Featured
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Article
| Open AccessEpithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling
IL-17 mediated inflammation in the lung is mediated by different effector molecules. Here the authors show that the epigenetic regulator epithelial sirtuin 6 (Sirt6) is associated with lung inflammation in asthma patients and that Sirt6 contributes to promotion of inflammation in mouse asthma models.
- Jingyun Quan
- , Xiaoxia Wen
- & Tianwen Lai
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Article
| Open AccessWithin-host genetic diversity of extended-spectrum beta-lactamase-producing Enterobacterales in long-term colonized patients
The diversity of ESBL-producing Klebsiella pneumoniae species complex and ESBL-Escherichia coli within patients is low and colonization with the same strain may persist for long periods. Authors utilise clinical and microbiological data from electronic health records to investigate genetic diversity of colonizing and infecting strains.
- Lisandra Aguilar-Bultet
- , Ana B. García-Martín
- & Sarah Tschudin-Sutter
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Article
| Open AccessEpidemic graph diagrams as analytics for epidemic control in the data-rich era
Approaches for assessing epidemic risks meet challenges when dealing with high-resolution data available nowadays, that includes behaviors, disease progression, and interventions. The authors propose an analytical framework to compute the epidemic threshold for arbitrary models of diseases, interventions, and hosts contact patterns.
- Eugenio Valdano
- , Davide Colombi
- & Vittoria Colizza
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Article
| Open AccessNeoadjuvant durvalumab plus radiation versus durvalumab alone in stages I–III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial
The authors previously reported the primary outcomes of a randomized phase II trial comparing neoadjuvant durvalumab (anti-PD-L1) alone or in combination with stereotactic radiotherapy in patients with early-stage NSCLC. Here, the authors report the secondary outcomes of the trial and post hoc analysis.
- Nasser K. Altorki
- , Zachary H. Walsh
- & Timothy E. McGraw
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Article
| Open AccessMutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD
Intronic GGGGCC repeat expansion in the C9orf72 gene causes ALS/FTD. Here the authors show that mutant GGGGCC RNA triggers YY1-Fuzzy transcriptional dysregulation which subsequently induces Wnt/β-catenin pathway and activates cell death in C9ALS/FTD.
- Zhefan Stephen Chen
- , Mingxi Ou
- & Ho Yin Edwin Chan
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Article
| Open AccessPotent latency reversal by Tat RNA-containing nanoparticle enables multi-omic analysis of the HIV-1 reservoir
Reactivating latent HIV reservoirs could be beneficial towards a functional cure. Here, the authors show that Tat-LNP effectively reactivates HIV while preserving the cell transcriptome. Upon reactivation, p24+ cells exhibit distinct genes and pathways potentially contributing to their persistence.
- Marion Pardons
- , Basiel Cole
- & Linos Vandekerckhove
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Article
| Open AccessCdo1-Camkk2-AMPK axis confers the protective effects of exercise against NAFLD in mice
The role of Cdo1 in exercise-mediated metabolic health and NAFLD is not clear. Here, the authors show that hepatic Cdo1 tethers Camkk2 to AMPK by interacting with both of them, thereby activating AMPK signaling to blunt hepatosteatosis and to promote exercise-mediated alleviation of NAFLD in mice.
- Min Chen
- , Jie-Ying Zhu
- & Liang Guo
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Article
| Open AccessIntranasal mask for protecting the respiratory tract against viral aerosols
The spread of many infectious diseases substantially relies on aerosol transmission to the respiratory tract. Here, the authors design an intranasal mask with the ability to intercept viral aerosols, entrap and inactivate virus, thus preventing respiratory tract infection.
- Xiaoming Hu
- , Shuang Wang
- & Wei Wei
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Article
| Open AccessProteomics-driven noninvasive screening of circulating serum protein panels for the early diagnosis of hepatocellular carcinoma
Hepatocellular carcinoma is often diagnosed at a late stage which limits treatment efficacy. Here, the authors utilise proteomics to identify serum proteomic biomarkers for early diagnosis, and validate using a prospective validation cohort.
- Xiaohua Xing
- , Linsheng Cai
- & Xiaolong Liu
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Article
| Open AccessGenome-wide association study meta-analysis of blood pressure traits and hypertension in sub-Saharan African populations: an AWI-Gen study
Hypertension is a major risk factor for cardiovascular disease prevalent in Africa. Here the authors report a genome-wide study providing insights into the genetics and physiology of blood pressure variation in African populations.
- Surina Singh
- , Ananyo Choudhury
- & Michèle Ramsay
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Article
| Open AccessOptimal timing of nirmatrelvir/ritonavir treatment after COVID-19 symptom onset or diagnosis: target trial emulation
Nirmatrelvir/ritonavir can reduce COVID-19 severity when initiated within five days of symptom onset but the optimal timing within this window is unknown. Here, the authors emulate a randomised trial using electronic health records from Hong Kong and find evidence for a benefit of early treatment initiation.
- Carlos K. H. Wong
- , Jonathan J. Lau
- & Joseph T. Wu
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Article
| Open AccessIdentification of 5-HT2A receptor signaling pathways associated with psychedelic potential
Serotonin 5-HT2A receptor signaling mechanisms associated with predicting psychedelic potential remain elusive. Using 5-HT2A-selective β-arrestin-biased ligands, here the authors show that a threshold level of 5-HT2A-Gq efficacy and not β-arrestin recruitment is associated with psychedelic potential.
- Jason Wallach
- , Andrew B. Cao
- & John D. McCorvy
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Article
| Open AccessPrion protein conversion at two distinct cellular sites precedes fibrillisation
In this work, the authors investigated the cellular mode of prion propagation. The report that proteopathic seeds of abnormal PrP are N-terminally truncated and detected within minutes after infection. These seeds reach the plasma membrane by regulated secretory pathways where phenotypically distinct fibril-like PrP aggregates are formed with a lag of 24 h after infection.
- Juan Manuel Ribes
- , Mitali P. Patel
- & Peter-Christian Klöhn
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Article
| Open AccessTandem gene duplications contributed to high-level azole resistance in a rapidly expanding Candida tropicalis population
Candida tropicalis is a cause of invasive candidiasis infection in humans that has been increasingly associated with azole drug resistance. In this study, the authors investigate the genetic basis for azole resistance through analysis of whole-genome sequencing and multilocus sequence typing data.
- Xin Fan
- , Rong-Chen Dai
- & Meng Xiao
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Article
| Open AccessAutomating General Movements Assessment with quantitative deep learning to facilitate early screening of cerebral palsy
General Movements Assessment (GMA) is useful in early prediction of cerebral palsy but necessitates trained professionals. Here, the authors show a quantitative deep learning-based method to automate GMA with strong performance, adhering to GMA principles and exhibiting robust interpretability.
- Qiang Gao
- , Siqiong Yao
- & Hui Lu
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Article
| Open AccessAtherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation
Accumulation of lipid-laden macrophages in the arterial wall is a critical step in atherosclerosis. Here, the authors show that downregulation of Zeb1 in macrophages promotes lipid accumulation and atherosclerotic plaque formation while its restoration with macrophage-targeted nanoparticles reverses these effects.
- M. C. Martinez-Campanario
- , Marlies Cortés
- & Antonio Postigo
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Article
| Open AccessDietary circadian rhythms and cardiovascular disease risk in the prospective NutriNet-Santé cohort
The relation between daily meal and fasting timing with cardiovascular disease incidence remains unclear. Here, authors show that a later daily meal timing is associated with increased cardiovascular disease risk, especially in women. This study suggests that adopting earlier daily eating patterns may be beneficial for cardiovascular prevention.
- Anna Palomar-Cros
- , Valentina A. Andreeva
- & Bernard Srour
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Article
| Open AccessRepurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms
Three drugs initially developed for other conditions, 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat and varespladib, have shown promise in preventing the lethality of snakebite envenoming. Here, Hall et al., show that a combination of these drugs can combat the local dermonecrotic effects caused by diverse cytotoxic venoms.
- Steven R. Hall
- , Sean A. Rasmussen
- & Nicholas R. Casewell
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Article
| Open AccessActivation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis
Idiopathic Pulmonary Fibrosis (IPF) consists of lung inflammation and collagen deposition leading to reduced lung function and non-inducible mouse models are needed. Here the authors show a spontaneous mouse IPF model where Ifngr1-/-Rag2-/- mice show enhanced ILC2 activation and function along with pathology similar to IPF.
- Natsuko Otaki
- , Yasutaka Motomura
- & Kazuyo Moro
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Article
| Open AccessHigh monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials
Antibody Mediated Prevention (AMP) trials showed that the broadly neutralizing antibody VRC01 could prevent some HIV-1 acquisitions. Here the authors use VRC01 levels and the sensitivity of each acquired HIV virus to predict viral loads in the AMP studies and show that VRC01 influenced viral loads, though potency was lower in vivo than expected.
- Daniel B. Reeves
- , Bryan T. Mayer
- & Srilatha Edupuganti
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Article
| Open AccessMaternal antibiotic exposure enhances ILC2 activation in neonates via downregulation of IFN1 signaling
Treatment of pregnant animals with antibiotics can have unexpected effects on offspring. Here the authors use mouse models to show that antibiotic treatment of mothers leads to changes in ILC2 phenotype in neonatal lungs accompanied by changes in the microbiota and microbiota derived butyrate.
- Haixu Xu
- , Xianfu Yi
- & Jie Zhou
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Article
| Open AccessSphingosine-1-phosphate suppresses GLUT activity through PP2A and counteracts hyperglycemia in diabetic red blood cells
Red blood cells (RBC) carry the majority of sphingosine-1-phosphate (S1P). Here, the authors show that RBC dynamically regulate S1P levels in response to metabolic stress and employ them to regulate glucose uptake, glycolysis and the pentose phosphate pathway as protection against lipid peroxidation.
- Nadine Thomas
- , Nathalie H. Schröder
- & Bodo Levkau
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Article
| Open AccessAnti-VEGFR2 F(ab′)2 drug conjugate promotes renal accumulation and glomerular repair in diabetic nephropathy
Poor renal distribution of antibody-based drugs limits the treatment efficiency for diabetic nephropathy and causes side effects. Here, the authors prepare an antibody fragment drug conjugate, antiVEGFR2 F(ab′)2-SS31, improving renal distribution and meriting drug validation in diabetic nephropathy therapy.
- Di Liu
- , Yanling Song
- & Yongzhong Du
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Article
| Open AccessLate gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa
Is there a critical period to deliver gene therapies in photoreceptor degeneration? Using a mouse model of retinitis pigmentosa, the authors show that once 70% of rods are lost, gene replacement fails to restore normal retinal output.
- Miranda L. Scalabrino
- , Mishek Thapa
- & Greg D. Field
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Article
| Open AccessTemperature-related death burden of various neurodegenerative diseases under climate warming: a nationwide modelling study
Examining non-optimal temperatures’ influence on neurodegenerative diseases amid climate warming is vital for public health. Here, the authors project a notable net increase of death burden from neurodegenerative diseases after the mid-21st century.
- Peng Yin
- , Ya Gao
- & Haidong Kan
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Article
| Open AccessInteractions between climate change, urban infrastructure and mobility are driving dengue emergence in Vietnam
The geographic distribution of dengue has been expanding in recent decades, and Vietnam is one of the most severely affected countries. In this study, the authors use Bayesian hierarchical modelling to investigate the socio-environmental and climatic drivers of dengue incidence in Vietnam and how they vary across the country.
- Rory Gibb
- , Felipe J. Colón-González
- & Rachel Lowe
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Article
| Open AccessPhase-separated CCER1 coordinates the histone-to-protamine transition and male fertility
Here the authors reveal that phase‐separated nuclear CCER1 condensates are required for male fertility by mediating chromatin condensation and histone epigenetic modification, while loss‐of‐function variants of human CCER1 are pathogenic in patients with nonobstructive azoospermia (NOA).
- Dongdong Qin
- , Yayun Gu
- & Zhibin Hu
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Article
| Open AccessInhibition of host PARP1 contributes to the anti-inflammatory and antitubercular activity of pyrazinamide
The mode of action of the tuberculosis antibiotic pyrazinamide is poorly understood. Here, Krug et al show that pyrazinamide inhibits the immune regulator PARP1 and demonstrate PARP1 inhibition as a host-directed therapy.
- Stefanie Krug
- , Manish Gupta
- & William R. Bishai
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Article
| Open AccessThe DNA glycosylase NEIL2 is protective during SARS-CoV-2 infection
NEIL2, a mammalian DNA repair enzyme, has been reported to suppress infection induced inflammation. Here, the authors characterize its role in modulating the severity of SARS-CoV-2 infection.
- Nisha Tapryal
- , Anirban Chakraborty
- & Tapas K. Hazra
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Article
| Open AccessAmplified fluorogenic immunoassay for early diagnosis and monitoring of Alzheimer’s disease from tear fluid
Accurate diagnosis of Alzheimer’s disease in its earliest stage can prevent the disease and delay the symptoms. Here the authors identify a potential Alzheimer’s biomarker from tear fluid, and develop a nanoparticle-based immunoassay for its detection, demonstrating potential in Alzheimer’s diagnosis.
- Sojeong Lee
- , Eunjung Kim
- & Seungjoo Haam
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Article
| Open AccessHarnessing PROTAC technology to combat stress hormone receptor activation
Stress-hormone receptors are important therapeutic targets for many diseases but the currently clinically approved inhibitor lacks specificity. Here the authors present a stress hormone receptor depletion tool that differs in its mode of action making it specific in counteracting the effects of stress.
- Mahshid Gazorpak
- , Karina M. Hugentobler
- & Katharina Gapp
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Article
| Open AccessChiral metal-organic frameworks incorporating nanozymes as neuroinflammation inhibitors for managing Parkinson’s disease
The treatment of Parkinson’s disease (PD) is hampered by the lack of effective blood–brain barrier (BBB) traversing drugs. Here, the authors report nanozyme-integrated metal-organic frameworks with antioxidant activity and chiral-dependent BBB transendocytosis as anti-neuroinflammatory agents for PD treatment.
- Wei Jiang
- , Qing Li
- & Kelong Fan
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Article
| Open AccessA naturally occurring polyacetylene isolated from carrots promotes health and delays signatures of aging
Ameliorating or preventing signatures of aging in humans using natural compounds is an exciting area of research. Here the authors isolate a previously unknown phytochemical from carrots which activates defence mechanisms against oxidative stress and extends lifespan in worms, and improves glucose metabolism, promotes exercise capacity, and protects from frailty at higher age in mice.
- Carolin Thomas
- , Reto Erni
- & Michael Ristow
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Article
| Open AccessFunctional divergence of a bacterial enzyme promotes healthy or acneic skin
Cutibacterium acnes phylotypes can be catalogued based on their association with acneic or healthy skin. Here, Hajam et al show that the functional divergence of a hyaluronidase enzyme expressed by the phylotypes is a major determinant of acne severity.
- Irshad A. Hajam
- , Madhusudhanarao Katiki
- & George Y. Liu
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Article
| Open AccessShuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo
Gene editing strategies for cystic fibrosis are challenging. Here the authors improve on their previously reported shuttle peptide noncovalently combined with Cas ribonucleoprotein (RNP), and derive the S315 peptide for delivery: they show base editing in the respiratory tract of the rhesus macaques.
- Katarina Kulhankova
- , Soumba Traore
- & Paul B. McCray Jr.
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Comment
| Open AccessTime for global health policy and research leaders to prioritize endometriosis
Endometriosis is an incurable, under-diagnosed, systemic inflammatory disease affecting millions world-wide. Common symptoms include life-impacting pain, gastrointestinal/urinary symptoms, excessive fatigue, and infertility. Global public health policies are urgently needed to promote awareness, implement multidisciplinary care, and fund research for aetiology, biomarker discovery, and effective therapies for symptoms associated with endometriosis.
- Linda C. Giudice
- , Andrew W. Horne
- & Stacey A. Missmer
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Article
| Open AccessEstimating the potential impact and diagnostic requirements for SARS-CoV-2 test-and-treat programs
Antivirals are now available for treating COVID-19 but must be used early in the course of infection to be effective. Here, the authors use mathematical modelling to assess the potential public health impacts of antiviral use considering different levels of testing and country sociodemographic characteristics.
- Alvin X. Han
- , Emma Hannay
- & Colin A. Russell
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Article
| Open AccessSelenoprotein deficiency disorder predisposes to aortic aneurysm formation
Aortic aneurysms have a heritable basis. Here, the authors report that a selenoprotein deficiency disorder due to mutations in SECISBP2, causes oxidative stress-mediated aortic cell death, predisposing to thoracic aortic aneurysm formation.
- Erik Schoenmakers
- , Federica Marelli
- & Krishna Chatterjee
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Article
| Open AccessFructose overconsumption impairs hepatic manganese homeostasis and ammonia disposal
Manganese is an essential trace element for the activity of arginase in the process of urea generation and ammonia disposal in the liver. Here, the authors show that fructose overconsumption impairs hepatic Mn homeostasis and ammonia disposal in male mice.
- Jian-Hui Shi
- , Yu-Xia Chen
- & Weiping J. Zhang
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Article
| Open AccessTrue prevalence of long-COVID in a nationwide, population cohort study
Determining the prevalence of Long COVID is challenging because many symptoms attributed to the syndrome could have other causes. Here, the authors estimate the prevalence of Long COVID in Scotland by comparing rates of symptoms reported by people with and without history of SARS-CoV-2 infection.
- Claire E. Hastie
- , David J. Lowe
- & Jill P. Pell
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Article
| Open AccessData-driven grading of acute graft-versus-host disease
Acute GVHD severity grading is based on target organ assessments. Here, the authors show that data-driven grading can identify 12 distinct grades with specific aGVHD phenotypes, which are associated with clinical outcomes, and that their method outperformed conventional gradings.
- Evren Bayraktar
- , Theresa Graf
- & Amin T. Turki
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Article
| Open AccessPlasma proteomic profiles predict individual future health risk
The predictive capability of future health risk using plasma proteomic profiles remains largely unexplored. Using 1461 proteins collected from 50k individuals, authors show proteins can derive much better or equivalent performance than established clinical indicators for more than 40 endpoints.
- Jia You
- , Yu Guo
- & Jin-Tai Yu
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Article
| Open AccessAdults on pre-exposure prophylaxis (tenofovir-emtricitabine) have faster clearance of anti-HIV monoclonal antibody VRC01
Small molecule drugs can affect clearance of monoclonal antibodies, but this hasn’t been assessed for oral HIV-1 pre-exposure prophylaxis. Here, the authors find that faster serum clearance of an experimental IgG1 monoclonal antibody, VRC01, is associated with use of tenofovir-emtricitabine, possibly explained by increased epithelial intestinal permeability.
- Yunda Huang
- , Lily Zhang
- & Maria P. Lemos
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Article
| Open AccessMutual modulation of gut microbiota and the immune system in type 1 diabetes models
Type-1 diabetes pathogenesis has been strongly linked with changes in the intestinal microbiota. Here, the authors demonstrate that mice susceptible to type-1 diabetes become resistant when co-housed with resistant mice, an effect that was associated with changes in gut microbiota, gut permeability, and the immune system.
- Estela Rosell-Mases
- , Alba Santiago
- & Chaysavanh Manichanh
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Article
| Open AccessCytolytic circumsporozoite-specific memory CD4+ T cell clones are expanded during Plasmodium falciparum infection
It is important to understand why some individuals in endemic regions acquire natural immunity against malaria while others remain susceptible. Here authors show that during episodes of Plasmodium falciparum malaria, circumsporozoite-specific cytolytic memory CD4+ T cells are clonally expanded in patients, and those with clinical immunity demonstrate reduction in the chemotactic and inhibitory receptor expression in ZEB2+ memory CD4+ T cells.
- Raquel Furtado
- , Mahinder Paul
- & Grégoire Lauvau
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Article
| Open AccessEpidemiology, mortality, and health service use of local-level multimorbidity patterns in South Spain
Multimorbidity—the occurrence of chronic diseases together—represents a major challenge for healthcare systems. Here, the authors characterise multimorbidity patterns in a large dataset of patients residing in southern Spain and show the unequal distribution of multimorbidity patterns along different socioeconomic areas at the local level.
- Javier Alvarez-Galvez
- , Esther Ortega-Martin
- & Jesus Carretero-Bravo
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Article
| Open AccessThe genomic epidemiology of shigellosis in South Africa
As a leading cause of diarrhoeal mortality and morbidity, authors examine the epidemiology and genome dynamics of shigellosis in South Africa, utilising whole genome sequence analysis.
- George E. Stenhouse
- , Karen H. Keddy
- & Kate S. Baker
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Article
| Open AccessThe extrafollicular B cell response is a hallmark of childhood idiopathic nephrotic syndrome
Although B cell-targeting therapies can provide clinical benefits to children with idiopathic nephrotic syndrome (INS), B lymphocyte subsets have not been extensively studied in this disease. Here, using single-cell RNA sequencing, the authors identify an extrafollicular B cell signature in children with INS.
- Tho-Alfakar Al-Aubodah
- , Lamine Aoudjit
- & Tomoko Takano
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Article
| Open AccessSLC35D3 promotes white adipose tissue browning to ameliorate obesity by NOTCH signaling
White adipose tissue is closely associated with energy expenditure and obesity. Here, the authors show that SLC35D3 promotes white adipose tissue browning through the NOTCH1 signalling pathway and SLC35D3 may be a potential therapeutic target for obesity and related complications.
- Hongrui Wang
- , Liang Yu
- & Yibo Wang
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