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| Open AccessIndividual level analysis of digital proximity tracing for COVID-19 in Belgium highlights major bottlenecks
Digital proximity tracing apps were widely used during the COVID-19 pandemic but have not been thoroughly evaluated. Here, the authors use data from students in Leuven, Belgium and estimate that apps notified only ~4% exposed contacts, had a 1–2 day delay for notification, and identified fewer infected contacts than manual contact tracing.
- Caspar Geenen
- , Joren Raymenants
- & Emmanuel André
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Article
| Open AccessActivation of coagulation and proinflammatory pathways in thrombosis with thrombocytopenia syndrome and following COVID-19 vaccination
Adenovirus-based vaccination for SARS-CoV-2 has a rare chance to cause thrombosis with thrombocytopenia (TTS). Here the authors compare proteomic and transcriptomic data from vaccinated participants with or without TTS to find distinct activations of coagulation and innate immune pathways in patient with TTS, or following initial or boosting vaccination.
- Malika Aid
- , Kathryn E. Stephenson
- & Dan H. Barouch
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Article
| Open AccessA genomic appraisal of invasive Salmonella Typhimurium and associated antibiotic resistance in sub-Saharan Africa
Invasive Salmonella Typhimurium bloodstream infection causes a significant public health burden in sub-Saharan Africa. Here, the authors analyse whole genome sequences of 1,302 S. Typhimurium isolates from Africa and describe its evolution, geographic spread, and antimicrobial resistance characteristics.
- Sandra Van Puyvelde
- , Tessa de Block
- & Octavie Lunguya
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Article
| Open AccessAn innate granuloma eradicates an environmental pathogen using Gsdmd and Nos2
Pathogens often persist within granulomas which form to control infection. Here, Harvest et al describe an innate granuloma that eradicates a ubiquitous environmental pathogen without inducing adaptive immunity.
- Carissa K. Harvest
- , Taylor J. Abele
- & Edward A. Miao
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Article
| Open AccessDisease-specific loss of microbial cross-feeding interactions in the human gut
Gut microbes rely on nutrient exchange for survival, but these cross-feeding interactions remain poorly characterized. Here, Marcelino et al. present a metabolite-exchange scoring system derived from metagenome-scale metabolic models, designed to identify the potential microbial cross-feeding interactions most affected in human diseases.
- Vanessa R. Marcelino
- , Caitlin Welsh
- & Samuel C. Forster
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Article
| Open AccessPreservation versus resection of Denonvilliers’ fascia in total mesorectal excision for male rectal cancer: follow-up analysis of the randomized PUF-01 trial
Total mesorectal excision (TME) for rectal cancer can require partial resection of Denonvilliers’ fascia (DVF). Here the authors report the secondary outcomes of a randomized trial to evaluate the safety and effect of DVF preservation during laparoscopic TME on postoperative urogenital function and oncological safety in male patients with mid-low rectal cancer.
- Jiafeng Fang
- , Bo Wei
- & Hongbo Wei
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Article
| Open AccessCD8+ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production
Control of HIV and SIV infection is largely thought to be achieved through direct lysis of target cells. Here, using mathematical modelling of viral load data from rhesus macaques, the authors propose that virus control is best explained by the combination of cytolytic and non-cytolytic effects.
- Benjamin B. Policicchio
- , Erwing Fabian Cardozo-Ojeda
- & Ruy M. Ribeiro
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Article
| Open AccessThe airway microbiota of neonates colonized with asthma-associated pathogenic bacteria
Here, Thorsen et al. bridge new and previous results from the COPSAC2000 prospective birth cohort and the later COPSAC2010 cohort, by constructing a combined bacterial pathogen score with implications for the early-life airway microbiota and the risk of asthma later in childhood
- Jonathan Thorsen
- , Xuan Ji Li
- & Jakob Stokholm
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Article
| Open AccessRING finger protein 13 protects against nonalcoholic steatohepatitis by targeting STING-relayed signaling pathways
The STING-relayed inflammation response has been increasingly identified as one of the key drivers of NAFLD progression. Here the authors show that an E3 ubiquitin ligase, RNF13, can ameliorate NAFLD phenotypes by facilitating the TRIM29-mediated degradation of STING.
- Zhibin Lin
- , Peijun Yang
- & Lin Wang
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Article
| Open AccessEpidemiology of Plasmodium malariae and Plasmodium ovale spp. in Kinshasa Province, Democratic Republic of Congo
Non-falciparum malaria may cause a significant disease burden in highly endemic regions, but epidemiological data is limited. In this study, the authors estimate the incidence and prevalence of P. malariae, P. ovale spp., in Kinshasa, Democratic Republic of Congo and compare to P. falciparum, which known to be common in the region.
- Rachel Sendor
- , Kristin Banek
- & Jonathan B. Parr
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Article
| Open AccessObesity dysregulates the pulmonary antiviral immune response
Obesity is a risk factor for severe influenza infection. Here, Almond et al show that increased susceptibility is due to increased airway concentrations of the hormone leptin which dampens interferon responses and facilitates severe infection.
- Mark Almond
- , Hugo A. Farne
- & Aran Singanayagam
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Article
| Open AccessmRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy
Large genes require dual adeno-associated viral (AAV) vectors for in vivo delivery/expression, but current methods have limitations. Here the authors develop and functionally evaluate REVeRT, an efficient and flexible dual AAV vector technology based on reconstitution via mRNA trans-splicing.
- Lisa Maria Riedmayr
- , Klara Sonnie Hinrichsmeyer
- & Elvir Becirovic
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Article
| Open AccessCryptococcus neoformans adapts to the host environment through TOR-mediated remodeling of phospholipid asymmetry
Here, Ristow et al show that the environmental fungus Cryptococcus adapts to the higher carbon dioxide levels present in human tissue through activation of the Target-of-Rapamycin stress response pathway leading to reorganization of its outer membrane lipids and host adaptation.
- Laura C. Ristow
- , Andrew J. Jezewski
- & Damian J. Krysan
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Article
| Open AccessMetabolic fingerprinting on retinal pigment epithelium thickness for individualized risk stratification of type 2 diabetes mellitus
The retina’s role in type 2 diabetes is not well understood. Here, the authors show that retinal pigment epithelium thickness, with its metabolic fingerprints, might offer improved predictability and clinical utility beyond traditional indicators.
- Shaopeng Yang
- , Zhuoting Zhu
- & Wei Wang
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Article
| Open AccessAssessing the global risk of typhoid outbreaks caused by extensively drug resistant Salmonella Typhi
Extensively drug resistant (XDR) typhoid fever is an emerging global health threat. This study compares data on air travel patterns and typhoid incidence to identify countries at high risk for XDR typhoid outbreaks.
- Joseph Walker
- , Chrispin Chaguza
- & Virginia E. Pitzer
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Article
| Open AccessCryptic susceptibility to penicillin/β-lactamase inhibitor combinations in emerging multidrug-resistant, hospital-adapted Staphylococcus epidermidis lineages
Staphylococcus epidermidis can cause invasive infections that are difficult to treat due to multi-resistance to most clinically relevant drugs, including methicillin and other β-lactam antibiotics, vancomycin, and rifampicin. In this work, the authors use in vitro assays and a mouse infection model to explore cryptic susceptibility and development of resistance to penicillin/β-lactamase combinations.
- Xiaoliang Ba
- , Claire L. Raisen
- & Jesper Larsen
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Article
| Open AccessFGFR2 is essential for salivary gland duct homeostasis and MAPK-dependent seromucous acinar cell differentiation
Restoring salivary acinar cells after gland damage is a major clinical challenge. Here, authors identify FGF7-FGFR2-MAPK signaling as a regenerative target, critical for myoepithelial-acinar crosstalk that regulates seromucous acinar differentiation.
- Marit H. Aure
- , Jennifer M. Symonds
- & Matthew P. Hoffman
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Article
| Open AccessSpatial and temporal dynamics of West Nile virus between Africa and Europe
West Nile virus is an animal pathogen that has spread rapidly in Europe in recent years, causing several human deaths. This study investigates the spatial and temporal dynamics of the virus circulation between Africa (its place of origin) and Europe.
- Giulia Mencattelli
- , Marie Henriette Dior Ndione
- & Giovanni Savini
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Article
| Open AccessDevelopmental atlas of phase-amplitude coupling between physiologic high-frequency oscillations and slow waves
It remains unclear how cortical high-frequency oscillations (HFOs) and their relation with slow waves change with age. Here, the authors found that while HFO rate widely decreases over time, its coupling with slow waves strengthens in the occipital lobe during childhood.
- Kazuki Sakakura
- , Naoto Kuroda
- & Eishi Asano
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Article
| Open AccessExtracellular vesicles could be a putative posttranscriptional regulatory mechanism that shapes intracellular RNA levels in Plasmodium falciparum
Here, Kioko et al. describe a putative posttranscriptional RNA regulation mechanism involving secreted extracellular vesicles to maintain the intracellular steady-state RNA levels during the asexual blood stage of malaria parasites.
- Mwikali Kioko
- , Alena Pance
- & Abdirahman I. Abdi
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Article
| Open AccessBile acids-mediated intracellular cholesterol transport promotes intestinal cholesterol absorption and NPC1L1 recycling
Intestinal cholesterol is taken into endocytic recycling compartment via NPC1L1-mediated endocytosis. Here the authors show that certain bile acids facilitate cholesterol transport to the endoplasmic reticulum from endocytic recycling compartment in cells and NPC1L1 is then recycled back to the plasma membrane.
- Jian Xiao
- , Le-Wei Dong
- & Bao-Liang Song
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Article
| Open AccessStructure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir
In this study, the authors report the structure-based discovery and preclinical evaluation of 2 simnotrelvir, an orally bioavailable 3CLpro inhibitor that blocks replication of SARS-CoV-2 variants in 3 vitro, shows robust efficacy in a mouse model and good safety and pharmacokinetic profiles in rats 4 and monkeys.
- Xiangrui Jiang
- , Haixia Su
- & Yechun Xu
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Article
| 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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Article
| Open AccessSARS-CoV-2 infection of human lung epithelial cells induces TMPRSS-mediated acute fibrin deposition
Severe SARS-CoV-2 infection has been associated with extensive diffuse alveolar damage and fibrin formation. Here, Erickson et al describe an infection-induced coagulation mechanism which involves activation of prothrombin by members of TMPRSS genes.
- Rachel Erickson
- , Chang Huang
- & Peter D. Sun
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Article
| Open AccessTripartite motif containing 26 prevents steatohepatitis progression by suppressing C/EBPδ signalling activation
Nonalcoholic steatohepatitis (NASH) is a heterogeneous disease with complicated pathogenesis. Here the authors identify that the E3 ligase TRIM26 confers protection against NASH development via suppression of CCAAT/enhancer binding protein delta (C/EBPδ).
- Minxuan Xu
- , Jun Tan
- & Lianyi Han
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Article
| Open AccessCSTF2 mediated mRNA N6-methyladenosine modification drives pancreatic ductal adenocarcinoma m6A subtypes
N6-methyladenosine (m6A) modification has important implications in different cancer subtypes. Here, the authors perform transcriptomic m6A profiling to identify two subtypes of pancreatic ductal adenocarcinoma with differential m6A modifications and different clinical outcomes, which is driven by m6A regulator CSTF2.
- Yanfen Zheng
- , Xingyang Li
- & Zhixiang Zuo
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Article
| Open AccessDevelopment and validation of the pandemic fatigue scale
In this study the authors introduce a measure of pandemic fatigue and report the existence of, and changes in, pandemic fatigue during the COVID-19 pandemic. They also identify correlates of pandemic fatigue and show that those who experienced more pandemic fatigue were less likely to adhere to various health-protective behaviors.
- Lau Lilleholt
- , Ingo Zettler
- & Robert Böhm
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Article
| Open AccessSubventricular zone cytogenesis provides trophic support for neural repair in a mouse model of stroke
The functions of newborn cells arising from the subventricular zone in response to stroke have been unclear. Here, the authors show that cells migrating from the subventricular zone after stroke promote brain repair and functional recovery in mice.
- Michael R. Williamson
- , Stephanie P. Le
- & Michael R. Drew
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Article
| Open AccessBone disease imaging through the near-infrared-II window
Skeletal disorders are commonly diagnosed by X-ray imaging, but the radiation limits its use. Here, the authors show that intravital NIR-II bone imaging is effective in diagnosis of a series of common bone diseases non-invasively in mice.
- Chao Mi
- , Xun Zhang
- & Dayong Jin
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Article
| Open AccessMetabolic phenotyping of BMI to characterize cardiometabolic risk: evidence from large population-based cohorts
A substantial proportion of patients with cardiometabolic conditions appear to have normal BMI. Conversely, not all obese individuals exhibit these disorders. Here, we show that a metabolic BMI score derived from lipidomic models, allows quantify metabolic dysregulation in obesity independently of BMI.
- Habtamu B. Beyene
- , Corey Giles
- & Peter J. Meikle
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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 AccessImproving model fairness in image-based computer-aided diagnosis
Deep learning models can reflect and amplify human bias, potentially resulting inaccurate missed diagnoses. Here, the authors show that by leveraging the marginal pairwise equal opportunity, their model reduces bias in medical image classification by over 35% compared to baseline models, with minimal impact on AUC values.
- Mingquan Lin
- , Tianhao Li
- & Yifan Peng
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Article
| Open AccessA molecular staging model for accurately dating the endometrial biopsy
Natural variability in menstrual cycle length with rapid changes in gene expression makes it difficult to accurately compare different stages of the endometrial cycle. Here, the authors show a method for precisely determining endometrial cycle stage based on global gene expression that reveals remarkably synchronised daily changes for over 3,400 endometrial genes.
- W. T. Teh
- , J. Chung
- & P. A. W. Rogers
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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 AccessDecreased liver B vitamin-related enzymes as a metabolic hallmark of cancer cachexia
Cancer cachexia is a multifactorial metabolic syndrome affecting a large fraction of patients with advanced cancer. Here the authors report a decrease in B vitamin-related liver enzymes in mouse models and gastric cancer patients with cachexia.
- Yasushi Kojima
- , Emi Mishiro-Sato
- & Masahiro Aoki
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Article
| Open AccessViral kinetics of sequential SARS-CoV-2 infections
In this study, the authors compare the viral kinetics of first and second SARS-CoV-2 infections using data from an occupational surveillance scheme in the National Basketball League. They find that second infections tend to have a faster clearance time, and that clearance times in first and second infections were positively correlated.
- Stephen M. Kissler
- , James A. Hay
- & Yonatan H. Grad
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Article
| 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 AccessIntravenous administration of BCG in mice promotes natural killer and T cell-mediated antitumor immunity in the lung
Intravesical administration of BCG is a standard treatment for bladder cancer. In this study, the authors examine the effect of systemic BCG administration in murine models of primary lung cancer and melanoma metastasis, demonstrating a beneficial effect either alone or in combination with PD-L1.
- Eduardo Moreo
- , Aitor Jarit-Cabanillas
- & Nacho Aguiló
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Article
| Open AccessMYL3 protects chondrocytes from senescence by inhibiting clathrin-mediated endocytosis and activating of Notch signaling
Age is the greatest risk factor for osteoarthritis (OA) and chondrocyte senescence is an important cellular event that contributes to OA development. This study shows that clathrin-mediated endocytosis and activation of Notch signaling promotes articular chondrocyte senescence and OA development, which is negatively regulated by myosin light chain 3 (MYL3).
- He Cao
- , Panpan Yang
- & Kai Li
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Article
| Open AccessAlternative splicing in lung influences COVID-19 severity and respiratory diseases
Alternative splicing of transcripts can influence human traits, such as immune response to infection. Here, the authors use mendelian randomization to reveal a role of alternative splicing in lung on COVID-19 severity and susceptibility, offering potential drug discovery avenues.
- Tomoko Nakanishi
- , Julian Willett
- & J. Brent Richards
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Article
| Open AccessGlyco-engineered MDCK cells display preferred receptors of H3N2 influenza absent in eggs used for vaccines
Evolution of human H3N2 influenza has limited the specificity of hemagglutinin to a subset of glycan receptors, which brings challenges. By glyco-engineering cell lines, authors show the importance of extended glycan receptors for growth of recent H3N2 viruses and relevance to their production for vaccines.
- Chika Kikuchi
- , Aristotelis Antonopoulos
- & James C. Paulson
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Article
| Open AccessCytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress
Endonuclease G is known to translocate to the nucleus during apoptosis, but less is known about its role in the cytosol. Here, the authors show that cytoplasmic endonuclease G activates mTORC2 signaling and ER stress to promote NAFLD in female mice.
- Wenjun Wang
- , Junyang Tan
- & Qinghua Zhou
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Article
| Open AccessTET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression
TET2 and GATA2 are two frequently co-mutated genes in CEBPA double mutated acute myeloid leukemia (AML). Here the authors show that the underlying mechanism for this cooccurrence is for TET2 loss-of-function mutation to counteract the increase in GATA2 expression, which is disadvantageous to these type of AML cells.
- Elizabeth Heyes
- , Anna S. Wilhelmson
- & Bo T. Porse
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Article
| Open AccessEuropean and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation
The genetic basis of atopic dermatitis is not fully understood. Here, the authors find 91 genetic loci associated with atopic dermatitis in a GWAS of >1million individuals, which highlight the importance of systemic immune regulation.
- Ashley Budu-Aggrey
- , Anna Kilanowski
- & Lavinia Paternoster
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Perspective
| Open AccessThe uncertain role of substandard and falsified medicines in the emergence and spread of antimicrobial resistance
Substandard and falsified medicines are a problem, particularly in low- and middle-income countries, and effects on antimicrobial resistance development aren’t well understood. Here, the authors discuss mechanisms by which they can increase or decrease levels of resistance and the need for improved data collection and analytical approaches.
- Sean Cavany
- , Stella Nanyonga
- & Ben S. Cooper
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Article
| Open AccessStructural insights into the conformational changes of BTR1/SLC4A11 in complex with PIP2
BTR1 is an electrogenic H+ transporter belonging to the bicarbonate transporter family. Here, the authors present structures of BTR1 in different conformations and uncover PIP2 as the activator of BTR1.
- Yishuo Lu
- , Peng Zuo
- & Yuxin Yin
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Article
| Open AccessRepressed Blautia-acetate immunological axis underlies breast cancer progression promoted by chronic stress
Chronic stress can promote breast cancer progression. Here the authors show that a reduction in the levels of Blautia and its metabolite acetate contributes to chronic stress-promoted breast cancer progression, associated with decreased CD8 + T cell anti-tumor immunity.
- Ling Ye
- , Yuanlong Hou
- & Haiping Hao
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