Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

PurposePathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort.MethodsWe perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays.ResultsOur data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants.ConclusionInsights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.     

DNA adsorption on nanoscale zeolitic imidazolate framework-8 enabling rational design of a DNA-based nanoprobe for gene detection and regulation in living cells

DNA functionalized nanomaterials have attracted tremendous attention for bioanalytical applications. Owing to exceptional fluorescence quenching ability, most DNA-based nanoprobes were designed with turn-on signals for target gene detection, while only a few of them could simultaneously achieve gene detection and regulation in one system. In this study, we explored the use of nanoscale zeolitic imidazolate framework-8 (ZIF-8) as a building block to construct a DNA-based nanoprobe. We found ZIF-8 could stably adsorb DNA to resist the dissociation by various biological ligands, enabling potential biological applications. However, ZIF-8 was not a nano-quencher to turn off the fluorophore labeling on the adsorbed DNA. We therefore designed a DNAzyme embedded molecular beacon (DMB) to functionalize ZIF-8. After endocytosis, ZIF-8 was disintegrated to release DMB for target mRNA detection, and the co-released Zn²⁺ acted as an effective cofactor to activate the embedded DNAzyme for mRNA regulation. This study provides a versatile nano-platform to realize multiple functions inside cells by using functional nucleic acids, which holds great promise for theranostic applications.

Boosting DNA-based nanotheranostics for gene detection and regulation by ZIF-8.     

黄柳向治疗胃癌前病变经验

介绍黄柳向教授运用益气健脾,柔肝理气,化痰祛瘀法治疗胃癌前病变的经验。黄教授认为,胃癌前病变的根本病机为本虚标实,即脾胃亏虚为本,气滞痰凝血瘀为标;治疗当以益气健脾,柔肝理气,化痰祛瘀为法。临床上采用莪蚕健胃方加减治疗,对胃癌前病变的阻断与逆转效果确切,并附典型案例1则。     

基于专利数据库中药复方治疗溃疡性结肠炎的用药规律与作用机制分析

目的：研究溃疡性结肠炎专利复方的用药规律和作用机制。方法：从专利数据库中筛选治疗溃疡性结肠炎的中医专利复方,录入数据库,进行频数、聚类和关联分析,再通过中药系统药理学数据库与分析平台（Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP）筛选排名前十的高频药的活性成分,然后通过DrugBank数据库找到这些成分对应的作用靶点,并通过基因免疫功能和基因通路富集分析找到这些靶点对应的免疫功能和信号通路。结果：总共发现治疗溃疡性结肠炎的专利复方224个,涉及中药387味;排名前十的高频药依次是黄连、甘草、白术、白芍、黄芪、白及、党参、白头翁、地榆、木香,主要使用的是补益药和清热药;发现中药配伍10对、关联规则16条;在排名前十的高频药中筛选出83个活性成分及其146个作用靶点,这些靶点作用于B细胞增殖、T细胞因子分泌等27个免疫功能,以及TNF信号通路、IL-17信号通路等47条信号通路。结论：专利数据库中治疗溃疡性结肠炎的中药复方用药规律符合临床实际,其作用机制和溃疡性结肠炎的病理机制较符合。     

Decoding the processing of lying using functional connectivity MRI

Background

Previous functional MRI (fMRI) studies have demonstrated group differences in brain activity between deceptive and honest responses. The functional connectivity network related to lie-telling remains largely uncharacterized.

Methods

In this study, we designed a lie-telling experiment that emphasized strategy devising. Thirty-two subjects underwent fMRI while responding to questions in a truthful, inverse, or deceitful manner. For each subject, whole-brain functional connectivity networks were constructed from correlations among brain regions for the lie-telling and truth-telling conditions. Then, a multivariate pattern analysis approach was used to distinguish lie-telling from truth-telling based on the functional connectivity networks.

Results

The classification results demonstrated that lie-telling could be differentiated from truth-telling with an accuracy of 82.81% (85.94% for lie-telling, 79.69% for truth-telling). The connectivities related to the fronto-parietal networks, cerebellum and cingulo-opercular networks are most discriminating, implying crucial roles for these three networks in the processing of deception.

Conclusions

The current study may shed new light on the neural pattern of deception from a functional integration viewpoint.

Electronic supplementary material

The online version of this article (doi:10.1186/s12993-014-0046-4) contains supplementary material, which is available to authorized users.     

CD26 a cancer stem cell marker and therapeutic target

Cancer stem cells (CSCs) comprise a tumor subpopulation responsible for tumor maintenance, resistance to chemotherapy, recurrence and metastasis. The identification of this cell group is very important, but there is still no consensus on its characterization. Several CSC markers have been described, like CD133, CD24, CD44 and ALDH1, but more research to identify new markers to facilitate the identification of CSC in a heterogeneous tumoral mass is required. Thus, this article describes the CD26 expression as a CSC marker and the role that it plays in different types of cancer. CD26 expression correlates with some characteristics of CSCs, like the formation of spheres in vitro, formation of new tumors, and resistance to chemotherapy. CD26 is therefore suggested as an auxiliary marker for CSC in different types of cancer, and as a potential therapeutic target.     

Genome-wide pathway-based association study implicates complement system in the development of Kashin-Beck disease in Han Chinese

Kashin-Beck disease (KBD) is a chronic osteochondropathy. The pathogenesis of KBD remains unknown. To identify relevant biological pathways for KBD, we conducted a genome-wide pathway-based association study (GWPAS) following by replication analysis, totally using 2743 Chinese Han adults. A modified gene set enrichment algorithm was used to detect association between KBD and 963 biological pathways. Cartilage gene expression analysis and serum complement measurement were performed to evaluate the functional relevance of identified pathway with KBD. We found that the Complement and Coagulation Cascades (CACC) pathway was significantly associated with KBD (P value = 3.09 × 10^− 5, false-discovery rate = 0.042). Within the CACC pathway, the most significant association was observed at rs1656966 (P value = 1.97 × 10^− 4) of KNG1 gene. Further replication study observed that rs1656966 (P value = 0.037) was significantly associated with KBD in an independent validation sample of 1026 subjects. Gene expression analysis observed that CFD (ratio = 3.39 ± 2.68), A2M (ratio = 3.67 ± 5.63), C5 (ratio = 2.65 ± 2.52) and CD46 (ratio = 2.29 ± 137) genes of the CACC pathway were up-regulated in KBD articular cartilage compared to healthy articular cartilage. The serum level of complement C5 in KBD patients were significantly higher than that in healthy controls (P value = 0.038). Our study is the first to suggest that complement system-related CACC pathway contributed to the development of KBD.     

Refinement of collagen–mineral interaction: A possible role for osteocalcin in apatite crystal nucleation,growth and development

Mineralization of vertebrate tissues such as bone, dentin, cementum, and calcifying tendon involves type I collagen, which has been proposed as a template for calcium and phosphate ion binding and subsequent nucleation of apatite crystals. Type I collagen thereby has been suggested to be responsible for the deposition of apatite mineral without the need for non-collagenous proteins or other extracellular matrix molecules. Based on studies in vitro, non-collagenous proteins, including osteocalcin and bone sialoprotein, are thought to mediate vertebrate mineralization associated with type I collagen. These proteins, as possibly related to mineral deposition, have not been definitively localized in vivo. The present study has reexamined their localization in the leg tendons of avian turkeys, a representative model of vertebrate mineralization. Immunocytochemistry of osteocalcin demonstrates its presence at the surface of, outside and within type I collagen while that of bone sialoprotein appears to be localized at the surface of or outside type I collagen. The association between osteocalcin and type I collagen structure is revealed optimally when calcium ions are added to the antibody solution in the methodology. In this manner, osteocalcin is found specifically located along the a_4–1, b₁, c₂ and d bands defining in part the hole and overlap zones within type I collagen. From these data, while type I collagen itself may be considered a stereochemical guide for intrafibrillar mineral nucleation and subsequent deposition, osteocalcin bound to type I collagen may also possibly mediate nucleation, growth and development of platelet-shaped apatite crystals. Bone sialoprotein and osteocalcin as well, each immunolocalized at the surface of or outside type I collagen, may affect mineral deposition in these portions of the avian tendon.     

胶体果胶铋干混悬剂治疗幽门螺杆菌阳性消化性溃疡的疗效分析

背景:对于胶体果胶铋干混悬剂治疗幽门螺杆菌(Hp)阳性消化性溃疡的疗效是否优于胶体果胶铋胶囊,目前尚无相关的临床研究。目的:比较胶体果胶铋干混悬剂与胶体果胶铋胶囊对Hp阳性消化性溃疡的临床疗效。方法:选取2012年1月~2013年4月中南大学湘雅二医院门诊初治的126例Hp阳性的消化性溃疡患者,随机分为观察组和对照组,分别给予胶体果胶铋干混悬剂+标准三联方案以及胶体果胶铋胶囊+标准三联方案,评估比较临床症状缓解情况、内镜下溃疡愈合情况以及Hp根除率。结果:观察组患者胃溃疡(84.6%对55.6%)、十二指肠溃疡(84.8%对62.1%)2周末症状消失率均显著高于对照组(P0.05),但两组4周末症状消失率无明显差异(P0.05)。观察组的溃疡治疗总有效率(98.2%对84.0%)、总体Hp的PP根除率(89.5%对72.7%)和ITT根除率(81.0%对63.5%)均显著高于对照组(P0.05)。两组均未见严重不良反应。结论:胶体果胶铋干混悬剂治疗Hp阳性消化性溃疡的疗效优于胶体果胶铋胶囊。     

Pancreatic perfusion imaging method that reduces radiation dose and maintains image quality by combining volumetric perfusion CT with multiphasic contrast enhanced-CT

ObjectivesThe aim of this study is to propose and evaluate a new method of volumetric perfusion computed tomography (PCT) incorporated into pancreatic multiphasic contrast enhanced (CE)-CT in the clinical setting.MethodsIn this ethically approved study, PCT was incorporated into our existing scanning protocol in 17 patients and effective doses related to PCT were evaluated. CT values and signal-to-noise ratio (SNR) of anatomical structure were compared in diagnostic images that were acquired using 320-detector volumetric scan mode and 64-detector helical scan mode. In addition, focal lesion depiction was qualitatively assessed in the two groups. Perfusion parameters in normal pancreas were measured by two radiologists and the interobserver-reliability was assessed.ResultsThe effective dose of PCT was 5.1 ± 0.3 mSv. The actual effective dose (AED) including the dose used in volumetric scans for diagnostic imaging was 22.8 ± 5.3 mSv and the putative effective dose (PED) was 21.9 ± 9.1 mSv on average. There was no significant difference between AED and PED (p = 0.404). Compared with conventional helical scans, volumetric scans did not decrease CT values or SNR, but rather significantly increased those of the aorta in the arterial phase. Both groups had acceptable qualitatively assessed image quality with no significant difference in the depiction of each structure. There was almost perfect interobserver agreement in the measurement of perfusion parameters (mean ICCs > 0.9).ConclusionsOur scanning protocol for pancreatic perfusion CT provides high-quality images while requiring lower radiation doses than conventional methods.