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Swine are proposed as 'mixing vessels' to generate novel influenza A viruses (IAVs) by facilitating reassortment among IAVs and providing a potential pathway in which these viruses can move from [...]

Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy that can infect mammals in the family Cervidae, which includes deer, elk, and moose, among other species. Initially detected in a [...]

Viridans group streptococci (VGS), a genetically heterogeneous group of bacteria, are the predominant bacteria in the human oropharynx (1). VGS cause a wide range of infections in humans, including bacteremia [...]

Human settlement in New Zealand is relatively recent compared with that of many countries and extends back ≅800 years to when early Polynesian explorers first arrived (1). A wide variety [...]

Hepatitis E virus (HEV) is a single-stranded positivesense RNA virus that belongs to the family Hepeviridae, genus Hepevirus, and is the causative agent of hepatitis E (1,2). Because the transmission [...]

Hantavirus pulmonary syndrome (HPS) is an acute viral disease, characterized by a nonspecific febrile illness followed by severe noncardiogenic pulmonary edema and cardiogenic shock. It is also referred to as [...]

Hendra virus (HeV) is an emerging zoonotic paramyxovirus for which natural reservoirs are the 4 species of flying fox (Pteropus bats) found on mainland Australia (1). HeV was discovered in [...]

Renal tubular dysgenesis (RTD) is a severe foetal disorder characterised by the absence or poor development of proximal tubules, early onset and persistent anuria (leading to oligohydramnios and the Potter sequence) and ossification defects of the skull. In most cases, early death occurs from pulmonary hypoplasia, anuria and refractory arterial hypotension. RTD may be acquired during foetal development or inherited as an autosomal recessive disease. Inherited RTD is genetically heterogeneous and linked to mutations in the genes encoding the major components of the renin-angiotensin system (RAS): angiotensinogen, renin, angiotensin-converting enzyme or angiotensin II receptor type 1. Mutations result in either the absence of production or lack of efficacy of angiotensin II. Secondary RTD has been observed in various situations, particularly in the donor twin of severe twin-to-twin transfusion syndrome, in foetuses affected with congenital haemochromatosis or in foetuses exposed to RAS blockers. All cases result in renal hypoperfusion. These examples illustrate the importance of a functional RAS in the maintenance of blood pressure and renal blood flow for humans during foetal life. The diagnosis of RTD in an anuric foetus with normal renal sonography results is important for the management of the foetus or neonate. Depending on the genetic or secondary cause of the disease, such findings can lead to genetic counselling or the prevention of recurrence in subsequent pregnancies. Keywords Renal tubular dysgenesis * RAS genes * RAS Blockers * Haemochromatosis * Twin-to-twin transfusion syndrome, Introduction The term renal tubular dysgenesis (RTD) was coined by Allanson et al. to describe a peculiar renal lesion (the absence of differentiated proximal tubules) in two stillborn foetuses who [...]

Bovine spongiform encephalopathy (BSE) is the transmissible spongiform encephalopathy (TSE) or prion disease of domestic cattle. The BSE prion is an epizootic agent and causes variant Creutzfeldt-Jakob disease (vCJD) in [...]

Introduction High mobility group box 1 (HMGB1), a ubiquitous nuclear protein, induces several inflammatory diseases and functions as a fatal factor when released extracellularly. The effect of HMGB1 on vascular reactivity during sepsis remains to be clarified. Methods A rat model of abdominal sepsis was produced by cecal ligation and puncture (CLP) under sevoflurane anesthesia (n = 28). Anti-HMGB1 antibody at a dose of 4 or 0.4 mg/kg, or normal saline was injected twice intravenously, i.e., immediately after the CLP surgery and 4 h thereafter. Rats in the sham group underwent laparotomy, and the cecum was manipulated but not ligated or punctured. The descending thoracic aorta was excised 12 h after the CLP surgery and cut into rings of approximately 3 mm in length. Changes in the expression of HMGB1 and vascular reactivity were examined in the rings shortly after harvest and 4 h thereafter. Results HMGB1 was identified immunohistochemically and by Western blotting in the nuclei of vascular endothelial and smooth muscle cells in all groups shortly after excision of the aorta, but its expression was augmented only in the CLP groups 4 h thereafter. Degenerated smooth muscle cells were also observed after CLP. Anti-HMGB1 antibody dose-dependently inhibited the augmentation of HMGB1 expression and the morphological changes induced by CLP. The expression of HMGB1 partly correlated with suppression of vascular reactivity. Conclusion The present results strongly suggest that HMGB1 plays an important role in vascular malfunction from an early phase of sepsis. Keywords HMGB1 * Vascular smooth muscle * Endothelium * Sepsis * Rat aorta, Introduction High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein present in many eukaryotic cells that stabilizes nucleosomes and enables gene transcription by binding to DNA [1]. When [...]

Macrophages are prominent in the uterus and ovary at conception. Here we utilize the Cd11b-Dtr mouse model of acute macrophage depletion to define the essential role of macrophages in early [...]

Chronic pancreatitis is an inflammatory disease that causes progressive destruction of pancreatic acinar cells and, ultimately, loss of pancreatic function. We investigated the role of IκB kinase α (IKKα) in [...]

Heterozygous loss-of-function SMAD3 (Mothers against decapentaplegic homolog 3) mutations lead to aneurysm-osteoarthritis syndrome (AOS). In the present study, we found that mice lacking Smad3 had a vascular phenotype similar to [...]

Eosinophils are abundant in inflammatory demyelinating lesions in neuromyelitis optica (NMO). We used cell culture, ex vivo spinal cord slices, and in vivo mouse models of NMO to investigate the [...]

Treating neuropathic pain is a major clinical challenge, and the underlying mechanisms of neuropathic pain remain elusive. We hypothesized that neuropathic pain--inducing nerve injury may elicit neuronal alterations that recapitulate [...]

Muscular dystrophies are a class of disorders that cause progressive muscle wasting. A major hurdle for discovering treatments for the muscular dystrophies is a lack of reliable assays to monitor [...]

Reverse cholesterol transport (RCT) refers to the mobilization of cholesterol on HDL particles (HDL-C) from extravascular tissues to plasma, ultimately for fecal excretion. Little is known about how HDL-C leaves [...]

BACKGROUND: Bisphenol A (BPA) is a well-known endocrine disruptor that imperfectly mimics the effects of physiologic estrogens via membrane-bound estrogen receptors (mER [alpha], mER[beta], and GPER/GPR30), thereby initiating nongenomic signaling. [...]

BACKGROUND: We have previously shown that exposure to tributyltin (TBT) modulates critical steps of adipogenesis through RXR/PPAR[gamma] and that prenatal TBT exposure predisposes multi-potent mesenchymal stem cells (MSCs) to become [...]

Arsenic is a toxic metalloid contaminant in drinking water sources throughout the world, affecting hundreds of millions of people (Mandal and Suzuki 2002). Exposure to arsenic via drinking water in [...]

BACKGROUND: Anogenital distance in animals is used as a measure of fetal androgen action. Prenatal exposure to dioxins and dioxin-like compounds in rodents causes reproductive changes in male offspring and [...]

BACKGROUND: Exposure to dioxins has been associated with delayed pubertal onset in both epidemiologic and animal studies. Whether genetic polymorphisms may modify this association is currently unknown. Identifying such genes [...]

BACKGROUND: Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote proinflammatory gene expression in adipocytes. PCBs are highly lipophilic and accumulate in adipose tissue, a site of insulin resistance in [...]

BACKGROUND: Exposure to lead (Pb) from environmental and industrial sources remains an overlooked serious public health risk. Elucidating the effect of Pb on bone cell function is therefore critical for [...]

Meiosis is a germ-cell-specific cell division process through which haploid gametes are produced for sexual reproduction (1). Before the initiation of meiosis, mouse primordial germ cells undergo a series of epigenetic reprogramming steps (2,3), including the global erasure of DNA methylation at the 5-position of cytosine (5mC) in CpG-rich DNA (4,5). Although several epigenetic regulators, such as Dnmt3l and the histone methyltransferases G9a and Prdm9, have been reported to be crucial for meiosis (6), little is known about how the expression of meiotic genes is regulated and how their expression contributes to normal meiosis. Using a loss-of-function approach in mice, here we show that the 5mC-specific dioxygenase Tet1 has an important role in regulating meiosis in mouse oocytes. Tet1 deficiency significantly reduces female germ-cell numbers and fertility. Univalent chromosomes and unresolved DNA double-strand breaks are also observed in Tet1-deficient oocytes. Tet1 deficiency does not greatly affect the genome-wide demethylation that takes place in primordial germ cells, but leads to defective DNA demethylation and decreased expression of a subset of meiotic genes. Our study thus establishes a function for Tet1 in meiosis and meiotic gene activation in female germ cells., Mouse primordial germ cells (PGCs) first appear at embryonic day (E)7.25 on the base of the allantois, and then migrate through the hindgut to the genital ridge (3). During migration [...]

Protease-activated receptor 1 (PAR1) is the prototypical member of a family of G-protein-coupled receptors that mediate cellular responses to thrombin and related proteases. Thrombin irreversibly activates PAR1 by cleaving the amino-terminal exodomain of the receptor, which exposes a tethered peptide ligand that binds the heptahelical bundle of the receptor to affect G-protein activation. Here we report the 2.2 A resolution crystal structure of human PAR1 bound to vorapaxar, a PAR1 antagonist. The structure reveals an unusual mode of drug binding that explains how a small molecule binds virtually irreversibly to inhibit receptor activation by the tethered ligand of PAR1. In contrast to deep, solvent-exposed binding pockets observed in other peptide-activated G- protein-coupled receptors, the vorapaxar-binding pocket is superficial but has little surface exposed to the aqueous solvent. Protease-activated receptors are important targets for drug development. The structure reported here will aid the development of improved PAR1 antagonists and the discovery of antagonists to other members of this receptor family., Protease-activated receptors (PARs) are G-protein-coupled receptors (GPCRs) that mediate cellular responses to specific proteases (1,2). The coagulation protease thrombin activates the prototypical PAR, PAR1, by specific cleavage of the N-terminal [...]

BACKGROUND: Chlorinated phosphate esters (CPEs) are widely used as additive flame retardants for low-density polyurethane foams and have frequently been detected at elevated concentrations within indoor environmental media. OBJECTIVES: To [...]