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The blood–brain barrier (BBB) establishes a protective interface between the central neuronal system and peripheral blood circulation and is crucial for homeostasis of the CNS. BBB formation startswhen the endothelial cells (ECs) invade the CNS and pericytes are recruited to the nascent vessels during embryogenesis. Despite the essential function of pericyte–EC interaction during BBB development, the molecular mechanisms coordinating the pericyte–EC behavior and communication remain incompletely understood. Here, we report a single cell receptor, CD146, that presents dynamic expression patterns in the cerebrovasculature at the stages of BBB induction and maturation, coordinates the interplay of ECs and pericytes, and orchestrates BBB development spatiotemporally. In mouse brain, CD146 is first expressed in the cerebrovascular ECs of immature capillaries without pericyte coverage; with increased coverage of pericytes, CD146 could only be detected in pericytes, but not in cerebrovascular ECs. Specific deletion of Cd146 in mice ECs resulted in reduced brain endothelial claudin-5 expression and BBB breakdown. By analyzing mice with specific deletion of Cd146 in pericytes, which have defects in pericyte coverage and BBB integrity, we demonstrate that CD146 functions as a coreceptor of PDGF receptor-β to mediate pericyte recruitment to cerebrovascular ECs. Moreover, we found that the attached pericytes in turn down-regulate endothelial CD146 by secreting TGF-β1 to promote further BBB maturation. These results reveal that the dynamic expression of CD146 controls the behavior of ECs and pericytes, thereby coordinating the formation of a mature and stable BBB.

Abnormal 5-methylcytosine (m5C) methylation has been proved to be closely related to gastric carcinogenesis, progression, and prognosis. Dysregulated long noncoding RNAs (lncRNAs) participate in a variety of biological processes in cancer. However, to date, m5C-methylated lncRNAs are rarely researched in gastric cancer (GC). Here, we found that RNA cytosine-C(5)-methyltransferase (NSUN2) was upregulated in GC and high NSUN2 expression was associated with poor prognosis. NR_033928 was identified as an NSUN2-methylated and upregulated lncRNA in GC. Functionally, NR_033928 upregulated the expression of glutaminase (GLS) by interacting with IGF2BP3/HUR complex to promote GLS mRNA stability. Increased glutamine metabolite, α-KG, upregulated NR_033928 expression by enhancing its promoter 5-hydroxymethylcytosine (hm5C) demethylation. In conclusion, our results revealed that NSUN2-methylated NR_033928 promoted GC progression and might be a potential prognostic and therapeutic target for GC.

CRISPR system has been widely used due to its precision and versatility in gene editing. Un1Cas12f1 from uncultured archaeon (hereafter referred to as Cas12f), known for its compact size (529 aa), exhibits obvious delivery advantage for gene editing in vitro and in vivo. However, its activity remains suboptimal. In this study, we engineer circular guide RNA (cgRNA) for Cas12f and significantly improve the efficiency of gene activation about 1.9–19.2-fold. When combined with a phase separation system, the activation efficiency is further increased about 2.3–3.9-fold. In addition, cgRNA enhances the editing efficiency and narrows the editing window of adenine base editing about 1.2–2.5-fold. Importantly, this optimization strategy also boosts the Cas12f-induced gene activation efficiency in mouse liver. Therefore, we demonstrate that cgRNA is able to enhance Cas12f-based gene activation and adenine base editing, which holds great potential for gene therapy. The compact Cas12f enzyme exhibits obvious delivery advantage for gene editing, but its activity remains suboptimal. Here, the authors have designed and optimized circular guide RNA (cgRNA) for Cas12f, which significantly improves the efficiency of gene activation and adenine base editing.

Background The CRISPR/Cas12a and CRISPR/Cas13d systems are widely used for fundamental research and hold great potential for future clinical applications. However, the short half-life of guide RNAs (gRNAs), particularly free gRNAs without Cas nuclease binding, limits their editing efficiency and durability. Results Here, we engineer circular free gRNAs (cgRNAs) to increase their stability, and thus availability for Cas12a and Cas13d processing and loading, to boost editing. cgRNAs increases the efficiency of Cas12a-based transcription activators and genomic DNA cleavage by approximately 2.1- to 40.2-fold for single gene editing and 1.7- to 2.1-fold for multiplexed gene editing than their linear counterparts, without compromising specificity, across multiple sites and cell lines. Similarly, the RNA interference efficiency of Cas13d is increased by around 1.8-fold. In in vivo mouse liver, cgRNAs are more potent in activating gene expression and cleaving genomic DNA. Conclusions CgRNAs enable more efficient programmable DNA and RNA editing for Cas12a and Cas13d with broad applicability for fundamental research and gene therapy.

Background: Pelareorep is an oncolytic virus that causes oncolytic effects in many solid tumors, and it has shown therapeutic benefits. However, few studies have compared pelareorep combined with chemotherapy to traditional chemotherapy alone in advanced solid tumors. Consequently, we intended to evaluate the effectiveness and safety of pelareorep plus chemotherapy in this paper. Methods: We searched four databases including PubMed, Embase, Cochrane Library and Web of Science comprehensively for studies comparing pelareorep combined with chemotherapy to chemotherapy alone in the treatment of advanced solid tumors. The outcomes measures were 1-year overall survival (OS), 2-year OS, 4-month progression-free survival (PFS), 1-year PFS, objective response rate (ORR), any-grade adverse events (any-grade AEs), and severe AEs (grade ≥ 3). Results: There were five studies involving 492 patients included in the study. Combination therapy did not significantly improve clinical outcomes in terms of 1-year OS [RR = 1.02, 95%CI = (0.82–1.25)], 2-year OS [RR = 1.00, 95%CI = (0.67–1.49)], 4-month PFS [RR = 1.00, 95%CI = (0.67–1.49)], 1-year PFS [RR = 0.79, 95%CI = (0.44–1.42)], and ORR [OR = 0.79, 95%CI = (0.49–1.27)] compared to chemotherapy alone, and the subgroup analysis of 2-year OS, 1-year PFS, and ORR based on countries and tumor sites showed similar results. In all grades, the incidence of AEs was greater with combination therapy, including fever [RR = 3.10, 95%CI = (1.48–6.52)], nausea [RR = 1.19, 95%CI = (1.02–1.38)], diarrhea [RR = 1.87, 95%CI = (1.39–2.52)], chills [RR = 4.14, 95%CI = (2.30–7.43)], headache [RR = 1.46, 95%CI = (1.02–2.09)], vomiting [RR = 1.38, 95%CI = (1.06–1.80)] and flu-like symptoms [RR = 4.18, 95%CI = (2.19–7.98)]. However, severe adverse events did not differ significantly between the two arms. Conclusion: Pelareorep addition to traditional chemotherapy did not lead to significant improvements in OS, PFS, or ORR in advanced solid tumor patients, but it did partially increase AEs in all grades, with no discernible differences in serious AEs. Therefore, the combination treatment is not recommended in patients with advanced solid tumors. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=400841 , identifier CRD42023400841

In recent years, the vegetation cover in the Selinco region of the Qinghai-Tibet Plateau has undergone significant changes due to the influence of global warming and intensified human activity. Consequently, comprehending the distribution and change patterns of vegetation in this area has become a crucial scientific concern. To address this concern, the present study employed MODIS-NDVI and elevation data, integrating methodologies such as trend analysis, Hurst exponent analysis, and sequential cluster analysis to explore vegetation cover changes over the past 21 years and predict future trends, while examining their correlation with topographic factors. The study findings indicate a fluctuating upward trend in vegetation cover, with a notable decrease in 2015. Spatially, the overall fractional vegetation cover (FVC) in the study area showed a basic stability with a percentage of 78%. The analysis of future trends in vegetation cover revealed that the majority of areas (68.26%) exhibited an uncertain trend, followed by stable regions at 15.78%. The proportion of areas showing an increase and decrease in vegetation cover accounted for only 9.63% and 5.61%, respectively. Elevation and slope significantly influence vegetation cover, with a trend of decreasing vegetation cover as elevation increases, followed by an increase, and then another decrease. Likewise, as the slope increases, initially, there is a rise in vegetation cover, followed by a subsequent decline. Notably, significant abrupt changes in vegetation cover are observed within the 4800 m elevation band and the 4° slope band in the Selinco region. Moreover, aspect has no significant effect on vegetation cover. These findings offer comprehensive insights into the spatial and temporal variations of vegetation cover in the Selinco region and their association with topographic factors, thus serving as a crucial reference for future research.

There are nearly 40% of cervical cancer patients showing poor response to neoadjuvant chemotherapy that can be induced by autophagy, however, the underlying mechanism has not yet been fully clarified. We previously found that Sex-determining region of Y-related high-mobility-group box 6 ( SOX6 ), a tumor suppressor gene or oncogene in several cancers, could induce autophagy in cervical cancer. Accordingly, this study aims to investigate the mechanism of SOX6-induced autophagy and its potential significance in the platinum-based chemotherapy of cervical cancer. Firstly, we found that SOX6 could promote autophagy in cervical cancer cells depending on its HMG domain. Mitogen-activated protein kinase kinase kinase kinase-4 ( MAP4K4 ) gene was identified as the direct target gene of SOX6, which was transcriptionally upregulated by binding the HMG domain of SOX6 protein to its double-binding sites within MAP4K4 gene promoter. MAP4K4 mediated the SOX6-induced autophagy through inhibiting PI3K-Akt-mTOR pathway and activating MAPK/ERK pathway. Further, the sensitivity of cervical cancer cells to cisplatin chemotherapy could be reduced by the SOX6-induced autophagy in vitro and in vivo, while such a phenomenon could be turned over by autophagy-specific inhibitor and MAP4K4 inhibitor, respectively. Moreover, cisplatin itself could promote the expression of endogenous SOX6 and subsequently the MAP4K4-mediated autophagy in cervical cancer cells, which might in turn reduce the sensitivity of these cells to cisplatin treatment. These findings uncovered the underlying mechanism and potential significance of SOX6-induced autophagy, and shed new light on the usage of MAP4K4 inhibitor or autophagy-specific inhibitor for sensitizing cervical cancer cells to the platinum-based chemotherapy.

Background The CRISPR-Cas12a (formerly Cpf1) system is a versatile gene-editing tool with properties distinct from the broadly used Cas9 system. Features such as recognition of T-rich protospacer-adjacent motif (PAM) and generation of sticky breaks, as well as amenability for multiplex editing in a single crRNA and lower off-target nuclease activity, broaden the targeting scope of available tools and enable more accurate genome editing. However, the widespread use of the nuclease for gene editing, especially in clinical applications, is hindered by insufficient activity and specificity despite previous efforts to improve the system. Currently reported Cas12a variants achieve high activity with a compromise of specificity. Here, we used structure-guided protein engineering to improve both editing efficiency and targeting accuracy of Acidaminococcus sp. Cas12a ( As Cas12a) and Lachnospiraceae bacterium Cas12a ( Lb Cas12a). Results We created new As Cas12a variant termed “ As Cas12a-Plus” with increased activity (1.5~2.0-fold improvement) and specificity (reducing off-targets from 29 to 23 and specificity index increased from 92% to 94% with 33 sgRNAs), and this property was retained in multiplex editing and transcriptional activation. When used to disrupt the oncogenic BRAF V600E mutant, As Cas12a-Plus showed less off-target activity while maintaining comparable editing efficiency and BRAF V600E cancer cell killing. By introducing the corresponding substitutions into Lb Cas12a, we also generated Lb Cas12a-Plus (activity improved ~1.1-fold and off-targets decreased from 20 to 12 while specificity index increased from 78% to 89% with 15 sgRNAs), suggesting this strategy may be generally applicable across Cas12a orthologs. We compared Cas12a-Plus, other variants described in this study, and the reported enCas12a-HF, enCas12a, and Cas12a-ultra, and found that Cas12a-Plus outperformed other variants with a good balance for enhanced activity and improved specificity. Conclusions Our discoveries provide alternative As Cas12a and Lb Cas12a variants with high specificity and activity, which expand the gene-editing toolbox and can be more suitable for clinical applications.

Objective This study investigates operational efficiency in public general hospitals using a system dynamics (SD) model, focusing on resource allocation, patient flow and policy interventions. It explores the interactions between human resources, financial subsidies and patient visitation rates and their impact on hospital performance. Methods An SD model was developed to simulate various scenarios, incorporating data on hospital capacity, staffing and financial inputs, along with patient flow dynamics. Key performance metrics, including bed occupancy rate (BOR), average length of stay (ALOS), average cost per visit and workload index, were analysed under different policy scenarios. Results Simulation of four policy scenarios revealed that increased fiscal subsidies (scenario 2) consistently improved operational efficiency by reducing ALOS, staff workload and cost per visit. In contrast, scenarios involving human resource cuts or rapid patient growth triggered adverse feedback loops that undermined performance. Conclusions The SD model effectively captures the dynamic interactions within hospital operations and enables assessment of policy interventions over time. Enhanced government funding contributes most positively to efficiency, while demand surges and resource reductions introduce system strain and performance trade-offs.

In recent years, remarkable progress has been achieved in generating multiple orbital angular momentum beams, primarily in classical physics, exemplified by technologies such as the vertical-cavity surface-emitting laser (VCSEL). However, the study of multiple orbital angular momentum and on-demand single photons using straightforward and efficient methods still faces limitations in the quantum domain. For example, numerous existing methods necessitate a relatively extensive optical path, posing challenges for optical integration. On-chip generation of OAM single photons lacks the versatility to manipulate various degrees of freedom simultaneously. Here, we propose a design that combines quantum dots with metalens. This method integrates phase multiplexing and spatial multiplexing techniques, enabling the generation of multiple single-photon beams with distinct topological charges and spatial separation through a simpler fabrication process. Our simulation results not only introduce a novel design paradigm but also significantly advance the ongoing research efforts related to multiple orbital angular momentum and on-demand single photons in the quantum realm.