Featured
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Article
| Open AccessNumerosity estimation of virtual humans as a digital-robotic marker for hallucinations in Parkinson’s disease
Virtual reality, robotics and digital online technologies reveal heightened visual overestimation when estimating the number of humans, indexing presence hallucinations in healthy participants and patients with Parkinson’s disease.
- Louis Albert
- , Jevita Potheegadoo
- & Olaf Blanke
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Article
| Open AccessUnderstanding the infection severity and epidemiological characteristics of mpox in the UK
Mpox cases without known travel links to endemic countries began to be detected in the UK in mid-2022. In this study, the authors characterise the severity of mpox cases in the UK and estimate the overall infection hospitalisation risk at ~4%.
- Thomas Ward
- , Christopher E. Overton
- & Martyn Fyles
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Article
| Open AccessDrivers and impact of the early silent invasion of SARS-CoV-2 Alpha
The SARS-CoV-2 Alpha variant of concern emerged in the UK in late 2020 but spread internationally before it was detected. Here, the authors reconstruct the dynamics of dissemination of this variant out of the UK by combining extent of genomic sequencing, travel volume, and local epidemic dynamics in a Bayesian model.
- Benjamin Faucher
- , Chiara E. Sabbatini
- & Chiara Poletto
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Article
| Open AccessAcidity-activatable upconversion afterglow luminescence cocktail nanoparticles for ultrasensitive in vivo imaging
Activatable afterglow luminescence nanoprobes reduce unspecific signals and improve imaging fidelity, but their utility is limited by a requisition of donor-acceptor distance (>10 nm) in common biomarker-activatable designs. Here, the authors address this issue by developing organic afterglow luminescence cocktail nanoparticles for acid-activatable upconversion afterglow luminescence imaging.
- Yue Jiang
- , Min Zhao
- & Qingqing Miao
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Article
| Open AccessPMI-controlled mannose metabolism and glycosylation determines tissue tolerance and virus fitness
Glucose metabolism is crucial for cellular energy regulation and affects the immune response. Here the authors show that nutritional supplementation of mannose may be beneficial during virus infections by rewiring glucose metabolic dysregulation and alleviating inflammatory tissue damage.
- Ronghui Liang
- , Zi-Wei Ye
- & Shuofeng Yuan
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Article
| Open AccessPla2g12b drives expansion of triglyceride-rich lipoproteins
Thierer and colleagues identify PLA2G12B as a key gene driving triglyceride incorporation into lipoproteins and show that disruption of this activity provides protection from atherosclerosis.
- James H. Thierer
- , Ombretta Foresti
- & Steven A. Farber
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Article
| Open AccessSingle-cell profiling identifies IL1Bhi macrophages associated with inflammation in PD-1 inhibitor-induced inflammatory arthritis
Patients undergoing treatment with PD-1 blockade can experience inflammatory arthritis as an adverse event. Here, the authors use single-cell RNA sequencing to identify IL1Bhi macrophages in PD-1-inhibitor-induced arthritis, but not rheumatoid arthritis.
- Ziyue Zhou
- , Xiaoxiang Zhou
- & Xuan Zhang
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Article
| Open AccessTargeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis
P2Y14R regulates necroptosis of intestinal epithelial cells though PKA/CREB/RIPK1 axis in the pathogenesis of ulcerative colitis (UC). Targeting P2Y14R with a small molecule inhibitor improves dextran sulfate sodium-induced UC in mice, suggesting P2Y14R as a promising target for treatment of UC.
- Chunxiao Liu
- , Hui Wang
- & Qinghua Hu
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Article
| Open AccessKdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons
Kdm1a is a histone demethylase implicated in intellectual disability. Here, the authors show that removing Kdm1a in neurons of the adult mouse forebrain disrupts silencing of nonneuronal genes and chromatin organization, emphasizing its role in preserving neuronal genome integrity.
- Beatriz del Blanco
- , Sergio Niñerola
- & Ángel Barco
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Article
| Open AccessFrequency, kinetics and determinants of viable SARS-CoV-2 in bioaerosols from ambulatory COVID-19 patients infected with the Beta, Delta or Omicron variants
SARS-CoV-2 can be spread by aerosols. Here the authors show that between 50-60% of ambulatory COVID-19 patients exhale culturable virus and that this is associated with lower neutralizing antibody titers and suppression of immune related transcriptomic pathways.
- S. Jaumdally
- , M. Tomasicchio
- & K. Dheda
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Article
| Open AccessCentrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells
People living with HIV-1 are at an increased risk of developing various cancers. Here, the authors suggest that HIV-1-encoded Vpr can promote oncogenesis by forming a ternary complex with VprBP and Plk4 and inducing Plk4-dependent centriole overduplication and aneuploidy.
- Jung-Eun Park
- , Tae-Sung Kim
- & Kyung S. Lee
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Article
| Open AccessNeuronal miR-9 promotes HSV-1 epigenetic silencing and latency by repressing Oct-1 and Onecut family genes
Here, the authors identify neuron-specific miR-9 that potentially blocks HSV-1 neuronal replication by targeting host OCT-1 and ONECUT transcription factors involved in epigenetic activation of HSV-1 productive-cycle genes. Thus miR-9 promotes viral epigenetic silencing and latent infection in neurons.
- Yue Deng
- , Yuqi Lin
- & Dongli Pan
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Article
| Open AccessQTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration
Here, the authors perform genome-wide mapping of DNA methylation and expression quantitative trait loci, revealing associations among genotype, epigenome and transcriptome, uncovering genes and gene-environment interactions contributing to age-related macular degeneration (AMD).
- Jayshree Advani
- , Puja A. Mehta
- & Anand Swaroop
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Article
| Open AccessDeregulated protein homeostasis constrains fetal hematopoietic stem cell pool expansion in Fanconi anemia
In this manuscript, the authors show deregulated protein synthesis as a novel, noncanonical defect in Fanconi Anemia. The observed deficits reflect the impact of proteostasis during fetal hematopoietic stem cell expansion and define the origins of hematopoietic failure in this disorder.
- Narasaiah Kovuru
- , Makiko Mochizuki-Kashio
- & Peter Kurre
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Article
| Open AccessMYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation
Several molecular mechanisms, including retinoblastoma protein RB1 deficiency, explain CDK4/6 inhibitors resistance in cancer. Here, the authors show that MYC amplification induces CDK4/6 inhibitors resistance through transcriptional regulation of KLHL42, leading to RB1 degradation and targeting MYC overcomes CDK4/6 resistance in preclinical cancer models.
- Jian Ma
- , Lei Li
- & Lei Li
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Article
| Open AccessApplying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis
People who experience optic neuritis, a cause of potentially serious sudden vision loss, have up to a 50% chance of ultimately being diagnosed with multiple sclerosis. Here, the authors find that genetic information combined with age and sex helps predict risk of future diagnosis of multiple sclerosis.
- Pavel Loginovic
- , Feiyi Wang
- & Tasanee Braithwaite
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Article
| Open AccessBTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion
Acute-on-chronic liver failure (ACLF) is characterized by rapid deterioration of liver function in patients with chronic liver disease. Here, the authors show that BTLA expression in CD4+ T cells is associated with disease severity and inflammation in hepatitis B virus-related ACLF.
- Xueping Yu
- , Feifei Yang
- & Jiming Zhang
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Article
| Open AccessDevelopment of pathophysiologically relevant models of sickle cell disease and β-thalassemia for therapeutic studies
Sickle cell disease (SCD) and β-thalassemia (BT) are globally prevalent inherited blood disorders but, despite extensive research, no ex vivo system exists for SCD and BT. Here, the authors generate pathophysiologically relevant erythroid progenitor models of SCD and BT.
- Pragya Gupta
- , Sangam Giri Goswami
- & Sivaprakash Ramalingam
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Article
| Open AccessBicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury
The acid–base balance regulates cellular responses, but little has been known about its molecular mechanism. Here, the authors unveil a bicarbonate-sensing GPCR, GPR30, that underlies cerebral ischemia–reperfusion injury by regulating blood flow recovery.
- Airi Jo-Watanabe
- , Toshiki Inaba
- & Takehiko Yokomizo
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Article
| Open AccessSNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation
SNURPORTIN-1, encoded by the SNUPN gene, plays a key role in the nuclear import of spliceosomal small nuclear ribonucleoproteins, however its physiological function remains unclear. Here the authors report that recessive SNUPN mutations cause a distinct subtype of childhood muscular dystrophy and reveal SNURPORTIN-1’s role in muscle homeostasis, offering insights for new therapeutic strategies.
- Marwan Nashabat
- , Nasrinsadat Nabavizadeh
- & Nathalie Escande-Beillard
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Article
| Open AccessGlobal fungal-host interactome mapping identifies host targets of candidalysin
Candidalysin is a toxin secreted by Candida albicans. Although critical for pathogenesis, its intracellular targets are not well mapped. Here, Zhang et al screen for interacting proteins and identify that candidalysin can modulate the DNA damage repair pathway to promote fungal infection.
- Tian-Yi Zhang
- , Yao-Qi Chen
- & Ning-Ning Liu
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Article
| Open AccessA distinct class of pan-cancer susceptibility genes revealed by an alternative polyadenylation transcriptome-wide association study
Alternative polyadenylation (APA) can play a key role in cancer initiation and progression. Here, the authors conducted a comprehensive pan-cancer APA TWAS analysis and discovered a distinct class of APA-mediated cancer susceptibility genes across 22 cancer types.
- Hui Chen
- , Zeyang Wang
- & Lei Li
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Article
| Open AccessPersistence in risk and effect of COVID-19 vaccination on long-term health consequences after SARS-CoV-2 infection
The long-term health consequences of COVID-19 infection are not fully understood. In this retrospective cohort study from Hong Kong, the authors describe changes in the risk of various clinical outcomes including all-cause mortality for one year following COVID-19 infection and how they vary by vaccination status.
- Ivan Chun Hang Lam
- , Ran Zhang
- & Eric Yuk Fai Wan
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Article
| Open AccessWhole-exome sequencing in UK Biobank reveals rare genetic architecture for depression
Despite many common genetic variants being linked to depression, the impact of rare coding variants on depression remains largely unknown. Here, the authors perform a whole-exome sequencing study of depression, providing insights into the rare genetic architecture of depression.
- Ruoyu Tian
- , Tian Ge
- & Chia-Yen Chen
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Article
| Open AccessA wireless battery-free eye modulation patch for high myopia therapy
The proper axial length of the eye is crucial for achieving emmetropia. Here, authors introduce a wireless battery-free eye modulation patch designed to correct high myopia and prevent relapse.
- Tianyan Zhong
- , Hangjin Yi
- & Xinyu Xue
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Article
| Open AccessTargeting HDAC6 to treat heart failure with preserved ejection fraction in mice
HFpEF has few effective treatments. Here, the authors show that inhibition of histone deacetylase 6 (HDAC6) with TYA-018 reverses established HFpEF symptoms in mice, comparably to the use of a sodium-glucose cotransporter 2 inhibitor; highlighting HDAC6 as a potential target to treat HFpEF.
- Sara Ranjbarvaziri
- , Aliya Zeng
- & Jin Yang
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Article
| Open AccessSingle-cell transcriptomics identifies the differentiation trajectory from inflammatory monocytes to pro-resolving macrophages in a mouse skin allergy model
Classical monocytes can differentiate into pro-inflammatory or pro-resolving macrophages. Here the authors characterise mouse macrophage differentiation and show that Ly6Chi classical monocytes can differentiate into Ly6Clo pro-resolving macrophages which are involved in the resolution of skin allergic inflammation.
- Kensuke Miyake
- , Junya Ito
- & Hajime Karasuyama
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Article
| Open AccessImmune signature of Chlamydia vaccine CTH522/CAF®01 translates from mouse-to-human and induces durable protection in mice
Authors present a comparative immunological characterisation of Chlamydia vaccine, CTH522/CAF®01, in mice and humans. Findings suggest the mouse to be a good predictor of human immunity to the Chlamydia vaccine CTH522/CAF®01, and long-lasting protection in the mouse further supports the development of this promising vaccine candidate.
- Anja W. Olsen
- , Ida Rosenkrands
- & Frank Follmann
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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
- , William 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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