Featured
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Article
| Open AccessTcrXY is an acid-sensing two-component transcriptional regulator of Mycobacterium tuberculosis required for persistent infection
Stupar et al. describe a new role for the Mycobacterium tuberculosis two-component system, TcrXY, in the modulation of up to 70 genes, including two effectors, TarA and TarB which mitigate intracellular redox stress.
- Miljan Stupar
- , Lendl Tan
- & Nicholas P. West
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Article
| Open AccessThe gut ileal mucosal virome is disturbed in patients with Crohn’s disease and exacerbates intestinal inflammation in mice
Gut bacteriome dysbiosis has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Here, they authors characterize the small bowel (terminal ileum) virome and bacteriome of patients with Crohn´s Disease (CD), and show that ileal virions from CD patients causally exacerbate intestinal inflammation in IBD mouse models.
- Zhirui Cao
- , Dejun Fan
- & Tao Zuo
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Article
| Open AccessThe plasmidome associated with Gram-negative bloodstream infections: A large-scale observational study using complete plasmid assemblies
Plasmids carry antimicrobial resistance genes and contribute to the rapid dissemination of resistance. Here, the authors sequence 1,880 complete plasmids from 738 isolates from bloodstream infections, shedding light on the links between plasmid types, bacterial hosts and antimicrobial resistance.
- Samuel Lipworth
- , Willam Matlock
- & Nicole Stoesser
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Article
| Open AccessDeep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome
Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined and the pathophysiology unknown. Here, the authors conduct deep phenotyping of a cohort of PI-ME/CFS patients.
- Brian Walitt
- , Komudi Singh
- & Avindra Nath
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Article
| Open AccessStructure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies
The T cell receptor β-chain is expressed in two isoforms, TRBC1 and TRBC2, with clonally expanded mature T cell lymphomas expressing one of them exclusively, while healthy T cells randomly express either TRBC1 or TRBC2. Here authors show structure-based design of a TRBC2-specific antibody, and depletion of malignant T cells carrying TRBC1 or TRBC2 with CAR-T cells against the cognate receptor chain in murine models.
- Mathieu Ferrari
- , Matteo Righi
- & Martin Pule
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Article
| Open AccessA convergent evolutionary pathway attenuating cellulose production drives enhanced virulence of some bacteria
Extra-intestinal pathogenic Escherichia coli cause urinary tract and bloodstream infections. Here, the authors show how mutations that disrupt the production of cellulose, a polysaccharide produced by many bacteria, drive enhanced virulence.
- Nguyen Thi Khanh Nhu
- , M. Arifur Rahman
- & Mark A. Schembri
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Article
| Open AccessIntestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders
Interleukin (IL)-22 is critical in ameliorating obesity-induced metabolic disorders; however, it is unclear where IL-22 acts to mediate these outcomes. Here, the authors show in tissue-specific IL-22 receptor knockout mice a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating obesity-associated disorders.
- Stephen J. Gaudino
- , Ankita Singh
- & Pawan Kumar
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Article
| Open AccessWASH interventions and child diarrhea at the interface of climate and socioeconomic position in Bangladesh
Household water, sanitation, and handwashing (WASH) interventions can reduce diarrhoea-related morbidity in young children. Here, the authors report findings from a pre-specified secondary analysis of a cluster-randomised trial assessing how WASH impacts vary by socioeconomic position and season.
- Pearl Anne Ante-Testard
- , Francois Rerolle
- & Benjamin F. Arnold
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Article
| Open AccessChronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release
Myotonic dystrophy type 2 is characterized by large CCUG repeats in the CNBP gene that result in myopathy. Here, the authors show that recognition of aberrant protein translation derived from these repeats leads to ER stress and mitochondrial DNA release, leading to cGAS/STING activation and type-I IFN responses.
- Sarah Rösing
- , Fabian Ullrich
- & Claudia Günther
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Article
| Open AccessA SPLICS reporter reveals \({{{{{\boldsymbol{\alpha }}}}}}\)-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation
Mitochondria-lysosome interactions are fundamental to cellular physiology. Here, the authors describe a genetically-encoded SPLICS reporter to study short- and long-juxtapositions between mitochondria and lysosomes.
- Flavia Giamogante
- , Lucia Barazzuol
- & Marisa Brini
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Article
| Open AccessLong-term exposure to ambient PM2.5, particulate constituents and hospital admissions from non-respiratory infection
The study evaluated the impact of PM2.5 and its constituents on hospital admissions from non-respiratory infection. Here, the authors showed that nonrespiratory infections are an under-appreciated health effect of PM2.5 while Sulfates contributed the largest weights in the observed associations
- Yijing Feng
- , Edgar Castro
- & Joel Schwartz
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Article
| Open AccessCellular hierarchy insights reveal leukemic stem-like cells and early death risk in acute promyelocytic leukemia
The cellular hierarchies in acute promyelocytic leukemia (APL) remain to be explored. Here, the authors perform single-cell RNA sequencing of 16 APL patients to characterise its cellular composition and develop an APL-specific stemness score for assessing the risk of early death in APL.
- Wen Jin
- , Yuting Dai
- & Kankan Wang
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Article
| Open AccessCell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing
Cell softness protects cytotoxic T lymphocytes (CTL) from autolysis by own soluble factors such as perforin secreted for killing target cells. Here the authors show that softness can be induced by YAP activation, and that T leukemic cells are more sensitive to YAP inhibition than CTLs, thereby hinting YAP inhibitors as a potential therapy for T leukemia.
- Yabo Zhou
- , Dianheng Wang
- & Bo Huang
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Article
| Open AccessFlexible and cost-effective genomic surveillance of P. falciparum malaria with targeted nanopore sequencing
Genomic surveillance of Plasmodium falciparum could improve monitoring of drug resistance, but implementation has been hampered due to the large and complex genome. Here, de Cesare et al. develop a flexible and cost-effective nanopore sequencing approach to detect drug resistance and diagnostic escape for P. falciparum malaria.
- Mariateresa de Cesare
- , Mulenga Mwenda
- & Jason A. Hendry
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Article
| Open AccessAssessing emergence risk of double-resistant and triple-resistant genotypes of Plasmodium falciparum
Emergence of malaria parasites resistant to artemisinin has prompted the need for new drug regimens to ensure effective treatment. In this simulation study, the authors evaluate the risk of multidrug resistance under regimens with either concurrent or cyclic use of different first-line therapies.
- Eric Zhewen Li
- , Tran Dang Nguyen
- & Maciej F. Boni
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Article
| Open AccessMultigenerational paternal obesity enhances the susceptibility to male subfertility in offspring via Wt1 N6-methyladenosine modification
The mechanisms through which multigenerational paternal obesity affects spermatogenesis in offspring remain poorly understood. Here, the authors show that it affects Wt1 m6A modifications, decreasing the fertility of offspring.
- Yong-Wei Xiong
- , Hua-Long Zhu
- & Hua Wang
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Article
| Open AccessModeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip
Here the authors develop perfusable inner blood-retinal barrier-specific microvascular networks with human primary retinal microvascular cells. They show that chronic diabetic stimulation leads to the generation of early hallmarks of diabetic retinopathy, including pericyte and capillary dropout, ghost vessels, and inflammation.
- Thomas L. Maurissen
- , Alena J. Spielmann
- & Héloïse Ragelle
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Article
| Open AccessNatural selection and genetic diversity maintenance in a parasitic wasp during continuous biological control application
Parasitoid wasps are reared and released as biocontrol agents to manage aphids and protect crops. Here, the authors use genomes from 542 wasps to show that, in spite of wide scale release of low-diversity captive individuals, diversity in wild populations is maintained.
- Bingyan Li
- , Yuange Duan
- & Hu Li
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Q&A
| Open AccessA spotlight on the tuberculosis epidemic in South Africa
Tuberculosis is the leading cause of death from a single infectious agent, with over 25% of these occurring in the African region. Multi-drug resistant strains which do not respond to first-line antibiotics continue to emerge, putting at risk numerous public health strategies which aim to reduce incidence and mortality. Here, we speak with Professor Valerie Mizrahi, world-leading researcher and former director of the Institute of Infectious Disease and Molecular Medicine at the University of Cape Town, regarding the tuberculosis burden in South Africa. We discuss the challenges faced by researchers, the lessons that need to be learnt and current innovations to better understand the overall response required to accelerate progress.
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Article
| Open AccessPredicting proximal tubule failed repair drivers through regularized regression analysis of single cell multiomic sequencing
A profibrotic, proinflammatory kidney cell population has been identified as a driver of chronic kidney disease. Here, authors generate a human kidney single cell multiomic dataset and apply a regularised regression approach to identify transcription factors underpinning this cell population.
- Nicolas Ledru
- , Parker C. Wilson
- & Benjamin D. Humphreys
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Article
| Open AccessKisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src
The authors of this manuscript identify that Gpr54 activation by its natural ligand Kisspeptin-10 can abrogate bone resorption. Mechanistically, Gpr54 recruits both active Src and the Dusp18 phosphatase, which causes Dusp18 to dephosphorylate Src at Tyr 416.
- Zhenxi Li
- , Xinghai Yang
- & Jianru Xiao
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Article
| Open AccessIncome determines the impact of cash transfers on HIV/AIDS: cohort study of 22.7 million Brazilians
Brazil has operated a conditional cash transfer program to support families living in precarious conditions since 2004. Here, the authors use linked administrative and health data to investigate the impacts of the program on HIV/AIDS-related outcomes, demonstrating strong positive associations.
- Andréa F. Silva
- , Inês Dourado
- & Davide Rasella
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Article
| Open AccessApplying valency-based immuno-selection to generate broadly cross-reactive antibodies against influenza hemagglutinins
Here the authors develop a DNA vaccine, mixing 18 hemagglutinin (HA) subtypes monovalently into heterodimeric molecules, and show that it induces broadly reactive antibodies against subdominant HA epitopes and heterologous protection against influenza A viruses in mice.
- Daniëla Maria Hinke
- , Ane Marie Anderson
- & Ranveig Braathen
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Article
| Open AccessComparative effectiveness of alternative intervals between first and second doses of the mRNA COVID-19 vaccines
The optimal timing between first and second mRNA COVID-19 vaccine doses has not been established. Here, the authors use electronic health record data from Georgia, USA in a target trial emulation study to estimate vaccine effectiveness against infection for different dose intervals.
- Kayoko Shioda
- , Alexander Breskin
- & Elizabeth T. Rogawski McQuade
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Article
| Open AccessGlucocorticoids increase adiposity by stimulating Krüppel-like factor 9 expression in macrophages
Glucocorticoids, potent anti-inflammatory drugs, can cause or exacerbate obesity, yet the underlying molecular mechanisms remain largely unknown. Here, the authors show KLF9 in macrophages integrates the beneficial anti-inflammatory and adverse metabolic effects of glucocorticoids.
- Yinliang Zhang
- , Chunyuan Du
- & Yongsheng Chang
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Article
| Open AccessProtection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R
Overfeeding triggers a mechanistically ill-defined compensatory response that counteracts weight gain. Here, the authors show that the defence against overfeeding is preserved in obesity, and that it is independent from FGF21 and MC4R.
- Camilla Lund
- , Pablo Ranea-Robles
- & Christoffer Clemmensen
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Article
| Open AccessDisease clusters subsequent to anxiety and stress-related disorders and their genetic determinants
In this study, the authors found five disease clusters associated with a prior diagnosis of anxiety/stress-related disorders, and identified several underlying genetic components. These findings may aid mechanistic exploration and risk management for health decline among those patients.
- Xin Han
- , Qing Shen
- & Huan Song
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Article
| Open AccessRegulating protein corona on nanovesicles by glycosylated polyhydroxy polymer modification for efficient drug delivery
The dynamic protein corona hinders the uptake of nanocarriers in desired target cell populations, limiting their bench-to-bedside translation. Here the authors reveal that the modification of hydroxyl and amino functional groups on nanovesicles can rationally regulate the composition of protein coronas to improve the efficiency of targeted drug delivery.
- Yunqiu Miao
- , Lijun Li
- & Yong Gan
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Article
| Open AccessA multicenter clinical AI system study for detection and diagnosis of focal liver lesions
Early detection and accurate diagnosis of focal liver lesions are crucial for effective treatment and prognosis. Here, the authors present a fully automated diagnostic system that leverages multi-phase CT scans and clinical features, for diagnosing liver lesions.
- Hanning Ying
- , Xiaoqing Liu
- & Xiujun Cai
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Article
| Open AccessPredicting the risk and speed of drug resistance emerging in soil-transmitted helminths during preventive chemotherapy
Resistance to chemotherapy for soil-transmitted helminth infection has been detected in veterinary settings but not yet in human infections. Here, the authors investigate the risk of resistance in humans and how it may change as a result of scaling-up preventative deworming programs.
- Luc E. Coffeng
- , Wilma A. Stolk
- & Sake J. de Vlas
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Article
| Open AccessTumor reactive γδ T cells contribute to a complete response to PD-1 blockade in a Merkel cell carcinoma patient
Immune checkpoint blockade cancer therapy has been designed to enable tumor killing by conventional αβ T cells. Here authors show that in a Merkel cell carcinoma patient showing complete response to anti-PD-1 treatment, innate-like γδ T cells that specifically recognize the tumor cells expand, and likely contribute to therapeutic success.
- Scott C. Lien
- , Dalam Ly
- & Pamela S. Ohashi
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Article
| Open AccessMAIVeSS: streamlined selection of antigenically matched, high-yield viruses for seasonal influenza vaccine production
Vaccines combat global influenza threats, relying on timely selection of optimal seed viruses. Here, authors introduce MAIVeSS, a machine learning assisted framework to streamline vaccine seed virus selection using genomic sequence, expediting seasonal flu vaccine production and supply.
- Cheng Gao
- , Feng Wen
- & Xiu-Feng Wan
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Article
| Open AccessPathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production
Gain-of-function mutations in NLRP3 result in Cryopyrin-Associated Periodic Syndrome in human patients. Here authors show that although these NLRP3 variants are constitutively active, they preserve their responsiveness to external pro-inflammatory stimuli, and they interfere with the immune-metabolic inflammatory pathways in monocytes.
- Cristina Molina-López
- , Laura Hurtado-Navarro
- & Pablo Pelegrin
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Article
| Open AccessSynchrony of Bird Migration with Global Dispersal of Avian Influenza Reveals Exposed Bird Orders
Highly pathogenic avian influenza virus subtype H5 is an important pathogen of wild birds and poultry that has also caused infection in humans and other mammals. Here the authors use wild bird movement tracking data and virus genome sequences to quantify how seasonal bird migration facilitates global dispersal of the virus.
- Qiqi Yang
- , Ben Wang
- & Bryan Grenfell
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Article
| Open AccessHealth effects associated with chewing tobacco: a Burden of Proof study
While the number of chewing tobacco users is increasing in many countries, it is often under-emphasized in tobacco control. Here, the authors show that chewing tobacco is a risk factor for major causes of disease burden, including stroke and various cancers, meriting future research and policy attention.
- Gabriela F. Gil
- , Jason A. Anderson
- & Emmanuela Gakidou
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Article
| Open AccessTransport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain
Human ABC transporter ABCC2 transports conjugated bilirubin from hepatocyte to bile duct, dysfunction of which causes Dubin-Johnson syndrome. Here, the authors provide structural insights into the substrate specificity of ABCC2 and the transport mechanism regulated by the R domain.
- Yao-Xu Mao
- , Zhi-Peng Chen
- & Yuxing Chen
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Article
| Open AccessHIV-associated gut microbial alterations are dependent on host and geographic context
Here, the authors compare the fecal microbial community of individuals in the U.S., Uganda, and Botswana, and identify significant bacterial taxa alterations with both treated and untreated HIV infection although with a high degree of uniqueness in each cohort, and also significant differences between populations that report men who have sex with men (MSM) behavior and non-MSM populations.
- Muntsa Rocafort
- , David B. Gootenberg
- & Douglas S. Kwon
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Article
| Open AccessCamrelizumab and apatinib plus induction chemotherapy and concurrent chemoradiotherapy in stage N3 nasopharyngeal carcinoma: a phase 2 clinical trial
The antiangiogenic agent apatinib has been shown to clinically improve responses to immune checkpoint inhibitors in several cancer types. Here the authors report the results of a phase II clinical trial of camrelizumab (anti-PD1) and apatinib plus induction chemotherapy and concurrent chemoradiotherapy in stage N3 nasopharyngeal carcinoma.
- Hu Liang
- , Yao-Fei Jiang
- & Yan-Qun Xiang
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Article
| Open AccessGestational diabetes augments group B Streptococcus infection by disrupting maternal immunity and the vaginal microbiota
Here, Marcado-Evans et al show that gestational diabetes enhances group B Streptococcus infection through altering host-microbe dynamics, disrupting maternal immunity, and perturbing the vaginal microbiota in a murine pregnancy model.
- Vicki Mercado-Evans
- , Marlyd E. Mejia
- & Kathryn A. Patras
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Article
| Open AccessLocal structural preferences in shaping tau amyloid polymorphism
In this work, using a combination of Cryo-EM, in-cell experiments and biophysical analysis, the authors decoded the aggregation propensity of tau, revealing 5 central hot spots in its primary sequence and identify PAM4 as short segment that determines both the structure, as well as the cellular propagation of tau aggregates extracted from Alzheimer’s disease, corticobasal degeneration, and progressive supranuclear palsy patients.
- Nikolaos Louros
- , Martin Wilkinson
- & Joost Schymkowitz
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Article
| Open AccessProgrammed microalgae-gel promotes chronic wound healing in diabetes
The treatment of infected diabetic wounds faces obstacles of bacterial infection, hypoxia, hyperexpression of reactive oxygen species, and inflammation. Here, the authors address these issues by developing a programmed treatment strategy that utilizes live Haematococcus to promote healing of diabetic wounds in a comprehensive manner.
- Yong Kang
- , Lingling Xu
- & Xiaoyuan Ji
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Article
| Open AccessPhosphorylation of human glioma-associated oncogene 1 on Ser937 regulates Sonic Hedgehog signaling in medulloblastoma
Upregulation of GLI1 of has previously been reported in sonic hedgehog (SHH) driven medulloblastoma and basal cell carcinoma (BCC). Here, the authors find that SHH-inactivation of p38 results in stabilization of the transcription factor GLI1 via dephosphorylation at Ser937, resulting in expression of SHH genes and presenting a potential therapy strategy for medulloblastoma and BCC.
- Ling-Hui Zeng
- , Chao Tang
- & Jirong Wang
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Article
| Open AccessRisk of SARS-CoV-2 reinfection during multiple Omicron variant waves in the UK general population
The factors influencing risk of reinfection with SARS-CoV-2 are poorly understood. Here, the authors use data from the UK COVID-19 Infection Survey, a community based longitudinal study, to assess characteristics of ~45,000 reinfections compared to initial infections.
- Jia Wei
- , Nicole Stoesser
- & Chris Cunningham
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Article
| Open AccessEarly onset diagnosis in Alzheimer’s disease patients via amyloid-β oligomers-sensing probe in cerebrospinal fluid
In this work, the authors characterize a small molecule fluorescent probe pioneering early diagnosis of Alzheimer’s disease through identification of amyloid-β oligomers in patients’ cerebrospinal fluid, demonstrating potential for clinical application.
- Jusung An
- , Kyeonghwan Kim
- & Jong Seung Kim
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Article
| Open AccessIdentification of potential aggregation hotspots on Aβ42 fibrils blocked by the anti-amyloid chaperone-like BRICHOS domain
This study identifies potential aggregation hotspots on the fibril surface of Alzheimer’s disease associated Aβ42 fibrils, which are blocked by the anti-amyloid chaperone-like domain BRICHOS.
- Rakesh Kumar
- , Tanguy Le Marchand
- & Axel Abelein
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Article
| Open AccessCongenital heart disease detection by pediatric electrocardiogram based deep learning integrated with human concepts
Congenital heart disease is life threatening, and its screening is complex and costly. Here, authors use AI to detect the disease based on pediatric electrocardiogram, suggesting superior performance over cardiologists.
- Jintai Chen
- , Shuai Huang
- & Huiying Liang
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Article
| Open AccessMaternal pertussis immunization and the blunting of routine vaccine effectiveness: a meta-analysis and modeling study
Pertussis immunisation for pregnant women has been introduced to protect newborns, but immunological evidence suggests that this lessens subsequent infant immune response to vaccination. Here, the authors assess the epidemiological impacts of both consequences of maternal immunisation on infant infection.
- Michael Briga
- , Elizabeth Goult
- & Matthieu Domenech de Cellès
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Article
| Open AccessDimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.
- Peter Sandercock
- , Janet Darbyshire
- & Martin J. Landray
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Comment
| Open AccessAfrican leadership is critical in responding to public health threats
The African continent demonstrated decisive leadership throughout its response to the COVID-19 pandemic, leveraging lessons learned from previous outbreaks and acting quickly to limit the impact of the SARS-CoV-2 virus. We propose a framework to build on these successes that calls for greater collaboration between African leaders, and greater inclusion of African voices in the global health ecosystem.
- Nicaise Ndembi
- , Aggrey Aluso
- & Jean Kaseya
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