Hydroxygenkwanin suppresses peritoneal metastasis in colorectal cancer by modulating tumor-associated macrophages polarization.

Peritoneal metastasis is an important cause of high mortality and poor prognosis in colorectal cancer (CRC) patients. Therefore, the development of compounds with unique anti-CRC Peritoneal metastasis activities is urgently needed to improve the survival of CRC patients. Hydroxygenkwanin (HGK),a natural flavonoid compound, have been shown to display anti-inflammatory, antioxidant, antitumor, and immunoregulatory effects. Here, we employed CRC peritoneal metastasis mouse model with MC38 cells to examine the antitumor activity of HGK. The result showed that HGK not only inhibited peritoneal metastasis, but also significantly increased the proportion of M1-like macrophages while decreasing the proportion of M2-like macrophages within the tumor microenvironment (TME). Furthermore, we demonstrated that the inhibitory effect of HGK on peritoneal metastasis of CRC depended on macrophages in vitro and in vivo. Moreover, we revealed that HGK promoted the polarization of TAMs into M1-like macrophages and inhibited their polarization into M2-like macrophages in a LPS- or IL-4-induced bone marrow-derived macrophages (BMDMs) model and co-culture system. Finally, we also investigated the regulatory mechanism of HGK on TAMs polarization that HGK may active p-STAT5, p-NF-κB signaling in M1-like macrophages and inhibit p-STAT6, JMJD3, PPARγ expression in M2-like macrophages. Taken together, our findings suggest that HGK is a natural candidate for effective prevention of peritoneal metastasis in colorectal cancer, which provides a potential strategy for clinical treatment of colorectal cancer.

Validation and Evaluation of 5 Scoring Systems for Predicting Metastatic Risk in Pheochromocytoma and Paraganglioma.

Currently, 5 scoring systems have been proposed in the literature for predicting metastatic risk in pheochromocytoma and paraganglioma (PPGL): Pheochromocytoma of the Adrenal Gland Scaled Score (PASS), Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP), Composite Pheochromocytoma/paraganglioma Prognostic Score (COPPS), Age, Size, Extra-adrenal location, Secretion type (ASES) score, and Size, Genetic, Age, and PASS (SGAP) model. To validate and evaluate these 5 scoring systems, we conducted a retrospective review of cases diagnosed as PPGL at the Department of Pathology, West China Hospital of Sichuan University, between January 2012 and December 2019. A total of 185 PPGL cases were included, comprising 35 cases with metastasis and 150 cases remained metastasis-free for over 8 years after surgery. The criteria of the 5 scoring systems were used for scoring and risk classification. The predictive performance of the 5 scoring systems was validated, compared, and evaluated using concordance index (C-index) and decision curve analysis (DCA). The C-indices for PASS, GAPP, and SGAP were 0.600, 0.547, and 0.547, respectively, indicating low discriminative ability. In contrast, COPPS and ASES had C-indices of 0.740 and 0.706, respectively, indicating better discriminative performance. DCA also showed that the predictive capability of COPPS was superior to that of ASES, with both outperformed PASS, while PASS had better predictive ability than GAPP and SGAP. Our analysis indicated that pathology-based scoring systems cannot accurately predict metastatic risk of PPGL. Establishing a precise prediction system requires integrating clinical, pathologic, and molecular information, using a scientific methodology for predictive factor selection and weight assessment.

Spatial-temporal drivers and incidence heterogeneity of hemorrhagic fever with renal syndrome transmission in Shandong Province, China, 2016-2022.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) signals a recurring risk in Eurasia in recent years owing to its continued rise in case notifications and the extension of geographical distribution. This study was undertaken to investigate the spatiotemporal drivers and incidence heterogeneity of HFRS transmission in Shandong Province. METHODS: The epidemiological data for HFRS, meteorological data and socioeconomic data were obtained from China Information System for Disease Control and Prevention, China Meteorological Data Sharing Service System, and Shandong Statistical Yearbook, respectively. The spatial-temporal multicomponent model was employed to analyze the values of spatial-temporal components and the heterogeneity of HFRS transmission across distinct regions. RESULTS: The total effect values of the autoregressive, epidemic, and endemic components were 0.451, 0.187, and 0.033, respectively, exhibiting significant heterogeneity across various cities. This suggested a pivotal role of the autoregressive component in propelling HFRS transmission in Shandong Province. The epidemic component of Qingdao, Weifang, Yantai, Weihai, and Jining declined sharply at the onset of 2020. The random effect identified distinct incidence levels associated with Qingdao and Weifang, signifying regional variations in HFRS occurrence. CONCLUSIONS: The autoregressive component emerged as a significant driver in the transmission of HFRS in Shandong Province. Targeted preventive measures should be strategically implemented across various regions, taking into account the predominant component influencing the epidemic.

A Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRASG12C Inhibitor.

AMG510, as the first approved inhibitor for KRASG12C mutation, has shown promising efficacy in nonsmall-cell lung cancer and colorectal cancer harboring KRASG12C mutation. However, the moderate response rate and the rapid emergence of acquired resistance limit the therapeutic potential of AMG510, highlighting the need for the development of combination strategies. Here, we observed the suppression of RAS-MAPK signaling induced by AMG510 was prolonged and enhanced by SOS1 knockdown. Thus, we design, synthesize, and characterize a potent and specific SOS1 degrader 23. Compound 23 showed efficient SOS1 degradation in KRAS-driven cancer cells and achieved significant antiproliferative potency. Importantly, the combination of 23 with AMG510 suppressed RAS signaling feedback activation, showing synergistic effects against KRASG12C mutant cells in vitro and in vivo. Our findings demonstrated that KRASG12C inhibition plus SOS1 degradation as a potential therapeutic strategy to improve antitumor response and overcome acquired resistance to KRASG12C inhibitor.

Antibody and transcription landscape in peripheral blood mononuclear cells of elderly adults over 70 years of age with third dose of COVID-19 BBIBP-CorV and ZF2001 booster vaccine.

BACKGROUND: In the context of the COVID-19 pandemic and extensive vaccination, it is important to explore the immune response of elderly adults to homologous and heterologous booster vaccines of COVID-19. At this point, we detected serum IgG antibodies and PBMC sample transcriptome profiles in 46 participants under 70 years old and 25 participants over 70 years old who received the third dose of the BBIBP-CorV and ZF2001 vaccines. RESULTS: On day 7, the antibody levels of people over 70 years old after the third dose of booster vaccine were lower than those of young people, and the transcriptional responses of innate and adaptive immunity were also weak. The age of the participants showed a significant negative correlation with functions related to T-cell differentiation and costimulation. Nevertheless, 28 days after the third dose, the IgG antibodies of elderly adults reached equivalence to those of younger adults, and immune-related transcriptional regulation was significantly improved. The age showed a significant positive correlation with functions related to "chemokine receptor binding", "chemokine activity", and "chemokine-mediated signaling pathway". CONCLUSIONS: Our results document that the response of elderly adults to the third dose of the vaccine was delayed, but still able to achieve comparable immune effects compared to younger adults, in regard to antibody responses as well as at the transcript level.

Spatiotemporal distribution and environmental influences of severe fever with thrombocytopenia syndrome in Shandong Province, China.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease discovered in China in 2009. The purpose of this study was to describe the spatiotemporal distribution of SFTS and to identify its environmental influencing factors and potential high-risk areas in Shandong Province, China. METHODS: Data on the SFTS incidence from 2010 to 2021 were collected. Spatiotemporal scan statistics were used to identify the time and area of SFTS clustering. The maximum entropy (MaxEnt) model was used to analyse environmental influences and predict high-risk areas. RESULTS: From 2010 to 2021, a total of 5705 cases of SFTS were reported in Shandong. The number of SFTS cases increased yearly, with a peak incidence from April to October each year. Spatiotemporal scan statistics showed the existence of one most likely cluster and two secondary likely clusters in Shandong. The most likely cluster was in the eastern region, from May to October 2021. The first secondary cluster was in the central region, from May to October 2021. The second secondary cluster was in the southeastern region, from May to September 2020. The MaxEnt model showed that the mean annual wind speed, NDVI, cattle density and annual cumulative precipitation were the key factors influencing the occurrence of SFTS. The predicted risk map showed that the area of high prevalence was 28,120 km2, accounting for 18.05% of the total area of the province. CONCLUSIONS: The spatiotemporal distribution of SFTS was heterogeneous and influenced by multidimensional environmental factors. This should be considered as a basis for delineating SFTS risk areas and developing SFTS prevention and control measures.

QTL analysis of traits related to seed size and shape in sesame (Sesamum indicum L.).

Seed size and shape are important traits that determine seed yield in sesame. Understanding the genetic basis of seed size and shape is essential for improving the yield of sesame. In this study, F2 and BC1 populations were developed by crossing the Yuzhi 4 and Bengal small-seed (BS) lines for detecting the quantitative trait loci (QTLs) of traits related to seed size and shape. A total of 52 QTLs, including 13 in F2 and 39 in BC1 populations, for seed length (SL), seed width (SW), and length to width ratio (L/W) were identified, explaining phenotypic variations from 3.68 to 21.64%. Of these QTLs, nine stable major QTLs were identified in the two populations. Notably, three major QTLs qSL-LG3-2, qSW-LG3-2, and qSW-LG3-F2 that accounted for 4.94-16.34% of the phenotypic variations were co-localized in a 2.08 Mb interval on chromosome 1 (chr1) with 279 candidate genes. Three stable major QTLs qSL-LG6-2, qLW-LG6, and qLW-LG6-F2 that explained 8.14-33.74% of the phenotypic variations were co-localized in a 3.27 Mb region on chr9 with 398 candidate genes. In addition, the stable major QTL qSL-LG5 was co-localized with minor QTLs qLW-LG5-3 and qSW-LG5 to a 1.82 Mb region on chr3 with 195 candidate genes. Gene annotation, orthologous gene analysis, and sequence analysis indicated that three genes are likely involved in sesame seed development. These results obtained herein provide valuable in-formation for functional gene cloning and improving the seed yield of sesame.

Discovery of Novel 2,3-Dihydro-1H-indene-5-sulfonamide NLRP3 Inflammasome Inhibitors Targeting Colon as a Potential Therapy for Colitis.

The NLRP3 inflammasome is a multiprotein complex that plays a crucial role in the pathophysiology of multiple inflammation-related diseases. In this study, we designed and synthesized a series of novel 2,3-dihydro-1H-indene-5-sulfonamide analogues as NLRP3 inflammasome inhibitors, and then identified compound 15z as a potent and specific inhibitor (IC50: 0.13 µM) with low toxicity. Mechanistic studies indicate that 15z binds directly to NLRP3 protein (KD: 102.7 nM), blocking the assembly and activation of the NLRP3 inflammasome and effectively inhibiting cell pyroptosis. Given the notable distribution of 15z in the colon, the DSS-induced colitis model was employed to evaluate its in vivo effectiveness. 15z significantly impacted NLRP3 inflammasome activation and relieved inflammatory bowel disease symptoms in this model. Acute and subacute toxicity studies suggested that 15z has a favorable safety profile. Our results indicate that 15z has great potential to be further developed as a candidate for the treatment of inflammatory bowel disease.

Pangenome analysis provides insight into the evolution of the orange subfamily and a key gene for citric acid accumulation in citrus fruits.

The orange subfamily (Aurantioideae) contains several Citrus species cultivated worldwide, such as sweet orange and lemon. The origin of Citrus species has long been debated and less is known about the Aurantioideae. Here, we compiled the genome sequences of 314 accessions, de novo assembled the genomes of 12 species and constructed a graph-based pangenome for Aurantioideae. Our analysis indicates that the ancient Indian Plate is the ancestral area for Citrus-related genera and that South Central China is the primary center of origin of the Citrus genus. We found substantial variations in the sequence and expression of the PH4 gene in Citrus relative to Citrus-related genera. Gene editing and biochemical experiments demonstrate a central role for PH4 in the accumulation of citric acid in citrus fruits. This study provides insights into the origin and evolution of the orange subfamily and a regulatory mechanism underpinning the evolution of fruit taste.

Novel Epitope Mapping of African Swine Fever Virus pI215L Protein Using Monoclonal Antibodies.

The African swine fever virus (ASFV) is one of the most important pathogens that causes huge damage to worldwide swine production. The pI215L protein is found within the virion and expressed at a high level in infected porcine alveolar macrophages (PAMs), indicating a possible role of pI215L protein in ASFV detection and surveillance. In the present study, female BALB/c mice (5-6-week-old) were immunized with rpI215L protein, and six hybridomas, 1C1, 2F6, 2F10, 3C8, 5E1 and 5B3, steadily secreted anti-pI215L monoclonal antibodies (mAbs). Among them, 1C4, 5E1, and 5B3 had the IgG1 isotype with a Lambda light chain, 2F10 and 3C8 had the IgG1 isotype with a Kappa light chain, and 2F6 had the IgG2a isotype with a Kappa light chain. Western blot showed a good reactivity of the six mAbs against ASFV. Eight truncated polypeptides were produced for epitope mapping. Two novel B cell epitopes, 67LTFTSEMWHPNIYS80 and 167IEYFKNAASN176, were identified by the mAbs. Further analysis revealed that 2F6 mAb could be widely used in ASFV surveillance and 5B3 mAb might serve as a tool in the distinguishment of different ASFV genotypes. This study provides tools of monoclonal antibodies for further study of I215L function and contributes to the development of serological diagnosis and vaccine research.

Novel Sulfonylurea-Based NLRP3 Inflammasome Inhibitor for Efficient Treatment of Nonalcoholic Steatohepatitis, Endotoxic Shock, and Colitis.

The NLRP3 inflammasome is a critical component of innate immunity involved in the pathophysiology of various inflammatory diseases. In this study, we designed and synthesized a series of NLRP3 inflammasome inhibitors based on MCC950. Specifically, we optimized the furan moiety, which is considered to be potentially associated with drug-induced liver injury. The representative inhibitor N14, 4-(2-(dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonamide, not only maintains the NLRP3 inhibitory activity of MCC950 with IC50 of 25 nM but also demonstrates improved tolerability in human hepatic cells line and mouse primary hepatocytes. In addition, N14 exhibits superior pharmacokinetic properties, with an oral bioavailability of 85.2%. In vivo studies demonstrate that N14 is more effective than MCC950 in multiple NLRP3-related animal model diseases, including nonalcoholic steatohepatitis, lethal septic shock, and colitis. Our research has provided a lead compound that directly targets the NLRP3 inflammasome and can be developed as a novel therapeutic candidate for NLRP3-driven diseases.

High-Performance Branched Polymer Elastomer Based on a Topological Network Structure and Dynamic Bonding.

High performance has always been the research focus of elastomers. However, there are inherent conflicts among properties of elastomers, such as strength and toughness, strength and damping performance, strength and self-healing ability, etc. Herein, first, we synthesized a unique structure of the dangling chain containing proton donors and receptors. Then, we design and fabricate a kind of high-performance elastomer with a gradient distribution of a dangling chain and a dynamic bond structure. The dangling chains of different lengths intertwine with each other and self-assemble to form a "dense accumulation" structure driven by hydrogen bonds, and the elastomer exhibits special micro/nano scale aggregated states and microphase separation. The "dense accumulation" structure plays a vital role in the increase of mechanical properties. Meanwhile, under the joint action of a dangling chain and a dynamic bond, the damping performance and self-healing performance of the elastomer are greatly enhanced. High strength (27.5 MPa), toughness (121.9 MJ·m-3), 94.8% healing efficiency and outstanding damping performance (tan δ ≥ 0.4, high damping temperature range up to 144 °C) are simultaneously achieved beyond the current state-of-the-art. This topoarchitected polymer with a gradient distribution of dangling chains successfully solves the defects of conventional branched polymers in deteriorating their mechanical properties. This material design provides a new strategy for the development of high-performance structural and functional integrated elastomers.

Natural products targeting Nrf2/ARE signaling pathway in the treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a special chronic intestinal inflammatory disease, which is mainly divided into Crohn's disease (CD) and ulcerative colitis (UC). Its occurrence is a complex process that regulated by multiple signaling pathways, including nuclear factor erythroid 2-related factor (Nrf2)/ antioxidant response element (ARE) signaling pathway. Nrf2/ARE pathway as the central defense mechanism against oxidative stress controls the expression of many antioxidant and anti-inflammatory genes in the nucleus, and plays a crucial role in the treatment of IBD. Various studies have proved that many natural compounds target Nrf2/ARE signaling pathway to treat IBD. Here, we introduced the regulatory mechanism of the Nrf2/ARE pathway, and its role in IBD and IBD complications (intestinal fibrosis and colorectal cancer (CRC)); summarized the research progress of Nrf2 targeted natural compounds and extracts in the treatment of IBD; and finally described the intestinal microbiota that alleviate or treat IBD via activating Nrf2/ARE signaling pathway. This review highlights the potential for targeting Nrf2/ARE pathway to treat IBD.

A Self-Oscillating Driving Circuit for Low-Q MEMS Vibratory Gyroscopes.

This article establishes a circuit model with which to analyze the difficulty of auto-gain control driving for low-Q micromechanical gyroscopes at room temperature and normal pressure. It also proposes a driving circuit based on frequency modulation to eliminate the same-frequency coupling between the drive signal and displacement signal using a second harmonic demodulation circuit. The results of the simulation indicate that a closed-loop driving circuit system based on the frequency modulation principle can be established within 200 ms with a stable average frequency of 4504 Hz and a frequency deviation of 1 Hz. After the system was stabilized, the root mean square of the simulation data was taken, and the frequency jitter was 0.0221 Hz.

TRIM7 inhibits encephalomyocarditis virus replication by activating interferon-ß signaling pathway.

Tripartite motif-containing protein 7 (TRIM7), the member of tripartite motif (TRIM) family, plays an important role in innate immune responses against viral infection. Among them, the function of TRIM7 in Encephalomyocarditis virus (EMCV) infection has not been reported. Here, we found that TRIM7 inhibited the replication of EMCV through the type I interferon (IFN) signaling pathway. Interestingly, TRIM7 was down-regulated after EMCV infection in HEK293T cells. Further, overexpression of TRIM7 suppressed the replication of EMCV in HEK293T cells and enhanced the activity of IFN-ß promoter. On the other hand, knockdown of the endogenous TRIM7 promoted EMCV infection and impaired the activity of IFN-ß promoter. TRIM7 could regulate retinoic acid-inducible gene I (RIG-I)/ melanoma differentiation-associated gene 5 (MDA5)/ mitochondrial antiviral-signaling protein (MAVS) mediated IFN-ß signaling pathway. Moreover, TRIM7 interacted with MAVS and they were co-located in HEK293T cells. We demonstrate that TRIM7 plays a positive role in IFN-ß signaling pathway during EMCV infection and suppresses EMCV replication. Taken together, the presented results suggest that TRIM7 has a pivotal function in anti-EMCV infection, thereby providing a potential target for further development of anti-EMCV inhibitors.

Detection and identification of Mucorales and Aspergillus in paraffin-embedded samples by real-time quantitative PCR.

Background: In this study, we used real-time quantitative PCR (RQ-PCR) to rapidly detect Mucorales and Aspergillus in formalin-fixed, paraffin-embedded (FFPE) samples, targeting 18SrRNA gene and 28SrRNA gene. Identification of Mucorales and Aspergillus was analysed by combining Mucorales RQ-PCR (Mucorales18SrRNA and Mucorales28SrRNA) with Aspergillus RQ-PCR (Aspergillus18SrRNA and Aspergillus28SrRNA). Objectives: The aims of this study were to compare the diagnostic performances of four RQ-PCR assays as single and combined diagnostic and identification tools. Methods: We collected 12 control group samples and 81 experimental group samples diagnosed by histopathology, including mucormycosis (19 patients, 21 FFPE samples), aspergillosis (54 patients, 57 FFPE samples) and mucormycosis with aspergillosis (3 patients, 3 FFPE samples). All samples were detected by four RQ-PCR tests to compare and analyze diagnostic performance. Results: The sensitivities of Mucorales18SrRNA and Mucorales28SrRNA were both 75%, with the tests having specificities of 97.10% and 94.20%. The sensitivities of Aspergillus18SrRNA and Aspergillus28SrRNA were 73.33% and 65%, with the tests having specificities of 87.88% and 81.82%. The values of the evaluation indexes of the combined detection of Mucorales28SrRNA and Aspergillus18SrRNA (M28A18) were the highest with a kappa coefficient value of 0.353, followed by M18A18. M28A18 had a sensitivity of 67.90% and a specificity of 100%. Conclusions: We recommend using the combination of Mucorales RQ-PCR and Aspergillus RQ-PCR as a screening tool to detect samples suspected of mucormycosis and/or aspergillosis.

Durability of neutralization against Omicron subvariants after vaccination and breakthrough infection.

Booster immunizations and breakthrough infections can elicit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant neutralizing activity. However, the durability of the neutralization response is unknown. We characterize the sensitivity of BA.1, BA.2, BA.2.75, BA.4/BA.5, BF.7, BQ.1.1, and XBB against neutralizing antibodies from vaccination, hybrid immunity, and breakthrough infections 4-6 months after vaccination and infection. We show that a two-dose CoronaVac or a third-dose ZF2001 booster elicits limited neutralization against Omicron subvariants 6 months after vaccination. Hybrid immunity as well as Delta, BA.1, and BA.2 breakthrough infections induce long-term persistence of the antibody response, and over 70% of sera neutralize BA.1, BA.2, BA.4/BA.5, and BF.7. However, BQ.1.1 and XBB, followed by BA.2.75, are more resistant to neutralization, with neutralizing titer reductions of ∼9- to 41-fold, ∼16- to 63-fold, and ∼4- to 25-fold, respectively. These data highlight additional vaccination in CoronaVac- or ZF2001-vaccinated individuals and provide insight into the durability of neutralization against Omicron subvariants.

Polyacrylonitrile@TiO2 nanofibrous membrane decorated by MOF for efficient filtration and green degradation of PM2.5.

A systematic study was performed on PM2.5 filtration and photodegradation performance of polyacrylonitrile @TiO2/ zeolitic imidazolate framework-8（PTZ）hybrid membrane. The hybrid membrane was prepared by electrospinning technique and in situ Metal-organic frameworks (MOFs) synthesis. The optimized membrane maintained a good PM2.5 capture efficiency (greater than 99%) and a pressure drop of 34 Pa. The larger specific surface area and higher pore structure enhance the filter interception effect and electrostatic interaction, which can have high applications for the filtering of PM2.5. In addition, zeolitic imidazolate framework-8 (ZIF-8) is uniformly coated on the surface of polyacrylonitrile @ TiO2 (PT) nanofiber to form N-Ti-O bonds, thus reducing the reorganization of electron-hole pairs and improving the efficiency of photodegradation. Compared with PT, the hybrid structure formed by PTZ has a higher degradation efficiency for PM2.5 (increased from 66% to 85%). The produced PTZ membrane exhibits a promising future in the collection and green degradation of PM2.5.