A complex microcephaly syndrome in a Pakistani family associated with a novel missense mutation in RBBP8 and a heterozygous deletion in NRXN1

We report on a consanguineous Pakistani family with a severe congenital microcephaly syndrome resembling the Seckel syndrome and Jawad syndrome. The affected individuals in this family were born to consanguineous parents of whom the mother presented with mild intellectual disability (ID), epilepsy and diabetes mellitus. The two living affected brothers presented with microcephaly, white matter disease of the brain, hyponychia, dysmorphic facial features with synophrys, epilepsy, diabetes mellitus and ID. Genotyping with a 250K SNP array in both affected brothers revealed an 18 MB homozygous region on chromosome 18p11.21-q12.1 encompassing the SCKL2 locus of the Seckel and Jawad syndromes. Sequencing of the RBBP8 gene, underlying the Seckel and Jawad syndromes, identified the novel mutation c.919A > G, p.Arg307Gly, segregating in a recessive manner in the family. In addition, in the two affected brothers and their mother we have also found a heterozygous 607 kb deletion, encompassing exons 13–19 of NRXN1. Bidirectional sequencing of the coding exons of NRXN1 did not reveal any other mutation on the other allele. It thus appears that the phenotype of the mildly affected mother can be explained by the NRXN1 deletion, whereas the more severe and complex microcephalic phenotype of the two affected brothers is due to the simultaneous deletion in NRXN1 and the homozygous missense mutation affecting RBBP8.     

Detection of phytochrome-like genes from Rhazya stricta (Apocynaceae) using de novo genome assembly

Phytochrome-like genes in the wild plant species Rhazya stricta Decne were characterized using a de novo genome assembly of next generation sequence data. Rhazya stricta contains more than 100 alkaloids with multiple pharmacological properties, and leaf extracts have been used to cure chronic rheumatism, to treat tumors, and in the treatment of several other diseases. Phytochromes are known to be involved in the light-regulated biosynthesis of some alkaloids. Phytochromes are soluble chromoproteins that function in the absorption of red and far-red light and the transduction of intracellular signals during light-regulated plant development. De novo assembly of the nuclear genome of R. stricta recovered 45,641 contigs greater than 1000 bp long, which were used in constructing a local database. Five sequences belonging to Arabidopsis thaliana phytochrome gene family (i.e., AtphyABCDE) were used to identify R. stricta contigs with phytochrome-like sequences using BLAST. This led to the identification of three contigs with phytochrome-like sequences covering AtphyA-, AtphyC- and AtphyE-like full-length genes. Annotation of the three sequences showed that each contig consists of one phytochrome-like gene with three exons and two introns. BLASTn and BLASTp results indicated that RsphyA mRNA and protein sequences had homologues in Wrightia coccinea and and Solanum tuberosum, respectively. RsphyC-like mRNA and protein sequence were homologous to Vitis vinifera and Vitis riparia. RsphyE-like mRNA coding and protein sequences were homologous to Ipomoea nil. Multiple-sequence alignment of phytochrome proteins indicated a homology with 30 sequences from 23 different species of flowering plants. Phylogenetic analysis confirmed that each R. stricta phytochrome gene is related to the same phytochrome gene of other flowering plants. It is proposed that the absence of phyB gene in R. stricta is due to RsphyA gene taking over the role of phyB.     

Withanolide biosynthesis recruits both mevalonate and DOXP pathways of isoprenogenesis in Ashwagandha Withania somnifera L. (Dunal)

Withanolides are pharmaceutically important C(28)-phytochemicals produced in most prodigal amounts and diversified forms by Withania somnifera. Metabolic origin of withanolides from triterpenoid pathway intermediates implies that isoprenogenesis could significantly govern withanolide production. In plants, isoprenogenesis occurs via two routes: mevalonate (MVA) pathway in cytosol and non-mevalonate or DOXP/MEP pathway in plastids. We have investigated relative carbon contribution of MVA and DOXP pathways to withanolide biosynthesis in W. somnifera. The quantitative NMR-based biosynthetic study involved tracing of (13)C label from (13)C(1)-D-glucose to withaferin A in withanolide producing in vitro microshoot cultures of the plant. Enrichment of (13)C abundance at each carbon of withaferin A from (13)C(1)-glucose-fed cultures was monitored by normalization and integration of NMR signal intensities. The pattern of carbon position-specific (13)C enrichment of withaferin A was analyzed by a retro-biosynthetic approach using a squalene-intermediated metabolic model of withanolide (withaferin A) biosynthesis. The pattern suggested that both DOXP and MVA pathways of isoprenogenesis were significantly involved in withanolide biosynthesis with their relative contribution on the ratio of 25:75, respectively. The results have been discussed in a new conceptual line of biosynthetic load-driven model of relative recruitment of DOXP and MVA pathways for biosynthesis of isoprenoids. Key message The study elucidates significant contribution of DOXP pathway to withanolide biosynthesis. A new connotation of biosynthetic load-based role of DOXP/MVA recruitment in isoprenoid biosynthesis has been proposed.     

Xenia and metaxenia in grapes: differences in berry and seed characteristics of maternal grape cv. ‘Narince’ (Vitis vinifera L.) as influenced by different pollen sources

Literature investigations indicate that the grapes have quite complex fertilisation biology. This complexity necessitates extensive investigations to obtain reliable knowledge for both well‐organised hybridisation studies and maximising grape yield. Therefore, this study was conducted to investigate the influences of self‐, free‐ and cross‐pollination on berry and seed characteristics in grape. Five different pollination treatments were applied to ‘Narince’, the most widely known and popular white wine grape in Turkey. Pollen tests indicated that all the cultivars had satisfactory in vitro pollen viability percentages. Free‐pollination produced a significantly higher percentage berry set. Among the pollinizers, the use of pollen of ‘Thompson Seedless’ and ‘Cardinal’ varieties resulted in higher berry set percentage in ‘Narince’. The free‐pollination was also superior in giving the highest weight, length and width of the berry, as well as number of seeds per berry. These findings revealed that there were strong xenial and metaxenial effects in the studied grape cultivars. Among the pollinizer cultivars, the most effective pollinator was ‘Thompson Seedless’. Hence, for better berry set and quality, the use of ‘Thompson Seedless’ as a pollinizer may be an attractive option in both grape production and breeding studies.     

Hydromagnetic Steady Flow of Maxwell Fluid over a Bidirectional Stretching Surface with Prescribed Surface Temperature and Prescribed Surface Heat Flux

This paper investigates the steady hydromagnetic three-dimensional boundary layer flow of Maxwell fluid over a bidirectional stretching surface. Both cases of prescribed surface temperature (PST) and prescribed surface heat flux (PHF) are considered. Computations are made for the velocities and temperatures. Results are plotted and analyzed for PST and PHF cases. Convergence analysis is presented for the velocities and temperatures. Comparison of PST and PHF cases is given and examined.     

The role of endogenous bromotyrosine in health and disease

Abstract

Bromotyrosine is a stable by-product of eosinophil peroxidase activity, a result of eosinophil activation during an inflammatory immune response. The elevated presence of bromotyrosine in tissue, blood, and urine in medical conditions involving eosinophil activation has highlighted the potential role of bromotyrosine as a medical biomarker. This is highly beneficial in a paediatric setting as a urinary noninvasive biomarker. However, bromotyrosine and its derivatives may exert biological effects, such as protective effects in the brain and pathogenic effects in the thyroid. Understanding these pathways may yield therapeutic advancements in medicine. In this review, we summarize the existing evidence present in literature relating to bromotyrosine formation and metabolism, identify the biological actions of bromotyrosine and evaluate the feasibility of bromotyrosine as a medical biomarker.     

Malat-1-PRC2-EZH1 interaction supports adaptive oxidative stress dependent epigenome remodeling in skeletal myotubes

PRC2-mediated epigenetic function involves the interaction with long non-coding RNAs (lncRNAs). Although the identity of some of these RNAs has been elucidated in the context of developmental programs, their counterparts in postmitotic adult tissue homeostasis remain uncharacterized. To this aim, we used terminally differentiated postmitotic skeletal muscle cells in which oxidative stress induces the dynamic activation of PRC2-Ezh1 through Embryonic Ectoderm Develpment (EED) shuttling to the nucleus. We identify lncRNA Malat-1 as a necessary partner for PRC2-Ezh1-dependent response to oxidative stress. We show that in this pathway, PRC2-EZH1 dynamic assembly, and in turn stress induced skeletal muscle targeted genes repression, depends specifically on Malat-1. Our study reports about PRC2–RNA interactions in the physiological context of adaptive oxidative stress response and identifies the first lncRNA involved in PRC2-Ezh1 function.Subject terms: Gene silencing, Long non-coding RNAs     

A database for anti-diabetic plants with clinical / experimental trials

A number of plants have been described in Ayurveda and other traditional medicine for the management of diabetes. However, information about them is not easily available. Active constituents of any medicinal plant define the efficacy and safety of treatment to control hyperglycemia. We describe the database to maintain the record of medicinal plants having anti-hyperglycemic or anti-diabetic activity. The database contains information such as plant name, its geographical distribution, useful plant part, known dosage, active constituents, mechanism of action and clinical/experimental data. The database also includes information about plant raw material suppliers or manufacturers in India. The current database includes 238 plants species and 123 Indian industries using them. AVAILABILITY: The database is freely available at http://www.biotechpark.org.in/antidia/index.html.     

Histo-Blood Group Gene Polymorphisms as Potential Genetic Modifiers of Infection and Cystic Fibrosis Lung Disease Severity

Background

The pulmonary phenotype in cystic fibrosis (CF) is variable; thus, environmental and genetic factors likely contribute to clinical heterogeneity. We hypothesized that genetically determined ABO histo-blood group antigen (ABH) differences in glycosylation may lead to differences in microbial binding by airway mucus, and thus predispose to early lung infection and more severe lung disease in a subset of patients with CF.

Methods and Principal Findings

Clinical information and DNA was collected on >800 patients with the ΔF508/ΔF508 genotype. Patients in the most severe and mildest quartiles for lung phenotype were enrolled. Blood samples underwent lymphocyte transformation and DNA extraction using standard methods. PCR and sequencing were performed using standard techniques to identify the 9 SNPs required to determine ABO blood type, and to identify the four SNPs that account for 90–95% of Lewis status in Caucasians. Allele identification of the one nonsynonymous SNP in FUT2 that accounts for >95% of the incidence of nonsecretor phenotype in Caucasians was completed using an ABI Taqman assay. The overall prevalence of ABO types, and of FUT2 (secretor) and FUT 3 (Lewis) alleles was consistent with that found in the Caucasian population. There was no difference in distribution of ABH type in the severe versus mild patients, or the age of onset of Pseudomonas aeruginosa infection in the severe or mild groups. Multivariate analyses of other clinical phenotypes, including gender, asthma, and meconium ileus demonstrated no differences between groups based on ABH type.

Conclusions and Significance

Polymorphisms in the genes encoding ABO blood type, secretor or Lewis genotypes were not shown to associate with severity of CF lung disease, or age of onset of P. aeruginosa infection, nor was there any association with other clinical phenotypes in a group of 808 patients homozygous for the ΔF508 mutation.