bluuebunny/crossref_metadata_2025_split huggingface dataset:
Robust metabolomic age prediction based on a wide selection of metabolites
Authors: Faquih Tariq , van Hylckama Vlieg Astrid , Surendran Praveen , Butterworth Adam S. , Li-Gao Ruifang , de Mutsert Renée , Rosendaal Frits R. , Noordam Raymond , van Heemst Diana , van Dijk Ko Willems , Mook-Kanamori Dennis O. 
Published: June 2023

AbstractChronological age is a major risk factor for numerous diseases. However, chronological age does not capture the complex biological aging process. Biological aging can occur at a different pace in individuals of the same chronological age. Therefore, the difference between the chronological age and biologically driven aging could be more informative in reflecting health status. Metabolite levels are thought to reflect the integrated effects of both genetic and environmental factors on the rate of aging, and may thus provide a stronger signature for biological age than those previously developed using methylation and proteomics. Here, we set out to develop a metabolomic age prediction model by applying ridge regression and bootstrapping with 826 metabolites (of which 678 endogenous and 148 xenobiotics) measured by an untargeted high-performance liquid chromatography mass spectrometry platform (Metabolon) in 11,977 individuals (50.2% men) from the INTERVAL study (Cambridge, UK). Participants of the INTERVAL study are relatively healthy blood donors aged 18-75 years. After internal validation using bootstrapping, the models demonstrated high performance with an adjusted R2of 0.82 using the endogenous metabolites only and an adjusted R2of 0.83 when using the full set of 826 metabolites with age as outcome. The latter model performance could be indicative of xenobiotics predicting frailty. In summary, we developed robust models for predicting metabolomic age in a large relatively healthy population with a wide age range.
The genetics of idiopathic intracranial hypertension (IIH): Integration of population studies and clinical data
Authors: Zucker Roei , Kovalerchik Michael , Davidovich Zvika , Banne Ehud , Maharshak Idit , Linial Michal 
Published: June 2023

AbstractBackgroundIdiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure without a known cause. IIH mainly affects overweight and reproductive-age women. Due to elevated intracranial pressure in IIH patients, papilledema (PAP), a disease caused by swelling of the optic disc, often co-occurs. Previous genome-wide association studies (GWAS) of common variants failed to find significant associations.MethodsWe applied genetic association protocols to a cohort of 173 patients diagnosed with IIH or PAP from the UK Biobank (UKB). The results were compared to the FinnGen data. We applied routine and coding GWAS (cGWAS) to a unified cohort of IIH/PAP. We also employed SKAT, which considers all variants within a given segment, and PWAS, which estimates the damage of variants to protein function and models a gene by aggregating its coding variants.ResultsThe detection power of standard GWAS methods is restricted by cohort size and false discovery. To overcome these limitations, we considered gene-centric approaches for the unified group of IIH and PAP patients. Notably, the dominant comorbidity of IIH is PAP in the UKB and FinnGen populations. Seeking shared genes by GWAS for IIH and PAP identified VLDLR and SHANK2 genes in the UKB and FinnGen cohorts, respectively. By utilizing complementary gene-centric association protocols (coding GWAS, SKAT, and PWAS) for the unified IIH/PAP group, we identified 16 genes that were recognized by at least two methods, with FOXF1 and RGCC recognized by all three. Employing a functional enrichment scheme emphasized the significance of cilium, microtubule, and cytoskeletal functions. To gain insight into IIH etiology, we focused on the choroid plexus, a brain structure that produces and secretes the cerebrospinal fluid (CSF). Altogether, 7 of the 16 candidate genes are listed among the 281 genes with enhanced expression in the choroid plexus epithelium. Among them, MAPK15, DNAH5, and SLC28A3 are involved in ciliary microtubule dysregulation.ConclusionsThis study highlights the strength of integrative genetic association approaches with functional and clinical knowledge. By identifying potential genetic effects, we propose the biological and cellular relevance of the choroid plexus for IIH etiology and suggest candidate genes for further investigation.
Identification of Novel Syncytiotrophoblast Membrane Extracellular Vesicles Derived Protein Biomarkers in Early-onset Preeclampsia: A Cross-Sectional Study
Authors: Awoyemi Toluwalase , Jiang Shuhan , Bjarkadóttir Bríet , Rahbar Maryam , Logenthiran Prasanna , Collett Gavin , Zhang Wei , Cribbs Adam , Cerdeira Ana Sofia , Vatish Manu 
Published: June 2023

AbstractBackgroundPreeclampsia (PE), a multi-systemic hypertensive pregnancy disease that affects 2-8% of pregnancies worldwide, is a leading cause of adverse maternal and fetal outcomes. Current clinical PE tests have a low positive predictive value for PE prediction and diagnosis. The placenta notably releases extracellular vesicles from the syncytiotrophoblast (STB-EV) into the maternal circulation.ObjectiveTo identify a difference in placenta and STB-EV proteome between PE and normal pregnancy (NP), which could lead to identifying potential biomarkers and mechanistic insights.MethodsUsing ex-vivo dual lobe perfusion, we performed mass spectrometry on placental tissue, medium/large and small STB-EVs isolated from PE (n = 6) and NP (n = 6) placentae. Bioinformatically, mass spectrometry was used to identify differentially carried proteins. Western blot was used to validate the identified biomarkers. We finished our investigation with an in-silico prediction of STB-EV mechanistic pathways.ResultsWe identified a difference in the STB-EVs proteome between PE and NP. Filamin B, collagen 17A1, pappalysin-A2, and scavenger Receptor Class B Type 1) were discovered and verified to have different abundances in PE compared to NP. In silico mechanistic prediction revealed novel mechanistic processes (such as abnormal protein metabolism) that may contribute to the clinical and pathological manifestations of PE.ConclusionsWe identified potentially mechanistic pathways and identified differentially carried proteins that may be important in the pathophysiology of PE and are worth investigating because they could be used in future studies of disease mechanisms and as biomarkers.FundingThis research was funded by the Medical Research Council (MRC Programme Grant (MR/J0033601) and the Medical & Life Sciences translational fund (BRR00142 HE01.01)
Vinorelbine causes a neuropathic pain-like state in mice via STING and MNK1 signaling associated with type I interferon induction
Authors: Franco-Enzástiga Úrzula , Natarajan Keerthana , David Eric T. , Patel Krish J. , Ravirala Abhira , Price Theodore J. 
Published: June 2023

AbstractType I interferons (IFNs) increase the excitability of dorsal root ganglion (DRG) neurons via activation of MNK-eIF4E translation signaling to promote pain sensitization in mice. Activation of STING signaling is a key component of type I IFN induction. Manipulation of STING signaling is an active area of investigation in cancer and other therapeutic areas. Vinorelbine is a chemotherapeutic that activates STING and has been shown to cause pain and neuropathy in oncology clinical trials in patients. There are conflicting reports on whether STING signaling promotes or inhibits pain in mice. We hypothesized that vinorelbine would cause a neuropathic pain-like state in mice via STING and signaling pathways in DRG neurons associated with type I IFN induction. Vinorelbine (10 mg/kg, i.v.) induced tactile allodynia and grimacing in WT male and female mice and increased p-IRF3 and type I IFN protein in peripheral nerves. In support of our hypothesis, vinorelbine-mediated pain was absent in male and female StingGt/Gtmice. Vinorelbine also failed to induce IRF3 and type I IFN signaling in these mice. Since type I IFNs engage translational control via MNK1-eIF4E in DRG nociceptors, we assessed vinorelbine-mediated p-eIF4E changes. Vinorelbine increased p-eIF4E in DRG in WT animals but not in StingGt/GtorMknk1-/-(MNK1 KO) mice. Consistent with these biochemical findings, vinorelbine had an attenuated pro-nociceptive effect in male and female MNK1 KO mice. Our findings support the conclusion that activation of STING signaling in the peripheral nervous system causes a neuropathic pain-like state that is mediated by type I IFN signaling to DRG nociceptors.
BILE ACIDS IN LOWER AIRWAYS AS A NOVEL INDICATOR OF AIRWAY MICROBIOTA CHANGES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Authors: Caparrós-Martín Jose A. , Saladié Montserrat , Agudelo-Romero S. Patricia , Nichol Kristy S. , Reen F. Jerry , Moodley Yuben , Mulrennan Siobhain , Stick Stephen M. , Wark Peter A , O’Gara Fergal 
Published: June 2023

AbstractBackgroundChronic obstructive pulmonary disease (COPD) is a complex disorder with a high degree of interindividual variability. Gastrointestinal dysfunction is common in COPD patients and has been proposed to influence the clinical progression of the disease. Using the presence of bile acid(s) (BA) in bronchoalveolar lavage fluid (BAL) as a marker of gastric aspiration, we evaluated the relationships between BAs, clinical outcomes, and bacterial lung colonisation.MethodsWe used BAL specimens from a cohort of COPD patients and healthy controls. Bile acids were profiled and quantified in BAL supernatants using mass spectrometry. Microbial DNA was extracted from BAL cell pellets and quantified using qPCR. We profiled the BAL microbiota using an amplicon sequencing approach targeting the V3-V4 region of the 16S rRNA gene.ResultsDetection of BAs in BAL was more likely at earliest clinical stages of COPD and was independent of the degree of airway obstruction. BAL specimens with BAs demonstrated higher bacterial biomass and lower diversity. Likewise, the odds of recovering bacterial cultures from BAL were higher if BAs were also detected. Detection of BAs in BAL was not associated with either inflammatory markers or clinical outcomes. We also observed different bacterial community types in BAL, which were associated with different clinical groups, levels of inflammatory markers, and the degree of airway obstruction.ConclusionDetection of BAs in BAL was associated with different parameters of airway ecology. Further studies are needed to evaluate whether BAs in BAL can be used to stratify patients and for predicting disease progression trajectories.
Testing the Feasibility, Acceptability and Effectiveness of the Problem Management Plus for Moms: Protocol of a Randomized Control Trial
Authors: Falgas-Bague Irene , Melero-Dominguez Maria , de Vernisy-Romero Daniela , Tembo Thandiwe , Chembe Mpela , Lubozha Theresa , Paul Ravi , Parkerson Doug , Rockers Peter C. , Sikazwe Dorothy , Fink Günther 
Published: June 2023

ABSTRACTBackgroundMental health disorders are one of the most common causes that limit the ability of mothers to care for themselves and their children. Recent data suggest high rates of distress among women in charge of young children in Zambia. Nevertheless, Zambia’s public healthcare offers very limited treatment for common mental health distress. To address this treatment gap, this study aims to test the feasibility, acceptability, and potential efficacy of a context-adapted psychosocial intervention.MethodsA total of 270 mothers with mental health needs (defined as SRQ-20 scores above 7) will be randomly assigned with equal probability to the intervention or control group. The intervention group will receive a locally adapted version of the Problem-Management Plus and “Thinking positively” interventions developed by the World Health Organization (WHO) combined with specific parts of the Strong Minds-Strong Communities intervention. Trained and closely supervised wellbeing-community health workers will provide the psychosocial intervention. Mental health distress and attendance to the intervention will be assessed at enrollment and 6 months after the intervention. We will estimate the impact of the intervention on mental health distress using an intention-to-treat approach.DiscussionWe previously found that there is a large necessity for interventions that aim to address mother anxiety/depression problems. In this study, we will test the feasibility and efficacy of an innovative intervention, demonstrating that implementing these mental health treatments in low-income settings, such as Zambia, is viable with an adequate support system. If successful, larger studies will be needed to test the effectiveness of the intervention with increased precision.Trial registrationThis study is registered atclinicaltrials.govasNCT05627206.https://www.clinicaltrials.gov/ct2/show/NCT05627206
Association between sleep and seroconversion after vaccination with inactivated SARS-CoV-2 in pregnant women
Authors: Han Xue , Yang Wenhan , Zhang Xi , Chen Baolan , Fu Xi , Huang Jitian , Xu Yingxia , Gong Yajie , Chen Qingsong 
Published: June 2023

AbstractTo assess the association between sleep and seroconversion after receipt of two doses of inactivated severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) vaccines in pregnant women. The serum level of immunoglobulin (Ig)G antibodies against the nucleic acids of SARS-CoV-2 was measured. Logistic regression was used to analyze the association between sleep and seroconversion. After two doses of SARS-CoV-2 vaccine, 41.2% of the study cohort reached seroconversion. Analysis revealed that pregnant women with poor quality of sleep had a lower serum level of IgG antibodies (P= 0.008, 95%CI = 0.285–0.826) and that sleeping late at night (SLaN) may be a risk factor for a low serum level of IgG antibodies (P= 0.025, 95%CI = 0.436–0.946). Besides sleep, age and the time since vaccination were important influences on seroconversion. A stratified analysis revealed that the effects of sleep quality and SLaN on seroconversion occurred mainly in pregnant women aged <35 years. Thus, sleep quality and SLaN can affect the serum level of IgG antibodies in pregnant women after vaccination with inactivated SARS-CoV-2.
An Endpoint Adjudication Committee for the Assessment of Computed Tomography Scans in Fracture Healing
Authors: Elliott Chloe , Patterson Ethan , Mattiello Brenna , Tarcea Adina , Frizzell Bevan , Walker Richard E. , Hildebrand Kevin A. , White Neil J. 
Published: June 2023

AbstractThe use of endpoint adjudication committees (EACs) has the potential to reduce subjectivity and potential bias in clinical research trials and contribute to a higher quality of research. In a recent randomized control trial (RCT), we used serial computed tomography (CT) imaging to visualize fracture healing of the scaphoid as a primary outcome. The scaphoid bone poses a challenge in the diagnosing of fractures and non-unions due to its complicated shape. An EAC was created to increase the quality of the data and the validity of our findings. While an adjudication process has long been proposed and described for X-rays, this study outlines a rational approach to CT scan adjudication for bone fracture healing. A total of 364 scans were acquired in the RCT and of these, 101 were adjudicated for a binary endpoint of union vs. non-union. The application of EACs such as described in this paper is a useful tool in orthopaedic research requiring the adjudication of fracture healing as a study outcome.
The impact of common variants on gene expression in the human brain: from RNA to protein to schizophrenia risk
Authors: Liang Qiuman , Jiang Yi , Shieh Annie W. , Zhou Dan , Chen Rui , Wang Feiran , Xu Meng , Niu Mingming , Wang Xusheng , Pinto Dalila , Wang Yue , Cheng Lijun , Vadukapuram Ramu , Zhang Chunling , Grennan Kay , Giase Gina ,   The PsychENCODE Consortium, White Kevin P , Peng Junmin , Li Bingshan , Liu Chunyu , Chen Chao , Wang Sidney H. 
Published: June 2023

AbstractBackgroundThe impact of genetic variants on gene expression has been intensely studied at the transcription level, yielding in valuable insights into the association between genes and the risk of complex disorders, such as schizophrenia (SCZ). However, the downstream impact of these variants and the molecular mechanisms connecting transcription variation to disease risk are not well understood.ResultsWe quantitated ribosome occupancy in prefrontal cortex samples of the BrainGVEX cohort. Together with transcriptomics and proteomics data from the same cohort, we performed cis-Quantitative Trait Locus (QTL) mapping and identified 3,253 expression QTLs (eQTLs), 1,344 ribosome occupancy QTLs (rQTLs), and 657 protein QTLs (pQTLs) out of 7,458 genes quantitated in all three omics types from 185 samples. Of the eQTLs identified, only 34% have their effects propagated to the protein level. Further analysis on the effect size of prefrontal cortex eQTLs identified from an independent dataset showed clear post-transcriptional attenuation of eQTL effects. To investigate the biological relevance of the attenuated eQTLs, we identified 70 expression-specific QTLs (esQTLs), 51 ribosome-occupancy-specific QTLs (rsQTLs), and 107 protein-specific QTLs (psQTLs). Five of these omics-specific QTLs showed strong colocalization with SCZ GWAS signals, three of them are esQTLs. The limited number of GWAS colocalization discoveries from omics-specific QTLs and the apparent prevalence of eQTL attenuation prompted us to take a complementary approach to investigate the functional relevance of attenuated eQTLs. Using S-PrediXcan we identified 74 SCZ risk genes, 34% of which were novel, and 67% of these risk genes were replicated in a MR-Egger test. Notably, 52 out of 74 risk genes were identified using eQTL data and 70% of these SCZ-risk-gene-driving eQTLs show little to no evidence of driving corresponding variations at the protein level.ConclusionThe effect of eQTLs on gene expression in the prefrontal cortex is commonly attenuated post-transcriptionally. Many of the attenuated eQTLs still correlate with SCZ GWAS signal. Further investigation is needed to elucidate a mechanistic link between attenuated eQTLs and SCZ disease risk.
Macrophages modulate fibrosis during newt lens regeneration
Authors: Tsissios Georgios , Sallese Anthony , Raul Perez-Estrada J. , Tangeman Jared A. , Chen Weihao , Smucker Byran , Ratvasky Sophia C. , Grajales-Esquivel Erika , Martinez Arielle , Visser Kimberly J. , Araus Alberto Joven , Wang Hui , Simon Andras , Yun Maximina H. , Del Rio-Tsonis Katia 
Published: June 2023

AbstractPrevious studies indicated that macrophages play a role during lens regeneration in newts, but their function has not been tested experimentally. Here we generated a transgenic newt reporter line in which macrophages can be visualizedin vivo. Using this new tool, we analyzed the location of macrophages during lens regeneration. We uncovered early gene expression changes using bulk RNAseq in two newt species,Notophthalmus viridescensandPleurodeles waltl. Next, we used clodronate liposomes to deplete macrophages, which inhibited lens regeneration in both newt species. Macrophage depletion induced the formation of scar-like tissue, an increased and sustained inflammatory response, an early decrease in iris pigment epithelial cell (iPEC) proliferation and a late increase in apoptosis. Some of these phenotypes persisted for at least 100 days and could be rescued by exogenous FGF2. Re-injury alleviated the effects of macrophage depletion and re-started the regeneration process. Together, our findings highlight the importance of macrophages in facilitating a pro-regenerative environment in the newt eye, helping to resolve fibrosis, modulating the overall inflammatory landscape and maintaining the proper balance of early proliferation and late apoptosis.
Mesostriatal dopamine is sensitive to specific cue-reward contingencies
Authors: Garr Eric , Cheng Yifeng , Jeong Huijeong , Brooke Sara , Castell Laia , Bal Aneesh , Magnard Robin , Namboodiri Vijay Mohan K. , Janak Patricia H. 
Published: June 2023

AbstractLearning causal relationships relies on understanding how often one event precedes another. To gain an understanding of how dopamine neuron activity and neurotransmitter release change when a retrospective relationship is degraded for a specific pair of events, we used outcome-selective Pavlovian contingency degradation in rats. Two cues were paired with distinct food rewards, one of which was also delivered in the absence of either cue. Conditioned approach was attenuated for the cue-reward contingency that was degraded. Dopamine neuron activity in the midbrain and dopamine release in the ventral striatum showed a profile of changes in cue- and reward-evoked responding that was not easily explained by a standard reinforcement learning model. An alternative model based on learning causal relationships was better able to capture evoked dopamine responses during contingency degradation, as well as conditioned behavior following optogenetic manipulations of dopamine during noncontingent rewards. Our results suggest that mesostriatal dopamine encodes the contingencies between meaningful events during learning.
Genetic basis of historical pea mutants that hyper-accumulate iron
Authors: Harrington Sophie A. , Franceschetti Marina , Balk Janneke 
Published: June 2023

AbstractThePisum sativum(pea) mutantsdegenerate leaves(dgl) andbronze(brz) accumulate large amounts of iron in leaves. First described several decades ago, the two mutants have provided important insights into iron homeostasis in plants but the underlying mutations have remained unknown. Using exome sequencing we identified an in-frame deletion associated withdglin aBRUTUShomologue. The deletion is absent from wild type and the original parent line. BRUTUS belongs to a small family of E3 ubiquitin ligases acting as negative regulators of iron uptake in plants. Thebrzmutation was previously mapped to chromosome 4, and superimposing this region to the pea genome sequence uncovered a mutation inOPT3, encoding an oligopeptide transporter with a plant-specific role in metal transport. The causal nature of the mutations was confirmed by additional genetic analyses. Identification of the mutated genes rationalises many of the previously described phenotypes and provides new insights into shoot-to-root signalling of iron deficiency. Furthermore, the non-lethal mutations in these essential genes suggest new strategies for biofortification of crops with iron.Significance statementTwo iron-accumulating pea mutants first described more than 30 years ago have greatly contributed to our understanding of iron homeostasis in plants, but the mutations were never identified. Here we show that the phenotypes are caused by mutations in theBRUTUSandOPT3genes and how this leads to specific defects in iron signalling and leaf development.