Vasodilatation in the rat dorsal hindpaw induced by activation of sensory neurons is reduced by Paclitaxel

Peripheral neuropathy is a major side effect following treatment with the cancer chemotherapeutic drug paclitaxel. Whether paclitaxel-induced peripheral neuropathy is secondary to altered function of small diameter sensory neurons remains controversial. To ascertain whether the function of the small diameter sensory neurons was altered following systemic administration of paclitaxel, we injected male Sprague Dawley rats with 1 mg/kg paclitaxel every other day for a total of four doses and examined vasodilatation in the hindpaw at day 14 as an indirect measure of calcitonin gene related peptide (CGRP) release. In paclitaxel-treated rats, the vasodilatation induced by either intradermal injection of capsaicin into the hindpaw or electrical stimulation of the sciatic nerve was significantly attenuated in comparison to vehicle-injected animals. Paclitaxel treatment, however, did not affect direct vasodilatation induced by intradermal injection of methacholine or CGRP, demonstrating that the blood vessels’ ability to dilate was intact. Paclitaxel treatment did not alter the compound action potentials or conduction velocity of C-fibers. The stimulated release of CGRP from the central terminals in the spinal cord was not altered in paclitaxel-injected animals. These results suggest that paclitaxel affects the peripheral endings of sensory neurons to alter transmitter release, and this may contribute to the symptoms seen in neuropathy

Herring gull aversion to gaze in urban and rural human settlements

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordWith an increasing human population and expansion of urban settlements, wild animals are often exposed to humans. As humans may be a threat, a neutral presence, or a source of food, animals will benefit from continuously assessing the potential risk posed by humans in order to respond appropriately. Herring gulls (Larus argentatus) are increasingly breeding and foraging in urban areas, and thus have many opportunities to interact with humans. We recently found that herring gulls take longer to approach food when being watched by a human. However, it is not known whether aversion to human gaze arises from experience with humans, and whether individual differences in responsiveness are a result of differential exposure. Here, we test whether herring gulls’ responses to human gaze differ according to their age class and urbanisation of their habitat. We measured the gulls’ flight initiation distance when an experimenter approached with either a direct or averted gaze. Neither gull age class nor urbanisation significantly influenced the effect of human gaze on flight initiation distance. However, as recently fledged juveniles responded strongly to the experimenter’s gaze, aversion to human gaze may not require extensive exposure to humans to develop. Gulls in urban areas could be approached more closely than those in rural areas, consistent with findings in other species. These results indicate that gaze aversion is present early in development and that exposure to humans may influence gulls’ responses to perceived risk from humans. Investigating the processes generating individual differences in responses to humans will provide further insights into human-wildlife interactions and the effects of urbanisation.Royal Societ

Public policy action and CCC implementation: benefits and hurdles

Policy change continues to be an increasingly effective means of advancing the agenda of comprehensive cancer control. Efforts have moved progressively from describing how public policy can enhance the comprehensive cancer control agenda to implementation of public policy best practices at both the state and federal levels. The current political and economic contexts bring additional challenges and opportunities to the efforts surrounding comprehensive cancer control and policy. The purpose of this paper is to highlight recent policy successes, to illustrate the importance of policy as a means of advancing the comprehensive cancer control agenda, and to discuss continued policy action as we move forward in a time of healthcare reform and continuing economic uncertainty

Caloric Restriction Alters the Metabolic Response to a Mixed-Meal: Results from a Randomized, Controlled Trial

OBJECTIVES: To determine if caloric restriction (CR) would cause changes in plasma metabolic intermediates in response to a mixed meal, suggestive of changes in the capacity to adapt fuel oxidation to fuel availability or metabolic flexibility, and to determine how any such changes relate to insulin sensitivity (S(I)). METHODS: Forty-six volunteers were randomized to a weight maintenance diet (Control), 25% CR, or 12.5% CR plus 12.5% energy deficit from structured aerobic exercise (CR+EX), or a liquid calorie diet (890 kcal/d until 15% reduction in body weight)for six months. Fasting and postprandial plasma samples were obtained at baseline, three, and six months. A targeted mass spectrometry-based platform was used to measure concentrations of individual free fatty acids (FFA), amino acids (AA), and acylcarnitines (AC). S(I) was measured with an intravenous glucose tolerance test. RESULTS: Over three and six months, there were significantly larger differences in fasting-to-postprandial (FPP) concentrations of medium and long chain AC (byproducts of FA oxidation) in the CR relative to Control and a tendency for the same in CR+EX (CR-3 month P = 0.02; CR-6 month P = 0.002; CR+EX-3 month P = 0.09; CR+EX-6 month P = 0.08). After three months of CR, there was a trend towards a larger difference in FPP FFA concentrations (P = 0.07; CR-3 month P = 0.08). Time-varying differences in FPP concentrations of AC and AA were independently related to time-varying S(I) (P<0.05 for both). CONCLUSIONS: Based on changes in intermediates of FA oxidation following a food challenge, CR imparted improvements in metabolic flexibility that correlated with improvements in S(I). TRIAL REGISTRATION: ClinicalTrials.gov NCT00099151

A prospective study of XRCC1 (X-ray cross-complementing group 1) polymorphisms and breast cancer risk

INTRODUCTION: The gene XRCC1 (X-ray repair cross-complementing group 1) encodes a protein involved in DNA base excision repair. Two non-synonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) have been shown to alter DNA repair capacity in some studies in vitro. However, results of previous association studies of these two XRCC1 variants and breast cancer have been inconsistent. We examined the association between polymorphisms in XRCC1 and breast cancer in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort, a large prospective study of cancer incidence in the USA. METHODS: Among the 21,965 women who were cancer-free in 1992 and gave blood between 1998 and 2001, 502 postmenopausal breast cancer cases were diagnosed between 1992 and 2001; 502 controls were matched to cases on age, race/ethnicity, and date of blood collection. Genotyping on DNA extracted from buffy coat was performed with Taqman. Conditional logistic regression was used to examine the association between each polymorphism and breast cancer risk controlling for breast cancer risk factors. We also examined whether factors associated with DNA damage, such as smoking and antioxidant intake, modified the association between XRCC1 polymorphisms and breast cancer. RESULTS: We observed a significant inverse association between Trp194 carriers (Trp/Trp and Trp/Arg) compared with Trp194 non-carriers in relation to breast cancer (Arg/Arg) (odds ratio (OR) 0.62, 95% confidence interval (CI) 0.40 to 0.95). The inverse association between breast cancer and Trp194 carriers compared with non-carriers was slightly stronger among smokers (OR 0.47, 95% CI 0.24 to 0.94) than never smokers (OR 0.78, 95% CI 0.43 to 1.40). An increased risk associated with the Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was observed only among women who reported ever smoking cigarettes (OR 2.76, 95% CI 1.36 to 5.63), and not in women who were lifelong non-smokers (OR 0.64, 95% CI 0.33 to 1.26). No other factor examined modified the association between XRCC1 polymorphisms and breast cancer risk. CONCLUSION: Our results support the hypothesis that genetic variation in XRCC1, particularly in Arg194Trp, may influence postmenopausal breast cancer risk. In our study, genetic variation in XRCC1 Arg399Gln was associated with breast cancer risk only among women with a history of smoking cigarettes

How contemporary bioclimatic and human controls change global fire regimes

Anthropogenically driven declines in tropical savannah burnt area have recently received attention due to their effect on trends in global burnt area. Large-scale trends in ecosystems where vegetation has adapted to infrequent fire, especially in cooler and wetter forested areas, are less well understood. Here, small changes in fire regimes can have a substantial impact on local biogeochemistry. To investigate trends in fire across a wide range of ecosystems, we used Bayesian inference to quantify four primary controls on burnt area: fuel continuity, fuel moisture, ignitions and anthropogenic suppression. We found that fuel continuity and moisture are the dominant limiting factors of burnt area globally. Suppression is most important in cropland areas, whereas savannahs and boreal forests are most sensitive to ignitions. We quantify fire regime shifts in areas with more than one, and often counteracting, trends in these controls. Forests are of particular concern, where we show average shifts in controls of 2.3–2.6% of their potential maximum per year, mainly driven by trends in fuel continuity and moisture. This study gives added importance to understanding long-term future changes in the controls on fire and the effect of fire trends on ecosystem function

Phosphoinositide 3-kinase: a critical signalling event in pulmonary cells

Phosphoinositide 3-kinases (PI-3Ks) are enzymes that generate lipid second messenger molecules, resulting in the activation of multiple intracellular signalling cascades. These events regulate a broad array of cellular responses including survival, activation, differentiation and proliferation and are now recognised to have a key role in a number of physiological and pathophysiological processes in the lung. PI-3Ks contribute to the pathogenesis of asthma by influencing the proliferation of airways smooth muscle and the recruitment of eosinophils, and affect the balance between the harmful and protective responses in pulmonary inflammation and infection by the modulation of granulocyte recruitment, activation and apoptosis. In addition they also seem to exert a critical influence on the malignant phenotype of small cell lung cancer. PI-3K isoforms and their downstream targets thus provide novel therapeutic targets for intervention in a broad spectrum of respiratory diseases

Deep Brain Stimulation Reveals a Dissociation of Consummatory and Motivated Behaviour in the Medial and Lateral Nucleus Accumbens Shell of the Rat

Following the successful application of deep brain stimulation (DBS) in the treatment of Parkinson's disease and promising results in clinical trials for obsessive compulsive disorder and major depression, DBS is currently being tested in small patient-populations with eating disorders and addiction. However, in spite of its potential use in a broad spectrum of disorders, the mechanisms of action of DBS remain largely unclear and optimal neural targets for stimulation in several disorders have yet to be established. Thus, there is a great need to examine site-specific effects of DBS on a behavioural level and to understand how DBS may modulate pathological behaviour. In view of the possible application of DBS in the treatment of disorders characterized by impaired processing of reward and motivation, like addiction and eating disorders, we examined the effect of DBS of the nucleus accumbens (NAcc) on food-directed behavior. Rats were implanted with bilateral stimulation electrodes in one of three anatomically and functionally distinct sub-areas of the NAcc: the core, lateral shell (lShell) and medial shell (mShell). Subsequently, we studied the effects of DBS on food consumption, and the motivational and appetitive properties of food. The data revealed a functional dissociation between the lShell and mShell. DBS of the lShell reduced motivation to respond for sucrose under a progressive ratio schedule of reinforcement, mShell DBS, however, profoundly and selectively increased the intake of chow. DBS of the NAcc core did not alter any form of food-directed behavior studied. DBS of neither structure affected sucrose preference. These data indicate that the intake of chow and the motivation to work for palatable food can independently be modulated by DBS of subregions of the NAcc shell. As such, these findings provide important leads for the possible future application of DBS as a treatment for eating disorders such as anorexia nervosa

E. coli metabolic protein aldehydealcohol dehydrogenase-E binds to the ribosome: a unique moonlighting action revealed

It is becoming increasingly evident that a high degree of regulation is involved in the protein synthesis machinery entailing more interacting regulatory factors. A multitude of proteins have been identified recently which show regulatory function upon binding to the ribosome. Here, we identify tight association of a metabolic protein aldehyde-alcohol dehydrogenase E (AdhE) with the E. coli 70S ribosome isolated from cell extract under low salt wash conditions. Cryo-EM reconstruction of the ribosome sample allows us to localize its position on the head of the small subunit, near the mRNA entrance. Our study demonstrates substantial RNA unwinding activity of AdhE which can account for the ability of ribosome to translate through downstream of at least certain mRNA helices. Thus far, in E. coli, no ribosome-associated factor has been identified that shows downstream mRNA helicase activity. Additionally, the cryo-EM map reveals interaction of another extracellular protein, outer membrane protein C (OmpC), with the ribosome at the peripheral solvent side of the 50S subunit. Our result also provides important insight into plausible functional role of OmpC upon ribosome binding. Visualization of the ribosome purified directly from the cell lysate unveils for the first time interactions of additional regulatory proteins with the ribosom

ConDeTri - A Content Dependent Read Trimmer for Illumina Data

During the last few years, DNA and RNA sequencing have started to play an increasingly important role in biological and medical applications, especially due to the greater amount of sequencing data yielded from the new sequencing machines and the enormous decrease in sequencing costs. Particularly, Illumina/Solexa sequencing has had an increasing impact on gathering data from model and non-model organisms. However, accurate and easy to use tools for quality filtering have not yet been established. We present ConDeTri, a method for content dependent read trimming for next generation sequencing data using quality scores of each individual base. The main focus of the method is to remove sequencing errors from reads so that sequencing reads can be standardized. Another aspect of the method is to incorporate read trimming in next-generation sequencing data processing and analysis pipelines. It can process single-end and paired-end sequence data of arbitrary length and it is independent from sequencing coverage and user interaction. ConDeTri is able to trim and remove reads with low quality scores to save computational time and memory usage during de novo assemblies. Low coverage or large genome sequencing projects will especially gain from trimming reads. The method can easily be incorporated into preprocessing and analysis pipelines for Illumina data