NPHS2 mutation analysis shows genetic heterogeneityof steroid-resistant nephrotic syndrome and lowpost-transplant recurrence

NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence.BackgroundMutations of NPHS2 are causative in familial autosomal-recessive (AR) and sporadic steroid-resistant nephrotic syndrome (SRNS). This study aimed to determine the spectrum of NPHS2 mutations and to establish genotype-phenotype correlations.MethodsNPHS2 mutation analysis was performed in 338 patients from 272 families with SRNS: 81 families with AR SRNS, 172 patients with sporadic SRNS, and 19 patients with diffuse mesangial sclerosis (DMS).ResultsTwenty-six different pathogenic NPHS2 mutations were detected, including 13 novel mutations. The mutation detection rate was 43% for familial AR and 10.5% for sporadic SRNS, confirming genetic heterogeneity. No pathogenic NPHS2 mutations were found in DMS patients. Age at onset in patients with two pathogenic mutations was earlier, especially in cases with frameshift, truncating, and the R138Q missense mutations. Patients with only one NPHS2 mutation or variant had late-onset NS. Triallelic inheritance was observed in one patient with a homozygous R138Q mutation and a de novo NPHS1 mutation. Among 32 patients with two NPHS2 mutations who underwent kidney transplantation, only one developed late recurrence of focal segmental glomerulosclerosis (FSGS). Among 25 patients with sporadic SRNS and post-transplantation recurrence, we detected a heterozygous NPHS2 mutation in one case, and heterozygous variants/polymorphisms in 3 cases.ConclusionPatients with two pathogenic NPHS2 mutations present with early-onset SRNS and very low incidence of post-transplantation recurrence. Heterozygous NPHS2 variants may play a role in atypical cases with mild, late-onset course, and recurrence after transplantation

NPHS2 mutation analysis shows genetic heterogeneityof steroid-resistant nephrotic syndrome and lowpost-transplant recurrence

NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence.BackgroundMutations of NPHS2 are causative in familial autosomal-recessive (AR) and sporadic steroid-resistant nephrotic syndrome (SRNS). This study aimed to determine the spectrum of NPHS2 mutations and to establish genotype-phenotype correlations.MethodsNPHS2 mutation analysis was performed in 338 patients from 272 families with SRNS: 81 families with AR SRNS, 172 patients with sporadic SRNS, and 19 patients with diffuse mesangial sclerosis (DMS).ResultsTwenty-six different pathogenic NPHS2 mutations were detected, including 13 novel mutations. The mutation detection rate was 43% for familial AR and 10.5% for sporadic SRNS, confirming genetic heterogeneity. No pathogenic NPHS2 mutations were found in DMS patients. Age at onset in patients with two pathogenic mutations was earlier, especially in cases with frameshift, truncating, and the R138Q missense mutations. Patients with only one NPHS2 mutation or variant had late-onset NS. Triallelic inheritance was observed in one patient with a homozygous R138Q mutation and a de novo NPHS1 mutation. Among 32 patients with two NPHS2 mutations who underwent kidney transplantation, only one developed late recurrence of focal segmental glomerulosclerosis (FSGS). Among 25 patients with sporadic SRNS and post-transplantation recurrence, we detected a heterozygous NPHS2 mutation in one case, and heterozygous variants/polymorphisms in 3 cases.ConclusionPatients with two pathogenic NPHS2 mutations present with early-onset SRNS and very low incidence of post-transplantation recurrence. Heterozygous NPHS2 variants may play a role in atypical cases with mild, late-onset course, and recurrence after transplantation

Технологическая подготовка производства изготовления детали «Корпус функционной муфты» на станках с ЧПУ

Выпускная квалификационная работа 72 страницы, 13 рисунков, 23 таблицы, 15 источников, страниц альбомной документации. Ключевые слова: крышка, крышка для выходного вала, машиностроение, технологический процесс. Объектом исследования является деталь типа «Крышка». Цель работы – разработка технологии производства детали “Крышка”. В процессе работы проведены теоретические исследования существующих технологических процессов, используемых в машиностроительном производстве, сделан сравнительный анализ их достоинств и недостатков. Результатом данной работы является технологический процесс изготовление детали “Крышка”, применимого для реального производства, где есть необходимые оборудование.Abschlusstraining Arbeit beträgt 72 Seiten, 13 Abbildungen, 23 Tabellen, 15 Quellen der Landschafts Seiten der Dokumentation. Stichworte: Abdeckung, Abdeckung für die Abtriebswelle, Maschinenbau, Verfahrenstechnik. Das Ziel der Forschung ist Teil der "Deckel". Ziel - zu Produktionstechnologie Details "Deckel" zu entwickeln. In dem Verfahren der theoretischen Forschung der bestehenden technologischen Prozessen in der Maschinenbauindustrie verwendet wird, aus einer vergleichenden Analyse ihrer Stärken und Schwächen. Das Ergebnis dieser Arbeit ist es, die Produktion von Teilen "Deckel", die für die reale Produktion zu verarbeiten, die die notwendige Ausrüstung

Podocin Inactivation in Mature Kidneys Causes Focal Segmental Glomerulosclerosis and Nephrotic Syndrome

Podocin is a critical component of the glomerular slit diaphragm, and genetic mutations lead to both familial and sporadic forms of steroid-resistant nephrotic syndrome. In mice, constitutive absence of podocin leads to rapidly progressive renal disease characterized by mesangiolysis and/or mesangial sclerosis and nephrotic syndrome. Using established Cre-loxP technology, we inactivated podocin in the adult mouse kidney in a podocyte-specific manner. Progressive loss of podocin in the glomerulus recapitulated albuminuria, hypercholesterolemia, hypertension, and renal failure seen in nephrotic syndrome in humans. Lesions of FSGS appeared after 4 wk, with subsequent development of diffuse glomerulosclerosis and tubulointerstitial damage. Interestingly, conditional inactivation of podocin at birth resulted in a gradient of glomerular lesions, including mesangial proliferation, demonstrating a developmental stage dependence of renal histologic patterns of injury. The development of significant albuminuria in this model occurred only after early and focal foot process effacement had progressed to diffuse involvement, with complete absence of podocin immunolabeling at the slit diaphragm. Finally, we identified novel potential mediators and perturbed molecular pathways, including cellular proliferation, in the course of progression of renal disease leading to glomerulosclerosis, using global gene expression profiling

Application of heuristic algorithms in analyzing data to solve the problem of detection of electric centrifugal pumping units

Обеспечение эффективного контроля и предотвращение отказов электроцентробежных насосных установок ввиду их широкого распространения является актуальной и востребованной задачей. Применение систем автоматизированного контроля электроцентробежных насосных установок позволяет повысить качество и скорость принимаемых решений о их техническом состоянии. Все методы диагностирования установок электроцентробежных насосов направлены на контроль состояния составных узлов и сводятся к анализу временных рядов, являющихся временными развёртками параметров эксплуатации. Традиционно применяемые линейные методы исследования временных рядов в последние десятилетия были существенно расширены нелинейными методами, среди которых значительное развитие получили эвристические алгоритмы. Цель работы: повышение эффективности определения технического состояния установок электроцентробежных насосов в процессе эксплуатации. Методы исследования. Предложенный в работе подход основывается на решении задачи диагностирования путём декомпозиции на следующие подзадачи: автоматическая сегментация, формализация и интерпретация полученных данных. Сегментация рассмотрена как задача кластеризации, цель которой - установление автокорреляционных связей между значениями временного ряда с формированием темпоральных кластеров и адаптивной аппроксимации в рамках установленных участков при сохранении локальных особенностей сигналов. Для каждого выделяемого класса отклонений работы электроцентробежных насосных установок сформированы решающие правила на основании экспертных знаний. Основными отличиями от классического подхода к задаче диагностирования являются: отсутствие необходимости участия эксперта при решении задачи кластеризации; обеспечение адаптивной аппроксимации в рамках выделенных временных участков; возможность реализации интерпретируемых подходов распознавания неисправностей. Результаты. Предложен подход, основанный на решении задачи диагностирования путём её декомпозиции на следующие подзадачи: автоматическая сегментация, формализация и интерпретация полученных данных. Определён необходимый перечень контролируемых параметров эксплуатации электроцентробежных насосных установок, позволяющий реализовать процесс технического диагностирования.Ensuring effective control and preventing failures of electrical submersible pumps, because of their wide distribution is the relevant and demanded task. The use of automated control systems of electric centrifugal pumping units allows improving the quality and speed of decisions made about their technical condition. All methods of diagnosing the installation of electrical submersible pumps are aimed at monitoring the state of the composite nodes, and are reduced to the analysis of time series, which are the time scans of the operation parameters. Traditionally applied linear methods of time series research in the last decades have been substantially expanded by nonlinear methods, among which heuristic algorithms were developed significantly. The main aim is to increase the efficiency of determining the technical state of installations of electric centrifugal pumps during operation. Methods. The approach proposed in this paper is based on solving the diagnostic problem by decomposition into the following subtasks: automatic segmentation, formalization and interpretation of the data obtained. Segmentation is considered as a clustering problem, the purpose of which is the establishment of autocorrelation links between the values of the time series with the formation of temporal clusters and adaptive approximation within the established areas while preserving the local features of the signals. For each allocated class of deviations in operation of electric centrifugal pumping units, the decisive rules are formed based on expert knowledge. The main differences from the classical approach to the problem of diagnosis are: the lack of the need for expert participation in solving the clustering problem; providing adaptive approximation within the allocated time intervals; the possibility of implementing interpretable approaches to fault recognition. Results. The authors have proposed the approach based on solving the diagnostic problem by its decomposition into the following subtasks: automatic segmentation, formalization and interpretation of the data obtained. The necessary list of controlled parameters of operation of the electric centrifugal pumping units is determined. The list allows technical diagnosis

Maternal Environment Interacts with Modifier Genes to Influence Progression of Nephrotic Syndrome

Mutations in the NPHS2 gene, which encodes podocin, are responsible for some cases of sporadic and familial autosomal recessive steroid-resistant nephrotic syndrome. Inter- and intrafamilial variability in the progression of renal disease among patients bearing NPHS2 mutations suggests a potential role for modifier genes. Using a mouse model in which the podocin gene is constitutively inactivated, we sought to identify genetic determinants of the development and progression of renal disease as a result of the nephrotic syndrome. We report that the evolution of renal disease as a result of nephrotic syndrome in Nphs2-null mice depends on genetic background. Furthermore, the maternal environment significantly interacts with genetic determinants to modify survival and progression of renal disease. Quantitative trait locus mapping suggested that these genetic determinants may be encoded for by genes on the distal end of chromosome 3, which are linked to proteinuria, and on the distal end of chromosome 7, which are linked to a composite trait of urea, creatinine, and potassium. These loci demonstrate epistatic interactions with other chromosomal regions, highlighting the complex genetics of renal disease progression. In summary, constitutive inactivation of podocin models the complex interactions between maternal and genetically determined factors on the progression of renal disease as a result of nephrotic syndrome in mice