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| Open AccessmRNA 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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Article
| Open AccessDecoding 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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Article
| Open AccessThe 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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Article
| Open AccessSRC 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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Article
| Open AccessExploiting 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
| Open AccessHyodeoxycholic 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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Article
| Open AccessControl 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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Article
| Open AccessThe 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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Article
| Open AccessImpact 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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Article
| Open AccessThe 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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Article
| Open AccessDiagnostic 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
| Open AccessCircRREB1 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
| Open AccessCullin-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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Article
| Open AccessElastin 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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Article
| Open AccessEngineering 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
| Open AccessInhibition 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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Article
| Open AccessCell 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 AccessAn 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 AccessDirect 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 AccessIn 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 AccessSplicing 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 AccessNative 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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Article
| Open AccessStructural 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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Article
| Open AccessDirect 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 AccessA 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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Article
| Open AccessNarcolepsy 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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Article
| Open AccessGermline 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 AccessMonoterpenoid 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 AccessA 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 AccessMini-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
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Article
| Open AccessMitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria
Mitochondria modulate both normal and premature aging, yet if primary oxidative phosphorylation deficiency can cause progeria has been unclear. Here, the authors show that mice with severe isolated respiratory complex III deficiency display cellular senescence and juvenile-onset segmental progeria.
- Janne Purhonen
- , Rishi Banerjee
- & Jukka Kallijärvi
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Article
| Open AccessDirect correction of haemoglobin E β-thalassaemia using base editors
The authors demonstrate efficient and direct correction of the DNA mutation causing Haemoglobin E β-thalassaemia with CRISPR Cas9 base editors. The work includes profiling of off-target effects using deep neural networks.
- Mohsin Badat
- , Ayesha Ejaz
- & James O. J. Davies
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Article
| Open AccessPhosphorylation and stabilization of EZH2 by DCAF1/VprBP trigger aberrant gene silencing in colon cancer
DCAF1/VprBP contributes to epigenetic gene inactivation and cancer development. Here the authors show that DCAF1/VprBP phosphorylates and stabilises EZH2 to induce oncogenic gene silencing and colon cancer growth.
- Nikhil B. Ghate
- , Sungmin Kim
- & Woojin An
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Article
| Open AccessFOXI3 pathogenic variants cause one form of craniofacial microsomia
Most cases of craniofacial microsomia are sporadic but familial cases have been reported. Here the authors report that variants in FOXI3 can cause a small fraction of cases with different modes of inheritance including autosomal dominant with reduced penetrance.
- Ke Mao
- , Christelle Borel
- & Stylianos E. Antonarakis
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Article
| Open AccessMEK inhibition reduced vascular tumor growth and coagulopathy in a mouse model with hyperactive GNAQ
Life-threatening vascular tumors can be associated with uncontrolled activity of the guanine nucleotide-binding protein subunit alpha (Gαq). Here, the authors develop a murine model for these tumors and show that MEK inhibition prevents formation of vascular lesions and improves survival.
- Sandra Schrenk
- , Lindsay J. Bischoff
- & Elisa Boscolo
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Article
| Open AccessLacking mechanistic disease definitions and corresponding association data hamper progress in network medicine and beyond
Large-scale disease-association data are widely used for pathomechanism mining, even if disease definitions used for annotation are mostly phenotype-based. Here, the authors show that this bias can lead to a blurred view on disease mechanisms, highlighting the need for close-up studies based on molecular data for well-characterized patient cohorts.
- Sepideh Sadegh
- , James Skelton
- & David B. Blumenthal
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Article
| Open AccessThe protective role of conjunctival goblet cell mucin sialylation
Conjunctival goblet cells secrete mucins that are heavily glycosylated. Here, the authors show that sialylation of mucins is essential for capturing and encapsulates allergen particles and thus reduces the risk for developing allergic conjunctivitis.
- Moe Matsuzawa
- , Tomoaki Ando
- & Jiro Kitaura
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Article
| Open AccessAn integrated single cell and spatial transcriptomic map of human white adipose tissue
Single-cell studies of human white adipose tissue (WAT) provide insights into the specialized cell types in the tissue. Here the authors combine publicly available and newly generated high-resolution and bulk transcriptomic results from multiple human datasets to provide a comprehensive cellular map of white adipose tissue.
- Lucas Massier
- , Jutta Jalkanen
- & Niklas Mejhert
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Article
| Open AccessLantern-shaped flexible RNA origami for Smad4 mRNA delivery and growth suppression of colorectal cancer
mRNA delivery has shown great potential in the treatment of various diseases. Here, the authors develop a lantern-shaped flexible origami for nanolization of single mRNA molecules and demonstrate efficient delivery of Smad4 mRNA, achieving suppression of colorectal cancer tumour growth.
- Muren Hu
- , Chang Feng
- & Xiaoli Zhu
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Article
| Open AccessFibroblastic reticular cells in lymph node potentiate white adipose tissue beiging through neuro-immune crosstalk in male mice
Beiging and thermogenesis in white adipose tissue (WAT) is an important adaptive response to cold exposure, but how the brain senses cold and subsequently induces beiging remains unclear. Here, the authors show that sympathetic nerves stimulate lymph nodes to release IL-33, thereby mediating cold-induced beiging of WAT.
- Lai Yee Cheong
- , Baile Wang
- & Aimin Xu
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Article
| Open AccessSingle-cell transcriptome profiling of the stepwise progression of head and neck cancer
Head and neck squamous cell carcinomas (HNSCCs) undergo a stepwise progression from normal tissues. In order to better understand the molecular mechanisms behind such progression, here the authors profile HNSCC tumors at different stages using single-cell RNA-seq, and observe the role of interactions with the tumor microenvironment.
- Ji-Hye Choi
- , Bok-Soon Lee
- & Chul-Ho Kim
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Article
| Open Access11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial
Glucocorticoids prescribed to limit inflammation, have significant adverse effects. Here the authors show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects.
- Nantia Othonos
- , Riccardo Pofi
- & Jeremy W. Tomlinson
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Article
| Open AccessMethionine adenosyltransferase2A inhibition restores metabolism to improve regenerative capacity and strength of aged skeletal muscle
Aged myoblasts suffer from impaired glycolysis and insulin resistance, but increase methionine catabolism, possibly to meet energetic demands. Here, authors show that inhibiting methionine metabolism via NANOG reprogramming or MAT2A inhibition restores the function and regeneration capacity of aged muscle.
- Nika Rajabian
- , Izuagie Ikhapoh
- & Stelios T. Andreadis
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Article
| Open AccessPersonalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation
PREGCARE is a new strategy for families who had a child with a pathogenic de novo mutation, that efficiently identifies couples at higher recurrence risk due to parental mosaicism, while reassuring many others that their recurrence risk is negligible.
- Marie Bernkopf
- , Ummi B. Abdullah
- & Anne Goriely
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Article
| Open AccessDefective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle
Marchioretti and colleagues show that in the skeletal muscle of SBMA mice and patients there is an early, but reversible alteration of expression of genes involved in muscle contraction and of mitochondrial respiration, followed by accumulation of calcium inside the mitochondria, which is concomitant with the onset of motor dysfunction, and late alteration of muscle structure.
- Caterina Marchioretti
- , Giulia Zanetti
- & Maria Pennuto
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Article
| Open AccessAtlas of plasma NMR biomarkers for health and disease in 118,461 individuals from the UK Biobank
The authors report a systematic analyses of blood biomarkers for metabolism against the whole spectrum of diseases in 100,000 individuals and reveals a prominent role of numerous metabolic biomarkers as risk markers beyond heart disease and diabetes.
- Heli Julkunen
- , Anna Cichońska
- & Peter Würtz
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Article
| Open AccessFTO-dependent m6A modification of Plpp3 in circSCMH1-regulated vascular repair and functional recovery following stroke
The mechanisms behind how vascular repair is regulated after ischemic stroke are yet to be elucidated. Here, the authors describe that a circular RNA interacts with FTO to promote vascular repair following stroke in mice and primates via mediating m6 A modification.
- Bin Li
- , Wen Xi
- & Honghong Yao
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Article
| Open AccessGenome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure
Otosclerosis is a common form of hearing loss, with an unclear genetic etiology. Here, the authors perform a genome-wide association study meta-analysis of otosclerosis identifying 27 genetic loci, pointing to genes involved in bone remodeling, skeletal disorders and transforming growth factor β signaling.
- Joel T. Rämö
- , Tuomo Kiiskinen
- & Aarno Palotie
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Article
| Open AccessDynamic 18F-Pretomanid PET imaging in animal models of TB meningitis and human studies
Pretomanid has been approved for use in cases of multi-drug resistant pulmonary tuberculosis, yet the penetration of this antibiotic into other target tissues is not well established. Authors provide insight on pretomanid pharmacokinetics in the central nervous system, using positron emission tomography in animal models, and human studies.
- Filipa Mota
- , Camilo A. Ruiz-Bedoya
- & Sanjay K. Jain