A protein kinase C α and β inhibitor blunts hyperphagia to halt renal function decline and reduces adiposity in a rat model of obesity-driven type 2 diabetes.

Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences for afflicted individuals. The disease can be difficult to control, and therapeutic strategies to prevent T2D-induced tissue and organ damage are needed. Here we describe the results of administering a potent and selective inhibitor of Protein Kinase C (PKC) family members PKCα and PKCβ, Cmpd 1, in the ZSF1 obese rat model of hyperphagia-induced, obesity-driven T2D.

Evaluating the Sensitivity and Specificity of Promising Circulating Biomarkers to Diagnose Liver Injury in Humans.

Early diagnosis of drug-induced liver injury (DILI) continues to be a major hurdle during drug development and postmarketing. The objective of this study was to evaluate the diagnostic performance of promising biomarkers of liver injury-glutamate dehydrogenase (GLDH), cytokeratin-18 (K18), caspase-cleaved K18 (ccK18), osteopontin (OPN), macrophage colony-stimulating factor (MCSF), MCSF receptor (MCSFR), and microRNA-122 (miR-122) in comparison to the traditional biomarker alanine aminotransferase (ALT). Biomarkers were evaluated individually and as a multivariate model in a cohort of acetaminophen overdose (n = 175) subjects and were further tested in cohorts of healthy adults (n = 135), patients with liver damage from various causes (n = 104), and patients with damage to the muscle (n = 74), kidney (n = 40), gastrointestinal tract (n = 37), and pancreas (n = 34).

Spontaneous Axonal Dystrophy in the Brain and Spinal Cord in Naïve Beagle Dogs.

Axonal dystrophy (AD) is a common age-related neurohistological finding in vertebrates that can be congenital or induced by xenobiotics, vitamin E deficiency, or trauma/compression. To understand the incidence and location of AD as a background finding in Beagle dogs used in routine toxicity studies, we examined central nervous system (CNS) and selected peripheral nervous system (PNS) tissues in twenty 18- to 24-month-old and ten 4- to 5-year-old control males and females. Both sexes were equally affected.

Modulation of the IL-33/IL-13 Axis in Obesity by IL-13Rα2.

In obesity, IL-13 overcomes insulin resistance by promoting anti-inflammatory macrophage differentiation in adipose tissue. Endogenous IL-13 levels can be modulated by the IL-13 decoy receptor, IL-13Rα2, which inactivates and depletes the cytokine. In this study, we show that IL-13Rα2 is markedly elevated in adipose tissues of obese mice.

CXCL10/CXCR3 axis is associated with disease activity and the development of mucocutaneous lesions in patients with Behçet's disease.

The objective of this study was to investigate CXC chemokines and its receptor in patients with Behcet's disease (BD) and their associations with disease activity. Blood samples were collected from 109 BD patients and 36 age- and sex-matched healthy controls (HCs). Twenty-two follow-up blood samples were collected in BD patients.

Polyomavirus-associated Prostatitis in Wistar Han Rats Following Immunosuppression in a Chronic Toxicity Study.

Chronic prostatitis characterized on light microscopic examination by moderate, multifocal, predominantly lymphocytic inflammation associated with epithelial atypia and intranuclear and cytoplasmic inclusion-like material was identified in the prostate gland of 2 Wistar Han rats administered an immunomodulatory test article in a 6-month chronic toxicity study. Transmission electron microscopy of the prostate glands identified 45-nm, nonenveloped, icosahedral virions arranged in paracrystalline array within the cell nuclei in 1 of the 2 rats. The size, shape, location, and array pattern were most consistent with a polyomavirus.

Live simian immunodeficiency virus vaccine correlate of protection: local antibody production and concentration on the path of virus entry.

We sought design principles for a vaccine to prevent HIV transmission to women by identifying correlates of protection conferred by a highly effective live attenuated SIV vaccine in the rhesus macaque animal model. We show that SIVmac239Δnef vaccination recruits plasma cells and induces ectopic lymphoid follicle formation beneath the mucosal epithelium in the rhesus macaque female reproductive tract. The plasma cells and ectopic follicles produce IgG Abs reactive with viral envelope glycoprotein gp41 trimers, and these Abs are concentrated on the path of virus entry by the neonatal FcR in cervical reserve epithelium and in vaginal epithelium.

NK cell responses to simian immunodeficiency virus vaginal exposure in naive and vaccinated rhesus macaques.

NK cell responses to HIV/SIV infection have been well studied in acute and chronic infected patients/monkeys, but little is known about NK cells during viral transmission, particularly in mucosal tissues. In this article, we report a systematic study of NK cell responses to high-dose vaginal exposure to SIVmac251 in the rhesus macaque female reproductive tract (FRT). Small numbers of NK cells were recruited into the FRT mucosa following vaginal inoculation.

Interleukin-6 neutralization alleviates pulmonary inflammation in mice exposed to cigarette smoke and poly(I:C).

Increased systemic and pulmonary levels of IL-6 (interleukin-6) are associated with the severity of exacerbations and decline of lung function in patients with COPD (chronic obstructive pulmonary disease). Whether IL-6 is directly involved or plays a bystander role in the pathophysiology of COPD remains unclear. Here we hypothesized that neutralizing circulating levels of IL-6 would modulate episodes of acute pulmonary inflammation following CS (cigarette smoke) exposure and virus-like challenges.

Adenovirus serotype 26 utilizes CD46 as a primary cellular receptor and only transiently activates T lymphocytes following vaccination of rhesus monkeys.

The cellular receptor utilized by adenovirus serotype 26 (Ad26) has remained unclear. Here we show that Ad26 transduction is CD46-dependent and is efficiently blocked by anti-CD46 but not anti-CAR antibodies, demonstrating that Ad26 utilizes CD46 as a primary cellular receptor. Moreover, following Ad26 vaccination of rhesus monkeys, we did not observe sustained activation of peripheral or mucosal vector-specific CD4(+) T lymphocytes.

Multiple endocardial neurofibromas in a rosy-billed pochard (Netta peposaca).

Endocardial neoplasms are uncommon in veterinary species with most cases restricted to endocardial schwannomas in aged rats. A 15-year-old male rosy-billed pochard (Netta peposaca) was diagnosed following necropsy with numerous, proliferative endocardial masses. Histologically, these masses were composed of interlacing streams and bundles of neoplastic spindle cells supported by a fine fibrovascular stroma.

Mucosal trafficking of vector-specific CD4+ T lymphocytes following vaccination of rhesus monkeys with adenovirus serotype 5.

Post hoc analysis of the phase 2b Step study evaluating a recombinant adenovirus serotype 5 (rAd5)-based HIV-1 vaccine candidate suggested a potential increased risk of HIV-1 acquisition in subjects who were baseline Ad5 seropositive and uncircumcised. These concerns had a profound impact on the HIV-1 vaccine development field, although the mechanism underlying this observation remains unknown. It has been hypothesized that rAd5 vaccination of baseline Ad5-seropositive individuals may have resulted in anamnestic, vector-specific CD4(+) T lymphocytes that could have trafficked to mucosal sites and served as increased targets for HIV-1 infection.