Overwintering energetics of Lepidoptera: the effects of winter warming and thermal variability.

Winter temperatures are changing rapidly, and although winter warming reduces cold stress for overwintering ectotherms, temperature-mediated increases in metabolic rate can decrease fitness in dormant insects by increasing consumption of energy reserves. Increases in thermal variability also increase energetic demands, due to non-linear thermal response curves. My objective was to quantify the negative effects of winter warming and increases in thermal variability on a range of Lepidopteran species. As overwintering insects rely on lipid catabolism, accurate lipid measurement is central to my dissertation; so I first compared four methods of lipid quantification; concluding thin layer chromatography was the only method sufficiently accurate and robust to variation in lipid composition. I then examined the physiological and life-history costs of winter warming in Erynnis propertius [EP], Papilio glaucus [PG], P. troilus [PT], and Hyphantria cunea [HC]. A simple increase in temperature caused lipid depletion in EP, but PT, PG and HC were insensitive to winter warming. In HC, this insensitivity was mediated by a plastic suppression of metabolism and a decrease in development time in the warmer winter. HC from their northern range edge had increased thermal sensitivity at the end of winter, as predicted by metabolic cold adaptation theory. In EP, I also investigated the impact of daily thermal variability on overwintering energetics, demonstrating a facultative and obligate suppression of thermal sensitivity in response to high daily thermal variability, which partially compensated for the increased energetic demands of the more variable environment. Modelling energy use with meteorological data demonstrated that phenology changes had disproportionate influence on energetics in variable environments; thus timing of entry into winter dormancy will strongly influence ectotherm fitness in temperate environments. Metabolic suppression in EP and HC are the first demonstrations of metabolic compensation in overwintering insects. Finally, I outline a framework to predict insect vulnerability to winter warming. Winter warming and increases in thermal variability may negatively impact the fitness of some overwintering insects, but diverse physiological mechanisms compensate for increased energetic demands over winter

Low temperatures impact species distributions of jumping spiders across a desert elevational cline.

Temperature is known to influence many aspects of organisms and is frequently linked to geographical species distributions. Despite the importance of a broad understanding of an animal's thermal biology, few studies incorporate more than one metric of thermal biology. Here we examined an elevational assemblage of Habronattus jumping spiders to measure different aspects of their thermal biology including thermal limits (CTmin, CTmax), thermal preference, V̇CO2 as proxy for metabolic rate, locomotor behavior and warming tolerance. We used these data to test whether thermal biology helped explain how species were distributed across elevation. Habronattus had high CTmax values, which did not differ among species across the elevational gradient. The highest-elevation species had a lower CTmin than any other species. All species had a strong thermal preference around 37 °C. With respect to performance, one of the middle elevation species was significantly less temperature-sensitive in metabolic rate. Differences between species with respect to locomotion (jump distance) were likely driven by differences in mass, with no differences in thermal performance across elevation. We suggest that Habronattus distributions follow Brett's rule, a rule that predicts more geographical variation in cold tolerance than heat. Additionally, we suggest that physiological tolerances interact with biotic factors, particularly those related to courtship and mate choice to influence species distributions. Habronattus also had very high warming tolerance values (> 20 °C, on average). Taken together, these data suggest that Habronattus are resilient in the face of climate-change related shifts in temperature

The Genetic Basis of Cognitive Impairment and Dementia in Parkinson's Disease.

Cognitive dysfunction is a common feature of Parkinson's disease (PD) with mild cognitive impairment affecting around a quarter of patients in the early stages of their disease, and approximately half developing dementia by 10 years from diagnosis. However, the pattern of cognitive impairments and their speed of evolution vary markedly between individuals. While some of this variability may relate to extrinsic factors and comorbidities, inherited genetic heterogeneity is also known to play an important role. A number of common genetic variants have been identified, which contribute to cognitive function in PD, including variants in catechol-O-methyltransferase, microtubule-associated protein tau, and apolipoprotein E. Furthermore, rarer mutations in glucocerebrosidase and α-synuclein and are strongly associated with dementia risk in PD. This review explores the functional impact of these variants on cognition in PD and discusses how such genotype-phenotype associations provide a window into the mechanistic basis of cognitive heterogeneity in this disorder. This has consequent implications for the development of much more targeted therapeutic strategies for cognitive symptoms in PD.This is the final version of the article. It first appeared from Frontiers via http://dx.doi.org/10.3389/fpsyt.2016.0008

Absence of the Filarial Endosymbiont Wolbachia in Seal Heartworm (Acanthocheilonema spirocauda) but Evidence of Ancient Lateral Gene Transfer

The symbiotic relationship of Wolbachia spp. was first observed in insects and subsequently in many parasitic filarial nematodes. This bacterium is believed to provide metabolic and developmental assistance to filarial parasitic nematodes, although the exact nature of this relationship remains to be fully elucidated. While Wolbachia is present in most filarial nematodes in the familyOnchocercidae, it is absent in several disparate species such as the human parasite Loa loa. All tested members of the genusAcanthocheilonema, such as Acanthocheilonema viteae, have been shown to lack Wolbachia. Consistent with this, we show thatWolbachia is absent from the seal heartworm (Acanthocheilonema spirocauda), but lateral gene transfer (LGT) of DNA sequences between Wolbachia and A. spirocauda has occurred, indicating a past evolutionary association. Seal heartworm is an important pathogen of phocid seals and understanding its basic biology is essential for conservation of the host. The findings presented here may allow for the development of future treatments or diagnostics for the disease and also aid in clarification of the complicated nematode–Wolbachia relationship

Demonstration of an online tool to assist managed care formulary evidence-based decision making: meta-analysis of topical prostaglandin analog efficacy

BACKGROUND: The purpose of this paper was to demonstrate the use of an online service for conducting a systematic review and meta-analysis of the efficacy of topical prostaglandin analogs in reducing intraocular pressure (IOP) in glaucoma and ocular hypertension. METHODS: An online service provider (Doctor Evidence) reviewed and extracted data from the peer-reviewed literature through September 2009. Randomized controlled studies of at least three months’ duration assessing at least two prostaglandin analogs in patients with primary open-angle glaucoma, ocular hypertension, or normal-tension glaucoma were included. The primary endpoint was mean IOP. Summary estimates were created using random-effects models. The Q Chi-square test was used to assess statistical heterogeneity. RESULTS: Sixteen studies satisfied the inclusion criteria and were analyzed. On average, greater IOP-lowering was seen with bimatoprost relative to latanoprost (1 mmHg, P = 0.025) and travoprost (0.8 mmHg, P = 0.033) based on mean IOP after 12–26 weeks of treatment. No statistical difference was observed in IOP-lowering between latanoprost and travoprost (P = 0.841). Findings were similar to previously published meta-analyses of topical prostaglandin analogs. CONCLUSION: Systematic reviews relying on meta-analytic techniques to create summary statistics are considered to be the “gold standard” for synthesizing evidence to support clinical decision-making. However, the process is time-consuming, labor-intensive, and outside the capability of most formulary managers. We have demonstrated the effectiveness of a commercial service that facilitates the process of conducting such reviews

A Novel Quantitative Real-Time PCR Diagnostic Assay for Seal Heartworm (Acanthocheilonema spirocauda) Provides Evidence for Possible Infection in the Grey Seal (Halichoerus grypus)

The distinct evolutionary pressures faced by Pinnipeds have likely resulted in strong coevolutionary ties to their parasites (Leidenberger et al., 2007). This study focuses on the phocid seal filarial heartworm speciesAcanthocheilonema spirocauda. A. spirocauda is known to infect a variety of phocid seals, but does not appear to be restricted to a single host species (Measures et al., 1997; Leidenberger et al., 2007; Lehnert et al., 2015). However, to date, seal heartworm has never been reported in grey seals (Halichoerus grypus) (Measures et al., 1997; Leidenberger et al., 2007; Lehnert et al., 2015). The proposed vector for seal heartworm is Echinophthirius horridus, the seal louse. Seal lice are known to parasitize a wide array of phocid seal species, including the grey seal. With the advent of climate change, disease burden is expected to increase across terrestrial and marine mammals (Harvell et al., 2002). Accordingly, increased prevalence of seal heartworm has recently been reported in harbor seals (Phoca vitulina) (Lehnert et al., 2015). Thus, the need for improved, rapid, and cost-effective diagnostics is urgent. Here we present the first A. spirocauda-specific rapid diagnostic test (a quantitative real- time PCR assay), based on a highly repetitive genomic DNA repeat identified using whole genome sequencing and subsequent bioinformatic analysis. The presence of an insect vector provides the opportunity to develop a multifunctional diagnostic tool that can be used not only to detect the parasite directly from blood or tissue specimens, but also as a molecular xenomonitoring (XM) tool that can be used to assess the epidemiological profile of the parasite by screening the arthropod vector. Using this assay, we provide evidence for the first reported case of seal heartworm in a grey seal

Infant Serum and Maternal Milk Vitamin B-12 Are Positively Correlated in Kenyan Infant-Mother Dyads at 1-6 Months Postpartum, Irrespective of Infant Feeding Practice.

BackgroundVitamin B-12 is an essential nutrient required for many functions including DNA synthesis, erythropoiesis, and brain development. If maternal milk vitamin B-12 concentrations are low, infants may face elevated risks of deficiency when exclusively breastfed.ObjectiveWe evaluated cross-sectional associations between infant serum vitamin B-12 concentrations and maternal milk vitamin B-12 concentrations at 1-6 mo postpartum among an unsupplemented population in rural western Kenya, and assessed biological demographic, and dietary characteristics associated with adequate infant serum vitamin B-12.MethodsWe modeled 1) infant serum vitamin B-12 using maternal milk vitamin B-12 concentration with linear regression; and 2) adequate (>220 pmol/L) infant serum vitamin B-12 using hypothesized biological, demographic, and dietary predictors with logistic regression. In both models, we used generalized estimating equations to account for correlated observations at the cluster-level.ResultsThe median (quartile 1, quartile 3) infant serum vitamin B-12 concentration was 276 pmol/L (193, 399 pmol/L) and approximately one-third of infants had serum vitamin B-12 ≤220 pmol/L, indicating that they were vitamin B-12 depleted or deficient. There was a positive correlation between maternal milk and infant serum vitamin B-12 (r = 0.36, P < 0.001) and in multivariable analyses, maternal milk vitamin B-12 concentration was significantly associated with infant serum vitamin B-12 adequacy (P-trend = 0.03).ConclusionsDespite a high prevalence (90%) of maternal milk vitamin B-12 concentrations below the level used to establish the Adequate Intake (<310 pmol/L), there was a low prevalence of infant vitamin B-12 deficiency. We found few factors that were associated with infant vitamin B-12 adequacy in this population, including infant feeding practices, although maternal vitamin B-12 status was not measured. The contribution of maternal milk to infant vitamin B-12 status remains important to quantify across populations, given that maternal milk vitamin B-12 concentration is modifiable with supplementation. This trial was registered at clinicaltrials.gov as NCT01704105

A caspase-3 'death-switch' in colorectal cancer cells for induced and synchronous tumor apoptosis in vitro and in vivo facilitates the development of minimally invasive cell death biomarkers

Novel anticancer drugs targeting key apoptosis regulators have been developed and are undergoing clinical trials. Pharmacodynamic biomarkers to define the optimum dose of drug that provokes tumor apoptosis are in demand; acquisition of longitudinal tumor biopsies is a significant challenge and minimally invasive biomarkers are required. Considering this, we have developed and validated a preclinical 'death-switch' model for the discovery of secreted biomarkers of tumour apoptosis using in vitro proteomics and in vivo evaluation of the novel imaging probe [ 18 F]ML-10 for non-invasive detection of apoptosis using positron emission tomography (PET). The 'death-switch' is a constitutively active mutant caspase-3 that is robustly induced by doxycycline to drive synchronous apoptosis in human colorectal cancer cells in vitro or grown as tumor xenografts. Deathswitch induction caused caspase-dependent apoptosis between 3 and 24 hours in vitro and regression of 'death-switched' xenografts occurred within 24 h correlating with the percentage of apoptotic cells in tumor and levels of an established cell death biomarker (cleaved cytokeratin-18) in the blood. We sought to define secreted biomarkers of tumor apoptosis from cultured cells using Discovery Isobaric Tag proteomics, which may provide candidates to validate in blood. Early after caspase-3 activation, levels of normally secreted proteins were decreased (e.g. Gelsolin and Midkine) and proteins including CD44 and High Mobility Group protein B1 (HMGB1) that were released into cell culture media in vitro were also identified in the bloodstream of mice bearing death-switched tumors. We also exemplify the utility of the death-switch model for the validation of apoptotic imaging probes using [ 18 F]ML-10, a PET tracer currently in clinical trials. Results showed increased tracer uptake of [ 18 F]ML-10 in tumours undergoing apoptosis, compared with matched tumour controls imaged in the same animal. Overall, the death-switch model represents a robust and versatile tool for the discovery and validation of apoptosis biomarkers. © 2013 Macmillan Publishers Limited. All rights reserved

The pathogenesis of Parkinson's disease

Parkinson's disease is a progressive neurodegenerative condition associated with the deposition of aggregated α-synuclein. Insights into the pathogenesis of Parkinson's disease have been derived from genetics and molecular pathology. Biochemical studies, investigation of transplanted neurons in patients with Parkinson's disease, and cell and animal model studies suggest that abnormal aggregation of α-synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson's disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson's disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson's disease. Although there are currently no disease-modifying treatments for Parkinson's disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition