Identification of Spliceogenic Variants beyond Canonical GT-AG Splice Sites in Hereditary Cancer Genes

Pathogenic/likely pathogenic variants in susceptibility genes that interrupt RNA splicing are a well-documented mechanism of hereditary cancer syndromes development. However, if RNA studies are not performed, most of the variants beyond the canonical GT-AG splice site are characterized as variants of uncertain significance (VUS). To decrease the VUS burden, we have bioinformatically evaluated all novel VUS detected in 732 consecutive patients tested in the routine genetic counseling process. Twelve VUS that were predicted to cause splicing defects were selected for mRNA analysis. Here, we report a functional characterization of 12 variants located beyond the first two intronic nucleotides using RNAseq in APC, ATM, FH, LZTR1, MSH6, PALB2, RAD51C, and TP53 genes. Based on the analysis of mRNA, we have successfully reclassified 50% of investigated variants. 25% of variants were downgraded to likely benign, whereas 25% were upgraded to likely pathogenic leading to improved clinical management of the patient and the family members.     

带有理因子的有理样条函数空间的维数级数

考虑了应用吴方法求解多元有理样条函数的计算问题，将多项式样条函数的维数级数理论推广到带有理因子的有理样条空间，建立了相应的维数公式。     

脱硫微生物氧化亚铁硫杆菌遗传特性的分子生物学试验

利用现代生物学研究方法和手段,对煤系与非煤系氧化亚铁硫杆菌的遗传特性进行了质粒抽提和琼脂糖凝胶电泳等分子生物学水平的基础性探索试验,对于质粒在硫杆菌中普遍存在的观点提出了质疑.研究结果表明,氧化亚铁硫杆菌对Fe²⁺,S等的氧化能力可能只是与拟核染色体DNA有关,而氧化亚铁硫杆菌的遗传物质就是拟核染色体DNA.     

Expanding Phenotype of Schimke Immuno-Osseous Dysplasia: Congenital Anomalies of the Kidneys and of the Urinary Tract and Alteration of NK Cells

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1. A phenotype–genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD—both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.     

The Discovery of Endoplasmic Reticulum Storage Disease. The Connection between an H&E Slide and the Brain

The revolutionary evolution in science and technology over the last few decades has made it possible to face more adequately three main challenges of modern medicine: changes in old diseases, the appearance of new diseases, and diseases that are unknown (mostly genetic), despite research efforts. In this paper we review the road travelled by pathologists in search of a method based upon the use of routine instruments and techniques which once were available for research only. The application to tissue studies of techniques from immunology, molecular biology, and genetics has allowed dynamic interpretations of biological phenomena with special regard to gene regulation and expression. That implies stepwise investigations, including light microscopy, immunohistochemistry, in situ hybridization, electron microscopy, molecular histopathology, protein crystallography, and gene sequencing, in order to progress from suggestive features detectable in routinely stained preparations to more characteristic, specific, and finally, pathognomonic features. Hematoxylin and Eosin (H&E)-stained preparations and appropriate immunohistochemical stains have enabled the recognition of phenotypic changes which may reflect genotypic alterations. That has been the case with hepatocytic inclusions detected in H&E-stained preparations, which appeared to correspond to secretory proteins that, due to genetic mutations, were retained within the rough endoplasmic reticulum (RER) and were deficient in plasma. The identification of this phenomenon affecting the molecules alpha-1-antitrypsin and fibrinogen has led to the discovery of a new field of cell organelle pathology, endoplasmic reticulum storage disease(s) (ERSD). Over fifty years, pathologists have wandered through a dark forest of complicated molecules with strange conformations, and by detailed observations in simple histopathological sections, accompanied by a growing background of molecular techniques and revelations, have been able to recognize and identify arrays of grotesque polypeptide arrangements.     

广义路代数及其Hochschild上同调

为了研究quiver △上的A-广义路代数R=k(△,A),基于本原正交幂等元完全集,给出了广义路代数R=k(△,A)的不可分解投射模与内射模以及单模的构造形式。基于遗传代数性质得到了广义路代数是遗传代数的充要条件,并进一步在同调理论和有限维代数的Hochschild上同调的基础上得到了广义路代数的Hochschild上同调。     

基于遗传算法的灌区水资源管理与灌溉决策系统研究

在北方引黄灌区灌溉水资源优化配置与管理理论研究的基础上,结合彭楼灌区的具体情况,研制了灌区水资源管理与灌溉决策系统．该系统具有完整的数据处理功能,具有较强的定性及定量分析能力,为灌区水资源监测和供需分析提供管理和计算平台,为灌区管理提供水资源优化分配和灌溉模式优选的决策支持．     

最大似然估计在辐射噪声源近场定位中的应用

为有效解决水下噪声源近场定位问题,本文针对常规聚焦波束形成及MVDR聚焦波束形成定位方法的空间分辨率不高及无法处理相干声源的缺点,介绍了基于最大似然估计的辐射噪声源近场定位方法,并利用遗传算法寻求最大似然估计的全局最优解,从而实现水下噪声源近场高分辨定位.通过计算机仿真及湖试数据处理验证了该方法可以实现辐射噪声源近场高分辨定位,且仅利用小孔径基阵就可以清晰分辨间距大约1 m的两相干声源,具有很高的工程应用价值.     

Alport综合征肾脏的超微病理观察

Alport综合征（Alport syndrome,AS）是一种遗传进行性肾病。本文对32例AS患者肾脏的超微结构进行病理观察,并结合其临床表现、HE、特殊染色（PAS、PAM-Masson）、免疫组化（IgG、IgM、IgA、C3c、HBsAg、HBcAg）结果进行分析。患者多以浮肿、肉眼血尿就诊,中位年龄12岁。5例有家族史,4例患者曾做过肾穿刺活检,6例有治疗史。肾活检组织光镜及免疫组化检查无特异性表现。电镜下肾小球基底膜出现特征性的厚薄不均及分层撕裂。肾小管和Bowman氏囊壁上皮细胞及小动脉壁内皮细胞也可查见分层撕裂。AS在电镜下的特异性超微结构改变在病理诊断中具有重要诊断价值。     

热粘弹性有限元法

本文依据变温下一般热粘弹性材料的蠕变型本构方程，通过对记忆积分的化简，推导出了变温粘弹性有限元方法的一般列式．它适用于各种热粘弹性材料在变温下的有限元计算。