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A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence
Chemotherapy-induced peripheral neuropathy (CIPN) represents a major reason for discontinuation of treatment. Here, the authors show that LEI-515, a peripherally restricted monoacylglycerol lipase inhibitor, suppresses CIPN without inducing central nervous system side effects or physical dependence.
- Ming Jiang
- , Mirjam C. W. Huizenga
- & Mario van der Stelt
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Article
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Acetyl-CoA is a key molecule for nephron progenitor cell pool maintenance
Cell metabolism plays pivotal roles during kidney embryogenesis. This research shows that glycolysis modulation affects nephron progenitor cells via Acetyl-CoA-modulated pathways, influencing both kidney development, and nephron endowment at birth.
- Fabiola Diniz
- , Nguyen Yen Nhi Ngo
- & Giovane G. Tortelote
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Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site
Antibodies targeting the HIV-1 fusion peptide rarely achieve more than 60% neutralization breadth. Here, the authors develop an anti-FP antibody enhancing its potency to 80% and structurally resolve the expanded FP-binding site that allows the antibody to target diverse viral variants.
- Bailey B. Banach
- , Sergei Pletnev
- & Brandon J. DeKosky
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Eicosanoid and eicosanoid-related inflammatory mediators and exercise intolerance in heart failure with preserved ejection fraction
Systemic inflammation is recognized as a central pathobiologic feature in heart failure with preserved ejection fraction (HFpEF). Here, the authors report 70 pro- and anti-inflammatory eicosanoid and eicosanoid-related metabolites associated with HFpEF status.
- Emily S. Lau
- , Athar Roshandelpoor
- & Jennifer E. Ho
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The Imageable Genome
The impact of genomic discoveries on global health depends on their efficient translation into clinically applicable testing. Here, the authors present the Imageable Genome - the part of the human genome whose expression can be assessed via molecular imaging - to accelerate translation and to bridge the fields of genomics and molecular imaging.
- Pablo Jané
- , Xiaoying Xu
- & Martin A. Walter
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Article
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HSP47 levels determine the degree of body adiposity
A complex interplay of various backgrounds and conditions determines the body fat levels of individuals. Here, the authors identify HSP47 as a pivotal determinant of body adiposity which is abundantly expressed in fat tissue and influenced by factors such as diet, exercise, hormones, and genetics.
- Jihoon Shin
- , Shinichiro Toyoda
- & Iichiro Shimomura
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Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin
Therapeutic modulation of Janus kinase family enzymes is an established approach for inflammatory and autoimmune skin diseases. Here the authors rationally design small interfering RNAs to enable single Janus kinase targeting and test this new therapeutic approach in a skin disease model for maintaining efficacy and improving selectivity.
- Qi Tang
- , Hassan H. Fakih
- & John E. Harris
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Regulation of eDHFR-tagged proteins with trimethoprim PROTACs
The ability to control proteins in cells and animals is important for experimental research and may have therapeutic applications. Here, the authors developed a new set of heterobifunctional small molecules based on the antibiotic trimethoprim that can degrade proteins that are genetically tagged with E. coli dihydrofolate reductase (eDHFR).
- Jean M. Etersque
- , Iris K. Lee
- & Mark A. Sellmyer
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Article
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Inhibition 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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Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing
Targeted sequencing panels such as MSK-IMPACT have been successfully used to profile solid tumours in clinical settings. Here, the authors develop and implement the MSK-IMPACT Heme sequencing panel and platform to profile haematologic malignancies using paired tumor and normal tissues.
- Ryan N. Ptashkin
- , Mark D. Ewalt
- & Maria E. Arcila
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ZFYVE28 mediates insulin resistance by promoting phosphorylated insulin receptor degradation via increasing late endosomes production
Insulin receptor levels are closely related to insulin sensitivity. Here, the authors show that ZFYVE28 is involved in insulin resistance by promoting the degradation of phosphorylated insulin receptor and ZFYVE28 may be a potential therapeutic target to improve insulin sensitivity.
- Liang Yu
- , Mengchen Xu
- & Yibo Wang
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Article
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Nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial
Standard of care for unfavorable-risk cancer of unknown primary (CUP) comprises platinum-based chemotherapy as first-line treatment, however therapeutic options remain limited. Here the authors report the results of a phase II trial of combined nivolumab (anti-PD1) and ipilimumab (anti-CTLA4) in patients with unfavorable CUP.
- Maria Pouyiourou
- , Bianca N. Kraft
- & Alwin Krämer
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RING 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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Comment
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Glucocerebrosidase mutations disrupt the lysosome and now the mitochondria
β-Glucocerebrosidase (GCase) mutations lead to glucosylceramide build-up in the lysosome, impacting α-synuclein aggregation and autophagy. Recently, Baden and colleagues found GCase in mitochondria, supporting mitochondrial complex I function and energy metabolism. We believe the newly described role of GCase in the mitochondria will inform new Parkinson’s and Gaucher’s disease therapeutics.
- Andrés D. Klein
- & Tiago Fleming Outeiro
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Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas
Hedgehog signalling is known to be linked to oncogenic proliferation. Here, the authors identify structural events as a mechanism of Hedgehog activation in over one-third of driver unknown meningiomas.
- Mark W. Youngblood
- , Zeynep Erson-Omay
- & Murat Günel
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A 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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NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections
Streptococcus pneumoniae is a common cause of lower respiratory tract infection. Here, Klabunde et al. present a transcriptomic, metabolomic and proteomic characterisation of the bronchial epithelial cell response to infection and show that NAD+ has a role in controlling bacterial replication.
- Björn Klabunde
- , André Wesener
- & Bernd Schmeck
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Genotypic diversity and unrecognized antifungal resistance among populations of Candida glabrata from positive blood cultures
Candida glabrata bloodstream infections are thought to be mostly caused by a single strain. Here, the authors describe genotypic and phenotypic diversity of Candida glabrata in ten individual blood cultures, and find diversity in drug susceptibility and virulence within patients.
- Hassan Badrane
- , Shaoji Cheng
- & M. Hong Nguyen
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Comprehensive proteomics and meta-analysis of COVID-19 host response
Babačić et al. performed systematic analyses of blood proteins in COVID-19 patients through mass-spectrometry proteomics, showing that a large part of the soluble blood proteome is altered. The authors then developed an open-access resource, CoViMAPP, for meta-analysis of MS proteomics studies of COVID-19 patients.
- Haris Babačić
- , Wanda Christ
- & Maria Pernemalm
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mRNA vaccine quality analysis using RNA sequencing
mRNA vaccines must be rigorously analysed to measure their integrity and detect contaminants, which can be time-consuming and costly. Here, authors describe a method to analyse mRNA vaccine quality using long-read sequencing and a custom bioinformatic pipeline.
- Helen M. Gunter
- , Senel Idrisoglu
- & Tim R. Mercer
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Decoding the endometrial niche of Asherman’s Syndrome at single-cell resolution
Asherman’s Syndrome is characterized by intrauterine scarring and infertility. Here, the authors decode the Asherman’s Syndrome endometrial cell niche by single-cell RNA sequencing and in vitro analyses of patient-derived endometrial organoids.
- Xavier Santamaria
- , Beatriz Roson
- & Carlos Simon
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The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of the transcription factor ERG
ETS transcription factor ERG has been implicated in numerous cancers, including leukemia. Here, the authors show that ERG interaction with the NCoR-HDAC3 co-repressor complex is essential for its leukemogenic activity. Highlighting this interaction as a potential therapeutic target, HDAC3 inhibition led to reduced growth of ERG-dependent leukemia cells in vitro and in vivo.
- Eitan Kugler
- , Shreyas Madiwale
- & Shai Izraeli
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SRC and TKS5 mediated podosome formation in fibroblasts promotes extracellular matrix invasion and pulmonary fibrosis
The activation and accumulation of lung fibroblasts resulting in aberrant deposition of extracellular matrix components is a pathogenic hallmark of idiopathic pulmonary fibrosis. Here, the authors show that the formation of podosomes in lung fibroblasts stimulates extracellular matrix invasion in a mouse model of the disease, suggesting that pharmacological targeting of podosome formation or organization might be a therapeutic option.
- Ilianna Barbayianni
- , Paraskevi Kanellopoulou
- & Vassilis Aidinis
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Exploiting the aggregation propensity of beta-lactamases to design inhibitors that induce enzyme misfolding
Here the authors show that beta-lactamase have an intrinsic aggregation propensity that can be exploited to inactivate these enzymes that mediate antibiotic resistance, using peptides that are based on aggregation prone regions in the sequence of the beta-lactamase.
- Ladan Khodaparast
- , Laleh Khodaparast
- & Joost Schymkowitz
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Article
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Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling
Nonalcoholic fatty liver disease (NAFLD) is often linked to disrupted bile acid homeostasis. Here, the authors show hyodeoxycholic acid (HDCA) ameliorates nonalcoholic fatty liver disease by inhibiting the formation of RAN/CRM1/PPARα nuclear export heterotrimer, resulting in increased nuclear localization of PPARα and activated fatty acid oxidation.
- Jing Zhong
- , Xiaofang He
- & Houkai Li
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Control of intracellular pH and bicarbonate by CO2 diffusion into human sperm
Bicarbonate (HCO3−) is critical in sperm for stimulation of cAMP synthesis during fertilization, though there is dispute over how HCO3− is transported into sperm. Here the authors use limit-of-detection LC/MS to characterize sperm protein expression and show that HCO3− is produced from CO2 diffusion into sperm rather than active transport.
- Elena Grahn
- , Svenja V. Kaufmann
- & U.Benjamin Kaupp
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The Oncology Biomarker Discovery framework reveals cetuximab and bevacizumab response patterns in metastatic colorectal cancer
Identifying actionable biomarkers remains a challenge. Here, the authors develop a framework Oncology Biomarker Discovery (OncoBird), apply it to a phase III trial and investigate the molecular and biomarker landscape of metastatic colorectal carcinoma patients.
- Alexander J. Ohnmacht
- , Arndt Stahler
- & Michael P. Menden
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Impact of dietary interventions on pre-diabetic oral and gut microbiome, metabolites and cytokines
Here, analyzing data from a six-month clinical trial in pre-diabetes, the authors found 166 of 2,803 measured features, including oral and gut microbiome, metabolites and cytokines, significantly changed in response to dietary interventions; highlighting the microbiome’s role in cardiometabolic health and revealing potential therapeutic avenues.
- Saar Shoer
- , Smadar Shilo
- & Eran Segal
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The interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis
Here, Schoeler et al. investigate how interaction between dietary lipids and the gut microbiota affect hepatic steatosis and host metabolism, showing that dietary lipids impact the gut microbiota composition independent on fiber intake in humans and mice.
- Marc Schoeler
- , Sandrine Ellero-Simatos
- & Robert Caesar
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Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families
Despite large sequencing and data sharing efforts it often remains challenging to provide a genetic diagnosis for individuals with suspected Mendelian (single-gene) disorders. Here, the authors describe their experiences in identifying likely causal genetic variants in thousands of families and highlight the need to consider a wide range of challenges rather than a narrow focus on sequencing technologies.
- Lama AlAbdi
- , Sateesh Maddirevula
- & Fowzan S. Alkuraya
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Article
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CircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications
Osteoarthritis is a prevalent age-related disease. Here, the authors show that that CircRREB1 is highly expressed in second generation chondrocytes and its deficiency can alleviate FASN related senescent phenotypes and osteoarthritis progression.
- Zhe Gong
- , Jinjin Zhu
- & Shuying Shen
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Article
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Cullin-associated and neddylation-dissociated protein 1 (CAND1) alleviates NAFLD by reducing ubiquitinated degradation of ACAA2
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder with high morbidity and mortality, and there is no specific drug to treat it. Here, the authors show that the AR-CAND1-ACAA2 axis regulates the development of NAFLD, and enhancing the function of CAND1 is a promising strategy for the development of a therapeutic agent for NAFLD.
- Xiang Huang
- , Xin Liu
- & Zhenwei Pan
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Elastin stabilization prevents impaired biomechanics in human pulmonary arteries and pulmonary hypertension in rats with left heart disease
Pulmonary hypertension due to left heart disease is characterized by pulmonary arterial stiffening that results from extracellular matrix remodeling. Here, the authors show that elastin stabilization improves arterial biomechanics and attenuates pulmonary hypertension.
- Mariya M. Kucherenko
- , Pengchao Sang
- & Christoph Knosalla
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Engineering broad-spectrum inhibitors of inflammatory chemokines from subclass A3 tick evasins
Tick evasin proteins block the inflammatory activity of mammalian chemokines. In this work, the authors report that structure-based modification of class A3 evasins alters their chemokine selectivity, suggesting these evasins could be engineered for targeted anti-inflammatory therapy.
- Shankar Raj Devkota
- , Pramod Aryal
- & Martin J. Stone
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Article
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Inhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice
Brown adipose tissue is a promising target for the treatment of obesity with the potential to increase energy expenditure. Here, the authors use pharmacological and genetic approaches to block AXL receptor activation and show that its inhibition enhances brown adipocyte functionality and thermogenesis, leading to weight loss and metabolic improvements in mice.
- Vissarion Efthymiou
- , Lianggong Ding
- & Christian Wolfrum
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Cell cycle arrest and p53 prevent ON-target megabase-scale rearrangements induced by CRISPR-Cas9
ON-target genotoxicity in gene editing is generally underestimated. Here the authors report Fluorescence-Assisted Megabase-scale Rearrangements Detection (FAMReD) systems to detect and characterize rare large loss of heterozygosity: they show that ON-target genotoxicity can be prevented by p53 and cell cycle arrest.
- G. Cullot
- , J. Boutin
- & A. Bedel
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Article
| Open Access
An immunostimulatory glycolipid that blocks SARS-CoV-2, RSV, and influenza infections in vivo
7DW8-5 is a glycolipid that binds CD1d and stimulates invariant natural killer T (iNKT) cells. Here the authors show that 7DW8-5, when administered intranasally, provides prophylactic anti-viral effects against influenza, RSV, and SARS-CoV-2 in mice or hamsters, and that this effect is mediated by iNKT cells and IFN-γ.
- Moriya Tsuji
- , Manoj S. Nair
- & David D. Ho
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Article
| Open Access
Direct mapping of kidney function by DCE-MRI urography using a tetrazinanone organic radical contrast agent
Current clinical methods for assessing kidney function report an aggregate value for both kidneys, and lack the ability to say which kidney is dysfunctioning or even to localize the dysfunction to a region of renal pathology. Here, the authors show that an injectable dye can be used to map kidney function by magnetic resonance imaging, offering a safer alternative than existing dyes for the spatial evaluation of kidney health.
- Nicholas D. Calvert
- , Alexia Kirby
- & Adam J. Shuhendler
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Article
| Open Access
In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting
The entry receptor for SARS-CoV-2, ACE2, translocates to the nucleus following infection with this virus. Here, the authors demonstrate that a peptide targeting the ACE2 nuclear localization signal promotes its methylation and abrogates viral replication of SARS-CoV-2 in Syrian hamsters.
- Wen Juan Tu
- , Michelle Melino
- & Sudha Rao
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Article
| Open Access
Splicing activates transcription from weak promoters upstream of alternative exons
Few therapeutic strategies are able to upregulate gene expression. Here, the authors developed an approach to activate expression of human genes through small molecules and antisense oligonucleotides that modulate splicing.
- Maritere Uriostegui-Arcos
- , Steven T. Mick
- & Ana Fiszbein
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Article
| Open Access
Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain
Drugs that rescue function of episodic ataxia 1 (EA1) mutant potassium channels are lacking. Here, Manville et al identify and describe the molecular basis for Native American botanical ataxia remedies that directly rescue EA1 mutant channels.
- Rían W. Manville
- , J. Alfredo Freites
- & Geoffrey W. Abbott
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| Open Access
Structural interplay of anesthetics and paralytics on muscle nicotinic receptors
Here the authors use a structural approach to reveal how neuromuscular blockers and a general anesthetic antagonize the muscle-type nicotinic receptor through competitive and allosteric mechanisms.
- Umang Goswami
- , Md Mahfuzur Rahman
- & Ryan E. Hibbs
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| Open Access
Direct haplotype-resolved 5-base HiFi sequencing for genome-wide profiling of hypermethylation outliers in a rare disease cohort
HiFi genome sequencing accesses DNA methylation and nucleotide variation in long sequence reads. Here, the authors apply this approach in a rare disease cohort to identify DNA hypermethylation linked to genetic variants including rare disease alleles.
- Warren A. Cheung
- , Adam F. Johnson
- & Tomi Pastinen
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Article
| Open Access
A blocking monoclonal antibody reveals dimerization of intracellular domains of ALK2 associated with genetic disorders
Mutant forms of the transmembrane receptor activin receptor-like kinase 2 are associated with different genetic diseases. Here, the authors report that disease-associated forms of this receptor cause intracellular domains to dimerize in response to ligand binding of extracellular domains.
- Takenobu Katagiri
- , Sho Tsukamoto
- & Kiyosumi Takaishi
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| Open Access
Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy
Narcolepsy has genetic and environmental risk factors, but the specific genetic risk loci and interaction with environmental triggers are not well understood. Here, the authors identify genetic loci for narcolepsy, suggesting infection as a trigger and dendritic and helper T cell involvement.
- Hanna M. Ollila
- , Eilon Sharon
- & Emmanuel J. Mignot
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| Open Access
Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response
The contribution of genetic factors to the tumour immune microenvironment (TIME) remains to be investigated. Here, the authors suggest the role of TIME eQTLs for target genes involved in reversing immune suppressive features.
- Meghana Pagadala
- , Timothy J. Sears
- & Hannah Carter
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Article
| Open Access
Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice
The aryl hydrocarbon receptor regulates the expression of genes involved in many cell processes and its dysregulation has been implicated in different diseases. Here, the authors identify dietary monoterpenoid carvone as an atypical non-competitive antagonist of human aryl hydrocarbon receptor and demonstrate that it can protect against ultraviolet skin damage in female mice.
- Karolína Ondrová
- , Iveta Zůvalová
- & Zdeněk Dvořák
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Perspective
| Open Access
A precision environmental health approach to prevention of human disease
Precision environmental health leverages environmental and system-level data to understand underlying environmental causes of disease, identify biomarkers of exposure, and develop new prevention and intervention strategies. In this Perspective, the authors provide real-life illustrations of the utility of precision environmental health approaches and identify current challenges in the field.
- Andrea Baccarelli
- , Dana C. Dolinoy
- & Cheryl Lyn Walker
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Article
| Open Access
Mini-PCDH15 gene therapy rescues hearing in a mouse model of Usher syndrome type 1F
Mutations in PCDH15 cause deafness and blindness in Usher syndrome 1 F, but gene therapy is difficult because the PCDH15 sequence is too large for AAV vectors. Here, the authors engineered a miniPCDH15 that fits in AAV and rescues hearing in mouse Usher syndrome 1F models.
- Maryna V. Ivanchenko
- , Daniel M. Hathaway
- & David P. Corey
Systemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function