BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we ...conducted whole-genome CRISPR-Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, 'Shieldin' (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1-deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP-inhibitor resistance.
This paper investigates the influences of nonperiodic rainbow resonators on the vibration attenuation of two-dimensional metamaterial plates. Rainbow metamaterial plates composed of thin host plates ...and nonperiodic stepped resonators are considered and compared with periodic metamaterial plates. The metamaterial plates are modelled with the finite element modelling method and verified by the plane wave expansion method. It was found that the rainbow metamaterial plates with spatially varying resonators possess broader vibration attenuation bands than the periodic metamaterial plate with the same host plates and total mass. The extension of attenuation bands was found not to be attributed to the extended bandgaps for the two-dimensional metamaterial plates, as is generally believed for a one-dimensional metamaterial beam. The complete local resonance bandgap of the metamaterial plates is separated to discrete bandgaps by the modes of nonperiodic resonators. Although the additional modes stop the formation of integrated bandgaps, the vibration of the plate is much smaller than that of resonators at these modal frequencies, the rainbow metamaterial plates could have a distinct vibration attenuation at these modal frequencies and achieve broader integrated attenuation bands as a result. The present paper could offer a new idea for the development of plate structures with broadband vibration attenuation by introducing non-periodicity.
The thermal characteristic of the ball screw feed drive system has great influence on machining accuracy as its thermal deformation would induce the positioning deviation. In this paper, finite ...difference method was applied to simulate the temperature distribution and thermal growth of the ball screw feed drive system under various working conditions. When simulating, the nut was considered a moving heat source, and the boundary conditions were optimized based on response surface methodology. By comparing the simulation results with the testing data, it was verified that the accuracy of the simulation could be improved by using the proposed method.
Tool wear and breakage detection technologies are of vital importance for the development of automatic machining systems and improvement in machining quality and efficiency. The monitoring of ...integral spiral end milling cutters, however, has rarely been investigated due to their complex structures. In this paper, an image acquisition system and image processing methods are developed for the wear and breakage detection of milling cutters based on machine vision. The image acquisition system is composed of three light sources and two cameras mounted on a moving frame, which renders the system applicable in cutters of different dimensions and shapes. The images captured by the acquisition system are then preprocessed with denoising and contrast enhancing operations. The failure regions on the rake face, flank face and tool tip of the cutter are extracted with the Otsu thresholding method and the Markov Random Field image segmentation method afterwards. Eventually, the feasibility of the proposed image acquisition system and image processing methods is demonstrated through an experiment of titanium alloy machining. The proposed image acquisition system and image processing methods not only provide high quality detection of the integral spiral end milling cutter but can also be easily converted to detect other cutting systems with complex structures.
The aim of this study was to provide a comprehensive understanding of similarities and differences in mRNAs, lncRNAs, and circRNAs within cartilage for Kashin-Beck disease (KBD) compared to ...osteoarthritis (OA). We conducted a comparison of the expression profiles of mRNAs, lncRNAs, and circRNAs via whole-transcriptome sequencing in eight KBD and ten OA individuals. To facilitate functional annotation-enriched analysis for differentially expressed (DE) genes, DE lncRNAs, and DE circRNAs, we employed bioinformatic analysis utilizing Gene Ontology (GO) and KEGG. Additionally, using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), we validated the expression levels of four cartilage-related genes in chondrocytes. We identified a total of 43 DE mRNAs, 1451 DE lncRNAs, and 305 DE circRNAs in KBD cartilage tissue compared to OA (
value < 0.05; |log
FC| > 1). We also performed competing endogenous RNA network analysis, which identified a total of 65 lncRNA-mRNA interactions and 4714 miRNA-circRNA interactions. In particular, we observed that
had binding sites for three miRNAs targeting
, while
had binding sites for seven miRNAs targeting
. Our results add a novel set of genes and non-coding RNAs that could potentially serve as candidate diagnostic biomarkers or therapeutic targets for KBD patients.
SHLD1 is part of the Shieldin (SHLD) complex, which acts downstream of 53BP1 to counteract DNA double-strand break (DSB) end resection and promote DNA repair via non-homologous end-joining (NHEJ). ...While 53BP1 is essential for immunoglobulin heavy chain class switch recombination (CSR), long-range V(D)J recombination and repair of RAG-induced DSBs in XLF-deficient cells, the function of SHLD during these processes remains elusive. Here we report that SHLD1 is dispensable for lymphocyte development and RAG-mediated V(D)J recombination, even in the absence of XLF. By contrast, SHLD1 is essential for restricting resection at AID-induced DSB ends in both NHEJ-proficient and NHEJ-deficient B cells, providing an end-protection mechanism that permits productive CSR by NHEJ and alternative end-joining. Finally, we show that this SHLD1 function is required for orientation-specific joining of AID-initiated DSBs. Our data thus suggest that 53BP1 promotes V(D)J recombination and CSR through two distinct mechanisms: SHLD-independent synapsis of V(D)J segments and switch regions within chromatin, and SHLD-dependent protection of AID-DSB ends against resection.
Genetic approaches are increasingly advantageous in characterizing treatment-resistant schizophrenia (TRS). We aimed to identify TRS-associated functional brain proteins, providing a potential ...pathway for improving psychiatric classification and developing better-tailored therapeutic targets.
TRS-related proteome-wide association studies (PWAS) were conducted on genome-wide association studies (GWAS) from CLOZUK and the Psychiatric Genomics Consortium (PGC), which provided TRS individuals (
= 10,501) and non-TRS individuals (
= 20,325), respectively. The reference datasets for the human brain proteome were obtained from ROS/MAP and Banner, with 8,356 and 11,518 proteins collected, respectively. We then performed colocalization analysis and functional enrichment analysis to further explore the biological functions of the proteins identified by PWAS.
In PWAS, two statistically significant proteins were identified using the ROS/MAP and then replicated using the Banner reference dataset, including CPT2 (
= 4.15 × 10
and
= 3.38 × 10
) and APOL2 (
= 4.49 × 10
and
= 8.26 × 10
). Colocalization analysis identified three variants that were causally related to protein expression in the human brain, including
(PP4 = 0.981),
(PP4 = 0.894), and
(PP4 = 0.757). We extended PWAS results from gene-based analysis to pathway-based analysis, identifying 14 gene ontology (GO) terms and the only candidate pathway for TRS, metabolic pathways (
0.05).
Our results identified two protein biomarkers, and cautiously support that the pathological mechanism of TRS is linked to lipid oxidation and inflammation, where mitochondria-related functions may play a role.
Habitual coffee consumption is an addictive behavior with unknown genetic variations and has raised public health issues about its potential health-related outcomes. We performed exome-wide ...association studies to identify rare risk variants contributing to habitual coffee consumption utilizing the newly released UK Biobank exome dataset (n = 200,643). A total of 34,761 qualifying variants were imported into SKAT to conduct gene-based burden and robust tests with minor allele frequency <0.01, adjusting the polygenic risk scores (PRS) of coffee intake to exclude the effect of common coffee-related polygenic risk. The gene-based burden and robust test of the exonic variants found seven exome-wide significant associations, such as OR2G2 (PSKAT = 1.88 × 10−9, PSKAT-Robust = 2.91 × 10−17), VEZT1 (PSKAT = 3.72 × 10−7, PSKAT-Robust = 1.41 × 10−7), and IRGC (PSKAT = 2.92 × 10−5, PSKAT-Robust = 1.07 × 10−7). These candidate genes were verified in the GWAS summary data of coffee intake, such as rs12737801 (p = 0.002) in OR2G2, and rs34439296 (p = 0.008) in IRGC. This study could help to extend genetic insights into the pathogenesis of coffee addiction, and may point to molecular mechanisms underlying health effects of habitual coffee consumption.
Objective: Bitter or sweet beverage perception is associated with alterations in brain structure and function. Our aim is to analyze the genetic association between bitter or sweet beverage ...perception and human brain proteins. Materials and methods: In our study, 8356 and 11,518 proteins were first collected from two reference datasets of human brain proteomes, the ROS/MAP and Banner. The bitter or sweet beverage perception-related proteome-wide association studies (PWAS) were then conducted by integrating recent genome-wide association study (GWAS) data (n = 422,300) of taste perception with human brain proteomes. The human brain gene expression profiles were collected from two reference datasets, including the brain RNA-seq (CBR) and brain RNA-seq splicing (CBRS). The taste perception-related transcriptome-wide association studies (TWAS) were finally performed by integrating the same GWAS data with human brain gene expression profiles to validate the PWAS findings. Results: In PWAS, four statistically significant proteins were identified using the ROS/MAP and then replicated using the Banner reference dataset (all permutated p < 0.05), including ABCG2 for total bitter beverages and tea, CPNE1 for total bitter beverage, ACTR1B for artificially sweetened beverages, FLOT2 for alcoholic bitter beverages and total sweet beverages. In TWAS analysis, six statistically significant genes were detected by CBR and confirmed by the CBRS reference dataset (all permutated p < 0.05), including PIGG for total bitter beverages and non-alcoholic bitter beverages, C3orf18 for total bitter beverages, ZSWIM7 for non-alcoholic bitter beverages, PEX7 for coffee, PKP4 for tea and RPLP2 for grape juice. Further comparison of the PWAS and TWAS found three common statistically significant proteins/genes identified from the Banner and CBR reference datasets, including THBS4 for total bitter beverages, CA4 for non-alcoholic bitter beverages, LIAS for non-grape juices. Conclusions: Our results support the potential effect of bitter or sweet beverage perception on brain function and identify several candidate brain proteins for bitter or sweet beverage perception.
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