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| Open AccessCompound mortality impacts from extreme temperatures and the COVID-19 pandemic
Extreme weather and pandemics are classified as two of the most serious risks facing the UK in its National Risk Register. Here, the authors investigate the compound mortality impacts of extreme high and low temperatures and COVID-19 in England and Wales.
- Y. T. Eunice Lo
- , Dann M. Mitchell
- & Antonio Gasparrini
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Article
| Open AccessPost-COVID conditions following COVID-19 vaccination: a retrospective matched cohort study of patients with SARS-CoV-2 infection
The impact of COVID-19 vaccination on post-COVID conditions is not well understood. Here, the authors use electronic health record data from a network of eight integrated healthcare systems in the United States to compare rates of post-COVID conditions in those with and without vaccination.
- Debbie E. Malden
- , In-Lu Amy Liu
- & Sara Y. Tartof
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Article
| Open AccessUnveiling unique clinical phenotypes of hip fracture patients and the temporal association with cardiovascular events
Cardiovascular events (CVEs) are the leading cause of death among hip fracture patients. Here, the authors show the findings on subphenotyping the heterogeneous spectrum of hip fracture patients in both Hong Kong and the United Kingdom older adult populations and temporal associations with CVEs across all subphenotypes.
- Warrington W. Q. Hsu
- , Xiaowen Zhang
- & Ching-Lung Cheung
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Article
| Open AccessIntegrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions
Duarte et al. report that common genetic variants linked to psychiatric disorders influence the regulation of ancient retroviruses integrated into the genome. This suggests ancient viruses acquired millions of years ago may have shaped modern human brain function.
- Rodrigo R. R. Duarte
- , Oliver Pain
- & Timothy R. Powell
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Article
| Open AccessArtificial intelligence enables precision diagnosis of cervical cytology grades and cervical cancer
Cervical screening is a key method for detecting cervical cancer, but is limited by pathologist detection. Here, the authors use artificial intelligence to predict cytology grades from whole slide images.
- Jue Wang
- , Yunfang Yu
- & Herui Yao
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Article
| Open AccessDrug screening on digital microfluidics for cancer precision medicine
In-vitro platforms for personalized cancer diagnosis is required high sensitivity. Here, the authors developed a digital microfluidic system for drug screening using primary tumor cells and established a working protocol for precision medicine.
- Jiao Zhai
- , Yingying Liu
- & Yanwei Jia
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Article
| Open AccessHippocampal sharp-wave ripples correlate with periods of naturally occurring self-generated thoughts in humans
Whether and how sharp-wave ripples (SWRs) accompany mental states that are less closely linked to events in the immediate environment are not fully understood. Here authors recorded SWRs from hippocampus of 10 epilepsy patients for up to 15 days with experience sampling. SWR rates showed circadian fluctuation and were associated with self-generated thoughts such as mind wandering.
- Takamitsu Iwata
- , Takufumi Yanagisawa
- & Haruhiko Kishima
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Article
| Open AccessCiliary tip actin dynamics regulate photoreceptor outer segment integrity
Photoreceptor outer segment abnormalities cause retinitis pigmentosa, a form of blindness. Here, authors show that the disease-associated gene RPGR regulates actin-mediated outer segment turnover through its interaction with the actin severer, cofilin.
- Roly Megaw
- , Abigail Moye
- & Pleasantine Mill
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Article
| Open AccessDisruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis
Macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is implicated in a range of immunopathology. Here the authors show TIGAR drives inflammation and sepsis via activation of TAK1 and that disruption of TIGAR-TAK1 interaction in a murine model of sepsis reduces immunopathology.
- Dongdong Wang
- , Yanxia Li
- & Jingjing Ben
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Article
| Open AccessIn vivo neutralization of coral snake venoms with an oligoclonal nanobody mixture in a murine challenge model
Oligoclonal mixtures of neutralising antibodies can target multiple antigen components and represent a potential therapeutic solution for the treatment of envenomation. Here, the authors generate mixtures of nanobodies against coral snake venom toxins and demonstrate they can prevent lethality of coral snake venoms in pre-clinical animal models.
- Melisa Benard-Valle
- , Yessica Wouters
- & Andreas Hougaard Laustsen
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Article
| Open AccessFluorescent fatty acid conjugates for live cell imaging of peroxisomes
The array of tools to image peroxisome regulation is still limited. Here, the authors develop improved fatty acid-based probes with high peroxisome specificity and bright fluorescence in the red/far-red spectrum, which makes them ideal to study peroxisomes in live cells and whole organisms.
- Daria Korotkova
- , Anya Borisyuk
- & Triana Amen
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Article
| Open AccessDeep learning of left atrial structure and function provides link to atrial fibrillation risk
In this study, a deep learning-based model of left atrial size in UK Biobank enabled genome-wide association studies in 35,049 healthy participants. Several lines of evidence, including the PITX2 locus, linked left atrial dysfunction to atrial fibrillation risk.
- James P. Pirruccello
- , Paolo Di Achille
- & Patrick T. Ellinor
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Article
| Open AccessPost-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia
The post-resolution phase of inflammation is not simply a linear path towards cessation of immune response but rather a regulated process involving fluctuating immune activity. Here authors show a pivotal role for post-resolution macrophages in driving a wave of T cell recruitment and activation via prostaglandin E2 and α-integrin signalling during the resolution phase of murine pneumococcal pneumonia.
- Karen T. Feehan
- , Hannah E. Bridgewater
- & Derek W. Gilroy
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Article
| Open AccessMultiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer
Intratumoral heterogeneity has been documented in multiple cancer types, and can be linked to treatment resistance. Here, the authors analyse multiregional samples from colorectal cancers and show gene expression subtypes which are less vulnerable to heterogeneity and may partly contribute to differential patient survival.
- Jonas Langerud
- , Ina A. Eilertsen
- & Anita Sveen
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Article
| Open AccessPriming with LSD1 inhibitors promotes the persistence and antitumor effect of adoptively transferred T cells
Phenotypic changes in exhausted T cells are linked to chromatin remodeling. Here the authors show that pharmacological inhibition of the H3K4me1/2 demethylase LSD1 promotes the persistence and enhances the therapeutic activity of adoptively transferred T cells for cancer therapy.
- Fengqi Qiu
- , Peishan Jiang
- & Wanqiang Sheng
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Article
| Open AccessDevelopment of a long noncoding RNA-based machine learning model to predict COVID-19 in-hospital mortality
Identifying biomarkers associated with risk of severe COVID-19 disease could inform clinical management. Here, the authors identify a long noncoding RNA associated with severe disease using data from three European countries, and validate their finding in data from Canada.
- Yvan Devaux
- , Lu Zhang
- & Hüseyin Firat
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Article
| Open AccessMedical history predicts phenome-wide disease onset and enables the rapid response to emerging health threats
Preventive interventions often require strategies to identify high-risk individuals. Here, the authors illustrate the potential utility of medical history in predicting the onset risk for thousands of diseases across clinical specialties including COVID-19.
- Jakob Steinfeldt
- , Benjamin Wild
- & Roland Eils
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Article
| Open AccessProduction of deoxycholic acid by low-abundant microbial species is associated with impaired glucose metabolism
Secondary bile acids are microbially produced metabolites linked to metabolic diseases. A challenge in microbiota research is to understand how bacteria collaborate to produce such bioactive molecules. Here, the authors show that adding a single low-abundance bacterial species to a community can significantly affect the metabolic output and host physiology.
- Annika Wahlström
- , Ariel Brumbaugh
- & Fredrik Bäckhed
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Article
| Open AccessInflammatory and neurodegenerative serum protein biomarkers increase sensitivity to detect clinical and radiographic disease activity in multiple sclerosis
Inflammatory and degenerative processes are thought to play a role in the pathophysiology of multiple sclerosis. Here, the authors identified twenty serum proteins associated with increased clinical and radiographic disease activity.
- Tanuja Chitnis
- , Ferhan Qureshi
- & Sergio E. Baranzini
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Perspective
| Open AccessPlacing engineering in the earthquake response and the survival chain
This Perspective provides insightful discussion in how engineers can aid human health and safety during earthquake disasters. From search and rescue, helping mobilize patients, and securing medical facilities and treatment engineering can work towards bettering earthquake response.
- Luis Ceferino
- , Yvonne Merino
- & Baturalp Ozturk
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Article
| Open AccessElevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart
Heart failure is characterised by a detrimental rise in the intracellular sodium concentration. Here the authors show that this reversibly reprogrammes energy metabolism in the heart making this a possible therapeutic target for the development of new drugs.
- Yu Jin Chung
- , Zoe Hoare
- & Michael J. Shattock
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Article
| Open AccessTargeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer
The ability of anti-cancer therapies such as radiotherapy, chemotherapy and immunotherapy to induce ferroptosis has been linked to their efficacy. Here, the authors demonstrate that SOX13 promotes ferroptosis-resistance via transactivation of SCAF1, identifying SOX13 as a targeted therapeutic vulnerability in gastric cancer.
- Hui Yang
- , Qingqing Li
- & Mingzhe Ma
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Article
| Open AccessThe sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
Antifungal triazoles inhibit biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Here, Xie et al. show that Erg6, the enzyme that catalyzes a previous step in ergosterol biosynthesis, is essential for the viability of Aspergillus fumigatus, and its repression reduces the virulence of this fungal pathogen in an animal model of infection.
- Jinhong Xie
- , Jeffrey M. Rybak
- & Jarrod R. Fortwendel
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Article
| Open AccessHomozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility
Here the authors show that a homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters the accessibility of variant-distal methylation sites in EPRS1 mRNA, revealing a new RNA-dependent mechanism by which genetic variants can influence gene expression and disease.
- Debjit Khan
- , Iyappan Ramachandiran
- & Paul L. Fox
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Article
| Open AccessHistopathologic image–based deep learning classifier for predicting platinum-based treatment responses in high-grade serous ovarian cancer
Predicting the response to platinum-based chemotherapy in high-grade serous ovarian carcinoma (HGSOC) remains challenging. Here, the authors develop the histopathology image-based Pathologic Risk Classifier for HGSOC - PathoRiCH - to predict and stratify HGSOC patient response to therapy, especially when combined with molecular biomarkers.
- Byungsoo Ahn
- , Damin Moon
- & Eunhyang Park
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Article
| Open AccessAI-enhanced integration of genetic and medical imaging data for risk assessment of Type 2 diabetes
Type 2 diabetes is a global health threat demanding precise healthcare methods. Here, the authors show that their AI-driven risk assessment models, integrating genetic, imaging, and demographic data, achieve high accuracy in identifying high-risk groups, promising advancements in prevention strategies.
- Yi-Jia Huang
- , Chun-houh Chen
- & Hsin-Chou Yang
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Article
| Open AccessSpatial disparities in the mortality burden of the covid-19 pandemic across 569 European regions (2020-2021)
Excess mortality can be used as an indicator of the impacts of the COVID-19 pandemic. Here, the authors estimate excess mortality in 569 European regions in 25 countries for 2020 and 2021 and describe how impacts changed over time.
- Florian Bonnet
- , Pavel Grigoriev
- & Carlo-Giovanni Camarda
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Article
| Open AccessCerebral microstructural alterations in Post-COVID-condition are related to cognitive impairment, olfactory dysfunction and fatigue
After contracting COVID-19, a substantial number of individuals develop a Post-COVID-Condition with neurological symptoms. Here, the authors show symptom-specific brain microstructure alterations in these patients, providing insights into the underlying pathophysiology.
- Jonas A. Hosp
- , Marco Reisert
- & Alexander Rau
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Article
| Open AccessStimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse
Despite initial treatment with surgical resection, glioblastoma multiforme (GBM) frequently recurs. Here the authors report the design of an immunostimulatory autolysing Salmonella based-nanocapsule delivery system, promoting anti-tumor immune responses and preventing postoperative relapse in preclinical GBM models.
- Yulin Zhang
- , Kaiyan Xi
- & Shilei Ni
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Article
| Open AccessHsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation
Hsc70 (heat shock protein family A member 8) is a cytoplasmic chaperone protein involved in endosomal micro-autophagy and chaperone-mediated autophagy. Here the authors report that Hsc70 promotes lysosomal degradation of PD-L1 and that its overexpression promotes anti-tumor immune responses in preclinical cancer models.
- Xiaoyan Xu
- , Tingxue Xie
- & Hongguang Xia
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Article
| Open AccessEnhanced CD95 and interleukin 18 signalling accompany T cell receptor Vβ21.3+ activation in multi-inflammatory syndrome in children
Multi-Inflammatory Syndrome in Children (MIS-C) is a severe post-infectious presentation related to SARS-CoV-2 infection. Here authors used multi-omics approaches to characterise MIS-C cases and found increased CD95 and IL-18 signalling accompanying the expansion of TCR Vβ 21.3+ T cells.
- Zhenguang Zhang
- , Iain R. L. Kean
- & Nazima Pathan
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Article
| Open AccessEnhancing in vivo cell and tissue targeting by modulation of polymer nanoparticles and macrophage decoys
Targeted drug delivery in vivo is a complex challenge, and understanding the characteristics that define the behavior of delivery vehicles in vivo is vital for advancing delivery vehicle design. Here the authors use a library of polymeric delivery vehicles and high-throughput tools to study the structure-function relationships guiding the physiological fate of nanomedicines.
- Alexandra S. Piotrowski-Daspit
- , Laura G. Bracaglia
- & W. Mark Saltzman
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Article
| Open AccessOriginal COVID-19 priming regimen impacts the immunogenicity of bivalent BA.1 and BA.5 boosters
Waning immunity and the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness and required vaccine updates. Here, the authors assess how different priming regimens affect the immunogenicity of BA.1 and BA.5 bivalent boosters.
- Luca M. Zaeck
- , Ngoc H. Tan
- & Rory D. de Vries
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Article
| Open AccessMycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine
In this work, authors mechanistically investigate the reduced induction of antimicrobial peptides in Mycobacterium tuberculosis infected macrophages.
- Cheng Peng
- , Yuanna Cheng
- & Lin Wang
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Article
| Open AccessLiver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling
The peroxisomal β-oxidation enzyme ACOX1 increases in liver with obesity, but the physiological significance is unclear. Here, the authors show that liver-specific knockout of Acox1 leads to accumulation of omega-3 VLCFAs that promote metabolic health through activation of GPR120 in adipose tissue.
- Dongliang Lu
- , Anyuan He
- & Irfan J. Lodhi
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Article
| Open AccessGenomic insights unveil the plasmid transfer mechanism and epidemiology of hypervirulent Klebsiella pneumoniae in Vietnam
Hypervirulent Klebsiella pneumoniae (hvKp) is a significant cause of severe community-acquired infection, primarily in Asia. Here, the authors characterise the genetic profile, phylogenetic structure, and plasmid features of hvKp in Vietnam.
- Quynh Nguyen
- , Nguyen Yen Thi Phuong
- & Duy Thanh Pham
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Article
| Open AccessFerritinophagy mediates adaptive resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer
The mechanisms leading to acquired resistance to targeted therapy in cancer are not completely understood. Here, the authors show that ferritinophagy mediates adaptive resistance to Osimertinib, and that combining this EGFR tyrosine kinase inhibitor with copper ionophores improves its therapeutic efficacy in preclinical models of non-small cell lung cancer.
- Hui Wang
- , Qianfan Hu
- & Feng Jiang
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Article
| Open AccessImpacts of human mobility on the citywide transmission dynamics of 18 respiratory viruses in pre- and post-COVID-19 pandemic years
Population mobility is associated with SARS-CoV-2 transmission but its impacts on other respiratory viruses are not well understood. Here, the authors investigate associations between mobile phone-derived mobility metrics and the dynamics of 18 respiratory viruses in Seattle, Washington from 2018 to 2022.
- Amanda C. Perofsky
- , Chelsea L. Hansen
- & Cécile Viboud
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Article
| Open AccessImportance of social inequalities to contact patterns, vaccine uptake, and epidemic dynamics
Contact patterns influence the spread of infectious diseases, but mathematical models of epidemics typically only account for age differences in contacts. Here, the authors investigate the importance of other sociodemographic characteristics in shaping contact patterns and vaccine uptake using survey data from Hungary.
- Adriana Manna
- , Júlia Koltai
- & Márton Karsai
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Article
| Open AccessTDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression
Amyotrophic Lateral Sclerosis is characterized by TDP-43 proteinopathy in the brain. Here, the authors find TDP-43 aggregation might be mediated by the loss of Asparaginase-like 1, an enzyme that degrades detrimental isoaspartates and is downregulated by the endogenous retrovirus HML-2.
- Marta Garcia-Montojo
- , Saeed Fathi
- & Avindra Nath
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Article
| Open AccessBone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes
Bone marrow stromal cells (BMSCs) are known to promote the development of drug resistance. Here, the authors investigate the chromatin remodeling and associated changes in gene expression in the multiple myeloma (MM) cells following their interactions with BMSCs, which are also observed in extramedullary disease (EMD).
- Moritz Binder
- , Raphael E. Szalat
- & Nikhil C. Munshi
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Article
| Open AccessThe vacuolar fusion regulated by HOPS complex promotes hyphal initiation and penetration in Candida albicans
The transition between yeast and hyphae is crucial for the pathogenicity of Candida albicans. Here, Liu et al. show that vacuole fusion is active during hyphal extension and that large vacuoles increase the mechanical forces of hyphae penetrating into organs.
- Yu Liu
- , Ruina Wang
- & Lan Yan
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Article
| Open AccessDynamic microfluidic single-cell screening identifies pheno-tuning compounds to potentiate tuberculosis therapy
Tuberculosis is a major global health threat. Here, the authors develop a single-cell drug discovery approach and identify a compound that tunes bacterial phenotypic variation. This enhances the activity of anti-tubercular drugs against the pathogen.
- Maxime Mistretta
- , Mena Cimino
- & Giulia Manina
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Article
| Open AccessMechanically robust and personalized silk fibroin-magnesium composite scaffolds with water-responsive shape-memory for irregular bone regeneration
The regeneration of critical-size bone defects, especially those with irregular shapes, remains a clinical challenge. Here, the authors report a shape-memory, tailorable, self-adaptive and bioactive silk fibroin/magnesium composite scaffold that can quickly match irregular defects by simple trimming and lead to good interface integration.
- Zhinan Mao
- , Xuewei Bi
- & Yufeng Zheng
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Article
| Open AccessSerological evidence of zoonotic filovirus exposure among bushmeat hunters in Guinea
In a serological analysis, Bore et al. utilise serum samples, collected from a cohort of individuals associated with bushmeat hunting and butchering, in the forested region of Guinea, a region close to the epicentre of the 2013–2016 West Africa Ebola virus disease epidemic.
- Joseph Akoi Boré
- , Joseph W. S. Timothy
- & Miles W. Carroll
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Article
| Open AccessE-cardiac patch to sense and repair infarcted myocardium
Infarted myocardium hampers the synchronous electroactivity of the cardiac tissue. Here, the authors showcase a battery-free conductive cardiac patch made of reduced graphene and its therapeutic efficacy for cardiac repair.
- Renjie Qiu
- , Xingying Zhang
- & Leyu Wang
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Article
| Open AccessSevere drought exposure in utero associates to children’s epigenetic age acceleration in a global climate change hot spot
The study suggests a positive association between in utero drought exposure and faster biological aging in children in a global climate change hot spot. Drought experienced during pregnancy may reduce life expectancy.
- Xi Qiao
- , Bilinda Straight
- & Belinda L. Needham
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Article
| Open AccessFOXC1 regulates endothelial CD98 (LAT1/4F2hc) expression in retinal angiogenesis and blood-retina barrier formation
FOXC1 transcription factor plays a role in vascular development, but its mechanism is not well defined. Here, the authors show FOXC1 regulates retinal angiogenesis by promoting CD98 amino acid transporter expression to activate mTOR signalling, and also by promoting blood-retina barrier formation.
- Teena Bhakuni
- , Pieter R. Norden
- & Tsutomu Kume
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Article
| Open AccessIdentifying proteomic risk factors for cancer using prospective and exome analyses of 1463 circulating proteins and risk of 19 cancers in the UK Biobank
Plasma proteins are a potential diagnostic tool to detect multiple diseases, including cancer. Here, the authors leverage multi-omics data to identify 1,463 proteins associated with 19 common cancers in UK Biobank participants. Reviewer Recognition:
- Keren Papier
- , Joshua R. Atkins
- & Ruth C. Travis