Hypoxia stimulates CTC-platelet cluster formation to promote breast cancer metastasis.

Circulating tumor cell clusters/micro-emboli (CTM) possess greater metastatic capacity and survival advantage compared to individual circulating tumor cell (CTC). However, the formation of CTM subtypes and their role in tumor metastasis remain unclear. In this study, we used a microfluidic Cluster-Chip with easy operation and high efficiency to isolate CTM from peripheral blood, which confirmed their correlation with clinicopathological features and identified the critical role of CTC-platelet clusters in breast cancer metastasis. The correlation between platelets and CTM function was further confirmed in a mouse model and RNA sequencing of CTM identified high-expressed genes related to hypoxia stimulation and platelet activation which possibly suggested the correlation of hypoxia and CTC-platelet cluster formation. In conclusion, we successfully developed the Cluster-Chip platform to realize the clinical capture of CTMs and analyze the biological properties of CTC-platelet clusters, which could benefit the design of potential treatment regimens to prevent CTM-mediated metastasis and tumor malignant progression.

Correlation Between Anesthesia Methods and Adverse Short-Term Postoperative Outcomes Depending on Frailty: A Prospective Cohort Study.

Purpose: This study aims to investigate how the type of anesthesia used during major orthopedic surgery may impact adverse short-term postoperative outcomes depending on frailty. Methods: To conduct this investigation, we recruited individuals aged 65 years and older who underwent major orthopedic surgery between March 2022 and April 2023 at a single institution. We utilized the FRAIL scale to evaluate frailty. The primary focus was on occurrences of death or the inability to walk 60 days after the surgery. Secondary measures included death within 60 days; inability to walk without human assistance at 60 days; death or the inability to walk without human assistance at 30 days after surgery, the first time out of bed after surgery, postoperative blood transfusion, length of hospital stay, hospital costs, and the occurrence of surgical complications such as dislocation, periprosthetic fracture, infection, reoperation, wound complications/hematoma. Results: In a study of 387 old adult patients who had undergone major orthopedic surgery, 41.3% were found to be in a frail state. Among these patients, 262 had general anesthesia and 125 had neuraxial anesthesia. Multifactorial logistic regression analyses showed that anesthesia type was not linked to complications. Instead, frailty (OR 4.04, 95% CI 1.04 to 8.57, P< 0.001), age (OR 1.05, 95% CI 1.00-1.10, P= 0.017), and aCCI scores, age-adjusted Charlson Comorbidity Index, (OR 1.36, 95% CI 1.12 to 1.66, P= 0.002) were identified as independent risk factors for death or new walking disorders in these patients 60 days after surgery. After adjusting for frailty, anesthesia methods was not associated with the development of death or new walking disorders in these patients (P > 0.05). Conclusion: In different frail populations, neuraxial anesthesia is likely to be comparable to general anesthesia in terms of the incidence of short-term postoperative adverse outcomes.

[Comparative analysis of plastomes of Rubus chingii and R. chingii var. suavissimus].

Rubus chingii and R. chingii var. suavissimus are unique dual-purpose plant resources, with significant nutraceutical, pharmaceutical, and economic value, as well as promising prospects for further development. To investigate the genetic structure and evolutionary characteristics of these two varieties, this study conducted plastome sequencing using the Illumina HiSeq XTen sequencing platform. Subsequently, the study performed assembly, annotation, and characterization of the genomes, followed by a comparative plastome and phylogenetic analysis using bioinformatics techniques. The results revealed that the plastomes of R. chingii and R. chingii var. suavissimus exhibited a tetrad structure, comprising a large single-copy region(LSC), a small single-copy region(SSC), and two inverted repeat regions(IRs). The study identified a total of 56 simple sequence repeats(SSRs) after comparative analysis, predominantly consisting of A and T. Furthermore, the structure of the IR boundary genes in both varieties was found to be highly conserved, with only minor nucleotide variations. Additionally, the study identified three highly variable regions: rps16-trnQ-psbK, trnR-atpA, and trnT-trnL, which held promise as potential identification marks for further development and utilization. Phylogenetic analysis results obtained by the maximum likelihood and Bayesian inference methods demonstrated a close clustering of R. chingii and R. chingii var. suavissimus(100% support), with their closest relatives being R. trianthus. This study, focusing on plastome-level genetic distinctions between these two varieties, lays a foundation for future species protection, development, and utilization.

Involvement of the ABCB1 C3435T Variant but Not the MTHFR C677T or MTHFR A1298C Variant in High-Dose Methotrexate-Induced Toxicity in Pediatric Acute Lymphoblastic Leukemia Patients in China.

Purpose: It remains unclear whether the MTHFR C677T, MTHFR A1298C and ABCB1 C3435T genetic variants are associated with methotrexate (MTX) elimination delay and high-dose MTX (HD-MTX) toxicities in the treatment of pediatric acute lymphoblastic leukemia (ALL). The aim of our study was to analyze the potential predictive role of MTHFR C677T, MTHFR A1298C and ABCB1 C3435T in toxicities and the relationship between these variants and MTX elimination delay during HD-MTX therapy in pediatric ALL patients. Patients and Methods: We conducted a retrospective study on ALL patients receiving HD-MTX treatment with available MTHFR C677T, MTHFR A1298C and ABCB1 C3435T genotype and 44-h plasma MTX levels. Logistic regression analyses and chi-square tests were used to assess the relationship between the variants and HD-MTX toxicities and MTX elimination delay. Results: Genotype frequencies were in Hardy-Weinberg equilibrium. MTX elimination delay did not significantly differ between MTHFR C677T and MTHFR A1298C or ABCB1 C3435T. Leukopenia (P=0.028), neutropenia (P=0.034) and oral mucositis (P=0.023) were 6.444-fold, 4.978-fold and 9.643-fold increased, respectively, in ABCB1 C3435T homozygous genotype (TT) patients compared to wild-type (CC) patients. No significant association was found between the toxicities investigated and MTHFR C677T or MTHFR A1298C. Conclusion: This study showed that the ABCB1 C3435T homozygous allele genotype (TT) is associated with increased MTX-related toxicities (leukopenia, neutropenia and oral mucositis). These results may help to distinguish pediatric ALL patients with a relatively high risk of MTX-related toxicities before HD-MTX infusion and optimize MTX treatment.

Shizukaol C alleviates trimethylamine oxide-induced inflammation through activating Keap1-Nrf2-GSTpi pathway in vascular smooth muscle cell.

BACKGROUND: Cardiovascular disease is one of the main causes of global mortality, and there is an urgent need for effective treatment strategies. Gut microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) promotes the development of cardiovascular diseases, and shizukaol C, a natural sesquiterpene isolated from Chloranthus multistachys with various biological activities, might exhibit beneficial role in preventing TMAO-induced vascular inflammation. PURPOSE: The purpose of this study was to investigate the anti-inflammatory effects and the underlying mechanisms of shizukaol C on TMAO-induced vascular inflammation. METHODS: The effect and underlying mechanism of shizukaol C on TMAO-induced adhesion molecules expression, bone marrow-derived macrophages (BMDM) adhesion to VSMC were evaluated by western blot, cell adhesion assay, co-immunoprecipitation, immunofluorescence assay, and quantitative Real-Time PCR, respectively. To verify the role of shizukaol C in vivo, TMAO-induced vascular inflammation model were established using guidewire-induced injury on mice carotid artery. Changes in the intima area and the expression of GSTpi, VCAM-1, CD68 were examined using haematoxylin-eosin staining, and immunofluorescence assay. RESULTS: Our data demonstrated that shizukaol C significantly suppressed TMAO-induced adhesion molecule expression and the bone marrow-derived macrophages (BMDM) adhesion in vascular smooth muscle cells (VSMC). Mechanically, shizukaol C inhibited TMAO-induced c-Jun N-terminal kinase (JNK)-nuclear factor-kappa B (NF-κB)/p65 activation, and the JNK inhibition was dependent on the shizukaol C-mediated glutathione-S-transferase pi (GSTpi) expression. By further molecular docking and protein-binding analysis, we demonstrated that shizukaol C directly binds to Keap1 to induce Nrf2 nuclear translocation and upregulated GSTpi expression. Consistently, our in vivo experiment showed that shizukaol C elevated the expression level of GSTpi in carotid arteries and alleviates TMAO-induced vascular inflammation. CONCLUSION: Shizukaol C exerts anti-inflammatory effects in TMAO-treated VSMC by targeting Keap1 and activating Nrf2-GSTpi signaling and resultantly inhibits the downstream JNK-NF-κB/p65 activation and VSMC adhesion, and alleviates TMAO-induced vascular inflammation in vivo, suggesting that shizukaol C may be a potential drug for treating TMAO-induced vascular diseases.

Ascorbic acid releases dormancy and promotes germination by an integrated regulation of abscisic acid and gibberellin in Pyrus betulifolia seeds.

Seed dormancy is an important life history state in which intact viable seeds delay or prevent germination under suitable conditions. Ascorbic acid (AsA) acts as a small molecule antioxidant, and breaking seed dormancy and promoting subsequent growth are among its numerous functions. In this study, a germination test using Pyrus betulifolia seeds treated with exogenous AsA or AsA synthesis inhibitor lycorine (Lyc) and water absorption was conducted. The results indicated that AsA released dormancy and increased germination and 20 mmol L-1 AsA promoted cell division, whereas Lyc reduced germination. Seed germination showed typical three phases of water absorption; and seeds at five key time points were sampled for transcriptome analysis. It revealed that multiple pathways were involved in breaking dormancy and promoting germination through transcriptome data, and 12 differentially expressed genes (DEGs) related to the metabolism and signal transduction of abscisic acid (ABA) and gibberellins (GA) were verified by subsequent RT-qPCR. For metabolites, exogenous AsA increased endogenous AsA and GA3 but reduced ABA and the ABA/GA3 ratio. In addition, three genes regulating ABA synthesis were downregulated by AsA, while five genes mediating ABA degradation were upregulated. Taken together, AsA regulates the pathways associated with ABA and GA synthesis, catalysis, and signal transduction, with subsequent reduction in ABA and increase in GA and further the balance of ABA/GA, ultimately releasing dormancy and promoting germination.

Upregulation of GPR133 expression impaired the phagocytosis of macrophages in recurrent spontaneous miscarriage.

Decidual macrophages are the second-largest immune cell group at the maternal-foetal interface. They participate in apoptotic cell removal, and protect the foetus from microorganisms or pathogens. Dysfunction of decidual macrophages gives rise to pregnancy complications such as preeclampsia and recurrent spontaneous miscarriage (RSM). However, the mechanisms by which decidual macrophages are involved in the occurrence of adverse pregnancy outcomes have not been elucidated. Here we integrated DNA methylation and gene expression data from decidua macrophages to identify potential risk factors related to RSM. GPR133 was significantly hypomethylated and upregulated in decidual macrophages from RSM patients. Further demethylation analysis demonstrated that GPR133 expression in decidual macrophages was significantly increased by 5-Aza-dC treatment. In addition, the influence of GPR133 on the phagocytic ability of macrophages was explored. Phagocytosis was impaired in the decidual macrophages of RSM patients with increased GPR133 expression. Increased GPR133 expression induced by demethylation treatment in the decidual macrophages of healthy control patients led to a significant decrease in phagocytic function. Importantly, knockdown of GPR133 resulted in a significant improvement in the phagocytic function of THP-1 macrophages. In conclusion, the existing studies have shown the influence of GPR133 on the phagocytic function of decidual macrophages and pregnancy outcomes, providing new data and ideas for future research on the role of decidual macrophages in RSM.

Active Constituents with Tyrosinase Inhibitory Activities from Waste Tobacco leaves.

One novel compound, (R)-3, 6-diethoxy-4-hydroxycyclohex-3-en-1-one (1) and thirteen known compounds was isolated from the waste leaves of Nicotiana tabacum. The structures of three compounds (1-3) were confirmed and attributed firstly by the extensive spectroscopic data, including 1D/2D NMR, IR, HR-ESI-MS, CD, and ECD spectra. Notably,  seven compounds (2, 3, 9, 10, 11, 12, and 13) exhibited better tyrosinase inhibitory activity than the positive control, kojic acid. The binding modes of these compounds revealed that their structure formed strong hydrogen bonds and van der Waals force with the active sites of tyrosinase. These results indicated that waste tobacco leaves are good resources for developing tyrosinase inhibitors.

[High Resolution Emission Inventory of Greenhouse Gas and Its Characteristics in Guangdong，China].

Based on the typical city survey data and statistics of Guangdong Province， a 2018-based 3 km×3 km gridded greenhouse gas emissions inventory was developed for Guangdong Province using the combination of top-down and bottom-up emission factor methods. The inventory covered the CO2， CH4， and N2O emissions from energy， industrial processes， agriculture， land use change and forest， waste management， and indirect sources. The results showed that estimates for CO2， CH4， and N2O in Guangdong Province for the year 2018 were 8.5×108， 1.9×106， and 1.1×105 t， respectively， and 8.5×108， 4.0×107， and 3.4×107 t by equivalent carbon dioxide， totaling 9.2×108 t. CO2 was the main greenhouse gas in Guangdong Province， accounting for 92.0% of the total emissions. Energy and indirect sources were the main emission sources， accounting for 77.9% and 7.6%， respectively， totaling 85.5%. Spatial distributions illustrated that most grids were greenhouse gas emissions， whereas some others were greenhouse gas sinks； the greenhouse gas emissions were distributed mainly in the Pearl River Delta region and had certain characteristics of distribution along the road network and channels. The greenhouse gas grids of high emission were mainly the locations of high energy-consuming enterprises such as large power plants， steel mills， and cement plants.

Immediate and delayed risk of breast cancer associated with classic lobular carcinoma in situ and its variants.

OBJECTIVE: To determine the risk of breast cancer due to lobular carcinoma in situ (LCIS). METHODS: This retrospective IRB-approved study identified cases of LCIS after percutaneous breast biopsy from 7/2005 to 7/2022. Excluded were cases with less than 2 years of imaging surveillance or a concurrent ipsilateral breast cancer diagnosis within 6 months of the LCIS diagnosis. Final outcomes of cancer versus no cancer were determined by pathology at surgical excision or the absence of cancer on imaging surveillance. RESULTS: A total of 116 LCIS lesions were identified. The primary imaging findings targeted for percutaneous biopsy included calcifications (50.0%, 58/116), MR enhancing lesions (25.0%, 29/116), noncalcified mammographic architectural distortions (10.3%, 12/116), or masses (14.7%, 17/116). Surgical excision was performed in 49.1% (57/116) and imaging surveillance was performed in 50.9% (59/116) of LCIS cases. There were 22 cancers of which 11 cancers were discovered at immediate excision [19.3% (11/57) immediate upgrade] and 11 cancers developed later while on imaging surveillance [18.6% (11/59) delayed risk for cancer]. Among all 22 cancers, 63.6% (14/22) occurred at the site of LCIS (11 at immediate excision and 3 at surveillance) and 36.4% (8/22) occurred at a location away from the site of LCIS (6 in a different quadrant and 2 in the contralateral breast). CONCLUSION: LCIS has both an immediate risk (19.3%) and a delayed risk (18.6%) for cancer with 90.9% occurring in the ipsilateral breast (63.6% at and 27.3% away from the site of LCIS) and 9.1% occurring in the contralateral breast.

Transcriptome profiling of longissimus dorsi during different prenatal stages to identify genes involved in intramuscular fat deposition in lean and obese pig breeds.

BACKGROUND: There was significant difference in muscle development between fat-type and lean-type pig breeds. METHODS AND RESULTS: In current study, transcriptome analysis and bioinformatics analysis were used to compare the difference in longissimus dorsi (LD) muscle at three time-points (38 days post coitus (dpc), 58 dpc, and 78 dpc ) between Huainan (HN) and Large white (LW) pig breeds. A total of 24500 transcripts were obtained in 18 samples, and 2319, 2799, and 3713 differently expressed genes (DEGs) were identified between these two breeds at 38 dpc, 58 dpc, and 78 dpc, respectively. And the number and foldchange of DEGs were increased, the alternative splice also increased. The cluster analysis of DEGs indicated the embryonic development progress of LD muscle between these two breeds was different. There were 539 shared DEGs between HN and LW at three stages, and the top-shared DEGs were associated with muscle development and lipid deposition, such as KLF4, NR4A1, HSP70, ZBTB16 and so on. CONCLUSIONS: The results showed DEGs between Huainan (HN) and Large white (LW) pig breeds, and contributed to the understanding the muscle development difference between HN and LW, and provided basic materials for improvement of meat quality.

Efficacy of the posterior nasal nerve resection combined with hormone transnasal nebulization on difficult-to-treat rhinosinusitis: a retrospective analysis.

OBJECTIVE: A retrospective analysis was performed to explore the clinical effect of the Posterior Nasal Nerve (PNN) resection combined with hormone transnasal nebulization on Difficult-to-Treat Rhinosinusitis (DTRS). METHODS: A total of 120 DTRS patients were selected and divided into a control group (n = 60) and a study group (n = 60) according to different treatments. The control group patients were treated via PNN resection, followed by normal saline transnasal nebulization; the study group patients were given PNN resection and then treated with budesonide suspension transnasal nebulization. Subsequently, the comparison was performed between the two groups in terms of (1) Clinical baseline characteristics; (2) Sino-nasal Outcome Test (SNOT)-22 scores before treatment and after 3-months, 6-months and 12-months of treatment; (3) Lund-MacKay scores before treatment and after 10, 30, 90, and 180 days of treatment; (4) Incidence of adverse reactions during treatment. RESULTS: There was no significant difference in SNOT-22 or Lund-Kennedy scores between the two groups before treatment (p > 0.05). After treatment, the SNOT-22 and Lund-Kennedy scores of the control and the study groups were decreased, and compared with the control group, the SNOT-22 and Lund-Kennedy scores in the study group improved more significantly (p < 0.05). In addition, the study group and the control group presented with 1 and 4 cases of nasal adhesion, 2 and 3 cases of epistaxis, 1 and 4 cases of sinus orifice obstruction, 1 and 3 cases of lacrimal duct injuries, respectively. The incidence of adverse reactions in the study group was significantly lower than that in the control group (8.3% vs. 23.3%) (p < 0.05). CONCLUSION: PNN resection combined with hormone transnasal nebulization treatment can improve the symptoms and quality of life of DTRS patients, with good clinical efficacy but few adverse reactions. Therefore, such combination treatment deserves a promotion and application clinically. LEVEL OF EVIDENCE: Level 3.

Aniline antioxidants in road dust, parking lot dust, and green-belt soil in Harbin, a megacity in China: Occurrence, profile, and seasonal variation.

Aniline antioxidants (ANs) are widely used as industrial chemicals in products composed of rubber. ANs originate mainly from vehicles, where tire wear particles end up in dust and soil after being deposited on roads. Nowadays, limited information is available on the fate and seasonal variation of ANs in the road environment. In this study, we investigated the occurrence of 32 ANs in dust and soil from different road environments, including road dust, garage dust, parking lot dust, and green-belt soil. The total concentrations of ANs were 369 ng g-1 in road dust, 712 ng g-1 in garage dust, and 687 ng g-1 in parking lot dust. These concentrations are several times higher than that in green-belt soil (128 ng g-1). The highest concentrations of N-(1,3-dimethylbutyl)-N'-phenyl-1,4-phenylenediamine (6PPD) were found in dust and soil. Furthermore, notable seasonal differences were observed, with significantly higher concentrations of ANs in autumn than those in spring. In the main urban area, roads with high traffic volume exhibited higher concentrations of ANs than those with low traffic volume, indicating that ANs were produced by vehicle-related sources.

Geographic differences in psychological symptoms, sleep quality, and quality of life in patients with inflammatory bowel disease: A multicenter study in China.

OBJECTIVE: We aimed to explore the geographic differences in psychological symptoms, sleep quality, and quality of life (QoL) among adult patients with inflammatory bowel disease (IBD). METHODS: A unified questionnaire was developed to collect data on psychological status and QoL of IBD patients from 42 hospitals across 22 provinces, municipalities, and autonomous regions in China's mainland from September 2021 to May 2022. RESULTS: A total of 2478 patients with IBD were surveyed. The proportions of patients with anxiety (28.5% vs 23.1%), depression (32.3% vs 27.8%), and poor QoL (44.8% vs 32.2%) were significantly higher in patients from the northern region compared to the southern region (all P < 0.05). In the western region, the proportions of patients with anxiety (31.9% vs 23.0%), depression (37.7% vs 26.7%), sleep disturbances (64.5% vs 58.5%), and poor QoL (44.9% vs 34.8%) were significantly higher than in the eastern and central regions (all P < 0.01). Patients from inland regions had significantly higher rates of anxiety (27.1% vs 23.3%), depression (32.5% vs 26.0%), sleep disturbance (62.0% vs 57.7%), and poor QoL (43.5% vs 29.9%) compared to those from coastal regions (all P < 0.05). In economically underdeveloped areas, the proportions of patients with depression (33.1% vs 28.5%) and poor QoL (52.0% vs 32.4%) were significantly higher than in economically (relatively) developed areas (both P < 0.05). CONCLUSION: There are significant geographic differences in psychological symptoms, sleep quality, and QoL among Chinese patients with IBD, which might provide valuable insights for global IBD research and clinical practice.

Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 3 Expression and Its Correlation with Prognosis and Growth of Serous Ovarian Cancer: Correlation of DYRK3 with Ovarian Cancer Survival.

Background: Epithelial ovarian cancer, primarily serous ovarian cancer (SOC), stands as a predominant cause of cancer-related mortality among women globally, emphasizing the urgent need for comprehensive research into its molecular underpinnings. Within this context, the dual-specificity tyrosine phosphorylation-regulated kinase 3 (DYRK3) has emerged as a potential key player with implications for prognosis and tumor progression. Methods: This study conducted a meticulous retrospective analysis of 254 SOC cases from our medical center to unravel the prognostic significance of DYRK3. Survival analyses underscored DYRK3 as an independent adverse prognostic factor in SOC, with a hazard ratio of 2.60 (95% CI 1.67-4.07, P < 0.001). Experimental investigations involved DYRK3 knockdown in serous ovarian cancer cell lines (CAOV3 and OVCAR-3) through a shRNA strategy, revealing substantial decreases in cell growth and invasion capabilities. Bioinformatics analyses further hinted at DYRK3's involvement in modulating the tumor immune microenvironment. In vivo experiments with DYRK3-knockdown cell lines validated these findings, demonstrating a notable restriction in the growth of ovarian cancer xenografts. Results: Our findings collectively illuminate DYRK3 as a pivotal tumor-promoting oncogene in SOC. Beyond its adverse prognostic implications, DYRK3 knockdown exhibited promising therapeutic potential by impeding cancer progression and potentially influencing the tumor immune microenvironment. Conclusions: This study establishes a compelling foundation for further research into DYRK3's intricate role and therapeutic potential in ovarian cancer treatment. As we unravel the complexities surrounding DYRK3, our work not only contributes to the understanding of SOC pathogenesis but also unveils new prospects for targeted therapeutic interventions, holding promise for improved outcomes in ovarian cancer management.

Hydrogen exerts neuroprotective effects after subarachnoid hemorrhage by attenuating neuronal ferroptosis and inhibiting neuroinflammation.

OBJECTIVE: Spontaneous subarachnoid hemorrhage (SAH), the third most common stroke subtype, is associated with high mortality and disability rates. Therefore, finding effective therapies to improve neurological function after SAH is critical. The objective of this study was to investigate the potential neuroprotective effects of hydrogen in the context of SAH, specifically, by examining its role in attenuating neuronal ferroptosis and inhibiting neuroinflammation, which are exacerbated by excess iron ions after SAH. METHODS: Mice were exposed to chambers containing 3% hydrogen, and cells were cultured in incubators containing 60% hydrogen. Neurological function in mice was assessed using behavioral scores. Protein changes were detected using western blotting. Inflammatory factors were detected using enzyme linked immunosorbent assay. Probes, electron microscopy, and related kits were employed to detect oxidative stress and ferroptosis. RESULTS: Hydrogen improved the motor function, sensory function, and cognitive ability of mice after SAH. Additionally, hydrogen facilitated Nuclear factor erythroid 2 -related factor 2 activation, upregulated Glutathione peroxidase 4, and inhibited Toll-like receptor 4, resulting in downregulation of inflammatory responses, attenuation of oxidative stress after SAH, and inhibition of neuronal ferroptosis. CONCLUSION: Hydrogen exerts neuroprotective effects by inhibiting neuronal ferroptosis and attenuating neuroinflammation after SAH.

Evaluating the Demand for Nucleic Acid Testing in Different Scenarios of COVID-19 Transmission: A Simulation Study.

INTRODUCTION: The 2019 novel coronavirus (COVID-19) has been recognized as the most severe human infectious disease pandemic in the past century. To enhance our ability to control potential infectious diseases in the future, this study simulated the influence of nucleic acid testing on the transmission of COVID-19 across varied scenarios. Additionally, it assessed the demand for nucleic acid testing under different circumstances, aiming to furnish a decision-making foundation for the implementation of nucleic acid screening measures, the provision of emergency materials, and the allocation of human resources. METHODS: Considering the transmission dynamics of COVID-19 and the preventive measures implemented by countries, we explored three distinct levels of epidemic intensity: community transmission, outbreak, and sporadic cases. Integrating the theory of scenario analysis, we formulated six hypothetical epidemic scenarios, each corresponding to possible occurrences during different phases of the pandemic. We developed an improved SEIR model, validated its accuracy using real-world data, and conducted a comprehensive analysis and prediction of COVID-19 infections under these six scenarios. Simultaneously, we assessed the testing resource requirements associated with each scenario. RESULTS: We compared the predicted number of infections simulated by the modified SEIR model with the actual reported cases in Israel to validate the model. The root mean square error (RMSE) was 350.09, and the R-squared (R2) was 0.99, indicating a well-fitted model. Scenario 4 demonstrated the most effective prevention and control outcomes. Strengthening non-pharmaceutical interventions and increasing nucleic acid testing frequency, even under low testing capacity, resulted in a delayed epidemic peak by 78 days. The proportion of undetected cases decreased from 77.83% to 31.21%, and the overall testing demand significantly decreased, meeting maximum demand even with low testing capacity. The initiation of testing influenced case detection probability. Under high testing capacity, increasing testing frequency elevated the detection rate from 36.40% to 77.83%. Nucleic acid screening proved effective in reducing the demand for testing resources under diverse epidemic prevention and control strategies. While effective interventions and nucleic acid screening measures substantially diminished the demand for testing-related resources, varying degrees of insufficient testing capacity may still persist. CONCLUSIONS: The nucleic acid detection strategy proves effective in promptly identifying and isolating infected individuals, thereby mitigating the infection peak and extending the time to peak. In situations with constrained testing capacity, implementing more stringent measures can notably decrease the number of infections and alleviate resource demands. The improved SEIR model demonstrates proficiency in predicting both reported and unreported cases, offering valuable insights for future infection risk assessments. Rapid evaluations of testing requirements across diverse scenarios can aptly address resource limitations in specific regions, offering substantial evidence for the formulation of future infectious disease testing strategies.

Repolarization of immunosuppressive macrophages by targeting SLAMF7-regulated CCL2 signaling sensitizes hepatocellular carcinoma to immunotherapy.

Immune checkpoint inhibitors have limited efficacy in hepatocellular carcinoma (HCC). Macrophages are the most abundant immune cells in HCC, suggesting that a better understanding of the intrinsic processes by which tumor cells regulate macrophages could help identify strategies to improve response to immunotherapy. As signaling lymphocytic activation molecule (SLAM) family members regulate various immune functions, we investigated the role of specific SLAM receptors in the immunobiology of HCC. Comparison of the transcriptomic landscapes of immunotherapy-responsive and non-responsive advanced HCC patients identified SLAMF7 upregulation in immunotherapy-responsive HCC, and HCC patients who responded to immunotherapy also displayed higher serum levels of SLAMF7. Loss of Slamf7 in liver-specific knockout mice led to increased hepatocarcinogenesis and metastasis, elevated immunosuppressive macrophage infiltration, and upregulated PD-1 expression in CD8+ T cells. HCC cell-intrinsic SLAMF7 suppressed MAPK/ATF2-mediated CCL2 expression to regulate macrophage migration and polarization in vitro. Mechanistically, SLAMF7 associated with SH2 domain-containing adaptor protein B (SHB) through its cytoplasmic 304 tyrosine site to facilitate the recruitment of SHIP1 to SLAMF7 and inhibit the ubiquitination of TRAF6, thereby attenuating MAPK pathway activation and CCL2 transcription. Pharmacological antagonism of the CCL2/CCR2 axis potentiated the therapeutic effect of anti-PD-1 antibody in orthotopic HCC mouse models with low SLAMF7 expression. In conclusion, this study highlights SLAMF7 as a regulator of macrophage function and a potential predictive biomarker of immunotherapy response in HCC. Strategies targeting CCL2 signaling to induce macrophage repolarization in HCC with low SLAMF7 might enhance the efficacy of immunotherapy.

A pharynx-to-brain axis controls pharyngeal inflammation-induced anxiety.

Anxiety is a remarkably common condition among patients with pharyngitis, but the relationship between these disorders has received little research attention, and the underlying neural mechanisms remain unknown. Here, we show that the densely innervated pharynx transmits signals induced by pharyngeal inflammation to glossopharyngeal and vagal sensory neurons of the nodose/jugular/petrosal (NJP) superganglia in mice. Specifically, the NJP superganglia project to norepinephrinergic neurons in the nucleus of the solitary tract (NTSNE). These NTSNE neurons project to the ventral bed nucleus of the stria terminalis (vBNST) that induces anxiety-like behaviors in a murine model of pharyngeal inflammation. Inhibiting this pharynx→NJP→NTSNE→vBNST circuit can alleviate anxiety-like behaviors associated with pharyngeal inflammation. This study thus defines a pharynx-to-brain axis that mechanistically links pharyngeal inflammation and emotional response.

Multicomponent Reductive Coupling for Selective Access to Functional γ-Lactams by a Single-Atom Cobalt Catalyst.

Despite their significant importance to numerous fields, the difficulties in direct and diverse synthesis of α-hydroxy-γ-lactams pose substantial obstacles to their practical applications. Here, we designed a nitrogen and TiO2 co-doped graphitic carbon-supported material with atomically dispersed cobalt sites (CoSA-N/NC-TiO2), which was successfully applied as a multifunctional catalyst to establish a general method for direct construction of α-hydroxy-γ-lactams from cheap and abundant nitro(hetero)arenes, aldehydes, and H2O with alkynoates. The striking features of operational simplicity, broad substrate and functionality compatibility (>100 examples), high step and atom efficiency, good selectivity, and exceptional catalyst reusability highlight the practicality of this new catalytic transformation. Mechanistic studies reveal that the active CoN4 species and the dopants exhibit a synergistic effect on the formation of key acid-masked nitrones; their subsequent nucleophilic addition to the alkynoates followed by successive reduction, alkenyl hydration, and intramolecular ester ammonolysis delivers the desired products. In this work, the concept of reduction interruption leading to new reaction route will open a door to further develop useful transformations by rational catalyst design.