bluuebunny/crossref_metadata_2025_split huggingface dataset:
Advanced variant classification framework reduces the false positive rate of predicted loss of function (pLoF) variants in population sequencing data
Authors: Singer-Berk Moriel , Gudmundsson Sanna , Baxter Samantha , Seaby Eleanor G. , England Eleina , Wood Jordan C. , Son Rachel G. , Watts Nicholas A. , Karczewski Konrad J. , Harrison Steven M. , MacArthur Daniel G. , Rehm Heidi L. , O’Donnell-Luria Anne 
Published: March 2023

ABSTRACTPredicted loss of function (pLoF) variants are highly deleterious and play an important role in disease biology, but many of these variants may not actually result in loss-of-function. Here we present a framework that advances interpretation of pLoF variants in research and clinical settings by considering three categories of LoF evasion: (1) predicted rescue by secondary sequence properties, (2) uncertain biological relevance, and (3) potential technical artifacts. We also provide recommendations on adjustments to ACMG/AMP guidelines’s PVS1 criterion. Applying this framework to all high-confidence pLoF variants in 22 autosomal recessive disease-genes from the Genome Aggregation Database (gnomAD, v2.1.1) revealed predicted LoF evasion or potential artifacts in 27.3% (304/1,113) of variants. The major reasons were location in the last exon, in a homopolymer repeat, in low per-base expression (pext) score regions, or the presence of cryptic splice rescues. Variants predicted to be potential artifacts or to evade LoF were enriched for ClinVar benign variants. PVS1 was downgraded in 99.4% (162/163) of LoF evading variants assessed, with 17.2% (28/163) downgraded as a result of our framework, adding to previous guidelines. Variant pathogenicity was affected (mostly from likely pathogenic to VUS) in 20 (71.4%) of these 28 variants. This framework guides assessment of pLoF variants beyond standard annotation pipelines, and substantially reduces false positive rates, which is key to ensure accurate LoF variant prediction in both a research and clinical setting.
Prospective Bidirectional Relations Between Depression and Metabolic Health: 30 Year Follow-up from the NHLBI CARDIA Study
Authors: Moorehead Nicholas R. , Goodie Jeffrey L. , Krantz David S. 
Published: March 2023

ABSTRACTObjectiveThis study investigated prospective bidirectional relationships between depression and metabolic syndrome (MetS), and the moderating effects of race, sex, and health behaviors in a diverse cohort followed for 30 years.MethodsData were analyzed from the NHLBI CARDIA study, a 30 year-prospective study of young adults (N= 5113;Mage = 24.76 (SD= 3.63) at baseline; 45% male) who were tested every 5 years between 1985-2015. Measures included biological assessments of MetS components, and self-reported depressive symptoms based on the Center for Epidemiologic Studies Depression (CESD) scale. Data analyses included bi-directional general estimating equations analyses of time-lagged associations between depressive symptoms and MetS.ResultsThere was a consistent, bi-directional relationship between depressive symptoms and MetS over time. Individuals with more CESD depressive symptoms were more likely to develop MetS over time compared to those reporting fewer symptoms (Wald Chi-Square = 7.09 (1),p <0.008), and MetS was similarly predictive of CESD. MetS more consistently predicted depressive symptoms at each 5-year exam than depressive symptoms predicted MetS. Race and sex moderated relationships between depression and MetS, with White females, White individuals overall, and females overall demonstrating significant relationships. Health behaviors were not related to depression-MetS associations.ConclusionIn a diverse young adult population prospectively followed into late middle age, MetS more consistently predicted depression over time than depression predicted MetS. The relation between MetS and depressive symptoms was moderated by race and sex, but not health behaviors.
Influence of socioeconomic status on the presence of obstructive coronary artery disease and cardiovascular outcomes in patients undergoing invasive coronary angiography
Authors: Chung Jaehoon , Kim Hack-Lyoung , Joh Hyun Sung , Lim Woo-Hyun , Seo Jae-Bin , Kim Sang-Hyun , Zo Joo-Hee , Kim Myung-A 
Published: March 2023

AbstractBackgroundAlthough it has been documented that low socioeconomic status (SES) is associated with increased risk of mortality and cardiovascular disease (CVD), this issue has not been addressed in patients at high CVD risk. This study was performed to investigate the association of the patient’s SES with the presence of obstructive coronary artery disease (CAD) and long-term cardiovascular outcomes who undergo invasive coronary angiography (ICA).MethodsA total of 9,530 patients who underwent ICA for the evaluation and treatment of CAD (66.0±12.3 years and 60.2% male) were retrospectively reviewed. The patients were divided into two groups according to the health insurance type: those with low SES who had the Medical aid program (Medical aid beneficiary [MAB] group; n=1,436) and those with high SES who had the National Health Insurance program (National Health Insurance beneficiary [NHIB] group; n=8,094). The primary outcome was a composite of cardiac death, acute myocardial infarction, coronary revascularization, and ischemic stroke.ResultsOf the study patients, 1,436 (15.1%) were in the MAB group. The prevalence of cardiovascular risk factors was higher in the MAB group compared to the NHIB group. However, the prevalence of obstructive CAD was similar between the two groups (62.8% vs. 64.2%;P=0.306). During a median follow-up period of 3.5 years (interquartile range, 1.0 to 5.9 years), the incidence of the composite cardiovascular event was significantly higher in the MAB group than in the NHIB group (20.2% vs. 16.2%,P<0.001). In multivariable Cox regression analysis, compared to the NHIB group, the MAB group was independently associated with worse clinical outcomes even after controlling for potential confounders (adjusted odds ratio, 1.28; 95% confidence interval, 1.07 to 1.54;P=0.006).ConclusionsAlthough CAD prevalence was similar, MABs showed an increased risk of composite cardiovascular events than NHIBs in Korean adults undergoing ICA. This provides additional evidence for the association between low SES and an increased risk of CVD, even in high-risk subjects.Clinical perspectiveWhat is new?This study provided evidence for a relationship between low socioeconomic status and increased cardiovascular disease risk in a high-risk population.What are the clinical implications?Subjects with low socioeconomic status are more likely to develop cardiovascular disease and to have a higher frequency of related risk factors, so cardiovascular disease tests and treatments should be performed more aggressively.Appropriate risk stratification of low socioeconomic status patients with traditional risk factors for cardiovascular disease is important for identifying high-risk patients.
Causal Effect ofHelicobacter PyloriInfection on Coronary Heart Disease is mediated by Body Mass Index: A Mendelian Randomization Study
Authors: Li Bing , Zhang Yaoting , Zheng Yang , Cai He 
Published: March 2023

AbstractBackgroundMore than half of the world’s population have been infected withH. pylori, however the relationship betweenH. pyloriinfection and coronary heart disease (CHD) is unknown.MethodsThis study used mendelian randomization (MR) analyses. The instrument variables forH. pyloriinfection were genetic variables (rs10004195 and rs368433) obtained from a published study. The outcome data included diagnosis, prognosis, and pathogenesis data for CHD, which were extracted from the public genome-wide association studies database, mainly from the CARDIoGRAMplusC4D consortium, UK Biobank, IEU database, and FinnGen database. MR analyses were performed per outcome database and were conducted by reverse analysis. Two step MR analyses were used to explore indirect pathogenic factors ofH. pyloriinfection.ResultsGenetically-predictedH. pyloriinfection was causally associated with body mass index (BMI) (β, 0.022; 95% CI, 0.008–0.036;p-value = 0.001), but not with the diagnosis of CHD (OR, 0.991; 95%CI, 0.904–1.078;p-value = 0.842, IEU database; OR, 1.049; 95% CI, 0.980–1.118;p-value = 0.178, FinnGen database) and prognosis of CHD (OR, 0.999; 95% CI, 0.997–1.001;p-value = 0.391, IEU database; OR, 1.022; 95% CI, 0.922–1.123;p-value = 0.663, FinnGen database). The causal effect ofH. pyloriinfection on CHD is mediated by BMI. Inverse MR showed no causal effect of CHD onH. pyloriinfection.ConclusionsOur findings confirm the causal effect ofH. pyloriinfection on CHD is mediated by BMI. Eradication or prevention ofH. pyloriinfection may have a clinical benefit for patients with CHD indirectly.Clinical PerspectiveWhat Is New?Genetically-predictedH. pyloriinfection was causally associated with body mass index, but not with the diagnosis and prognosis (major adverse cardiovascular events) of coronary heart disease.The causal effect ofH. pyloriinfection on coronary heart disease is mediated by body mass index. Inverse mendelian randomization analyses showed no causal effect of coronary heart disease onH. pyloriinfection.What Are the Clinical Implications?Our findings confirm that the causal effect of H. pylori infection on coronary heart disease is partially mediated by body mass index.Eradication or prevention of H. pylori infection may have a clinical benefit for patients with CHD indirectly.
Further evidences of an emerging stingless bee-yeast symbiosis
Authors: de Paula Gabriela Toninato , da Paixão Melo Weilan Gomes , de Castro Ivan , Menezes Cristiano , Paludo Camila Raquel , Rosa Carlos Augusto , Pupo Mônica Tallarico 
Published: March 2023

AbstractSymbiotic interactions between microorganisms and social insects have been described as crucial for the maintenance of these multitrophic systems, as observed for the stingless beeScaptotrigona depilisand the yeastZygosaccharomycessp. The larvae ofS. depilisingest fungal filaments ofZygosaccharomycessp. to obtain ergosterol, which is the precursor for the biosynthesis of ecdysteroids that modulate insect metamorphosis. In this work we verified that nutritional fungal symbioses also occur in other species of stingless bees. We analyzed brood cell samples from 19 species of stingless bees collected in Brazil. The osmophilic yeastZygosaccharomycesspp. was isolated from eight bee species, namelyScaptotrigona bipuctata, S. postica, S. tubiba, Tetragona clavipes, Melipona quadrifasciata, M. fasciculata, M. bicolorandPartamona helleri. These yeasts form pseudohyphae and also accumulate ergosterol in lipid droplets, similar to the pattern observed forS. depilis. The phylogenetic analyses including variousZygosaccharomycesrevealed that strains isolated from the brood cells formed a branch separated from the previously describedZygosaccharomycesspecies, suggesting that they are new species of this genus and reinforcing the symbiotic interaction with the host insects.ImportanceBenefits exchanged in insect–fungus mutualisms include nutrition, protection, and dispersal. Fungal nutritional roles are well described for some eusocial insects, such as fungus growing ants and termites, but similar interaction in stingless bees was so far observed just inScaptotrigona depilis. Here we expand the knowledge of yeast-bee symbiosis by analyzing the presence, cell morphologies, lipid accumulation and phylogenetic relationships of fungi isolated from brood cells and other locations of bee colonies.Zygosaccharomycesisolates were recovered from 42% of the bee species assessed, and probably represent new species showing pseudohyphae formation and lipid accumulation similar toS. depilisassociatedZygosaccharomycesstrains. The phylogenetic analyses suggested an evolutionary adaptation ofZygosaccharomycesspp. to the brood cell environment to provide nutritional benefits for the developing insect. Stingless bees play important ecosystem services, and our results raise the concern that fungicidal agents used in agriculture could disrupt this symbiosis, impacting bee health.
Spatial immunosampling of MRI-defined glioblastoma regions reveals immunologic fingerprint of non-contrast enhancing, infiltrative tumor margins
Authors: Grabowski Matthew M. , Watson Dionysios C. , Chung Kunho , Lee Juyeun , Bayik Defne , Lauko Adam , Alban Tyler , Melenhorst Jan Joseph , Chan Timothy , Lathia Justin D. , Ahluwalia Manmeet S. , Mohammadi Alireza M. 
Published: March 2023

SummaryGlioblastoma (GBM) treatment includes maximal safe resection of the core and MRI contrast-enhancing (CE) tumor. Complete resection of the infiltrative non-contrast-enhancing (NCE) tumor rim is rarely achieved. We established a safe, semi-automated workflow for spatially-registered sampling of MRI-defined GBM regions in 19 patients with downstream analysis and biobanking, enabling studies of NCE, wherefrom recurrence/progression typically occurs. Immunophenotyping revealed underrepresentation of myeloid cell subsets and CD8+ T cells in the NCE. While NCE T cells phenotypically and functionally resembled those in matching CE tumor, subsets of activated (CD69hi) effector memory CD8+ T cells were overrepresented. Contrarily, CD25hiTregs and other subsets were underrepresented. Overall, our study demonstrated that MRI-guided, spatially-registered, intraoperative immunosampling is feasible as part of routine GBM surgery. Further elucidation of the shared and spatially distinct microenvironmental biology of GBM will enable development of therapeutic approaches targeting the NCE infiltrative tumor to decrease GBM recurrence.
Usability and acceptability of oral fluid- and blood-based hepatitis C virus self-testing among the general population and men who have sex with men in Malaysia
Authors: Chan Huan-Keat , Sem Xiaohui , Ivanova Elena , Pannir Selvam Sheela Bai A/P , Salleh Narul Aida , Mohamad Gani Abdul Hafiz Bin , Fajardo Emmanuel , Shilton Sonjelle , Abu Hassan Muhammad Radzi 
Published: March 2023

AbstractHepatitis C self-testing (HCVST) is emerging as an additional strategy that could help to expand access to HCV testing. We conducted a study to assess the usability and acceptability of two types of HCVST, oral fluid- and blood-based, among the general population and men who have sex with men (MSM) in Malaysia.An observational study was conducted in three primary care centres in Malaysia. Participants who were layman users performed the oral fluid- and blood-based HCVST sequentially. Usability was assessed by calculating the rate of errors observed, the rate of difficulties faced by participants as well as inter-reader (self-test interpreted by self-tester vs interpreted by trained user) and inter-operator concordances (self-test vs test performed by trained user). The acceptability of HCV self-testing was assessed using an interviewer-administered semi-structured questionnaire. Participants were also required to read contrived test results which included “positive”, “negative”, and “invalid”.There was a total of 200 participants (100 general population, 100 MSM; mean age 33.6 ± 14.0 years). We found a high acceptability of oral fluid- and blood-based HCVST across both general population and MSM. User errors, related to timekeeping and reading within stipulated time, were common. However, the majority of the participants were still able to obtain and interpret results correctly, including that of contrived results. The high acceptability of HCVST among the participants did not appreciably change after they had experienced both tests, with 97.0% of all participants indicating they would be willing to use HCVST again and 98.5% of them indicating they would recommend it to people they knew. There was no significant difference between the general population and MSM in these aspects.Our study demonstrates that both oral fluid- and blood-based HCVST are highly acceptable among both the general population and MSM. Both populations also showed comparable ability to conduct the tests and interpret the results. Overall, this study suggests that HCVST could be introduced as an addition to existing HCV testing services in Malaysia. Further studies are needed to establish the optimal positioning of self-testing alongside facility-based testing to expand access to HCV diagnosis in the country.
S100A9 induces neuroinflammation and aggravates early brain injury after subarachnoid hemorrhage by activating the TLR4/MYD88/NF-κB pathway
Authors: Wang Guijun , Huang Kesheng , Zhang Zhan , Guo Yujia , Tian Qi , Liu Chengli , Li Zhijie , Yu Zhui , Li Mingchang 
Published: March 2023

AbstractBackgroundSubarachnoid hemorrhage (SAH) is a stroke subtype with an extremely high mortality rate, and its severity is closely related to the short-term prognosis of patients with SAH. The S100 calcium-binding protein A9 (S100A9) has been shown to be associated with some neurological diseases, and this study aimed to investigate the relationship between S100A9 and neuroinflammation, as well as its mechanism in SAH.MethodsAn enzyme-linked immunosorbent assay (ELISA) was used to detect the concentration of S100A9 in clinical cerebrospinal fluid samples. Furthermore, an in vivo mouse SAH model was established using intravascular perforation; S100A9 knockout mice were used for the in vivo experiments. S100A9 recombinant protein was administered via lateral ventricular injection 1 h before SAH model induction. SAH grade, neurological function score, and brain water content were measured after a specific time. BV2 and HT22 cells and co-culture models were treated with heme chloride to establish an in vitro model of SAH. Paquinimod was used to explore the potential neuroprotective mechanisms of S100A9 inhibition. Western blotting and immunofluorescence staining were used to explore microglial activation, inflammatory responses, and its related protein pathways.ResultsThe expression of S100A9 protein in the cerebrospinal fluid of patients with SAH increased and was related to the short-term prognosis of patients with SAH; S100A9 was highly expressed in the microglia. S100A9 knockout significantly improved neurological function scores, reduced brain edema, and reduced neuronal apoptosis. S100A9 inhibition with Paquinimod restrained neuronal apoptosis, while administration of recombinant S100A9 aggravated neuroinflammation, activated the TLR4 receptor, promoted NF-κB nuclear transcription, and ultimately aggravated nerve injury.ConclusionS100A9 protein expression increased after SAH, which induced neuroinflammation and promote neuronal apoptosis by activating the TLR4/MYD88/ NF-κB pathway, ultimately aggravating nerve injury after SAH.
Is the Juice Worth the Squeeze? Overall Survival gain per unit treatment time as a metric of clinical benefit of systemic treatment in incurable cancers
Authors: Joseph Nuradh , Bamunuarachchi Vodathi , Peiris Vimukthini , Wijeskera Sidath , Rajapakse Daminda , Gunasekera Sanjeeva 
Published: March 2023

AbstractIntroductionNovel systemic therapeutic options such as enzyme inhibitors and monoclonal antibodies have transformed the practice of medical oncology in the recent past. However, survival gains remain modest in most cases. Quantifying the magnitude of benefit against financial and non-financial toxicity of treatment is pivotal in deciding treatment. We describe a novel metric which can be used to assess effectiveness novel therapeutics for incurable cancers.MethodsThe median overall survival was divided by the median duration of treatment to obtain the overall survival gain per treatment time which was the primary end-point of the study. This parameter was compared with the European Society of Medical Oncology Magnitude of clinical benefit scale (ESMO-MCBS) score. Spearman’s rank correlation coefficient was used to test the association between the novel metric and the ESMO-MCBS scores.ResultsData were available for 30 drugs across 60 indications. The median overall survival per unit treatment time ranged from 0.68 (range 0.2-0.51). Only 18/60 indications had a ratio greater than 1 while 13/60 indications had a ratio less than 0.5. The median treatment duration was not mentioned in 11 indications and median progression free survival was substituted for the analysis. The ESMO-MCBS score was available for 49 of the indications. The Spearman’s rank correlation coefficient was 0.44575 and showed a statistically significant association between survival gain per unit treatment time and the ESMO-MCBS score (p = 0.00133).ConclusionsAlong with other metrics, the ratio of survival gain over treatment duration is a useful parameter to assess effectiveness of novel therapeutics in the palliative setting.
Sanglifehrin A mitigates multi-organ fibrosis in vivo by inducing secretion of the collagen chaperone cyclophilin B
Authors: Flaxman Hope A. , Chrysovergi Maria-Anna , Han Hongwei , Kabir Farah , Lister Rachael T. , Chang Chia-Fu , Black Katharine E. , Lagares David , Woo Christina M. 
Published: March 2023

AbstractPathological deposition and crosslinking of collagen type I by activated myofibroblasts drives progressive tissue fibrosis. Therapies that inhibit collagen synthesis by myofibroblasts have clinical potential as anti-fibrotic agents. Lysine hydroxylation by the prolyl-3-hydroxylase complex, comprised of cartilage associated protein, prolyl 3-hydroxylase 1, and cyclophilin B, is essential for collagen type I crosslinking and formation of stable fibers. Here, we identify the collagen chaperone cyclophilin B as a major cellular target of the macrocyclic natural product sanglifehrin A (SfA) using photo-affinity labeling and chemical proteomics. Our studies reveal a unique mechanism of action in which SfA binding to cyclophilin B in the endoplasmic reticulum (ER) induces the secretion of cyclophilin B to the extracellular space, preventing TGF-β1–activated myofibroblasts from synthesizing collagen type Iin vitrowithout inhibiting collagen type I mRNA transcription or inducing ER stress. In addition, SfA prevents collagen type I secretion without affecting myofibroblast contractility or TGF-β1 signaling.In vivo,we provide chemical, molecular, functional, and translational evidence that SfA mitigates the development of lung and skin fibrosis in mouse models by inducing cyclophilin B secretion, thereby inhibiting collagen synthesis from fibrotic fibroblastsin vivo. Consistent with these findings in preclinical models, SfA reduces collagen type I secretion from fibrotic human lung fibroblasts and precision cut lung slices from patients with idiopathic pulmonary fibrosis, a fatal fibrotic lung disease with limited therapeutic options. Our results identify the primary liganded target of SfA in cells, the collagen chaperone cyclophilin B, as a new mechanistic target for the treatment of organ fibrosis.
ZC3H11A interacts with PABPN1 and alters polyadenylation of viral transcripts
Authors: Kases Katharina , Schubert Erik , Hajikhezri Zamaneh , Larsson Mårten , Andersson Leif , Akusjärvi Göran , Punga Tanel , Younis Shady 
Published: March 2023

AbstractNuclear mRNA metabolism is regulated by multiple proteins, which either directly bind to RNA or form multi-protein complexes. The RNA-binding protein ZC3H11A is involved in nuclear mRNA export, and NF-κB signaling and is essential during mouse embryo development. Furthermore, previous studies have shown that ZC3H11A is important for nuclear-replicating viruses. However, detailed biochemical characterization of the ZC3H11A protein has been lacking. In this study, we established the ZC3H11A protein interactome in human and mouse cells. We demonstrate that the nuclear poly(A)-binding protein PABPN1 interacts specifically with the ZC3H11A protein and controls ZC3H11A localization into nuclear speckles. We report that ZC3H11A specifically interacts with the human adenovirus type 5 (HAdV-5) capsid mRNA in a PABPN1-dependent manner. Notably, ZC3H11A uses the same zinc finger motifs to interact with PABPN1 and mRNA, with a single zinc finger motif responsible for these functions. Further, we demonstrate that the lack of ZC3H11A alters the polyadenylation of HAdV-5 capsid mRNA. Taken together, our results suggest that the ZC3H11A protein acts as a novel regulator of polyadenylation of nuclear mRNA.