Featured
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Article
| Open AccessEvaluation of pragmatic oxygenation measurement as a proxy for Covid-19 severity
There is a need for an accurate measure of pulmonary oxygenation function that can be used as an intermediate endpoint in pragmatic clinical trials, to increase statistical power and efficiency. Here, the authors show that the S/F94, a modification of the S/F ratio, is a simple, meaningful and effective intermediate outcome measure.
- Maaike C. Swets
- , Steven Kerr
- & J. Kenneth Baillie
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Article
| Open AccessTLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase
Toll-like receptor 7 (TLR7) normally recognizes exogenous single-stranded RNA for the activation of innate immunity. Here the authors show that TLR7 may also contribute, via the modulation of mast cell functions, to experimental, cigarette smoke-induced mouse models of emphysema, thereby hinting TLR7 as a potential therapeutic target for human lung inflammation.
- Gang Liu
- , Tatt Jhong Haw
- & Philip M. Hansbro
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Article
| Open AccessDeciphering a critical role of uterine epithelial SHP2 in parturition initiation at single cell resolution
The mechanism of parturition initiation remains elusive. Here, authors show that epithelium is an underestimated site for parturition initiation via epithelial PGF2a regulated by SHP2-COX1/COX2.
- Meng Liu
- , Mengjun Ji
- & Wenbo Deng
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Article
| Open AccessMechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks
The 24-hour circadian clocks in cartilage and intervertebral disc play key roles in regulating tissue physiology, yet how they are reset on a daily basis remains elusive. Here the authors show that daily patterns of mechanical loading and associated changes in osmolarity provide a tissue-type specific entrainment time cue for these skeletal clocks.
- Michal Dudek
- , Dharshika R. J. Pathiranage
- & Qing-Jun Meng
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Article
| Open AccessDietary L-Tryptophan consumption determines the number of colonic regulatory T cells and susceptibility to colitis via GPR15
Environmental factors such as diet have been shown to be involved with the development of colitis. Here the authors show that L-tryptophan promotes the development of GPR15+ Treg cells via the host IDO1/2 pathway and that tryptophan consumption in mice reduces severity of colitis in a C. rodentium mouse model.
- Nguyen T. Van
- , Karen Zhang
- & Sangwon V. Kim
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Article
| Open AccessMultiplexed detection of viral antigen and RNA using nanopore sensing and encoded molecular probes
Fast discrimination of SARS-CoV-2 variants in clinical samples remains a challenge. Here, authors report on single molecule nanopore sensing combined with DNA molecular probes to simultaneously detect various antigens and RNA mutations of SARS-CoV-2 variants in patient samples.
- Ren Ren
- , Shenglin Cai
- & Joshua B. Edel
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Article
| Open AccessRNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis
The function of METTL3 and RNA methylation is important in various biological processes. Here the authors show that METTL3 is reduced in childhood asthma patients and that conditional knockout of Mettl3 in mouse myeloid cells enhances Th2 response and allergic asthma associated with changes in macrophage function.
- Xiao Han
- , Lijuan Liu
- & Yufeng Zhou
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Article
| Open AccessIntegrating human activity into food environments can better predict cardiometabolic diseases in the United States
Previous studies on the connection between food environments and cardiometabolic diseases have yielded inconclusive results. Here, the authors show that integrating human activity into assessments of food environments can better predict the prevalence of cardiometabolic diseases.
- Ran Xu
- , Xiao Huang
- & Xiang Chen
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Article
| Open AccessImpact of vaccinations, boosters and lockdowns on COVID-19 waves in French Polynesia
In this study, the authors develop a mathematical modelling framework to estimate the impacts of non-pharmaceutical interventions and vaccination on COVID-19 incidence. The model accounts for changes in SARS-CoV-2 variant and population immunity, and here they use it to investigate epidemic dynamics in French Polynesia.
- Lloyd A. C. Chapman
- , Maite Aubry
- & Adam J. Kucharski
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Article
| Open AccessEnhanced pericyte-endothelial interactions through NO-boosted extracellular vesicles drive revascularization in a mouse model of ischemic injury
Treatment alternatives are not available for a significant portion of critical limb ischemia patients. Here, the authors show a strategy to engineer mesenchymal stem cells-derived extracellular vesicles to induce revascularization in mice.
- Ling Guo
- , Qiang Yang
- & Min Feng
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Article
| Open AccessA large meta-analysis identifies genes associated with anterior uveitis
Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.
- Sahar Gelfman
- , Arden Moscati
- & Giovanni Coppola
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Article
| Open AccessMalaria surveillance reveals parasite relatedness, signatures of selection, and correlates of transmission across Senegal
Senegal has initiated a national sentinel surveillance program for malaria parasite genetics. Here, the authors report data from the first year of the program and use it to investigate local malaria incidence, patterns of transmission, and genetic loci under selection.
- Stephen F. Schaffner
- , Aida Badiane
- & Sarah K. Volkman
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Article
| Open AccessSphingomyelin-derived nanovesicles for the delivery of the IDO1 inhibitor epacadostat enhance metastatic and post-surgical melanoma immunotherapy
Epacadostat is a selective IDO1 inhibitor shown to promote anti-tumor immune responses in preclinical models, however it has failed in a Phase III clinical trial for treating metastatic melanoma. Here the authors design a sphingomyelin-derived nanovesicle system for epacadostat delivery with improved pharmacokinetics and anti-tumor activity when combined with a PD-1 inhibitor in melanoma preclinical models.
- Zhiren Wang
- , Wenpan Li
- & Jianqin Lu
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Article
| Open AccessEnterohaemorrhagic E. coli utilizes host- and microbiota-derived L-malate as a signaling molecule for intestinal colonization
Here, Liu et al show that enterohaemorrhagic Escherichia coli utilizes host- and microbiota-derived L-malate as an essential nutrient and signalling molecule to promote its growth and colonization in the large intestine.
- Bin Liu
- , Lingyan Jiang
- & Bin Yang
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Article
| Open AccessNeural circuit selective for fast but not slow dopamine increases in drug reward
The faster a drug enters the brain, the greater its addictive potential. Using simultaneous PET-fMRI in humans, here the authors report a neural circuit responding to fast but not slow dopamine increases from intravenous versus oral methylphenidate delivery.
- Peter Manza
- , Dardo Tomasi
- & Nora D. Volkow
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Article
| Open AccessPoor sleep and shift work associate with increased blood pressure and inflammation in UK Biobank participants
Circadian disruption is linked to increased blood pressure and heart disease risk. Here, the authors show a positive association between circadian disruption and blood pressure (SBP/DBP) regulation in males and females irrespective of age, weight and inflammatory status.
- Monica Kanki
- , Artika P. Nath
- & Morag J. Young
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Article
| Open AccessA combined adjuvant approach primes robust germinal center responses and humoral immunity in non-human primates
Protein antigens, such as HIV envelope protein, require adjuvants for high immunogenicity. Here the authors show that a combined adjuvant approach with slow antigen delivery and potent ISCOMs adjuvant primes robust germinal center activity and humoral immunity in non-human primates. pSer-modified antigen shifts immunodominance to allow subdominant epitope-targeting of rare B cells.
- Ivy Phung
- , Kristen A. Rodrigues
- & Shane Crotty
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Article
| Open AccessTranscriptional repression of beige fat innervation via a YAP/TAZ-S100B axis
Sympathetic innervation is essential for the development of functional beige fat that maintains metabolic homeostasis. Qiu and colleagues discover that YAP/TAZ can act as a brake on the beige fat innervation by blocking PRDM16-C/EBPβ-mediated S100b expression.
- Xun Huang
- , Xinmeng Li
- & Yifu Qiu
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Article
| Open AccessStructural basis for the toxicity of Legionella pneumophila effector SidH
Legionella pneumophila secretes hundreds of effectors to facilitate infection. Here, Sharma et al show that the virulence effector SidH adopts a unique α-helical conformation, leading to toxicity via tRNA binding site and resolve the structural basis of SidH regulation through ubiquitination.
- Rahul Sharma
- , Michael Adams
- & Sagar Bhogaraju
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Article
| Open AccessSpecific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia
Biallelic loss-of-function variants in the gene encoding Matrix Gla Protein (MGP) are known to cause a recessive disorder called Keutel syndrome. Here, the authors report that heterozygous missense variants affecting one particular cysteine residue of MGP can cause a clinically distinct, dominant disorder, likely via impaired signal peptide processing leading to cellular stress and apoptosis.
- Ophélie Gourgas
- , Gabrielle Lemire
- & Monzur Murshed
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Article
| Open AccessDiurnal oscillations of MRI metrics in the brains of male participants
Whether temporal variations in brain MRI metrics can be attributed to circadian or diurnal oscillations is unclear. Here, the authors show evidence for diurnal oscillations in MRI metrics in both healthy controls and participants with bipolar disorder.
- Matthew Carlucci
- , Tristram Lett
- & Art Petronis
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Article
| Open AccessProduction of leishmanin skin test antigen from Leishmania donovani for future reintroduction in the field
As leishmaniasis control programs and new vaccines are advancing, it is necessary to re-introduce the leishmanin skin test to monitor transmission and immunity. This study describes the generation and validation of a new leishmanin skin test antigen for future re-introduction into endemic countries.
- Ranadhir Dey
- , Jalal Alshaweesh
- & Greg Matlashewski
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Article
| Open AccessInhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer
A tumor cell-intrinsic hyperglycolytic state has been associated with immunosuppression and resistance to immune checkpoint blockade in triple negative breast cancer (TNBC). Here the authors describe an aptamer-based nanoassembly for tumor cell selective inhibition of glycolysis combined with bispecific immune checkpoint blockade, promoting anti-tumor immune responses in preclinical TNBC models.
- Xijiao Ren
- , Zhuo Cheng
- & Zhong Luo
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Article
| Open AccessDistinct receptor binding domain IgG thresholds predict protective host immunity across SARS-CoV-2 variants and time
Evidence from trials suggests SARS-CoV-2 binding antibody thresholds could serve as surrogate markers of neutralising capacity, but whether this is accurate in the context of variants of concerns, or in the event of prior infection or vaccination remains unclear. Authors explore the performance of receptor binding domain IgG thresholds in predicting a level of neutralising capacity that has demonstrated protection against infection in vaccine trials
- Grace Kenny
- , Sophie O’Reilly
- & Patrick Mallon
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Article
| Open AccessSingle-nucleus DNA sequencing reveals hidden somatic loss-of-heterozygosity in Cerebral Cavernous Malformations
Here the authors establish somatic loss-of-heterozygosity as a genetic underpinning of Cerebral Cavernous Malformations (CCMs): using single-nucleus DNA sequencing, they show homozygosity of chromosomes 7p and/or 7q leads to biallelic inactivation of CCM genes in resected lesions.
- Andrew K. Ressler
- , Daniel A. Snellings
- & Douglas A. Marchuk
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Article
| Open AccessDevelopment and validation of an age-sex-ethnicity-specific metabolic syndrome score in the Chinese adults
Metabolic syndrome (MetS) could predict future risk for cardiovascular diseases (CVDs), but the traditionally defined dichotomous MetS cannot reflect MetS severity and demographic variations. Here, the authors develop a continuous, age-sex-ethnicity-specific MetS score to better identify CVD risk in a Chinese population.
- Shujuan Yang
- , Bin Yu
- & Peng Jia
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Article
| Open AccessARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling
Self-derived DNA may trigger interferon-driven autoinflammation mediated by the cGAS-STING axis. Here, the authors find that mutations in the GTPase ARF1 cause an interferonopathy by promoting aberrant mitochondrial DNA release and impairing STING recycling.
- Maximilian Hirschenberger
- , Alice Lepelley
- & Konstantin M. J. Sparrer
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Article
| Open AccessFollicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets
Follicle-stimulating hormone (FSH) is involved in mammalian reproduction, but several studies have suggested a role of FSH and its receptor in extragonadal tissue. Here, the authors show that FSH orchestrates glucose-stimulated insulin secretion (GSIS) via its receptor on pancreatic β-cells, with pre-menopausal FSH levels dose-dependently promoting GSIS and postmenopausal FSH levels inhibiting this effect.
- Yi Cheng
- , Hong Zhu
- & He-Feng Huang
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Comment
| Open AccessLessons for cross-species viral transmission surveillance from highly pathogenic avian influenza Korean cat shelter outbreaks
In this Comment, the authors describe recent outbreaks of highly pathogenic avian influenza in cat shelters in Seoul, South Korea. They discuss potential routes of transmission and describe implications for surveillance of spillover infections in animals in non-agricultural settings.
- Younjung Kim
- , Guillaume Fournié
- & Pierre Nouvellet
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Article
| Open AccessContinually recruited naïve T cells contribute to the follicular helper and regulatory T cell pools in germinal centers
B cell clonal expansion and affinity maturation takes place in germinal centers (GC) and is orchestrated by follicular T cells. Here authors show that naïve conventional T cells are continuously recruited to the GCs during the GC reaction and develop into follicular helper and regulatory T cells, thus quantitatively contribute to remodelling the GC overtime.
- Julia Merkenschlager
- , Riza-Maria Berz
- & Michel C. Nussenzweig
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Article
| Open AccessSelf-promoted electroactive biomimetic mineralized scaffolds for bacteria-infected bone regeneration
Infected bone defects are a major challenge in orthopedic treatment. Here, the authors develop an electroactive mineralized scaffold that achieves nearly complete in situ healing of infected bone in rats, rabbits and beagle dogs.
- Zixin Li
- , Danqing He
- & Yan Liu
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Article
| Open AccessInferring bacterial transmission dynamics using deep sequencing genomic surveillance data
Studying rare genetic changes that arose as an infectious bacterium spread between lab mice, here the authors show that using the relative abundance of any changes rather than just whether they occurred can more precisely identify who likely infected who.
- Madikay Senghore
- , Hannah Read
- & Siouxsie Wiles
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Article
| Open AccessLoss of Grem1-lineage chondrogenic progenitor cells causes osteoarthritis
This study reveals an important chondrocytic progenitor population for maintenance of adult articular cartilage marked by Gremlin 1. Loss of these progenitors causes osteoarthritis and suggests methods to sustain them may be effective future targets for management of osteoarthritis.
- Jia Q. Ng
- , Toghrul H. Jafarov
- & Siddhartha Mukherjee
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Article
| Open AccesseQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk
Fetal development plays an important role in defining adult diabetes risk. Here, authors identified a genetic link between fetal pancreatic gene expression, obesity, and diabetes risk through eQTL mapping of iPSC-derived pancreatic progenitor cells.
- Jennifer P. Nguyen
- , Timothy D. Arthur
- & Kelly A. Frazer
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Article
| Open AccessImpact of COVID-19 on mortality in coastal Kenya: a longitudinal open cohort study
SARS-CoV-2-associated mortality estimates for sub-Saharan Africa are uncertain due to lack of comprehensive surveillance systems. Here, the authors analyse data from a detailed surveillance system in Kilifi, Kenya and find that excess mortality rates were relatively low, except for older adults.
- M. Otiende
- , A. Nyaguara
- & J. A. G. Scott
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Article
| Open AccessA circular RNA activated by TGFβ promotes tumor metastasis through enhancing IGF2BP3-mediated PDPN mRNA stability
TGFbeta is known to promote cancer metastasis through the promotion of epithelial-mesenchymal transition (EMT). Here, the authors demonstrate that a TGFbeta induced circular RNA (circITGB6) promotes colorectal cancer metastasis via activation of the m6A reader protein, IGF2BP3, resulting in stabilization of an EMT-promoting gene, PDPN.
- Ke Li
- , Jiawei Guo
- & Yong Peng
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Article
| Open AccessEffectiveness of the second COVID-19 booster against Omicron: a large-scale cohort study in Chile
This study assesses the effectiveness of a second COVID-19 mRNA booster vaccine against severe disease using data from Chile. The authors find that the effectiveness of the second mRNA booster was high with a range of different background vaccination schemes, but there was evidence of waning over time.
- Alejandro Jara
- , Cristobal Cuadrado
- & Rafael Araos
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Article
| Open AccessReconstructing disease dynamics for mechanistic insights and clinical benefit
Understanding disease progression dynamics is critical for diagnostics and treatment, but capturing dynamics is difficult. Here, the authors present a method for modelling disease progression from high dimensional molecular data that enables patient stratification and high-risk disease state identification, showcased in bladder cancer.
- Amit Frishberg
- , Neta Milman
- & Shai S. Shen-Orr
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Article
| Open AccessPasteurella sp. associated with fatal septicaemia in six African elephants
A series of unexplained elephant mortalities occurred in northwest Zimbabwe in 2020. Here the authors show that six elephants died of bacterial septicaemia associated with a little-reported Pasteurella species.
- Chris M. Foggin
- , Laura E. Rosen
- & Falko Steinbach
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Article
| Open AccessIDH1 mutation impairs antiviral response and potentiates oncolytic virotherapy in glioma
The role of human glioma IDH1 mutations in regulation of antiviral response is unclear. Here, the authors show that D2HG produced by mutant IDH1 inhibits IFN antiviral responses in glioma cells, which confers sensitivity to oncolytic virotherapy.
- Xueqin Chen
- , Jun Liu
- & Haipeng Zhang
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Article
| Open AccessSingle-atom catalysts-based catalytic ROS clearance for efficient psoriasis treatment and relapse prevention via restoring ESR1
Psoriasis is a common inflammatory disease, and the overproduction of reactive oxygen species (ROS) in skin lesions plays a critical role in the progress of psoriasis. Here, the authors report the use of multienzyme-inspired biomimetic iron single-atom catalysts (FeN4O2-SACs) with broad-spectrum ROS-scavenging capability for psoriasis treatment and relapse prevention via related gene restoration.
- Xiangyu Lu
- , Le Kuai
- & Jianlin Shi
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Article
| Open AccessUncertainty-inspired open set learning for retinal anomaly identification
Failure to recognize samples from unseen classes is a major limitation of AI recognition and classification of retinal anomalies. Here, the authors present the Uncertainty-inspired Open Set learning model that categorises fundus images into pre-trained categories, and provides an uncertainty score that alerts the need for manual inspection when dealing with out-of-distribution images.
- Meng Wang
- , Tian Lin
- & Huazhu Fu
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Article
| Open AccessLong-term health impacts of COVID-19 among 242,712 adults in England
The duration of symptomatic COVID-19 and its impacts on health and quality of life are not well understood. In this study, the authors report results from a survey of ~275,000 adults in England and find that persistent COVID-19 is relatively rare but is associated with poorer mental health and health-related quality of life.
- Christina J. Atchison
- , Bethan Davies
- & Paul Elliott
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Article
| Open AccessHealthy dietary patterns and the risk of individual chronic diseases in community-dwelling adults
Dietary patterns have been linked to a limited number of major chronic diseases. Here, the authors show greater adherence to healthy dietary patterns, especially Alternate Mediterranean Diet, is associated with a lower risk of most of the 48 tested chronic diseases.
- Xianwen Shang
- , Jiahao Liu
- & Mingguang He
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Article
| Open AccessC-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity
Receptor dimerization can modulate immune responses during various microbial infections. Here, the authors show that C-type lectin receptor-2d (CLEC2D) negatively regulates antifungal immunity through forming homodimers or heterodimers with TLR2.
- Fan Li
- , Hui Wang
- & Xin-Ming Jia
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Article
| Open AccessPathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infections
Group A streptococcus causes a wide range of human diseases and significantly contributes to morbidity and mortality worldwide. Here, Toledo et al show how streptococcus alters the structure and function of endogenous and therapeutic antibodies during infection and how this is affected by the host microenvironment.
- Alejandro Gomez Toledo
- , Eleni Bratanis
- & Johan Malmström
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Article
| 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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