Some advances in constrained inference for ordered circular parameters in oscillatory systems

Constraints on parameters arise naturally in many applications. Statistical methods that honor the underlying constraints tend to be more powerful and result in better interpretation of the underlying scientific data. In the context of Euclidean space data, there exists over five decades of statistical literature on constrained statistical inference and at least four books on the subject (e.g. Robertson et al. 1988; Silvapulle and Sen 2005). However, it was not until recently that these methods have been used extensively in applied research. For example, constrained statistical inference is gaining considerable interest among applied researchers in a variety of fields, such as, for example, toxicology (Peddada et al. 2007), genomics (Hoenerhoff et al. 2013; Perdivara et al. 2011; Peddada et al. 2003), epidemiology (Cao et al. 2011; Peddada et al. 2005), clinical trials (Conaway et al. 2004), or cancer trials (Conde et al. 2012, 2013).Ministerio de Ciencia e Innovación grant (MTM2012-37129)Junta de Castilla y León, Consejería de Educación and the European Social FundIntramural Research Program of the National Institute of Environmental Health Sciences (NIEHS) [Z01 ES101744-04

A precursor‐inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154358/1/fsb2030005012.pd

Development of Mast Cell and Eosinophil Hyperplasia and HLH/MAS-Like Disease in NSG-SGM3 Mice Receiving Human CD34+ Hematopoietic Stem Cells or Patient-Derived Leukemia Xenografts.

Immunocompromised mouse strains expressing human transgenes are being increasingly used in biomedical research. The genetic modifications in these mice cause various cellular responses, resulting in histologic features unique to each strain. The NSG-SGM3 mouse strain is similar to the commonly used NSG (NOD scid gamma) strain but expresses human transgenes encoding stem cell factor (also known as KIT ligand), granulocyte-macrophage colony-stimulating factor, and interleukin 3. This report describes 3 histopathologic features seen in these mice when they are unmanipulated or after transplantation with human CD34+ hematopoietic stem cells (HSCs), virally transduced hCD34+ HSCs, or a leukemia patient-derived xenograft. The first feature is mast cell hyperplasia: unmanipulated, naïve mice develop periductular pancreatic aggregates of murine mast cells, whereas mice given the aforementioned human cells develop a proliferative infiltrative interstitial pancreatic mast cell hyperplasia but with human mast cells. The second feature is the predisposition of NSG-SGM3 mice given these human cells to develop eosinophil hyperplasia. The third feature, secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS)-like disease, is the most pronounced in both its clinical and histopathologic presentations. As part of this disease, a small number of mice also have histiocytic infiltration of the brain and spinal cord with subsequent neurologic or vestibular signs. The presence of any of these features can confound accurate histopathologic interpretation; therefore, it is important to recognize them as strain characteristics and to differentiate them from what may be experimentally induced in the model being studied

Ruminant neurological disease: a retrospective cohort study

Between January 2006 and June 2016, 96 ruminants with neurological signs were donated to the Scottish Centre for Production Animal Health and Food Safety (SCPAHFS), University of Glasgow, by veterinarians in the field representing 5.4 per cent of all submissions. Forty-seven different neurological presenting signs were reported with 79 per cent of the donated patients presenting with abnormal gait. All cases presenting with abnormalities in more than 4 out of 10 neurological categories died or were euthanased on welfare grounds. Calves were significantly more likely to present with neurological disorders than adult cattle compared with the proportion of calves: cows in the Scottish cattle population and total case population donated to SCPAHFS. Lesions were most commonly localised to the spinal cord in sheep 47 per cent (16), the peripheral nervous system in cattle 45 per cent (28) and to the brain in the overall population 41 per cent (39). The most common aetiology of neurological pathologies observed was infectious or inflammatory 28 per cent (27). Definitive diagnoses could be reached in 84 per cent (81) of patients. When postmortem reports were available, they produced a diagnosis in 70 per cent (52) of cases and contradicted clinical diagnoses in 38 per cent (26) of cases. The most frequently diagnosed conditions in ruminants over the 10 years were spastic paresis, vertebral osteomyelitis and listeriosis

New Hosts for Equine Herpesvirus 9

Equine herpesvirus 9 was detected in a polar bear with progressive encephalitis; the source was traced to 2 members of a potential equid reservoir species, Grevy’s zebras. The virus was also found in an aborted Persian onager. Thus, the natural host range is extended to 6 species in 3 mammalian orders

Perfluorooctanoic Acid (PFOA)–induced Liver Lesions in Two Strains of Mice Following Developmental Exposures: PPARα Is Not Required

Perfluorooctanoate acid (PFOA) is a ubiquitous pollutant that causes liver toxicity in rodents, a process believed to be dependent on peroxisome proliferation activated receptor alpha (PPARα) activation. Differences between humans and rodents have made the human relevance of some health effects caused by PFOA controversial. We analyzed liver toxicity at 18 months following gestational PFOA exposure in CD-1 and 129/Sv strains of mice and compared PFOA-induced effects between strains and in wild type (WT) and PPARα-knockout (KO) 129/Sv mice. Pregnant mice were exposed daily to doses (0.01–5mg/kg/BW) of PFOA from gestation days 1–17. The female offspring were necropsied at 18 months and liver sections underwent a full pathology review. Hepatocellular adenomas formed in PFOA-exposed PPARα-KO 129/Sv and CD-1 mice, and were absent in untreated controls from those groups and WT 129/Sv. Hepatocellular hypertrophy was significantly increased by PFOA exposure in CD-1 and an increased severity was found in WT 129/Sv mice. PFOA significantly increased non-neoplastic liver lesions in PPARα-KO mice (hepatocyte hypertrophy, bile duct hyperplasia and hematopoietic cell proliferation). Low dose gestational exposures to PFOA induced latent PPARα independent liver toxicity that was observed in aged mice. Evidence of liver toxicity in PPARα-KO mice warrants further investigation into PPARα independent pathways

Hepatic Mitochondrial Alteration in CD-1 Mice Associated with Prenatal Exposures to Low Doses of Perfluorooctanoic Acid (PFOA)

Perfluorooctanoic acid (PFOA) is a perfluoroalkyl acid primarily used as an industrial surfactant. It persists in the environment and has been linked to potentially toxic and/or carcinogenic effects in animals and people. As a known activator of peroxisome proliferator-activated receptors (PPARs), PFOA exposure can induce defects in fatty acid oxidation, lipid transport, and inflammation. Here, pregnant CD-1 mice were orally gavaged with 0, 0.01, 0.1, 0.3 and 1 mg/kg of PFOA from gestation days (GD) 1 through 17. On postnatal day (PND) 21, histopathologic changes in the livers of offspring included hepatocellular hypertrophy and periportal inflammation that increased in severity by PND 91 in an apparent dose-dependent response. Transmission electron microscopy (TEM) of selected liver sections from PND 91 mice revealed PFOA-induced cellular damage and mitochondrial abnormalities with no evidence of peroxisome proliferation. Within hypertrophied hepatocytes, mitochondria were not only increased in number, but also exhibited altered morphologies suggestive of increased and/or uncontrolled fission and fusion reactions. These findings suggest that peroxisome proliferation is not a component of PFOA-induced hepatic toxicity in animals that are prenatally exposed to low doses of PFOA

Genetic and epigenetic changes in fibrosis-associated hepatocarcinogenesis in mice: Genetic and epigenetic changes in mouse hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and is rising in incidence worldwide. The molecular mechanisms leading to the development of HCC are complex and include both genetic and epigenetic events. To determine the relative contribution of these alterations in liver tumorigenesis, we evaluated epigenetic modifications at both global and gene specific levels, as well as the mutational profile of genes commonly altered in liver tumors. A mouse model of fibrosis-associated liver cancer that was designed to emulate cirrhotic liver, a prevailing disease state observed in most humans with HCC, was used. Tumor and non-tumor liver samples from B6C3F1 mice treated with N-nitrosodiethylamine (DEN; a single ip injection of 1 mg/kg at 14 days of age) and carbon tetrachloride (CCl4; 0.2 ml/kg, 2 times/week ip starting at 8 weeks of age for 14 weeks), as well as corresponding vehicle control animals, were analyzed for genetic and epigenetic alterations. H-ras, Ctnnb1, and Hnf1α genes were not mutated in tumors in mice treated with DEN+CCl4. In contrast, the increased tumor incidence in mice treated with DEN+CCl4 was associated with marked epigenetic changes in liver tumors and non-tumor liver tissue, including demethylation of genomic DNA and repetitive elements, a decrease in histone 3 lysine 9 trimethylation (H3K9me3), and promoter hypermethylation and functional down-regulation of Riz1, a histone lysine methyltransferase tumor suppressor gene. Additionally, the reduction in H3K9me3 was accompanied by increased expression of long interspersed nucleotide elements (LINE) 1 and short interspersed nucleotide elements (SINE) B2, which is an indication of genomic instability. In summary, our results suggest that epigenetic events, rather than mutations in known cancer-related genes, play a prominent role in increased incidence of liver tumors in this mouse model of fibrosis-associated liver cancer