A variant in IL6ST with a selective IL-11 signaling defect in human and mouse

The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6 st p.R279 Q. We show that human GP130 p.R281 Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6 st p.R279 Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11 RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.

Helplessness-like escape deficits of NIH-HS rats predict passive behavior in the forced swimming test:Relevance for the concurrent validity of rat models of depression

The genetically heterogeneous NIH-HS rat stock has been characterized by its response to anxiety- and fear-inducing situations, thus leading to the conclusion that they are a rather anxious and passive coping type of rats. Taking advantage of these profiles, and knowing that they show very poor performance in the two-way active (shuttle box) escape/avoidance task, we have tested NIH-HS rats (n = 80) in the forced swimming test (FST) as well as we have studied escape response deficits (i.e. response failures) of the same animals in the two-way shuttle box task. They were also tested for anxiety in the elevated zero-maze. The goal of such a study was that of investigating whether there are associations or relationships among helplessness-like or passive coping responses between both models of depression, i.e. the FST and the helplessness-like escape deficits in the shuttle box task. The results for the first time show associations among responses from both depression models and that selecting rats for displaying extreme (active or passive) responses in one of the models predict in a coherent manner (according to the hypothesis) their behaviour in the other model. These findings are discussed in the context of the concurrent validity of both models of depression as well as concerning the possible relevance of NIH-HS rats as a tool for future studies on this field.

中国和英国子宫内膜异位症患者的发病相关因素分析

目的研究子宫内膜异位症发病的相关因素及其在中国和英国患者之间可能的差异。方法采用病例对照研究方法,选取英国牛津John Radcliffe Hospital收治的子宫内膜异位症患者387例和非子宫内膜异位症患者199例、广州中医药大学第一附属医院收治的子宫内膜异位症患者101例和非子宫内膜异位症患者50例分别为病例组和对照组。通过标准化的WERF EPHect调查问卷,收集4组人群的身高、体质量、体质量指数、婚姻状况、工作状况、月经情况、生育情况、手术原因等临床资料并进行统计分析。结果多因素Logistic回归分析结果显示,英国患者中体质量指数、因痛经进行手术、怀孕史、既往子宫内膜异位症手术次数、工作情况等均与子宫内膜异位症的发生相关(P<0.05),而中国患者中痛经史与子宫内膜异位症的发生相关(P<0.05)。结论痛经可能是中国和英国子宫内膜异位症患者最主要的相关因素;同时,子宫内膜异位症发生的相关因素在中国和英国患者之间可能存在差异。

Evaluation of biomarkers, genetic mutations, and epigenetic modifications in early diagnosis of pancreatic cancer

BACKGROUND Pancreatic cancer(PC)is one of the deadliest malignancies with an alarming mortality rate.Despite significant advancement in diagnostics and therapeutics,early diagnosis remains elusive causing poor prognosis,marred by mutations and epigenetic modifications in key genes which contribute to disease progression.AIM To evaluate the various biological tumor markers collectively for early diagnosis which could act as prognostic biomarkers and helps in future therapeutics of PC in Kashmir valley.METHODS A total of 50 confirmed PC cases were included in the study to evaluate the levels of carbohydrate antigen 19-9(CA 19-9),tissue polypeptide specific antigen(TPS),carcinoembryonic antigen(CEA),vascular endothelial growth factor-A(VEGF-A),and epidermal growth factor receptor(EGFR).Mutational analysis was performed to evaluate the mutations in Kirsten rat sarcoma(KRAS),Breast cancer type 2(BRCA-2),and deleted in pancreatic cancer-4(DPC-4)genes.However,epigenetic modifications(methylation of CpG islands)were performed in the promoter regions of cyclin-dependent kinase inhibitor 2A(p16;CDKN2A),MutL homolog 1(hMLH1),and Ras association domain-containing protein 1(RASSF1A)genes.RESULTS We found significantly elevated levels of biological markers CA 19-9(P≤0.05),TPS(P≤0.05),CEA(P≤0.001),and VEGF(P≤0.001).Molecular genetic analysis revealed that KRAS gene mutation is predominant in codon 12(16 subjects,P≤0.05),and 13(12 subjects,P≤0.05).However,we did not find a mutation in DPC-4(1203G>T)and BRCA-2(617delT)genes.Furthermore,epigenetic modification revealed that CpG methylation in 21(P≤0.05)and 4 subjects in the promoter regions of the p16 and hMLH1 gene,respectively.CONCLUSION In conclusion,CA 19-9,TPS,CEA,and VEGF levels were significantly elevated and collectively have potential as diagnostic and prognostic markers in PC.Global data of mutation in the KRAS gene commonly in codon 12 and rare in codon 13 could augment the predisposition towards PC.Additionally,methylation of the p16 gene could also modulate transcription of genes thereby increasing the predisposition and susceptibility towards PC.

Analysis of the Hox epigenetic code

Archetypes of histone modifications associated with diverse chromosomal states that regulate access to DNA are leading the hypothesis of the histone code(or epigenetic code). However, it is still not evident how these post-translational modifications of histone tails lead to changes in chromatin structure. Histone modifications are able to activate and/or inactivate several genes and can be transmitted to next generation cells due to an epigenetic memory. The challenging issue is to identify or "decrypt" the code used to transmit these modifications to descent cells. Here, an attempt is made to describe how histone modifications operate as part of histone code that stipulates patterns of gene expression. This papers emphasizes particularly on the correlation between histone modifications and patterns of Hox gene expression in Caenorhabditis elegans. This work serves as an example to illustrate the power of the epigenetic machinery and its use in drug design and discovery.

Mutation Identification in A 5-Generation Pedigree with Autosomal Dominant Retinitis Pigmentosa

An extended 5-generation family has been investigated in which 32 of the 111 family members were diagnosed as having retinitis pigmentosa (RP) The proband was a 58-year old male in whom night-blindness was first observed in early childhood, with almost loss of vision by 52 years of age The symptoms observed in other family members included night-blindness, impaired vision and visual field loss Dementia, digital abnormalities, deaf-mutism and mental retardation were variously diagnosed in a number of individuals with RP The affected and unaffected family members were tested for mutations in a range of candidate genes The 8 exons of three candidate genes have been analyzed by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing techniques A novel mutation was identified in the rhodopsin gene at codon 52 of exon 1 (TTC-TAC) that resulted in a substitution of Phe to Tyr

Evaluation of Risk Related to MTHFR 677C>T Gene Polymorphism in Migraine Patients in Kashmiri Population

Objective: Migraine, a common chronic neurological disorder involves a pathophysiology having both multiple genetic and environmental factors. 5, 10-Methylenetetrahydrofolate reductase (MTHFR) involved in folate metabolism has an important role in a cell for folate availability which is critical for DNA integrity. Methods: This case-control study conducted in Srinagar, Kashmir (North India) between 2013 and 2015 was designed to evaluate risk induced due to MTH-FR 677C>T gene polymorphisms to contribute in susceptibility for migraine in Kashmir population (North India). Using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, we tested the genotype distribution of 100 migraine patients in comparison with 120 healthy migraine-free controls from the same geographical region. Results: The genotypic frequencies of the patients and controls were not significantly associated (p > 0.05). Higher distribution of TT mutant genotype was found in controls as against the cases (5% versus 1%) but association was not significant (p > 0.05). Per copy frequency of T allele (Val) was found to be 0.14 in cases versus 0.19 in controls (p 0.05). Similar scenario was observed when migraine without aura was compared with controls where variant genotype (16% cases versus 39.0% controls: p > 0.05) as well as allele frequency was found to be less in cases (cases 0.15 versus 0.19 controls: p > 0.05). Conclusions: We conclude that MTHFR gene C677T polymorphism has no role in predisposition to the migraine in our population and cannot serve as a predictive factor for the risk of migraine.

Identification of Genetic Variants Underlying Anxiety and Multiple Sclerosis in Heterogeneous Stock Rats

Identifying genetic variants that contribute to phenotypic variation is expected to provide insights into the etiology of complex traits. Here we show how combining genetic mapping in an outbred population of rats with sequence data from the progenitors of the population made it possible to identify causal variants and genes for a large number of phenotypes. We identified 355 genomic loci contributing to 122 measures relevant to six models of disease, including fear-related behaviors and experimental autoimmune encephalomyelitis. At 35 of those loci we identified the responsible gene, and in some cases, the responsible variant.

What can we learn on rodent fearfulness/anxiety from the genetically heterogeneous NIH-HS rat stock?

The “National Institutes of Health” genetically heterogeneous (NIH-HS) rat stock was created in the 1980s through an eight-way cross of as much as possible separate inbred rat strains (i.e. the MR/N, WN/N, WKY/N, M520/N, F344/N, ACI/N, BN/SsN and BUF/N strains) which were readily available at that time. Hansen and Spuhler [1] developed a more naturalistic, genetically heterogeneous rat stock with the aim of optimizing the distribution of genotypic frequencies and recombination and under the hypothesis that the NIH-HS stock could yield a broad-range distribution of responses (broader than commonly used laboratory rat strains) to experimental conditions, and thus serve as a base population for selection studies. Along the last decade, in a series of studies we have phenotypically characterized the NIH-HS rat stock (a colony exists at our laboratory since 2004) for their anxiety/fearfulness profiles (using a battery of both unconditioned and conditioned tests/tasks), as well as regarding their stress-induced hormonal responses, coping style under inescapable stress and spatial learning ability. We have also compared the phenotypic profiles of NIH-HS rats with those of the low anxious RHA-I and the high anxious RLA-I rat strains. The NIH-HS rat stock is, as a population, a rather anxious type of rat, with predominantly reactive/passive coping style in unlearned and learned anxiety/fear tests, and elevated stress hormone responses (as well as enhanced “depressive” symptoms in the forced swimming test). Genetic studies currently under way have thus far revealed that the genetically heterogeneous NIH-HS rat stock constitutes a unique tool for fine mapping of QTL (for multiple behavioural and biological complex traits) to megabase resolution levels, thus enabling candidate gene identification. We give some examples of this in the present paper, while also highlighting that microarray gene expression studies reveal that HPA-axis- and prolactin-related genes (among others) in the amygdala appear to be related with (or associated to) the coping style and anxiety/fearfulness responses of NIH-HS rats.

I3:A Self-organising Learning Workflow for Intuitive Integrative Interpretation of Complex Genetic Data

We propose a computational workflow(I3)for intuitive integrative interpretation of complex genetic data mainly building on the self-organising principle.We illustrate the use in interpreting genetics of gene expression and understanding genetic regulators of protein phenotypes,particularly in conjunction with information from human population genetics and/or evolutionary history of human genes.We reveal that loss-of-function intolerant genes tend to be depleted of tissue-sharing genetics of gene expression in brains,and if highly expressed,have broad effects on the protein phenotypes studied.We suggest that this workflow presents a general solution to the challenge of complex genetic data interpretation.I3 is available at http://suprahex.r-forge.r-project.org/I3.html.

Single probes and resonant four-wave-mixing enabling novel correlative light electron microscopy workflow

Correlative light electron microscopy prefers single probes with stable performance in both optical and electron microscopy.Now researchers have shown how to harness gold nanoparticles featuring exceptional photostability and four-wave-mixing nonlinearity to realize a new correlation imaging approach.

常染色体显性遗传视网膜色素变性家系的基因筛查

目的 确定一个常染色体显性遗传视网膜色素变性 (autosomaldominantretinitispigmentosa ,ADRP)家系的致病基因及其突变位点和类型。方法 应用聚合酶链反应 单链构象多态性结合DNA测序技术 ,对来自同一家系的 4例RP患者及 4名正常人外周血DNA进行分子遗传学分析 ,筛查 3个候选基因共 8个外显子。结果 来自同一家系的 4例RP患者均发现有视紫红质基因 (rhodopsin ,RHO)第 1外显子第 5 2密码子存在TTC→TAC的点突变 (Phe5 2Tyr) ,而 4名正常人未发现这种突变。结论 在这个中国ADRP大家系中 ,发现RHO基因的致病突变 ,表明ADRP存在明显遗传异质性。

Apert’s syndrome:Study by whole exome sequencing

In the present study we attempted a parente-child trio,whole exome sequencing(WES)approach to study Apert’s syndrome.Clinical characteristics of the child were noted down and WES was carried out using Ion Torrent System that revealed the presence of previously reported P253R mutation in FGFR2 gene.Presence of two SNPs rs1047057 and rs554851880 in FGFR2 gene with an allelic frequency of 0.5113 and 0.001176 respectively and 161 complete damaging mutations were found.This study is the first reported case of exome sequencing approach on an Apert’s syndrome patient aimed at providing better genetic counselling in a non-consanguineous relationship.

1型糖尿病患儿的筛查 值得深思和进一步研究

1921年胰岛素的发现,使糖尿病成为一种慢性疾病,患者不再被判"死刑"。100年后胰岛素仍然是1型糖尿病唯一的治疗手段。但是,新策略的出现正在为患儿的生活提供一条不同的道路。