bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive genetic analysis of the human lipidome identifies novel loci controlling lipid homeostasis with links to coronary artery disease
Authors: Cadby Gemma , Giles Corey , Melton Phillip E , Huynh Kevin , Mellett Natalie A , Duong Thy , Nguyen Anh , Cinel Michelle , Smith Alex , Olshansky Gavriel , Wang Tingting , Brozynska Marta , Inouye Mike , McCarthy Nina S , Ariff Amir , Hung Joseph , Hui Jennie , Beilby John , Dubé Marie-Pierre , Watts Gerald F , Shah Sonia , Wray Naomi R , Lim Wei Ling Florence , Chatterjee Pratishtha , Martins Ian , Laws Simon M , Porter Tenielle , Vacher Michael , Bush Ashley I , Rowe Christopher C , Villemagne Victor L , Ames David , Masters Colin L , Taddei Kevin , Arnold Matthias , Kastenmüller Gabi , Nho Kwangsik , Saykin Andrew J , Han Xianlin , Kaddurah-Daouk Rima , Martins Ralph N , Blangero John , Meikle Peter J , Moses Eric K 
Published: August 2021

AbstractWe integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species that are putatively in the mechanistic pathway to coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 phenotyped individuals from the Busselton Health Study. In our discovery GWAS we identified 667 independent loci associations with these lipid species (479 novel), followed by meta-analysis and validation in two independent cohorts. Lipid endophenotypes (134) identified for CAD were associated with variation at 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P<1×10−3), 43 loci were associated with at least one of the 134 lipid endophenotypes. The findings of this study illustrate the value of integrative biology to investigate the genetics and lipid metabolism in the aetiology of atherosclerosis and CAD, with implications for other complex diseases.
A multidimensional Mendelian randomization study on the impact of gut dysbiosis on chronic diseases and human longevity
Authors: Gagnon Éloi , Mitchell Patricia L. , Manikpurage Hasanga , Abner Erik , Taba Nele , Esko Tõnu , Ghodsian Nooshin , Thériault Sébastien , Mathieu Patrick , Arsenault Benoit J. 
Published: August 2021

AbstractAlterations of the gut microbiota, often referred to as gut dysbiosis, have been associated with several chronic diseases and longevity in pre-clinical models as well as in observational studies. Whether these relationships underlie causal associations in humans remains to be established. We aimed to determine whether gut dysbiosis influences the risk of chronic diseases and longevity using a comprehensive 2-Sample Mendelian randomization (2SMR) approach. We included as exposures inflammatory bowel disease (IBD) as a human model of gut dysbiosis, 11 gut-associated metabolites and pathways and 48 microbial taxa. Study outcomes included eight chronic diseases previously linked with gut dysbiosis using observational studies (Alzheimer’s disease, depression, type 2 diabetes, non-alcoholic fatty liver disease, coronary artery disease (CAD), stroke, osteoporosis and chronic kidney disease) as well as parental longevity and life expectancy. Neither IBD, nor gut-associated metabolites were causally associated with chronic disease or lifespan. After multiple testing correction for 582 tests, no microbial taxa-chronic disease associations remained significant. After robustness analyses and multivariate MR to correct for body mass index and alcohol intake on all 42 nominally significant causal relationships, four associations remained. Altogether, results of this multidimensional Mendelian randomization study suggest that gut dysbiosis has little impact on chronic diseases and human longevity and that previous documented associations may not underly causal relationships. Studies with larger sample sizes and more optimal taxonomic discrimination may ultimately be required to determine whether the human gut microbiota plays a causal role in the etiology of chronic diseases and longevity.
A composite biomarker for esophageal cancer risk from automated analysis of a non-endoscopic device
Authors: Berman Adam G. , Fitzgerald Rebecca C. , Markowetz Florian 
Published: August 2021

AbstractBarrett’s esophagus containing intestinal metaplasia predisposes to cancer, yet the majority of cases are undiagnosed. The length of a Barrett’s segment is a key indicator of cancer risk, but measuring it has so far relied on endoscopy, which is expensive and invasive. Cytosponge-TFF3 is a minimally-invasive test that identifies intestinal metaplasia for endoscopic confirmation. We report a machine learning technique to quantify the extent of intestinal metaplasia and predict Barrett’s segment length from whole-slide image tile counts automatically generated from Cytosponge-TFF3 histology slides. Utilizing data from 529 patients, our segment length prediction model achieves an average validation fold accuracy of 0.84. Applying this algorithm to an independent test set of 162 patients from a screening trial shows a precision of 0.90 for identifying short-segment disease. This advance will enable higher-risk patients to be prioritized for endoscopy while saving more than half of Cytosponge-TFF3-positive patients from endoscopy in the screening setting.
COVID-19 and Vitamin D (Co-VIVID Study): a systematic review and meta-analysis of randomized controlled trials
Authors: Varikasuvu Seshadri Reddy , Thangappazham Balachandar , Raj Hemanth 
Published: August 2021

AbstractBackgroundVitamin D levels have been reported to be associated with COVID-19 susceptibility, severity and mortality events.. We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the use of vitamin D intervention on COVID-19 outcomes.MethodsLiterature search was conducted using PubMed, Cochrane library, and ClinicalTrials.gov databases (latest search on August 5, 2021). We included RCTs reporting the use of vitamin D intervention to control/placebo group in COVID-19. Two independent researchers did literature search, abstracted data, and the risk of bias assessment.ResultsA total of 6 RCTs with 551 COVID-19 patients were included. The overall collective evidence pooling all the outcomes across all RCTs indicated the beneficial use of vitamin D intervention in COVID-19 (relative risk, RR = 0.60, 95% CI 0.40 to 0.92, Z=2.33, p=0.02, I2 = 48%). However, no statistical significance was observed for individual outcomes of ICU care (RR = 0.11, 95% CI 0.15 to 1.30, Z=1.48, p=0.14, I2 = 66%) and mortality (RR = 0.78, 95% CI 0.25 to 2.40, Z=0.66, p=0.02, I2 = 33%), though decreased rates were noted. The rates of RT-CR positivity was significantly decreased in the intervention group as compared to the non-vitamin D groups (RR = 0.46, 95% CI 0.24 to 0.89, Z=2.31, p=0.02, I2 = 0%).ConclusionCOVID-19 patients supplemented with vitamin D are more likely to demonstrate fewer rates of ICU admission, mortality events and RT-PCR positivity. However, no statistical significance has been achieved for individual outcomes of ICU and deaths. More RCTs and completion of ongoing trials largely needed to precisely establish the association between vitamin D use and COVID-19.
A Lagrangian Approach Towards Quantitative Analysis Of Flow-mediated Infection Transmission In Indoor Spaces With Application To SARS-COV-2
Authors: Wilson Joseph , Miller Shelly L. , Mukherjee Debanjan 
Published: August 2021

AbstractThe ongoing SARS-CoV-2 (Covid-19) pandemic has ushered an unforeseen level of global health and economic burden. As a respiratory infection, Covid-19 is known to have a dominant airborne transmission modality, wherein fluid flow plays a central role. Quantification of complex non-intuitive dynamics and transport of pathogen laden respiratory particles in indoor flows has been of specific interest. Here we present a Lagrangian computational approach towards quantification of human-to-human exposure quantifiers, and identification of pathways by which flow organizes transmission. We develop a Lagrangian viral exposure index in a parametric form, accounting for key parameters such as building and layout, ventilation, occupancy, biological variables. We also employ a Lagrangian computation of the Finite Time Lyapunov Exponent field to identify hidden patterns of transport. A systematic parametric study comprising a set of 120 simulations, yielding a total of 1,320 different exposure index computations are presented. Results from these simulations enable: (a) understanding the otherwise hidden ways in which air flow organizes the long-range transport of such particles; and (b) translating the micro-particle transport data into a quantifier for understanding infection exposure risks.
A conformational variant of p53 (U-p53AZ) as blood-based biomarker for the prediction of the onset of symptomatic Alzheimer’s disease
Authors: Piccirella Simona , Van Neste Leander , Fowler Christopher , Masters Colin L , Fripp Jurgen , Doecke James D. , Xiong Chengjie , Uberti Daniela , Kinnon Paul 
Published: August 2021

AbstractBackgroundOngoing research seeks to identify blood-based biomarkers able to predict the onset and progression of Alzheimer’s disease (AD). A potential biomarker is the unfolded conformational variant of p53, previously observed in individuals in the prodromal and clinical AD stages. In this retrospective study, we compare diagnostic and prognostic performances of measures of the amyloid β load with those of a conformational variant of U-p53 in plasma samples from individuals participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort.MethodsImmunoprecipitation (IP) followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS) and protein sequencing in plasma samples from the AIBL study identified the clinically relevant AZ 284®peptide, representing a measure of the U-p53 conformational variant (U-p53AZ). Based on U-p53AZquantification via IP/LC electrospray ionisation-coupled MS/MS (AlzoSure®Predict test) on 515 samples from 482 individuals from the AIBL cohort, the predictive performance of U-p53AZwas assessed and compared with amyloid load as measured by amyloid β-positron emission tomography (Aβ-PET). Its predictive performance was determined at 36, 54, 72 and 90 months following baseline assessment.ResultsU-p53AZwas able to identify individuals with AD dementia with an area under the receiver operating characteristic curve (AUC) of 99%. U-p53AZoutperformed the conventional Aβ-PET measures in predicting the onset of AD dementia both from preclinical (AUC=98%) and prodromal stages (AUC=89%), even 90 months prior to onset (AUC=99%). Additionally, the estimated predictive performance of U-p53AZwas superior (AUC ≥98%) to other risk factors (i.e., gender, Aβ-PET andAPOEε4 allele status) in identifying individuals at high risk for progression to AD.ConclusionThese findings support use of U-p53AZas blood-based biomarker predicting if individuals, at both asymptomatic and MCI stages, would progress to AD at least six years prior to the onset of clinical AD dementia.
Loss of nucleoporin Nup50 is a risk factor for amyotrophic lateral sclerosis
Authors: Megat Salim , Mora Natalia , Sanogo Jason , Catanese Alberto , Alami Najwa Ouali , Freischmidt Axel , Mingaj Xhuljana , de Calbiac Hortense , Muratet François , Dirrig-Grosch Sylvie , Dieterle Stéphane , Van Bakel Nick , Müller Kathrin , Sieverding Kirsten , Weishaupt Jochen , Andersen Peter Munch , Weber Markus , Neuwirth Christoph , Margelisch Markus , Sommacal Andreas , van Eijk Kristel R. , Veldink Jan H ,   Project Mine ALS sequencing consortium, Lautrette Géraldine , Couratier Philippe , Boeckers Tobias , Ludolph Albert C. , Roselli Francesco , Yilmazer-Hanke Deniz , Millecamps Stéphanie , Kabashi Edor , Storkebaum Erik , Sellier Chantal , Dupuis Luc 
Published: August 2021

AbstractThe genetic basis of amyotrophic lateral sclerosis (ALS) is still incompletely understood. Using two independent genetic strategies, we show here that a large part of ALS heritability lies in genes expressed in inhibitory and excitatory neurons, especially at splicing sites regulated by a defined set of RNA binding proteins including TDP-43 and FUS. We conducted a transcriptome wide association study (TWAS) and identified 59 loci associated with ALS, including 14 previously identified genes, some of them not previously reaching significance in genome wide association studies. Among the 45 novel genes, several genes are involved in pathways known to be affected in ALS such as mitochondrial metabolism (including ATP5H, ATP5D, BCS1L), proteostasis (including COPS7A, G2E3, TMEM175, USP35) or gene expression and RNA metabolism (including ARID1B, ATXN3, PTBP2, TAF10). Interestingly, decreased expression of NUP50, a constrained gene encoding a nuclear pore basket protein, was associated with ALS in TWAS (Zscore = −4, FDR = 0.034). 11 potentially pathogenic variants (CADD score > 20) in 23 patients were identified in the NUP50 gene, most of them in the region of the protein mediating interaction with Importin alpha, and including 2 frameshift mutations. In cells from two patients carrying NUP50 variants, we showed decreased levels of NUP50 protein. Importantly, knocking down Nup50 led to increased neuronal death associated with p62 and nucleoporin inclusions in cultured neurons, and motor defects in Drosophila and zebrafish models. In all, our study identifies alterations in splicing in neurons as a critical pathogenic process in ALS, uncovers several new loci potentially contributing to ALS missing heritability, and provides genetic evidence linking nuclear pore defects to ALS.
Cost-effectiveness of internet-delivered cognitive behaviour therapy for body dysmorphic disorder: results from a randomised controlled trial
Authors: Flygare Oskar , Andersson Erik , Glimsdal Gjermund , Mataix-Cols David , Djurfeldt Diana , Rück Christian , Enander Jesper 
Published: August 2021

AbstractObjectivesTo evaluate the cost-effectiveness of internet-delivered cognitive behaviour therapy for body dysmorphic disorder (BDD-NET).DesignSecondary cost-effectiveness analysis from a randomised controlled trial on BDD-NET versus online supportive psychotherapy.SettingAcademic medical centre.ParticipantsSelf-referred adult patients with a primary diagnosis of body dysmorphic disorder and a score of 20 or higher on the modified Yale-Brown obsessive compulsive scale (n = 94). Patients receiving concurrent psychotropic drug treatment were included if the dose had been stable for at least two months and remained unchanged during the trial.InterventionsParticipants received either BDD-NET (n = 47) or online supportive psychotherapy (n = 47) for 12 weeks.Primary and secondary outcome measuresThe primary outcome measures were cost-effectiveness and cost-utility from a societal perspective, using remission status from a diagnostic interview and quality-adjusted life years from EQ-5D, respectively. Secondary outcome measures were cost-effectiveness and cost-utility from a health care perspective and the clinic’s perspective.ResultsCompared to supportive psychotherapy, BDD-NET produced one additional remission for an average societal cost of $4132. The cost-utility analysis showed that BDD-NET generated one additional QALY to an average cost of $14319 from a societal perspective.ConclusionsBDD-NET is a cost-effective treatment for body dysmorphic disorder, compared to online supportive psychotherapy. The efficacy and cost-effectiveness of BDD-NET should be directly compared to face-to-face cognitive behaviour therapy.Trial registrationNCT02010619Strengths and limitations of this studyThis is the first cost-effectiveness evaluation of a novel internet-delivered treatment designed to increase access to cognitive behaviour therapy for patients with body dysmorphic disorderCost estimations were self-rated and might not capture all costs associated with treatmentThe self-referred participants were likely motivated to undergo treatment.
Asymmetric depth-filtration – a versatile and scalable approach for isolation and purification of extracellular vesicles
Authors: Chernyshev Vasiliy S. , Chuprov-Netochin Roman N. , Tsydenzhapova Ekaterina , Svirshchevskaya Elena V. , Poltavtseva Rimma A. , Merdalimova Anastasiia , Yashchenok Alexey , Keshelava Amiran , Sorokin Konstantin , Keshelava Varlam , Sukhikh Gennadiy T. , Gorin Dmitry , Leonov Sergey , Skliar Mikhail 
Published: August 2021

AbstractA novel asymmetric depth filtration (DF) approach for isolation of extracellular vesicles (EVs) from biological fluids is presented, and its performance is compared with established methods. The developed workflow is simple, inexpensive, and relatively fast. Compared with ultracentrifugation and size-exclusion chromatography, the developed method isolates EVs with higher purity and yield. Only standard laboratory equipment is needed for its implementation, which makes it suitable for low-resource locations. The described implementation of the method is suitable for EV isolation from small biological samples in diagnostic and treatment guidance applications. Following the scale-up routes adopted in the biomanufacturing of therapeutics, which routinely rely on DF as one of the product purification steps, the developed method may be scaled up to harvesting therapeutic EVs from large volumes of growth medium.
Spectral fiber-photometry derives hemoglobin concentration changes for accurate measurement of fluorescent sensor activity
Authors: Zhang Wei-Ting , Chao Tzu-Hao Harry , Yang Yue , Wang Tzu-Wen , Lee Sung-Ho , Oyarzabal Esteban A. , Zhou Jingheng , Nonneman Randy , Pegard Nicolas C. , Zhu Hongtu , Cui Guohong , Shih Yen-Yu Ian 
Published: August 2021

SummaryFiber-photometry is an emerging technique for recording fluorescent sensor activity in the brain. However, significant hemoglobin-absorption artifacts in fiber-photometry data may be misinterpreted as sensor activity changes. Because hemoglobin exists in nearly every location in the brain and its concentration varies over time, such artifacts could impede the accuracy of many photometry recording results. Here we present a novel use of spectral photometry technique and propose computational methods to quantify photon absorption effects by using activity-independent fluorescence signals, which can be used to derive oxy- and deoxy-hemoglobin concentration changes. Following time-locked neuronal activationin vivo, we observed that a 20% increase in CBV contributes to about a 4% decrease in green fluorescence signal and a 2% decrease in red fluorescence signal. While these hemoglobin concentration changes are often temporally delayed than the fast-responding fluorescence spikes, we found that erroneous interpretation may occur when examining pharmacology-induced sustained activity changes, and in some cases, hemoglobin-absorption could flip the GCaMP signal polarity. We provided hemoglobin-based correction methods to restore fluorescence signals across spectra and compare our results against the commonly used regression approach. We also demonstrated the utility of spectral fiber-photometry for delineating brain regional differences in hemodynamic response functions.HighlightsHemoglobin-absorption compromises fiber-photometry recordingin vivoSpectral photometry allows quantification of hemoglobin concentration changes for correctionThe proposed platform allows measuring regional differences in neurovascular transfer function
Engineering a dynamic, controllable infectivity switch in bacteriophage T7
Authors: Chitboonthavisuk Chutikarn , Luo Chun Huai , Huss Phil , Fernholz Mikayla , Raman Srivatsan 
Published: August 2021

AbstractTranscriptional repressors play an important role in regulating phage genomes. Here, we examined how synthetic regulation based on repressors can be to create a dynamic, controllable infectivity switch in bacteriophage T7. We engineered T7 by replacing a large region of the early phage genome with combinations of ligand-responsive promoters and ribosome binding sites (RBS) designed to control the phage RNA polymerase. Phages with the engineered switch showed virulence comparable to wildtype when not repressed, indicating the phage can be engineered without a loss of fitness. When repressed, the most effective switch used a TetR promoter and a weak RBS, resulting in a two-fold increase in latent period (time to lyse host) and change in phage titer. Further, phage activity could be tuned by varying inducer concentrations. Our study provides a proof of concept for a simple circuit for user control over phage infectivity.
Information Flow in the Fibroblast Growth Factor Receptor Communication Channel
Authors: Díaz José , Martínez-Mekler Gustavo 
Published: August 2021

AbstractIn this work we analyze the flow of information through the Fibroblast Growth Factor Receptor (FGFR) communication channel when different types of signals are transmitted by the MAPK cascade to the gene regulatory network (GRN) formed by the genes C-Myc, DUSP, and Cdc25A, which control fibroblast proliferation. We used the canonical mathematical model of the MAPK cascade coupled to a stochastic model for the activation of the gene regulatory network, subject to different types of FGF inputs (step, quadratic pulses, Dirac delta, and white noise), in order to analyze the response of the gene regulatory network to each type of signal, and determine the temporal variation of the value of its Shannon entropy in each case. Our model suggests that the sustained activation of the FGFR communication channel with a step of FGF > 1 nM is required for cell cycle progression and that during the G1/S transition the amount of uncertainty of the GRN remains at a steady value of ∼ 2.75 bits, indicating that while the fibroblast stimulation with FGF continues the G1/S transition does not require an additional interchange of information between the emitter and the gene regulatory network to be completed. We also found that either low frequency pulses of FGF or low frequency noise, both with a frequency f ≤ 2.77 Hz, are not filtered by the MAPK cascade and can modify the output of the communication channel, i.e., the amount of the effector proteins c-myc, cdc25A and DUSP. An additional effect suggested by our model is that o low frequency periodic signals and noise possibly blockage cell cycle progression because the threshold value concentration of cdc25A for the G1/S transition is not sustained in the in the nucleus during the 10 hours that this process lasts. Finally, from our model we can estimate the capacity of this communication channel in 0.96 bits/min.