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Aug 1, 2014
Spectrum of statin hepatotoxicity: Experience of the drug-induced liver injury network
The HMG-CoA reductase inhibitors (statins) are widely prescribed for patients with hyperlipidemia and are generally well tolerated. Mild elevations in serum aminotransferases arise in up to 3% of treated patients, but clinically apparent drug-induced liver injury is rare. The aim of this study is to report the presenting features and outcomes of 22 patients with clinically apparent liver injury due to statins.
Jul 1, 2014
Myosin Vb uncoupling from RAB8A and RAB11A elicits microvillus inclusion disease
Microvillus inclusion disease (MVID) is a severe form of congenital diarrhea that arises from inactivating mutations in the gene encoding myosin Vb (MYO5B). We have examined the association of mutations in MYO5B and disruption of microvillar assembly and polarity in enterocytes. Stable MYO5B knockdown (MYO5B-KD) in CaCo2-BBE cells elicited loss of microvilli, alterations in junctional claudins, and disruption of apical and basolateral trafficking; however, no microvillus inclusions were observed in MYO5B-KD cells.
Jun 19, 2014
The Diabetes Susceptibility Gene Clec16a Regulates Mitophagy
Clec16a has been identified as a disease susceptibility gene for type 1 diabetes, multiple sclerosis, and adrenal dysfunction, but its function is unknown. Here we report that Clec16a is a membrane-associated endosomal protein that interacts with E3 ubiquitin ligase Nrdp1. Loss of Clec16a leads to an increase in the Nrdp1 target Parkin, a master regulator of mitophagy. Islets from mice with pancreas-specific deletion of Clec16a have abnormal mitochondria with reduced oxygen consumption and ATP concentration, both of which are required for normal β cell function.
Jun 17, 2014
α-Intercalated cells defend the urinary system from bacterial infection
α-Intercalated cells (A-ICs) within the collecting duct of the kidney are critical for acid-base homeostasis. Here, we have shown that A-ICs also serve as both sentinels and effectors in the defense against urinary infections. In a murine urinary tract infection model, A-ICs bound uropathogenic E. coli and responded by acidifying the urine and secreting the bacteriostatic protein lipocalin 2 (LCN2; also known as NGAL). A-IC-dependent LCN2 secretion required TLR4, as mice expressing an LPS-insensitive form of TLR4 expressed reduced levels of LCN2.
Jun 5, 2014
Meteorin-like Is a Hormone that Regulates Immune-Adipose Interactions to Increase Beige Fat Thermogenesis
Exercise training benefits many organ systems and offers protection against metabolic disorders such as obesity and diabetes. Using the recently identified isoform of PGC1-α (PGC1-α4) as a discovery tool, we report the identification of meteorin-like (Metrnl), a circulating factor that is induced in muscle after exercise and in adipose tissue upon cold exposure. Increasing circulating levels of Metrnl stimulates energy expenditure and improves glucose tolerance and the expression of genes associated with beige fat thermogenesis and anti-inflammatory cytokines.
Jun 5, 2014
Eosinophils and Type 2 Cytokine Signaling in Macrophages Orchestrate Development of Functional Beige Fat
Beige fat, which expresses the thermogenic protein UCP1, provides a defense against cold and obesity. Although a cold environment is the physiologic stimulus for inducing beige fat in mice and humans, the events that lead from the sensing of cold to the development of beige fat remain poorly understood. Here, we identify the efferent beige fat thermogenic circuit, consisting of eosinophils, type 2 cytokines interleukin (IL)-4/13, and alternatively activated macrophages. Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis of beige fat.
Jun 5, 2014
Eosinophils in Fat: Pink is the New Brown
Subcutaneous white adipose tissue can be induced to undergo “browning” and acquire thermogenic capacity in response to physiological stimuli such as cold exposure or exercise. In this issue of Cell, Qiu et al. and Rao et al. demonstrate that pink-staining eosinophils and alternatively activated macrophages play key roles in an immune cascade mediating this metabolic switch.
May 21, 2014
Null Mutation in Hormone-Sensitive Lipase Gene and Risk of Type 2 Diabetes
Lipolysis regulates energy homeostasis through the hydrolysis of intracellular triglycerides and the release of fatty acids for use as energy substrates or lipid mediators in cellular processes. Genes encoding proteins that regulate energy homeostasis through lipolysis are thus likely to play an important role in determining susceptibility to metabolic disorders.
May 21, 2014
Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase.
Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia1, 2. For over half a century, this agent has been prescribed to patients with type 2 diabetes worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown.
May 6, 2014
Chloride sensing by WNK1 involves inhibition of autophosphorylation
WNK1 [with no lysine (K)] is a serine-threonine kinase associated with a form of familial hypertension. WNK1 is at the top of a kinase cascade, leading to phosphorylation of several cotransporters, in particular those transporting sodium, potassium, and chloride (NKCC), sodium and chloride (NCC), and potassium and chloride (KCC). The responsiveness of NKCC, NCC, and KCC to changes in extracellular chloride parallels their phosphorylation state, provoking the proposal that these transporters are controlled by a chloride-sensitive protein kinase.
May 6, 2014
Opiorphin is a master regulator of the hypoxic response in corporal smooth muscle cells
Men with sickle cell disease (SCD) risk developing priapism. Recognizing that SCD is a disease of hypoxia, we investigated the effect of hypoxia on gene expression in corporal smooth muscle (CSM) cells. Rat CSM cells in vitro were treated with CoCl2 or low oxygen tension to mimic hypoxia. Hypoxic conditions increased expression of genes previously associated with priapism in animal models.
May 4, 2014
Persistent gut microbiota immaturity in malnourished Bangladeshi children
Therapeutic food interventions have reduced mortality in children with severe acute malnutrition (SAM), but incomplete restoration of healthy growth remains a major problem1, 2. The relationships between the type of nutritional intervention, the gut microbiota, and therapeutic responses are unclear. In the current study, bacterial species whose proportional representation define a healthy gut microbiota as it assembles during the first two postnatal years were identified by applying a machine-learning-based approach to 16S ribosomal RNA data sets generated from monthly faecal samples obtained from birth onwards in a cohort of children living in an urban slum of Dhaka, Bangladesh, who exhibited consistently healthy growth.
Apr 1, 2014
PPARγ in Vagal Neurons Regulates High-Fat Diet Induced Thermogenesis
The vagus nerve innervates visceral organs providing a link between key metabolic cues and the CNS. However, it is not clear whether vagal neurons can directly respond to changing lipid levels and whether altered “lipid sensing” by the vagus nerve regulates energy balance. In this study, we systematically profiled the expression of all known nuclear receptors in laser-captured nodose ganglion (NG) neurons. In particular, we found PPARγ expression was reduced by high-fat-diet feeding. Deletion of PPARγ in Phox2b neurons promoted HFD-induced thermogenesis that involved the reprograming of white adipocyte into a brown-like adipocyte cell fate.
Mar 20, 2014
The number of fetal nephron progenitor cells limits ureteric branching and adult nephron endowment
Nephrons, the functional units of the kidney, develop from progenitor cells (cap mesenchyme [CM]) surrounding the epithelial ureteric bud (UB) tips. Reciprocal signaling between UB and CM induces nephrogenesis and UB branching. Although low nephron number is implicated in hypertension and renal disease, the mechanisms that determine nephron number are obscure. To test the importance of nephron progenitor cell number, we genetically ablated 40% of these cells, asking whether this would limit kidney size and nephron number or whether compensatory mechanisms would allow the developing organ to recover.
Feb 14, 2014
Risk of end-stage renal disease following live kidney donation
Risk of end-stage renal disease (ESRD) in kidney donors has been compared with risk faced by the general population, but the general population represents an unscreened, high-risk comparator. A comparison to similarly screened healthy nondonors would more properly estimate the sequelae of kidney donation.
Jan 30, 2014
Nonstochastic reprogramming from a privileged somatic cell state
Reprogramming somatic cells to induced pluripotency by Yamanaka factors is usually slow and inefficient and is thought to be a stochastic process. We identified a privileged somatic cell state, from which acquisition of pluripotency could occur in a nonstochastic manner. Subsets of murine hematopoietic progenitors are privileged whose progeny cells predominantly adopt the pluripotent fate with activation of endogenous Oct4 locus after four to five divisions in reprogramming conditions.
Jan 16, 2014
Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells
Coevolution of beneficial microorganisms with the mammalian intestine fundamentally shapes mammalian physiology. Here, we report that the intestinal microbe Bacteroides fragilis modifies the homeostasis of host invariant natural killer T (iNKT) cells by supplementing the host’s endogenous lipid antigen milieu with unique inhibitory sphingolipids. The process occurs early in life and effectively impedes iNKT cell proliferation during neonatal development.
Nov 21, 2013
Chromogranin A is a T cell antigen in human type 1 diabetes
In this study the authors compared responses of human CD4 T cells from recent onset type 1 diabetic (T1D) and control subjects to WE14 and to an enzymatically modified version of this peptide. This work suggests that ChgA is an important target antigen in human T1D subjects and that post–translational modification may play a role in its reactivity and relationship to disease.
Sep 19, 2013
Bacterial colonization factors control specificity and stability of the gut microbiota
Mammals harbour a complex gut microbiome, comprising bacteria that confer immunological, metabolic and neurological benefits1. Despite advances in sequence-based microbial profiling and myriad studies defining microbiome composition during health and disease, little is known about the molecular processes used by symbiotic bacteria to stably colonize the gastrointestinal tract. We sought to define how mammals assemble and maintain the Bacteroides, one of the most numerically prominent genera of the human microbiome.
Jul 23, 2013
Fat cells directly sense temperature to activate thermogenesis
[Harvard Medical School] Classic brown fat and inducible beige fat both dissipate chemical energy in the form of heat through the actions of mitochondrial uncoupling protein 1. This nonshivering thermogenesis is crucial for mammals as a defense against cold and obesity/diabetes.
Jul 8, 2013
Mechanism-based corrector combination restores ΔF508-CFTR folding and function.
[McGill University] To better understand the difficulty of looking for a cure, or even effective treatment, one must understand the large and complex nature of the CFTR protein. It is made up of 1,480 amino acids strung together in five three-dimensional strands (called domains) that spin together and fold to act as building blocks for the CFTR protein.
May 8, 2013
Genomic Diversity and Fitness of E. coli Strains Recovered from the Intestinal and Urinary Tracts of Women with Recurrent Urinary Tract Infection
[Washington University in St. Louis] Urinary tract infections (UTIs) are common in women, and recurrence is a major clinical problem. Most UTIs are caused by uropathogenic Escherichia coli (UPEC). UPEC are generally thought to migrate from the gut to the bladder to cause UTI. UPEC form specialized intracellular bacterial communities in the bladder urothelium as part of a pathogenic mechanism to establish a foothold during acute stages of infection. Evolutionarily, such a specific adaptation to the bladder environment would be predicted to result in decreased fitness in other habitats, such as the gut. To examine this prediction, we characterized 45 E. coli strains isolated from the feces and urine of four otherwise healthy women with recurrent UTI.
May 1, 2013
Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH
[Albert Einstein College of Medicine] While the search continues for the Fountain of Youth, researchers may have found the body’s “fountain of aging”: the brain region known as the hypothalamus. For the first time, scientists at Albert Einstein College of Medicine of Yeshiva University report that the hypothalamus of mice controls aging throughout the body. Their discovery of a specific age-related signaling pathway opens up new strategies for combating diseases of old age and extending lifespan.
Apr 4, 2013
Renoprotective effect of combined inhibition of Angiotensin-converting enzyme and histone deacetylase
[Mt. Sinai School of Medicine] The Connectivity Map database contains microarray signatures of gene expression derived from approximately 6000 experiments that examined the effects of approximately 1300 single drugs on several human cancer cell lines. We used these data to prioritize pairs of drugs expected to reverse the changes in gene expression observed in the kidneys of a mouse model of HIV-associated nephropathy (Tg26 mice).
Mar 31, 2013
Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome
[Yale University School of Medicine] Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation.
Mar 13, 2013
Differential stem- and progenitor-cell trafficking by prostaglandin E2
[Indiana University School of Medicine] INDIANAPOLIS -- Scientists say that non-steroidal anti-inflammatory drugs may be a boon to doctors gathering stem cells for transplants to treat patients with blood or bone marrow cancers, including non-Hodgkin’s lymphoma and multiple myeloma.
The compounds, known as NSAIDs and which include aspirin, ibuprofen and other painkillers, increased the number of stem and progenitor cells harvested from the blood in animal testing and a small human study, according to work published online Wednesday in the journal Nature by a research team led by Indiana University School of Medicine scientists.
Mar 7, 2013
High Resolution Helium Ion Scanning Microscopy of the Rat Kidney
[Harvard Medical School] Helium ion scanning microscopy is a novel imaging technology with the potential to provide sub-nanometer resolution images of uncoated biological tissues. So far, however, it has been used mainly in materials science applications. Here, we took advantage of helium ion microscopy to explore the epithelium of the rat kidney with unsurpassed image quality and detail. In addition, we evaluated different tissue preparation methods for their ability to preserve tissue architecture.
Feb 26, 2013
Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation
[Johns Hopkins University School of Med] Researchers at The Johns Hopkins University and Yale University have discovered that a specialized receptor, normally found in the nose, is also in blood vessels throughout the body, sensing small molecules created by microbes that line mammalian intestines, and responding to these molecules by increasing blood pressure. The finding suggests that gut bacteria are an integral part of the body’s complex system for maintaining a stable blood pressure.
Jan 10, 2013
How insulin engages its primary binding site on the insulin receptor
[University of Melbourne and Case Western Reserve University] Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R).
Jan 7, 2013
Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP
[University of Pennsylvania] For fifty years, one of the few classes of therapeutics effective in reducing the overactive glucose production associated with diabetes has been the biguanides, which includes metformin, the most frequently prescribed drug for type 2 diabetes. The inability of insulin to keep liver glucose output in check is a major factor in the high blood sugar of type 2 diabetes and other diseases of insulin resistance.