Spacer acquisition step in CRISPR-Cas system involves the recognition and subsequent integration of protospacer by the Cas1-Cas2 complex in CRISPR-Cas systems. Here we report an anti-CRISPR protein, ...AcrVA5, and reveal the mechanisms by which it strongly inhibits protospacer integration. Our biochemical data shows that the integration by Cas1-Cas2 was abrogated in the presence of AcrVA5. AcrVA5 exhibits low binding affinity towards Cas2 and acetylates Cas2 at Lys
on the binding interface of the Cas2 and AcrVA5 N-terminal peptide complex to inhibit the Cas2-mediated endonuclease activity. Moreover, a detailed structural comparison between our crystal structure and homolog structure shows that binding of AcrVA5 to Cas2 causes steric hindrance to the neighboring protospacer resulting in the partial disassembly of the Cas1-Cas2 and protospacer complex, as demonstrated by electrophoretic mobility shift assay. Our study focuses on this mechanism of spacer acquisition inhibition and provides insights into the biology of CRISPR-Cas systems.
Emerging studies show that long noncoding RNAs (lncRNAs) play important roles in carcinogenesis and cancer progression. The lncRNA ZEB1 antisense 1 (ZEB1-AS1) derives from the promoter region of ZEB1 ...and we still know little about its expressions, roles and mechanisms.
RACE was used to obtain the sequence of ZEB1-AS1. RNA interference was used to decrease ZEB1-AS1 expression. Adenovirus expression vector was used to increase ZEB1-AS1 expression. CHIP and RIP were used to detect the epigenetic mechanisms by which ZEB1-AS1 regulated ZEB1. CCK8 assay, wound healing assay and transwell assay were used to measure proliferation and migration of prostate cancer cells.
In this study, in prostate cancer cells, we found that RNAi-mediated downregulation of ZEB1-AS1 induced significant ZEB1 inhibition while artificial overexpression of ZEB1-AS1 rescued ZEB1 expression, which means that ZEB1-AS1 promotes ZEB1 expression. Also, ZEB1-AS1 indirectly inhibited miR200c, the well-known target of ZEB1, and upregulated miR200c's target BMI1. Mechanistically, ZEB1-AS1 bound and recruited histone methyltransferase MLL1 to the promoter region of ZEB1, induced H3K4me3 modification therein, and activated ZEB1 transcription. Biologically, ZEB1-AS1 promoted proliferation and migration of prostate cancer cells.
Collectively, ZEB1-AS1 functions as an oncogene in prostate cancer via epigenetically activating ZEB1 and indirectly regulating downstream molecules of ZEB1.
Ground-based multi-axis differential optical absorption spectroscopy (MAX-DOAS) observations were performed from 27 December 2018 to 16 January 2019 in Changshou, one of subdistricts of Chongqing, ...China. Primary atmospheric pollutant in Changshou during wintertime was PM2.5, whose contribution averaged about 70.15% ± 9.5% of PM10. The ratio of PM2.5/PM10 decreased when PM2.5 pollution became worse, and it should attribute to biomass burning and the contribution of hygroscopic growth and enhanced heterogeneous chemistry under high relative humidity condition. Moreover, nitrogen dioxide (NO2), formaldehyde (HCHO) and glyoxal (CHOCHO) vertical profiles during the campaign period were retrieved separately. TROPOMI HCHO vertical column densities (VCDs) and MAX-DOAS HCHO VCDs were correlated well (R = 0.93). In order to identify the sources of volatile organic compound (VOC) in Changshou, the ratio of CHOCHO to HCHO (RGF) in five different layers were estimated. The estimated daily averaged RGF were 0.0205 ± 0.0077, 0.0727 ± 0.0286, 0.0864 ± 0.0296, 0.0770 ± 0.0275 and 0.0746 ± 0.0263 in 0–100 m, 100–200 m, 300–400 m, 500–600 m and 700–800 m layers, respectively. The estimated RGF will increase when biomass burnings were dominated. Using NO2 as a tracer of anthropogenic emissions, we found the RGF values gradually decrease with the increase of NO2 levels. RGF values in 0–100 m layer and all the other upper layers are 0.015–0.025 and 0.06–0.14, and that means the dominant sources of VOCs in 0–100 m layer and all the other upper layers are biogenic emission and anthropogenic emission (especially biomass burning), respectively. In addition, we found that RGF has site dependence which is in compliance with several previous studies.
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•The ratio of PM2.5/PM10 decreased when PM2.5 pollution became worse•HCHO and CHCOHO mainly distributed in 0-100 m and 100-200 m, respectively.•The sources of VOCs above 100 m are mainly from biomass burning.
V600E colorectal cancers are insensitive to RAF inhibitor monotherapy due to feedback reactivation of receptor tyrosine kinase signaling. Combined RAF and EGFR inhibition exerts a therapeutic effect, ...but resistance invariably develops through undefined mechanisms. In this study, we determined that colorectal cancer progression specimens invariably harbored lesions in elements of the RAS-RAF-MEK-ERK pathway. Genetic amplification of wild-type RAS was a recurrent mechanism of resistance in colorectal cancer patients that was not seen in similarly resistant melanomas. We show that wild-type RAS amplification increases receptor tyrosine kinase-dependent activation of RAS more potently in colorectal cancer than in melanoma and causes resistance only in the former. Currently approved RAF inhibitors inhibit RAF monomers but not dimers. All the drug-resistant lesions we identified activate BRAF V600E dimerization directly or by elevating RAS-GTP. Overall, our results show that mechanisms of resistance converge on formation of RAF dimers and that inhibiting EGFR and RAF dimers can effectively suppress ERK-driven growth of resistant colorectal cancer.
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Viewport-dependent streaming (VDS) of immersive video typically devises the attentive viewport (or FoV - Field of View) with high-quality compression but low-quality compressed content outside of it ...to reduce bandwidth. It, however, assumes uniform compression within the viewport, completely neglecting visual redundancy caused by non-uniform perception in central and peripheral vision areas when consuming the content using a head-mounted display (HMD). Our work models the unequal retinal perception within the instantaneous viewport and explores using it in the VDS system for non-uniform viewport compression to further save the data volume. To this end, we assess the just-noticeable-distortion moment of the rendered viewport frame by carefully adapting image quality-related compression factors like quantization stepsize q and/or spatial resolution s zone-by-zone to explicitly derive the imperceptible quality perception threshold with respect to the eccentric angle. Independent validations show that the visual perception of the immersive images with non-uniform FoV quality guided by our model is indistinguishable from that of images with default uniform FoV quality. Our model can be flexibly integrated with the tiling strategy in popular video codecs to facilitate non-uniform viewport compression in practical VDS systems for significant bandwidth reduction (e.g., about 40% reported in our experiments) at similar visual quality.
Conductance quantization phenomena are observed in oxide‐based resistive switching memories. These phenomena can be understood by the formation and disruption of atomic‐scale conductive filaments in ...the insulating oxide matrix. The quantum conductance effect can be artificially modulated by controlling the electrical parameters in Set and Reset processes, and can be used for multi‐level data storage and help understand and design one‐dimensional structures at atomic scales in various materials systems.
Targeting active RAS with molecular glue Su, Wenjing; Hou, Xuben
Pharmaceutical Science Advances,
December 2024, 2024-12-00, 2024-12-01, Letnik:
2
Journal Article
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Activating mutations in RAS genes, notably KRASG12C, are pervasive in numerous cancers, presenting formidable challenges to therapy due to their elusive druggability. The landmark discovery of ...KRASG12C allosteric inhibitors marked a transformative milestone in cancer treatment, resulting in the approval of sotorasib and adagrasib. However, limitations in the depth and duration of response prompted the quest for alternative strategies. Recently, Holderfield et al., Wasko et al., and Jiang et al. reported on tri-complex inhibitors, namely RMC-7977 and RMC-6236, targeting activated RAS variants, demonstrating promising preclinical efficacy surpassing adagrasib. These advancments signify a paradigm shift in RAS oncology, promising enduring therapeutic benefits and warranting further clinical exploration.
This paper demonstrates the first-of-its-kind additively manufactured microfluidics-based flexible RF sensor, combining microfluidics, inkjet-printing technology, and soft lithography, which could ...potentially enable the first "real-world" wearable "smart skin" applications. A low-cost, rapid, low-temperature, and zero-waste fabrication process is introduced, which can be used to realize complex microfluidic channel networks with virtually any type of sensing element embedded. For proof-of-concept purposes, a reusable and flexible microfluidics sensor was prototyped using this process, which only requires 0.6-μL fluid volume to produce a 44% frequency shift between an empty (ε r = 1) and a water-filled channel (ε r = 73), demonstrating a sensitivity that is higher than most previously reported microfluidics-based microwave sensors. Seven different fluids were used to measure the sensitivity of the prototype and an overall sensitivity of 24% / log (ε r ) was observed. The "peel-and-replace" capability of the presented sensor not only facilitates the cleaning process for sensor reusability, but it also enables sensitivity tunability. For bent/conformed configurations, the sensor's functionality is good even for a bending radius down to 7 mm, demonstrating its great flexibility. After bending multiple times, the sensor still exhibits a very good performance repeatability, which verifies its reusability feature. The introduced additively manufactured RF microfluidics-based sensor would be well suited for numerous wearable and conformal fluid sensing applications (e.g., bodily fluids analyzing and food monitoring), while it could also be utilized in a variety of microfluidics-reconfigurable microwave components.
Polycystic ovary syndrome (PCOS), a common reproductive endocrine disease, has clinically heterogeneous characteristics. Recently, cuproptosis causes several diseases by killing cells. Hence, we ...aimed to explore cuproptosis-related molecular clusters in PCOS and construct a prediction model. Based on the GSE5090, GSE43264, GSE98421, and GSE124226 datasets, an analysis of cuproptosis regulators and immune features in PCOS was conducted. In 25 cases of PCOS, the molecular clusters of cuproptosis-related genes and the immune cell infiltration associated with PCOS were investigated. Weighted gene co-expression network analysis was used to identify differentially expressed genes within clusters. Next, we compared the performance of the random forest model, support vector machine model, generalized linear model, and eXtreme Gradient Boosting for deciding the optimum machine model. Validation of the predictive effectiveness was accomplished through nomogram, calibration curve, decision curve analysis, and using other two datasets. PCOS and non-PCOS controls differed in the dysregulation of cuproptosis-related genes and the activation of immunoreaction. Two cuproptosis-related molecular clusters associated with PCOS were identified. Significant heterogeneity was noted in immunity between the two clusters based on the analysis of immune infiltration. The immune-related pathways related to cluster-specific differentially expressed genes in Cluster1 were revealed by functional analysis. With a relatively low residual error and root mean square error and a higher area under the curve (1.000), the support vector machine model demonstrated optimal discriminative performance. An ultimate 5-gene-based support vector machine model was noted to perform satisfactorily in the other two validation datasets (area under the curve = 1.000 for both). Moreover, the nomogram, calibration curve, and decision curve analysis showed that PCOS subtypes can be accurately predicted. Our study results helped demonstrate a comprehensive understanding of the complex relationship between cuproptosis and PCOS and establish a promising prediction model for assessing the risk of cuproptosis in patients with PCOS.
Formaldehyde (HCHO) is a toxic and hazardous air pollutant that widely exists in atmosphere. Insufficient spatial and temporal coverage of surface HCHO measurements is limiting studies on surface ...HCHO-related air quality management and health risk assessment. This study develops a method to derive global ground-level HCHO concentrations from satellite-based tropospheric HCHO columns using TM5-simulated surface-to-column conversion factor with coarse spatial resolution. The method improves the factor more representative in finer grids by constraining TM5-simulated vertical profile shapes with satellite HCHO columns. The surface HCHO concentrations derived by the Ozone Mapping and Profiler Suite (OMPS) show good correlation with in situ HCHO measurements (R = 0.59) from the U.S. Environmental Protection Agency surface network. We investigated how surface HCHO relates to urbanization and population aggregation over seven regions with high HCHO pollution. The results show urban HCHO increases as a power function with population size in China, India, and West Asia. HCHO concentrations in rural aeras also present strong log–log relationship with population aggregation in China, India, the United States, and Europe. Moreover, OMPS-derived ground-level HCHO concentrations were used to estimate global cancer burden caused by long-term outdoor HCHO exposure. The results show that up to 418188 more people worldwide will develop this cancer during the human life cycle. The global cancer burden is mainly from the South-East Asia region (33.11 %) and the Western Pacific region (22.95 %). This cancer occurrence in India and China is ranked 1st and 2nd in the world due to the large population size and serious HCHO pollution. Besides, global surface HCHO concentrations and cancer burden derived from the Environmental Trace Gases Monitoring Instrument which is China’s first hyperspectral space-based spectrometer are found similar patterns with that from OMPS. Our results provide new insight into the impact of population urbanization on HCHO pollution and global outdoor HCHO-caused health risks.
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