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| Open AccessZSP1601, a novel pan-phosphodiesterase inhibitor for the treatment of NAFLD, A randomized, placebo-controlled phase Ib/IIa trial
Non-alcoholic fatty liver disease is a growing health burden with limited treatment options worldwide. Herein the authors report a randomized, double-blind, placebo-controlled, multiple-dose trial of a first-in-class pan-phosphodiesterase inhibitor ZSP1601 in NAFLD patients.
- Yue Hu
- , Haijun Li
- & Yanhua Ding
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Article
| Open AccessFertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model
Successful engraftment of human hematopoietic stem cells during gene therapy requires myeloablative conditioning of the recipient, at the expense of toxicity. Authors show here that a single-dose of anti-CD117 antibody-drug conjugate achieves similar engraftment results as traditional multi-dose busulfan conditioning but preserves fertility in a non-human primate model.
- Naoya Uchida
- , Ulana Stasula
- & John F. Tisdale
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Article
| Open AccessClinically relevant atovaquone-resistant human malaria parasites fail to transmit by mosquito
Malaria parasites from patients who fail atovaquone therapies are highly drug-resistant, with mutations at Y268 in cytochrome b. Here the authors show that this mutation results in multiple defects in the parasite’s development and prevents transmission from mosquitoes to mice.
- Victoria A. Balta
- , Deborah Stiffler
- & Theresa A. Shapiro
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| Open AccessProteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis
Myelofibrosis is a form of myeloproliferative neoplasm with few treatment options available. Here, the authors profiled drug responses and proteomics ex vivo and identify molecularly-guided treatment strategies, including HDAC and BET inhibitors for CALR mutant myelofibrosis patients.
- Mattheus H. E. Wildschut
- , Julien Mena
- & Berend Snijder
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| Open AccessPerinatal murine cytomegalovirus infection reshapes the transcriptional profile and functionality of NK cells
Early life infections are known to impact and modulate the immune response in later life. Here the authors show that perinatal infection with murine cytomegalovirus results in a modified transcriptional profile and functionality in murine NK cells.
- Carmen Rožmanić
- , Berislav Lisnić
- & Ilija Brizić
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Article
| Open AccessProteomics of CKD progression in the chronic renal insufficiency cohort
Progression of chronic kidney disease may lead to kidney failure and cardiovascular, metabolic and bone disease complications. Here, the authors conduct a large-scale proteomic study in patients with chronic kidney disease, identify numerous proteins that predict kidney failure, some of which are likely causal mediators and hence potential therapeutic targets.
- Ruth F. Dubin
- , Rajat Deo
- & Peter Ganz
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Article
| Open AccessThe Personalized Nutrition Study (POINTS): evaluation of a genetically informed weight loss approach, a Randomized Clinical Trial
Genotype patterns may modify diet effects on weight loss, with greater weight loss on genotype-concordant diets. Here, the authors show that with the current ability to genotype participants as fat- or carbohydrate-responders, evidence does not support greater weight loss on genotype-concordant diets.
- Christoph Höchsmann
- , Shengping Yang
- & Corby K. Martin
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Article
| Open AccessIn vivo noninvasive systemic myography of acute systemic vasoactivity in female pregnant mice
The assessment of selective therapeutics targeted to treat altered vasoactivity, a major characteristic of cardiovascular and oncological diseases, is still challenging due to unknown whole-body selectivity. Here the authors demonstrate that photoacoustic tomography has the potential to capture significant acute vasodilation of major arteries and vasculature selectivity.
- Kristie Huda
- , Dylan J. Lawrence
- & Carolyn L. Bayer
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Article
| Open AccessDalpiciclib and pyrotinib in women with HER2-positive advanced breast cancer: a single-arm phase II trial
Dalpiciclib is a CDK4/6 inhibitor, recently approved for treatment in advanced breast cancer patients in China. Here, the authors report the results of a phase II trial investigating oral dalpiciclib (CDK4/6 inhibitor) and pyrotinib (pan-HER inhibitor) in patients with HER2-positive metastatic breast cancer.
- Min Yan
- , Limin Niu
- & Huajun Li
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| Open AccessA hybrid register and questionnaire study of Covid-19 and post-acute sick leave in Denmark
Authors utilise a questionnaire-based approach to survey self-reported, post-acute sick leave and risk factors in cases of SARS-CoV-2.
- Elisabeth O’Regan
- , Ingrid Bech Svalgaard
- & Anders Hviid
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Article
| Open AccessImmunosuppression causes dynamic changes in expression QTLs in psoriatic skin
Psoriasis is a chronic, systemic inflammatory condition primarily affecting skin. Here, the authors investigate the genetic basis of gene expression in skin biopsies from psoriasis patients and interactions with inflammation to better understand mechanisms of the disease.
- Qian Xiao
- , Joseph Mears
- & Soumya Raychaudhuri
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Article
| Open AccessHuman cellular model systems of β-thalassemia enable in-depth analysis of disease phenotype
β-thalassemia is a prevalent genetic disorder causing severe anemia, with study of the underlying molecular defects impeded by paucity of suitable patient material. Here, the authors show that cellular model systems of βthalassemia can be used to identify new therapeutic targets and as screening platforms for new drugs and reagents.
- Deborah E. Daniels
- , Ivan Ferrer-Vicens
- & Jan Frayne
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Article
| Open AccessInjectable and biodegradable piezoelectric hydrogel for osteoarthritis treatment
The use of biomaterial scaffolds-based cartilage grafts could potentially innovate the Osteoarthritis (OA) treatment, but has been limited by toxicity concerns and invasive surgical procedures. Here, the authors report an injectable and biodegradable piezoelectric hydrogel with ultrasound activation to offer a minimally invasive approach for OA treatment.
- Tra Vinikoor
- , Godwin K. Dzidotor
- & Thanh D. Nguyen
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| Open AccessGlobal burden of disease due to rifampicin-resistant tuberculosis: a mathematical modeling analysis
Rifampicin-resistant tuberculosis (RR-TB) requires longer, more toxic therapy than rifampicin-sensitive disease and is associated with a higher occurrence of long-term sequelae. In this mathematical modeling study, the authors estimate that incident RR-TB in 2020 will be responsible for ~6.9 million disability-adjusted life years; 44% due to post-tuberculosis sequelae.
- Nicolas A. Menzies
- , Brian W. Allwood
- & Ted Cohen
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Article
| Open AccessSugar-sweetened beverage intakes among adults between 1990 and 2018 in 185 countries
Recent estimates of sugar-sweetened beverages (SSBs) intake are generally unavailable. Here the authors show a global SSBs intake of 2.7 servings/week in 2018 in adults (range: 0.7 South Asia, 7.8 Latin America/Caribbean); intakes were higher among males, younger, more educated, and urban adults.
- Laura Lara-Castor
- , Renata Micha
- & Rubina Hakeem
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Article
| Open AccessUncovering the complex relationship between balding, testosterone and skin cancers in men
Male-pattern baldness (MPB) is related to dysregulation of androgens. Here, authors show that MPB (but not androgens) is associated with skin cancer risk, particularly in the scalp region, suggesting that sun exposure, rather than androgens, is the main driver.
- Jue-Sheng Ong
- , Mathias Seviiri
- & Matthew H. Law
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Article
| Open AccessSelf-sampling monkeypox virus testing in high-risk populations, asymptomatic or with unrecognized Mpox, in Spain
The monkeypox outbreak in 2022 was of global concern. Here the authors present results from an observational study providing self-sampling testing to a high-risk population in a community center in Spain and diagnose monkeypox infection in asymptomatic individuals.
- Cristina Agustí
- , Héctor Martínez-Riveros
- & Jordi Casabona
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Article
| Open AccessHypersensitive MR angiography based on interlocking stratagem for diagnosis of cardiac-cerebral vascular diseases
Current contrast-enhanced magnetic resonance angiography approaches are sub-optimal. Here the authors present a hypersensitive MR angiography strategy based on interlocking stratagem of zwitterionic Gd-chelate contrast agents (PAA-Gd), enabling sophisticated micro-vessel angiography of cardiac-cerebrovascular diseases with ultrahigh resolution.
- Peisen Zhang
- , Junwei Cheng
- & Yi Hou
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Article
| Open AccessDeleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality
Mitochondrial DNA is known to exhibit heterogeneity of variants, even within a single cell. Here, the authors assessed this heteroplasmy of mitochondrial DNA within the UK Biobank cohort and showed that the presence of heteroplasmy and a functional score generated from heteroplasmic SNVs were associated with all-cause mortality and certain cancers.
- Yun Soo Hong
- , Stephanie L. Battle
- & Dan E. Arking
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Article
| Open AccessGenome-wide association studies and cross-population meta-analyses investigating short and long sleep duration
Here, the authors investigate the genetic basis of short ( ≤ 5 h) and long ( ≥ 10 h) sleep duration, identifying 84 independent significant risk loci for short sleep and 1 locus for long sleep, and causal associations between sleep and psychiatric traits.
- Isabelle Austin-Zimmerman
- , Daniel F. Levey
- & Joel Gelernter
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Article
| Open AccessLung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis
Idiopathic pulmonary fibrosis has been associated with aberrant expansion of KRT5-expressing basal cells. Here the authors show how changes in the ECM glycoprotein SPARC restrict the movement of KRT5+ cells, affecting their retention within fibrotic tissue.
- Richard J. Hewitt
- , Franz Puttur
- & Clare M. Lloyd
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Article
| Open AccessMultimodal analysis of cell-free DNA whole-methylome sequencing for cancer detection and localization
cfDNA is a promising tool to detect early cancer, however, it has been limited by detection limits and technological ability. Here, the authors develop a method for simultaneous cfDNA methylation, fragmentation and copy number alteration sequencing and apply to a cohort of healthy and cancer patients.
- Fenglong Bie
- , Zhijie Wang
- & Shugeng Gao
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Article
| Open AccessLarge-scale capture of hidden fluorescent labels for training generalizable markerless motion capture models
Deep learning-based models for tracking behavior are often constrained by manual annotation. Here, authors present GlowTrack, an approach using fluorescence to generate large and diverse training sets that improve model robustness and tracking coverage.
- Daniel J. Butler
- , Alexander P. Keim
- & Eiman Azim
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Article
| Open AccessBifidobacteria shape antimicrobial T-helper cell responses during infancy and adulthood
The human immune system changes with age which impacts pathogen clearance. Here, Vogel et al. probe how CD4 + T-cells from different age groups respond to bacteria and show that activation with staphylococcal antigen induces T cells to become Th1-like cells, whilst stimulation with Bifidobacterium infantis induces a regulatory phenotype.
- Katrin Vogel
- , Aditya Arra
- & Monika C. Brunner-Weinzierl
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Article
| Open AccessCamel nanobody-based B7-H3 CAR-T cells show high efficacy against large solid tumours
Chimeric antigen receptor T (CAR-T) cells represent an emerging form of immune therapy but success, especially in solid tumors, is limited by the scarcity of suitable target epitopes. Here authors show that a distinct epitope motif on the transmembrane protein B7-H3, recognized by a camel nanobody, triggers robust activation and anti-tumor function in cognate CAR-T cells.
- Dan Li
- , Ruixue Wang
- & Mitchell Ho
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Article
| Open AccessGenotypic diversity and unrecognized antifungal resistance among populations of Candida glabrata from positive blood cultures
Candida glabrata bloodstream infections are thought to be mostly caused by a single strain. Here, the authors describe genotypic and phenotypic diversity of Candida glabrata in ten individual blood cultures, and find diversity in drug susceptibility and virulence within patients.
- Hassan Badrane
- , Shaoji Cheng
- & M. Hong Nguyen
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Article
| Open AccessDecoding the endometrial niche of Asherman’s Syndrome at single-cell resolution
Asherman’s Syndrome is characterized by intrauterine scarring and infertility. Here, the authors decode the Asherman’s Syndrome endometrial cell niche by single-cell RNA sequencing and in vitro analyses of patient-derived endometrial organoids.
- Xavier Santamaria
- , Beatriz Roson
- & Carlos Simon
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Article
| Open AccessmRNA vaccine quality analysis using RNA sequencing
mRNA vaccines must be rigorously analysed to measure their integrity and detect contaminants, which can be time-consuming and costly. Here, authors describe a method to analyse mRNA vaccine quality using long-read sequencing and a custom bioinformatic pipeline.
- Helen M. Gunter
- , Senel Idrisoglu
- & Tim R. Mercer
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Article
| Open AccessSocial and psychological adversity are associated with distinct mother and infant gut microbiome variations
Here, in a cohort of mother-child dyads, the authors show that maternal prenatal social disadvantage and psychosocial stressors associate with distinct gut microbiome taxonomic and functional diversity in both the mothers and their four-month children.
- Barbara B. Warner
- , Bruce A. Rosa
- & Makedonka Mitreva
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| Open AccessBreastfeeding and impact on childhood hospital admissions: a nationwide birth cohort in South Korea
Benefits of breastfeeding are well established, but a comprehensive study about its impacts on hospitalizations is lacking. Here, the authors use Korean nationwide birth cohort data (n = 1,608,540) and find that breastfeeding for at least 6 months was associated with a lower risk for subsequent hospital admissions.
- Jeong-Seon Lee
- , Jae Il Shin
- & Dong Keon Yon
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Article
| Open AccessGenetic reversal of the globin switch concurrently modulates both fetal and sickle hemoglobin and reduces red cell sickling
The authors report in full the primary endpoint data of a pilot clinical trial (NCT 03282656) that used post-transcriptional gene silencing of BCL11A expression to reverse the fetal to adult hemoglobin switch in sickle cell disease. They develop new single-cell flow cytometry and microfluidic techniques to predict the efficacy of HbF induction and show that red blood cells from these patients exhibit greater resistance to deoxygenation-induced polymerization than red blood cells from hydroxyurea-responsive patients.
- Daniel C. De Souza
- , Nicolas Hebert
- & John M. Higgins
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Article
| Open AccessPredictors of the post-COVID condition following mild SARS-CoV-2 infection
In this study, the authors investigate the incidence and risk factors for post-COVID condition among people who had a mild initial SARS-CoV-2 infection in Norway. They use national linked registry data including ~215,000 individuals with a positive SARS-CoV-2 test who were not hospitalised and followed them up for 180 days after infection.
- B-A. Reme
- , J. Gjesvik
- & K. Magnusson
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| Open AccessTranslating genomic tools to Raman spectroscopy analysis enables high-dimensional tissue characterization on molecular resolution
Spatial transcriptomics of histological sections have revolutionized basic research, while the actual biomolecular composition of the sample has fallen behind. Here, the authors propose a novel approach to analyze untargeted spatiomolecular Raman spectroscopy data through bioinformatic tools developed for transcriptomic analyses, and integrate them with additional Omics techniques.
- Manuel Sigle
- , Anne-Katrin Rohlfing
- & Meinrad Paul Gawaz
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| Open AccessA comparative study of postnatal anthropometric growth in very preterm infants and intrauterine growth
The majority of growth references for preterm infants were assumed to reflect intrauterine growth. Here, the authors identify postnatal growth patterns of very preterm infants that are distinctly different than intrauterine growth.
- Fu-Sheng Chou
- , Hung-Wen Yeh
- & Reese H. Clark
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Article
| Open AccessPlasma metabolomic profiles associated with mortality and longevity in a prospective analysis of 13,512 individuals
The metabolic alterations underpinning aging processes and mortality in humans are not well understood. Here, the authors show that differences in levels of nucleosides, amino acids, and several lipid subclasses can predict mortality and longevity.
- Fenglei Wang
- , Anne-Julie Tessier
- & Marta Guasch-Ferré
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| Open AccessShared and distinct genetic etiologies for different types of clonal hematopoiesis
Types of clonal hematopoiesis (CH) differ in frequency and fitness. These findings uncover shared genetic architecture, suggest evolutionary trade-offs between CH types, and detail elevated leukemia risk in individuals with overlapping types of CH.
- Derek W. Brown
- , Liam D. Cato
- & Mitchell J. Machiela
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Article
| Open AccessExosomal circEZH2_005, an intestinal injury biomarker, alleviates intestinal ischemia/reperfusion injury by mediating Gprc5a signaling
Currently, intestinal ischemia/reperfusion injury lacks ideal diagnostic markers and effective therapeutic targets. Here, the authors show exosomal circEZH2_005 is an intestinal injury biomarker and protects the intestine from ischemia/reperfusion injury by promoting crypt cell proliferation via affecting hnRNPA1- mediated Gprc5a stability.
- Wenjuan Zhang
- , Bowei Zhou
- & Ke-Xuan Liu
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Article
| Open AccessHyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling
Nonalcoholic fatty liver disease (NAFLD) is often linked to disrupted bile acid homeostasis. Here, the authors show hyodeoxycholic acid (HDCA) ameliorates nonalcoholic fatty liver disease by inhibiting the formation of RAN/CRM1/PPARα nuclear export heterotrimer, resulting in increased nuclear localization of PPARα and activated fatty acid oxidation.
- Jing Zhong
- , Xiaofang He
- & Houkai Li
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Article
| Open AccessMetagenomic sequencing of post-mortem tissue samples for the identification of pathogens associated with neonatal deaths
Rapid identification of pathogens in neonatal infection, and corresponding antimicrobial susceptibility profiles, would improve patient outcomes and assist in antibiotic stewardship. In this work, the authors utilize metagenomic next-generation sequencing of post-mortem tissue samples to identify pathogens associated with neonatal deaths.
- Vicky L. Baillie
- , Shabir A. Madhi
- & Courtney P. Olwagen
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Article
| Open AccessAtezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial
Stereotactic ablative radiotherapy (SABR) is standard-of-care for patients with medically inoperable early-stage non-small cell lung cancer (NSCLC), however the risk of systemic recurrences remains high. Here the authors report the results of a phase I study testing the addition of atezolizumab (anti-PD-L1) to SABR in high risk, medically inoperable, early-stage, NSCLC.
- Arta M. Monjazeb
- , Megan E. Daly
- & Karen Kelly
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Article
| Open AccessAddressing mechanism bias in model-based impact forecasts of new tuberculosis vaccines
The complex transmission chain of tuberculosis (TB) forces mathematical modelers to make mechanistic assumptions when modelling vaccine effects. Here, authors posit a Bayesian formalism that unlocks mechanism-agnostic impact forecasts for TB vaccines.
- M. Tovar
- , Y. Moreno
- & J. Sanz
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Article
| Open AccessSynthesize high-dimensional longitudinal electronic health records via hierarchical autoregressive language model
The paper presents HALO, a Hierarchical Autoregressive Language Model, for generating high-fidelity, longitudinal electronic health records (EHR) data. HALO maintains statistical property, supports machine learning modeling without privacy concerns.
- Brandon Theodorou
- , Cao Xiao
- & Jimeng Sun
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Article
| Open AccessPortosystemic shunt placement reveals blood signatures for the development of hepatic encephalopathy through mass spectrometry
Patients with liver disease undergoing transjugular intrahepatic portosystemic shunt (TIPS) are at a higher risk of hepatic encephalopathy (HE). Here, the authors show intrahepatic shunting and specific metabolites, especially bile acids, as potential biomarkers and treatment targets for HE.
- Ana Carolina Dantas Machado
- , Stephany Flores Ramos
- & Amir Zarrinpar
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| Open AccessNeonatal and maternal outcomes following SARS-CoV-2 infection and COVID-19 vaccination: a population-based matched cohort study
The impacts of SARS-CoV-2 infection and COVID-19 vaccination in pregnancy are not fully understood. Here, the authors perform a cohort study using data from Scotland and find that infection was associated with increased risk of preterm birth and some adverse maternal outcomes, but there was no evidence of adverse outcomes associated with vaccination.
- Laura Lindsay
- , Clara Calvert
- & Sarah J. Stock
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Article
| Open AccessDiagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families
Despite large sequencing and data sharing efforts it often remains challenging to provide a genetic diagnosis for individuals with suspected Mendelian (single-gene) disorders. Here, the authors describe their experiences in identifying likely causal genetic variants in thousands of families and highlight the need to consider a wide range of challenges rather than a narrow focus on sequencing technologies.
- Lama AlAbdi
- , Sateesh Maddirevula
- & Fowzan S. Alkuraya
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Article
| Open AccessA versatile, fast and unbiased method for estimation of gene-by-environment interaction effects on biobank-scale datasets
Identification of gene-by-environment interactions is crucial to understand the interplay of environmental effects on complex traits. Here, the authors present MonsterLM, a method for estimating the proportion of trait variance explained by gene-by-environment interactions in a fast, unbiased manner on biobank-scale datasets.
- Matteo Di Scipio
- , Mohammad Khan
- & Guillaume Paré
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Article
| Open AccessPropensity of selecting mutant parasites for the antimalarial drug cabamiquine
Authors utilize a number of models (mathematical, in vitro and in vivo infection) to analyse pre-clinical and Phase I clinical trial data, in regard to potential risk of resistance associated with a Plasmodium falciparum inhibitor, cabamiquine.
- Eva Stadler
- , Mohamed Maiga
- & Thomas Spangenberg
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| Open AccessGut microbiota and fecal short chain fatty acids differ with adiposity and country of origin: the METS-microbiome study
Here, using amplicon sequencing and metabolomics in a large multi-country cohort, the authors find that adiposity-related microbiota differences differ between low-to-middle-income compared to high-income countries.
- Gertrude Ecklu-Mensah
- , Candice Choo-Kang
- & Lara R. Dugas
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Article
| Open AccessDiurnal rhythms of wrist temperature are associated with future disease risk in the UK Biobank
Many chronic diseases present with desynchronized sleep-wake cycles, indicative of disrupted biorhythms. Here, the authors propose peripheral thermoregulation as a digital biomarker based on the association between lower temperature rhythms measured from wearable activity trackers with future onset of disease, such as type 2 diabetes, non-alcoholic fatty liver disease, hypertension and pneumonia.
- Thomas G. Brooks
- , Nicholas F. Lahens
- & Carsten Skarke