14 research outputs found
A New Guide Lifter for the Transceiver of USBL
A new guide lifter has been put forward for the transceiver of Ultra Short Base Line (USBL) with a worm gear reducer applied as self-locking of the lifter and a chain structure applied to drive the sliding shaft moving up and down. The new device is 7500 mm long and connected to the end of the transceiver. Linear motion products are introduced to ensure the shaft unable to rotate and the position measurements are provided by position sensors. A heavy self-sealing sliding bearing, which is 800 mm in length, keeps the shaft running reliably. Then the three-dimensional model is built and the structure parameters of the lifter are calculated. Later, the working process of the lifter is simulated to guarantee the movement parameters meet the request of USBL. Finally, the experiment on the intensity and stiffness of the lifter is carried out via the finite element model of the lifter built in ANSYS with the maximum load conditions and the result has been experimentally verified. This device provides a reliable approach of operating USBL which plays a vitally important role in ocean exploration and the research results are successfully applied to the scientific research vessels of Dayang No. 1 as well as Xiangyanghong No. 9
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Atypical Case Of Wolfram Syndrome Revealed Through Targeted Exome Sequencing In A Patient With Suspected Mitochondrial Disease
Background: Mitochondrial diseases comprise a diverse set of clinical disorders that affect multiple organ systems with varying severity and age of onset. Due to their clinical and genetic heterogeneity, these diseases are difficult to diagnose. We have developed a targeted exome sequencing approach to improve our ability to properly diagnose mitochondrial diseases and apply it here to an individual patient. Our method targets mitochondrial DNA (mtDNA) and the exons of 1,600 nuclear genes involved in mitochondrial biology or Mendelian disorders with multi-system phenotypes, thereby allowing for simultaneous evaluation of multiple disease loci. Case Presentation: Targeted exome sequencing was performed on a patient initially suspected to have a mitochondrial disorder. The patient presented with diabetes mellitus, diffuse brain atrophy, autonomic neuropathy, optic nerve atrophy, and a severe amnestic syndrome. Further work-up revealed multiple heteroplasmic mtDNA deletions as well as profound thiamine deficiency without a clear nutritional cause. Targeted exome sequencing revealed a homozygous c.1672C > T (p.R558C) missense mutation in exon 8 of WFS1 that has previously been reported in a patient with Wolfram syndrome. Conclusion: This case demonstrates how clinical application of next-generation sequencing technology can enhance the diagnosis of patients suspected to have rare genetic disorders. Furthermore, the finding of unexplained thiamine deficiency in a patient with Wolfram syndrome suggests a potential link between WFS1 biology and thiamine metabolism that has implications for the clinical management of Wolfram syndrome patients
Inversion of Bubble Size Distribution Based on Whale Optimization Algorithm
A particle size inversion method based on whale optimization algorithm (WOA) is presented. In the experiment, the small angle forward scattering measurement system is used to conduct experimental research on the inversion of bubble particle size. WOA is used to invert and simulate the bubbles that follow a certain distribution, adding different levels of random noise to verify the stability of the algorithm. The results verify the feasibility and stability of applying WOA to particle size inversion
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Abstract B018: MTA-cooperative PRMT5 inhibitors selectively modulate RNA splicing in MTAP-deleted cancer cells across histologies
Abstract PRMT5 is a type II arginine methyltransferase that forms an active complex with methylosome protein 50 (MEP50) to catalyze the symmetric dimethylation (SDMA) of arginine residues in proteins that regulate biological roles including modulation of apoptosis, DNA damage response and RNA processing. Some of the best characterized PRMT5 substrates are SNRPB, SNRPD1 and SNRPD3, which are necessary for the formation of the spliceosome and therefore RNA splicing fidelity. The development of MTA-cooperative PRMT5 inhibitors, including the clinical stage inhibitors TNG908 and TNG462, have been shown in preclinical studies to selectively inhibit PRMT5 in MTAP-deleted cancer cells while sparing normal, MTAP-intact cells. Consistent with this selective, on-target mechanism, treatment with TNG908 in preclinical studies results in increased aberrant RNA splicing in MTAP-deleted cells relative to MTAP-intact cells. As MTAP loss occurs in 10-15% of all human cancer, the identification of a signature of alternative splicing events may report pharmacodynamic activity of PRMT5 inhibitors and potentially predict patient response. Similar splicing alterations caused by PRMT5 inhibition were identified in preclinical MTAP-deleted cancer models representing glioblastoma, non-small cell lung cancer, among others, suggesting the events are histology-agnostic. Additionally, titration of exogenous MTA, an endogenous inhibitor of PRMT5, recapitulated the observed splicing events in preclinical MTAP-proficient cells. Similar findings were observed utilizing a pharmacological inhibitor of MTAP suggesting that the identified alternative splicing events are dependent on accumulation of MTA. Collectively, these data suggest that a PRMT5-dependent RNA splicing signature can be developed to identify solid tumors that may best respond to MTA-cooperative PRMT5 inhibitors as well as monitor their pharmacodynamic activity. Citation Format: Matthew R Tonini, Samuel R Meier, Shangtao Liu, Kevin M Cottrell, John P Maxwell, Jannik N Andersen, Alan Huang, Luisa Cimmino, Kimberly J Briggs. MTA-cooperative PRMT5 inhibitors selectively modulate RNA splicing in MTAP-deleted cancer cells across histologies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B018
Kdm2b Regulates Somatic Reprogramming through Variant PRC1 Complex-Dependent Function
Polycomb repressive complex 1 (PRC1) plays essential roles in cell-fate determination. Recent studies have found that the composition of mammalian PRC1 is particularly varied and complex; however, little is known about the functional consequences of these variant PRC1 complexes on cell-fate determination. Here, we show that Kdm2b promotes Oct4-induced somatic reprogramming through recruitment of a variant PRC1 complex (PRC1.1) to CpG islands (CGIs). Furthermore, we find that bone morphogenetic protein (BMP) represses Oct4/Kdm2b-induced somatic reprogramming selectively. Mechanistically, BMP-SMAD pathway attenuates PRC1.1 occupation and H2AK119 ubiquitination at genes linked to development, resulting in the expression of mesendodermal factors such as Sox17 and a consequent suppression of somatic reprogramming. These observations reveal that PRC1.1 participates in the establishment of pluripotency and identify BMP4 signaling as a modulator of PRC1.1 function
Next-Generation Sequencing Strategies Enable Routine Detection of Balanced Chromosome Rearrangements for Clinical Diagnostics and Genetic Research
The contribution of balanced chromosomal rearrangements to complex disorders remains unclear because they are not detected routinely by genome-wide microarrays and clinical localization is imprecise. Failure to consider these events bypasses a potentially powerful complement to single nucleotide polymorphism and copy-number association approaches to complex disorders, where much of the heritability remains unexplained. To capitalize on this genetic resource, we have applied optimized sequencing and analysis strategies to test whether these potentially high-impact variants can be mapped at reasonable cost and throughput. By using a whole-genome multiplexing strategy, rearrangement breakpoints could be delineated at a fraction of the cost of standard sequencing. For rearrangements already mapped regionally by karyotyping and fluorescence in situ hybridization, a targeted approach enabled capture and sequencing of multiple breakpoints simultaneously. Importantly, this strategy permitted capture and unique alignment of up to 97% of repeat-masked sequences in the targeted regions. Genome-wide analyses estimate that only 3.7% of bases should be routinely omitted from genomic DNA capture experiments. Illustrating the power of these approaches, the rearrangement breakpoints were rapidly defined to base pair resolution and revealed unexpected sequence complexity, such as co-occurrence of inversion and translocation as an underlying feature of karyotypically balanced alterations. These findings have implications ranging from genome annotation to de novo assemblies and could enable sequencing screens for structural variations at a cost comparable to that of microarrays in standard clinical practice