bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protocol on Establishing a National Disease Registry – Swiss Pediatric Inflammatory Brain Disease Registry
Authors: Hulliger Lorena Freya , Tscherter Anne , Kühni Claudia , Bigi Sandra 
Published: August 2023

AbstractBackgroundPediatric-onset inflammatory brain diseases are a group of potentially life-threatening central nervous system disorders. Overall, pediatric-onset inflammatory brain diseases are rare and therefore difficult to study. Patient registries are well suited to study the natural history of (rare) diseases and have markedly advanced the knowledge on pediatric-onset inflammatory brain diseases in other countries. Following their example, we established a national pediatric-onset inflammatory brain disease registry in Switzerland (Swiss-Ped-IBrainD).AimsThe Registry aims to describe epidemiology, demographics, diagnostics, management, and treatment, since these areas remain understudied in Switzerland. Additionally, we want to promote research by fostering the knowledge exchange between study centers and setting up studies such as national quality of life surveys. We further aim to facilitate the access to national and international studies for patients with a pediatric-onset inflammatory brain disease living and/or treated in Switzerland.MethodsThe Swiss-Ped-IBrainD is a multicentric, population-based, observational cohort study (IRB number: 2019-00377) collaborating with 11 neuropediatric centers in Switzerland. Patient screening, information and recruitment is mainly conducted by the local principal investigators. The data collection is organized centrally by the Executive Office of the registry. The collected data is purely observational. Medical records are the primary data source. All patients who have been diagnosed with a pediatric-onset inflammatory brain disease since 2005 are eligible. We aim to include all pediatric-onset inflammatory brain disease patients living and/or treated in Switzerland who meet the inclusion criteria. Considering existing literature and our single-center experience we anticipate 300-400 eligible patients.StatusCurrently, all 11 neuropediatric centers have been initiated and are recruiting. As of the first of May 2023, we have identified 275 eligible participants and obtained informed consent from 101 patients and/or families. None of the informed patients and/or families have refused participation.
The effect of recall period on reported out-of-pocket health expenditure in Ghana
Authors: Agorinya Isaiah Awintuen , Ross Amanda , Flores Gabriela , Akazili James , Edejer Tessa Tan-torres , van Wilgenburg Kim , Dalaba Maxwell , Mensah Nathan , Lan Le My , Bacha YadetaDassie , Sumboh Jemima , Tediosi Fabrizio 
Published: August 2023

AbstractBackgroundOut-of-pocket health payments (OOPs) are a key indicator of health financing systems’ performance. Measuring OOPs through household surveys is challenging and yet it is the primary source of information in the absence of comprehensive data on user charges in the public sector and market data from the private sector. The choice of the recall period has been identified as a source of bias in previous studies. This study investigates the effect of two different types of recall periods on the agreement between OOPs reported by households and providers.MethodsHouseholds were sampled for the community survey from the Navrongo Health and Demographic Surveillance System, Ghana. Two versions of a health expenditure module were developed differing only in the recall periods, “shorter recall periods”2weeks for medicines and outpatient care, 3monthsfor preventive care and 6months for inpatient care and medical products. The longer recall periods were 4 weeks, 6months and 12months.Households from both community and provider sampling were randomly assigned to the two questionnaires. The providers included the hospital, one clinic and health facilities and drug shops in the area. We estimated the ratio between the overall mean household OOPs and overall mean provider OOPs. We assessed agreement between the individual matched household-provider OOPs using the Bland-Altman analysis.FindingsThe short and long recall period versions of the questionnaires were administered to746 and 480 households with matching success to provider records of 72% and 84%, respectively. The most common spending categories were inpatient care and medicines in this sample. The overall mean OOPs reported by the households were higher than provider records for both recall periods. For matched household-provider data, there was no evidence of a difference in the agreement between the household and provider OOPs for inpatient care, the ratio of household to provider for the 12 months recall was estimated to be 0.74 (95% CI 0.45, 1.19; p=0.22) that of the ratio of household to provider for the 6-month period, where less than 1 indicates better agreement. For medicines, the ratio of 4 weeks to 2 weeks was 1.26 (0.93, 1.39; p=0.39).ConclusionThere were considerable challenges in using provider data to assess the accuracy of reported OOPs in this setting. There was no evidence from this study that the agreement between household and provider data differed by recall period, however the confidence intervals of the effect were wide, and an effect cannot be ruled out.
A thrombus is formed by a gradient of platelet activation and procoagulant endothelium
Authors: Carminita Estelle , Tourn Julie , Crescence Lydie , Brouilly Nicolas , Merrill-Skoloff Glenn , Mazharian Alexandra , Dubois Christophe , Panicot-Dubois Laurence 
Published: August 2023

AbstractIntroductionThe contribution of platelets in thrombosis within microcirculation has been extensively documented in the literature. We previously showed,in vivo,that platelet activation revealed by intracellular calcium mobilization was a crucial step in the growth of thrombi following laser-induced injury, a model of thromboinflammation.AimWe employed a multimodal, correlative microscopy approach and computational biology to investigate the extent of platelet activation and the spatial distribution of platelets throughout a growing thrombus.ResultsWe observed a reversible intracellular platelet calcium mobilization that correlates with the time a platelet resides during thrombus growth. Our bioinformatics analysis displayed three distinct platelet subpopulations resident within a thrombus:(1)resting,(2)partially activated, and(3)“fully” activated platelets. The spatial distribution of the platelet subpopulations in the thrombus creates a double gradient in both the transversal and longitudinal axis, with the maximal percentage of fully activated platelets close to the site of injury. However, these activated platelets did not express negative phospholipids. The injured endothelium was identified to play a vital role in activating the blood coagulation cascade in this model of thrombosis.ConclusionFollowing a laser-induced injury, thrombi are formed by a gradient of activated platelets from the injury site to the periphery of the thrombus. These different activation states of platelets throughout the thrombi regulate the biomechanics of the thrombus. The injured endothelium, rather than platelets, was identified to play a key role in the activation of the blood coagulation cascade in this model of thromboinflammation.EssentialsComputational biology was used to analyze thrombosis.Non-activated, low- and fully-activated platelets are part of a thrombus.The activation of the platelets forms a gradient from the site of injury to the periphery.The endothelium, and not platelets, expressed negative phospholipids.Graphical abstractA thrombus is formed by a gradient of platelet activation and procoagulant endothelium
Acylation of MLKL impacts its function in necroptosis
Authors: Pradhan Apoorva J. , Chitkara Shweta , Ramirez Ricardo X. , Monje-Galvan Viviana , Sancak Yasemin , Atilla-Gokcumen G. Ekin 
Published: August 2023

ABSTRACTMixed lineage kinase domain-like (MLKL) is a key signaling protein of necroptosis. Upon activation by phosphorylation, MLKL translocates to the plasma membrane and induces membrane permeabilization which contributes to the necroptosis-associated inflammation. Membrane binding of MLKL is initially initiated by the electrostatic interactions between the protein and membrane phospholipids. We previously showed that MLKL and its phosphorylated form (pMLKL) areS-acylated during necroptosis. Here, we characterize acylation sites of MLKL and identify multiple cysteines that can undergo acylation with an interesting promiscuity at play. Our results show that MLKL and pMLKL undergo acylation at a single cysteine, C184, C269 and C286 are the possible acylation sites. Using all atom molecular dynamic simulations, we identify differences that the acylation of MLKL causes at the protein and membrane level. Through systematic investigations of theS-palmitoyltransferases that might acylate MLKL in necroptosis, we showed that zDHHC21 activity has the strongest effect on pMLKL acylation, inactivation of which profoundly reduced the pMLKL levels in cells and improved membrane integrity. These results suggest that blocking the acylation of pMLKL destabilizes the protein at the membrane interface and causes its degradation, ameliorating necroptotic activity. At a broader level, our findings shed light on the effect ofS-acylation on MLKL functioning in necroptosis and MLKL-membrane interactions mediated by its acylation.
Phospho-signaling couples polar asymmetry and proteolysis within a membraneless microdomain inC. crescentus
Authors: Ahmed Yasin M , Bowman Grant R 
Published: August 2023

AbstractAsymmetric cell division in bacteria is achieved through cell polarization, where regulatory proteins are directed to specific cell poles. Curiously, both poles contain a membraneless microdomain, established by the polar assembly hub PopZ, through most of the cell cycle, yet many PopZ clients are unipolar and transiently localized. We find that PopZ’s interaction with the response regulator CpdR is controlled by phosphorylation, via the histidine kinase CckA. Phosphorylated CpdR does not interact with PopZ and is not localized to cell poles. At poles where CckA acts as a phosphatase, de-phosphorylated CpdR binds directly with PopZ and subsequently recruits ClpX, substrates, and other members of a protease complex to the cell pole. We also find that co-recruitment of protease components and substrates to polar microdomains enhances their coordinated activity. This study connects phosphosignaling with polar assembly and the activity of a protease that triggers cell cycle progression and cell differentiation.
Genome-wide Bioinformatics Analysis of Human Protease Specificity Identified Potential Cathepsin L Cleavage Site at K790 Position of the SARS-CoV-2 Spike Glycoprotein
Authors: Matveev Eugenii V. , Ponomarev Gennady V. , Kazanov Marat D. 
Published: August 2023

AbstractThe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) primarily enters the cell by binding the virus’s spike (S) glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell surface, followed by proteolytic cleavage by host proteases. Studies have identified furin and TMPRSS2 proteases in priming and triggering cleavages of the S glycoprotein, converting it into a fusion-competent form and initiating membrane fusion, respectively. Alternatively, SARS-CoV-2 can enter the cell through the endocytic pathway, where activation is triggered by lysosomal cathepsin L. However, other proteases are also suspected to be involved in both entry routes. In this study, we conducted a genome-wide bioinformatics analysis to explore the capacity of human proteases in hydrolyzing peptide bonds of the S glycoprotein. Predictive models of sequence specificity for 169 human proteases were constructed and applied to the S glycoprotein together with the method for predicting structural susceptibility to proteolysis of protein regions. After validating our approach on extensively studied S2’ and S1/S2 cleavage sites, we applied our method to each peptide bond of the S glycoprotein across all 169 proteases. Our results indicate that various members of the PCSK, TTSP, and kallikrein families, as well as specific coagulation factors, are capable of cleaving S2’ or S1/S2 sites. We have also identified a potential cleavage site of cathepsin L at the K790 position within the S2’ loop. Structural analysis suggests that cleavage of this site induces conformational changes similar to the cleavage at the R815 (S2’) position, leading to the exposure of the fusion peptide and subsequent fusion with the membrane. Other potential cleavage sites and the influence of mutations in common SARS-CoV-2 variants on proteolytic efficiency are discussed.
Striatal dopamine release reflects a domain-general prediction error
Authors: Costa Kauê Machado , Raheja Nishika , Mirani Jash , Sercander Courtney , Schoenbaum Geoffrey 
Published: August 2023

SummaryDopamine is classically thought to drive learning based on errors in the prediction of rewards and punishments1. However, animals also learn to predict cues with no intrinsic value2, and it is unclear if such latent learning also relies on dopaminergic prediction errors. Here, we tested this by recording dopamine release in the nucleus accumbens and dorsomedial striatum while rats executed a sensory preconditioning task that incorporates both types of learning3. We found that dopamine release in both regions correlated with errors in predicting value-neutral cues during latent learning and with errors in predicting reward during reward-based conditioning. Moreover, dopamine in the nucleus accumbens reflected inferred value in the probe test, supported by orbitofrontal cortex activity. Our findings suggest that dopamine signals a domain- general, multi-factorial prediction error, capable of supporting model-based learning.
No evidence for enhanced disease with polyclonal SARS-CoV-2 antibody in the ferret model
Authors: Reed Douglas S. , McElroy Anita K. , Barbeau Dominique J. , McMillen Cynthia M. , Tilston-Lunel Natasha L. , Nambulli Shamkumar , Cottle Emily , Gilliland Theron C. , Rannulu Hasala , Lundy Jeneveve , Olsen Emily L. , O’Malley Katherine J. , Xia Mengying , Hartman Amy L. , Luke Thomas C , Egland Kristi , Bausch Christoph , Wu Hua , Sullivan Eddie J. , Klimstra William B. , Duprex W. Paul 
Published: August 2023

ABSTRACTSince SARS-CoV-2 emerged in late 2019, it spread from China to the rest of the world. An initial concern was the potential for vaccine- or antibody-enhanced disease (AED) as had been reported with other coronaviruses. To evaluate this, we first developed a ferret model by exposing ferrets to SARS-CoV-2 by either mucosal inoculation (intranasal/oral) or inhalation using a small particle aerosol. Mucosal inoculation caused a mild fever and weight loss that resolved quickly; inoculation via either route resulted in virus shedding detected in the nares, throat, and rectum for 7-10 days post-infection. To evaluate the potential for AED, we then inoculated groups of ferrets intravenously with 0.1, 0.5, or 1 mg/kg doses of a human polyclonal anti-SARS-CoV-2 IgG from hyper-immunized transchromosomic bovines (SAB-185). Twelve hours later, ferrets were challenged by mucosal inoculation with SARS-CoV-2. We found no significant differences in fever, weight loss, or viral shedding after infection between the three antibody groups or the controls. Signs of pathology in the lungs were noted in infected ferrets but no differences were found between control and antibody groups. The results of this study indicate that healthy, young adult ferrets of both sexes are a suitable model of mild COVID-19 and that low doses of specific IgG in SAB-185 are unlikely to enhance the disease caused by SARS-CoV-2.
Phospholipase A2activity is required for immune defense of European (Apis mellifera) and Asian (Apis cerana) honeybees against the American foulbrood pathogen,Paenibacillus larvae
Authors: Jin Gahyeon , Hrithik Md Tafim Hossain , Mandal Eeshita , Kil Eui-Joon , Jung Chuleui , Kim Yonggyun 
Published: August 2023

AbstractHoneybees require a functioning immune system to defend against microbial pathogens. The American foulbrood pathogen,Paenibacillus larvae, is lethal to honeybees and one of the main causes of colony collapse. This study investigated the immune responses ofApis melliferaandApis ceranahoneybees against the bacterial pathogenP. larvae. Both species of honeybee larvae exhibited significant mortalities even at 102∼ 103cfu/mL ofP. larvaeby diet-feeding, althoughA. melliferaappeared to be more tolerant to the bacterial pathogen thanA. cerana. Upon bacterial infection, the two honeybee species expressed both cellular and humoral immune responses. Hemocytes of both species exhibited characteristic spreading behaviors by cytoskeletal extension along with F-actin growth, and formed nodules uponP. larvaeinfection. Larvae of both species also expressed an antimicrobial peptide called apolipophorin III (ApoLpIII) in response to bacterial infection. However, these immune responses were significantly suppressed by a specific inhibitor to phospholipase A2(PLA2). Each honeybee genome encodes four PLA2genes (PLA2A∼PLA2D), representing four orthologous combinations between the two species. In response toP. larvaeinfection, both species significantly up-regulated PLA2enzyme activities and the expression of all four PLA2genes. To determine the roles of the four PLA2s in the immune responses, RNA interference (RNAi) was performed by injecting gene-specific double stranded RNAs (dsRNAs). All four RNAi treatments significantly suppressed the immune responses, and specific inhibition of the two secretory PLA2s (PLA2AandPLA2B) potently suppressed nodule formation andApoLpIIIexpression. These results demonstrate the cellular and humoral immune responses ofA. melliferaandA. ceranaagainstP. larvae. This study suggests that eicosanoids play a crucial role in mediating common immune responses in two closely related honeybees.
Spatial Transcriptomics Reveals Alterations in Perivascular Macrophage Lipid Metabolism: Insights into the onset of Wooden Breast Myopathy in Broiler Chickens
Authors: Wang Ziqing , Khondowe Paul , Brannick Erin , Abasht Behnam 
Published: August 2023

AbstractThis study aims to use spatial transcriptomics to characterize the cell-type-specific expression profile associated with the microscopic features observed in Wooden Breast myopathy. 1 cm3muscle sample was dissected from the cranial part of the right pectoralis major muscle from three randomly sampled broiler chickens at 23 days post-hatch and processed with Visium Spatial Gene Expression kits (10X Genomics), followed by high-resolution imaging and sequencing on the Illumina Nextseq 2000 system. WB classification was based on histopathologic features identified. Sequence reads were aligned to the chicken reference genome (Galgal6) and mapped to histological images. Unsupervised K-means clustering and Seurat integrative analysis differentiated histologic features and their specific gene expression pattern, including lipid laden macrophages (LLM), unaffected myofibers, myositis and vasculature. In particular, LLM exhibited reprogramming of lipid metabolism with up-regulated lipid transporters and genes in peroxisome proliferator-activated receptors pathway, possibly through CD36-mediated signaling. Moreover, overexpression of fatty acid binding protein 5 could enhance fatty acid uptake in adjacent veins. In myositic regions, increased expression of cathepsins may play a role in muscle homeostasis and repair by mediating lysosomal activity and apoptosis. A better knowledge of different cell-type interactions at early stages of WB is essential in developing a comprehensive understanding.
Method to Test Etiologic Heterogeneity Among Non-Competing Diagnoses that Accrue Over Time: Application to Discriminating the Impact of Perinatal Exposures on Autism and Attention Deficit Hyperactivity Disorder
Authors: Kalkbrenner Amy E. , Zheng Cheng , Yu Justin , Jenson Tara E. , Kuhlwein Thomas , Ladd-Acosta Christine , Grove Jakob , Schendel Diana 
Published: August 2023

AbstractBackgroundTesting etiologic heterogeneity – whether a disorder subtype is more or less impacted by a risk factor, is important toward understanding causal pathways and optimizing statistical power. The study of mental health disorders especially benefits from strategic sub-categorization because these disorders are heterogenous and frequently co-occur. Existing methods to quantify etiologic heterogeneity are not appropriate for non-competing events in an open cohort of variable-length follow-up. Thus, we developed a new method.MethodsWe estimated risks from urban residence, maternal smoking during pregnancy, and parental psychiatric history, with subtypes defined by the presence or absence of a co-diagnosis: autism alone, attention deficit hyperactivity disorder (ADHD) alone, and joint diagnoses of autism+ADHD. To calculate the risk of a single diagnosis (e.g. autism alone), we subtracted the risk for autism+ADHD from the risk for autism overall. We tested the equivalency of average risk ratios over time, using a Wald-type test and bootstrapped standard errors.ResultsUrban residence was most strongly linked with autism+ADHD and least with ADHD only; maternal smoking was associated with ADHD only but not autism only; and parental psychiatric history exhibited similar associations with all subgroups.ConclusionsOur method allowed the calculation of appropriate p values to test strength of association, showing etiologic heterogeneity wherein 2 of these 3 risk factors exhibited different impacts across diagnostic subtypes. The method used all available data, avoided neurodevelopmental outcome misclassification, exhibited robust statistical precision, and is applicable to similar heterogeneous complex conditions using common diagnostic data with variable follow-up.
Blunted glucocorticoid responsiveness to stress causes behavioral and biological alterations that lead to posttraumatic stress disorder vulnerability
Authors: Monari Silvia , Guillot de Suduiraut Isabelle , Grosse Jocelyn , Zanoletti Olivia , Walker Sophie E. , Mesquita Michel , Wood Tobias C. , Cash Diana , Astori Simone , Sandi Carmen 
Published: August 2023

ABSTRACTBACKGROUNDUnderstanding why only a subset of trauma-exposed individuals develop posttraumatic stress disorder (PTSD) is critical for advancing clinical strategies. A few behavioral (deficits in fear extinction) and biological (blunted glucocorticoid levels, small hippocampal size, and rapid-eye movement sleep (REMS) disturbances) traits have been identified as potential vulnerability factors. However, whether and to what extent these traits are interrelated and whether one of them could causally engender the others are not known.METHODSIn a genetically selected rat model of reduced corticosterone responsiveness to stress, we explored PTSD-related biobehavioral traits usingex vivomagnetic resonance imaging, cued fear conditioning, and polysomnographic recordings combined within vivophotometric measurements.RESULTSWe showed that genetic selection for blunted glucocorticoid responsiveness leads to a correlated multitrait response, including impaired fear extinction, small hippocampal volume, and REMS disturbances, supporting their interrelatedness. Fear extinction deficits and concomitant disruptions in REMS could be normalized through postextinction corticosterone administration, causally implicating glucocorticoid deficiency in two core PTSD-related risk factors and manifestations. Furthermore, reduced REMS was accompanied by higher norepinephrine levels in the hippocampal dentate gyrus that were also reverted by postextinction corticosterone treatment.CONCLUSIONSOur results indicate a predominant role for glucocorticoid deficiency over the contribution of reduced hippocampal volume in engendering both REMS alterations and associated deficits in fear extinction consolidation, and causally implicate blunted glucocorticoids in sustaining neurophysiological disturbances leading to fear extinction deficits.