Spatial accessibility and inequality analysis of rabies-exposed patients to rabies post-exposure prophylaxis clinics in Guangzhou City, China.

BACKGROUND: The incidence of rabies exposure is high and increasing in China, leading to an urgent demand of rabies post-exposure prophylaxis (PEP) clinics for the injured. However, the spatial accessibility and inequality of rabies-exposed patients to rabies PEP clinics is less known in China. METHODS: Based on rabies exposure data, PEP clinic data, and resident travel origin-destination (OD) matrix data in Guangzhou City, China, we first described the incidence of rabies exposure in Guangzhou from 2020 to 2022. Then, the Gaussian two-step floating catchment area method (2SFCA) was used to analyze the spatial accessibility of rabies-exposed patients to rabies PEP clinics in Guangzhou, and the Gini coefficient and Moran's I statistics were utilized to evaluate the inequality and clustering of accessibility scores. RESULTS: From 2020 to 2022, a total of 524,160 cases of rabies exposure were reported in Guangzhou, and the incidence showed a significant increasing trend, with an average annual incidence of 932.0/100,000. Spatial accessibility analysis revealed that the overall spatial accessibility scores for three scenarios (threshold of driving duration [d0] = 30 min, 45 min, and 60 min) were 0.30 (95% CI: 0.07, 0.87), 0.28 (95% CI: 0.11, 0.53) and 0.28 (95% CI: 0.14, 0.44), respectively. Conghua, Huangpu, Zengcheng and Nansha districts had the higher accessibility scores, while Haizhu, Liwan, and Yuexiu districts exhibited lower spatial accessibility scores. The Gini coefficient and Moran's I statistics showed that there were certain inequality and clustering in the accessibility to rabies PEP clinics in Guangzhou. CONCLUSIONS: This study clarifies the heterogeneity of spatial accessibility to rabies PEP clinics, and provide valuable insights for resource allocation to achieve the WHO target of zero human dog-mediated rabies deaths by 2030.

Design, synthesis and mechanistic studies of novel arylformylhydrazone butylphenyltin complexes as potential anticancer agents.

Many diorganotin complexes with various alkyl groups exhibit excellent in vitro anticancer activity. However, most diorganotin is the same alkyl group, and the asymmetric alkyl R group has been rarely reported. Hence, in this paper, twenty butylphenyl mixed dialkyltin arylformylhydrazone complexes have been synthesized by microwave "one-pot" reaction with arylformylhydrazine, substituted α-keto acid or its sodium salt and butylphenyltin dichloride. The crystal structures of nine complexes were determined, indicating that the complexes C1, C2, C11, C12, and C16 âˆ¼ C19 possessed a central symmetric structure of a dinuclear Sn2O2 tetrahedral ring; while the complex C9 is a trinuclear tin-oxygen cluster with a 6-membered ring encased in a 12-membered macrocyclic structure. The inhibiting activity of complexes was tested against the human cell lines NCI-H460, MCF-7, HepG2, Huh-7 and HL-7702. Complex C2 demonstrated the optimal inhibitory effect on HepG2 cells, with an IC50 value of 0.82 ± 0.03 µM. Cellular biology experiments revealed that complex C2 could induce apoptosis and G2/M phase cell cycle arrest in HepG2 and Huh-7 cells. The complex also caused the collapse of the mitochondrial membrane potential and increased intracellular reactive oxygen species in HepG2 and Huh-7 cells. Western blot analysis further clarified that complex C2 could induce cell apoptosis through the mitochondrial pathway along with the release of reactive oxygen species.

Development and validation of prognostic nomogram for T1-3N0M0 non-small cell lung cancer after curative resection.

BACKGROUND: Radical resection plus lymph node dissection is a common treatment for patients with T1-3N0M0 non-small cell lung cancer (NSCLC). Few models predicted the survival outcomes of these patients. This study aimed to developed a nomogram for predicting their overall survival (OS). MATERIALS AND METHODS: This study involved 3002 patients with T1-3N0M0 NSCLC after curative resection between January 1999 and October 2013. 1525 Patients from Sun Yat-sen University Cancer Center were randomly allocated to training cohort and internal validation cohort in a ratio of 7:3. 1477 patients from ten institutions were recruited as external validation cohort. A nomogram was constructed based on the training cohort and validated by internal and external validation cohort to predict the OS of these patients. The accuracy and practicability were tested by Harrell's C-indexes, calibration plots and decision curve analyses (DCA). RESULTS: Age, sex, histological classification, pathological T stage, and HI standard were independent factors for OS and were included in our nomogram. The C-index of the nomogram for OS estimates were 0.671 (95% CI, 0.637-0.705),0.632 (95% CI, 0.581-0.683), and 0.645 (95% CI, 0.617-0.673) in the training cohorts, internal validation cohorts, and external validation cohort, respectively. The calibration plots and DCA for predictions of OS were in excellent agreement. An online version of the nomogram was built for convenient clinical practice. CONCLUSIONS: Our nomogram can predict the OS of patients with T1-3N0M0 NSCLC after curative resection. The online version of our nomogram offer opportunities for fast personalized risk stratification and prognosis prediction in clinical practice.

Inhibitory Effects of 3-Methylcholanthrene Exposure on Porcine Oocyte Maturation.

3-methylcholanthrene (3-MC) is a highly toxic environmental pollutant that impairs animal health. 3-MC exposure can cause abnormal spermatogenesis and ovarian dysfunction. However, the effects of 3-MC exposure on oocyte maturation and embryo development remain unclear. This study revealed the toxic effects of 3-MC exposure on oocyte maturation and embryo development. 3-MC with different concentrations of 0, 25, 50, and 100 µM was applied for in vitro maturation of porcine oocytes. The results showed that 100 µM 3-MC significantly inhibited cumulus expansion and the first polar body extrusion. The rates of cleavage and blastocyst of embryos derived from 3-MC-exposed oocytes were significantly lower than those in the control group. Additionally, the rates of spindle abnormalities and chromosomal misalignments were higher than those in the control group. Furthermore, 3-MC exposure not only decreased the levels of mitochondria, cortical granules (CGs), and acetylated α-Tubulin, but also increased the levels of reactive oxygen species (ROS), DNA damage, and apoptosis. The expression of cumulus expansion and apoptosis-related genes was abnormal in 3-MC-exposed oocytes. In conclusion, 3-MC exposure disrupted the nuclear and cytoplasmic maturation of porcine oocytes through oxidative stress.

Predicting response to immunotherapy plus chemotherapy in patients with esophageal squamous cell carcinoma using non-invasive Radiomic biomarkers.

OBJECTIVES: To develop and validate a radiomics model for evaluating treatment response to immune-checkpoint inhibitor plus chemotherapy (ICI + CT) in patients with advanced esophageal squamous cell carcinoma (ESCC). METHODS: A total of 64 patients with advance ESCC receiving first-line ICI + CT at two centers between January 2019 and June 2020 were enrolled in this study. Both 2D ROIs and 3D ROIs were segmented. ComBat correction was applied to minimize the potential bias on the results due to different scan protocols. A total of 788 features were extracted and radiomics models were built on corrected/uncorrected 2D and 3D features by using 5-fold cross-validation. The performance of the radiomics models was assessed by its discrimination, calibration and clinical usefulness with independent validation. RESULTS: Five features and support vector machine algorithm were selected to build the 2D uncorrected, 2D corrected, 3D uncorrected and 3D corrected radiomics models. The 2D radiomics models significantly outperformed the 3D radiomics models in both primary and validation cohorts. When ComBat correction was used, the performance of 2D models was better (p = 0.0059) in the training cohort, and significantly better (p < 0.0001) in the validation cohort. The 2D corrected radiomics model yielded the optimal performance and was used to build the nomogram. The calibration curve of the radiomics model demonstrated good agreement between prediction and observation and the decision curve analysis confirmed the clinical utility. CONCLUSIONS: The easy-to-use 2D corrected radiomics model could facilitate noninvasive preselection of ESCC patients who would benefit from ICI + CT.

The impacts of precipitation patterns on dengue epidemics in Guangzhou city.

Some studies have demonstrated that precipitation is an important risk factor of dengue epidemics. However, current studies mostly focused on a single precipitation variable, and few studies focused on the impact of precipitation patterns on dengue epidemics. This study aims to explore optimal precipitation patterns for dengue epidemics. Weekly dengue case counts and meteorological data from 2006 to 2018 in Guangzhou of China were collected. A generalized additive model with Poisson distribution was used to investigate the association between precipitation patterns and dengue. Precipitation patterns were defined as the combinations of three weekly precipitation variables: accumulative precipitation (Pre_A), the number of days with light or moderate precipitation (Pre_LMD), and the coefficient of precipitation variation (Pre_CV). We explored to identify optimal precipitation patterns for dengue epidemics. With a lead time of 10 weeks, minimum temperature, relative humidity, Pre_A, and Pre_LMD were positively associated with dengue, while Pre_CV was negatively associated with dengue. A precipitation pattern with Pre_A of 20.67-55.50 mm per week, Pre_LMD of 3-4 days per week, and Pre_CV less than 1.41 per week might be an optimal precipitation pattern for dengue epidemics in Guangzhou. The finding may be used for climate-smart early warning and decision-making of dengue prevention and control.

Optical Limiting Based on Huygens' Metasurfaces.

Optical limiting is desirable or necessary in a variety of applications that employ high-power light sources or sensitive photodetectors. However, the most prevalent methods compromise between on-state transmission and turndown ratio or rely on narrow transmission windows. We demonstrate that a metasurface-based architecture incorporating phase-change materials enables both high and broadband on-state transmission (-4.8 dB) while also providing a large turndown ratio (25.2 dB). Additionally, this design can be extended for broadband multiwavelength limiting due to the high off-resonance transmittance and readily scalable resonant wavelength. Furthermore, our choice of active material allows for protection in ultrafast laser environments due to the speed of the phase transition. These benefits offer a strong alternative to state-of-the-art optical limiters in technologies ranging from sensor protection to protective eyewear.

An assessment of the hydrologic effectiveness of low impact development (LID) practices for managing runoff with different objectives.

This study represents an approach to assess the hydrologic effectiveness of low impact development (LID) practices based on the expected runoff process with different objectives and land utilization. The proposed approach is to simulate runoff hydrograph rather than several indices (e.g., runoff initiation, peak flow, and runoff volume) to avoid the uncertainties under a certain rainfall scenario. A rainfall-runoff model of a residential district in China, constructed based on the stormwater management model (SWMM), is auto-calibrated (validated) based on 12 (25) observed rainfall and runoff events using model-independent parameter estimation (PEST). The priority sites and parameters for LID practices for different objectives are auto-calculated using PEST based on the calibrated model and different expected runoff processes. The expected runoff processes are simulated from the calibrated model with four impervious cover scenarios corresponding to 5-year, 2-h duration design storm. The study illustrates that (i) the proposed approach can auto-optimize runoff manage strategies based on LID practices and land; (ii) the design parameters of LID practices can be auto-calculated and that simulated runoff processes are in near perfect agreement with expected runoff processes; (iii) this approach can auto-optimize any specific parameters of the SWMM and LID practices without changing those determined parameters. Our simple, but quantitative, approach for identifying potential LID sites and design parameters based on land can better inform the hydrologic effectiveness of LID practices for managing runoff.

Comparison between microwave ablation and lobectomy for stage I non-small cell lung cancer: a propensity score analysis.

PURPOSE: To compare the effectiveness and complication between microwave ablation and lobectomy for stage I non-small cell lung cancer. MATERIALS AND METHODS: This retrospective study was approved by two institutional ethics committees and all patients were provided with informed consent. From January 2000 to December 2010, 54 and 795 stage I patients who underwent microwave ablation and lobectomy were included in this study. A matched cohort composed of 54 and 108 patients in the microwave ablation and the lobectomy group were selected after adjustment with 1:2 propensity score matching. The overall survival and disease-free survival were evaluated. Survival curves were constructed with the Kaplan-Meier method and compared by using the log-rank test. RESULTS: The 1, 3 and 5-year Overall survive were 100, 92.6 and 50.0% for MWA group and 100, 90.7 and 46.3% for lobectomy group. The 1, 3 and 5-year disease free survival was 98.1, 79.6 and 37.0% for MWA group and 98.1, 81.5 and 29.6% for lobectomy group. There was no significant difference between two groups in overall survival (p = 0.608) and disease free survival (p = 0.672). Additionally, local or distant metastasis rate (p = 0.544) were not significantly different between two groups while the complication rate in the MWA group was significantly lower than the lobectomy group (p = 0.008). CONCLUSION: Microwave ablation has similar therapeutic effect compared with lobectomy for stage I non-small cell lung cancer, but with fewer complication and less pain.

Dynamically Reconfigurable Metadevice Employing Nanostructured Phase-Change Materials.

Mastering dynamic free-space spectral control and modulation in the near-infrared (NIR) and optical regimes remains a challenging task that is hindered by the available functional materials at high frequencies. In this work, we have realized an efficient metadevice capable of spectral control by minimizing the thermal mass of a vanadium dioxide phase-change material (PCM) and placing the PCM at the feed gap of a bow-tie field antenna. The device has an experimentally measured tuning range of up to 360 nm in the NIR and a modulation depth of 33% at the resonant wavelength. The metadevice is configured for integrated and local heating, leading to faster switching and more precise spatial control compared with devices based on phase-change thin films. We envisage that the combined advantages of this device will open new opportunities for signal processing, memory, security, and holography at optical frequencies.

Enantioselective Recognition for Many Different Kinds of Chiral Guests by One Chiral Receptor Based on Tetraphenylethylene Cyclohexylbisurea.

A neutral chiral receptor based on TPE cyclohexylbisurea was synthesized and could discriminate the enantiomers of many different kinds of chiral reagents, including chiral acidic compounds, basic compounds, amino acids, and even neutral alcohols. The (1)H NMR spectra disclosed that the ability of chiral recognition could be ascribed to the multiple hydrogen bonds and CH-π interactions between the TPE urea receptor and the enantiomer of the chiral guest, which led to the selective aggregation of the receptor with one of the two enantiomers. This result exhibited a great potential in enantiomer discernment and high-throughput analysis of enantiomer composition of these chiral analytes by one chiral AIE molecule.

E2F1 promote the aggressiveness of human colorectal cancer by activating the ribonucleotide reductase small subunit M2.

As the ribonucleotide reductase small subunit, the high expression of ribonucleotide reductase small subunit M2 (RRM2) induces cancer and contributes to tumor growth and invasion. In several colorectal cancer (CRC) cell lines, we found that the expression levels of RRM2 were closely related to the transcription factor E2F1. Mechanistic studies were conducted to determine the molecular basis. Ectopic overexpression of E2F1 promoted RRM2 transactivation while knockdown of E2F1 reduced the levels of RRM2 mRNA and protein. To further investigate the roles of RRM2 which was activated by E2F1 in CRC, CCK-8 assay and EdU incorporation assay were performed. Overexpression of E2F1 promoted cell proliferation in CRC cells, which was blocked by RRM2 knockdown attenuation. In the migration and invasion tests, overexpression of E2F1 enhanced the migration and invasion of CRC cells which was abrogated by silencing RRM2. Besides, overexpression of RRM2 reversed the effects of E2F1 knockdown partially in CRC cells. Examination of clinical CRC specimens demonstrated that both RRM2 and E2F1 were elevated in most cancer tissues compared to the paired normal tissues. Further analysis showed that the protein expression levels of E2F1 and RRM2 were parallel with each other and positively correlated with lymph node metastasis (LNM), TNM stage and distant metastasis. Consistently, the patients with low E2F1 and RRM2 levels have a better prognosis than those with high levels. Therefore, we suggest that E2F1 can promote CRC proliferation, migration, invasion and metastasis by regulating RRM2 transactivation. Understanding the role of E2F1 in activating RRM2 transcription will help to explain the relationship between E2F1 and RRM2 in CRC and provide a novel predictive marker for diagnosis and prognosis of the disease.

Wearable sensor systems for infants.

Continuous health status monitoring of infants is achieved with the development and fusion of wearable sensing technologies, wireless communication techniques and a low energy-consumption microprocessor with high performance data processing algorithms. As a clinical tool applied in the constant monitoring of physiological parameters of infants, wearable sensor systems for infants are able to transmit the information obtained inside an infant's body to clinicians or parents. Moreover, such systems with integrated sensors can perceive external threats such as falling or drowning and warn parents immediately. Firstly, the paper reviews some available wearable sensor systems for infants; secondly, we introduce the different modules of the framework in the sensor systems; lastly, the methods and techniques applied in the wearable sensor systems are summarized and discussed. The latest research and achievements have been highlighted in this paper and the meaningful applications in healthcare and behavior analysis are also presented. Moreover, we give a lucid perspective of the development of wearable sensor systems for infants in the future.

Comparison of pain relief between patient-controlled epidural analgesia and patient-controlled intravenous analgesia for patients undergoing spinal fusion surgeries.

INTRODUCTION: This meta-analysis aimed to compare the postoperative analgesic effects of patient-controlled epidural analgesia (PCEA) and patient-controlled intravenous analgesia (PCIA) for patients undergoing spinal fusion surgeries. METHOD: Relevant articles were identified using computerized and manual search strategies. Statistical analyses were undertaken by the CMA 2.0 statistical software. RESULTS: Nine cohort studies with a total of 436 patients undergoing spinal fusion surgeries were incorporated in the present meta-analysis. There were significant differences between the PCEA and PCIA groups in the visual analogue scale score of patients undergoing spinal fusion [standardized mean difference = 0.27, 95 % confidence interval (95 % CI) = 0.070-0.470, P = 0.008]. However, no obvious difference was observed in the rate of side effects between the PCIA and PCEA groups (side effects: odds ratio = 0.957, 95 % CI = 0.536-1.708, P = 0.882). CONCLUSION: Our findings suggested that PCEA may be more effective in relieving pain than PCIA for patients undergoing spinal fusion surgeries.

The ABO blood group predicts survival in esophageal squamous cell carcinoma in patients who ever smoked: a retrospective study from China.

The association between clinical characteristics, prognosis, and the ABO blood group of esophageal squamous cell carcinoma (ESCC) is rarely discussed. The aims of the current study were to investigate the correlation of the ABO blood group with the clinicopathological characteristics in a consecutive cohort of patients with ESCC and to assess whether the ABO blood group was associated with prognosis. A total of 511 patients with locoregional ESCC who underwent curative treatment were retrospectively analyzed at a single institution between January 2007 and December 2008. The relationship between the ABO blood group and clinicopathological variables was assessed by chi-squared analysis. The Kaplan-Meier method was used to estimate the 5-year overall survival (OS). The Cox proportional hazards model was used in univariate and multivariate analyses of OS. There were no significant differences in the clinicopathological characteristics among patients with different ABO blood groups. The 5-year OS rates were 50.0 % for patients with blood type A, 45.4 % for type B, 50.8 % for type O, and 60.7 % for type AB. In a subgroup analysis of 321 patients who ever smoked, the B/O group had a poorer OS compared with the A/AB group (p = 0.0245). Multivariate analysis revealed an unfavorable and independent impact of the B/O group on patient survival with ESCC who ever smoked (p = 0.011). Findings suggest the B/O blood type as a predictor of mortality in ESCC patients who ever smoked. Future studies conducted prospectively are warranted to confirm this work and to better understand the underlying biological mechanisms.

Significance of combined detection of LunX mRNA and tumor markers in diagnosis of lung carcinoma.

OBJECTIVE: To evaluate the significance of combined detection of LunX mRNA, carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and cytokeratin 21-1 fragment (CYFRA21-1) in clinical diagnosis of lung carcinoma. METHODS: Based on the quantitative RT-PCR and chemiluminescence immunoassay, the expression levels of LunX mRNA, CEA, NSE, and CYFRA21-1 in 113 patients with lung carcinoma (case group) and 30 healthy participants (control group) were detected. Meantime, the sensitivity, specificity, and accuracy of the combination detection were also explored. RESULTS: The positive rates of LunX mRNA in peripheral blood and CEA, NSE, and CYFRA21-1 in serum were significantly higher in case group than those in control group ((χ) (2)=17.295, 16.825, 19.148, and 17.450; P<0.05). There was no statistical significance when positive rate of LunX mRNA was evaluated among different pathological types ((χ) (2)=0.047, P>0.05). The positive rate of LunX mRNA in stage I + II, III, and IV had a significantly increasing tendency ((χ) (2)=10.565, 32.462, P<0.05). The positive rate of CYFRA21-1 was highest in squamous carcinoma (78.5%), the positive rate of NSE was highest in small cell carcinoma (86.7%), and the positive rate of CEA wag highest in lung adenocarcinoma (80.4%). The sensitivity and accuracy of the combination detection were 91.1% and 88.1%, respectively. CONCLUSIONS: The combined detection of LunX mRNA and tumor markers (TMs) including CEA, NSE, and CYFRA21-1 in peripheral blood is helpful to increase the diagnostic accuracy of lung cancer. Also, it can inform the pathological typing of lung carcinoma.

Gut Microbiota, Human Blood Metabolites, and Esophageal Cancer: A Mendelian Randomization Study.

BACKGROUND: Unbalances in the gut microbiota have been proposed as a possible cause of esophageal cancer (ESCA), yet the exact causal relationship remains unclear. PURPOSE: To investigate the potential causal relationship between the gut microbiota and ESCA with Mendelian randomization (MR) analysis. METHODS: Genome-wide association studies (GWASs) of 207 gut microbial taxa (5 phyla, 10 classes, 13 orders, 26 families, 48 genera, and 105 species) and 205 gut microbiota metabolic pathways conducted by the Dutch Microbiome Project (DMP) and a FinnGen cohort GWAS of esophageal cancer specified the summary statistics. To investigate the possibility of a mediation effect between the gut microbiota and ESCA, mediation MR analyses were performed for 1091 blood metabolites and 309 metabolite ratios. RESULTS: MR analysis indicated that the relative abundance of 10 gut microbial taxa was associated with ESCA but all the 12 gut microbiota metabolic pathways with ESCA indicated no statistically significant association existing. Two blood metabolites and a metabolite ratio were discovered to be mediating factors in the pathway from gut microbiota to ESCA. CONCLUSION: This research indicated the potential mediating effects of blood metabolites and offered genetic evidence in favor of a causal correlation between gut microbiota and ESCA.

The Impact of Australian Bushfires on Asthma Medicine Prescription Dispensing.

BACKGROUND: Air pollution can cause numerous health problems and increase the need for medicines to treat and prevent asthma in affected areas. There is limited evidence about the association between airborne particles with a diameter of 2.5 micrometres or smaller (PM2.5) and asthma medicine usage. This study examined the potential association between the levels of PM2.5 and the supply of prescription asthma medicines in the Australian Capital Territory (ACT), Australia, during the severe bushfire season between November 2019-January 2020. METHODS: Daily data was obtained from an ACT air quality monitoring station from November 2019 to January 2020 (study period) and November 2018 to January 2019 (control period, no bushfire). The number and types of government-funded asthma medicine prescriptions were obtained from the Services Australia (government) website by searching under 'Pharmaceutical Benefits Scheme Item Reports' and using relevant item codes during the study and control periods. RESULTS: The medians for PM2.5 levels for the study period were significantly higher than those for the control period (p < 0.001). There were increases in the number of dispensed prescriptions of short-acting beta-2 agonists (SABA), inhaled corticosteroids, and long-acting beta-2 agonists combined with inhaled corticosteroids. The greatest difference was seen with the inhaled corticosteroids: a 138% increase. CONCLUSIONS: The increase in the number of dispensed asthma prescriptions during the bushfire season should be used to inform the stock holdings of these medicines in preparation for future events to ensure access to lifesaving asthma medicines.

Exploring the Mediation Effect of Metabolite Levels on the Association Between Gut Microbiota and HCC: A two-step, two-sample bidirectional Mendelian Randomization.

Background: Although the gut microbiota is one of the risk factors for liver cancer, it remains unclear whether the level of metabolites mediates this association. Methods: Utilizing summary data from genome-wide association studies (GWAS), we conducted a two-sample Mendelian Randomization (MR) analysis to explore the causal links between GM, metabolites, and HCC. A two-step MR analysis quantitatively assessed the effect of metabolite-mediated GM on HCC. Results: In our study, we demonstrated that Clostridium leptum was identified as a protective factor against HCC, with no evidence of reverse causality (Inverse-variance weighted [IVW], OR: 0.62 [95% CI, 0.42-0.91]; p = 0.016). Our study also found that the potential connection between the GM and HCC may be mediated by the level of metabolites. An increase of one standard deviation in C. leptum abundance led to a 38% decrease in HCC risk (OR: 0.62 [95% CI, 0.42-0.91]), with a 9% reduction in phosphoethanolamine (PE) levels (OR: 0.91 [95% CI: 0.84-0.99]). PE's mediation proportion was established as -6.725% (95% CI, 12.96% to -26.41%). Conclusion: Our results demonstrate that increasing specific GM abundance can lower HCC risk, mediated by PE levels. We offer new prevention and treatment targets for HCC by adjusting GM.

The protein methyltransferase TrSAM inhibits cellulase gene expression by interacting with the negative regulator ACE1 in Trichoderma reesei.

Protein methylation is a commonly posttranslational modification of transcriptional regulators to fine-tune protein function, however, whether this regulation strategy participates in the regulation of lignocellulase synthesis and secretion in Trichoderma reesei remains unexplored. Here, a putative protein methyltransferase (TrSAM) is screened from a T. reesei mutant with the ability to express heterologous ß-glucosidase efficiently even under glucose repression. The deletion of its encoding gene trsam causes a significant increase of cellulase activities in all tested T. reesei strains, including transformants of expressing heterologous genes using cbh1 promotor. Further investigation confirms that TrSAM interacts with the cellulase negative regulator ACE1 via its amino acid residue Arg383, which causes a decrease in the ACE1-DNA binding affinity. The enzyme activity of a T. reesei strain harboring ACE1R383Q increases by 85.8%, whereas that of the strains with trsam or ace1 deletion increases by more than 100%. By contrast, the strain with ACE1R383K shows no difference to the parent strain. Taken together, our results demonstrate that TrSAM plays an important role in regulating the expression of cellulase and heterologous proteins initiated by cbh1 promotor through interacting with ACE1R383. Elimination and mutation of TrSAM and its downstream ACE1 alleviate the carbon catabolite repression (CCR) in expressing cellulase and heterologous protein in varying degrees. This provides a new solution for the exquisite modification of T. reesei chassis.