Cystic fibrosis-related diabetes is caused by islet loss and inflammation

Cystic fibrosis-related (CF-related) diabetes (CFRD) is an increasingly common and devastating comorbidity of CF, affecting approximately 35% of adults with CF. However, the underlying causes of CFRD are unclear. Here, we examined cystic fibrosis transmembrane conductance regulator (CFTR) islet expression and whether the CFTR participates in islet endocrine cell function using murine models of beta cell CFTR deletion and normal and CF human pancreas and islets. Specific deletion of CFTR from murine beta cells did not affect beta cell function. In human islets, CFTR mRNA was minimally expressed, and CFTR protein and electrical activity were not detected. Isolated CF/CFRD islets demonstrated appropriate insulin and glucagon secretion, with few changes in key islet-regulatory transcripts. Furthermore, approximately 65% of beta cell area was lost in CF donors, compounded by pancreatic remodeling and immune infiltration of the islet. These results indicate that CFRD is caused by beta cell loss and intraislet inflammation in the setting of a complex pleiotropic disease and not by intrinsic islet dysfunction from CFTR mutation

Behavior of feral horses in response to culling and GnRH immunocontraception

AbstractWildlife management actions can alter fundamental behaviors of individuals and groups, which may directly impact their life history parameters in unforeseen ways. This is especially true for highly social animals because changes in one individual's behavior can cascade throughout its social network. When resources to support populations of social animals are limited and populations become locally overabundant, managers are faced with the daunting challenge of decreasing population size without disrupting core behavioral processes. Increasingly, managers are turning to fertility control technologies to supplement culling in efforts to suppress population growth, but little is quantitatively known about how either of these management tools affects behavior. Gonadotropin releasing hormone (GnRH) is a small neuropeptide that performs an obligatory role in mammalian reproduction and has been formulated into the immunocontraceptive GonaCon-B™. We investigated the influences of this vaccine on behavior of feral horses (Equus caballus) at Theodore Roosevelt National Park, North Dakota, USA, for a year preceding and a year following nonlethal culling and GnRH-vaccine treatment. We observed horses during the breeding season and found only minimal differences in time budget behaviors of free-ranging female feral horses treated with GnRH and those treated with saline. The differences observed were consistent with the metabolic demands of pregnancy and lactation. We observed similar social behaviors between treatment groups, reflecting limited reproductive behavior among control females due to high rates of pregnancy and suppressed reproductive behavior among treated females due to GnRH-inhibited ovarian activity. In the treatment year, band stallion age was the only supported factor influencing herding behavior (P<0.001), harem-tending behavior (P<0.001), and agonistic behavior (P=0.02). There was no difference between the mean body condition of control females (4.9 (95% CI=4.7–5.1)) and treated females (4.8 (95% CI=4.7–4.9)). Band fidelity among all females increased 25.7% in the year following vaccination and culling, despite the social perturbation associated with removal of conspecifics. Herding behavior by stallions decreased 50.7% following treatment and culling (P<0.001), while harem-tending behavior increased 195.0% (P<0.001). The amount of available forage influenced harem-tending, reproductive, and agonistic behavior in the year following culling and treatment (P<0.04). These changes reflected the expected nexus between a species with polygynous social structure and strong group fidelity and the large instantaneous change in population density and demography coincident with culling. Behavioral responses to such perturbation may be synergistic in reducing grazing pressure by decreasing energetically expensive competitive behaviors, but further investigation is needed to explicitly test this hypothesis

Detection of prion protein in the cerebrospinal fluid of elk (\u3ci\u3eCervus canadensis nelsoni\u3c/i\u3e) with chronic wasting disease using protein misfolding cyclic amplification

Cerebrospinal fluid (CSF) has been examined as a possible source for preclinical diagnosis of prion diseases in hamsters and sheep. The present report describes the detection of chronic wasting disease (CWD) in the CSF of elk and evaluates its usefulness as an antemortem test for CWD. The CSF from 6 captive and 31 free-ranging adult elk was collected at necropsy and evaluated for the presence of the abnormal isoform of the prion protein that has been associated with CWD (PrPCWD) via protein misfolding cyclic amplification. Additionally, the obex from each animal was examined by immunohistochemistry (IHC). Four out of 6 captive animals were CWD-positive and euthanized due to signs of terminal CWD. The remaining 2 were CWD negative. None of the 31 free-range animals showed overt signs of CWD, but 12 out of 31 tested positive for CWD by IHC. Protein misfolding cyclic amplification detected PrPCWD from 3 of the 4 captive animals showing clinical signs of CWD and none of the nonclinical animals that were CWD positive by IHC. The data suggests that CWD prions can be detected in the CSF of elk, but only relatively late in the course of the disease

Mother to offspring transmission of chronic wasting disease in Reeves' Muntjac deer

The horizontal transmission of prion diseases has been well characterized in bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD) of deer and elk and scrapie of sheep, and has been regarded as the primary mode of transmission. Few studies have monitored the possibility of vertical transmission occurring within an infected mother during pregnancy. To study the potential for and pathway of vertical transmission of CWD in the native cervid species, we used a small cervid model-the polyestrous breeding, indoor maintainable, Reeves' muntjac deer-and determined that the susceptibility and pathogenesis of CWD in these deer reproduce that in native mule and white-tailed deer. Moreover, we demonstrate here that CWD prions are transmitted from doe to fawn. Maternal CWD infection also appears to result in lower percentage of live birth offspring. In addition, evolving evidence from protein misfolding cyclic amplification (PMCA) assays on fetal tissues suggest that covert prion infection occurs in utero. Overall, our findings demonstrate that transmission of prions from mother to offspring can occur, and may be underestimated for all prion diseases

Reimmunization increases contraceptive effectiveness of gonadotropin-releasing hormone vaccine (GonaCon-Equine) in freeranging horses (\u3ci\u3eEquus caballus\u3c/i\u3e): Limitations and side effects

Wildlife and humans are increasingly competing for resources worldwide, and a diverse, innovative, and effective set of management tools is needed. Controlling abundance of wildlife species that are simultaneously protected, abundant, competitive for resources, and in conflict with some stakeholders but beloved by others, is a daunting challenge. Free-ranging horses (Equus caballus) present such a conundrum and managers struggle for effective tools for regulating their abundance. Controlling reproduction of female horses presents a potential alternative. During 2009±2017, we determined the long-term effectiveness of GnRH vaccine (GonaCon-Equine) both as a single immunization and subsequent reimmunization on reproduction and side effects in free-ranging horses. At a scheduled management roundup in 2009, we randomly assigned 57 adult mares to either a GonaCon-Equine treatment group (n = 29) or a saline control group (n = 28). In a second roundup in 2013, we administered a booster vaccination to these same mares. We used annual ground observations to estimate foaling proportions, social behaviors, body condition, and injection site reactions. We found this vaccine to be safe for pregnant females and neonates, with no overt deleterious behavioral side effects during the breeding season. The proportion of treated mares that foaled following a single vaccination was lower than that for control mares for the second (P = 0.03) and third (P = 0.08) post-treatment foaling seasons but was similar (P = 0.67) to untreated mares for the fourth season, demonstrating reversibility of the primary vaccine treatment. After two vaccinations, however, the proportion of females giving birth was lower (

Infectious Prions in Pre-Clinical Deer and Transmission of Chronic Wasting Disease Solely by Environmental Exposure

Key to understanding the epidemiology and pathogenesis of prion diseases, including chronic wasting disease (CWD) of cervids, is determining the mode of transmission from one individual to another. We have previously reported that saliva and blood from CWD-infected deer contain sufficient infectious prions to transmit disease upon passage into naïve deer. Here we again use bioassays in deer to show that blood and saliva of pre-symptomatic deer contain infectious prions capable of infecting naïve deer and that naïve deer exposed only to environmental fomites from the suites of CWD-infected deer acquired CWD infection after a period of 15 months post initial exposure. These results help to further explain the basis for the facile transmission of CWD, highlight the complexities associated with CWD transmission among cervids in their natural environment, emphasize the potential utility of blood-based testing to detect pre-clinical CWD infection, and could augur similar transmission dynamics in other prion infections

Vegetation and Topographic Control on Spatial Variability of Soil Organic Carbon

Soil organic carbon (SOC) is one of the most important parameters affecting the hydraulic characteristics of natural soils. Despite being rather easy to measure, SOC is known to be highly variable in space. In this study, vegetation, climate, and morphology factors were used to reproduce the spatial distribution of SOC in the mineral horizons of forest and grassland areas in north-western Italy and the feasibility of the approach was evaluated. When the overall sample (114 samples) was analyzed, average annual rainfall and elevation were significant descriptors of the SOC variability. However, a large part of the variability remains unexplained. Two stratification criteria were then adopted, based on vegetation and topographic properties. We obtained an improvement of the quality of the estimates, particularly for grasslands and forests in the absence of local curvatures. These results indicate that the spatial variability of soil organic matter is scarcely reproducible at the regional scale, unless an a-priori reduction of the heterogeneity is applied. A discussion on the feasibility of applying stratification criteria to deal with heterogeneous samples closes the pape