Aberrant Disgust Responses and Immune Reactivity in Cocaine-Dependent Men

Background: Infectious diseases are the most common and cost-intensive health complications associated with drug addiction. There is wide belief that drug-dependent individuals expose themselves more regularly to disease-related pathogens through risky behaviors such as sharing pipes and needles, thereby increasing their risk for contracting an infectious disease. However, evidence is emerging indicating that not only lifestyle but also the immunomodulatory effects of addictive drugs, such as cocaine, may account for their high infection risk. As feelings of disgust are thought to be an important psychological mechanism in avoiding the exposure to pathogens, we sought to investigate behavioral, physiological, and immune responses to disgust-evoking cues in both cocaine-dependent and healthy men. Methods: All participants (N = 61) were exposed to neutral and disgust-evoking photographs depicting food and nonfood images while response accuracy, latency, and skin conductivity were recorded. Saliva samples were collected before and after exposure to neutral and disgusting images, respectively. Attitudes toward disgust and hygiene behaviors were assessed using questionnaire measures. Results: Response times to disgust-evoking photographs were prolonged in all participants, and specifically in cocaine-dependent individuals. While viewing the disgusting images, cocaine-dependent individuals exhibited aberrant skin conductivity and increased the secretion of the salivary cytokine interleukin-6 relative to control participants. Conclusion: Our data provide evidence of a hypersensitivity to disgusting stimuli in cocaine-dependent individuals, possibly reflecting conditioned responses to noningestive sources of infection. Coupled with a lack of interoception of bodily signals, aberrant disgust responses might lead to increased infection susceptibility in affected individuals

C-reactive protein does not opsonize early apoptotic human neutrophils, but binds only membrane-permeable late apoptotic cells and has no effect on their phagocytosis by macrophages

BACKGROUND: It has been reported that C-reactive protein (CRP) binds both leukocyte FcγRIIA (CD32) and the plasma membrane of apoptotic cells. Since FcγRIIA becomes functionally enabled during neutrophil apoptosis, we sought to determine whether CRP bound to apoptotic neutrophils via FcγRIIA. METHODS: We prepared directly labelled CRP and demonstrated that it was essentially free of IgG. We looked for evidence of CRP binding to intact, membrane impermeable apoptotic human neutrophils and to FcγRIIA-transfected Jurkat cells. We examined the functional consequences of incubation with CRP upon phagocytosis of apoptotic cells by human monocyte-derived macrophages. RESULTS: We could not detect binding of purified soluble CRP to classical early apoptotic human neutrophils or to FcγRIIA-transfected Jurkat cells. In contrast, membrane-permeable late apoptotic neutrophils exhibited strong CRP binding, which comprised both Ca(2+)-dependent and heparin-inhibitable Ca(2+)-independent components. However, there was no effect of CRP binding upon phagocytosis of late apoptotic neutrophils by macrophages. CONCLUSION: Potential apoptotic cell opsonins such as CRP may bind only to intracellular structures in cells with leaky membranes that have progressed to a late stage of apoptosis

Association between neighbourhood fast-food and full-service restaurant density and BMI: A cross-sectional study of Canadian adults

OBJECTIVE: Frequent fast-food consumption is a well-known risk factor for obesity. This study sought to determine whether the availability of fast-food restaurants has an influence on body mass index (BMI). METHODS: BMI and individual-level confounding variables were obtained from the 2007-08 Canadian Community Health Survey. Neighbourhood socio-demographic variables were acquired from the 2006 Canadian Census. The geographic locations of all restaurants in Canada were assembled from a validated business registry database. The density of fast-food, full-service and non-chain restaurants per 10,000 individuals was calculated for respondents’ forward sortation area. Multivariable regression analyses were conducted to analyze the association between restaurant density and BMI. RESULTS: Fast-food, full-service and non-chain restaurant density variables were statistically significantly associated with BMI. Fast-food density had a positive association whereas full-service and non-chain restaurant density had a negative association with BMI (additional 10 fast-food restaurants per capita corresponded to a weight increase of 1 kilogram; p\u3c0.001). These associations were primarily found in Canada’s major urban jurisdictions. CONCLUSIONS: This research was the first to investigate the influence of fast-food and full-service restaurant density on BMI using individual-level data from a nationally representative Canadian survey. The finding of a positive association between fast-food restaurant density and BMI suggests that interventions aiming to restrict the availability of fast-food restaurants in local neighbourhoods may be a useful obesity prevention strategy

Metal-Rich SX Phe Stars in theKeplerField

High-resolution spectroscopic observations have been made for 32 of the 34 candidate SX Phe stars identified in the Kepler field by Balona & Nemec (2012). All available long- and short-cadence Q0-Q17 Kepler photometry has been analyzed for the 34 candidates. Radial velocities (RVs), space motions (U, V, W), projected rotation veloc- ities (v sin i), spectral types, and atmospheric characteristics (Teff , log g, [M/H], vmic, etc.) were derived from ∼160 spectra taken with the ESPaDOnS spectrograph on the Canada- France-Hawaii 3.6-m telescope and with the ARCES spectrograph on the Apache Point Observatory 3.5-m telescope. Two thirds of the stars are fast rotators with v sin i > 50 km/s, including four stars with v sin i > 200 km/s. Three of the stars have (negative) RVs > 250 km/s and retrograde space motions, and seven stars have total space motions > 400 km/s. All the spectroscopically measured SX Phe candidates have positions in a Toomre diagram that are consistent with being bona fide halo and thick-disk stars. Although several stars show a marked metal weakness, the mean [Fe/H] of the sample is near 0.0 dex (σ ∼ 0.25 dex), which is considerably more metal-rich than is normally expected for a sample of Pop. II stars. Observed pulsation frequency modulations and optical time delays suggest that at least eight of the SX Phe stars are in binary systems, some of which show signif- icant RV variations. Six of the time-delay binaries have secondary masses ranging from 0.05 to 0.70 Mo and orbital periods in the range 9 to 1570 days. Another star appears to be an ellipsoidal variable with a 2.3-day orbital period; and two other systems have orbital periods longer than the ∼4-year sampling interval of the Kepler data

Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes

The realisation of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702, described previously as a potent M1 receptor allosteric agonist, which showed pro-cognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side-effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702 together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. We conclude that these properties, whilst imparting beneficial effects on learning and memory, are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data supports the notion that "pure" positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses

Cytotoxic Hydrogen Bridged Ruthenium Quinaldamide Complexes Showing Induced Cancer Cell Death by Apoptosis

This report presents the first known p-cymene ruthenium quinaldamide complexes which are stablized by a hydrogenbridging atom, [[{(p-cym)RuIIX(N,N)}{H+ }{(N,N)XRuII(p-cym)}][PF6] (N,N = functionalised quinaldamide and X = Cl or Br). These complexes are formed by a reaction of [p-cymRu(-X)2]2 with a functionalised quinaldamide ligand. When filtered over NH4PF6, and under aerobic conditions the equilibrium of NH4PF6 NH3 + HPF6 enables incorporation of HPF6 and the stabilisation of two monomeric ruthenium complexes by a bridging H+ , which are counter-balanced by a PF6 counterion. Xray crystallographic analysis is presented for six new structures with O···O distances of 2.430(3)-2.444(17) Å, which is significant for strong hydrogen bonds. Chemosensitivity studies against HCT116, A2780 and cisplatin-resistant A2780cis human cancer cells showed the ruthenium complexes with a bromide ancillary ligand to be more potent than those with a chloride ligand. The 4'-fluoro compounds show a reduction in potency for both chloride and bromide complexes against all cell lines, but an increase in selectivity towards cancer cells compared to non-cancer ARPE-19 cells, with a selectivity index > 1. Mechanistic studies showed a clear correlation between IC50 values and induction of cell death by apoptosis

ASELL : the advancing science by enhancing learning in the laboratory project

Most science educators and researchers will agree that the laboratory experience ranks as a major factor that influences students’ attitudes to their science courses. Consequently, good laboratory programs should play a major role in influencing student learning and performance. The laboratory program can be pivotal in defining a student\u27s experience in the sciences, and if done poorly, can be a major contributing factor in causing disengagement from the subject area. The challenge remains to provide students with laboratory activities that are relevant, engaging and offer effective learning opportunities