In vivo Large-Scale Cortical Mapping Using Channelrhodopsin-2 Stimulation in Transgenic Mice Reveals Asymmetric and Reciprocal Relationships between Cortical Areas

We have mapped intracortical activity in vivo independent of sensory input using arbitrary point channelrhodopsin-2 (ChR2) stimulation and regional voltage sensitive dye imaging in B6.Cg-Tg (Thy1-COP4/EYFP)18Gfng/J transgenic mice. Photostimulation of subsets of deep layer pyramidal neurons within forelimb, barrel, or visual primary sensory cortex led to downstream cortical maps that were dependent on synaptic transmission and were similar to peripheral sensory stimulation. ChR2-evoked maps confirmed homotopic connections between hemispheres and intracortical sensory and motor cortex connections. This ability of optogentically activated subpopulations of neurons to drive appropriate downstream maps suggests that mechanisms exist to allow prototypical cortical maps to self-assemble from the stimulation of neuronal subsets. Using this principle of map self-assembly, we employed ChR2 point stimulation to map connections between cortical areas that are not selectively activated by peripheral sensory stimulation or behavior. Representing the functional cortical regions as network nodes, we identified asymmetrical connection weights in individual nodes and identified the parietal association area as a network hub. Furthermore, we found that the strength of reciprocal intracortical connections between primary and secondary sensory areas are unequal, with connections from primary to secondary sensory areas being stronger than the reciprocal

Non-Gaussianities in N-flation

We compute non-Gaussianities in N-flation, a string motivated model of assisted inflation with quadratic, separable potentials and masses given by the Marcenko-Pastur distribution. After estimating parameters characterizing the bi- and trispectrum in the horizon crossing approximation, we focus on the non-linearity parameter $f_{NL}$, a measure of the bispectrum; we compute its magnitude for narrow and broad spreads of masses, including the evolution of modes after horizon crossing. We identify additional contributions due to said evolution and show that they are suppressed as long as the fields are evolving slowly. This renders $\mathcal{N}$-flation indistinguishable from simple single-field models in this regime. Larger non-Gaussianities are expected to arise for fields that start to evolve faster, and we suggest an analytic technique to estimate their contribution. However, such fast roll during inflation is not expected in N-flation, leaving (p)re-heating as the main additional candidate for generating non-Gaussianities.Comment: 27 pages, 4 figures, extended references to match version accepted in JCA

In vivo activity of plant-based interleukin-12 in the lung of Balb/c mouse

<p>Abstract</p> <p>Background</p> <p>In the last years, plants are being used for the production of a wide variety of biopharmaceuticals, including cytokines, and have the potential to serve as vehicles for mucosal administration of these molecules. We had previously reported the expression of a cytokine, interleukin-12 (IL-12), in transgenic tomato plants and had demonstrated that it retained its biologic activity <it>in vitro</it>.</p> <p>Findings</p> <p>In this work, we administered crude extracts of IL-12-containing tomato fruits to mice through the intratracheal route, measuring endogenous IL-12 and determining biologic activity by quantification of interferon-gamma (IFN-γ) in lungs and by histological analysis. IFN-γ expression in lungs, as well as histological analysis, indicate that tomato-expressed IL-12 retains its biologic activity and, most importantly, its effects are restricted to the site of administration.</p> <p>Conclusion</p> <p>Our results indicate that the functional activity of tomato-expressed IL-12 is comparable to that of commercial recombinant IL-12 when given via the mucosal route. This opens the possibility of using crude extracts prepared from tomatoes expressing IL-12 for certain immunotherapies.</p

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Electromagnetic Wave Theory and Applications

Contains table of contents for Section 3, reports on six research projects and a list of publications and conference papers.Joint Services Electronics Program Contract DAAL03-89-C-0001National Science Foundation Grant ECS 86-20029Schlumberger- Doll ResearchU.S. Army Research Office Contract DAAL03 88-K-0057U.S. Navy - Office of Naval Research Contract N00014-90-J-1002National Aeronautics and Space Administration Grant NAGW-1617U.S. Navy - Office of Naval Research Grant N00014-89-J-1107National Aeronautics and Space Administration Grant NAGW-1272National Aeronautics and Space Administration Agreement 958461U.S. Army - Corps of Engineers Contract DACA39-87-K-0022U.S. Air Force - Electronic Systems Division Contract F19628-88-K-0013U.S. Navy - Office of Naval Research Grant N00014-89-J-1019Digital Equipment CorporationIBM CorporationU.S. Department of Transportation Contract DTRS-57-88-C-00078Defence Advanced Research Projects Agency Contract MDA972-90-C-002

Catheter ablation for AF improves global thrombotic profile and enhances fibrinolysis

© The Author(s) 2017. This article is an open access publication. The final authenticated version is available online at: https://doi.org/10.1007/s11239-017-1548-3Patients with atrial fibrillation (AF) are at increased risk of thrombotic events despite oral anticoagulation (OAC). Radiofrequency catheter ablation (RFCA) can restore and maintain sinus rhythm (SR) in patients with AF. To assess whether RFCA improves thrombotic status. 80 patients (71% male, 64 ± 12y) with recently diagnosed AF, on OAC and scheduled to undergo RFCA or DC cardioversion (DCCV) were recruited. Thrombotic status was assessed using the point-of-care global thrombosis test (GTT), before, and 4-6 weeks after DCCV and 3 months after RFCA. The GTT first measures the time taken for occlusive thrombus formation (occlusion time, OT), while the second phase of the test measures the time taken to spontaneously dissolve this clot through endogenous thrombolysis (lysis time, LT). 3 months after RFCA, there was a significant reduction in LT (1994s [1560; 2475] vs. 1477s [1015; 1878]) in those who maintained SR, but not in those who reverted to AF. At follow-up, LT was longer in those in AF compared to those in SR (AF 2966s [2038; 3879] vs. SR 1477s [1015; 1878]). RFCA resulted in no change in OT value, irrespective of rhythm outcome. Similarly, there was no change in OT or LT in response to DCCV, irrespective of whether SR was restored. Successful restoration and maintenance of SR following RFCA of AF is associated with improved global thrombotic status with enhanced fibrinolysis. Larger studies are required to confirm these early results and investigate whether improved thrombotic status translates into fewer thromboembolic events.Peer reviewedFinal Published versio

Developmental Expression of Kv Potassium Channels at the Axon Initial Segment of Cultured Hippocampal Neurons

Axonal outgrowth and the formation of the axon initial segment (AIS) are early events in the acquisition of neuronal polarity. The AIS is characterized by a high concentration of voltage-dependent sodium and potassium channels. However, the specific ion channel subunits present and their precise localization in this axonal subdomain vary both during development and among the types of neurons, probably determining their firing characteristics in response to stimulation. Here, we characterize the developmental expression of different subfamilies of voltage-gated potassium channels in the AISs of cultured mouse hippocampal neurons, including subunits Kv1.2, Kv2.2 and Kv7.2. In contrast to the early appearance of voltage-gated sodium channels and the Kv7.2 subunit at the AIS, Kv1.2 and Kv2.2 subunits were tethered at the AIS only after 10 days in vitro. Interestingly, we observed different patterns of Kv1.2 and Kv2.2 subunit expression, with each confined to distinct neuronal populations. The accumulation of Kv1.2 and Kv2.2 subunits at the AIS was dependent on ankyrin G tethering, it was not affected by disruption of the actin cytoskeleton and it was resistant to detergent extraction, as described previously for other AIS proteins. This distribution of potassium channels in the AIS further emphasizes the heterogeneity of this structure in different neuronal populations, as proposed previously, and suggests corresponding differences in action potential regulation

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes

Social factors influencing Russian male alcohol use over the life course: a qualitative study investigating age based social norms, masculinity, and workplace context

The massive fluctuations occurring in Russian alcohol-related mortality since the mid-1980s cannot be seen outside of the context of great social and economic change. There is a dearth of qualitative studies about Russian male drinking and especially needed are those that address social processes and individual changes in drinking. Conducted as part of a longitudinal study on men’s alcohol consumption in Izhevsk, this qualitative study uses 25 semi-structured biographical interviews with men aged 33–60 years to explore life course variation in drinking. The dominant pattern was decreasing binge and frequent drinking as men reached middle age which was precipitated by family building, reductions in drinking with work colleagues, and health concerns. A minority of men described chaotic drinking histories with periods of abstinence and heavy drinking. The results highlight the importance of the blue-collar work environment for conditioning male heavy drinking in young adulthood through a variety of social, normative and structural mechanisms. Post-Soviet changes had a structural influence on the propensity for workplace drinking but the important social function of male drinking sessions remained. Bonding with workmates through heavy drinking was seen as an unavoidable and essential part of young men’s social life. With age peer pressure to drink decreased and the need to perform the role of responsible breadwinner put different behavioural demands on men. For some resisting social pressure to drink became an important site of self-determination and a mark of masculine maturity. Over the lifetime the place where masculine identity was asserted shifted from the workplace to the home, which commonly resulted in a reduction in drinking. We contribute to existing theories of Russian male drinking by showing that the performance of age-related social roles influences Russian men’s drinking patterns, drinking contexts and their attitudes. Further research should be conducted investigating drinking trajectories in Russian men