The acetylcholine binding protein as a template for the ligand binding domains of the homologous nicotinic receptors

Leurs, R. [Promotor]Smit, A.B. [Promotor]Esch, I.J.P. de [Copromotor

Dear Colleagues;

The first issue of Turkish Online Journal of English Language Teaching (TOJELT) is online now with a rich academic content. In this first issue, 4 articles and a book review have been published with the meticulous collaboration of TOJELT's team. These are; Cho and Krashen's invited article on reading skill, Takkaç Tulgar's article on the use of pragmatic competence in language classrooms, Bambirra's article on a motivational attractor basin and Pacheco Salazar's assessment of blended learning in university level students, and a book review of Shojaei and Motallebzadeh about the relationship between teaching English and the use of technology.TOJELT is a double blind peer-reviewed and triannual International journal. The main goal of the journal is to create a new platform to exchange of the information on all aspects of English language teaching. Thus, TOJELT aims to report up-to-date high-quality empirical and original research contributions in the domain of English language teaching. The scope of the journal includes, but not limited to, theory and practice in English language teaching and learning, teaching and learning English as a second/foreign language, English language teachers and learners, teaching English to young learners, applied linguistics, psycholinguistics, sociolinguistics, literature in English language teaching and so forth. TOJELT also publishes book reviews, proceedings, dissertation reports – as long as they are expanded and revised regarding the expectations of TOJELT- of potential interest to readers of the journal. TOJELT completes the review process as early as possible. Any offer on publishing special issue is also welcomed by the editorial advisory board of the journal.Lastly, we sincerely thank all board members and the referees for their efforts in the publication process of the first issue. We send our gratitude to the organizers of The Self in Language Learning Conference held in 2015 for their advertising our journal. Hope to be in collaboration forever.With regards,Editors-in-Chief of the TOJEL

Design, synthesis and biological activity of selective hCAs inhibitors based on 2-(benzylsulfinyl)benzoic acid scaffold

A large library of derivatives based on the scaffold of 2-(benzylsulfinyl)benzoic acid were synthesised and tested as atypical inhibitors against four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). The exploration of the chemical space around the main functional groups led to the discovery of selective hCA IX inhibitors in the micromolar/nanomolar range, thus establishing robust structure-activity relationships within this versatile scaffold. HPLC separation of some selected chiral compounds and biological evaluation of the corresponding enantiomers was performed along with molecular modelling studies on the most active derivatives

Alchemilla vulgaris effects on egg production and quality expressed by heatstressed quail during the late laying period

Potential for mitigating effects of heat stress through dietary Alchemilla vulgaris (AV) supplementation during the late laying period of Japanese quail (Coturnix coturnix japonica) were investigated. A 2 x 3 factorial arrangement of environmental temperature (ET) regimes and levels of dietary supplementation with AV (0%, 1%, and 3%) was used in a 75-day experiment. Twenty-five quail were randomly assigned to each treatment with five replicate cages of five birds. The birds were housed in temperature-controlled rooms at 22 ± 2 °C for 24 h/day (TN) or 34 ± 2 °C between 09h00 and 17h00 followed by 22 ± 2 °C for 16 h/day (HS). The interaction of ET and supplement regimes was rarely significant. In HS quail supplemented with 1% AV, egg production was reduced and FCR was increased compared with the other treatments. Dietary AV was found to reduce egg production in TN conditions, but 3% AV supplementation in the HS group prevented decreased egg production and improved FCR. Various indicators of egg quality were significantly affected by supplementation with AV at certain times during the experiment. Most effects of HS on egg quality were manifest in the first 15 days of ET regimes. Although HS significantly decreased eggshell weight until 31–45 days, AV supplementation improved it on the 45th day and then maintained it through the end of the experiment. Thus, AV may mitigate some effects of HS by partially preventing decreased egg production and increased FCR during the late laying period of Japanese quail.Keywords: Coturnix coturnix japonica, flavonoids, supplemen

Whole-Exome Sequencing in Familial Parkinson Disease

IMPORTANCE: Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. OBJECTIVE: To identify genetic variants contributing to disease risk in familial PD. DESIGN, SETTING, AND PARTICIPANTS: A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD. MAIN OUTCOMES AND MEASURES: Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design. RESULTS: The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing. CONCLUSIONS AND RELEVANCE: TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD

Sequencing, Analysis, and Annotation of Expressed Sequence Tags for Camelus dromedarius

Despite its economical, cultural, and biological importance, there has not been a large scale sequencing project to date for Camelus dromedarius. With the goal of sequencing complete DNA of the organism, we first established and sequenced camel EST libraries, generating 70,272 reads. Following trimming, chimera check, repeat masking, cluster and assembly, we obtained 23,602 putative gene sequences, out of which over 4,500 potentially novel or fast evolving gene sequences do not carry any homology to other available genomes. Functional annotation of sequences with similarities in nucleotide and protein databases has been obtained using Gene Ontology classification. Comparison to available full length cDNA sequences and Open Reading Frame (ORF) analysis of camel sequences that exhibit homology to known genes show more than 80% of the contigs with an ORF>300 bp and ~40% hits extending to the start codons of full length cDNAs suggesting successful characterization of camel genes. Similarity analyses are done separately for different organisms including human, mouse, bovine, and rat. Accompanying web portal, CAGBASE (http://camel.kacst.edu.sa/), hosts a relational database containing annotated EST sequences and analysis tools with possibility to add sequences from public domain. We anticipate our results to provide a home base for genomic studies of camel and other comparative studies enabling a starting point for whole genome sequencing of the organism

Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.

Smith-Magenis syndrome (SMS) is a developmental disability/multiple congenital anomaly disorder resulting from haploinsufficiency of RAI1. It is characterized by distinctive facial features, brachydactyly, sleep disturbances, and stereotypic behaviors. We investigated a cohort of 15 individuals with a clinical suspicion of SMS who showed neither deletion in the SMS critical region nor damaging variants in RAI1 using whole exome sequencing. A combination of network analysis (co-expression and biomedical text mining), transcriptomics, and circularized chromatin conformation capture (4C-seq) was applied to verify whether modified genes are part of the same disease network as known SMS-causing genes. Potentially deleterious variants were identified in nine of these individuals using whole-exome sequencing. Eight of these changes affect KMT2D, ZEB2, MAP2K2, GLDC, CASK, MECP2, KDM5C, and POGZ, known to be associated with Kabuki syndrome 1, Mowat-Wilson syndrome, cardiofaciocutaneous syndrome, glycine encephalopathy, mental retardation and microcephaly with pontine and cerebellar hypoplasia, X-linked mental retardation 13, X-linked mental retardation Claes-Jensen type, and White-Sutton syndrome, respectively. The ninth individual carries a de novo variant in JAKMIP1, a regulator of neuronal translation that was recently found deleted in a patient with autism spectrum disorder. Analyses of co-expression and biomedical text mining suggest that these pathologies and SMS are part of the same disease network. Further support for this hypothesis was obtained from transcriptome profiling that showed that the expression levels of both Zeb2 and Map2k2 are perturbed in Rai1 (-/-) mice. As an orthogonal approach to potentially contributory disease gene variants, we used chromatin conformation capture to reveal chromatin contacts between RAI1 and the loci flanking ZEB2 and GLDC, as well as between RAI1 and human orthologs of the genes that show perturbed expression in our Rai1 (-/-) mouse model. These holistic studies of RAI1 and its interactions allow insights into SMS and other disorders associated with intellectual disability and behavioral abnormalities. Our findings support a pan-genomic approach to the molecular diagnosis of a distinctive disorder