Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration.

OBJECTIVE: To characterize clinically and molecularly an early-onset, variably progressive neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3 consanguineous families. METHODS: We used whole-exome sequencing (WES) (families 1 and 2) and a combined approach based on homozygosity mapping and WES (family 3). We performed in vitro studies to explore the effect of the nontruncating SQSTM1 mutation on protein function and the effect of impaired SQSTM1 function on autophagy. We analyzed the consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in vivo using zebrafish as a model. RESULTS: We identified 3 homozygous inactivating variants, including a splice site substitution (c.301+2T>A) causing aberrant transcript processing and accelerated degradation of a resulting protein lacking exon 2, as well as 2 truncating changes (c.875_876insT and c.934_936delinsTGA). We show that loss of SQSTM1 causes impaired production of ubiquitin-positive protein aggregates in response to misfolded protein stress and decelerated autophagic flux. The consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in zebrafish documented a variable but reproducible phenotype characterized by cerebellum anomalies ranging from depletion of axonal connections to complete atrophy. We provide a detailed clinical characterization of the disorder; the natural history is reported for 2 siblings who have been followed up for >20 years. CONCLUSIONS: This study offers an accurate clinical characterization of this recently recognized neurodegenerative disorder caused by biallelic inactivating mutations in SQSTM1 and links this phenotype to defective selective autophagy

Possibilities of improving contrast for the measurements of the 131I volume concentration by scintillation γ-spectrometers

The main problem of measuring the 131I volume concentration (364-keV g-line) with gamma spectrometers with low-resolution scintillation detectors (NaI:Tl, CsI:Tl) is due to the overlap with the Compton edge (384 keV) from the attendant radiation of 76As. The problem can be largely eliminated by improving the energy resolution of the spectrometer, increasing the volume of the crystal, or using an anti-Compton spectrometer. Using the Monte Carlo simulation (GEANT4 package), the last two methods of increasing the contrast of instrumental energy spectra were investigated. It was found that an 8-fold increase in the scintillator volume improves the ratio of the 131I peak area to the area of the Compton continuum below it from the 76As radiation only by 1.42 times. Therefore, the main attention was paid to the comparative studies of the constructions of anti-Compton detectors based on CsI:Tl crystals in a detector-analyzer and a detector-protector. Several designs of anti-Compton detectors suitable for harsh application conditions at nuclear power plants were proposed. In the first of them, the protector crystal is in the form of a disk with a diameter equal to the diameter of the crystal analyzer, and in the second - in the form of a “glass” put on the crystal analyzer. The thickness of the protector crystals in both cases was 10 mm. The expected improvement in contrast with respect to the single-crystal design was up to 3 or more times. Modern nuclear electronics and computers make possible the successful application of this method in industrial spectrometric installations. The contrast of the resulting spectra could be increased by an order of magnitude or more in comparison with the simple anticoincidence spectra.Основная проблема измерения объемной концентрации 131I (g-линия 364 кэВ) гамма-спектрометрами со сцинтилляционными детекторами низкого разрешения (NaI:Tl, CsI:Tl) обусловлена перекрытием с комптоновским краем (384 кэВ) от сопутствующего излучения 76As. Проблема может быть в значительной степени устранена улучшением энергетического разрешения спектрометра, увеличением объема кристалла или использованием антикомптоновского спектрометра. С применением моделирования методом Монте-Карло (пакет GEANT4) были исследованы два последних способа увеличения контрастности аппаратурных энергетических спектров. Выяснено, что 8-кратное увеличение объема сцинтиллятора улучшает отношение площади пика 131I к площади комптоновского континуума под ним от излучения 76As лишь в 1.42 раза. Поэтому основное внимание было уделено сравнительным исследованиям конструкций антикомптоновских детекторов на основе кристаллов CsI:Tl в детекторе-анализаторе и детекторе-протекторе. Предложены варианты конструкций антикомптоновских детекторов, пригодных для жестких условий применения на АЭС. В первой из них кристалл-протектор в виде диска с диаметром равным диаметру кристалла-анализатора, а во второй – в виде “стакана”, надеваемого на кристалл-анализатор. Толщина кристаллов-протекторов в обоих случаях равна 10 мм. Ожидаемое улучшение контрастности по отношению к однокристальной конструкции может достигать трех и более раз. Намечены направления дальнейшего совершенствования двухкристальных спектрометров, предназначенных для мониторирования содержания в воздухе радионуклида 131I. Наиболее перспективным представляется известный с 1960-х годов аппаратно-программный метод, использующий вычитание из спектра антисовпадений (антикомптоновский спектр) части спектра совпадений. Современные ядерная электроника и компьютеры делают возможным успешное применение этого метода в промышленных спектрометрических установках. Контрастность результирующих спектров может быть увеличена на порядок и более по сравнению с простыми спектрами антисовпадений

AN OPTIMIZATION PROBLEM FOR A PRODUCTION SYSTEM WITH REAL OPTION APPROACH (Nonlinear Analysis and Convex Analysis)

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes