Rapid and extensive SARS-CoV-2 Omicron variant infection wave revealed by wastewater surveillance in Shenzhen following the lifting of a strict COVID-19 strategy.

Wastewater-based epidemiology (WBE) has emerged as a promising tool for monitoring the spread of COVID-19, as SARS-CoV-2 can be shed in the faeces of infected individuals, even in the absence of symptoms. This study aimed to optimize a prediction model for estimating COVID-19 infection rates based on SARS-CoV-2 RNA concentrations in wastewater, and reveal the infection trends and variant diversification in Shenzhen, China following the lifting of a strict COVID-19 strategy. Faecal samples (n = 4337) from 1204 SARS-CoV-2 infected individuals hospitalized in a designated hospital were analysed to obtain Omicron variant-specific faecal shedding dynamics. Wastewater samples from 6 wastewater treatment plants (WWTPs) and 9 pump stations, covering 3.55 million people, were monitored for SARS-CoV-2 RNA concentrations and variant abundance. We found that the viral load in wastewater increased rapidly in December 2022 in the two districts, demonstrating a sharp peak in COVID-19 infections in late-December 2022, mainly caused by Omicron subvariants BA.5.2.48 and BF.7.14. The prediction model, based on the mass balance between total viral load in wastewater and individual faecal viral shedding, revealed a surge in the cumulative infection rate from <0.1 % to over 70 % within three weeks after the strict COVID-19 strategy was lifted. Additionally, 39 cryptic SARS-CoV-2 variants were identified in wastewater, in addition to those detected through clinical surveillance. These findings demonstrate the effectiveness of WBE in providing comprehensive and efficient assessments of COVID-19 infection rates and identifying cryptic variants, highlighting its potential for monitoring emerging pathogens with faecal shedding.

Au-modified ceria nanozyme prevents and treats hypoxia-induced pulmonary hypertension with greatly improved enzymatic activity and safety.

BACKGROUND: Despite recent advances the prognosis of pulmonary hypertension remains poor and warrants novel therapeutic options. Extensive studies, including ours, have revealed that hypoxia-induced pulmonary hypertension is associated with high oxidative stress. Cerium oxide nanozyme or nanoparticles (CeNPs) have displayed catalytic activity mimicking both catalase and superoxide dismutase functions and have been widely used as an anti-oxidative stress approach. However, whether CeNPs can attenuate hypoxia-induced pulmonary vascular oxidative stress and pulmonary hypertension is unknown. RESULTS: In this study, we designed a new ceria nanozyme or nanoparticle (AuCeNPs) exhibiting enhanced enzyme activity. The AuCeNPs significantly blunted the increase of reactive oxygen species and intracellular calcium concentration while limiting proliferation of pulmonary artery smooth muscle cells and pulmonary vasoconstriction in a model of hypoxia-induced pulmonary hypertension. In addition, the inhalation of nebulized AuCeNPs, but not CeNPs, not only prevented but also blunted hypoxia-induced pulmonary hypertension in rats. The benefits of AuCeNPs were associated with limited increase of intracellular calcium concentration as well as enhancement of extracellular calcium-sensing receptor (CaSR) activity and expression in rat pulmonary artery smooth muscle cells. Nebulised AuCeNPs showed a favorable safety profile, systemic arterial pressure, liver and kidney function, plasma Ca2+ level, and blood biochemical parameters were not affected. CONCLUSION: We conclude that AuCeNPs is an improved reactive oxygen species scavenger that effectively prevents and treats hypoxia-induced pulmonary hypertension.

Rapid and specific differentiation of Salmonella enterica serotypes typhi and Paratyphi by multicolor melting curve analysis.

Rapid and accurate identification of Salmonella enterica serotypes Typhi and Paratyphi (A, B and C), the causal agents of enteric fever, is critical for timely treatment, case management and evaluation of health policies in low and middle-income countries where the disease still remains a serious public health problem. The present study describes the development of a multiplex assay (EFMAtyping) for simultaneous identification of pathogens causing typhoid and paratyphoid fever in a single reaction by the MeltArray approach, which could be finished within 2.5 h. Seven specific genes were chosen for differentiation of typhoidal and nontyphoidal Salmonella. All gene targets were able to be detected by the EFMAtyping assay, with expected Tm values and without cross-reactivity to other relevant Salmonella serovars. The limit of detection (LOD) for all gene targets was 50 copies per reaction. The LOD reached 102-103 CFU/ml for each pathogen in simulated clinical samples. The largest standard deviation value for mean Tm was below 0.5 °C. This newly developed EFMAtyping assay was further evaluated by testing 551 clinical Salmonella isolates, corroborated in parallel by the traditional Salmonella identification workflow, and serotype prediction was enabled by whole-genome sequencing. Compared to the traditional method, our results exhibited 100% of specificity and greater than 96% of sensitivity with a kappa correlation ranging from 0.96 to 1.00. Thus, the EFMAtyping assay provides a rapid, high throughput, and promising tool for public health laboratories to monitor typhoid and paratyphoid fever.

Identification of Noncoding Functional Regulatory Variants of STIM1 Gene in Idiopathic Pulmonary Arterial Hypertension.

BACKGROUND: STIM1 (stromal interaction molecule 1) regulates store-operated calcium entry and is involved in pulmonary artery vasoconstriction and pulmonary artery smooth muscle cell proliferation, leading to pulmonary arterial hypertension (PAH). METHODS: Bioinformatics analysis and a 2-stage matched case-control study were conducted to screen for noncoding variants that may potentially affect STIM1 transcriptional regulation in 242 patients with idiopathic PAH and 414 healthy controls. Luciferase reporter assay, real-time quantitative polymerase chain reaction, western blot, 5-ethynyl-2'-deoxyuridine (EdU) assay, and intracellular Ca2+ measurement were performed to study the mechanistic roles of those STIM1 noncoding variants in PAH. RESULTS: Five noncoding variants (rs3794050, rs7934581, rs3750996, rs1561876, and rs3750994) were identified and genotyped using Sanger sequencing. Rs3794050, rs7934581, and rs1561876 were associated with idiopathic PAH (recessive model, all P<0.05). Bioinformatics analysis showed that these 3 noncoding variants possibly affect the enhancer function of STIM1 or the microRNA (miRNA) binding to STIM1. Functional validation performed in HEK293 and pulmonary artery smooth muscle cells demonstrated that the noncoding variant rs1561876-G (STIM1 mutant) had significantly stronger transcriptional activity than the wild-type counterpart, rs1561876-A, by affecting the transcriptional regulatory function of both hsa-miRNA-3140-5p and hsa-miRNA-4766-5p. rs1561876-G enhanced intracellular Ca2+ signaling in human pulmonary artery smooth muscle cells secondary to calcium-sensing receptor activation and promoted proliferation of pulmonary artery smooth muscle cells under both normoxia and hypoxia conditions, suggesting a possible contribution to PAH development. CONCLUSIONS: The potential clinical implications of the 3 noncoding variants of STIM1, rs3794050, rs7934581, and rs1561876, are 2-fold, as they may help predict the risk and prognosis of idiopathic PAH and guide investigations on novel therapeutic pathway(s).

Discovery of a Series of 4-Amide-thiophene-2-carboxyl Derivatives as Highly Potent P2Y14 Receptor Antagonists for Inflammatory Bowel Disease Treatment.

The P2Y14 receptor has been proven to be a potential target for IBD. Herein, we designed and synthesized a series of 4-amide-thiophene-2-carboxyl derivatives as novel potent P2Y14 receptor antagonists based on the scaffold hopping strategy. The optimized compound 39 (5-((5-fluoropyridin-2-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid) exhibited subnanomolar antagonistic activity (IC50: 0.40 nM). Moreover, compound 39 demonstrated notably improved solubility, liver microsomal stability, and oral bioavailability. Fluorescent ligand binding assay confirmed that 39 has the binding ability to the P2Y14 receptor, and molecular dynamics (MD) simulations revealed the formation of a unique intramolecular hydrogen bond (IMHB) in the binding conformation. In the experimental colitis mouse model, compound 39 showed a remarkable anti-IBD effect even at low doses. Compound 39, with a potent anti-IBD effect and favorable druggability, can be a promising candidate for further research. In addition, this work lays a strong foundation for the development of P2Y14 receptor antagonists and the therapeutic strategy for IBD.

Pannonibacter tanglangensis sp. nov., a New Species Isolated from Pond Sediment.

Two bacterial strains (XCT-34T and XCT-53) isolated from sediment samples of an artificial freshwater reservoir were analyzed using a polyphasic approach. The two isolates are aerobic, Gram-stain-negative, oxidase-negative, catalase-positive, motile with polar flagella, rod-shaped, and approximately 1.4-3.4 × 0.4-0.9 µm in size. Phylogenetic analyses based on 16S rRNA gene and whole-genome sequences showed that the two strains formed a distinct branch within the evolutionary radiation of the genus Pannonibacter, closest to Pannonibacter carbonis Q4.6T (KCTC 52466). Furthermore, lower than threshold average nucleotide identity values (ANI, 85.7-86.4%) and digital DNA-DNA hybridization values (dDDH, 22.3-30.5%) of the two strains compared to the nearest type strains also confirmed that they represented a novel species. Genomic analyses, including annotation of the KEGG pathways, prediction of the secondary metabolism biosynthetic gene clusters and PHI phenotypes, supported functional inference and differentiation of the strains from the closely related taxa. Results of chemotaxonomic and physiological studies revealed that their distinct phenotypic characteristics distinguished them from existing Pannonibacter species. Thus, the two strains are considered to represent a novel species of Pannonibacter, for which the name of Pannonibacter tanglangensis sp. nov. is proposed, with XCT-34T (= KCTC 82332T = GDMCC 1.1947T) as the respective type strain.

The viral trends and genotype diversity of norovirus in the wastewater of Shenzhen, China.

Norovirus (NoV) is the primary cause of acute gastroenteritis (AGE) on a global scale. Numerous studies have demonstrated the immense potential of wastewater surveillance in monitoring the prevalence and spread of NoV within communities. This study employed a one-step reverse transcription-quantitative PCR to quantify NoV GI/GII in wastewater samples (n = 2574), which were collected once or twice a week from 38 wastewater treatment plants from March 2023 to February 2024 in Shenzhen. The concentrations of NoV GI and GII ranged from 5.0 × 104 to 1.7 × 106 copies/L and 4.1 × 105 to 4.5 × 106 copies/L, respectively. The concentrations of NoV GII were higher than those of NoV GI. Spearman's correlation analysis revealed a moderate correlation between the concentration of NoV in wastewater and the detection rates of NoV infections in sentinel hospitals. Baseline values were established for NoV concentrations in Shenzhen's wastewater, providing a crucial reference point for implementing early warning systems and nonpharmaceutical interventions to mitigate the impact of potential outbreaks. A total of 24 NoV genotypes were identified in 100 wastewater samples by sequencing. Nine genotypes of NoV GI were detected, with the major genotypes being GI.4 (38.6 %) and GI.3 (21.8 %); Fifteen genotypes of NoV GII were identified, with GII.4 (53.6 %) and GII.17 (26.0 %) being dominant. The trends in the relative abundance of NoV GI/GII were significantly different, and the trends in the relative abundance of NoV GII.4 over time were similar across all districts, suggesting a potential risk of cross-regional spread. Our findings underscore the effectiveness of wastewater surveillance in reflecting population-level NoV infections, capturing the diverse array of NoV genotypes, and utilizing NoV RNA in wastewater as a specific indicator to supplement clinical surveillance data, ultimately enhancing our ability to predict the timing and intensity of NoV epidemics.

Metallothionein 3 Potentiates Pulmonary Artery Smooth Muscle Cell Proliferation by Promoting Zinc-MTF1-ATG5 Axis-mediated Autophagosome Formation.

Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the critical pathological mechanisms of pulmonary hypertension (PH), and therefore is gradually being adopted as an important direction for the treatment of PH. Metallothioneins (MTs) have been reported to be associated with PH, but the underlying mechanisms are not fully understood. Here, we demonstrated that the expression level of metallothionein 3 (MT3) was significantly increased in pulmonary arterioles from PH patients and chronic hypoxia-induced rat and mouse PH models, as well as in hypoxia-treated human PASMCs. Knockdown of MT3 significantly inhibited the proliferation of human PASMCs by arresting the cell cycle in the G1 phase, while overexpression of MT3 had the opposite effect. Mechanistically, we found that MT3 increased the intracellular zinc (Zn2+) concentration to enhance the transcriptional activity of metal-regulated transcription factor 1 (MTF1), which promoted the expression of autophagy-related gene 5 (ATG5), facilitating autophagosome formation. More importantly, MT3-induced autophagy and proliferation of human PASMCs were largely prevented by knockdown of MTF1 and ATG5. Therefore, in this study, we identified MT3-Zinc-MTF1-ATG5 as a novel pathway that affects PASMC proliferation by regulating autophagosome formation, suggesting that MT3 may be a novel target for the treatment of PH.

Early Detection of the Emerging SARS-CoV-2 BA.2.86 Lineage Through Wastewater Surveillance Using a Mediator Probe PCR Assay - Shenzhen City, Guangdong Province, China, 2023.

Introduction: The emergence of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineage, BA.2.86, has sparked global public health concerns for its potential heightened transmissibility and immune evasion. Utilizing data from Shenzhen's city-wide wastewater surveillance system, we highlight the presence of the BA.2.86 lineage in Shenzhen. Methods: A mediator probe polymerase chain reaction (PCR) assay was developed to detect the BA.2.86 lineage in wastewater by targeting a specific mutation (Spike: A264D). Between September 19 and December 10, 2023, 781 wastewater samples from 38 wastewater treatment plants (WWTPs) and 9 pump stations in ten districts of Shenzhen were examined. Through multiple short-amplicon sequencing, three positive samples were identified. Results: The BA.2.86 lineage was identified in the wastewater of Futian and Nanshan districts in Shenzhen on December 2, 2023. From December 2 to 10, a total of 21 BA.2.86-positive wastewater samples were found across 6 districts (Futian, Nanshan, Longhua, Baoan, Longgang, and Luohu) in Shenzhen. The weighted average viral load of the BA.2.86 lineage in Shenzhen's wastewater was 43.5 copies/L on December 2, increased to 219.8 copies/L on December 4, and then decreased to approximately 100 copies/L on December 6, 8, and 10. Conclusions: The mediator probe PCR assay, designed for swift detection of low viral concentrations of the BA.2.86 lineage in wastewater samples, shows promise for detecting different SARS-CoV-2 variants. Wastewater surveillance could serve as an early detection system for promptly identifying specific SARS-CoV-2 variants as they emerge.

Association between social capital and utilization of essential public health services among elderly migrants: a multilevel logistic study based on the 2017 China migrant dynamic survey (CMDS).

BACKGROUND: As the number of elderly migrants in China continues to grow, it is necessary to pay closer attention to their health and health services. Some studies have confirmed that social capital plays a significant role in the utilization of health services. Therefore, an in-depth exploration of the relationship between social capital and the utilization of essential public health services (EPHS) by elderly migrants will not only contribute to improving their overall health but also facilitate a more balanced development of public health service system in China. METHODS: Based on the cross-sectional data from the 2017 China Migrants Dynamic Survey (CMDS), this study examined the impact of social capital on the utilization of EPHS among elderly migrants. We evaluated social capital at two distinct levels: the individual and the community, and considered two dimensions of social capital: structural social capital (SSC) and cognitive social capital (CSC). The study aimed to delve into the impact of these forms of social capital on the utilization of EPHS among elderly migrants, and whether the migration range moderates this impact by multilevel logistic regression analysis. RESULTS: A total of 5,728 migrant elderly individuals were selected. The health records establishment rate and health education acceptance rate were approximately 33.0% and 58.6%, respectively. Social capital influenceed the utilization of EPHS among elderly migrants. Specifically, individual-level SSC and CSC have impacts on both the establishment of health records (OR = 1.598, 95%CI 1.366-1.869; OR = 1.705, 95%CI 1.433-2.028) and the acceptance of health education (OR = 1.345, 95%CI 1.154-1.567; OR = 2.297, 95%CI 1.906-2.768) among elderly migrants, while community-level SSC only affected the acceptance of health education (OR = 3.838, 95%CI 1.328-11.097). There were significant differences in individual-level SSC, health records, and health education among different migration range subgroups among elderly migrants. Migration range moderated the effect of social capital on the utilization of EPHS, crossing provinces could weaken the relationship between SSC and health education. CONCLUSIONS: Social capital is associated with a higher utilization rate of EPHS among elderly migrants. It is necessary to encourage them to actively participate in social activities, strengthen public services and infrastructure construction in the area, and improve their sense of belonging and identity.

RD-OpenMax: Rethinking OpenMax for Robust Realistic Open-Set Recognition.

Open-set recognition (OSR) toward a practical open-world setting has attracted increasing research attention in recent years. However, existing OSR settings are either too idealized or focus on specific scenes such as long-tailed distribution and few-shot samples, which fail to capture the complexity of real-world scenarios. In this article, we propose a realistic OSR (ROSR) setting that covers a diverse range of challenging and real-world scenarios, including fine-grained cases with strong semantic correlation and a large number of species, few-shot samples, long-tailed sample distribution, dynamic inputs (e.g., images, spatio-temporal, and multimodal signals) and cross-domain adaptation. In particular, we rethink the simple and basic OpenMax for the ROSR setting and introduce a novel method, regularized discriminative OpenMax (RD-OpenMax), to handle the challenges in the ROSR setting. RD-OpenMax improves upon the basic OpenMax approach by introducing a covariance attention-based covariance pooling (CACP) module as a global aggregation step before the deep architecture's classifier. This module explores rich statistical information on features and provides discriminative distance scores for OpenMax. To address the instability of extreme value theory (EVT) estimation due to insufficient training samples under few-shot and long-tailed scenarios, we propose a regularized EVT (REVT) method based on Monte Carlo sampling to recalibrate the distribution of distance scores. As such, our RD-OpenMax performs a REVT model of distance scores generated by discriminative CACP representations to distinguish known classes and recognize unknown ones effectively and robustly. Extensive experiments are conducted on more than ten visual benchmarks across several scenarios, and the empirical comparisons show that the ROSR setting challenges existing state-of-the-art OSR approaches. Moreover, our RD-OpenMax clearly outperforms its counterparts under the ROSR setting while performing favorably against state-of-the-arts under the traditional OSR setting.

SMYD2-Methylated PPARγ Facilitates Hypoxia-Induced Pulmonary Hypertension by Activating Mitophagy.

BACKGROUND: Hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs) and consequent pulmonary vascular remodeling are the crucial pathological features of pulmonary hypertension (PH). Protein methylation has been shown to be critically involved in PASMC proliferation and PH, but the underlying mechanism remains largely unknown. METHODS: PH animal models were generated by treating mice/rats with chronic hypoxia for 4 weeks. SMYD2-vTg mice (vascular smooth muscle cell-specific suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 (deformed epidural auto-regulatory factor-1) domain-containing protein 2 transgenic) or wild-type rats and mice treated with LLY-507 (3-cyano-5-{2-[4-[2-(3-methylindol-1-yl)ethyl]piperazin-1-yl]-phenyl}-N-[(3-pyrrolidin-1-yl)propyl]benzamide) were used to investigate the function of SMYD2 (suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 domain-containing protein 2) on PH development in vivo. Primary cultured rat PASMCs with SMYD2 knockdown or overexpression were used to explore the effects of SMYD2 on proliferation and to decipher the underlying mechanism. RESULTS: We demonstrated that the expression of the lysine methyltransferase SMYD2 was upregulated in the smooth muscle cells of pulmonary arteries from patients with PH and hypoxia-exposed rats/mice and in the cytoplasm of hypoxia-induced rat PASMCs. More importantly, targeted inhibition of SMYD2 by LLY-507 significantly attenuated hypoxia-induced pulmonary vascular remodeling and PH development in both male and female rats in vivo and reduced rat PASMC hyperproliferation in vitro. In contrast, SMYD2-vTg mice exhibited more severe PH phenotypes and related pathological changes than nontransgenic mice after 4 weeks of chronic hypoxia treatment. Furthermore, SMYD2 overexpression promoted, while SMYD2 knockdown suppressed, the proliferation of rat PASMCs by affecting the cell cycle checkpoint between S and G2 phases. Mechanistically, we revealed that SMYD2 directly interacted with and monomethylated PPARγ (peroxisome proliferator-activated receptor gamma) to inhibit the nuclear translocation and transcriptional activity of PPARγ, which further promoted mitophagy to facilitate PASMC proliferation and PH development. Furthermore, rosiglitazone, a PPARγ agonist, largely abolished the detrimental effects of SMYD2 overexpression on PASMC proliferation and PH. CONCLUSIONS: Our results demonstrated that SMYD2 monomethylates nonhistone PPARγ and inhibits its nuclear translocation and activation to accelerate PASMC proliferation and PH by triggering mitophagy, indicating that targeting SMYD2 or activating PPARγ are potential strategies for the prevention of PH.

Transcriptome analysis and functional validation reveal the novel role of LhCYCL in axillary bud development in hybrid Liriodendron.

Shoot branching significantly influences yield and timber quality in woody plants, with hybrid Liriodendron being particularly valuable due to its rapid growth. However, understanding of the mechanisms governing shoot branching in hybrid Liriodendron remains limited. In this study, we systematically examined axillary bud development using morphological and anatomical approaches and selected four distinct developmental stages for an extensive transcriptome analysis. A total of 9,449 differentially expressed genes have been identified, many of which are involved in plant hormone signal transduction pathways. Additionally, we identified several transcription factors downregulated during early axillary bud development, including a noteworthy gene annotated as CYC-like from the TCP TF family, which emerged as a strong candidate for modulating axillary bud development. Quantitative real-time polymerase chain reaction results confirmed the highest expression levels of LhCYCL in hybrid Liriodendron axillary buds, while histochemical ß-glucuronidase staining suggested its potential role in Arabidopsis thaliana leaf axil development. Ectopic expression of LhCYCL in A. thaliana led to an increase of branches and a decrease of plant height, accompanied by altered expression of genes involved in the plant hormone signaling pathways. This indicates the involvement of LhCYCL in regulating shoot branching through plant hormone signaling pathways. In summary, our results emphasize the pivotal role played by LhCYCL in shoot branching, offering insights into the function of the CYC-like gene and establishing a robust foundation for further investigations into the molecular mechanisms governing axillary bud development in hybrid Liriodendron.

Comprehensive insights into potential roles of purinergic P2 receptors on diseases: Signaling pathways involved and potential therapeutics.

BACKGROUND: Purinergic P2 receptors, which can be divided into ionotropic P2X receptors and metabotropic P2Y receptors, mediate cellular signal transduction of purine or pyrimidine nucleoside triphosphates and diphosphate. Based on the wide expression of purinergic P2 receptors in tissues and organs, their significance in homeostatic maintenance, metabolism, nociceptive transmission, and other physiological processes is becoming increasingly evident, suggesting that targeting purinergic P2 receptors to regulate biological functions and signal transmission holds significant promise for disease treatment. AIM OF REVIEW: This review highlights the detailed mechanisms by which purinergic P2 receptors engage in physiological and pathological progress, as well as providing prospective strategies for discovering clinical drug candidates. KEY SCIENTIFIC CONCEPTS OF REVIEW: The purinergic P2 receptors regulate complex signaling and molecular mechanisms in nervous system, digestive system, immune system and as a result, controlling physical health states and disease progression. There has been a significant rise in research and development focused on purinergic P2 receptors, contributing to an increased number of drug candidates in clinical trials. A few influential pioneers have laid the foundation for advancements in the evaluation, development, and of novel purinergic P2 receptors modulators, including agonists, antagonists, pharmaceutical compositions and combination strategies, despite the different scaffolds of these drug candidates. These advancements hold great potential for improving therapeutic outcomes by specifically targeting purinergic P2 receptors.

[Genetic characterization and drug resistance analysis of Salmonella Kentucky ST314 in Shenzhen in 2010-2021].

OBJECTIVE: To understand the prevalence, genetic characteristics and drug resistance features of Salmonella Kentucky ST314 in Shenzhen. METHODS: Whole genome sequencing of 14 strains of Salmonella Kentucky ST314 collected from 2010-2021 by the Foodborne Disease Surveillance Network of Shenzhen Center for Disease Control and Prevention for phylogenetic evolutionary analysis, drug resistance gene and plasmid detection; drug susceptibility experiments were performed by micro-broth dilution method. RESULTS: A total of 57 strains of Salmonella Kentucky were collected from the foodborne disease surveillance network, 14 of which were ST314. The Shenzhen isolates were clustered with isolates from Southeast Asian countries such as Vietnam and Thailand on clade 314.2, and the single nucleotide polymorphism distance between local strains in Shenzhen was large, indicating dissemination. In this study, a total of 17 drug resistance genes/mutations in 9 categories were detected in the genome of Salmonella Kentucky ST314, carrying 3 extended spectrum beta-lactamases(ESBLs), including bla_(CTX-M-24)(14.3%, 2/14), bla_(CTX-M-55)(7.1%, 1/14), and bla_(CTX-M-130)(14.3%, 2/14), all located on plasmids. Regarding quinolone resistance factors, two plasmid-mediated quinolone resistance(PMQR) genes were identified in the genome: qnrB6(71.4%, 10/14) and aac(6')Ib-cr(78.6%, 11/14), a quinolone resistance quinolone resistance-determining regions(QRDR) mutation T57 S(100%, 14/14). The multi-drug resistance rate of Salmonella Kentucky ST314 in Shenzhen was 92.86%(13/14)with the highest rate of resistance to tetracycline and cotrimoxazole(100%, 14/14), followed by chloramphenicol(92.86%, 13/14), cefotaxime and ampicillin(78.57%, 11/14), ciprofloxacin and nalidixic acid(71.43%, 10/14), and ampicillin-sulbactam had the lowest resistance rate(21.43%, 3/14). CONCLUSION: ST314 is the second most prevalent ST type among Salmonella Kentucky in Shenzhen, mainly isolated from food, especially poultry; phylogenetic analysis suggests that ST314 is a disseminated infection and the genome shows a highly genetically conserved phenotype. Drug resistance of Salmonella Kentucky ST314 is very serious, especially QRDR mutation, PMQR gene co-mediated quinolone resistance and plasmid-mediated cephalosporin resistance are prominent and deserve extensive attention.

Design, Synthesis, and Biological Evaluation of a Novel NIK Inhibitor with Anti-Inflammatory and Hepatoprotective Effects for Sepsis Treatment.

NIK plays a crucial role in the noncanonical NF-κB signaling pathway associated with diverse inflammatory and autoimmune diseases. Our study presents compound 54, a novel NIK inhibitor, designed through a structure-based scaffold-hopping approach from the previously identified B022. Compound 54 demonstrates remarkable selectivity and potency against NIK both in vitro and in vivo, effectively suppressing pro-inflammatory cytokines and nitric oxide production. In mouse models, compound 54 protected against LPS-induced systemic sepsis, reducing AST, ALT, and AKP liver injury markers. Additionally, it also attenuates sepsis-induced lung and kidney damage. Mechanistically, compound 54 blocks the noncanonical NF-κB signaling pathway by targeting NIK, preventing p100 to p52 processing. This work reveals a novel class of NIK inhibitors with significant potential for sepsis therapy.

CCP-GNN: Competitive Covariance Pooling for Improving Graph Neural Networks.

Graph neural networks (GNNs) have advanced graph classification tasks, where a global pooling to generate graph representations by summarizing node features plays a critical role in the final performance. Most of the existing GNNs are built with a global average pooling (GAP) or its variants, which however, take no full consideration of node specificity while neglecting rich statistics inherent in node features, limiting classification performance of GNNs. Therefore, this article proposes a novel competitive covariance pooling (CCP) based on observation of graph structures, i.e., graphs generally can be identified by a (small) key part of nodes. To this end, our CCP generates node-level second-order representations to explore rich statistics inherent in node features, which are fed to a competitive-based attention module for effectively discovering key nodes through learning node weights. Subsequently, our CCP aggregates node-level second-order representations in conjunction with node weights by summation to produce a covariance representation for each graph, while an iterative matrix normalization is introduced to consider geometry of covariances. Note that our CCP can be flexibly integrated with various GNNs (namely CCP-GNN) to improve the performance of graph classification with little computational cost. The experimental results on seven graph-level benchmarks show that our CCP-GNN is superior or competitive to state-of-the-arts. Our code is available at https://github.com/Jillian555/CCP-GNN.

Genome-wide investigation of SQUAMOSA promoter binding protein-like genes in Liriodendron and functional characterization of LcSPL2.

The plant-specific SQUAMOSA promoter-binding protein-like (SPL) transcription factors play a pivotal role in various developmental processes, including leaf morphogenesis and vegetative to reproductive phase transition. Liriodendron chinense and Liriodendron tulipifera are widely used in landscaping due to their tulip-like flowers and peculiar leaves. However, the SPL gene family in Liriodendron has not been identified and systematically characterized. We systematically identified and characterized the SPL family members in Liriodendron, including phylogeny, gene structure and syntenic analyses. Subsequently, we quantified the expression patterns of LcSPLs across various tissue sites through transcription-quantitative polymerase chain reaction (RT-qPCR) assays and identified the target gene, LcSPL2. Finally, we characterized the functions of LcSPL2 via ectopic transformation. Altogether, 17 LcSPL and 18 LtSPL genes were genome-widely identified in L. chinense and L. tulipifera, respectively. All the 35 SPLs were grouped into 9 clades. Both species had three SPL gene pairs arising from segmental duplication events, and the LcSPLs displayed high collinearity with the L. tulipifera genome. RT-qPCR assays showed that SPL genes were differentially expressed in different tissues, especially. Because LcSPL2 is highly expressed in pistils and leaves, it was selected to describe the SPL gene family of L. chinense by ectopic expression. We showed that overexpression of LcSPL2 in Arabidopsis thaliana resulted in earlier flowering and fewer rosette leaves. Moreover, we observed that overexpression of LcSPL2 in A. thaliana up-regulated the expression levels of four genes related to flower development. This study identified SPL genes in Liriodendron and characterized the function of LcSPL2 in advancing flower development.

Targeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis.

Purinergic signaling plays a causal role in the pathogenesis of inflammatory bowel disease. Among purinoceptors, only P2Y14R is positively correlated with inflammatory score in mucosal biopsies of ulcerative colitis patients, nevertheless, the role of P2Y14R in ulcerative colitis remains unclear. Here, based on the over-expressions of P2Y14R in the intestinal epithelium of mice with experimental colitis, we find that male mice lacking P2Y14R in intestinal epithelial cells exhibit less intestinal injury induced by dextran sulfate sodium. Mechanistically, P2Y14R deletion limits the transcriptional activity of cAMP-response element binding protein through cAMP/PKA axis, which binds to the promoter of Ripk1, inhibiting necroptosis of intestinal epithelial cells. Furthermore, we design a hierarchical strategy combining virtual screening and chemical optimization to develop a P2Y14R antagonist HDL-16, which exhibits remarkable anti-colitis effects. Summarily, our study elucidates a previously unknown mechanism whereby P2Y14R participates in ulcerative colitis, providing a promising therapeutic target for inflammatory bowel disease.

Layer-Specific Knowledge Distillation for Class Incremental Semantic Segmentation.

Recently, class incremental semantic segmentation (CISS) towards the practical open-world setting has attracted increasing research interest, which is mainly challenged by the well-known issue of catastrophic forgetting. Particularly, knowledge distillation (KD) techniques have been widely studied to alleviate catastrophic forgetting. Despite the promising performance, existing KD-based methods generally use the same distillation schemes for different intermediate layers to transfer old knowledge, while employing manually tuned and fixed trade-off weights to control the effect of KD. These KD-based methods take no consideration of feature characteristics from different intermediate layers, limiting the effectiveness of KD for CISS. In this paper, we propose a layer-specific knowledge distillation (LSKD) method to assign appropriate knowledge schemes and weights for various intermediate layers by considering feature characteristics, aiming to further explore the potential of KD in improving the performance of CISS. Specifically, we present a mask-guided distillation (MD) to alleviate the background shift on semantic features, which performs distillation by masking the features affected by the background. Furthermore, a mask-guided context distillation (MCD) is presented to explore global context information lying in high-level semantic features. Based on them, our LSKD assigns different distillation schemes according to feature characteristics. To adjust the effect of layer-specific distillation adaptively, LSKD introduces a regularized gradient equilibrium method to learn dynamic trade-off weights. Additionally, our LSKD makes an attempt to simultaneously learn distillation schemes and trade-off weights of different layers by developing a bi-level optimization method. Extensive experiments on widely used Pascal VOC 12 and ADE20K show our LSKD clearly outperforms its counterparts while achieving state-of-the-art results.