Association of neurexin 3 polymorphisms with smoking behavior.

The Neurexin 3 gene (NRXN3) has been associated with dependence on various addictive substances, as well as with the degree of smoking in schizophrenic patients and impulsivity among tobacco abusers. To further evaluate the role of NRXN3 in nicotine addiction, we analyzed single nucleotide polymorphisms (SNPs) and a copy number variant (CNV) within the NRXN3 genomic region. An initial study was carried out on 157 smokers and 595 controls, all of Spanish Caucasian origin. Nicotine dependence was assessed using the Fagerstrom index and the number of cigarettes smoked per day. The 45 NRXN3 SNPs genotyped included all the SNPs previously associated with disease, and a previously described deletion within NRXN3. This analysis was replicated in 276 additional independent smokers and 568 controls. Case-control association analyses were performed at the allele, genotype and haplotype levels. Allelic and genotypic association tests showed that three NRXN3 SNPs were associated with a lower risk of being a smoker. The haplotype analysis showed that one block of 16 Kb, consisting of two of the significant SNPs (rs221473 and rs221497), was also associated with lower risk of being a smoker in both the discovery and the replication cohorts, reaching a higher level of significance when the whole sample was considered [odds ratio = 0.57 (0.42-0.77), permuted P = 0.0075]. By contrast, the NRXN3 CNV was not associated with smoking behavior. Taken together, our results confirm a role for NRXN3 in susceptibility to smoking behavior, and strongly implicate this gene in genetic vulnerability to addictive behaviors

Understanding charge transport in lead iodide perovskite thin-film field-effect transistors

Fundamental understanding of the charge transport physics of hybrid lead halide perovskite semiconductors is important for advancing their use in high-performance optoelectronics. We use field-effect transistors (FETs) to probe the charge transport mechanism in thin films of methylammonium lead iodide (MAPbI$_{3}$). We show that through optimization of thin-film microstructure and source-drain contact modifications, it is possible to significantly minimize instability and hysteresis in FET characteristics and demonstrate an electron field-effect mobility (μ$_{FET}$) of 0.5 cm$^{2}$/Vs at room temperature. Temperature-dependent transport studies revealed a negative coefficient of mobility with three different temperature regimes. On the basis of electrical and spectroscopic studies, we attribute the three different regimes to transport limited by ion migration due to point defects associated with grain boundaries, polarization disorder of the MA$^{+}$ cations, and thermal vibrations of the lead halide inorganic cages.S.P.S. acknowledges funding from the Royal Society London for a Newton Fellowship. B.Y. acknowledges support from China Council Scholarship and Cambridge Overseas Trust. A.S. and R.H.F. acknowledge funding and support from the Engineering and Physical Sciences Research Council (EPSRC) through the India-U.K. APEX project. P.D. acknowledges support from the European Union through the award of a Marie Curie Intra-European Fellowship. X.M. is grateful for the support from the Royal Society. B.N. is grateful for the support from Gates Cambridge and the Winton Program for the Physics of Sustainability. We acknowledge funding from the EPSRC through a program grant (EP/M005143/1). We acknowledge funding from the German Federal Ministry of Education and Research under agreement number 01162525/1. This work was performed in part on the SAXS/WAXS beamline of the Australian Synchrotron, Victoria, Australia (55, 56). C.R.M. acknowledges support from the Australian Research Council (DP13012616)

Contribution of microscopy for understanding the mechanism of action against trypanosomatids

Transmission electron microscopy (TEM) has proved to be a useful tool to study the ultrastructural alterations and the target organelles of new antitrypanosomatid drugs. Thus, it has been observed that sesquiterpene lactones induce diverse ultrastructural alterations in both T. cruzi and Leishmania spp., such as cytoplasmic vacuolization, appearance of multilamellar structures, condensation of nuclear DNA, and, in some cases, an important accumulation of lipid vacuoles. This accumulation could be related to apoptotic events. Some of the sesquiterpene lactones (e.g., psilostachyin) have also been demonstrated to cause an intense mitochondrial swelling accompanied by a visible kinetoplast deformation as well as the appearance of multivesicular bodies. This mitochondrial swelling could be related to the generation of oxidative stress and associated to alterations in the ergosterol metabolism. The appearance of multilamellar structures and multiple kinetoplasts and flagella induced by the sesquiterpene lactone psilostachyin C indicates that this compound would act at the parasite cell cycle level, in an intermediate stage between kinetoplast segregation and nuclear division. In turn, the diterpene lactone icetexane has proved to induce the external membrane budding on T. cruzi together with an apparent disorganization of the pericellar cytoskeleton. Thus, ultrastructural TEM studies allow elucidating the possible mechanisms and the subsequent identification of molecular targets for the action of natural compounds on trypanosomatids.Fil: Lozano, Esteban Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Spina Zapata, Renata María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Barrera, Patricia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Tonn, Carlos Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; ArgentinaFil: Sosa Escudero, Miguel Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

Preparation of Single-Phase Films of CH3NH3Pb(I1-xBrx)3 with Sharp Optical Band Edges.

Organometallic lead-halide perovskite-based solar cells now approach 18% efficiency. Introducing a mixture of bromide and iodide in the halide composition allows tuning of the optical bandgap. We prepare mixed bromide-iodide lead perovskite films CH3NH3Pb(I1-xBrx)3 (0 ≤ x ≤ 1) by spin-coating from solution and obtain films with monotonically varying bandgaps across the full composition range. Photothermal deflection spectroscopy, photoluminescence, and X-ray diffraction show that following suitable fabrication protocols these mixed lead-halide perovskite films form a single phase. The optical absorption edge of the pure triiodide and tribromide perovskites is sharp with Urbach energies of 15 and 23 meV, respectively, and reaches a maximum of 90 meV for CH3NH3PbI1.2Br1.8. We demonstrate a bromide-iodide lead perovskite film (CH3NH3PbI1.2Br1.8) with an optical bandgap of 1.94 eV, which is optimal for tandem cells of these materials with crystalline silicon devices.We acknowledge funding from the Engineering and Physical Sciences Research Council (EPSRC) and the Winton Programme (Cambridge) for the Physics of Sustainability. THT acknowledges funding from Cambridge Australia Scholarships and the Cambridge Commonwealth Trust. D.C. acknowledges support from St. John's College Cambridge and the Winton Programme (Cambridge) for the Physics of Sustainability.This is the final published version. It's also available at: http://pubs.acs.org/doi/abs/10.1021/jz501332v

Blue-Green Color Tunable Solution Processable Organolead Chloride-Bromide Mixed Halide Perovskites for Optoelectronic Applications.

Solution-processed organo-lead halide perovskites are produced with sharp, color-pure electroluminescence that can be tuned from blue to green region of visible spectrum (425-570 nm). This was accomplished by controlling the halide composition of CH3NH3Pb(BrxCl1-x)3 [0 ≤ x ≤ 1] perovskites. The bandgap and lattice parameters change monotonically with composition. The films possess remarkably sharp band edges and a clean bandgap, with a single optically active phase. These chloride-bromide perovskites can potentially be used in optoelectronic devices like solar cells and light emitting diodes (LEDs). Here we demonstrate high color-purity, tunable LEDs with narrow emission full width at half maxima (FWHM) and low turn on voltages using thin-films of these perovskite materials, including a blue CH3NH3PbCl3 perovskite LED with a narrow emission FWHM of 5 nm.We acknowledge funding from the Engineering and Physical Sciences Research Council (EPSRC) and the Winton Programme (Cambridge) for the Physics of Sustainability. Support from the Deutsche Forschungsgemeinschaft (NIM Excellence Cluster) is gratefully acknowledged. A.S. acknowledges the funding and support from the Indo-UK APEX project. F.D. acknowledges funding and support from a Herchel Smith fellowship. M.D.V. acknowledges funding and support from the ERC-StG 337739-HIENA. A.S. thanks Dr. D. Di for the insightful discussions. P. D. gratefully acknowledges support from the European Union in the form of a Marie Curie Intra-European fellowship.This is the final version of the article. It first appeared from the American Chemical Society via http://dx.doi.org/10.1021/acs.nanolett.5b0236

Using detergent to enhance detection sensitivity of African trypanosomes in human CSF and blood by Loop-Mediated Isothermal Amplification (LAMP)

<p><b>Background:</b> The loop-mediated isothermal amplification (LAMP) assay, with its advantages of simplicity, rapidity and cost effectiveness, has evolved as one of the most sensitive and specific methods for the detection of a broad range of pathogenic microorganisms including African trypanosomes. While many LAMP-based assays are sufficiently sensitive to detect DNA well below the amount present in a single parasite, the detection limit of the assay is restricted by the number of parasites present in the volume of sample assayed; i.e. 1 per µL or 103 per mL. We hypothesized that clinical sensitivities that mimic analytical limits based on parasite DNA could be approached or even obtained by simply adding detergent to the samples prior to LAMP assay.</p> <p><b>Methodology/Principal Findings:</b> For proof of principle we used two different LAMP assays capable of detecting 0.1 fg genomic DNA (0.001 parasite). The assay was tested on dilution series of intact bloodstream form Trypanosoma brucei rhodesiense in human cerebrospinal fluid (CSF) or blood with or without the addition of the detergent Triton X-100 and 60 min incubation at ambient temperature. With human CSF and in the absence of detergent, the LAMP detection limit for live intact parasites using 1 µL of CSF as the source of template was at best 103 parasites/mL. Remarkably, detergent enhanced LAMP assay reaches sensitivity about 100 to 1000-fold lower; i.e. 10 to 1 parasite/mL. Similar detergent-mediated increases in LAMP assay analytical sensitivity were also found using DNA extracted from filter paper cards containing blood pretreated with detergent before card spotting or blood samples spotted on detergent pretreated cards.</p> <p><b>Conclusions/Significance:</b> This simple procedure for the enhanced detection of live African trypanosomes in biological fluids by LAMP paves the way for the adaptation of LAMP for the economical and sensitive diagnosis of other protozoan parasites and microorganisms that cause diseases that plague the developing world.</p&gt

Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA. METHODS: We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes. RESULTS: The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes. CONCLUSIONS: The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways

Current and Future Prospects of Nitro-compounds as Drugs for Trypanosomiasis and Leishmaniasis

Interest in nitroheterocyclic drugs for the treatment of infectious diseases has undergone a resurgence in recent years. Here we review the current status of monocyclic and bicyclic nitroheterocyclic compounds as existing or potential new treatments for visceral leishmaniasis, Chagas' disease and human African trypanosomiasis. Both monocyclic (nifurtimox, benznidazole and fexinidazole) and bicyclic (pretomanid (PA-824) and delamanid (OPC-67683)) nitro-compounds are prodrugs, requiring enzymatic activation to exert their parasite toxicity. Current understanding of the nitroreductases involved in activation and possible mechanisms by which parasites develop resistance is discussed along with a description of the pharmacokinetic / pharmacodynamic behaviour and chemical structure-activity relationships of drugs and experimental compounds.</p