bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatic IRE1 Protects Against Septic Cardiac Failure
Authors: Li Mark , Berton Roger R. , Qian Qingwen , Maschek J. Alan , Chen Biyi , Barroso Elizabeth , Rauckhorst Adam J. , Griffith Thomas S. , Taylor Eric B. , Badovinac Vladimir P. , Hotamisligil Gökhan S. , Song Long-Sheng , Yang Ling 
Published: March 2023

SUMMARYMetabolic reprogramming in response to infection plays a critical role for septic survival. During a septic episode, the heart heavily relies on hepatic lipid particles to prevent heart damage and failure. Inositol- Requiring Enzyme 1 (IRE1) is the most conserved unfolded protein response (UPR) regulator that governs homeostasis of the endoplasmic reticulum (ER), the major site for lipid synthesis and processing. Here we show that hepatocyte IRE1 is indispensable for protecting against septic mortality in two different rodent models of experimental sepsis. The protective effect of hepatic IRE1 was not attributed to the inflammatory response since hepatic IRE1 deletion did not alter hepatic or systemic cytokine response. However, loss of IRE1 in the liver significantly augmented septic cardiac dysfunction in part due to a skewed immune-metabolic balance. Lipidomic and metabolomic analyses further revealed that loss of IRE1 in the liver compromised adaptive intrahepatic and circulating lipid reprogramming, including VLDL, in response to septic challenge. Furthermore, we identified that the protective effects against septic mortality are mediated by a non-canonical IRE1-dependent mechanism. Together, our study provides the first insight into how a disruption of hepatic ER-mediated lipid metabolic regulation promotes sepsis-associated cardiac immuno-metabolic imbalance.
Multi-ancestry meta-analysis of tobacco use disorder prioritizes novel candidate risk genes and reveals associations with numerous health outcomes
Authors: Toikumo Sylvanus , Jennings Mariela V , Pham Benjamin K , Lee Hyunjoon , Mallard Travis T , Bianchi Sevim B , Meredith John J , Vilar-Ribó Laura , Xu Heng , Hatoum Alexander S , Johnson Emma C , Pazdernik Vanessa , Jinwala Zeal , Pakala Shreya R , Leger Brittany S , Niarchou Maria , Ehinmowo Michael ,   Penn Medicine BioBank, Million Veteran Program,   Psychemerge Substance Use Disorder Workgroup, Jenkins Greg D , Batzler Anthony , Pendegraft Richard , Palmer Abraham A , Zhou Hang , Biernacka Joanna M , Coombes Brandon J , Gelernter Joel , Xu Ke , Hancock Dana B , Nancy Cox J , Smoller Jordan W , Davis Lea K , Justice Amy C , Kranzler Henry R , Kember Rachel L , Sanchez-Roige Sandra 
Published: March 2023

ABSTRACTTobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviors, and although strides have been made using genome-wide association studies (GWAS) to identify risk variants, the majority of variants identified have been for nicotine consumption, rather than TUD. We leveraged five biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records,EHR) in 898,680 individuals (739,895 European, 114,420 African American, 44,365 Latin American). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviors in children, and hundreds of medical outcomes, including HIV infection, heart disease, and pain. This work furthers our biological understanding of TUD and establishes EHR as a source of phenotypic information for studying the genetics of TUD.
The rapid emergence ofSalmonellaTyphi with decreased ciprofloxacin susceptibility following an increase in ciprofloxacin prescriptions in Blantyre, Malawi
Authors: Ashton Philip M. , Chirambo Angeziwa Chunga , Meiring James E. , Patel Priyanka D. , Mbewe Maurice , Silungwe Niza , Chizani Kenneth , Banda Happy , Heyderman Robert S. , Dyson Zoe A. , MacPherson Peter , Henrion Marc Y.R. ,   STRATAA Study Group, Holt Kathryn E. , Gordon Melita A. 
Published: March 2023

AbstractCiprofloxacin is the first-line drug for treating typhoid fever in many high burden countries in Africa, but the emergence of non-susceptibility poses a grave challenge to public health programmes. Through enhanced surveillance as part of vaccine evaluation, we set out to investigate the occurrence and determinants of ciprofloxacin non-susceptibility in Blantyre, Malawi.We performed systematic typhoid fever and antibiotic prescription surveillance in two health centres in Blantyre, Malawi between 01/10/2016 and 31/10/2019, as part of the STRATAA and TyVAC studies. Blood culture isolates from study participants underwent i) pefloxacin screening and ciprofloxacin E-tests to identify ciprofloxcain non-susceptibility and ii) whole genome sequencing (WGS) to identify drug resistance mutations and phylogenetic relationships between non-susceptible and sensitive isolates. We constructed generalised linear regression models to investigate associations between ciprofloxacin prescription rates andS.Typhi isolates with Quinolone Resistance Determining Region (QRDR) mutations.We carried out 11295 blood cultures and microbiologically confirmed 239 cases of typhoid fever, with isolates from 193 participants sequenced (mean age of participants with sequenced genomes 12.8 years, 47% male). Between October 2016 and August 2019 2% (n=4/175) of WGS-confirmed typhoid fever cases were caused byS.Typhi with QRDR mutations, compared with 33% (n=6/18) in September and October 2019. Nine of the tenS.Typhi with QRDR mutations had a decreased ciprofloxacin susceptibility phenotype. Every additional prescription of ciprofloxacin given to study participants in the preceding month was associated with a 4.2% increase in the relative risk of isolatingS.Typhi with a QRDR mutation (95% CI, 1.8-7.0%, p=0.0008). Phylogenetic analysis showed thatS.Typhi isolates with QRDR mutations in September/October 2019 belonged to two distinct sub-clades encoding two different QRDR mutations, and were closely related (0-6 SNPs) to susceptibleS.Typhi endemic to Blantyre.We have shown a close temporal association between empiric antimicrobial usage with an increase of fluoroquinolone non-susceptibility inS. Typhi, with two sub-clades responsible for the increase. Decreasing ciprofloxacin usage by improving typhoid diagnostics could help to limit the emergence of resistance.
Advancing Understanding of Inequities in Rare Disease Genomics
Authors: Serrano Jillian G , O’Leary Melanie , VanNoy Grace , Holm Ingrid A , Fraiman Yarden S , Rehm Heidi L , O’Donnell-Luria Anne , Wojcik Monica H 
Published: March 2023

AbstractPurposeAdvances in genomic research have led to the diagnosis of rare, early-onset diseases for thousands of individuals. Unfortunately, the benefits of advanced genetic diagnostic technology are not distributed equitably among the population, as has been seen in many other healthcare contexts. Even quantifying and describing inequities in genetic diagnostic yield is challenging due to variation in referrals to clinical genetics practices and other barriers to clinical genetic testing.MethodsThe Rare Genomes Project (RGP) at the Broad Institute of MIT and Harvard offers research genome sequencing to individuals with rare disease who remain genetically undiagnosed through direct interaction with the individual or family. This presents an opportunity for diagnosis beyond the clinical context, thus eliminating many barriers to access.FindingsAn initial goal of RGP was to equalize access to genomic sequencing by decoupling testing access from proximity to a major medical center and physician referral. However, our study participants are overwhelmingly non-disadvantaged, as evidenced by their access to specialist care and genetic testing prior to RGP enrollment, and are also predominantly white.ImplicationsWe therefore describe our novel initiative to diversify RGP enrollment in order to advance equity in rare disease genetic diagnosis and research. In addition to the moral imperative of medical equity, this is also critical in order to fully understand the genomic underpinnings of rare disease. We utilize a mixed methods approach to understand the priorities and values of underrepresented communities, existing disparities, and the obstacles to addressing them: all of which is necessary to promote equity in future genomic medicine initiatives.
Amygdala-related electrical fingerprint is modulated with neurofeedback training and correlates with deep-brain activation: Proof-of-concept in borderline personality disorder
Authors: Zopfs Malte , Jindrová Miroslava , Gurevitch Guy , Keynan Jackob N. , Hendler Talma , Baumeister Sarah , Aggensteiner Pascal-M. , Cornelisse Sven , Brandeis Daniel , Schmahl Christian , Paret Christian 
Published: March 2023

AbstractBackgroundThe modulation of brain circuits of emotion is a promising pathway to treat Borderline Personality Disorder (BPD). Precise and scalable approaches have yet to be established. Two studies investigating the Amygdala-related Electrical Fingerprint (Amyg-EFP) in BPD are presented: One study addressing the deep-brain correlates of Amyg-EFP, and a second study investigating neurofeedback (NF) as a means to improve brain self-regulation.MethodsStudy 1 combined EEG and simultaneous fMRI to investigate the replicability of Amyg-EFP-related brain activation found in the reference dataset (N=24 healthy subjects, 8 female; re-analysis of published data) in the replication dataset (N=16 female individuals with BPD). In the replication dataset, we additionally explored how the Amyg-EFP would map to neural circuits defined by the Research Domain Criteria. Study 2 investigated a 10-session Amyg-EFP NF training in parallel to a 12-weeks residential Dialectical Behavior Therapy (DBT) program. N=15 patients with BPD completed the training, N=15 matched patients served as DBT-only controls.ResultsStudy 1 replicated previous findings and showed significant amygdala BOLD-activation in a whole-brain regression analysis with the Amyg-EFP. Neurocircuitry activation (negative affect, salience, and cognitive control) was correlated with the Amyg-EFP signal. Study 2 showed significant learning of Amyg-EFP modulation with NF training. No clinical benefits of NF beyond DBT-only were observed.ConclusionsRecorded via scalp EEG, the Amyg-EFP picks up brain activation of high relevance for emotion. Administering Amyg-EFP NF in addition to standardized BPD treatment was shown to be feasible. Clinical utility remains to be investigated.
Lasting first impression: Pre-existing immunity restricts mucosal antibody responses during Omicron breakthrough
Authors: Selva Kevin John , Ramanathan Pradhipa , Haycroft Ebene Regina , Reynaldi Arnold , Cromer Deborah , Tan Chee Wah , Wang Lin-Fa , Wines Bruce D , Hogarth P Mark , Downie Laura E , Davis Samantha K , Purcell Ruth Amy , Kent Helen E , Juno Jennifer A , Wheatley Adam K , Davenport Miles P , Kent Stephen John , Chung Amy W 
Published: March 2023

SummaryUnderstanding mucosal antibody responses from SARS-CoV-2 infection and/or vaccination is crucial to develop strategies for longer term immunity, especially against emerging viral variants. We profiled serial paired mucosal and plasma antibodies from: COVID-19 vaccinated only vaccinees (vaccinated, uninfected), COVID-19 recovered vaccinees (convalescent, vaccinated) and individuals with breakthrough Delta or Omicron BA.2 infections (vaccinated, infected). Saliva from COVID-19 recovered vaccinees displayed improved antibody neutralizing activity, FcγR engagement and IgA compared to COVID-19 uninfected vaccinees. Furthermore, repeated mRNA vaccination boosted SARS-CoV-2-specific IgG2 and IgG4 responses in both mucosa biofluids (saliva and tears) and plasma. IgG, but not IgA, responses to breakthrough COVID-19 variants were dampened and narrowed by increased pre-existing vaccine-induced immunity to the ancestral strain. Salivary antibodies delayed initiation of boosting following breakthrough COVID-19 infection, especially Omicron BA.2, however, rose rapidly thereafter. Our data highlight how pre-existing immunity shapes mucosal SARS-CoV-2-specific antibody responses and has implications for long-term protection from COVID-19.
Growth defect of domain III glycoprotein B mutants of human cytomegalovirus reverted by compensatory mutations co-localizing in post-fusion conformation
Authors: Madlen Mollik , Lukas Eisler , Büsra Külekci , Elisabeth Puchhammer-Stöckl , Irene Görzer 
Published: March 2023

AbstractCell entry is a crucial step for a virus to infect a host cell. Human cytomegalovirus (HCMV) utilizes the glycoprotein B (gB) to fuse the viral and host cell membrane upon receptor binding of gH/gL-containing complexes. Fusion is mediated by major conformational changes of gB from a metastable pre-fusion to a stable post-fusion whereby the central trimeric coiled-coils, formed by domain (D) III α helices, remain structurally nearly unchanged. To better understand the role of the stable core, we individually introduced three potentially helix-breaking and one disulfide bond-breaking mutation in the DIII α3 to alter the gB stability, and studied different aspects of the viral behavior upon long-term culturing. Two of the three helix-breaking mutations were lethal for the virus in either fibroblasts or epithelial cells and the third substitution led from mild to severe effects on viral replication and infection efficiency. gB_Y494P and gB_I495P suggest that the pre-fusion conformation was stabilized and the fusion process inhibited, gB_G493P on the other hand displayed a delayed replication increase and spread, more pronounced in epithelial cells, hinting at an impaired fusion. Interestingely, the disulfide bond-breaker mutation, gB_C507S, performed strikingly different in the two cell types – lethal in epithelial cells and an atypical phenotype in fibroblasts, respectively. Replication curve analyses paired with the infection efficiency and the spread morphology suggest a dysregulated fusion process which could be reverted by second-site mutations mapping predominantly to gB DV. This underlines the functional importance of a stable core for a well-regulated DV rearrangement during fusion.ImportanceHuman cytomegalovirus (HCMV) can establish a lifelong infection. In most people, the infection follows an asymptomatic course, however it is a major cause of morbidity and mortality in immunocompromised patients or neonates. HCMV has a very broad cell tropism, ranging from fibroblasts to epi- and endothelial cells. It uses different entry pathways utilizing the core fusion machinery consisting of glycoprotein complexes gH/gL and gB. The fusion protein gB undergoes severe rearrangements from a metastable pre-fusion to a stable post-fusion. Here, we were able to characterize the viral behavior after the introduction of four single point mutations in gBs central core. These led to various cell type-specific atypical phenotypes and the emergence of compensatory mutations, demonstrating an important interaction between domains III and V. We provide a new basis for the delevopment of recombinant stable pre-fusion gB which can further serve as a tool for the drug and vaccine development.
Untargeted metabolomics profiling in pediatric patients and adult populations indicates a connection between lipid imbalance and epilepsy
Authors: Oja Kaisa Teele , Ilisson Mihkel , Reinson Karit , Muru Kai , Reimand Tiia , Peterson Hedi , Fishman Dmytro , Esko Tõnu , Haller Toomas , Kronberg Jaanika , Wojcik Monica H. , Kennedy Adam , Michelotti Gregory , O’Donnell-Luria Anne , Õiglane-Šlik Eve , Pajusalu Sander , Õunap Katrin 
Published: March 2023

AbstractIntroductionEpilepsy is a common central nervous system disorder characterized by abnormal brain electrical activity. We aimed to compare the metabolic profiles of plasma from patients with epilepsy across different etiologies, seizure frequency, seizure type, and patient age to try to identify common disrupted pathways.Material and methodsWe used data from three separate cohorts. The first cohort (PED-C) consisted of 31 pediatric patients with suspicion of a genetic disorder with unclear etiology; the second cohort (AD-C) consisted of 250 adults from the Estonian Biobank (EstBB), and the third cohort consisted of 583 adults ≥ 69 years of age from the EstBB (ELD-C). We compared untargeted metabolomics and lipidomics data between individuals with and without epilepsy in each cohort.ResultsIn the PED-C, significant alterations (p-value <0.05) were detected in sixteen different glycerophosphatidylcholines (GPC), dimethylglycine and eicosanedioate (C20-DC). In the AD-C, nine significantly altered metabolites were found, mainly triacylglycerides (TAG), which are also precursors in the GPC synthesis pathway. In the ELD-C, significant changes in twenty metabolites including multiple TAGs were observed in the metabolic profile of participants with previously diagnosed epilepsy. Pathway analysis revealed that among the metabolites that differ significantly between epilepsy-positive and epilepsy-negative patients in the PED-C, the lipid superpathway (p = 3.2*10-4) and phosphatidylcholine (p = 9.3*10-8) and lysophospholipid (p = 5.9*10-3) subpathways are statistically overrepresented. Analogously, in the AD-C, the triacylglyceride subclass turned out to be statistically overrepresented (p = 8.5*10-5) with the lipid superpathway (p = 1.4*10-2). The presented p-values are FDR-corrected.ConclusionOur results suggest that cell membrane fluidity may have a significant role in the mechanism of epilepsy, and changes in lipid balance may indicate epilepsy. However, further studies are needed to evaluate whether untargeted metabolomics analysis could prove helpful in diagnosing epilepsy earlier.
Genome-wide polygenic risk score for muscle strength predicts lower risk for common diseases and longer life span among the Finnish population: a prospective population based cohort study of the 342 443 FinnGen participants
Authors: Herranen Päivi , Koivunen Kaisa , Palviainen Teemu ,   FinnGen, Kujala Urho M , Ripatti Samuli , Kaprio Jaakko , Sillanpää Elina 
Published: March 2023

ABSTRACTPurposeTo use a genome-wide polygenic risk score for hand grip strength (PRS HGS) to investigate whether the muscle strength genotype predicts the most common age related noncommunicable diseases, survival from acute adverse health events, and all cause mortality.MethodsThis study consisted of 342 443 Finnish biobank participants from FinnGen Data Freeze 10 (53% women) aged 40 to 108 with combined genotype and health registry data. Associations were explored with a linear or Cox proportional hazards regression models.ResultsA higher PRS HGS predicted a lower body mass index (BMI) (β = −0.112 kg/m2, standard error (SE) = 0.017,P= 1.69 × 10−11) in women but not in men (β = 0.004 kg/m2,P= 0.768, sex by PRS HGS interaction:P= 2.12 × 10−07). In all participants, a higher PRS HGS was associated with a lower risk for obesity diagnosis (hazard ratio 0.94, 95% confidence interval 0.93 to 0.95), type 2 diabetes (0.95, 0.94 to 0.96), ischemic heart diseases (0.97, 0.96 to 0.97), hypertension (0.97, 0.96 to 0.97), stroke (0.97, 0.96 to 0.98), asthma (0.94, 0.93 to 0.95), chronic obstructive pulmonary disease (0.94, 0.92 to 0.95), polyarthrosis (0.90, 0.88 to 0.92), knee arthrosis (0.98, 0.97 to 0.99), rheumatoid arthritis (0.95, 0.94 to 0.97), osteoporosis (0.95, 0.93 to 0.97), falls (0.98, 0.98 to 0.99), depression (0.95, 0.94 to 0.96), and vascular dementia (0.93, 0.89 to 0.96). In women only, a higher PRS predicted a lower hazard for any dementia (0.94, 0.92 to 0.96) and Alzheimer’s disease (0.96, 0.93 to 0.98). Participants with a higher PRS HGS had a decreased risk of cardiovascular (0.96, 0.95 to 0.98) and all cause mortality (0.97, 0.96 to 0.98). However, the predictive value of the PRS HGS for mortality was not pronounced after adverse acute health events compared to the non-diseased period.ConclusionsThe genotype that supports higher muscle strength protects against many future health adversities. Further research is needed to investigate whether or how a favourable lifestyle modifies this intrinsic capacity to resist diseases, and if the impacts of lifestyle behaviour on health differ due to polygenic risk.
Transcription decouples estrogen-dependent changes in enhancer-promoter contact frequencies and spatial proximity
Authors: Acuña Luciana I. Gómez , Flyamer Ilya , Boyle Shelagh , Friman Elias , Bickmore Wendy A. 
Published: March 2023

AbstractHow enhancers regulate their target genes in the context of 3D chromatin organization is extensively studied and models which do not require direct enhancer-promoter contact have recently emerged. Here, we use the activation of estrogen receptor-dependent enhancers in a breast cancer cell line to study enhancer-promoter communication. This allows high temporal resolution tracking of molecular events from hormone stimulation to efficient gene activation. We examine how both enhancer-promoter spatial proximity assayed by DNA fluorescence in situ hybridization, and contact frequencies resulting from chromatin in situ fragmentation and proximity ligation by Capture-C, change dynamically during enhancer-driven gene activation. These orthogonal methods produce seemingly paradoxical results: upon enhancer activation enhancer-promoter contact frequencies increase while spatial proximity decreases. We explore this apparent discrepancy using different estrogen receptor ligands and transcription inhibitors. Our data demonstrate that enhancer-promoter contact frequencies are transcription independent but are influenced by enhancer-bound protein complexes whereas altered enhancer-promoter proximity depends on transcription. Our results emphasize that the relationship between contact frequencies and physical distance in the nucleus, especially over short genomic distances, is not always a simple one.
Short Term Impact of Recycling-Derived Fertilizers on Their P Supply for Perennial Ryegrass (Lolium perenne)
Authors: Deinert Lea , Egeter Bastian , Ikoyi Israel , Forrestal Patrick , Schmalenberger Achim 
Published: March 2023

AbstractPhosphorus is a finite, essential macronutrient for agriculture. Various nutrient recycling technologies in waste streams management are currently under development in many European countries in order to alleviate the dependency of the EU on imports of non-renewable raw material for the production of mineral phosphorus fertilizers commonly used in agriculture. The resulting products such as struvites and ashes need to be assessed for their application as so-called recycling-derived fertilisers (RDF) in the agricultural sector prior to commercialisation. Albeit high phosphorus abundance in most soils, the phosphorus availability for plant growth promotion in the soil solution is usually low due to strong P sorption in soil and depends vastly on the microbial mobilisation capability of the soil.To investigate the impact of different phosphorus fertilizers on plant growth and the soil P cycling microbiota, a short-term pot trial was conducted over the period of 54 days.Lolium perenne(var. AberGreen) was grown with application of superphosphate (SP) as inorganic fertiliser, two ashes (poultry litter ash (PLA) and sewage sludge ash (SSA) and two struvites (municipal wastewater struvite (MWS) and commercial CrystalGreen®(CGS) in rates of 20 and 60 kg P ha-1in four replicates. A P-free control (SP0) was also included in the trial.Post-harvest, a positive correlation between dry weight yield and struvite application was detected, struvite P also was higher readily available and ACP activity was significantly improved for struvites at the high P application rate. The ash RDFs showed a liming effect at 60 kg P ha-1, and PLA60 negatively affected ACP activity, while PLA20 had significantly lowerphoDcopy numbers. P mobilization from phosphonates and phytates was not affected, TCP solubilization was negatively affected by mineral SP fertilizer application at both P concentrations. Overall, the bacterial andphoDharbouring community were not strongly affected by the P fertilization in this study.