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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 55 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. Here, the authors characterize an anti-CRISPR protein that prevents protospacer integration by Cas1-Cas2, providing structural insights that may benefit CRISPR-Cas systems research.

This study hypothesizes that elevated cerebral middle artery blood flow parameters (systolic peak velocity Vs, end-diastolic velocity Vd, and mean velocity Vm) detected by transcranial Doppler ultrasound (TCD) can predict postoperative intracranial infections in hypertensive intracerebral hemorrhage patients. The primary objective is to validate TCD’s predictive value for postoperative intracranial infections, with secondary objectives including analyzing the distribution characteristics of pathogenic bacteria and factors influencing infection. This retrospective cohort study enrolled 127 HICH patients who underwent surgery between April 2021 and March 2024. The participants were stratified into the infection ( n  = 26) and noninfection groups. TCD was used to measure peak systolic velocity (Vs), end-diastolic velocity (Vd), and mean velocity (Vm) in the bilateral middle cerebral arteries. Cerebrospinal fluid cultures were performed to identify pathogens. Multivariate logistic regression was used to identify risk factors for infection, and receiver operating characteristic (ROC) curves were used to assess the predictive performance of TCD parameters. This study identified postoperative intracranial infections in 20.47% (26/127) of HICH patients. Multivariate analysis revealed that a preoperative Glasgow Coma Scale (GCS) score > 8 (OR 0.096, P  = 0.003) was a protective factor against postoperative intracranial infections, while a drainage duration ≥ 3 days (OR  5.454, P  = 0.048) and elevated TCD hemodynamic parameters, including peak systolic velocity (Vs: OR  1.027, P  = 0.013), end-diastolic velocity (Vd: OR 1.037, P  = 0.011), and mean velocity (Vm: OR  1.045, P  = 0.006), were independent risk factors for postoperative intracranial infections. ROC analysis demonstrated superior predictive accuracy for the combined TCD parameters (AUC = 0.901, sensitivity = 84.6%, specificity = 88.1%). Pathogen profiling revealed a gram-positive predominance (64.71%), primarily Staphylococcus aureus (29.41%), followed by gram-negative Acinetobacter baumannii (17.65%). The study concluded that transcranial Doppler ultrasound (particularly the combined detection of Vs, Vd, and Vm) demonstrates high efficacy in predicting postoperative intracranial infections in hypertensive intracerebral hemorrhage patients. However, changes in cerebral blood flow velocity are not specific to intracranial infections, necessitating comprehensive clinical evaluation. Additionally, Gram-positive bacteria (with Staphylococcus aureus being the most common) dominate the causative pathogens, allowing guidance for initial empirical antibiotic therapy based on their distribution patterns.

Background 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. Methods 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. Results 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. Conclusions Collectively, ZEB1-AS1 functions as an oncogene in prostate cancer via epigenetically activating ZEB1 and indirectly regulating downstream molecules of ZEB1.

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) in the ambient air not only causes cancer but is also an ideal indicator of volatile organic compounds (VOCs), which are major precursors of ozone (O3) and secondary organic aerosol (SOA) near the surface. It is meaningful to differentiate between the direct emission and the secondary formation of HCHO for HCHO pollution control and sensitivity studies of O3 production. However, understanding of the sources of HCHO is still poor in China, due to the scarcity of field measurements (both spatially and temporally). In this study, tropospheric HCHO vertical column densities (VCDs) in the Yangtze River Delta (YRD), East China, where HCHO pollution is serious, were retrieved from the Ozone Mapping and Profiler Suite (OMPS) onboard the Suomi National Polar-orbiting Partnership (Suomi-NPP) satellite from 2014 to 2017; these retrievals showed good agreement with the tropospheric HCHO columns measured using ground-based high-resolution Fourier transform infrared spectrometry (FTS) with a correlation coefficient (R) of 0.78. Based on these results, the cancer risk was estimated both nationwide and in the YRD region. It was calculated that at least 7840 people in the YRD region would develop cancer in their lives due to outdoor HCHO exposure, which comprised 23.4 % of total national cancer risk. Furthermore, the contributions of primary and secondary sources were apportioned, in addition to primary and secondary tracers from surface observations. Overall, the HCHO from secondary formation contributed most to ambient HCHO and can be regarded as the indicator of VOC reactivity in Hangzhou and in urban areas of Nanjing and Shanghai from 2015 to 2017, due to the strong correlation between total HCHO and secondary HCHO. At industrial sites in Nanjing, primary emissions more strongly influenced ambient HCHO concentrations in 2015 and showed an obvious decreasing trend. Seasonally, HCHO from secondary formation reached a maximum in summer and a minimum in winter. In the spring, summer, and autumn, secondary formation had a significant effect on the variation of ambient HCHO in urban regions of Nanjing, Hangzhou, and Shanghai, whereas in the winter the contribution from secondary formation became less significant. A more thorough understanding of the variation of the primary and secondary contributions of ambient HCHO is needed to develop a better knowledge regarding the role of HCHO in atmospheric chemistry and to formulate effective control measures to decrease HCHO pollution and the associated cancer risk.

In response to the COVID-19 pandemic, governments worldwide imposed lockdown measures in early 2020, resulting in notable reductions in air pollutant emissions. The changes in air quality during the pandemic have been investigated in numerous studies via satellite observations. Nevertheless, no relevant research has been gathered using Chinese satellite instruments, because the poor spectral quality makes it extremely difficult to retrieve data from the spectra of the Environmental Trace Gases Monitoring Instrument (EMI), the first Chinese satellite-based ultraviolet–visible spectrometer monitoring air pollutants. However, through a series of remote sensing algorithm optimizations from spectral calibration to retrieval, we successfully retrieved global gaseous pollutants, such as nitrogen dioxide (NO2), sulfur dioxide (SO2), and formaldehyde (HCHO), from EMI during the pandemic. The abrupt drop in NO2 successfully captured the time for each city when effective measures were implemented to prevent the spread of the pandemic, for example, in January 2020 in Chinese cities, February in Seoul, and March in Tokyo and various cities across Europe and America. Furthermore, significant decreases in HCHO in Wuhan, Shanghai, Guangzhou, and Seoul indicated that the majority of volatile organic compounds (VOCs) emissions were anthropogenic. Contrastingly, the lack of evident reduction in Beijing and New Delhi suggested dominant natural sources of VOCs. By comparing the relative variation of NO2 to gross domestic product (GDP), we found that the COVID-19 pandemic had more influence on the secondary industry in China, while on the primary and tertiary industries in Korea and the countries across Europe and America.The changes of global gaseous pollutants during the COVID-19 pandemic in early 2020 were retrieved from Chinese ultraviolet–visible hyperspectral satellite instrument through a series of remote sensing algorithm optimizations.

Ground-based multi-axis differential optical absorption spectroscopy (MAX-DOAS) and lidar measurements were performed in Shanghai, China, during May 2016 to investigate the vertical distribution of summertime atmospheric pollutants. In this study, vertical profiles of aerosol extinction coefficient, nitrogen dioxide (NO2) and formaldehyde (HCHO) concentrations were retrieved from MAX-DOAS measurements using the Heidelberg Profile (HEIPRO) algorithm, while vertical distribution of ozone (O3) was obtained from an ozone lidar. Sensitivity study of the MAX-DOAS aerosol profile retrieval shows that the a priori aerosol profile shape has significant influences on the aerosol profile retrieval. Aerosol profiles retrieved from MAX-DOAS measurements with Gaussian a priori profile demonstrate the best agreements with simultaneous lidar measurements and vehicle-based tethered-balloon observations among all a priori aerosol profiles. Tropospheric NO2 vertical column densities (VCDs) measured with MAX-DOAS show a good agreement with OMI satellite observations with a Pearson correlation coefficient (R) of 0.95. In addition, measurements of the O3 vertical distribution indicate that the ozone productions do not only occur at surface level but also at higher altitudes (about 1.1 km). Planetary boundary layer (PBL) height and horizontal and vertical wind field information were integrated to discuss the ozone formation at upper altitudes. The results reveal that enhanced ozone concentrations at ground level and upper altitudes are not directly related to horizontal and vertical transportation. Similar patterns of O3 and HCHO vertical distributions were observed during this campaign, which implies that the ozone productions near the surface and at higher altitudes are mainly influenced by the abundance of volatile organic compounds (VOCs) in the lower troposphere.

Activating BRAF mutants and fusions signal as RAS-independent constitutively active dimers with the exception of BRAF V600 mutant alleles which can function as active monomers 1 . Current RAF inhibitors are monomer selective, they potently inhibit BRAF V600 monomers but their inhibition of RAF dimers is limited by induction of negative cooperativity when bound to one site in the dimer 1 – 3 . Moreover, acquired resistance to these drugs is usually due to molecular lesions that cause V600 mutants to dimerize 4 – 8 . We show here that PLX8394, a new RAF inhibitor 9 , inhibits ERK signaling by specifically disrupting BRAF-containing dimers, including BRAF homodimers and BRAF–CRAF heterodimers, but not CRAF homodimers or ARAF-containing dimers. Differences in the amino acid residues in the amino (N)-terminal portion of the kinase domain of RAF isoforms are responsible for this differential vulnerability. As a BRAF-specific dimer breaker, PLX8394 selectively inhibits ERK signaling in tumors driven by dimeric BRAF mutants, including BRAF fusions and splice variants as well as BRAF V600 monomers, but spares RAF function in normal cells in which CRAF homodimers can drive signaling. Our work suggests that drugs with these properties will be safe and useful for treating tumors driven by activating BRAF mutants or fusions. The new RAF inhibitor PLX8394 selectively blocks ERK signaling in tumors driven by class 1 and/or class 2 BRAF mutations and BRAF fusions while maintaining a broad therapeutic window.

Background Circular RNA (circRNA) is a novel class noncoding RNA (ncRNA) that plays a critical role in various cancers, including prostate cancer (PCa). However, the clinical significance, biological function, and molecular mechanisms of circRNAs in prostate cancer remain to be elucidated. Methods A circRNA array was performed to identified the differentially expressed circRNAs. circPDE5A was identified as a novel circRNA which downregulated in clinical samples. Functionally, the in vitro and in vivo assays were applied to explore the role of circPDE5A in PCa metastasis. Mechanistically, the interaction between circPDE5A and WTAP was verified using RNA pulldown followed by mass spectrometry, RNA Immunoprecipitation (RIP) assays. m 6 A methylated RNA immunoprecipitation sequencing (MeRIP-seq) was then used to identified the downstream target of circPDE5A. Chromatin immunoprecipitation assay (ChIP) and dual-luciferase reporter assay were used to identified transcriptional factor which regulated circPDE5A expression. Results circPDE5A was identified downregulated in PCa tissues compared to adjacent normal tissue and was negatively correlated with gleason score of PCa patients. circPDE5A inhibits PCa cells migration and invasion both in vitro and in vivo. circPDE5A blocks the WTAP-dependent N6-methyladenisine (m 6 A) methylation of eukaryotic translation initiation factor 3c (EIF3C) mRNA by forming the circPDE5A-WTAP complex, and finally disrupts the translation of EIF3C. Moreover, the circPDE5A-dependent decrease in EIF3C expression inactivates the MAPK pathway and then restrains PCa progression. Conclusions Our findings demonstrate that FOXO4-mediated upregulation of circPDE5A controls PCa metastasis via the circPDE5A-WTAP-EIF3C-MAPK signaling pathway and could serve as a potential therapeutic targer for PCa.

PurposeThis study aims to overcome the challenges of the current oral targeted drug delivery system, such as the complex preparation process, poor biocompatibility, and delayed drug release.MethodsHere, a non-covalent polymer hydrogel was prepared using the mechanochemical method, and the solid phase loading of 5-amino salicylic acid (5-ASA) was realized.ResultsThe results obtained from the thermodynamics study, particle size analysis, and electron microscopy show that chitosan (CS) and sodium alginate (SA) form a pH-sensitive hydrogel under the mechanochemical force and also maintain good stability in aqueous solution. Fluorescent tracers study showed that the pH-sensitive hydrogel could achieve the targeted drug release in the colon and the retention time was over 12 h. Next, in vivo efficacy studies, change in mice body weight, DAI (disease activity index) score, thymus, and spleen index, and the diseased state of the mice colon revealed that the pH-sensitive hydrogel is an improved drug delivery system over 5-ASA API commercial preparations as observed in the efficacy and toxicological studies.ConclusionThis method uses an innovative preparation technology that without the need of cross-linking agent to produce an efficient colon-targeted drug delivery system for the treatment of ulcerative colitis.