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The contagious prion disease “chronic wasting disease” (CWD) infects mule deer (Odocoileus hemionus) and related species. Unchecked epidemics raise ecological, socioeconomic, and public health concerns. Prion infection shortens a deer’s lifespan, and when prevalence (proportion of adults infected) becomes sufficiently high CWD can affect herd dynamics. Understanding population responses over time is key to forecasting long-term impacts. Here we describe unexpected stability in prevalence and abundance in a mule deer herd where CWD has been left unmanaged. High apparent prevalence (~30%) since at least 2005 likely drove observed changes in the proportion and age distribution of wild-type native prion protein (PRNP) gene homozygotes among deer sampled. Predation by mountain lions (Puma concolor) may be helping keep CWD in check. Despite stable appearances, prion disease nonetheless impairs adult survival and likely resilience in this deer herd, limiting its potential for growth despite refuge from hunter harvest and favorable habitat and winter conditions., Fischer and colleagues revisit the unmanaged Table Mesa mule deer herd to examine the impact and dynamics of chronic wasting disease. Their findings indicate that disease prevalence and deer abundance have been surprisingly stable overall since 2005, with the disease appearing to be kept naturally in check by predation from the local mountain lion population.

Tiger trout (Salmo trutta × Salvelinus fontinalis) are sterile hybrids often stocked as a biocontrol agent for undesirable fishes and to enhance recreational angling. Yet, how different ecological processes affect their post-stocking performance remain poorly understood. Rapid growth early in life can foster rapid transitions to piscivory, and improve survival. Identifying factors that benefit early growth can help managers optimize tiger trout stocking for meeting multiple fisheries management objectives. Here, we characterized the trophic ecology and growth of tiger trout stocked at varying densities into seven lentic subalpine systems in Colorado, USA. Study systems supported different species of undesirable fish (e.g., minnows or suckers). We used stable isotopes of carbon and nitrogen to quantify trophic relationships among tiger trout and other fishes in each system. We then evaluated several system-specific attributes as predictors for the size of tiger trout at age-1 using a Random Forest model. Stable isotopes demonstrated the potential for resource competition among tiger trout and other fishes, but potential varied by system. Indices of resource competition ranked highest in the Random Forest model, but the stocking density of tiger trout was most important, suggesting that intraspecific competition outweighed interspecific competition in driving early growth. These processes were mediated by system productivity. Thus, stocking density in combination with the realized carrying capacities of systems should be considered when making management decisions for tiger trout.

We analyzed retrospective data on harvest management practices and corresponding chronic wasting disease (CWD) prevalence trends in 36 western US and Canadian mule deer (Odocoileus hemionus) management units (units). Our analyses employed logistic regression and model selection, exploiting variation in practices within and among jurisdictions to examine relationships between harvest management and apparent prevalence (the proportion of positive animals among those sampled). Despite notable differences in hunting practices among jurisdictions, our meta-analysis of combined data revealed strong evidence that the amount of harvest was related to CWD prevalence trends among adult male mule deer in the 32 units where prevalence at the start of the analysis period was ≤5%. All competitive models included the number of male deer harvested or number of hunters 1-2 yr prior as an explanatory variable, with increasing harvest leading to lower prevalence among males harvested in the following year. Competitive models also included harvest timing. Although less definitive than the number harvested, median harvest dates falling closer to breeding seasons were associated with lower prevalence in the following year. Our findings suggest harvest-when sufficient and sustained-can be an effective tool for attenuating CWD prevalence in adult male mule deer across western ranges, especially early in the course of an epidemic. Evidence of a broad relationship between the amount of harvest and subsequent changes in CWD prevalence among adult male mule deer provides an empirical basis for undertaking adaptive disease management experimentation aimed at suppressing or curtailing CWD epidemics.

Incidence of chronic wasting disease infection showed strong, positive correlation (r≥0.944) with apparent prevalence among female and male mule deer (Odocoileus hemionus) in seven herds previously studied in Colorado and Wyoming, US. With attention to monitoring method consistency and context, inferring that observed prevalence trends reflect underlying epidemic dynamics in mule deer herds appears justifiable.

Following neurotoxic damage, cells repair their DNA, and survive or undergo apoptosis. This study tests the hypothesis that ethanol induces a DNA damage response (DDR) in neural stem cells (NSCs) that promotes excision repair (ER) and this repair is influenced by the growth factor environment. Non-immortalized NSCs treated with fibroblast growth factor 2 or transforming growth factor (TGF) β1 were exposed to ethanol. Ethanol increased total DNA damage, reactive oxygen species, and oxidized DNA bases. TGFβ1 potentiated these toxic effects. Transcriptional analyses of cultured NSCs revealed ethanol-induced increases in transcripts related to the DDR (e.g., Hus1 and p53), base ER (e.g., Mutyh and Nthl1), and nucleotide ER (e.g., Xpc), particularly in the presence of TGFβ1. Expression and activity of ER proteins were affected by ethanol. Similar changes occurred in proliferating cells of ethanol-treated mouse fetuses. Ethanol-induced DNA repair in NSCs depends on the ambient growth factors. Gene products for DNA repair in stem cells are among the first biomarkers identifying fetal alcohol-induced damage.

GPR40 (FFAR1 or FFA1) is a G protein-coupled receptor, primarily expressed in pancreatic islet β-cells and intestinal enteroendocrine cells. When activated by fatty acids, GPR40 elicits increased insulin secretion from islet β-cells only in the presence of elevated glucose levels. Towards this end, studies were undertaken towards discovering a novel GPR40 Agonist whose mode of action is via Positive Allosteric Modulation of the GPR40 receptor (AgoPAM). Efforts were made to identify a suitable GPR40 AgoPAM tool molecule to investigate mechanism of action and de-risk liver toxicity of GPR40 AgoPAMs due to reactive acyl-glucuronide (AG) metabolites.

Background Oral anticoagulants use has increased rapidly, internationally. Here we look at risks and benefits, based on Japanese data, of therapy with low risk non-valvular atrial fibrillation patients. Objectives Using a health insurance claims data set we assessed: (i) oral anticoagulants usage in Japan, and (ii) efficacy and safety of dabigatran compared with warfarin, in Japanese patients with non-valvular atrial fibrillation, aged 18–74 years. Methods We identified 4380 non-valvular atrial fibrillation patients treated with anticoagulants between 1 January 2005, and 28 February 2014, and estimated the adjusted hazard ratio for stroke or systemic embolism, and any hemorrhagic event (Cox proportional hazards regression model with stabilized inverse probability treatment weighting). Results The data included 101 989 anticoagulant prescriptions for 4380 patients, of which direct oral anticoagulants increased to 40.0% of the total by the end of the study. After applying exclusion criteria, 1536 new non-valvular atrial fibrillation patients were identified, including 1071 treated with warfarin and 465 with dabigatran. Mean ages were 56.11 ± 9.70 years for warfarin, and 55.80 ± 9.65 years for dabigatran. The adjusted hazard ratio (95% confidence interval), comparing dabigatran with warfarin, was 0.48 (0.25–0.91) for stroke or systemic embolism, and 0.91 (0.60–1.39) for any hemorrhage including intracranial and gastrointestinal. Conclusions Number of patients prescribed direct oral anticoagulants steadily increased, and incidence of all-cause bleeding related to dabigatran was similar to warfarin, in our study population of younger non-valvular atrial fibrillation patients. Dabigatran, compared with warfarin, generally reduced risk of all-cause stroke and systemic embolism.

Background Transforming growth factor (TGF) β1 and ethanol (EtOH) powerfully inhibit the proliferation, DNA repair, and survival of neural stem cells (NSCs). The present study tests the hypothesis that the EtOH-induced DNA damage response is mediated through p53 pathways and influenced by growth factor signals. Methods Cultures of nonimmortalized NSCs, NS-5 cells, were transfected with p53 siRNA, exposed to either the mitogenic fibroblast growth factor (FGF) 2 or antimitogenic TGFβ1, and to EtOH. Stage-specific cellular and genomic responses were examined. Results p53 status, EtOH exposure, and growth factor significantly affected the expression of transcripts related to the DNA damage response (including those coding for excision repair proteins), mitotic promoters, and regulators of cell death via the tumor necrosis factor pathway. There were significant compensatory increases in p53 family members, p63 and p73, notably in regard to the regulation of cell cycle restriction and apoptosis. Treatment with p53 siRNA potentiated EtOH- and TGFβ1-induced changes in the numbers of proliferating NSCs and increased the proportion of NSCs expressing the apoptotic marker annexin V. Conclusions Thus, it appears that EtOH and TGFβ1 affect proliferation, DNA repair, and survival of NSCs via p53-mediated activities.

This study investigated the use of a fixed-dose combination of 30 mg/ml butorphanol, 12 mg/ml azaperone, and 12 mg/ml medetomidine for the standing sedation of captive African elephants (Loxodonta africana). In total, seven females (mean age 19.6 yr; range 6-31 yr) and six males (mean age 33.5 yr; range 9-35 yr) were sedated. The estimated dose was 0.0005 ± 0.0001 ml/kg and 0.006 ± 0.001 ml/cm shoulder height, which resulted in a dose of 0.016 ± 0.002 mg/kg or 0.19 ± 0.04 mg/cm shoulder height butorphanol, 0.006 ± 0.0008 mg/ kg or 0.076 ± 0.015 mg/cm shoulder height azaperone, and 0.006 ± 0.0008 mg/kg or 0.076 ± 0.015 mg/cm medetomidine. First signs of sedation were observed within 3-10 min (mean 6 ± 2 min) after darting, and monitoring of the animals started on average at 24 ± 9 min after darting. No bradycardia was observed in any of the elephants (mean heart rate 40.0 ± 6.55 beats/min), although all the animals were mildly hypotensive (mean blood pressure 118.5/86 [94.5]). Rectal temperatures fell within acceptable ranges, and respiratory parameters were stable in all the animals throughout sedation and fell within the standard ranges reported for conscious, standing elephants. Only one elephant had clinically significant hypoxemia characterized by a partial pressure of oxygen (PaO2) 50 mm Hg), although pH and peripheral capillary oxygen saturation fell within acceptable ranges. None of the elephants reacted to moderately painful stimuli while sedated. The combination was reversed with intramuscular injections of naltrexone (1 mg for every 1 mg butorphanol) and atipamezole (5 mg for every 1 mg medetomidine). Recovery was smooth and calm in all the animals. Time from injection of the reversals until the first signs of recovery was 4.6 ± 2.01 min (range 1-8 min).

For nearly 18 yr, we evaluated susceptibility of captive mountain lions (Puma concolor) to chronic wasting disease (CWD) in the face of repeated exposure associated with consuming infected cervid carcasses. Three mountain lions with a monomorphic prion protein gene (PRNP) sequence identical to that described previously for the species had access to parts of ≥432 infected carcasses during ≥2,013 feeding occasions, conservatively representing >14,000 kg of infected feed material, during May 2002 to March 2020. The proportion of diet in infected carcass material averaged 43% overall but differed from year to year (minimally 11%-74%). Most infected carcasses were mule deer (Odocoileus hemionus; ∼75%). We observed no clinical signs suggestive of progressive encephalopathy or other neurologic disease over the ∼14.5-17.9 yr between first known exposure and eventual death. Histopathology revealed no spongiform changes or immunostaining suggestive of prion infection in multiple sections of nervous and lymphoid tissue. Similarly, none of 133 free-ranging mountain lion carcasses sampled opportunistically during 2004-2020 showed immunostaining consistent with prion infection in sections of brainstem or lymph node. These findings align with prior work suggesting that CWD-associated prions face strong barriers to natural transmission among species outside the family Cervidae.

Efforts to contain the spread of chronic wasting disease (CWD), a fatal, contagious prion disease of cervids, would be aided by the availability of additional diagnostic tools. RT-QuIC assays allow ultrasensitive detection of prion seeds in a wide variety of cervid tissues, fluids and excreta. The best documented antemortem diagnostic test involving RT-QuIC analysis targets lymphoid tissue in rectal biopsies. Here we have tested a more easily accessed specimen, ear pinna punches, using an improved RT-QuIC assay involving iron oxide magnetic extraction to detect CWD infections in asymptomatic mule and white-tailed deer. Comparison of multiple parts of the ear pinna indicated that a central punch spanning the auricular nerve provided the most consistent detection of CWD infection. When compared to results obtained from gold-standard retropharyngeal lymph node specimens, our RT-QuIC analyses of ear samples provided apparent diagnostic sensitivity (81%) and specificity (91%) that rivaled, or improved upon, those observed in previous analyses of rectal biopsies using RT-QuIC. These results provide evidence that RT-QuIC analysis of ear pinna punches may be a useful approach to detecting CWD infections in cervids.

The tranquilizer combination of butorphanol, azaperone, and medetomidine (BAM) has shown good efficacy for immobilization of wildlife, including black bears (Ursus americanus). BAM is antagonized with a combination of naltrexone and atipamezole. We immobilized 19 adult captive wild caught black bears and, except for three bears that were euthanized immediately, bears were recovered with naltrexone and atipamezole. Tissue residues (≥0.01 ppm) for the tranquilizers butorphanol, azaperone, and medetomidine were detected in liver and muscle of all three bears euthanized on day 0 postinjection (PI). Azaperone was not detected after 1 d PI. Residue for medetomidine was detected in two bears: in the liver 3 d PI and in the kidney 6 d PI. Butorphanol was reported in three bears: in fat 5 d PI, in kidney 6 d PI, and, surprisingly, in kidney, muscle, and fat 7 d PI. No tissue residues were detected in the three bears euthanized at 8 d PI. Tissue residues for the antagonists, naltrexone and atipamezole, were detected in bears euthanized 2 and 6 d PI, but not in tissues from animals euthanized at 7 or 8 d PI.

Bighorn sheep (Ovis canadensis) are predicted to have a degree of susceptibility to the transmissible spongiform encephalopathies (TSE) chronic wasting disease and scrapie. We opportunistically screened 127 captive bighorn sheep and 152 free-ranging bighorn sheep in Colorado, US for the presence of TSE over a period of 35 yr. None of the animals demonstrated clinical signs, gross pathology, histopathology, or immunohistochemical staining patterns suggestive of TSE.

The emergence of chronic wasting disease, an infectious prion disease of multiple deer species, has motivated international calls for sustainable, socially accepted control measures. Here, we describe long-term, spatially replicated relationships in Colorado, US, mule deer (Odocoileus hemionus) herds that show hunting pressure can modulate apparent epidemic dynamics as reflected by prevalence trends. Across 12 areas in Colorado studied between 2002–18, those with the largest declines in annual hunting license numbers (pressure) showed the largest increases in the proportion of infected adult (≥2–yr-old) male deer killed by hunters (prevalence); prevalence trends were comparatively flat in most areas where license numbers had been maintained or increased. The mean number of licenses issued in the 2 yr prior best explained observed patterns: increasing licenses lowered subsequent risk of harvesting an infected deer, and decreasing licenses increased that risk. Our findings suggest that harvesting mule deer with sufficient hunting pressure might control chronic wasting disease—especially when prevalence is low—but that harvest prescriptions promoting an abundance of mature male deer contribute to the exponential growth of epidemics.

Chronic wasting disease (CWD) is an infectious disease, but reported associations suggest several metals-especially copper (Cu) and manganese-potentially play a role in this and other prion diseases. To assess the utility of dietary Cu supplementation in protecting white-tailed deer (

Previous studies demonstrated that nalbuphine, medetomidine, and azaperone (NalMed-A) can effectively immobilize adult elk ( Cervus elaphus nelsoni), and be antagonized using naltrexone and atipamezole, with or without tolazoline. To assess duration of tissue residues for this immobilization package, we immobilized 14 captive adult elk with NalMed-A, then euthanized animals and collected tissues 0, 3, 6, 14, 21, or 28 d later. Except for two animals euthanized immediately, all elk were recovered using naltrexone, atipamezole, and tolazoline. Tissue residues (≥0.01 parts per million) for the tranquilizers nalbuphine, medetomidine, and azaperone were detected in liver and muscle tissue samples from elk euthanized within 40 min postinjection (PI) and one animal that died 12-24 h PI, but not in tissues from any of the animals euthanized at 3, 6, 14, 21, or 28 d PI. Tissue residues for the antagonists naltrexone, atipamezole, and tolazoline were detected in liver and muscle of the animal that died 12-24 h PI. Only naltrexone was detected in liver from the two elk euthanized at day 3, and no antagonist residues were detected thereafter.

Fetal alcohol spectrum disorder is associated with defects in neuronal generation, migration, and differentiation. The present study tested the hypothesis that ethanol exposure during the period of naturally occurring neuronal death causes a time- and Bax-dependent neuronal loss. Wild-type and Bax knockout mice were given a pair of injections (two hours apart) of ethanol (2.5 g/kg) or saline on postnatal day (P) 4, P7, P10, or P13. Mean blood ethanol concentration was 435 mg/dl one hour after the second injection. The total numbers of neurons in individual layers of somatosensory cortex were stereologically determined in 30-day-old mice and the expressions of active caspase 3 immunopositivity and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) were determined 2-36 h after the first injection. On P30, ethanol caused up to 36% neuronal loss in cortical laminae of wild-type mice. In contrast, no ethanol-induced loss was detected in Bax knockout mice. Ethanol also caused an acute bilaminar (layers II/III and V) increase in caspase 3 immunoexpression and TUNEL in wild-type mice. The changes in the expression of these markers were age- and lamina-dependent. No ethanol-induced expression of caspase 3 or TUNEL was detected in Bax knockout animals. Thus, ethanol-induced death of cortical neurons is Bax-dependent, occurs concurrently in all layers, but does not correspond to lamina- and age-dependent expression of DNA fragmentation. Both ethanol-induced and naturally occurring death of cortical neurons rely on caspase 3-dependent and independent mechanisms.

Introduction Several studies have described typical clinical manifestations, including fever, cough, diarrhea, and fatigue with COVID-19 infection. However, there are limited data on the association between the presence of neurological manifestations on hospital admission, disease severity, and outcomes. We sought to investigate this correlation to help understand the disease burden. Methods We delivered a multi-center retrospective study of positive laboratory-confirmed COVID-19 patients. Clinical presentation, laboratory values, complications, and outcomes data were reported. Our findings of interest were Intensive Care Unit (ICU) admission, intubation, mechanical ventilation, and in-hospital mortality. Results A total of 502 patients with a mean age of 60.83 ± 15.5 years, of them 71 patients (14.14%) presented with altered mental status, these patients showed higher odds of ICU admission (OR = 2.06, 95%CI = 1.18 to 3.59, p = 0.01), mechanical ventilation (OR = 3.28, 95%CI = 1.86 to 5.78, p < 0.001), prolonged (>4 days) mechanical ventilation (OR = 4.35, 95%CI = 1.89 to 10, p = 0.001), acute kidney injury (OR = 2.18, 95%CI = 1.28 to 3.74, p = 0.004), and mortality (HR = 2.82, 95%CI = 1.49 to 5.29, p = 0.01). Conclusion This cohort study found that neurological presentations are associated with higher odds of adverse events. When examining patients with neurological manifestations, clinicians should suspect COVID-19 to avoid delayed diagnosis or misdiagnosis and lose the chance to treat and prevent further transmission.

Prions are infectious proteins causing fatal, transmissible neurodegenerative diseases of animals and humans. Replication involves template-directed refolding of host encoded prion protein, PrPC, by its infectious conformation, PrPSc. Following its discovery in captive Colorado deer in 1967, uncontrollable contagious transmission of chronic wasting disease (CWD) led to an expanded geographic range in increasing numbers of free-ranging and captive North American (NA) cervids. Some five decades later, detection of PrPSc in free-ranging Norwegian (NO) reindeer and moose marked the first indication of CWD in Europe. To assess the properties of these emergent NO prions and compare them with NA CWD we used transgenic (Tg) and gene targeted (Gt) mice expressing PrP with glutamine (Q) or glutamate (E) at residue 226, a variation in wild type cervid PrP which influences prion strain selection in NA deer and elk. Transmissions of NO moose and reindeer prions to Tg and Gt mice recapitulated the characteristic features of CWD in natural hosts, revealing novel prion strains with disease kinetics, neuropathological profiles, and capacities to infect lymphoid tissues and cultured cells that were distinct from those causing NA CWD. In support of strain variation, PrPSc conformers comprising emergent NO moose and reindeer CWD were subject to selective effects imposed by variation at residue 226 that were different from those controlling established NA CWD. Transmission of particular NO moose CWD prions in mice expressing E at 226 resulted in selection of a kinetically optimized conformer, subsequent transmission of which revealed properties consistent with NA CWD. These findings illustrate the potential for adaptive selection of strain conformers with improved fitness during propagation of unstable NO prions. Their potential for contagious transmission has implications for risk analyses and management of emergent European CWD. Finally, we found that Gt mice expressing physiologically controlled PrP levels recapitulated the lymphotropic properties of naturally occurring CWD strains resulting in improved susceptibilities to emergent NO reindeer prions compared with over-expressing Tg counterparts. These findings underscore the refined advantages of Gt models for exploring the mechanisms and impacts of strain selection in peripheral compartments during natural prion transmission., Author summary Prions cause fatal, transmissible neurodegenerative diseases in animals and humans. They are composed of an infectious, neurotoxic protein (PrP) which replicates by imposing pathogenic conformations on its normal, host-encoded counterpart. Chronic wasting disease (CWD) is a contagious prion disorder threatening increasing numbers of free-ranging and captive North American deer, elk, and moose. While CWD detection in Norwegian reindeer and moose in 2016 marked the advent of disease in Europe, its origins and relationship to North American CWD were initially unclear. Here we show, using mice engineered to express deer or elk PrP, that Norwegian reindeer and moose CWD are caused by novel prion strains with properties distinct from those of North American CWD. We found that selection and propagation of North American and Norwegian CWD strains was controlled by a key amino acid residue in host PrP. We also found that particular Norwegian isolates adapted during their propagation in mice to produce prions with characteristics of the North American strain. Our findings defining the transmission profiles of novel Norwegian prions and their unstable potential to produce adapted strains with improved fitness for contagious transmission have implications for risk analyses and management of emergent European CWD.

Sylvatic plague, caused by Yersinia pestis, frequently afflicts prairie dogs (Cynomys spp.), causing population declines and local extirpations. We tested the effectiveness of bait-delivered sylvatic plague vaccine (SPV) in prairie dog colonies on 29 paired placebo and treatment plots (1–59 ha in size; average 16.9 ha) in 7 western states from 2013 to 2015. We compared relative abundance (using catch per unit effort (CPUE) as an index) and apparent survival of prairie dogs on 26 of the 29 paired plots, 12 with confirmed or suspected plague (Y. pestis positive carcasses or fleas). Even though plague mortality occurred in prairie dogs on vaccine plots, SPV treatment had an overall positive effect on CPUE in all three years, regardless of plague status. Odds of capturing a unique animal were 1.10 (95% confidence interval [C.I.] 1.02–1.19) times higher per trap day on vaccine-treated plots than placebo plots in 2013, 1.47 (95% C.I. 1.41–1.52) times higher in 2014 and 1.19 (95% C.I. 1.13–1.25) times higher in 2015. On pairs where plague occurred, odds of apparent survival were 1.76 (95% Bayesian credible interval [B.C.I.] 1.28–2.43) times higher on vaccine plots than placebo plots for adults and 2.41 (95% B.C.I. 1.72–3.38) times higher for juveniles. Our results provide evidence that consumption of vaccine-laden baits can protect prairie dogs against plague; however, further evaluation and refinement are needed to optimize SPV use as a management tool. Electronic supplementary material The online version of this article (doi:10.1007/s10393-017-1253-x) contains supplementary material, which is available to authorized users.

Plague impacts prairie dogs (Cynomys spp.), the endangered black-footed ferret (Mustela nigripes) and other sensitive wildlife species. We compared efficacy of prophylactic treatments (burrow dusting with deltamethrin or oral vaccination with recombinant “sylvatic plague vaccine” [RCN-F1/V307]) to placebo treatment in black-tailed prairie dog (C. ludovicianus) colonies. Between 2013 and 2015, we measured prairie dog apparent survival, burrow activity and flea abundance on triplicate plots (“blocks”) receiving dust, vaccine or placebo treatment. Epizootic plague affected all three blocks but emerged asynchronously. Dust plots had fewer fleas per burrow (P

Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40-MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.

GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs. Compound 24 demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.

Recent work with prion diseases and synucleinopathies indicates that accurate diagnostic methods for protein-folding diseases can be based on the ultrasensitive, amplified measurement of pathological aggregates in biospecimens. A better understanding of the physicochemical factors that control the seeded polymerization of such aggregates, and their amplification in vitro, should allow improvements in existing assay platforms, as well as the development of new assays for other proteopathic aggregates. Here, we systematically investigated the effects of the ionic environment on the polymerization of tau, [Formula: see text]-synuclein, and the prion protein (PrP) induced by aggregates in biospecimens. We screened salts of the Hofmeister series, a relative ordering of strongly and weakly hydrated salts that tend to precipitate or solubilize proteins. We found that sensitivities of tau-based assays for Alzheimer’s seeds and PrP-based assays for prions were best in weakly hydrated anions. In contrast, we saw an inverse trend with different tau-based assays, improving detection sensitivity for progressive supranuclear palsy seeds by [Formula: see text] 10(6). Hofmeister analysis also improved detection of sporadic Creutzfeldt–Jakob disease prions in human nasal brushings and chronic wasting disease prions in deer-ear homogenates. Our results demonstrate strong and divergent influences of ionic environments on the amplification and detection of proteopathic seeds as biomarkers for protein-folding diseases.

Fetal alcohol syndrome (FAS) is a prime cause of cognitive dysfunction. The present study tested the hypotheses (a) that gestational ethanol exposure results in deficits in hippocampal-related behaviors and associated neurogenesis and (b) that the period of gastrulation is a time of vulnerability. Pregnant macaques were intubated with ethanol or saline once per week for 3, 6, or 24 weeks. Exposures included or omitted the period of gastrulation. Offspring were given behavioral tests including a Visual-Paired Comparison (VPC), a hippocampal-associated memory task, and euthanized as adolescents. Their dentate gyri were processed for immunohistochemical identification of cells passing through the cell cycle (Ki-67 and proliferating cell nuclear antigen), exiting the cell cycle (p21), or passing through early stages of neuronal morphogenesis (Tuj1). Performance in neurobehavioral tasks was unaffected by ethanol exposure, the notable exception being performance in the VPC that was poorer for macaques exposed to ethanol including gastrulation. Anatomical studies show that the expression of Ki-67 was greater and ratio of p21-positive cells to the ratio of Ki-67-expressing cells was lower in animals in which the ethanol exposure included gastrulation. On the other hand, no ethanol-induced differences in TuJ1 expression were detected. Thus, the dentate gyrus is a bellwether of long-term consequences of gestational ethanol exposure. Targeted effects of ethanol on early neural generation (cell cycle and cycle exit) correlate with the timing-dependent degradation in VPC performance and exposure during gastrulation results in notable deficits. These changes evidence a pattern of fetal programming underlying FAS.

Millions of people rely on public-health insecticides for malaria prevention. Yet growing insecticide resistance may threaten malaria control programs through decreasing e ffectiveness and possibly unsustainable cost-increases. Insufficient investment by s takeholders in the search for new public-health insecticides in recent decades has left malaria control programs with limited alternatives with which to manage resistance and maintain program effectiveness. While alternative insecticides are available, short of an unforeseen, significant increase in funding, their higher cost would compel programs to reduce malaria control coverage, leading to increased mortality and morbidity. In order to limit these negative effects on cost and coverage, we propose that policymakers and malaria stakeholders consider adoption of existing policies from successful efforts to secure reduced prices and increased access to other essential health interventions.

We live in a world surrounded by sound. Throughout life, we are exposed to music: from lullabies and songs taught at school to instrumental music both heard and played for pleasure. Every nation, along with its own language, has unique forms of music and dance. "Music knows no boundaries," as the saying goes. Just as language impairment is known as "aphasia," impairment of the perception of music is called "amusia." In this article, we will first classify the types of amusia. This will be followed by an introduction to the classical research of Salomon Eberhard Henschen (1847-1930), and to a discussion of higher auditory functions in which we highlight cases of amusia encountered in a person and through the literature.

Despite a developing, immature nervous system, the human neonate feels pain. In the past, the predominant theory was that infants were not capable of experiencing “true” pain, as the response to a noxious stimulus was believed to be mediated by nociception rather than higher cortical pain processing. Indeed, the inability to communicate, paucity of memory formation, and underdeveloped cerebral processing of the fetus and newborn do suggest that only decorticate pain processing is well-established in early life. However, research has shown that the fetus and neonate possess the spinal and supraspinal neural connectivity required for advanced pain processing; the structure and function of this processing differ from the adult nervous system. Additionally, some of these developmental structures and mechanisms of pain processing in the fetus and neonate are not maintained into later stages of pain transmission and perception. Of note, many of the conclusions that are made about human neurodevelopment have been achieved through studies on rats and other mammals.

Reliable diagnostic tests are essential for disease investigation and management. This is particularly true for diseases of free-ranging wildlife where sampling is logistically difficult precluding retesting. Clinical assays for wildlife diseases frequently vary among laboratories because of lack of appropriate standardized commercial kits. Results of diagnostic testing may also be called into question when investigators report different etiologies for disease outbreaks, despite similar clinical and pathologic findings. To evaluate reliability of diagnostic testing for respiratory pathogens of bighorn sheep (Ovis canadensis), we conducted a series of ring tests across 6 laboratories routinely involved in detection of Mycoplasma ovipneumoniae, Pasteurellaceae, lktA (the Pasteurellaceae gene encoding leukotoxin), and 3 reference laboratories. Consistency of results for replicate samples within laboratories was high (median agreement = 1.0). Agreement between laboratories was high for polymerase chain reaction (PCR) detection of M. ovipneumoniae and culture isolation of Mannheimia spp. and Bibersteinia trehalosi (median agreement = 0.89–0.95, Kappa = 0.65–0.74), and lower for PCR detection of Mannheimia spp. lktA (median agreement = 0.58, Kappa = 0.12). Most errors on defined status samples were false negatives, suggesting test sensitivity was a greater problem than specificity. However, tests for M. haemolytica and lktA yielded some false positive results. Despite differences in testing protocols, median agreement among laboratories and correct classification of controls for most agents was ≥0.80, meeting or exceeding the standard required by federal proficiency testing programs. This information is valuable for interpreting test results, laboratory quality assessments, and advancing diagnosis of respiratory disease in wild sheep. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Introduction: A compelling, innovative approach to teaching gross anatomy is the use of computer-aided holographic models. They allow for clean, time-saving dissection, manipulation of structures and appreciation of anatomical relationships, and potential elimination of the need for cadavers. The present study tests the hypothesis that using holographic models improves mastery of anatomical information. Materials and Methods: First-year medical students were taught gross anatomy using the dissection of donor cadavers, manipulation of digitized 3-dimensional holographic renderings, and examination of plastinated specimens. The effectiveness of these approaches was assessed by comparing students' performance on identification questions on cadavers (qC), holographic models (qH), and plastinated specimens (qP). Results: Students in the top quintile of the class performed strongly on qC, qH, and qP. In contrast, performance by students in the bottom quintile was uneven; they scored best on qH. Performance on the qP was relatively non-discriminating. Students in the top quintile scored higher on the biological sciences section of the Medical College Admission Test (MCAT) than students in the lowest quintile, whereas students in the lowest quintile had higher scores on the verbal section of their MCATs. Conclusions: The availability of different approaches for presenting gross anatomy improves the success of students in mastering the material, particularly for students struggling with the information. The use of holographic models apparently reaches students who may be challenged to learn the material using traditional approaches. This may be linked to potentially predictive information gleaned through performance on the MCAT. Clin. Anat., 2016. © 2016 Wiley Periodicals, Inc.

Bighorn sheep sinus tumors are a recently described disease affecting the paranasal sinuses of Rocky Mountain bighorn sheep ( Ovis canadensis canadensis). Several features of this disease suggest an infectious cause, although a specific etiologic agent has not been identified. To test the hypothesis that bighorn sheep sinus tumors are caused by an infectious agent, we inoculated 4 bighorn sheep lambs and 4 domestic sheep lambs intranasally with a cell-free filtrate derived from a naturally occurring bighorn sheep sinus tumor; we held 1 individual of each species as a control. Within 18 months after inoculation, all 4 inoculated domestic sheep (100%) and 1 of the 4 inoculated bighorn sheep (25%) developed tumors within the ethmoid sinuses or nasal conchae, with features similar to naturally occurring bighorn sheep sinus tumors. Neither of the uninoculated sheep developed tumors. Histologically, the experimentally transmitted tumors were composed of stellate to spindle cells embedded within a myxoid matrix, with marked bone production. Tumor cells stained positively with vimentin, S100, alpha smooth muscle actin, and osteocalcin, suggesting origin from a multipotent mesenchymal cell. A periosteal origin for these tumors is suspected. Immunohistochemical staining for the envelope protein of JSRV (with cross-reactivity to ENTV) was equivocal, and PCR assays specific for these agents were negative.

Safe and effective but unscheduled drug combinations are needed for wildlife immobilization in some jurisdictions. To this end, we evaluated a combination of nalbuphine HCl (40 mg/mL), medetomidine HCl (10 mg/mL), and azaperone tartrate (10 mg/mL)—referred to as NalMed-A (or NAM)—in 28 American black bears (Ursus americanus), captured during June to August 2014 as part of an ongoing study conducted in and around Durango, Colorado, USA. We effectively immobilized all bears; induction (mean ± SE) was 16.2 ± 0.9 minutes (n = 25) and reversal was 19 ± 1.6 minutes (n = 24). Advantages of NalMed-A included low delivery volume, good sedation quality, and effective reversal. Moreover, NalMed-A does not contain compounds regulated by the U.S. Drug Enforcement Administration, making it a useful unscheduled immobilization combination. Based on these and subsequent field experiences, our dosing recommendations are 0.5–1 mL NalMed-A/45.5 kg estimated body mass (0.44–0.88 mg nalbuphine HCl/kg, 0.11–0.22 mg aza...

Chronic wasting disease (CWD) is an infectious disease, but reported associations suggest several metals—especially copper (Cu) and manganese—potentially play a role in this and other prio...

Diagonistic apraxia is a corpus callosal disconnection syndrome. Callosal lesions in Neuromyelitis optica spectrum disorder (NMOSD) have been reported, but callosal disconnection syndrome are rare. A 48-year-old woman was treated for fever and a cough before hospitalization. Her fever abated immediately, but she had balance problems in walking and standing. She also had slurred speech. On neurological examination, she had diagonistic apraxia. Her left hand moved in an uncoordinated way when she moved her right hand: changing her clothes for example or using a knife and fork. She had to instruct her left hand to stop. She had dysarthria and her gait was wide-based. She also had many callosal disconnection syndrome symptoms such as alexia of left visual field, left ear extinction, crossed optic ataxia. Using FLAIR and DWI MRI, a mixture of low and high signals, a so-called “marbled pattern,” was seen in the corpus callosum. Since the patient was positive for anti-aquaporin-4 antibody, she was diagnosed with NMOSD. After two courses of steroid pulse therapy, the symptoms improved. Here we report diagonistic apraxia and other symptoms of callosal disconnection syndrome in anti-AQP4-positive NMOSD.

We evaluated a test and cull strategy for lowering chronic wasting disease (CWD) prevalence in a naturally-infected, free-ranging mule deer ( Odocoileus hemionus) herd wintering in the town of Estes Park, Colorado, US and in nearby Rocky Mountain National Park. We tested 48-68% of the estimated number of adult (≥1 yr old) deer annually for 5 yr via tonsil biopsy immunohistochemistry (IHC), collecting 1,251 samples from >700 individuals and removing IHC-positive deer. Among males, CWD prevalence during the last 3 yr of selective culling was lower (one-sided Fisher's exact test P=0.014) than in the period prior. In contrast, CWD prevalence among females before culling and after culling were equivalent ( P=0.777). Relatively higher annual testing of males (mean 77%) compared to females (mean 51%) might have contributed to differences seen in responses to management. A more intensive and sustained effort or modified spatial approach might have reduced prevalence more consistently in both sexes. Limitations of this technique in wider management application include cost and labor as well as property access and animal tolerance to repeated capture. However, elements of this approach could potentially be used to augment harvest-based disease management.

The Marshall Plan marked the beginning of modern foreign assistance, and from the very outset national security and foreign aid have been inextricably linked. Successful development assistance can make the world a safer, more stable place, advancing U.S. national interests in direct and subtle ways. Aid can help struggling states avoid becoming failing states, where all manner of threats—from terrorists to international criminal networks to deadly pathogens—can find a safe haven. Aid helps stave off political strife that contributes to the rise of demagogues with interests antithetical to those of the United States. At its best, foreign assistance can reinforce country efforts to join the community of democracies. A world where there are fewer wars, terrorist safe havens, and political tyrants is a more secure world for the United States.