Molecular characterization of familial hypercholesterolemia in Iranian patients

Abstract Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism caused mainly by mutations in the low-density lipoprotein receptor (LDLR) and apolipoprotein B 100 (APOB) genes. Until now, the molecular basis of FH has been demonstrated in detail in many populations, but there is still very limited Molecular data concerning FH in Iran. The aim of this study was to characterize the LDLR and APOB gene mutations in an Iranian population. A total of 30 non-related Iranian possible FH subjects were studied. Diagnosis of FH was based on the Dutch Lipid Clinic Network diagnostic criteria. All samples were initially tested for three common APOB gene mutations including R3500Q, R3500 W and R3531C using PCR-RFLP assay. Subsequently, promoter and coding region of the LDLR gene was screened by PCRSSCP analysis and positive results were confirmed by DNA sequencing. Four previously reported polymorphisms 1413G [A, 1725C [T, 1773T [C and 2140 ? 5G[A were found in *17% (5/30) of population studied. Moreover, no variation was found in APOB gene. Our data indicated that LDLR and APOB gene mutations have not contribution to possible FH in Iranian population studied here. However, we examined three common APOB mutations and LDLR in only 30 patients, and to determine the role of these genes in developing FH in Iran, more FH samples and populations needed to be investigated for the mutations of the related gene

Synthetic long non-coding RNAs [SINEUPs] rescue defective gene expression in vivo

Non-coding RNAs provide additional regulatory layers to gene expression as well as the potential to being exploited as therapeutic tools. Non-coding RNA-based therapeutic approaches have been attempted in dominant diseases, however their use for treatment of genetic diseases caused by insufficient gene dosage is currently more challenging. SINEUPs are long antisense non-coding RNAs that up-regulate translation in mammalian cells in a gene-specific manner, although, so far evidence of SINEUP efficacy has only been demonstrated in in vitro systems. We now show that synthetic SINEUPs effectively and specifically increase protein levels of a gene of interest in vivo. We demonstrated that SINEUPs rescue haploinsufficient gene dosage in a medakafish model of a human disorder leading to amelioration of the disease phenotype. Our results demonstrate that SINEUPs act through mechanisms conserved among vertebrates and that SINEUP technology can be successfully applied in vivo as a new research and therapeutic tool for gene-specific up-regulation of endogenous functional proteins

Association of food allergies, cow�s milk allergy, and asthma with pediatric inflammatory bowel disease

There are controversies on the association of childhood allergic diseases with inflammatory bowel diseases (IBD). The aim of this study was to examine the association between food allergy, cow�s milk allergy (CMA), and asthma with pediatric IBD in Iranian population. This case-control study was conducted on 200 individuals less than 18-year-old (100 with IBD and 100 as control group). Medical records, clinical presentation, and laboratory and para-clinical findings related to food allergy, CMA, and asthma were reviewed for all participants in both groups and were recorded. Among 100 children with IBD, 40 had Crohn's disease, and 60 had ulcerative colitis. The frequency of food allergy, cow's milk allergy, and asthma in children with IBD was significantly higher than the control group (P<0.001). Asthma in children with Crohn's disease was significantly more prevalent than children with ulcerative colitis (P=0.008). Food allergy (OR: 22.1, 95 CI: 5.1-95.05, P<0.001), CMA (OR: 15, 95 CI: 3-67, P<0.001), and asthma (OR: 10, 95 CI: 3-37.05, P<0.001) were significantly associated with increased risk of IBD in children. Food allergy, CMA in infancy and asthma are more prevalent in children with different subtypes of IBD. The diagnosis of these risk factors is associated with increased risk of Crohn's disease and ulcerative colitis. © 2018 Tehran University of Medical Sciences. All rights reserved

Association of food allergies, cow�s milk allergy, and asthma with pediatric inflammatory bowel disease

There are controversies on the association of childhood allergic diseases with inflammatory bowel diseases (IBD). The aim of this study was to examine the association between food allergy, cow�s milk allergy (CMA), and asthma with pediatric IBD in Iranian population. This case-control study was conducted on 200 individuals less than 18-year-old (100 with IBD and 100 as control group). Medical records, clinical presentation, and laboratory and para-clinical findings related to food allergy, CMA, and asthma were reviewed for all participants in both groups and were recorded. Among 100 children with IBD, 40 had Crohn's disease, and 60 had ulcerative colitis. The frequency of food allergy, cow's milk allergy, and asthma in children with IBD was significantly higher than the control group (P<0.001). Asthma in children with Crohn's disease was significantly more prevalent than children with ulcerative colitis (P=0.008). Food allergy (OR: 22.1, 95 CI: 5.1-95.05, P<0.001), CMA (OR: 15, 95 CI: 3-67, P<0.001), and asthma (OR: 10, 95 CI: 3-37.05, P<0.001) were significantly associated with increased risk of IBD in children. Food allergy, CMA in infancy and asthma are more prevalent in children with different subtypes of IBD. The diagnosis of these risk factors is associated with increased risk of Crohn's disease and ulcerative colitis. © 2018 Tehran University of Medical Sciences. All rights reserved

A Novel RNA Transcript with Antiapoptotic Function Is Silenced in Fragile X Syndrome

Several genome-wide transcriptomics efforts have shown that a large percentage of the mammalian genome is transcribed into RNAs, however, only a small percentage (1–2%) of these RNAs is translated into proteins. Currently there is an intense interest in characterizing the function of the different classes of noncoding RNAs and their relevance to human disease. Using genomic approaches we discovered FMR4, a primate-specific noncoding RNA transcript (2.4 kb) that resides upstream and likely shares a bidirectional promoter with FMR1. FMR4 is a product of RNA polymerase II and has a similar half-life to FMR1. The CGG expansion in the 5′ UTR of FMR1 appears to affect transcription in both directions as we found FMR4, similar to FMR1, to be silenced in fragile X patients and up-regulated in premutation carriers. Knockdown of FMR4 by several siRNAs did not affect FMR1 expression, nor vice versa, suggesting that FMR4 is not a direct regulatory transcript for FMR1. However, FMR4 markedly affected human cell proliferation in vitro; siRNAs knockdown of FMR4 resulted in alterations in the cell cycle and increased apoptosis, while the overexpression of FMR4 caused an increase in cell proliferation. Collectively, our results demonstrate an antiapoptotic function of FMR4 and provide evidence that a well-studied genomic locus can show unexpected functional complexity. It cannot be excluded that altered FMR4 expression might contribute to aspects of the clinical presentation of fragile X syndrome and/or related disorders

RNA activation of haploinsufficient Foxg1 gene in murine neocortex

More than one hundred distinct gene hemizygosities are specifically linked to epilepsy, mental retardation, autism, schizophrenia and neuro-degeneration. Radical repair of these gene deficits via genome engineering is hardly feasible. The same applies to therapeutic stimulation of the spared allele by artificial transactivators. Small activating RNAs (saRNAs) offer an alternative, appealing approach. As a proof-of-principle, here we tested this approach on the Rett syndrome-linked, haploinsufficient, Foxg1 brain patterning gene. We selected a set of artificial small activating RNAs (saRNAs) upregulating it in neocortical precursors and their derivatives. Expression of these effectors achieved a robust biological outcome. saRNA-driven activation (RNAa) was limited to neural cells which normally express Foxg1 and did not hide endogenous gene tuning. saRNAs recognized target chromatin through a ncRNA stemming from it. Gene upregulation required Ago1 and was associated to RNApolII enrichment throughout the Foxg1 locus. Finally, saRNA delivery to murine neonatal brain replicated Foxg1-RNAa in vivo

Effective mechanical properties of multilayer nano-heterostructures

Two-dimensional and quasi-two-dimensional materials are important nanostructures because of their exciting electronic, optical, thermal, chemical and mechanical properties. However, a single-layer nanomaterial may not possess a particular property adequately, or multiple desired properties simultaneously. Recently a new trend has emerged to develop nano-heterostructures by assembling multiple monolayers of different nanostructures to achieve various tunable desired properties simultaneously. For example, transition metal dichalcogenides such as MoS2 show promising electronic and piezoelectric properties, but their low mechanical strength is a constraint for practical applications. This barrier can be mitigated by considering graphene-MoS2 heterostructure, as graphene possesses strong mechanical properties. We have developed efficient closed-form expressions for the equivalent elastic properties of such multi-layer hexagonal nano-hetrostructures. Based on these physics-based analytical formulae, mechanical properties are investigated for different heterostructures such as graphene-MoS2, graphene-hBN, graphene-stanene and stanene-MoS2. The proposed formulae will enable efficient characterization of mechanical properties in developing a wide range of application-specific nano-heterostructures