An Update on Gene Therapy for Inherited Retinal Dystrophy: Experience in Leber Congenital Amaurosis Clinical Trials

Inherited retinal dystrophies (IRDs) are a group of rare eye diseases caused by gene mutations that result in the degradation of cone and rod photoreceptors or the retinal pigment epithelium. Retinal degradation progress is often irreversible, with clinical manifestations including color or night blindness, peripheral visual defects and subsequent vision loss. Thus, gene therapies that restore functional retinal proteins by either replenishing unmutated genes or truncating mutated genes are needed. Coincidentally, the eye’s accessibility and immune-privileged status along with major advances in gene identification and gene delivery systems heralded gene therapies for IRDs. Among these clinical trials, voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy drug, was approved by the FDA for treating patients with confirmed biallelic RPE65 mutation-associated Leber Congenital Amaurosis (LCA) in 2017. This review includes current IRD gene therapy clinical trials and further summarizes preclinical studies and therapeutic strategies for LCA, including adeno-associated virus-based gene augmentation therapy, 11-cis-retinal replacement, RNA-based antisense oligonucleotide therapy and CRISPR-Cas9 gene-editing therapy. Understanding the gene therapy development for LCA may accelerate and predict the potential hurdles of future therapeutics translation. It may also serve as the template for the research and development of treatment for other IRDs.     

基于逻辑稳定判据的遗传系数学习方法

针对宝钢2050热轧粗轧后计算学习有时计算偏差大、学习不稳定以及为了满足新系统遗传系数学习的要求，首先提出学习方法逻辑稳定的概念，给出两个定理作为判据，然后对学习误差进行了分析，并通过推理决策的方式提出基于逻辑稳定判据的遗传系数学习方法，最后对实际系统进行了分析，表明本文提出的方法是正确、可行的。     

冷轧宽带钢板形控制降维功效继承调控方法

 基于高次勒让德正交多项式和调控功效函数,提出了降维功效调控模型及两级调控模型。首先,利用连续可导的高次曲线准确描述局部板形信息,同时降低影响系数矩阵的维数和功效函数的计算量,利用传统板形调控手段（倾辊、弯辊、横移）同步消除典型板形缺陷;然后,利用精细分段冷却实施剩余板形偏差的二级调控,改善局部浪形缺陷,提高成批钢卷的生产稳定性和板形质量。实例表明,当阶数为带钢覆盖检测通道数量的一半以上时,拟合曲线已包含所有的局部板形信息;对于相对较典型的板形问题（50 I左右）,一级调控后剩余板形偏差在15 I以内,二级调控后剩余板形偏差在8 I以内,综合调控效果比较理想。     

Weighting parameters for time‐step integration algorithms with predetermined coefficients

In this paper, the effect of using the predetermined coefficients in constructing time‐step integration algorithms is investigated. Both first‐ and second‐order equations are considered. The approximate solution is assumed to be in a form of polynomial in the time domain. It can be related to the truncated Taylor's series expansion of the exact solution. Therefore, some of the coefficients can be predetermined from the known initial conditions. If there are m predetermined coefficients and r unknown coefficients in the approximate solution, the unknowns can be solved by the weighted residual method. The weighting parameter method is used to investigate the resultant algorithm characteristics. It is shown that the formulation is consistent with a minimum order of accuracy m+r. The maximum order of accuracy achievable is m+2r. Unconditionally stable algorithms exist if m⩽r for first‐order equations and m+1⩽r for second‐order equations. Hence, the Dahlquist's theorem is generalized. Algorithms equivalent to the Padé approximations and unconditionally stable algorithms equivalent to the generalized Padé approximations are constructed. The corresponding weighting parameters and weighting functions for the Padé and generalized Padé approximations are given explicitly. Copyright © 2000 John Wiley & Sons, Ltd.     

Inherited Thrombophilia in the Era of Direct Oral Anticoagulants

Severe inherited thrombophilia includes rare deficiencies of natural anticoagulants (antithrombin and proteins C and S) and homozygous or combined factor V Leiden and FII G20210A variants. They are associated with a high thrombosis risk and can impact the duration of anticoagulation therapy for patients with a venous thromboembolism (VTE) event. Therefore, it is important to diagnose thrombophilia and to use adapted anticoagulant therapy. The widespread use of direct anticoagulants (DOACs) for VTE has raised new issues concerning inherited thrombophilia. Concerning inherited thrombophilia diagnosis, DOACs are directed toward either FIIa or FXa and can therefore interfere with coagulation assays. This paper reports DOAC interference in several thrombophilia tests, including the assessment of antithrombin, protein S, and protein C activities. Antithrombin activity and clot-based assays used for proteins C and S can be overestimated, with a risk of missing a deficiency. The use of a device to remove DOACs should be considered to minimize the risk of false-negative results. The place of DOACs in the treatment of VTE in thrombophilia patients is also discussed. Available data are encouraging, but given the variability in thrombosis risk within natural anticoagulant deficiencies, evidence in patients with well-characterized thrombophilia would be useful.     

A Multi-Strategy Sequencing Workflow in Inherited Retinal Dystrophies: Routine Diagnosis,Addressing Unsolved Cases and Candidate Genes Identification

The management of unsolved inherited retinal dystrophies (IRD) cases is challenging since no standard pipelines have been established. This study aimed to define a diagnostic algorithm useful for the diagnostic routine and to address unsolved cases. Here, we applied a Next-Generation Sequencing-based workflow, including a first step of panel sequencing (PS) followed by clinical-exome sequencing (CES) and whole-exome sequencing (WES), in 46 IRD patients belonging to 42 families. Twenty-six likely causal variants in retinal genes were found by PS and CES. CES and WES allowed proposing two novel candidate loci (WDFY3 and a X-linked region including CITED1), both abundantly expressed in human retina according to RT-PCR and immunohistochemistry. After comparison studies, PS showed the best quality and cost values, CES and WES involved similar analytical efforts and WES presented the highest diagnostic yield. These results reinforce the relevance of panels as a first step in the diagnostic routine and suggest WES as the next strategy for unsolved cases, reserving CES for the simultaneous study of multiple conditions. Standardizing this algorithm would enhance the efficiency and equity of clinical genetics practice. Furthermore, the identified candidate genes could contribute to increase the diagnostic yield and expand the mutational spectrum in these disorders.     

川中乐山—龙女寺古隆起震旦系天然气成藏条件分析

认为四川盆地中部乐山—龙女寺古隆起震旦系含油气系统属多源多期成藏的复合含油气系统，烃源主要来自下寒武统筇竹寺组底部腐泥型暗色泥岩，其次为震旦系灯影组三段暗色藻白云岩和页岩；最有利的储盖组合是以灯影组四段、三段为储集层和以下寒武统黑色页岩为盖层的组合，其次是灯影组三段中部的白云岩段储盖组合。灯三段烃源岩在奥陶纪末—志留纪进入大量生烃期，生成的液态烃在古隆起顶部形成古油藏，志留纪末的抬升终止了第一期成烃作用，晚二叠世以来进入二次生烃期；三叠纪—中侏罗世，筇竹寺组烃源岩进入主要生烃期，在古隆起顶部灯影组风化壳形成古油气藏；晚侏罗世—早白垩世，筇竹寺组烃源岩处于生气高峰期，古油气藏的液态烃热裂解成气态烃，这些气态烃聚集形成现今的气藏。乐山—龙女寺古隆起震旦系储盖和保存条件较好，高石梯—磨溪潜伏构造带及华蓥山构造带是有利勘探区。     

继承性构造与新生构造并存的时空发育特征——“盆”“山”耦合理论指导油气勘探的一个切入点

研究继承性构造与新生构造并存的时空发育特征是"盆""山"耦合理论指导油气勘探的一个切入点。文章从超大陆旋回,成盆动力学和含油气构造带研究3方面展开论述,强调"寻根溯源",在具体分析每一阶段的新生构造时注意基底/先存构造的影响,从含油气盆地的研究深入到含油气构造带的研究,从盆地的运动学研究发展到动力学(包括外动力和内动力)研究。在分析新生构造演化的2种趋势的基础上指出了海相油气勘探的3类主要靶区。以新生构造的演化为主线,结合"源""运""聚""藏"的研究,借鉴石油地质学研究的其它新思想,"盆""山"耦合将成为指导油气勘探尤其是海相油气勘探的创新思路之一。     

一种微观漏洞数量预测模型

全球每年因为软件漏洞造成的损失十分巨大,而软件漏洞分析方法的缺陷使得漏洞本身难以被发现,因此大家开始对漏洞数量进行预测,预测软件的漏洞数量对信息安全评估有着重要的意义.目前主要的估算方法是漏洞密度的方法,但此方法仅是宏观范围内估算,并不能反映漏洞软件本身的性质.提出从软件的微观角度进行软件漏洞数量的估算通过提取软件典型微观参数,从而发现软件漏洞数量与其微观参数的联系,相比漏洞密度的预测方法具有相当的优势.软件微观漏洞模型在提出漏洞继承假设的基础上,认为软件的漏洞数量与它的某些微观参数之间存在线性关系,并给出了根据软件微观参数以及其历史版本漏洞数据预测软件漏洞数量的方法.通过对7款软件进行验证,证明了软件微观漏洞模型在预测软件漏洞数量时的有效性与准确性.