bluuebunny/crossref_metadata_2025_split huggingface dataset:
Levels of high-sensitive troponin T and mid-regional pro-adrenomedullin after COVID-19 vaccination in vulnerable groups: a prospective study on subtle and persistent cardiovascular involvement
Authors: Möckel Martin , Pudasaini Samipa , Le Ngoc Han , Huscher Dörte , Holert Fabian , Hillus David , Tober-Lau Pinkus , Kurth Florian , Sander Leif Erik 
Published: May 2024

AbstractBackgroundThis study examines potential, subtle and persistent adverse effects of COVID-19 vaccines on the cardiovascular system. Vaccine-associated myocardial injury was analysed by measuring high-sensitive troponin T (hsTnT); mid-regional pro-adrenomedullin (MR-proADM) levels were evaluated to assess endothelial dysfunction.MethodsThis was a prospective study with a vulnerable population of healthcare workers (HCWs) and elderly patients (> 70 years) who were vaccinated with either one dose of ChAdOx1 nCov-19 adenoviral vector vaccine (AZ) followed by one dose of the BNT162b2 messenger RNA vaccine (BNT), or with two doses of BNT (12thof January - 30thof November 2021). HsTnT and MR-proADM were measured in blood samples at three visits (V1: 1stimmediately before vaccination; V2, 3: 3-4 weeks after 1stand 2ndvaccination). HsTnT of HCWs was compared to a healthy reference population.ResultsN=162 volunteers were included (V1=161; V2, V3=162 each). N=74 (45.7%) received AZ/BNT and n=88 (54.3%) received BNT/BNT (elderly: n=20 (12.3%), HCWs: n=68 (42.0%)). Median hsTnT levels were 4ng/L, 5ng/L and 4ng/L (V1-V3) for AZ/BNT and at 5ng/L, 6ng/L and 6ng/L (V1-V3) for BNT/BNT. Compared to the reference population (n=300), hsTnT was significantly higher at all visits for both vaccination groups (p<0.01), without differences between the AZ/BNT and BNT/BNT cohort. MR-proADM values were 0.43nmol/L, 0.45nmol/L, 0.44nmol/L (V1-V3) in the AZ/BNT cohort and 0.49nmol/L, 0.44nmol/L, 0.47nmol/L for BNT/BNT, respectively. Change of median hsTnT and MR-proADM between visits did not show significant increases. One HCW case had a permanent and three a transient hsTnT increase ≥14ng/L.ConclusionWith one individual exception, no overall subtle, persistent cardiovascular involvement was observed after the 2ndCOVID-19 vaccination.Structured graphical abstractSummary of the vaccination scheme and visiting points in the study population (of HCWs and seniors > 70 years) between the 12thof January and the 30thof November 2021. The results showed no overall subtle, chronic myocardial or vascular involvement in our COVID-19 vaccinated cohorts.Abbreviations:AZ ChAdOx1 nCov-19 adenoviral vector vaccine from Astra Zeneca, BNT BNT162b2 messenger ribonucleic acid vaccine from BioNTech, EDTA Ethylenediaminetetraacetic acid, HCWs health care workers, hsTnT high-sensitive troponin T, mid-regional pro-adrenomedullin, V1-V3visiting times 1-3, w week(s).
Pro-inflammatory macrophage activation does not require inhibition of mitochondrial respiration
Authors: Ball Andréa B. , Jones Anthony E. , Nguyễn Kaitlyn B. , Rios Amy , Marx Nico , Hsieh Wei Yuan , Yang Krista , Desousa Brandon R. , Kim Kristen K.O. , Veliova Michaela , del Mundo Zena Marie , Shirihai Orian S. , Benincá Cristiane , Stiles Linsey , Bensinger Steven J. , Divakaruni Ajit S. 
Published: May 2024

ABSTRACTPro-inflammatory macrophage activation is a hallmark example of how mitochondria serve as signaling organelles. Upon classical macrophage activation, oxidative phosphorylation sharply decreases and mitochondria are repurposed to accumulate signals that amplify effector function. However, evidence is conflicting as to whether this collapse in respiration is essential or largely dispensable. Here we systematically examine this question and show that reduced oxidative phosphorylation is not required for pro-inflammatory macrophage activation. Only stimuli that engage both MyD88- and TRIF-linked pathways decrease mitochondrial respiration, and different pro-inflammatory stimuli have varying effects on other bioenergetic parameters. Additionally, pharmacologic and genetic models of electron transport chain inhibition show no direct link between respiration and pro-inflammatory activation. Studies in mouse and human macrophages also reveal accumulation of the signaling metabolites succinate and itaconate can occur independently of characteristic breaks in the TCA cycle. Finally,in vivoactivation of peritoneal macrophages further demonstrates that a pro-inflammatory response can be elicited without reductions to oxidative phosphorylation. Taken together, the results suggest the conventional model of mitochondrial reprogramming upon macrophage activation is incomplete.
HYL001, a new potent TGFβ signaling inhibitor that is efficacious against microsatellite stable CRC metastasis in combination with immune checkpoint therapy in mice
Authors: Tauriello Daniele V. F. , Sancho Elena , Byrom Daniel , Sanchez-Zarzalejo Carolina , Salvany Maria , Henriques Ana , Palomo-Ponce Sergio , Sevillano Marta , Hernando-Momblona Xavier , Matarin Joan A. , Ramos Israel , Ruano Irene , Prats Neus , Batlle Eduard , Riera Antoni 
Published: May 2024

ABSTRACTBlockade of the TGFβ signalling pathway has emerged from preclinical studies as a potential treatment to enhance the efficacy of immune checkpoint inhibition in advanced colorectal cancer (CRC) and several other types of cancer. However, clinical translation of first-generation inhibitors has known little success. Here, we report the synthesis and characterization of HYL001, a potent inhibitor of TGFβ receptor 1 (ALK5), that is approximately 9 times more efficacious than the structurally related compound galunisertib, while maintaining a favourable safety profile. HYL001 in combination with immune checkpoint blockade (anti-PD1) eradicates liver metastases generated in mice by microsatellite stable, aggressive colorectal cancer tumours at doses where galunisertib is ineffective.GRAPHICAL ABSTRACT
Cerebrovascular health mediates processing speed change through anterior white matter alterations: A UK Biobank Study
Authors: Moran KL , Smith CJ , McManus E , Allan SM , Montaldi D , Muhlert N 
Published: May 2024

AbstractCerebrovascular disease is associated with an increased likelihood of developing dementia. While cardiovascular risk factors are modifiable and may reduce the risk of later-life cognitive dysfunction, the relationship between cerebrovascular risk factors, brain integrity and cognition remains poorly characterised. Using a large UK Biobank sample of predominantly middle-aged adults, without neurological disease, our structural equation mediation models showed that poor cerebrovascular health, indicated by the presence of cerebrovascular risk factors, was associated with slowed processing speed. This effect was best explained by anterior white matter microstructure changes, rather than posterior changes. Effects were also significantly reduced when considering other forms of cognition, demonstrating both regional- and cognitive-specificity of our effects. Critically, our findings also demonstrate that including measures of risk factor duration may be particularly important for improving estimations of cerebrovascular burden. In summary, our study demonstrates the specific impact of early cerebrovascular burden on brain structure and cognitive function, highlighting the necessary next steps for improving cerebrovascular burden quantification and improving clinical predictions.
Human metapneumovirus SH protein promotes JAK1 degradation to impair host IL-6 signaling
Authors: Brynes Adam , Zhang Yu , Williams John V. 
Published: May 2024

AbstractHuman metapneumovirus (HMPV) is a leading cause of respiratory infections in children, older adults, and those with underlying conditions1,2,3,4. HMPV must evade immune defenses to replicate successfully; however, the viral proteins used to accomplish this are poorly characterized. The HMPV small hydrophobic (SH) protein has been reported to inhibit signaling through type I and type II interferon (IFN) receptorsin vitro, in part by preventing STAT1 phosphorylation5. HMPV infection also inhibits IL-6 signaling. However, the mechanisms by which SH inhibits signaling, and its involvement in IL-6 signaling inhibition are unknown. Here, we used transfection of SH expression plasmids and SH-deleted virus (ΔSH) to show that SH is the viral factor responsible for inhibition of IL-6 signaling during HMPV infection. Transfection of SH-expression vectors or infection with wildtype, but not ΔSH virus, blocked IL-6 mediated STAT3 activation. Further, JAK1 protein (but not RNA) was significantly reduced in cells infected with wildtype but not ΔSH virus. The SH-mediated reduction of JAK1 was partially restored by addition of proteasome inhibitors, suggesting proteasomal degradation of JAK1. Confocal microscopy indicated that infection relocalized JAK1 to viral replication factories. Co-immunoprecipitation showed that SH interacts with JAK1 and ubiquitin, further linking SH to proteasomal degradation machinery. These data indicate that SH inhibits IL-6 and IFN signaling in infected cells in part by promoting proteasomal degradation of JAK1 and that SH is necessary for IL-6 and IFN signaling inhibition in infection. These findings enhance our understanding of the immune evasion mechanisms of an important respiratory pathogen.ImportanceHuman metapneumovirus (HMPV) is a common cause of severe respiratory illness, especially in children and older adults, in whom it is a leading cause of hospitalization. Prior research suggests that severe HMPV infection is driven by a strong immune response to the virus, and especially by inflammatory immune signals like interferons (IFN). HMPV produces a small hydrophobic protein (SH) that is known to block IFN signaling, but the mechanism by which it functions, and its ability to inhibit other important immune signals remains unexplored. This paper demonstrates that SH can inhibit another related immune signal, IL-6, and demonstrates that SH depletes JAKs, critical proteins involved in both IL-6 and IFN signaling. A robust understanding of how HMPV and related viruses interfere with immune signals important for disease could pave the way for future treatments aimed at mitigating severe infections.
THE PHYTOPHARMACOLOGICAL EVALUATION OF THE METHANOL ROOT EXTRACT OFAZANZA GARCKEANA(MALVACEAE) ON ISOLATED WISTAR RAT UTERINE SMOOTH MUSCLES
Authors: Chanda Alfred , Gono-Bwalya Angela , prashar Lavina 
Published: May 2024

AbstractEthnopharmacological relevancePregnant women in Chongwe, Zambia traditionally use the root ofAzanza garckeana(F.Hffm.) Exell & Hillc (Malvalceae) to induce or accelerate labour. A previous study on the plant showed the crude root extracts to possesses uterotonic potential on isolated Wistar rat uterine smooth muscles. The methanol crude root extract was found to be the most potent.AimThe aim of the study was to isolated by bioactivity-guided isolation method the compound with the major uterotonic activity in the root ofAzanza garckeana.Materials and methodsThis was a laboratory-based study designed using the uterus isolated from estrogenised adult non-gravid female virgin Wistar rats. The fresh plant materials (leaves and roots) were collected from Chongwe district. The methanol crude extract was obtained by continuous maceration and it was partitioned using hexane, chloroform, ethyl acetate and n-butanol in the increasing order of polarity. The most active fraction was fractionated using column chromatography. One-way ANOVA, Bonferroni post hoc tests were used to analyze data using STATA version 13. Bar charts and dose-response curves were done using Graphpad Prism version 5.00 for Windows (San Diego California USA).ResultsThe final aqueous suspension demonstrated the highest uterotonic potency (EC50= 2.49 x 10−3mg/ml; 95% CI 1.19 x 10−3to 5.23 x 10−3mg/ml, p=0.0001), while sub-fraction pool number 2 (subfractions number 41 to 61) demonstrated the highest uterotonic potency (EC50at 2.05 x 10−3mg/ml; 95% CI 2.09 x 10−3to 3.85 x 10−3mg/ml, p=0.0001). Sub-fraction pool number 2 was suggested to contain the compound with the major uterotonic activity which was suggested to be related to the family of glycosides after High Performance Liquid Chromatography (HPLC) and Fourier Transform Infrared Spectroscopy (FTIR) analysis.ConclusionsThe study suggests the presence of a major uterotonic phytochemical constituent in the methanol root crude extract ofAzanza garckeana, which was suggested to be related to the family of glycosides. The study has provided scientific evidence suggesting the root ofAzanza garckeana, a plant used traditionally for inducing or accelerating labor possess uterotonic activity. Further pharmacological and toxicological studies need to be undertaken on the plant.
Demographic, temporal, and spatial analysis of human rabid animal bite cases in Mymensingh District, Bangladesh
Authors: Chouhan Chandra Shaker , Raihan Abu , Mia Md. Manik , Banerjee Subarna , Shahriar Ishmam , Nath Proggananda , Uddin Jasim M. , Ehsan Md. Amimul , Ward Michael P. , Rahman A. K. M. Anisur 
Published: May 2024

AbstractObjectiveThis study aimed to analyze the demographic, temporal, and spatial characteristics of rabid animal bite (RAB) cases in humans across 12 upazilas within Mymensingh district of Bangladesh.MethodsRetrospective hospital-based data from RAB cases for 2022 and 2023 were collected from S.K Hospital. The dataset included information on victim demographics, bite details, vaccination information, and Rabies Immune Globulin (RIG) administration. Additionally, monthly case counts from 2016 to 2023 were sourced and analyzed to identify trends. Descriptive statistics and time series analysis using the seasonal decomposition technique were conducted. The risk maps for rabid animal bites in 2022 and 2023 were generated using a standardized incidence rate ratio (SIRR) approach.FindingsAn almost two-fold increase in the proportion of category 3 bites receiving Rabies Immune Globulin (RIG) from 3.6% in 2022 to 6.5% in 2023 was noted. Only 9.7% of bite cases in 2022 and 16.9% in 2023 received the vaccine promptly after the incident. However, the majority received vaccines within the first 24 hours after being bitten. Moreover, significant seasonal patterns and year-wise increasing trends in RAB cases were observed. Males and individuals <10 years old had a higher risk of being bitten. Dogs (48.2% in 2022) and cats (52.6% in 2023) were identified as the primary animals responsible for the bites. Notably, the legs were the body part most frequently bitten. The bites risk map identified four high risk upazilas.ConclusionThere is a significant gap in ensuring timely vaccination delivery. Study results also suggest other potential improvements in healthcare practices or treatment protocols. Increasing RAB cases highlights the need to enhance surveillance and control measures. Targeted awareness campaigns and preventive measures tailored to high-risk groups − including males, children <10 years old, dogs and cats − are imperative. Coordinated efforts among healthcare professionals, policymakers, and community stakeholders are crucial to effectively mitigate the incidence of RAB cases, safeguarding public health and eradicate dog mediated rabies by 2030 in the region.
Mismatch repair gene specifications to the ACMG/AMP classification criteria: Consensus recommendations from the InSiGHT ClinGen Hereditary Colorectal Cancer / Polyposis Variant Curation Expert Panel
Authors: Plazzer John Paul , Macrae Finlay , Yin Xiaoyu , Thompson Bryony A. , Farrington Susan M , Currie Lauren , Lagerstedt-Robinson Kristina , Frederiksen Jane Hübertz , van Overeem Hansen Thomas , Graversen Lise , Frayling Ian M. , Akagi Kiwamu , Yamamoto Gou , Al-Mulla Fahd , Ferber Matthew J. , Martins Alexandra , Genuardi Maurizio , Kohonen-Corish Maija , Baert-Desurmont Stéphanie , Spurdle Amanda B. , Capellá Gabriel , Pineda Marta , Woods Michael O. , Rasmussen Lene Juel , Heinen Christopher D. , Scott Rodney J. , Tops Carli M. , Greenblatt Marc S. , Dominguez-Valentin Mev , Ognedal Elisabet , Borras Ester , Leung Suet Y. , Mahmood Khalid , Holinski-Feder Elke , Laner Andreas 
Published: May 2024

AbstractBackgroundIt is known that gene- and disease-specific evidence domains can potentially improve the capability of the ACMG/AMP classification criteria to categorize pathogenicity for variants. We aimed to include gene–disease-specific clinical, predictive, and functional domain specifications to the ACMG/AMP criteria with respect to MMR genes.MethodsStarting with the original criteria (InSiGHT criteria) developed by the InSiGHT Variant Interpretation Committee, we systematically addressed specifications to the ACMG/AMP criteria to enable more comprehensive pathogenicity assessment within the ClinGen VCEP framework, resulting in an MMR gene-specific ACMG/AMP criteria.ResultsA total of 19 criteria were specified, 9 were considered not applicable and there were 35 variations of strength of the evidence. A pilot set of 48 variants was tested using the new MMR gene-specific ACMG/AMP criteria. Most variants remained unaltered, as compared to the previous InSiGHT criteria; however, an additional four variants of uncertain significance were reclassified to P/LP or LB by the MMR gene-specific ACMG/AMP criteria framework.ConclusionThe MMR gene-specific ACMG/AMP criteria have proven feasible for implementation, are consistent with the original InSiGHT criteria, and enable additional combinations of evidence for variant classification. This study provides a strong foundation for implementing gene–disease-specific knowledge and experience, and could also hold immense potential in a clinical setting.
Retrospective Analysis of Neonatal Hyperbilirubinemia at Hiwot Fana Specialized Hospital, Ethiopia: Prevalence, Associated Factors, and Treatment Outcomes
Authors: Shugri Mohamed Abdirahman , Libe Temesgen Teferi , Gebru Feven Mekonnen 
Published: May 2024

AbstractBackgroundNeonatal hyperbilirubinemia, also known as neonatal jaundice, is a condition characterized by yellowish discoloration of the skin and eyes caused by bilirubin buildup in the body. Understanding its prevalence, associated factors, and outcomes is crucial for effective management.ObjectivesThis study aimed to assess the prevalence, associated factors, and treatment outcomes of neonatal hyperbilirubinemia at Hiwot Fana Specialized Hospital, Eastern Ethiopia.MethodologyA hospital-based cross-sectional study was conducted from December 1, 2020, to December 30, 2020, involving 328 neonates admitted to the Neonatal Intensive Care Unit. Data were collected using a checklist and analyzed using SPSS version 22.ResultNeonatal hyperbilirubinemia prevalence was 44.2%, with 1.4% progressing to bilirubin encephalopathy. Sepsis (44.8%) and prematurity (22%) were major contributing factors. Most neonates were treated with phototherapy alone (82.3%), and 93.8% showed improvement.ConclusionThe study underscores the importance of early detection and management of neonatal hyperbilirubinemia to prevent adverse outcomes. Recommendations include integrating jaundice prevention into antenatal care and ensuring timely bilirubin level checks in neonates.
Supervised fine-tuning of pre-trained antibody language models improves antigen specificity prediction
Authors: Wang Meng , Patsenker Jonathan , Li Henry , Kluger Yuval , Kleinstein Steven H. 
Published: May 2024

AbstractAntibodies play a crucial role in adaptive immune responses by determining B cell specificity to antigens and focusing immune function on target pathogens. Accurate prediction of antibody-antigen specificity directly from antibody sequencing data would be a great aid in understanding immune responses, guiding vaccine design, and developing antibody-based therapeutics. In this study, we present a method of supervised fine-tuning for antibody language models, which improves on previous results in binding specificity prediction to SARS-CoV-2 spike protein and influenza hemagglutinin. We perform supervised fine-tuning on four pre-trained antibody language models to predict specificity to these antigens and demonstrate that fine-tuned language model classifiers exhibit enhanced predictive accuracy compared to classifiers trained on pretrained model embeddings. The change of model attention activations after supervised fine-tuning suggested that this performance was driven by an increased model focus on the complementarity determining regions (CDRs). Application of the supervised fine-tuned models to BCR repertoire data demonstrated that these models could recognize the specific responses elicited by influenza and SARS-CoV-2 vaccination. Overall, our study highlights the benefits of supervised fine-tuning on pre-trained antibody language models as a mechanism to improve antigen specificity prediction.Author SummaryAntibodies are vigilant sentinels of our adaptive immune system that recognize and bind to targets on foreign pathogens, known as antigens. This interaction between antibody and antigen is highly specific, akin to a fitting lock and key mechanism, to ensure each antibody precisely targets its intended antigen. Recent advancements in language modeling have led to the development of antibody language model to decode specificity information in the sequences of antibodies. We introduce a method based on supervised fine-tuning, which enhances the accuracy of antibody language models in predicting antibody-antigen interactions. By training these models on large datasets of antibody sequences, we can better predict which antibodies will bind to important antigens such as those found on the surface of viruses like SARS-CoV-2 and influenza. Moreover, our study demonstrates the potential of the models to “read” B cell repertoire data and predict ongoing responses, offering new insights into how our bodies respond to vaccination. These findings have significant implications for vaccine design, as accurate prediction of antibody specificity can guide the development of more effective vaccines.
Enhancing affinity of neutralizing SARS-CoV-2 nanobody through facile structure-guided mutations in CDRs
Authors: Singh Vishakha , Bhutkar Mandar , Choudhary Shweta , Nehul Sanketkumar , Kumar Rajesh , Singla Jitin , Kumar Pravindra , Tomar Shailly 
Published: May 2024

AbstractThe optimization of antibodies to attain the desired levels of affinity and specificity holds great promise for development of the next generation therapeutics. This study delves into the refinement and engineering of CDRs throughin silicoaffinity maturation followed by binding validation using ITC and pseudovirus-based neutralization assays. Specifically, it focuses on engineering CDRs targeting the epitopes of RBD of the spike protein of SARS-CoV-2. A structure-guided virtual library of 112 single mutations in CDRs was generated and screened against RBD to select the potential affinity-enhancing mutations. Subsequent biophysical studies using ITC provided insights into binding affinity and key thermodynamic parameters. Consistent within silicofindings, seven single mutations resulted in enhanced affinity. The mutants were further tested for neutralization activity against SARS-CoV-2 pseudovirus. L106T, L106Q, S107R, and S107Q generated mutants were more effective in virus-neutralizing with IC50values of ∼0.03 µM, ∼0.13 µM, ∼0.14 µM, and ∼0.14 µM, respectively as compared to the native nanobody (IC50∼0.77 µM). Thus, in this study, the developed computational pipeline guided by structure-aided interface profiles and thermodynamic analysis holds promise for the streamlined development of antibody-based therapeutic interventions against emerging variants of SARS-CoV-2 and other infectious pathogens.