Repeat expansion scanning of the NOTCH2NLC gene in patients with multiple system atrophy

© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. Objective: Trinucleotide GGC repeat expansion in the 5’UTR of the NOTCH2NLC gene has been recognized as the pathogenesis of neuronal intranuclear inclusion disease (NIID). Previous studies have described that some NIID patients showed clinical and pathological similarities with multiple system atrophy (MSA). This study aimed to address the possibility that GGC repeat expansion in NOTCH2NLC might be associated with some cases diagnosed as MSA. Methods: A total of 189 patients with probable or possible MSA were recruited to screen for GGC repeat expansion in NOTCH2NLC by repeat-primed PCR (RP-PCR). In addition, long-read sequencing (LRS) was performed for all patients with RP-PCR-positive expansion, five patients with RP-PCR-negative expansion, and five controls on the Nanopore platform. Skin biopsies were performed on two patients with GGC expansion. Results: Five of 189 patients (2.6%) were found to have GGC expansion in NOTCH2NLC. LRS results identified that the five patients had GGC expansion between 101 and 266, but five patients with RP-PCR-negative expansion and five controls had GGC expansion between 8 and 29. Besides the typical symptoms and signs of MSA, patients with GGC expansion might have longer disease duration, severe urinary retention, and prominent cognitive impairment. In the skin samples from the patients with GGC expansion, typical p62-postive but alpha-synuclein-negative intranuclear inclusions were found in fibroblasts, adipocyte and ductal epithelial cells of sweat glands. Conclusion: Trinucleotide GGC repeat expansion in NOTCH2NLC could be observed in patients with clinically diagnosed MSA. Adult-onset NIID should be considered as a differential diagnosis of MSA

U-Shaped Relationship Between Functional Outcome and Serum Uric Acid in Ischemic Stroke

Background/Aims: We sought to assess a consecutive number of patients with first-ever acute ischemic stroke (AIS), the clinical relevance in regard to functional outcome of the serum uric acid (SUA) measured at admission. Methods: In 2 prospective centers for observational study, serum concentrations of SUA were measured on admission in the serum of 710 consecutive patients with AIS. SUA concentrations were determined by high-performance liquid chromatography. SUA, NIH stroke scale (NIHSS), and conventional risk factors were evaluated to determine their value to predict functional outcome within 3 months. Results: During the follow-up, an unfavorable functional outcome (defined as a mRS score > 2) was found in 219 (30.8%) patients. The unfavorable functional outcome distribution across the SUA quartiles ranged between 12.4% (third quartile) and 50.6% (first quartile). After adjusting for all other significant outcome predictors, SUA concentration remained an independent unfavorable outcome predictor with an adjusted OR of 0.996 (95% CI, 0.993-0.998; P< 0.001). Conclusions: The data show that the U-shaped nature of the exposure-risk relationship was more prominent when the data were assessed in deciles (based on the SUA values). This model predicted the lowest relative risk of unfavorable outcome in the 67th percentile (corresponding to 309 µmol/L). SUA was significantly associated with the risk of poor functional outcomes in Chinese patients with stroke

Neural-Linear Attack Based on Distribution Data and Its Application on DES

The neural-differential distinguisher proposed by Gohr boosted the development of neural aided differential attack. As another significant cryptanalysis technique, linear attack has not been developing as rapidly in combination with deep learning technology as differential attack. In 2020, Hou et al. proposed the first neural-linear attack with one bit key recovery on 3, 4 and 5-round DES and restricted multiple bits recovery on 4 rounds, where the effective bits in one plain-ciphertext pair are spliced as one data sample. In this paper, we compare the neural-linear cryptanalysis with neural-differential cryptanalysis and propose a new data preprocessing algorithm depending on their similarities and differences. We call the new data structure distribution data. Basing on it, we mount our key recovery on round-reduced DES—first, we raise the accuracy of the neural-linear distinguisher by about 50%. Second, our distinguisher improves the effectiveness of one bit key recovery against 3, 4 and 5-round DES than the former one, and attack 6-round DES with success rate of 60.6% using 2048 plain-ciphertext pairs. Third, we propose a real multiple bit key recovery algorithm, leading neural-linear attack from theory to practice

3-D electrical structure and tectonic dynamics in the Yangbajing area based on the array magnetotelluric data

The well-known N-S-trending fault in the Yangbajing area plays a crucial role in the tectonic evolution of the Tibetan Plateau. Previous researches on a few E-W geophysical profiles suggested that the eastern shear at the base of the upper crust and/or lithosphere deformation brought on by asthenosphere upwelling are the major causes of the Yadong-Gulu rift’s creation. Here we propose a 3-D electrical resistivity model derived from the magnetotelluric (MT) array data spanning the Yadong-Gulu rift (YGR), and the distribution of temperature and melt fraction is estimated by the experimental calibrated relationships bridging electrical conductivity and temperature/melt fraction. The result reveals that the Indian slab subducted steeply in the east of the Yadong-Gulu rift, while Indian slab may have delaminated with a flat subduction angle in the west. The temperature distribution shows that the upper mantle of the northern Lhasa terrane is hotter than that of the southern Lhasa terrane. This is likely the result of mantle upwelling caused by either the subduction of the Indian slab or thickened Tibetan lithosphere delamination. Moreover, the strength of the mid-lower crust is so low that it may meet the conditions of the local crust flow in the west-east direction. The local crustal flow and the pulling force from the upwelling asthenosphere jointly contributed to the formation of the Yadong-Gulu rift. These main factors exist in different stages of the evolution of the Yadong-Gulu rift

Jump-seq: Genome-Wide Capture and Amplification of 5-Hydroxymethylcytosine Sites

5-Hydroxymethylcytosine (5hmC) arises from the oxidation of 5-methylcytosine (5mC) by Fe2+ and 2-oxoglutarate-dependent 10–11 translocation (TET) family proteins. Substantial levels of 5hmC accumulate in many mammalian tissues, especially in neurons and embryonic stem cells, suggesting a potential active role for 5hmC in epigenetic regulation beyond being simply an intermediate of active DNA demethylation. 5mC and 5hmC undergo dynamic changes during embryogenesis, neurogenesis, hematopoietic development, and oncogenesis. While methods have been developed to map 5hmC, more efficient approaches to detect 5hmC at base resolution are still highly desirable. Herein, we present a new method, Jump-seq, to capture and amplify 5hmC in genomic DNA. The principle of this method is to label 5hmC by the 6-N3-glucose moiety and connect a hairpin DNA oligonucleotide carrying an alkyne group to the azide-modified 5hmC via Huisgen cycloaddition (click) chemistry. Primer extension starts from the hairpin motif to the modified 5hmC site and then continues to “land” on genomic DNA. 5hmC sites are inferred from genomic DNA sequences immediately spanning the 5-prime junction. This technology was validated, and its utility in 5hmC identification was confirmed

Whole Exome Sequencing Identifies a Novel Pathogenic RET Variant in Hirschsprung Disease

Hirschsprung disease is a birth defect characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract. To uncover genetic variants contributing to HSCR, we performed whole exome sequencing on seven members of an HSCR family. With the minor allele frequency (MAF) calculated by gnomAD, we finally filtered a total of 1,059 rare variants in this family (MAF < 0.1%). With the mode of inheritance and pathogenicity scores by bioinformatics tools, we identified an in-frameshift variant p.Phe147del in RET as the disease-causing variant. Further analysis revealed that the in-frameshift variant may function by disrupting the glycosylation of RET protein. To our knowledge, this is the first study to report the in-frameshift variant p.Phe147del in RET responsible for heritable HSCR

Sciences for The 2.5-meter Wide Field Survey Telescope (WFST)

The Wide Field Survey Telescope (WFST) is a dedicated photometric survey facility under construction jointly by the University of Science and Technology of China and Purple Mountain Observatory. It is equipped with a primary mirror of 2.5m in diameter, an active optical system, and a mosaic CCD camera of 0.73 Gpix on the main focus plane to achieve high-quality imaging over a field of view of 6.5 square degrees. The installation of WFST in the Lenghu observing site is planned to happen in the summer of 2023, and the operation is scheduled to commence within three months afterward. WFST will scan the northern sky in four optical bands (u, g, r, and i) at cadences from hourly/daily to semi-weekly in the deep high-cadence survey (DHS) and the wide field survey (WFS) programs, respectively. WFS reaches a depth of 22.27, 23.32, 22.84, and 22.31 in AB magnitudes in a nominal 30-second exposure in the four bands during a photometric night, respectively, enabling us to search tremendous amount of transients in the low-z universe and systematically investigate the variability of Galactic and extragalactic objects. Intranight 90s exposures as deep as 23 and 24 mag in u and g bands via DHS provide a unique opportunity to facilitate explorations of energetic transients in demand for high sensitivity, including the electromagnetic counterparts of gravitational-wave events detected by the second/third-generation GW detectors, supernovae within a few hours of their explosions, tidal disruption events and luminous fast optical transients even beyond a redshift of 1. Meanwhile, the final 6-year co-added images, anticipated to reach g about 25.5 mag in WFS or even deeper by 1.5 mag in DHS, will be of significant value to general Galactic and extragalactic sciences. The highly uniform legacy surveys of WFST will also serve as an indispensable complement to those of LSST which monitors the southern sky.Comment: 46 pages, submitted to SCMP