Developing Physiological Profiles using Nuclear Magnetic Resonance Spectroscopy to Inform Bighorn Sheep Management

This study employs new techniques using nuclear magnetic resonance (NMR) to assess the relative health, physiological condition, and reproductive function of wild bighorn sheep (Ovis canadensis)  in Montana and Wyoming. Ongoing bighorn studies in Montana and the Greater Yellowstone Ecosystem are focused on herd attributes and the population dynamics which are affected by disease, climate, habitat and physiology. Indices of herd health and physiological status are typically obtained through expensive and time consuming lab assays and field measurements. Recently, NMR spectroscopy has been used to revolutionize the assessment of human metabolic health, and we expect that there is similar potential for studies of wildlife populations. Using NMR spectroscopy to assess metabolites associated with disease, nutrition and stress may eliminate the need for many traditional assays and techniques used today. NMR can be used to evaluate a large suite of metabolites associated with a variety of physiological functions from as little as 500 ?L of serum or plasma. Blood samples from 242 sheep from 13 different herds were collected during the winters of 2013-14 and 2014-15 to develop a comprehensive metabolite panel for bighorn sheep. We have used a recently developed statistical program known as MetaboAnalyst™ to begin to analyze and evaluate differences in NMR metabolic profiles among herds and across the fall-winter season when nutritional and physiological stress is expected to be acute. We will be presenting the results of this preliminary study and discussing the potential for application in wildlife management

11β-HSD1 suppresses cardiac fibroblast CXCL2, CXCL5 and neutrophil recruitment to the heart post MI

We have previously demonstrated that neutrophil recruitment to the heart following myocardial infarction (MI) is enhanced in mice lacking 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that regenerates active glucocorticoid within cells from intrinsically inert metabolites. The present study aimed to identify the mechanism of regulation. In a mouse model of MI, neutrophil mobilization to blood and recruitment to the heart were higher in 11β-HSD1-deficient (Hsd11b1(-)(/)(-) ) relative to wild-type (WT) mice, despite similar initial injury and circulating glucocorticoid. In bone marrow chimeric mice, neutrophil mobilization was increased when 11β-HSD1 was absent from host cells, but not when absent from donor bone marrow-derived cells. Consistent with a role for 11β-HSD1 in 'host' myocardium, gene expression of a subset of neutrophil chemoattractants, including the chemokines Cxcl2 and Cxcl5, was selectively increased in the myocardium of Hsd11b1(-)(/)(-) mice relative to WT. SM22α-Cre directed disruption of Hsd11b1 in smooth muscle and cardiomyocytes had no effect on neutrophil recruitment. Expression of Cxcl2 and Cxcl5 was elevated in fibroblast fractions isolated from hearts of Hsd11b1(-)(/)(-) mice post MI and provision of either corticosterone or of the 11β-HSD1 substrate, 11-dehydrocorticosterone, to cultured murine cardiac fibroblasts suppressed IL-1α-induced expression of Cxcl2 and Cxcl5 These data identify suppression of CXCL2 and CXCL5 chemoattractant expression by 11β-HSD1 as a novel mechanism with potential for regulation of neutrophil recruitment to the injured myocardium, and cardiac fibroblasts as a key site for intracellular glucocorticoid regeneration during acute inflammation following myocardial injury

Improving together: better science writing through peer learning

Science, in our case the climate and geosciences, is increasingly interdisciplinary. Scientists must therefore communicate across disciplinary boundaries. For this communication to be successful, scientists must write clearly and concisely, yet the historically poor standard of scientific writing does not seem to be improving. Scientific writing must improve, and the key to long-term improvement lies with the early-career scientist (ECS). Many interventions exist for an ECS to improve their writing, like style guides and courses. However, momentum is often difficult to maintain after these interventions are completed. Continuity is key to improving writing. This paper introduces the ClimateSnack project, which aims to motivate ECSs to develop and continue to improve their writing and communication skills. The project adopts a peer-learning framework where ECSs voluntarily form writing groups at different institutes around the world. The group members learn, discuss, and improve their writing skills together. Several ClimateSnack writing groups have formed. This paper examines why some of the groups have flourished and others have dissolved. We identify the challenges involved in making a writing group successful and effective, notably the leadership of self-organized groups, and both individual and institutional time management. Within some of the groups, peer learning clearly offers a powerful tool to improve writing as well as bringing other benefits, including improved general communication skills and increased confidence

Mouse screen reveals multiple new genes underlying mouse and human hearing loss.

Adult-onset hearing loss is very common, but we know little about the underlying molecular pathogenesis impeding the development of therapies. We took a genetic approach to identify new molecules involved in hearing loss by screening a large cohort of newly generated mouse mutants using a sensitive electrophysiological test, the auditory brainstem response (ABR). We review here the findings from this screen. Thirty-eight unexpected genes associated with raised thresholds were detected from our unbiased sample of 1,211 genes tested, suggesting extreme genetic heterogeneity. A wide range of auditory pathophysiologies was found, and some mutant lines showed normal development followed by deterioration of responses, revealing new molecular pathways involved in progressive hearing loss. Several of the genes were associated with the range of hearing thresholds in the human population and one, SPNS2, was involved in childhood deafness. The new pathways required for maintenance of hearing discovered by this screen present new therapeutic opportunities

How Does Blood-Retinal Barrier Breakdown Relate to Death and Disability in Pediatric Cerebral Malaria?

Background In cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling. Methods We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain MRI, and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria. Results Three types of retinal leakage were seen: Large focal leak (LFL), punctate leak (PL) and vessel leak. LFL and PL were associated with death (OR 13.20, 95%CI 5.21-33.78 and 8.58, 2.56-29.08 respectively), and brain swelling (p<0.05). Vessel leak and macular non-perfusion were associated with neurological disability (3.71, 1.26-11.02 and 9.06, 1.79-45.90). LFL was observed as an evolving retinal hemorrhage. A core of fibrinogen and monocytes was found in 39 (93%) white-centered hemorrhages. Conclusions Blood-retina barrier breakdown occurs in three patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak from barrier dysfunction, and non-perfusion were not associated with severe brain swelling, but with neurological deficits, suggesting hypoxic injury in survivors

Retinal Pathology of Pediatric Cerebral Malaria in Malawi

Introduction The causes of coma and death in cerebral malaria remain unknown. Malarial retinopathy has been identified as an important clinical sign in the diagnosis and prognosis of cerebral malaria. As part of a larger autopsy study to determine causes of death in children with coma presenting to hospital in Blantyre, Malawi, who were fully evaluated clinically prior to death, we examined the histopathology of eyes of patients who died and underwent autopsy. Methodology/Principal Findings Children with coma were admitted to the pediatric research ward, classified according to clinical definitions as having cerebral malaria or another cause of coma, evaluated and treated. The eyes were examined by direct and indirect ophthalmoscopy. If a child died and permission was given, a standardized autopsy was carried out. The patient was then assigned an actual cause of death according to the autopsy findings. The eyes were examined pathologically for hemorrhages, cystoid macular edema, parasite sequestration and thrombi. They were stained immunohistochemically for fibrin and CD61 to identify the components of thrombi, β-amyloid precursor protein to detect axonal damage, for fibrinogen to identify vascular leakage and for glial fibrillary acidic protein to detect gliosis. Sixty-four eyes from 64 patients were examined: 35 with cerebral malaria and 29 with comas of other causes. Cerebral malaria was distinguished by sequestration of parasitized erythrocytes, the presence and severity of retinal hemorrhages, the presence of cystoid macular edema, the occurrence and number of fibrin-platelet thrombi, the presence and amount of axonal damage and vascular leakage. Conclusions/Significance We found significant differences in retinal histopathology between patients who died of cerebral malaria and those with other diagnoses. These histopathological findings offer insights into the etiology of malarial retinopathy and provide a pathological basis for recently described retinal capillary non-perfusion in children with malarial retinopathy. Because of the similarities between the retina and the brain it also suggests mechanisms that may contribute to coma and death in cerebral malaria