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Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson’s-like movement disorder
Mitophagy selectively disposes of dysfunctional mitochondria and defects in this process lead to a variety of mitochondrial diseases. Here the authors report that the mitochondrial protein PGAM5 is required for the stabilization of mitophagy-inducing protein PINK1, and that mice deficient for the gene coding for PGAM5 show signs of neurodegeneration.
- Wei Lu
- , Senthilkumar S. Karuppagounder
- & Michael Lenardo
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Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients
TDP-43 proteinopathies are characterized by TDP-43 aggregates but the relationship of these aggregates to the pathogenesis is still not well defined. Here, the authors show that the recombinant full-length human TDP-43 forms oligomers that are neurotoxic, can promote the formation of A-beta amyloid oligomers in vitroand can be detected in postmortem brain of patients.
- Yu-Sheng Fang
- , Kuen-Jer Tsai
- & Yun-Ru Chen
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Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function
The transduction of mechanical forces into signals that alter cardiac contractility is important for heart function. Here the authors show that integrin-linked kinase acts as a mechanosensor in cardiomyocytes, and affects cardiac contractility by regulating SERCA-2a and phospholamban.
- Alexandra Traister
- , Mark Li
- & John G. Coles
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Circadian rhythm reprogramming during lung inflammation
Whether circadian rhythms occur in settings where clock gene expression is suppressed, such as systemic inflammation, is unclear. Here, the authors examine gene expression and metabolites in the lungs of endotoxemic mice and show that inflammation causes changes in circadian rhythms at the cellular and molecular level.
- Jeffrey A. Haspel
- , Sukrutha Chettimada
- & Augustine M.K. Choi
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| Open AccessMagnetic antibody-linked nanomatchmakers for therapeutic cell targeting
Cell therapy requires sufficient amounts of therapeutic cells to be delivered to the injured tissue. Here the authors use magnetic iron nanoparticles conjugated with antibodies that bind therapeutic cells and cardiomyocytes to treat myocardial ischemia/reperfusion injury in rats and show that targeting to the heart is enhanced upon local application of a magnetic field.
- Ke Cheng
- , Deliang Shen
- & Eduardo Marbán
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Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology
The Wdfy3gene has been associated with autism spectrum disorders in children. Here, the authors examine two separate mutant alleles of this gene in mice and identify its role in cortical neurogenesis, reproducing pathological changes characteristic of the disorder.
- Lori A. Orosco
- , Adam P. Ross
- & Konstantinos S Zarbalis
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Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers
Cellular defects in autophagy contribute to the development of fatty liver in obesity. Here, Park et al.reveal that hepatic autophagy is impaired by chronically elevated cytosolic calcium levels, and show that a clinically approved calcium channel blocker can improve metabolic parameters of obese mice.
- Hwan-Woo Park
- , Haeli Park
- & Jun Hee Lee
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Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott–Aldrich syndrome-like platelet defect
Patients with mutations in the gene encoding the cytoskeleton regulator WAS have platelet defects. Here the authors show that the WAS-binding protein, Profilin1, is essential for platelet formation in mice, and that its deficiency reproduces the bleeding disorder of patients with WAS mutations.
- Markus Bender
- , Simon Stritt
- & Bernhard Nieswandt
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Respiratory transmission of an avian H3N8 influenza virus isolated from a harbour seal
Avian influenza viruses constantly threaten human health as evidenced by the outbreaks of human H7N9 infections. Here, Karlsson et al. show that an avian H3N8 virus isolated from harbour seals has the potential to infect, cause disease and transmit in mammalian models of influenza virus infection.
- Erik A. Karlsson
- , Hon S. Ip
- & Stacey Schultz-Cherry
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| Open Accessptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease
Scoliosis is a complex genetic disorder characterized by spinal curvature. Here, the authors present experimental zebrafish models of idiopathic and congenital scoliosis and suggest a role for dysregulated Wnt activity in scoliosis aetiology.
- Madeline Hayes
- , Xiaochong Gao
- & Brian Ciruna
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IL-37 protects against obesity-induced inflammation and insulin resistance
Inflammation is a hallmark of obesity and driver of various associated pathologies. Here the authors show that mice overexpressing the anti-inflammatory cytokine IL-37 are protected from the metabolic consequences of a high-fat diet, and that plasma levels of IL-37 correlate with insulin sensitivity in humans.
- Dov B. Ballak
- , Janna A. van Diepen
- & Rinke Stienstra
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| Open AccessPPARα-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis
Bile acids have been linked to the development of inflammatory bowel diseases, such as colitis. Here the authors show that bile acid levels in mice are controlled by a circular feedback system involving the nuclear receptors PPARα and FXR, and that this system is dysregulated in colitis.
- Xueyan Zhou
- , Lijuan Cao
- & Haiping Hao
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Microbial genomic analysis reveals the essential role of inflammation in bacteria-induced colorectal cancer
Abundance of certain gut enterobacteria is correlated with inflammation and cancer development in humans, but the interplay between the three factors is unclear. Here the authors show that gut inflammation is required for bacteria-associated tumour development in mouse models.
- Janelle C. Arthur
- , Raad Z. Gharaibeh
- & Christian Jobin
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Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis
Metastases are known to preferentially spread through the lymphatic vessels. Here the authors uncover a self-reinforcing paracrine loop between breast cancer cells and lymphatic endothelial cells, which promotes seeding of cancer cells and angiogenesis in pre-metastatic niches but can be effectively blocked by repurposed therapeutic agents.
- Esak Lee
- , Elana J. Fertig
- & Aleksander S. Popel
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Loss of PIKfyve in platelets causes a lysosomal disease leading to inflammation and thrombosis in mice
PIKfyve is a lipid kinase essential for regulation of membrane homeostasis and vesicle trafficking along the endosomal-lysosomal pathway. Here the authors show that mice lacking PIKfyve exclusively in their platelets exhibit a systemic disorder characterized by multi-organ inflammation and thrombosis due to aberrant platelet lysosome function.
- Sang H. Min
- , Aae Suzuki
- & Charles S. Abrams
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Pseudomonas aeruginosa adaptation in the nasopharyngeal reservoir leads to migration and persistence in the lungs
Pseudomonas aeruginosa causes chronic infections in patients with lung damage. Here, Fothergill et al. develop an intranasal inhalation model of P. aeruginosainfection and describe genetic and phenotypic changes that the bacteria undergo during adaptation and spread through the respiratory tract.
- Joanne L. Fothergill
- , Daniel R. Neill
- & Aras Kadioglu
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High susceptibility to fatty liver disease in two-pore channel 2-deficient mice
Two-pore channel 2 has been implicated in coupling changes in cellular energy status with endolysosomal function. Grimm et al.show that mice lacking this channel display defects in endolysosomal trafficking of LDL-cholesterol and are susceptible to hepatic cholesterol overload and fatty liver disease.
- Christian Grimm
- , Lesca M. Holdt
- & Christian Wahl-Schott
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Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women
Ovarian cancer is common among women and is the leading cause of death from gynaecological malignancies. Here the authors identify two previously unknown genetic variants that increase the risk of epithelial ovarian cancer in Han Chinese women.
- Kexin Chen
- , Hongxia Ma
- & Qingyi Wei
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Carbon monoxide inhibits inward rectifier potassium channels in cardiomyocytes
Following myocardial infarction, patients are at risk for reperfusion-induced ventricular fibrillation, a life-threatening condition. Here, Liang et al. show that the known ventricular fibrillation preventive effects of carbon monoxide are mediated through the inhibition of a subset of inward-rectifying potassium channels.
- Shenghui Liang
- , Quanyi Wang
- & Yuchun Gu
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A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV
Mucolipidosis type IV is a lysosomal storage disorder caused by mutations in the endolysosomal cation channel TRPML1 and results in progressive neurodegeneration. Here, Chen et al. demonstrate that small molecules can be used to restore TRPML1 mutant channel function and rescue disease-associated symptoms.
- Cheng-Chang Chen
- , Marco Keller
- & Christian Grimm
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| Open AccessIdentification of a human neonatal immune-metabolic network associated with bacterial infection
Infection remains a leading cause of morbidity and mortality in neonates worldwide. Here the authors report disproportionate immune stimulatory, co-inhibitory and metabolic pathway responses that specifically mark bacterial infection and can be used to predict sepsis in neonatal patients at the first clinical signs of infection.
- Claire L. Smith
- , Paul Dickinson
- & Peter Ghazal
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Early-onset metabolic syndrome in mice lacking the intestinal uric acid transporter SLC2A9
Elevated blood levels of urate have been linked to metabolic diseases. Here the authors show that the urate transporter, GLUT9, in enterocytes is important for the extrarenal excretion of urate, and that primary hyperuricaemia in mice lacking Glut9 is sufficient to develop metabolic syndrome.
- Brian J DeBosch
- , Oliver Kluth
- & Kelle Moley
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| Open AccessIndividual diet has sex-dependent effects on vertebrate gut microbiota
Diet variations can alter gut microbial composition, but the potential influence of host genetic factors on these effects is unclear. Here, the authors show, in humans and in natural and laboratory fish populations, that such effects are dependent on the host’s sex, a genetically determined factor.
- Daniel I. Bolnick
- , Lisa K. Snowberg
- & Richard Svanbäck
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Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum
It remains unclear why iron deficiency can protect from malaria infection. Here the authors show that iron-deficient microcytic erythrocytes are less efficiently infected by Plasmodium falciparumparasites and that iron supplementation increases the proportion of young erythrocytes more susceptible to infection.
- Martha A. Clark
- , Morgan M. Goheen
- & Carla Cerami
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An infectious bat-derived chimeric influenza virus harbouring the entry machinery of an influenza A virus
An uncharacterized influenza A-like virus (H17N10) has been detected in bats. Here the authors show that flu viruses containing certain H17N10 genes can infect human cells and mice, but do not exchange genes with other viruses, indicating that H17N10 transmission to humans is not very likely.
- Mindaugas Juozapaitis
- , Étori Aguiar Moreira
- & Martin Schwemmle
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MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia
Reduced generation of multiple motile cilia (RGMC) is a rare mucociliary clearance disorder, characterized by chronic airway disease. Here, the authors identify mutations in the Multicilin gene, MCIDAS, and suggest that these mutations cause RGMC through disruption of multiciliated cell differentiation.
- Mieke Boon
- , Julia Wallmeier
- & Heymut Omran
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Elfn1 recruits presynaptic mGluR7 in trans and its loss results in seizures
The transmembrane protein Elfn1 is implicated in synaptic plasticity. Tomioka et al. identify Elfn1 mutations in epilepsy and attention deficit hyperactivity disorder (ADHD) patients, and show that loss of Elfn1in mice results in seizures, ADHD-like behaviour and impaired development of excitatory synapses.
- Naoko H. Tomioka
- , Hiroki Yasuda
- & Jun Aruga
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| Open AccessDevelopment of pro-apoptotic peptides as potential therapy for peritoneal endometriosis
Endometriosis is a painful condition in which endometrial cells are found outside the womb. Here, the authors identify a peptide that specifically binds to a receptor expressed on endometrial epithelial cells and use it to induce apoptosis in both cultured cells and baboons with endometriosis.
- K. Sugihara
- , Y. Kobayashi
- & M.N. Fukuda
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GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis
Liver fibrosis involves the activation of hepatic stellate cells (HSCs). Here the authors show that the guanine exchange factor GIV is specifically upregulated in HSCs, and that it serves as an integrator of multi-receptor driven pro-fibrotic signalling in the liver via its ability to activate G proteins.
- Inmaculada Lopez-Sanchez
- , Ying Dunkel
- & Pradipta Ghosh
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An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling
Polysaccharide A (PSA) from the human intestinal commensal Bacteroides fragilis mediates protection against the experimental autoimmune encephalomyelitis in mice. Here, Wang et al. show that the protective function of PSA is exerted through its action on CD39+regulatory CD4 T cells via Toll-like receptor 2 signalling.
- Yan Wang
- , Kiel M. Telesford
- & Lloyd H. Kasper
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| Open AccessRole of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells
Down’s syndrome is characterized by intellectual disability and other neuropathological symptoms. Here, the authors show that astroglia derived from induced pluripotent stem cells from Down’s syndrome patients impair the development of neurons, and that this can be attenuated with the drug minocycline.
- Chen Chen
- , Peng Jiang
- & Wenbin Deng
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Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction
It is becoming increasingly clear that the three-dimensional organization of chromatin within the nucleus plays a role in regulating gene expression. Here, Ito et al.demonstrate that the disruption of chromocenter clustering in mature neuronal cells results in specific transcriptional and behavioural defects in mice.
- Satomi Ito
- , Adriana Magalska
- & Angel Barco
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Treatment of acute lung injury by targeting MG53-mediated cell membrane repair
MG53 acts as a membrane repair protein in striatal muscle. Here the authors report that MG53 is also expressed in the lung, where it exerts a similar repair function in the context of pulmonary epithelial damage, and show that administration of recombinant MG53 ameliorates lung injury in mice.
- Yanlin Jia
- , Ken Chen
- & Jianjie Ma
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LRRC19 expressed in the kidney induces TRAF2/6-mediated signals to prevent infection by uropathogenic bacteria
The immune system plays an important role in preventing microbial colonization in the urinary tract but the mechanism of this protection is not completely understood. Here, the authors identify LRRC19 expressed in the kidneys as a pathogen-recognition receptor involved in the immune response to uropathogenic bacteria.
- Xiaomin Su
- , Siping Min
- & Rongcun Yang
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| Open AccessIdentification of platelet function defects by multi-parameter assessment of thrombus formation
Platelets from patients with bleeding disorders often display altered adherence to surface proteins. In this study, de Witt et al.design a flow chamber for the systematic interrogation of platelets attaching to 52 adhesive surfaces, which may be helpful for the diagnosis of platelet disorders.
- Susanne M. de Witt
- , Frauke Swieringa
- & Judith M.E.M. Cosemans
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Src-dependent impairment of autophagy by oxidative stress in a mouse model of Duchenne muscular dystrophy
Defective autophagy is associated with the pathogenesis of Duchenne muscular dystrophy (DMD). Pal et al. reveal that activation of Src kinase by oxidative stress is responsible for impairment of autophagy in the muscles of mdxmice, and show that reducing oxidative stress rescues autophagy in this DMD model.
- Rituraj Pal
- , Michela Palmieri
- & George G. Rodney
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| Open AccessGlucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR
Patients with cystic fibrosis harbour mutations in the CFTR chloride channel and often develop diabetes for reasons that are poorly understood. Here Guo et al.show that CFTR is involved in the regulation of glucose-stimulated insulin secretion from pancreatic β-cells.
- Jing Hui Guo
- , Hui Chen
- & Hsiao Chang Chan
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The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice
Retnla is an adipokine with known roles in tissue repair and inflammation. Here Lee et al. show that Retnla also promotes cholesterol metabolism and excretion, thereby lowering blood cholesterol levels and reducing the development of atherosclerosis in mice.
- Mi-Ran Lee
- , Chae-ji Lim
- & Goo Taeg Oh
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Amyloid-associated activity contributes to the severity and toxicity of a prion phenotype
The yeast prion Sup35/[PSI+] confers a translation termination defect in its amyloid form. Pezza et al.reveal that aggregated Sup35 retains translation termination activity, and find that fluctuations in the size and composition of aggregates play an important role in determining their activity and toxicity.
- John A. Pezza
- , Janice Villali
- & Tricia R. Serio
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| Open AccessAstrocyte response to motor neuron injury promotes structural synaptic plasticity via STAT3-regulated TSP-1 expression
Perineuronal astrocyte reactivity is implicated in functional recovery following nerve injury but exactly how this happens is unclear. Tyzack et al. show that perineuronal astrocytes facilitate the recovery of synaptic inputs to damaged neurons via STAT3-dependent upregulation of the astrocytic protein TSP-1.
- Giulia E. Tyzack
- , Sergey Sitnikov
- & András Lakatos
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Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men
Differential selection on sex-specific genes facilitates propagation of deleterious mutations. Here, the authors show that genes exclusively expressed in human testes harbour a greater number of deleterious mutations than genes expressed in both sexes, due to reduced selection in females.
- Moran Gershoni
- & Shmuel Pietrokovski
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| Open AccessThe Opisthorchis viverrini genome provides insights into life in the bile duct
The Asian liver fluke is a parasitic worm that is linked to an increased risk of malignant cancer. Here, the authors sequence the draft genome and transcriptome of this fluke and provide insight into how the species has adapted to be able to survive in the bile duct.
- Neil D. Young
- , Niranjan Nagarajan
- & Robin B. Gasser
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| Open AccessPrion neuropathology follows the accumulation of alternate prion protein isoforms after infective titre has peaked
Prions (PrP) are infectious agents that cause lethal neurodegenerative diseases. Here the authors study the kinetics of prion propagation in mice and show that the onset of neuropathology occurs during the late phase of disease and is hypothesized to be due to increases in a toxic isoform of PrP that is different from the infectious species.
- Malin K. Sandberg
- , Huda Al-Doujaily
- & John Collinge
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Sequencing-based approach identified three new susceptibility loci for psoriasis
Although psoriasis is a chronic disorder affecting approximately 2% of the population, little is known about the underlying genetic architecture. Here, the authors carry out exome sequencing in a large Han Chinese cohort of psoriasis patients and healthy controls, and identify three new genes that may increase risk of developing the disease.
- Yujun Sheng
- , Xin Jin
- & Xuejun Zhang
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Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs
Fanconi anaemia (FA) is a genetic disease associated with low levels of blood stem cells. Here Liu et al.report an improved method to generate genetically corrected induced pluripotent stem cells from an FA patient, and perform a screening to identify drugs that improve their differentiation into blood stem cells.
- Guang-Hui Liu
- , Keiichiro Suzuki
- & Juan Carlos Izpisua Belmonte
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| Open AccessEXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia
The exosome is responsible for mRNA degradation, which is an important step in the regulation of gene expression. Here the authors report that homozygous missense mutations in the exosome subunit, EXOSC8, may cause neurodegenerative disease in infants through the dysregulation of myelin expression.
- Veronika Boczonadi
- , Juliane S. Müller
- & Rita Horvath
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Rag GTPases are cardioprotective by regulating lysosomal function
Rag family proteins control activation of the mTORC1 complex at the lysosome. Here the authors show that loss of RagA/B causes cardiac hypertrophy in mice, revealing an mTORC-independent function of Rag GTPAses as regulators of lysosome function and autophagic flux in cardiomyocytes.
- Young Chul Kim
- , Hyun Woo Park
- & Kun-Liang Guan
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| Open AccessTM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is characterized by increased hepatic triglyceride content (HTGC) in the absence of high alcohol consumption. Here the authors show that a genetic variant in TM6SF2, which is known to be associated with HTGC, is a clinically relevant modifier of hepatic fibrogenesis and increases the risk of progressive NAFLD.
- Yang-Lin Liu
- , Helen L. Reeves
- & Quentin M. Anstee
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Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis
Mycobacterium tuberculosisis intrinsically resistant to most antibiotics. Here, the authors show that the pathogen’s tolerance to three antibiotics, each one targeting a distinct cellular process, is mediated by an antioxidant response that requires the activation of isocitrate lyases.
- Madhumitha Nandakumar
- , Carl Nathan
- & Kyu Y. Rhee
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