Safety, immunogenicity and protective effectiveness of heterologous boost with a recombinant COVID-19 vaccine (Sf9 cells) in adult recipients of inactivated vaccines.

Vaccines have proven effective in protecting populations against COVID-19, including the recombinant COVID-19 vaccine (Sf9 cells), the first approved recombinant protein vaccine in China. In this positive-controlled trial with 85 adult participants (Sf9 cells group: n = 44; CoronaVac group: n = 41), we evaluated the safety, immunogenicity, and protective effectiveness of a heterologous boost with the Sf9 cells vaccine in adults who had been vaccinated with the inactivated vaccine, and found a post-booster adverse events rate of 20.45% in the Sf9 cells group and 31.71% in the CoronaVac group (p = 0.279), within 28 days after booster injection. Neither group reported any severe adverse events. Following the Sf9 cells vaccine booster, the geometric mean titer (GMT) of binding antibodies to the receptor-binding domain of prototype SARS-CoV-2 on day 28 post-booster was significantly higher than that induced by the CoronaVac vaccine booster (100,683.37 vs. 9,451.69, p < 0.001). In the Sf9 cells group, GMTs of neutralizing antibodies against pseudo SARS-CoV-2 viruses (prototype and diverse variants of concern [VOCs]) increased by 22.23-75.93 folds from baseline to day 28 post-booster, while the CoronaVac group showed increases of only 3.29-10.70 folds. Similarly, neutralizing antibodies against live SARS-CoV-2 viruses (prototype and diverse VOCs) increased by 68.18-192.67 folds on day 14 post-booster compared with the baseline level, significantly greater than the CoronaVac group (19.67-37.67 folds). A more robust Th1 cellular response was observed with the Sf9 cells booster on day 14 post-booster (mean IFN-γ+ spot-forming cells per 2 × 105 peripheral blood mononuclear cells: 26.66 vs. 13.59). Protective effectiveness against symptomatic COVID-19 was approximately twice as high in the Sf9 cells group compared to the CoronaVac group (68.18% vs. 36.59%, p = 0.004). Our study findings support the high protective effectiveness of heterologous boosting with the recombinant COVID-19 vaccine (Sf9 cells) against symptomatic COVID-19 of diverse SARS-CoV-2 variants of concern, while causing no apparent safety concerns.

scSemiGCN: boosting cell-type annotation from noise-resistant graph neural networks with extremely limited supervision.

MOTIVATION: Cell-type annotation is fundamental in revealing cell heterogeneity for single-cell data analysis. Although a host of works have been developed, the low signal-to-noise-ratio single-cell RNA-sequencing data that suffers from batch effects and dropout still poses obstacles in discovering grouped patterns for cell types by unsupervised learning and its alternative-semi-supervised learning that utilizes a few labeled cells as guidance for cell-type annotation. RESULTS: We propose a robust cell-type annotation method scSemiGCN based on graph convolutional networks. Built upon a denoised network structure that characterizes reliable cell-to-cell connections, scSemiGCN generates pseudo labels for unannotated cells. Then supervised contrastive learning follows to refine the noisy single-cell data. Finally, message passing with the refined features over the denoised network structure is conducted for semi-supervised cell-type annotation. Comparison over several datasets with six methods under extremely limited supervision validates the effectiveness and efficiency of scSemiGCN for cell-type annotation. AVAILABILITY AND IMPLEMENTATION: Implementation of scSemiGCN is available at https://github.com/Jane9898/scSemiGCN.

The regulation of social factors on anxiety and microglial activity in nucleus accumbens of adolescent male mice: Influence of social interaction strategy.

BACKGROUND: Adolescence is a period characterized by a high vulnerability to emotional disorders, which are modulated by biological, psychological, and social factors. However, the underlying mechanisms remain poorly understood. METHODS: Combining physical or emotional social defeat stress (PS and ES) and pair or isolation rearing conditions, we investigated the effects of stress type and social support on emotional behavior and central immune molecules in adolescent mice, including anxiety, social fear, and social interaction strategies, as well as changes in microglia-specific molecules (ionized calcium-binding adaptor molecule 1 (Iba1) and a cluster of differentiation molecule 11b (CD11b)) in the medial prefrontal cortex (mPFC), hippocampus (HIP), amygdala (AMY), and nucleus accumbens (NAc). RESULTS: Mice exposed to both physical stress and isolated rearing condition exhibited the highest levels of anxiety, social fear, and microglial CD11b expression in the NAc. In terms of social support, pair-housing with siblings ameliorated social fear and NAc molecular changes in ES mice, but not in PS mice. The reason for the differential benefit from social support was attributed to the fact that ES mice exhibited more active and less passive social strategies in social environment compared to PS mice. Further, the levels of stress-induced social fear were positively associated with the expression of microglial CD11b in the NAc. CONCLUSION: These findings offer extensive evidence regarding the intricate effects of multiple social factors on social anxiety and immune alteration in the NAc of adolescent mice. Additionally, they suggest potential behavioral and immune intervention strategies for anxiety-related disorders in adolescents.

Factors Associated With Sleep Quality Among Undergraduate Nursing Students During Clinical Practicums.

BACKGROUND: Limited evidence exists on factors influencing nursing students' sleep quality during clinical practicums. PURPOSE: This study examined the sleep quality of nursing students and factors that affect sleep quality during clinical practicums. METHODS: Undergraduate nursing students (n = 135) enrolled in clinical practicums in 3 universities completed questionnaires including sociodemographics and the Pittsburgh Sleep Quality Index (PSQI). Stepwise linear regression evaluated factors predicating sleep quality. RESULTS: Seventy percent of nursing students reported poor sleep quality. Weekly work hours and clinical hours were significant factors in predicting global PSQI scores, subjective sleep quality, sleep duration, sleep efficiency, and daytime dysfunctions. The race was related to sleep latency and sleeping medication. Clinical hours and living on campus were associated with sleep disturbances. CONCLUSION: Knowing the factors that influence nursing students' sleep during clinical practicums, nurse educators can help students improve sleep health and clinical experience.

Ketamine alleviates fear memory and spatial cognition deficits in a PTSD rat model via the BDNF signaling pathway of the hippocampus and amygdala.

BACKGROUND: Post-traumatic stress disorder (PTSD) is associated with traumatic stress experiences. This condition can be accompanied by learning and cognitive deficits. Studies have demonstrated that ketamine can rapidly and significantly alleviate symptoms in patients with chronic PTSD. Nonetheless, the effects of ketamine on neurocognitive impairment and its mechanism of action in PTSD remain unclear. METHODS: In this study, different concentrations of ketamine (5, 10, 15, and 20 mg/kg, i.p.) were evaluated in rat models of single prolonged stress and electrophonic shock (SPS&S). Expression levels of brain-derived neurotrophic factor (BDNF) and post-synaptic density-95 (PSD-95) in the hippocampus (HIP) and amygdala (AMG) were determined by Western blot analysis and immunohistochemistry. RESULTS: The data showed that rats subjected to SPS&S exhibited significant PTSD-like cognitive impairment. The effect of ketamine on SPS&S-induced neurocognitive function showed a U-shaped dose effect in rats. A single administration of ketamine at a dosage of 10-15 mg/kg resulted in significant changes in behavioral outcomes. These manifestations of improvement in cognitive function and molecular changes were reversed at high doses (15-20 mg/kg). CONCLUSION: Overall, ketamine reversed SPS&S-induced fear and spatial memory impairment and the down-regulation of BDNF and BDNF-related PSD-95 signaling in the HIP and AMG. A dose equal to 15 mg/kg rapidly reversed the behavioral and molecular changes and promoted the amelioration of cognitive dysfunction. The enhanced association of BDNF signaling with PSD-95 effects could be involved in the therapeutic efficiency of ketamine for PTSD.

STOmicsDB: a comprehensive database for spatial transcriptomics data sharing, analysis and visualization.

Recent technological developments in spatial transcriptomics allow researchers to measure gene expression of cells and their spatial locations at the single-cell level, generating detailed biological insight into biological processes. A comprehensive database could facilitate the sharing of spatial transcriptomic data and streamline the data acquisition process for researchers. Here, we present the Spatial TranscriptOmics DataBase (STOmicsDB), a database that serves as a one-stop hub for spatial transcriptomics. STOmicsDB integrates 218 manually curated datasets representing 17 species. We annotated cell types, identified spatial regions and genes, and performed cell-cell interaction analysis for these datasets. STOmicsDB features a user-friendly interface for the rapid visualization of millions of cells. To further facilitate the reusability and interoperability of spatial transcriptomic data, we developed standards for spatial transcriptomic data archiving and constructed a spatial transcriptomic data archiving system. Additionally, we offer a distinctive capability of customizing dedicated sub-databases in STOmicsDB for researchers, assisting them in visualizing their spatial transcriptomic analyses. We believe that STOmicsDB could contribute to research insights in the spatial transcriptomics field, including data archiving, sharing, visualization and analysis. STOmicsDB is freely accessible at https://db.cngb.org/stomics/.

[Impact of Accelerated Electrification Under the Low Carbon Path in Dongguan City on the Coordinated Emission Reduction of CO2 and Pollutants].

Cities are the center of energy consumption. Electrification integrates urban energy structure and achieves the efficient use of clean energy. Exploring the urban impact of accelerated electrification under the low-carbon path is crucial to reducing urban pollution and carbon. Based on the Long-range Energy Alternative Planning System(LEAP-DG), this study set up three scenarios, including the baseline, low-carbon, and accelerated electrification scenarios, to evaluate the emission reduction potential of electrification under different power structures, quantify the contribution of key sectors, and discuss the coordinated emission reduction effect of Dongguan, a typical manufacturing city in Guangdong. The results showed that accelerated electrification under the low-carbon path would reduce the emission intensity of power pollutants, and in 2050, Dongguan will further reduce CO2, NOx, VOC, and CO by 7.35×106, 1.28×104, 1.62×104, and 8.13×104 t; SO2 and PM2.5 emission reductions on the consumption side and increased emissions on the production side had been balanced. Accelerated electrification in the industrial and transportation sectors would reduce CO2 and air pollutant emissions at the same time, and the transportation sector would benefit from the high conversion efficiency of fuel vehicles and electric vehicles, reducing CO2, CO, VOC, and NOx by 5.42×106, 7.76×104, 1.43×104, and 1.06×104 t, respectively, in 2050. In the building sector with high electrification rates, coal power was higher in extra electricity, increasing CO2 and pollutant emissions. Under the optimization of power supply structure, cities can reasonably adjust the electrification of different departments to achieve targeted pollution prevention and control.

Comparison of ACE-IQ and CTQ-SF for child maltreatment assessment: Reliability, prevalence, and risk prediction.

BACKGROUND: Child maltreatment has profound effects on mental health. The Childhood Trauma Questionnaire Short Form (CTQ-SF) and the Adverse Childhood Experiences International Questionnaire (ACE-IQ) are commonly used retrospective assessment tools for evaluating child maltreatment. OBJECTIVE: This study aims to conduct a comprehensive comparison of the CTQ-SF and ACE-IQ, encompassing internal consistency, prevalence, and the predictive efficacy of trauma-related outcomes. It also seeks to enhance the scoring method of ACE-IQ based on the established comparability between the two instruments. PARTICIPANTS AND SETTING: 1484 college students from northern China were recruited, assessing demographic characteristics and outcomes related to traumatic experiences, including post-traumatic stress disorder (PTSD), complex post-traumatic stress disorder (CPTSD), borderline personality disorder (BPD), anxiety, and depression. METHODS: A contingency correlation analysis was performed to evaluate the degree of agreement between the CTQ-SF and ACE-IQ. Binary logistic regression models were utilized to compare the predictive capabilities of distinct instruments. RESULTS: CTQ-SF and ACE-IQ instruments display favorable internal consistency and notable correlations across shared categories. However, the predictive relationships between trauma type and adverse outcomes are inconsistent across instruments. The ACE-IQ, encompassing 13 trauma categories, demonstrate a lower AIC and BIC index, indicating a superior model fit for elucidating outcomes. CONCLUSION: This study introduces a scoring methodology for ACE-IQ, improving the comparability of the two measures and emphasizing the importance of capturing the full range of maltreatment types a child may have experienced. These findings have significant implications for clinical and epidemiological research, providing valuable insights for understanding the impact of child maltreatment.

HLA-DRB1*14:54 Is Associated with Pulmonary Alveolar Proteinosis: A Retrospective Real-World Audit.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterized by abnormal accumulation of pulmonary surfactant lipids in alveoli or terminal bronchioles, leading to increased infection risk and progressive respiratory failure. Approximately more than 90% of all cases are autoimmune PAP (aPAP). Since one of the predisposing factors has been identified as genes located within the major-histocompatibility-complex region, an investigation of human leukocyte antigen (HLA) alleles associated with the risk of aPAP is warranted. METHODS: We retrospectively studied 60 patients pathologically diagnosed with PAP from 2019 to 2022. Patients were divided into the aPAP group or secondary PAP (sPAP) group according to their clinical information. Qualified DNA was extracted from the paraffin-embedded tissue of 28 patients, and the PCR-sequence-based typing method was used for HLA-DRB1 genotyping. RESULTS: A similar HLA-DRB1 allele profile (including the HLA-DRB1*08:03) between the aPAP group and sPAP group was revealed, except that HLA-DRB1*14:54, which has never been reported in aPAP patients, was only detected in the aPAP group rather than the sPAP group (19.4% vs. 0.0%, p = 0.030). Under inhaled granulocyte-macrophage colony-stimulating factor therapy, more clinical remission was observed in HLA-DRB1*14:54 carriers rather than in HLA-DRB1*08:03 carriers (80.0% vs. 57.1%). CONCLUSIONS: Our real-world study revealed for the first time that a population with HLA-DRB1*14:54 was subject to aPAP, and HLA-DRB1*14:54 might imply a response in aPAP patients to inhaled granulocyte-macrophage colony-stimulating factor in aPAP patients.

Impact of livelihood capital and rural site conditions on livelihood resilience of farm households: evidence from contiguous poverty-stricken areas in China.

Farm households around the world are increasingly exposed to both external and internal shocks and stressors. Enhancing the resilience of farm households to frequent disturbances holds paramount importance in fostering the sustainability of their livelihoods and the revitalization of rural areas. Based on 1500 household samples from 14 contiguous poverty-stricken areas (CPSA) in China, this study explores the causal pathways between livelihood capitals of farm households and rural site conditions of rural communities, as well as quantifying their impacts on farm households' livelihood resilience using structural equation models. In particular, the livelihood resilience of farm households is measured based on the "Exposure-Sensitivity-Adaptability" framework. The results show that livelihood resilience is positively represented by exposure and adaptability, but is negatively correlated with sensitivity. Specifically, households with lower mean health and higher dependency ratio are more sensitive to risks, while exposure to agroforestry pests and diseases will lead farm households to diversify their livelihood activities and increase crop and livestock variety to enhance their adaptability. The livelihood capital of farm households has a significant positive effect on livelihood resilience (ß = 0.874, p < 0.001). Rural site conditions have both significant direct and indirect impacts on livelihood resilience, with the direct impact (ß = - 0.207, p < 0.05) being negative and a bit larger than the positive indirect impact (ß = 0.163, p < 0.05), as mediated by livelihood capital. The government should, therefore, invest more in health insurance, education and training, financial support, and infrastructure, and implement village planning to enhance both the quality of household livelihood capitals and rural site conditions in CPSA.

Cell-Dependent Activation of ProTide Prodrugs and Its Implications in Antiviral Studies.

The ProTide prodrug design is a powerful tool to improve cell permeability and enhance the intracellular activation of nucleotide antiviral analogues. Previous in vitro studies showed that the activation of ProTide prodrugs varied in different cell lines. In the present study, we investigated the activation profiles of two antiviral prodrugs tenofovir alafenamide (TAF) and sofosbuvir (SOF) in five cell lines commonly used in antiviral research, namely, Vero E6, Huh-7, Calu-3, A549, and Caco-2. We found that TAF and SOF were activated in a cell-dependent manner with Vero E6 being the least efficient and Huh-7 being the most efficient cell line for activating the prodrugs. We also demonstrated that TAF was activated at a significantly higher rate than SOF. We further analyzed the protein expressions of the activating enzymes carboxylesterase 1, cathepsin A, histidine triad nucleotide-binding protein 1, and the relevant drug transporters P-glycoprotein and organic anion-transporting polypeptides 1B1 and 1B3 in the cell lines using the proteomics data extracted from the literature and proteome database. The results revealed significant differences in the expression patterns of the enzymes and transporters among the cell lines, which might partially contribute to the observed cell-dependent activation of TAF and SOF. These findings highlight the variability of the abundance of activating enzymes and transporters between cell lines and emphasize the importance of selecting appropriate cell lines for assessing the antiviral efficacy of nucleoside/nucleotide prodrugs.

DecentTree: scalable Neighbour-Joining for the genomic era.

MOTIVATION: Neighbour-Joining is one of the most widely used distance-based phylogenetic inference methods. However, current implementations do not scale well for datasets with more than 10 000 sequences. Given the increasing pace of generating new sequence data, particularly in outbreaks of emerging diseases, and the already enormous existing databases of sequence data for which Neighbour-Joining is a useful approach, new implementations of existing methods are warranted. RESULTS: Here, we present DecentTree, which provides highly optimized and parallel implementations of Neighbour-Joining and several of its variants. DecentTree is designed as a stand-alone application and a header-only library easily integrated with other phylogenetic software (e.g. it is integral in the popular IQ-TREE software). We show that DecentTree shows similar or improved performance over existing software (BIONJ, Quicktree, FastME, and RapidNJ), especially for handling very large alignments. For example, DecentTree is up to 6-fold faster than the fastest existing Neighbour-Joining software (e.g. RapidNJ) when generating a tree of 64 000 SARS-CoV-2 genomes. AVAILABILITY AND IMPLEMENTATION: DecentTree is open source and freely available at https://github.com/iqtree/decenttree. All code and data used in this analysis are available on Github (https://github.com/asdcid/Comparison-of-neighbour-joining-software).

Decoding key cell sub-populations and molecular alterations in glioblastoma at recurrence by single-cell analysis.

Glioblastoma (GBM) is the most frequent malignant brain tumor, the relapse of which is unavoidable following standard treatment. However, the effective treatment for recurrent GBM is lacking, necessitating the understanding of key mechanisms driving tumor recurrence and the identification of new targets for intervention. Here, we integrated single-cell RNA-sequencing data spanning 36 patient-matched primary and recurrent GBM (pGBM and rGBM) specimens, with 6 longitudinal GBM spatial transcriptomics to explore molecular alterations at recurrence, with each cell type characterized in parallel. Genes involved in extracellular matrix (ECM) organization are preferentially enriched in rGBM cells, and MAFK is highlighted as a potential regulator. Notably, we uncover a unique subpopulation of GBM cells that is much less detected in pGBM and highly expresses ECM and mesenchyme related genes, suggesting it may contribute to the molecular transition of rGBM. Further regulatory network analysis reveals that transcription factors, such as NFATC4 and activator protein 1 members, may function as hub regulators. All non-tumor cells alter their specific sets of genes as well and certain subgroups of myeloid cells appear to be physically associated with the mesenchyme-like GBM subpopulation. Altogether, our study provides new insights into the molecular understanding of GBM relapse and candidate targets for rGBM treatment.

Different regulatory mechanisms of the capsule in hypervirulent Klebsiella pneumonia: "direct" wcaJ variation vs. "indirect" rmpA regulation.

Introduction: Hypervirulent Klebsiella pneumoniae produce an increased amount of capsular substance and are associated with a hypermucoviscous phenotype. Capsule production is regulated by capsular regulatory genes and capsular gene cluster variations. In the present study, we focus on the effect of rmpA and wcaJon capsule biosynthesis. Methods: Phylogenetic trees were constructed to analyze wcaJ and rmpA sequence diversity in different serotypes hypervirulent strains. Then mutant strains (K2044ΔwcaJ, K2044K1wcaJ, K2044K2wcaJand K2044K64wcaJ) were used to verify the effects of wcaJ and its diversity on capsule synthesis and strain virulence. Furthmore, the role of rmpA in capsular synthesis and its mechanisms were detected in K2044ΔrmpA strain. Results: RmpA sequences are conversed in different serotypes. And rmpA promoted the production of hypercapsules by simultaneously acting on three promoters in cps cluster. Whereas wcaJ, its sequences are different in different serotypes, and its loss result in the termination of capsular synthesis. Moreover, the results verified that K2 wcaJ could form hypercapsule in K2044 strains (K1 serotype), but K64 wcaJ could not. Discussion: The interaction of multiple factors is involved in capsule synthesis, including wcaJ and rmpA. RmpA, an known conserved capsular regulator gene, acts on cps cluster promoters to promote the production of the hypercapsule. WcaJ as initiating enzyme of CPS biosynthesis, its presence determines the synthesis of capsule. Besides, different from rmpA, wcaJ sequence consistency is limited to the same serotype, which cause wcaJ functioning in different serotype strains with sequence recognition specificity.

Self-Powered Integrated Sensing System with In-Plane Micro-Supercapacitors for Wearable Electronics.

Self-powered integrated sensor with high-sensitivity physiological signals detection is indispensable for next-generation wearable electronic devices. Herein, a Ti3 C2 Tx /CNTs-based self-powered resistive sensor with solar cells and in-plane micro-supercapacitors (MSCs) is successfully realized on a flexible styrene-ethylene/butylene-styrene (SEBS) electrospinning film. The prepared Ti3 C2 Tx /CNTs@SEBS/CNTs nanofiber membranes exhibit high electrical conductivity and mechanical flexibility. The laser-assisted fabricated Ti3 C2 Tx /CNTs based-MSCs demonstrate a high areal energy density of 52.89 and 9.56 µWh cm-2 with a corresponding areal power density of 0.2 and 4 mW cm-2 . Additionally, the MSCs exhibit remarkable capacity retention of 90.62% after 10 000 cycles. Furthermore, the Ti3 C2 Tx /CNTs based-sensor exhibits real-time detection capability for human facial micro-expressions and pulse single under physiological conditions. The repeated bending/release tests indicate the long-time cycle stability of the Ti3 C2 Tx /CNTs based-sensor. Owing to the excellent sensing performance, the sensing array was also fabricated. It is believed that this work develops a route for designing a self-powered sensor system with flexible production, high performance, and human-friendly characteristics for wearable electronics.

IrPd Nanoalloy-Structured Bifunctional Electrocatalyst for Efficient and pH-Universal Water Splitting.

The lack of high efficiency and pH-universal bifunctional electrocatalysts for water splitting to hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) hinders the large-scale production of green hydrogen. Here, an IrPd electrocatalyst supported on ketjenblack that exhibits outstanding bifunctional performance for both HER and OER at wide pH conditions is presented. The optimized IrPd catalyst exhibits a specific activity of 4.46 and 3.98 A mgIr -1 in the overpotential of 100 and 370 mV for HER and OER, respectively, in alkaline conditions. When applied to the anion exchange membrane electrolyzer, the Ir44 Pd56 /KB catalyst shows a stability of >20 h at a current of 250 mA cm-2 for water decomposition, indicating promising prospects for practical applications. Beyond offering an advanced electrocatalyst, this work also guides the rational design of desirable bifunctional electrocatalysts for HER and OER by regulating the microenvironments and electronic structures of metal catalytic sites for diverse catalysis.

Hypercapsule is the cornerstone of Klebsiella pneumoniae in inducing pyogenic liver abscess.

Purpose: To investigate the mechanisms of Klebsiella pneumoniae-induced pyogenic liver abscess (PLA). Methods: Forty-three K. pneumoniae strains from PLAs and 436 from non-PLAs were collected. Their differences were compared for virulence genes and factors, sequence types, and serotypes. Virulence genes wzi, wzy-K1, and wzi+wzy-K1 were deleted in K. pneumoniae NTUH-K2044. Various analyses, such as transmission electron microscopy, neutrophil killing tests, and mouse lethality tests, were used to confirm the consequent changes. Results: Differences were found between K. pneumoniae strains from PLA and non-PLA samples for virulence genes and factors, including metabolism genes (allS and peg-344), capsular polysaccharide (CPS)-synthesis channel gene (wzy-K1), CPS-regulating genes (p-rmpA, p-rmpA2, and c-rmpA), and siderophore genes (iucA and iroN). When wzy-K1 was positive, the difference between PLA and non-PLA samples was only observed with c-rmpA. Δwzi, Δwzy-K1, and ΔwziΔwzy-K1 strains reverted to hypovirulence. In the Kupffer cell stimulation assay, interleukin (IL)-6, IL-12, IL-10, and transforming growth factor-ß secretions were found to be equivalent in NTUH-K2044, Δwzi, Δwzy-K1, and ΔwziΔwzy-K1 groups. Lower IL-1ß and higher tumor necrosis factor-α secretions were observed for Δwzi, Δwzy-K1, and ΔwziΔwzy-K1. Conclusions: Hypercapsule production is the cornerstone of hypervirulence, regardless of exopolysaccharides. K1 K. pneumoniae-induced PLA may decrease core inflammatory cytokines rather than increase anti-inflammatory cytokines. Exopolysaccharides could also attenuate the inflammatory response to aid in the immune escape of K. pneumoniae.

The direct catalytic synthesis of ultrasmall Cu2O-coordinated carbon nitrides on ceria for multimodal antitumor therapy.

Engineering chem-/sono-/photo-multimodal antitumor therapies has become an efficient strategy to combat malignant tumors. However, the existence of hypoxia in the tumor microenvironment (TME) leads to limited sonodynamic or photodynamic efficiency because O2 is the key reactant during the process of generation of reactive oxygen species (ROS). Here, to design a desirable platform that can simultaneously convert H2O2 in the TME into ROS and O2 for efficient chem-/sono-/photo-multimodal tumor therapies, we have created ultrasmall Cu2O-coordinated carbon nitride on a biocompatible ceria substrate (denoted as Cu2O-CNx@CeO2) via a self-assisted catalytic growth strategy. The chemical and morphological structures, ROS and O2 generation activities, and chemo-/photo-/sono-dynamic specificities of Cu2O-CNx@CeO2 when serving as multifunctional biocatalytic agents were systematically disclosed. The experimental studies validated that Cu2O-CNx@CeO2 presents state-of-the-art peroxidase-like and catalase-like activities. Moreover, the light excitation and ultrasound irradiation were also demonstrated to boost ROS production. The in vitro and in vivo experiments suggest that Cu2O-CNx@CeO2 can efficiently inhibit the growth of malignant melanoma via chem-/sono-/photo-multimodal antitumor ability. We believe that applying these new biocatalysts with dual catalytic activities of producing ROS and O2 will offer a new path for engineering multimodal nanoagents to combat malignant tumors.

Exploiting a conjugative endogenous CRISPR-Cas3 system to tackle multidrug-resistant Klebsiella pneumoniae.

BACKGROUND: Mobile plasmids play a key role in spurring the global dissemination of multidrug-resistant (MDR) K. pneumoniae, while plasmid curing has been recognized as a promising strategy to combat antimicrobial resistance. Here we exploited a K. pneumoniae native CRISPR system to cure the high-risk IncFII plasmids. METHODS: We examined matched protospacers in 725 completely sequenced IncFII plasmids from K. pneumoniae genomes. Then, we re-engineered a native CRISPR-Cas3 system and deliver the CRISPR-Cas3 system via conjugation. Plasmid killing efficiency and G. mellonella infection model were applied to evaluate the CRISPR-Cas3 immunity in vitro and in vivo. FINDINGS: Genomic analysis revealed that most IncFII plasmids could be targeted by the native CRISPR-Cas3 system with multiple matched protospacers, and the targeting regions were highly conserved across different IncFII plasmids. This conjugative endogenous CRISPR-Cas3 system demonstrated high plasmid curing efficiency in vitro (8-log decrease) and in vivo (∼100% curing) in a Galleria mellonella infection model, as well as provided immunization against the invasion of IncFII plasmids once the system entering a susceptible bacterial host. INTERPRETATION: Overall, our work demonstrated the applicability of using native CRISPR-mediated plasmid curing to re-sensitize drug-resistant K. pneumoniae to multiple antibiotics. This work provided strong support for the idea of utilizing native CRISPR-Cas systems to tackle AMR in K. pneumoniae. FUNDING: This work was supported by research grants National Natural Science Foundation of China [grant numbers 81871692, 82172315, 82102439, and 82202564], the Shanghai Science and Technology Commission [grant number 19JC1413002], and Shanghai Sailing Program [grant number 22YF1437500].

Potential impact of industrial transfer on PM2.5 and economic development under scenarios oriented by different objectives in Guangdong, China.

For sustainable regional development, industrial transfer is an important trend that will potentially change the spatial and temporal pattern of air pollution and economic development. Aiming to better regulate industrial transfer and guide policy-making, this study proposes an assessment framework for industrial transfer that combines precise enterprise data, GIS technology and a 3-D air quality model. Taking Guangdong Province as an example, this study simulates the redistribution of 4015 high-pollution and high-energy-consumption (double-high) enterprises in the Pearl River Delta (PRD) to surrounding areas, and the potential impact on air quality is further evaluated. Three mutually independent transfer scenarios with different objectives are designed-ENV (ENVironment), ENT (ENTerprise), and GOV (GOVernment)-which aim to maximize benefits from the standpoint of the residents of Guangdong, the enterprises themselves, and local governments, respectively. Results show that Western Guangdong (WG), Northern Guangdong (NG), and Eastern Guangdong (EG) would be the primary transfer-in regions under the ENV, ENT, and GOV scenarios due to different resource endowment. Controlled by the different scenarios, the redistribution of enterprises presented different characteristics regarding the transport of pollutant emissions and economic added value between the PRD and surrounding areas. The average concentration of PM2.5 and the related population-weighted concentrations (PWC) showed a slight decrease over the PRD (-0.75 to -0.62 µg/m3 and -0.35 to -0.49 µg/m3 per person) but increased dramatically in surrounding areas under the three scenarios (0.46-7.68 µg/m3 and 0.07-4.44 µg/m3 per person). The transfer of double-high enterprises could potentially decrease the industrial fossil fuel consumption intensity (fossil energy consumption per unit of industrial GDP) of most of the cities while exacerbating pollution intensity (concentration of PM2.5 per unit of industrial GDP), reflecting the huge gap in the regional industrial development pattern in Guangdong Province at this stage, and illustrating the importance of emission control of these enterprises for improvement of regional air quality in the future. The research perspective on industrial transfer proposed in this study could provide a reference for future studies.