Hamiltonian path analysis of viral genomes

Cryo-electron microscopy (EM) is undergoing a revolution, enabling the study of viral pathogens in unprecedented detail. The asymmetric EM reconstruction of bacteriophage MS2 at medium resolution (8.7 Å) by Koning et al.1, and the subsequent reconstruction at even higher resolution (3.6 Å) by Dai et al.2 revealed the structures of both the protein shell and the asym- metric genomic RNA and the unique maturation protein (A). It is the start of a wave of such structural data for viruses, and calls for the development of new analytical tools to describe the results. One approach is Hamiltonian path analysis (HPA) that we introduced to describe repeated, sequence-specific contacts between the MS2 genome and its protein shell3. Here, we describe how HPA is consistent with the new structures and, in turn, how it extends our understanding beyond the structural data alone

Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release.

Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7's role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential. Moreover, we confirm a role for Nav1.7 in influencing synaptic transmission in the dorsal horn of the spinal cord as well as peripheral neuropeptide release in the skin. These findings demonstrate multiple contributions of Nav1.7 to nociceptor signalling and shed new light on the relative functional contribution of this channel to peripheral and central noxious signal transmission.The funder provided support in the form of salaries for authors [AA, AB, MC, JT, MM, AW, EP, AG, PJC, RD, DP, ZL, BM, CW, NS, RS, PS, NC, DK, RB, ES], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section

Assay strategies for the discovery and validation of therapeutics targeting <i>Brugia pahangi</i> Hsp90

The chemotherapy of lymphatic filariasis relies upon drugs such as diethylcarbamazine and ivermectin that largely target the microfilarial stages of the parasite, necessitating continued treatment over the long reproductive life span of the adult worm. The identification of compounds that target adult worms has been a long-term goal of WHO. Here we describe a fluorescence polarization assay for the identification of compounds that target Hsp90 in adult filarial worms. The assay was originally developed to identify inhibitors of Hsp90 in tumor cells, and relies upon the ability of small molecules to inhibit the binding of fluorescently labelled geldanamycin to Hsp90. We demonstrate that the assay works well with soluble extracts of Brugia, while extracts of the free-living nematode C. elegans fail to bind the probe, in agreement with data from other experiments. The assay was validated using known inhibitors of Hsp90 that compete with geldanamycin for binding to Hsp90, including members of the synthetic purine-scaffold series of compounds. The efficacy of some of these compounds against adult worms was confirmed in vitro. Moreover, the assay is sufficiently sensitive to differentiate between binding of purine-scaffold compounds to human and Brugia Hsp90. The assay is suitable for high-throughput screening and provides the first example of a format with the potential to identify novel inhibitors of Hsp90 in filarial worms and in other parasitic species where Hsp90 may be a target

CB1 Cannabinoid Receptor Activation Dose-Dependently Modulates Neuronal Activity within Caudal but not Rostral Song Control Regions of Adult Zebra Finch Telencephalon

CB1 cannabinoid receptors are distinctly expressed at high density within several regions of zebra finch telencephalon including those known to be involved in song learning (lMAN and Area X) and production (HVC and RA). Because: (1) exposure to cannabinoid agonists during developmental periods of auditory and sensory-motor song learning alters song patterns produced later in adulthood and; (2) densities of song region expression of CB1 waxes-and-wanes during song learning, it is becoming clear that CB1 receptor-mediated signaling is important to normal processes of vocal development. To better understand mechanisms involved in cannabinoid modulation of vocal behavior we have investigated the dose-response relationship between systemic cannabinoid exposure and changes in neuronal activity (as indicated by expression of the transcription factor, c- Fos) within telencephalic brain regions with established involvement in song learning and/or control. In adults we have found that low doses (0.1 mg/kg) of the cannabinoid agonist WIN-55212-2 decrease neuronal activity (as indicated by densities of c-fos-expressing nuclei) within vocal motor regions of caudal telencephalon (HVC and RA) while higher doses (3 mg/kg) stimulate activity. Both effects were reversed by pretreatment with the CB1-selective antagonist rimonabant. Interestingly, no effects of cannabinoid treatment were observed within the rostral song regions lMAN and Area X, despite distinct and dense CB1 receptor expression within these areas. Overall, our results demonstrate that, depending on dosage, CB1 agonism can both inhibit and stimulate neuronal activity within brain regions controlling adult vocal motor output, implicating involvement of multiple CB1-sensitive neuronal circuits. Originally published Psychopharmacology, Vol. 199, No. 2, Aug 200

The effect of crystalloid versus medium molecular weight colloid solution on post-operative nausea and vomiting after ambulatory gynecological surgery - a prospective randomized trial.

UNLABELLED: ABSTRACT: BACKGROUND: Intravenous fluid is recommended in international guidelines to improve patient post-operative symptoms, particularly nausea and vomiting. The optimum fluid regimen has not been established. This prospective, randomized, blinded study was designed to determine if administration of equivolumes of a colloid (hydroxyethyl starch 130/0.4) reduced post operative nausea and vomiting in healthy volunteers undergoing ambulatory gynecologic laparoscopy surgery compared to a crystalloid solution (Hartmann\u27s Solution). METHODS: 120 patients were randomized to receive intravenous colloid (N = 60) or crystalloid (N = 60) intra-operatively. The volume of fluid administered was calculated at 1.5 ml.kg-1 per hour of fasting. Patients were interviewed to assess nausea, vomiting, anti-emetic use, dizziness, sore throat, headache and subjective general well being at 30 minutes and 2, 24 and 48 hours post operatively. Pulmonary function testing was performed on a subgroup. RESULTS: At 2 hours the proportion of patients experiencing nausea (38.2 % vs 17.9%, P = 0.03) and the mean nausea score were increased in the colloid compared to crystalloid group respectively (1.49 ± 0.3 vs 0.68 ± 0.2, P = 0.028). The incidence of vomiting and anti-emetic usage was low and did not differ between the groups. Sore throat, dizziness, headache and general well being were not different between the groups. A comparable reduction on post-operative FVC and FEV-1 and PEFR was observed in both groups. CONCLUSIONS: Intra-operative administration of colloid increased the incidence of early postoperative nausea and has no advantage over crystalloid for symptom control after gynaecological laparoscopic surgery

Systematic review of worldwide variations of the prevalence of wheezing symptoms in children

Background: Considerable variation in the prevalence of childhood asthma and its symptoms (wheezing) has been observed in previous studies and there is evidence that the prevalence has been increasing over time. Methods: We have systematically reviewed the reported prevalence and time trends of wheezing symptoms among children, worldwide and within the same country over time. All studies comprising more than 1000 persons and meeting certain other quality criteria published over a 16-year period, between January 1990 and December 2005, are reported and a comparison of ISAAC (International Study of Asthma and Allergies in Childhood) and non-ISAAC studies is made, in part as a way of expanding the power to examine time trends (the older studies tend to be non-ISAAC), but also to examine possible methodological differences between ISAAC and non-ISAAC questions. Results: A wide range of current prevalence of wheeze was observed between and within countries over time. The UK had the highest recorded prevalence of 32.2% in children aged 13–14 in 1994–5 and Ethiopia had the lowest prevalence, 1.7% in children aged 10–19 in 1996. All studies in Australia and the UK were compared using multiple logistic regression. ISAAC phase I and III studies reported significantly higher prevalence of current wheeze (OR = 1.638) compared with non-ISAAC studies, after adjusting for various other factors (country, survey year, age of child, parental vs child response to the survey). Australia showed a significantly higher prevalence of current wheezing (OR = 1.343) compared with the UK, there was a significant increase in the prevalence odds ratio per survey year (2.5% per year), a significant decrease per age of child (0.7% per year), and a significantly higher response in current wheezing if the response was self-completed by the child (OR = 1.290). These factors, when explored separately for ISAAC and non-ISAAC studies, showed very different results. In ISAAC studies, or non-ISAAC studies using ISAAC questions, there was a significant decrease in current wheezing prevalence over time (2.5% per year). In non-ISAAC studies, which tend to cover an earlier period, there was a significant increase (2.6% per year) in current wheezing prevalence over time. This is very likely to be a result of prevalence of wheezing increasing from the 1970s up to the early 1990s, but decreasing since then. Conclusion: The UK has the highest recorded prevalence of wheezing and Ethiopia the lowest. Prevalence of wheezing in Australia and the UK has increased from the 1970s up to the early 1990s, but decreased since then and ISAAC studies report significantly higher prevalences than non-ISAAC studies

Forward jet production in deep inelastic ep scattering and low-x parton dynamics at HERA

Differential inclusive jet cross sections in neutral current deep inelastic ep scattering have been measured with the ZEUS detector. Three phase-space regions have been selected in order to study parton dynamics where the effects of BFKL evolution might be present. The measurements have been compared to the predictions of leading-logarithm parton shower Monte Carlo models and fixed-order perturbative QCD calculations. In the forward region, QCD calculations at order alpha_s^1 underestimate the data up to an order of magnitude at low x. An improved description of the data in this region is obtained by including QCD corrections at order alpha_s^2, which account for the lowest-order t-channel gluon-exchange diagrams, highlighting the importance of such terms in parton dynamics at low x.Comment: 25 pages, 4 figure

Spatial navigation deficits — overlooked cognitive marker for preclinical Alzheimer disease?

Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities