot database. The set of localization data was rigorously curated for machine learning by employing group sampling following clustering of the protein sequences. The novel component of this approach lies in the development of a triplet neural network architecture capable of generating meaningful embeddings for classification of protein subcellular localization. We observed a robust predictive power for our classical gradient boosted machine learning models trained on these triplet embeddings in both cross validation and in generalization to the testing set. Importantly, we have made this extensive dataset of protein subcellular localizations publicly accessible, facilitating future, need-based, localization studies. Finally, we provide the relevant codebase to encourage a wider adoption and expansion of this methodology.GRAPHICAL ABSTRACT
Inflammation-Induced Claudin-2 Upregulation Limits Pancreatitis Progression by Enhancing Tight Junction-Controlled Pancreatic Ductal Transport
Authors: Kesaraju Sneha , Li Yueying , Xing Junjie , Tracy Melissa , Wannemo Kristin , Holder Aysha , Zhao Piao , Khan Mohammed Azizuddin , Kainov Joseph , Rana Niyati , Sidahmed Mohammed , Hyoju Sanjiv , Smith Lexi , Matthews Jonathan , Tay Savas , Khalili-Araghi Fatemeh , Rana Maunak , Oakes Scott A. , Shen Le , Weber Christopher R. 
Published: September 2023

ABSTRACTPancreatitis is an inflammatory disease of the pancreas that can arise due to various factors, including environmental risks such as diet, alcohol, and smoking, as well as genetic predispositions. In some cases, pancreatitis may progress and become chronic, leading to irreversible damage and impaired pancreatic function. Genome-wide association studies (GWAS) have identified polymorphisms at the X-linkedCLDN2locus as risk factors for both sporadic and alcohol-related chronic pancreatitis.CLDN2encodes claudin-2 (CLDN2), a paracellular cation-selective channel localized at tight junctions and expressed in the pancreas and other secretory organs. However, whether and how CLDN2 may modify pancreatitis susceptibility remains poorly understood. We aimed to clarify the potential role of CLDN2 in the onset and progression of pancreatitis.We employed multiple methodologies to examine the role of CLDN2 in human pancreatic tissue, caerulein-induced experimental pancreatitis mouse model, and pancreatic ductal epithelial organoids. In both human chronic pancreatitis tissues and caerulein-induced experimental pancreatitis, CLDN2 protein was significantly upregulated in pancreatic ductal epithelial cells. Our studies using pancreatic ductal epithelial organoids and mice demonstrated the inflammatory cytokine IFNγ upregulates claudin-2 expression at both RNA and protein levels. Following caerulein treatment,IfngKO mice had diminished upregulation of CLDN2 relative to WT mice, indicating that caerulein-induced claudin-2 expression is partially driven by IFNγ. Functionally,Cldn2knockout mice developed more severe caerulein-induced experimental pancreatitis, indicating CLDN2 plays a protective role in pancreatitis development. Pancreatic ductal epithelial organoid-based studies demonstrated that CLDN2 is critical for sodium-dependent water transport and necessary for cAMP-driven, CFTR-dependent fluid secretion. These findings suggest that functional crosstalk between CLDN2 and CFTR is essential for fluid transport in pancreatic ductal epithelium, which may protect against pancreatitis by adjusting pancreatic ductal secretion to prevent worsening autodigestion and inflammation.In conclusion, our studies suggest CLDN2 upregulation during pancreatitis may play a protective role in limiting disease development, and decreased CLDN2 function may increase pancreatitis severity. These results point to the possibility of modulating pancreatic ductal CLDN2 function as an approach for therapeutic intervention of pancreatitis.
Understanding the biosynthesis of human IgMs through a combinatorial expression of mutant subunits that affect different assembly steps
Authors: Hasegawa Haruki , Wang Songyu , Kast Eddie , Chou Hui-Ting , Kaur Mehma , Janlaor Tanakorn , Mostafavi Mina , Wang Yi-Ling , Li Peng 
Published: September 2023

AbstractPolymeric IgMs are secreted from plasma cells abundantly despite their structural complexity and intricate multimerization steps. To gain new insights into IgM’s assembly mechanics that underwrite the high-level secretion, we characterized the biosynthetic process of a natural human IgM, SAM-6, using a recombinant HEK293 cell system. By creating a series of mutant subunits that differentially disrupt specific sets of inter-chain disulfide bonds, we assessed their effects on various aspects of IgM biosynthesis in 48 different mutant subunit combinations. The analysis included the visualization of intracellular biosynthetic events such as steady-state subcellular subunit distribution, secretory trafficking bottlenecks, and the ER-associated Russell body formation by fluorescent microscopy. We also characterized various extracellular events including secreted IgM product quality, secretion output, and the release of various assembly intermediates using biochemical and biophysical assays. In this combinatorial mutagenesis approach, we unexpectedly found that the loss of multiple inter-chain disulfide bonds, including the one between μHC and λLC subunits, was tolerated in polymeric IgM formation and secretion. This finding revealed the vital role of underlying non-covalent protein-protein association not only during the orchestration of initial subunit interactions but also in maintaining the polymeric IgM product integrity during ER quality control steps, secretory pathway trafficking, and secretion. We suggest that the IgM assembly process is inherently robust and has a stopgap that permits the secretion of polymeric IgM even when not all the prescribed inter-chain disulfide bonds are formed. This study holistically presents the requirements and exemptions in polymeric IgM biosynthesis by encompassing the characterization of intracellular and extracellular events and the roles of covalent and non-covalent interactions. These findings can guide antibody engineering strategy when designing IgM-based multivalent modalities.
Gemcitabine therapeutically disrupts essential SIRT1-mediated p53 repression in Atypical Teratoid/Rhabdoid Tumors
Authors: Metselaar Dennis S. , Meel Michaël H. , Goulding Joshua R. , Waranecki Piotr , de Gooijer Mark C. , Breur Marjolein , Koster Jan , Veldhuijzen van Zanten Sophie E.M. , Bugiani Marianna , Wesseling Pieter , Kaspers Gertjan J.L. , Hulleman Esther 
Published: September 2023

AbstractBackgroundAtypical Teratoid/Rhabdoid Tumors (ATRT) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. Despite recent advances in understanding the molecular characteristics and subclasses of these tumors, effective therapeutic options remain scarce.MethodsIn this study, we developed and validated a novel patient-derived ATRT culture and xenograft model, which we used alongside a panel of other primary ATRT models for large-scale drug discovery assays. The identified hits were mechanistically and therapeutically investigated using an array of molecular assays and two orthotopic xenograft murine models.ResultsWe found that ATRT are selectively sensitive to the nucleoside analogue gemcitabine, with additional efficacy in Sonic Hedgehog (SHH)-subtype ATRT. Gene expression profiles and protein analyses indicated that gemcitabine treatment causes degradation of Sirtuin 1 (SIRT1), resulting in cell death through activation of NF-kB and p53. Furthermore, we discovered that gemcitabine-induced loss of SIRT1 results in a nucleus-to-cytoplasm translocation of the SHH signaling activator GLI2, explaining the additional gemcitabine sensitivity in SHH-subtype ATRT. Treatment of SHH-subgroup ATRT xenograft-bearing mice with gemcitabine resulted in a >30% increase in median survival (p<0.005, log-rank test) and yielded long-term survivors in two independent patient-derived xenograft models.ConclusionsThese findings demonstrate that ATRT are highly sensitive to gemcitabine treatment, and we propose that gemcitabine may form part of a future multimodal treatment strategy for ATRT.Key points-ATRT are specifically sensitive to gemcitabine treatment-SIRT1 may serve as a novel therapeutic target in ATRT-Gemcitabine should be considered for clinical use in ATRT patientsImportance of the studyAtypical Teratoid/Rhabdoid Tumors (ATRT) are highly malignant pediatric brain tumors with a 5-year survival of merely 30%, for which effective treatment options are limited. In this study, we propose a potential novel treatment strategy for ATRT patients. We show that ATRT are highly sensitive to the chemotherapeutic gemcitabine, that takes advantage of ATRT-specific SIRT1 overexpression and disrupts p53 suppression and hedgehog signaling. Importantly, we show that gemcitabine significantly prolongs survival of ATRT patient-derived xenograft models, prolonging survival by over 30%. This effect was achieved using gemcitabine concentrations that are achievable in human brain and well-tolerated in pediatric patients. As such, gemcitabine could be readily incorporated into clinical treatment protocols and expand the still very limited therapeutic options for ATRT-patients.
Route Retracing: Way-pointing in Trail Following Ants
Authors: Freas Cody A , Spetch Marcia L 
Published: September 2023

AbstractMaintaining positional estimates of goal locations is a fundamental task for navigating animals. Diverse animal groups, including both vertebrates and invertebrates, can accomplish this through path integration (PI). During PI, navigators integrate movement changes, tracking both distance and direction, to generate a spatial estimate of their start location, or global vector, allowing efficient direct return travel without retracing the outbound route. In ants, PI is accomplished through the coupling of pedometer and celestial compass estimates. Within the PI system, it has been theorized navigators may segment the global vector into local-vectors for way-pointing. However, this is controversial, as these navigators may instead be homing via the view alignment. Here, we present evidence trail-following ants can attend to segments of their global vector to retrace their non-straight pheromone trails, without the confound of familiar views.Veromessor pergandeiforagers navigate via directionally distinct segments of their PI by orienting along separate legs of their inbound route at unfamiliar locations, indicating these changes are not triggered by familiar external cues, but by the PI state. These findings contrast with the view of path integration as a singular memory estimate and underscore the system’s ability to way-point to intermediate goals along the inbound route. We discuss how the foraging ecology of ant species that rely on non-straight pheromone-marked trails may support attending vector segments to remain on the pheromone rather than attempting straight-line shortcuts back to the nest.
Sensitivity of BA.2.86 to prevailing neutralising antibody responses
Authors: Sheward Daniel J , Yang Yiqiu , Westerberg Michelle , Öling Sofia , Muschiol Sandra , Sato Kenta , Peacock Thomas P , Karlsson Hedestam Gunilla B , Albert Jan , Murrell Ben 
Published: September 2023

AbstractA new SARS-CoV-2 variant, designated BA.2.86, has recently emerged with over 30 spike mutations relative to its parental BA.2, raising questions about its degree of resistance to neutralising antibodies. Using a spike-pseudotyped virus model we characterise neutralisation of BA.2.86 by clinically relevant monoclonal antibodies and by two cohorts of serum sampled from Stockholm, including both a recent cohort, and one sampled prior to the arrival of XBB in Sweden.
SARS-CoV-2 quarantine mandated by contact tracing: burden and infection rate among close contacts in Zurich, Switzerland, 2020-2021
Authors: Aschmann Hélène E. , Domenghino Anja , Jung Ruedi , Ballouz Tala , Menges Dominik , Fehr Jan , Puhan Milo A. 
Published: September 2023

AbstractObjectivesBefore vaccines and effective treatments were available, quarantine of close contacts was important to limit the spread of SARS-CoV-2. To evaluate potential benefits and harms of quarantine, we aimed to estimate infection rates and describe experiences and mental health among persons in mandated quarantine during the early SARS-CoV-2 pandemic.MethodsWe invited adults in mandated quarantine after an exposure to SARS-CoV-2 identified through contact tracing of the Canton of Zurich, Switzerland, between August 2020 and January 2021. Participants completed two questionnaires and received up to two SARS-CoV-2 polymerase chain reaction tests, during and at the end of quarantine.ResultsAmong 395 participants, quarantine duration ranged from 2 to 20 days. By day 11 since the last contact, 11.1% [95% CI 8.4%–14.7%] were infected with SARS-CoV-2. The proportion of participants with symptoms of depression doubled from 9.3% before quarantine to 18.9% during quarantine, and 12.1% reported quarantine was very or extremely difficult.ConclusionsAlthough quarantine was only moderately burdensome for most participants, some experienced significant difficulties and burden. Policymakers need to balance infection control with potential harms placed on individuals.
Cold-induced muscle atrophy in zebrafish: Insights from swimming activity and gene expression analysis
Authors: Ikeda Daisuke , Fujita Seina , Toda Kaito , Yaginuma Yuma , Kan-no Nobuhiro , Watabe Shugo 
Published: September 2023

AbstractThe investigation into the effects of cold acclimation on fish skeletal muscle function and its potential implications for muscle atrophy is of great interest to us. This study examines how rearing zebrafish at low temperatures affects their locomotor activity and the expression of genes associated with muscle atrophy. Zebrafish were exposed to temperatures ranging from 10 °C to 25 °C, and their swimming distance was measured. The expression levels of important muscle atrophy genes, Atrogin-1 and MuRF1, were also evaluated. Our findings show that swimming activity significantly decreases when the water temperature ranges from 10 °C to 15 °C, indicating a decrease in voluntary movement. Additionally, gene expression analysis shows a significant increase in the expression of Atrogin-1 and MuRF1 at 10 °C. This up-regulation could lead to muscle atrophy caused by decreased activity in cold temperatures. To investigate the effects of exercise on reducing muscle atrophy, we subjected zebrafish to forced swimming at a temperature of 8 °C for ten days. This treatment significantly reduced the expression of Atrogin-1 and MuRF1, emphasizing the importance of muscle stimulation in preventing muscle atrophy in zebrafish. These findings suggest that zebrafish can serve as a valuable model organism for studying muscle atrophy and can be utilized in drug screening for muscle atrophy-related disorders. Cold-reared zebrafish provide a practical and ethical approach to inducing disuse muscle atrophy, providing valuable insights into potential therapeutic strategies for addressing skeletal muscle atrophy.
Small Extracellular Vesicles from Failing Heart Accelerate Tumor Growth
Authors: Caller Tal , Rotem Itai , Shaihov–Teper Olga , Lendengolts Daria , Schary Yeshai , Shai Ruty , Glick-Saar Efrat , Dominissini Dan , Motie Menachem , Katzir Idan , Popovtzer Rachela , Nahmoud Merav , Boomgarden Alex , D’Souza-Schorey Crislyn , Naftali-Shani Nili , Leor Jonathan 
Published: September 2023

ABSTRACTBackgroundMyocardial infarction (MI) and heart failure (HF) are associated with an increased incidence of cancer. The mechanism is complex and unclear. Here, we aimed to test our hypothesis that cardiac small extracellular vesicles (sEVs), particularly cardiac mesenchymal stromal cells-derived sEVs (cMSC-sEVs), contribute to the link between post-MI HF and cancer.MethodsWe purified and characterized sEVs from the whole heart and cultured cMSCs. Then, we analyzed cMSC-EV cargo and pro-neoplastic effects on several types of cancer cell lines, macrophages, and endothelial cells. Next, we modeled post-MI HF along with heterotopic and orthotopic lung and breast cancer tumors in mice. We used cMSC-sEV transfer to assess sEV biodistribution and its effect on tumor growth. Finally, we tested the effects of sEV depletion and spironolactone treatment on cMSC-EV release and tumor growth.ResultsPost-MI hearts, particularly cMSCs, produced more sEVs with pro-neoplastic cargo than non-failing hearts did. Proteomic analysis revealed unique protein profiles and higher quantities of tumor-promoting cytokines, proteins, and microRNAs in cMSC-sEVs from failing hearts. The pro-neoplastic effects of cMSC-sEVs varied with different types of cancer cells, substantially affecting lung cancer cells relative to other more aggressive cancer cell lines. We also found that post-MI cMSC-sEVs activated resting macrophages into pro-angiogenic and pro-tumorigenic states in vitro. At 28-day follow-up analysis, mice with post-MI HF developed larger lung tumors than did sham-MI mice. Adoptive transfer of cMSC-sEVs from failing hearts accelerated lung tumor growth, and biodistribution analysis revealed an accumulating cMSC- sEVs in tumor cells along with accelerated tumor cell proliferation. Significantly, sEV depletion reduced the tumor-promoting effects of HF, and adoptive transfer of cMSC-sEVs from failing hearts partially restored it. Finally, post-MI spironolactone treatment reduced the number of cMSC-sEVs and suppressed tumor growth during post-MI HF.ConclusionsFor the first time, we show that cardiac sEVs, specifically cMSC-sEVs from post-MI failing hearts, carry multiple pro-tumorigenic factors. Uptake of cMSC-sEVs by cancer cells accelerates tumor growth. Post-MI spironolactone treatment reduces the associated tumor growth. Thus, we provide new insight into the link between post-MI HF and cancer and propose a translational option to mitigate this deadly association.
Mutually exclusive teams-like patterns of gene regulation characterize phenotypic heterogeneity along the noradrenergic-mesenchymal axis in neuroblastoma
Authors: Sehgal Manas , Nayak Sonali Priyadarshini , Sahoo Sarthak , Somarelli Jason A , Jolly Mohit Kumar 
Published: September 2023

AbstractNeuroblastoma is the most frequent extracranial pediatric tumor and leads to 15% of all cancer-related deaths in children. Tumor relapse and therapy resistance in neuroblastoma are driven by phenotypic plasticity and heterogeneity between noradrenergic (NOR) and mesenchymal (MES) cell states. Despite the importance of this phenotypic plasticity, however, the dynamics and molecular patterns associated with these bidirectional cell-state transitions remain relatively poorly understood. Here, we analyze multiple RNA-seq datasets at both bulk and single-cell resolution, to understand the association between NOR- and MES-specific factors. We observed that NOR-specific and MES-specific expression patterns are largely mutually exclusive, exhibiting a “teams-like” behavior among the genes involved, reminiscent of our earlier observations in lung cancer and melanoma. This antagonism was noticed also in the association of NOR and MES phenotypes with metabolic reprogramming and with immunotherapy targets PD-L1 and GD2, and in experimental perturbations driving the NOR-MES and/or MES-NOR transition. Further, this “teams-like” patterns was seen only among the NOR- and MES-specific genes, but not in housekeeping genes, possibly highlighting a hallmark of network topology enabling cancer cell plasticity.
Predictors of voluntary uptake of modern contraceptive methods in rural Sindh, Pakistan
Authors: Memon Zahid , Ahmed Wardah , Mian Abeer , Jawwad Muhammad , Muhammad Shah , Noorani Abdul Qayyum , Bhutta Zulfiqar , Soltani Hora 
Published: September 2023

AbstractIntroductionThe use of modern contraceptive methods (MCMs) in Pakistan has been stagnant for the last decade. In Sindh, current contraceptive use is at 28.9%, of which 25% is MCMs use. Such a low uptake translates into high unmet need 17% amongst married women. To bridge the gap between the health system and beneficiaries, there is a need to assess predictors that influence voluntary uptake of MCMs among women, at the health services and individual levels.MethodsA cross-sectional household survey was conducted in two districts of Sindh, Pakistan namely Matiari and Badin. In total, 1684 Married Women of Reproductive Age (MWRA) 15-49 years were interviewed. For the selection of eligible respondents, a two-stage stratified cluster sampling strategy was used. Univariate and multivariable logistic regression was used to determine the predictive factors for the increase in the use of MCM.ResultsMean age was 32.3 ±SD 7.1 years. Average number of children per woman was 4.0 ± 2.0. Use of modern methods of contraceptive was 26.1% [n=441).Statistically significant socio demographic predictors of MCM included: Number of children 4 or more (AOR 5.234 95%CI 2.78-9.84), Mother having primary education (AOR 1.730 95% CI 1.26-2.36), and Husband having middle education [AOR 1.69 95% CI 1.03 – 2.76).Maternal health services indicators included postnatal checkup of mother (AOR 1.46 95% CI 1.09 – 2.05); women who were visited by Lady Health Workers in their postnatal period and were counseled on family planning (AOR 1.83 95% CI 1.386 - 2.424).ConclusionVoluntary uptake of modern contraceptive methods is higher in women having 2 or more children, having primary education and husband having middle education. Significantly, receiving post-natal checkup at facility, and Lady Health Worker visit after delivery have more likelihood to opt for contraception. Additionally, young couple counseling on family planning is imperative to bridge the gap between knowledge and its translation into practice. There is also a need to focus on the provision of integrated family planning and maternal, newborn, and child health services through facility-based and community engagement platforms.