Unbalanced segregation of a paternal t(9;11)(p24.3;p15.4) translocation causing familial Beckwith-Wiedemann syndrome: a case report.

BACKGROUND: The vast majority of cases with Beckwith-Wiedemann syndrome (BWS) are caused by a molecular defect in the imprinted chromosome region 11p15.5. The underlying mechanisms include epimutations, uniparental disomy, copy number variations, and structural rearrangements. In addition, maternal loss-of-function mutations in CDKN1C are found. Despite growing knowledge on BWS pathogenesis, up to 20% of patients with BWS phenotype remain without molecular diagnosis. CASE PRESENTATION: Herein, we report an Iranian family with two females affected with BWS in different generations. Bisulfite pyrosequencing revealed hypermethylation of the H19/IGF2: intergenic differentially methylated region (IG DMR), also known as imprinting center 1 (IC1) and hypomethylation of the KCNQ1OT1: transcriptional start site (TSS) DMR (IC2). Array CGH demonstrated an 8 Mb duplication on chromosome 11p15.5p15.4 (205,827-8,150,933) and a 1 Mb deletion on chromosome 9p24.3 (209,020-1,288,114). Chromosome painting revealed that this duplication-deficiency in both patients is due to unbalanced segregation of a paternal reciprocal t(9;11)(p24.3;p15.4) translocation. CONCLUSIONS: This is the first report of a paternally inherited unbalanced translocation between the chromosome 9 and 11 short arms underlying familial BWS. Copy number variations involving the 11p15.5 region are detected by the consensus diagnostic algorithm. However, in complex cases which do not only affect the BWS region itself, characterization of submicroscopic chromosome rearrangements can assist to estimate the recurrence risk and possible phenotypic outcomes

Analysis of design parameters in SIL-4 safety-critical computer

Nowadays, Safety-critical computers are extensively used in may civil domains like transportation including railways, avionics and automotive. We noticed that in design of some previous works, some critical safety design parameters like failure diagnostic coverage (DC) or common cause failure (CCF) ratio have not been seriously taken into account. Moreover, in some cases safety has not been compared with standard safety levels (IEC-61508 SIL1-SIL4) or even have not met them. Most often, it is not very clear that which part of the system is the Achilles' heel and how design can be improved to reach standard safety levels. Motivated by such design ambiguities, we aim to study the effect of various design parameters on safety in some prevalent safety configurations: 1oo2 and 2oo3. 1oo1 is also used as a reference. By employing Markov modeling, sensitivity of safety to each of the following critical design parameters is analyzed: failure rate of processing element, failure diagnostics coverage, common cause failures and repair rates. This study gives a deeper sense regarding influence of variation in design parameters over safety. Consequently, to meet appropriate safety integrity level, instead of improving some system parts blindly, it will be possible to make an informed decision on more relevant parameters. © 2017 IEEE

IDENTIFICATION OF RIEMANNIAN FOLIATIONS ON THE TANGENT BUNDLE VIA SODE STRUCTURE

Abstract. The geometry of a system of second order differential equations is the geometry of a semispray, which is a globally defined vector field on T M . The metric compatibility of a given semispray is of special importance. In this paper, the metric associated with the semispray S is applied in order to study some types of foliations on the tangent bundle which are compatible with SODE structure. Indeed, sufficient conditions for the metric associated with the semispray S are obtained to extend to a bundle-like metric for the lifted foliation on T M . Thus, the lifted foliation converts to a Riemanian foliation on the tangent space which is adapted to the SODE structure. Particularly, the metric compatibility property of the semispray S is applied in order to induce SODE structure on transversals. Finally, some equivalent conditions are presented for the transversals to be totally geodesic

Design, modeling, expression, and chemoselective PEGylation of a new nanosize cysteine analog of erythropoietin

Reza Ahangari Cohan1, Armin Madadkar-Sobhani2,3, Hossein Khanahmad1, Farzin Roohvand4, Mohammad Reza Aghasadeghi4, Mohammad Hossein Hedayati5, Zahra Barghi5, Mehdi Shafiee Ardestani4, Davoud Nouri Inanlou1, Dariush Norouzian11Research and Development Department, Production and Research Complex, Pasteur Institute of Iran, Tehran, Iran; 2Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; 3Department of Life Sciences, Barcelona Supercomputing Center, Barcelona, Spain; 4Hepatitis and AIDS Department, Pasteur Institute of Iran, Tehran, Iran; 5Quality Control Department, Production and Research Complex, Pasteur Institute of Iran, Tehran, IranBackground: Recombinant human erythropoietin (rhEPO) is considered to be one of the most pivotal pharmaceutical drugs in the market because of its clinical application in the treatment of anemia-associated disorders worldwide. However, like other therapeutic proteins, it does not have suitable pharmacokinetic properties for it to be administrated at least two to three times per week. Chemoselective cysteine PEGylation, employing molecular dynamics and graphics in in silico studies, can be considered to overcome such a problem.Methods: A special kind of EPO analog was elicited based on a literature review, homology modeling, molecular dynamic simulation, and factors affecting the PEGylation reaction. Then, cDNA of the selected analog was generated by site-directed mutagenesis and subsequently cloned into the expression vector. The construct was transfected to Chinese hamster ovary/dhfr- cells, and highly expressed clones were selected via methotrexate amplification. Ion-immobilized affinity and size exclusion (SE) chromatography techniques were used to purify the expressed analog. Thereafter, chemoselective PEGylation was performed and a nanosize PEGylated EPO was obtained through dialysis. The in vitro biologic assay and in vivo pharmacokinetic parameters were studied. Finally, E31C analog Fourier transform infrared, analytical SE-high-performance liquid chromatography, zeta potential, and size before and after PEGylation were characterized.Results: The findings indicate that a novel nanosize EPO31-PEG has a five-fold longer terminal half-life in rats with similar biologic activity compared with unmodified rhEPO in proliferation cell assay. The results also show that EPO31-PEG size and charge versus unmodified protein was increased in a nanospectrum, and this may be one criterion of EPO biologic potency enhancement.Discussion: This kind of novel engineered nanosize PEGylated EPO has remarkable advantages over rhEPO.Keywords: nanoPEGylated EPO, cysteine PEGylation, pharmacokinetic propert

Effects of Long-term Induced Hyperthyroidism on Egg Quality Traits in Cobb 500 Broiler Breeder Hens

Published data on 4-week-long administration of exogenous thyroxine in broiler breeder hens to decline the cold-induced ascites in their progeny suggest that the long-term maternal hyperthyroidism would affect egg quality characteristics traits in Cobb 500 broiler breeder hens. Seventy 47-w-old broiler breeder Cobb 500 hens (5 replicates and 7 hens each) were assigned in separate cages and allotted to two treatments, control and hyperthyroid. Thyroxine was orally administered to the hyperthyroid group (0.3 mg hen/day) for a period of 100 days consecutively. Simultaneously, distilled water was orally administered to the control group. The blood sampling was done every two weeks to analyze T3, T4, and estrogen assays, using commercially kits and the egg quality attributes were evaluated for weeks 0, 3, 6, 9, and 12. Thyroxine treatment resulted in an increase in plasma concentration of T4; however, the T3 level and estrogen were not affected. The results of this study showed that the long-term administration of thyroxine had adverse effect on the most of egg quality traits in broiler breeder hens; although the results may be distinct for treatments that using other birds, doses and duration of treatments, among the different egg quality traits of broiler breeder hens evaluated in this research. Therefore, further studies should be done to make a final conclusion to use of long-term maternal hyperthyroidism treatment to reduce the ascites incidence

Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B) caused by Pathogenic Splice and Missense Variants of DYSF Gene among Iranians with Muscular Dystrophy.

BACKGROUND: The phenotypic range of limb-girdle muscular dystrophies (LGMDs) varies significantly because of genetic heterogeneity ranging from very mild to severe forms. Molecular analysis of the DYSF gene is challenging due to the wide range of mutations and associated complications in interpretations of novel DYSF variants with uncertain significance. Thus, in the current study, we performed the NGS analysis and its results are confirmed with Sanger sequencing to find the plausible disease-causing variants in patients with muscular dystrophy and their relatives via segregation analysis. MATERIALS AND METHODS: Nine patients with LGMD type 2B (LGMD2B) characteristics were screened for putative mutations by the whole-exome sequencing (WES) test. Either the patients themselves or their parents and first relatives were investigated in the segregation analysis through Sanger sequencing. The majority of variants were classified as pathogenic through American College of Medical Genetics and Genomics (ACMG) guidelines, segregation results, and in silico predictions. RESULTS: Results revealed eight variants in DYSF gene, including three splicing (c.1149+4A>G, c.2864+1G>A, and c.5785-7G>A), two nonsense (p.Gln112Ter and p.Trp2084Ter), two missense (p.Thr1546Pro and p.Tyr1032Cys), and one frameshift (p.Asp1067Ilefs), among nine Iranian families. One of the eight identified variants was novel, including p.Asp1067Ilefs, which was predicted to be likely pathogenic based on the ACMG guidelines. Notably, prediction tools suggested the damaging effects of studied variants on dysferlin structure. CONCLUSION: Conclusively, the current report introduced eight variants including a novel frameshift in DYSF gene with noticeable pathogenic effects. This study significantly can broaden the diagnostic spectrum of LGMD2B in combination with previous reports about DYSF mutations and may pave the way for a rapidly high-ranked identification of the accurate type of dysferlinopathy

Expanding the clinical phenotype of IARS2-related mitochondrial disease.

BACKGROUND: IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies. METHODS: Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis. RESULTS: Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein. CONCLUSIONS: This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia

Biallelic variants in KIF14 cause intellectual disability with microcephaly.

Kinesin proteins are critical for various cellular functions such as intracellular transport and cell division, and many members of the family have been linked to monogenic disorders and cancer. We report eight individuals with intellectual disability and microcephaly from four unrelated families with parental consanguinity. In the affected individuals of each family, homozygosity for likely pathogenic variants in KIF14 were detected; two loss-of-function (p.Asn83Ilefs*3 and p.Ser1478fs), and two missense substitutions (p.Ser841Phe and p.Gly459Arg). KIF14 is a mitotic motor protein that is required for spindle localization of the mitotic citron rho-interacting kinase, CIT, also mutated in microcephaly. Our results demonstrate the involvement of KIF14 in development and reveal a wide phenotypic variability ranging from fetal lethality to moderate developmental delay and microcephaly