The ASH1-PEX16 regulatory pathway controls peroxisome biogenesis for appressorium-mediated insect infection by a fungal pathogen.

Entomopathogenic fungi infect insects by penetrating through the cuticle into the host body. To breach the host cuticle, some fungal pathogens produce specialized infection cells called appressoria, which develop enormous turgor pressure to allow cuticle penetration. However, regulatory mechanisms underlying appressorium turgor generation are poorly understood. Here, we show that the histone lysine methyltransferase ASH1 in the insecticidal fungus Metarhizium robertsii, which is strongly induced during infection of the mosquito cuticle, regulates appressorium turgor generation and cuticle penetration by activating the peroxin gene Mrpex16 via H3K36 dimethylation. MrPEX16 is required for the biogenesis of peroxisomes that participate in lipid catabolism and further promotes the hydrolysis of triacylglycerols stored in lipid droplets to produce glycerol for turgor generation, facilitating appressorium-mediated insect infection. Together, the ASH1-PEX16 pathway plays a pivotal role in regulating peroxisome biogenesis to promote lipolysis for appressorium turgor generation, providing insights into the molecular mechanisms underlying fungal pathogenesis.

Computational modeling of the physical features that influence breast cancer invasion into adipose tissue.

Breast cancer invasion into adipose tissue strongly influences disease progression and metastasis. The degree of cancer cell invasion into adipose tissue depends on both biochemical signaling and the mechanical properties of cancer cells, adipocytes, and other key components of adipose tissue. We model breast cancer invasion into adipose tissue using discrete element method simulations of active, cohesive spherical particles (cancer cells) invading into confluent packings of deformable polyhedra (adipocytes). We quantify the degree of invasion by calculating the interfacial area At between cancer cells and adipocytes. We determine the long-time value of At vs the activity and strength of the cohesion between cancer cells, as well as the mechanical properties of the adipocytes and extracellular matrix in which adipocytes are embedded. We show that the degree of invasion collapses onto a master curve as a function of the dimensionless energy scale Ec , which grows linearly with the cancer cell velocity persistence time and fluctuations, is inversely proportional to the system pressure, and is offset by the cancer cell cohesive energy. When E c > 1 , cancer cells will invade the adipose tissue, whereas for E c < 1 , cancer cells and adipocytes remain de-mixed. We also show that At decreases when the adipocytes are constrained by the ECM by an amount that depends on the spatial heterogeneity of the adipose tissue.

Computational modeling of the physical features that influence breast cancer invasion into adipose tissue.

Breast cancer invasion into adipose tissue strongly influences disease progression and metastasis. The degree of cancer cell invasion into adipose tissue depends on numerous biochemical and physical properties of cancer cells, adipocytes, and other key components of adipose tissue. We model breast cancer invasion into adipose tissue as a physical process by carrying out simulations of active, cohesive spherical particles (cancer cells) invading into confluent packings of deformable polyhedra (adipocytes). We quantify the degree of invasion by calculating the interfacial area At between cancer cells and adipocytes. We determine the long-time value of At versus the activity and strength of the cohesion between cancer cells, as well as mechanical properties of the adipocytes and extracellular matrix (ECM) in which the adipocytes are embedded. We show that the degree of invasion collapses onto a master curve by plotting it versus a dimensionless energy scale Ec, which grows linearly with mean-square fluctuations and persistence time of the cancer cell velocities, is inversely proportional to the pressure of the system, and has an offset that increases with the cancer cell cohesive energy. The condition, Ec≫1, indicates that cancer cells will invade the adipose tissue, whereas for Ec≪1, the cancer cells and adipocytes remain demixed. We also show that constraints on adipocyte positions by the ECM decrease At relative to that obtained for unconstrained adipocytes. Finally, spatial heterogeneity in structural and mechanical properties of the adipocytes in the presence of ECM impedes invasion relative to adipose tissue with uniform properties.

Unveiling a novel entry gate: Insect foregut as an alternative infection route for fungal entomopathogens.

Insects and their natural microbial pathogens are intertwined in constant arms races, with pathogens continually seeking entry into susceptible hosts through distinct routes. Entomopathogenic fungi are primarily believed to infect host insects through external cuticle penetration. Here, we report a new variety, Beauveria bassiana var. majus (Bbm), that can infect insects through the previously unrecognized foregut. Dual routes of infection significantly accelerate insect mortality. The pH-responsive transcription factor PacC in Bbm exhibits rapid upregulation and efficient proteolytic processing via PalC for alkaline adaptation in the foregut. Expression of PalC is regulated by the adjacent downstream gene Aia. Compared to non-enteropathogenic strains such as ARSEF252, Aia in Bbm lacks a 249-bp fragment, resulting in its enhanced alkaline-induced expression. This induction promotes PalC upregulation and facilitates PacC activation. Expressing the active form of BbmPacC in ARSEF252 enables intestinal infection. This study uncovers the pH-responsive Aia-PalC-PacC cascade enhancing fungal alkaline tolerance for intestinal infection, laying the foundation for developing a new generation of fungal insecticides to control destructive insect pests.

U-shaped association between online information exchange and app usage frequency: a large-scale survey of China 's online young and middle-aged people with pre diabetes and diabetes.

Background: China has the world's largest diabetic population, and the cost of caring for all these people every day is substantial. Online information exchange and app usage frequency have been demonstrated to play a significant influence in the management of blood glucose and enhancement of diabetes-related quality of life. However, the association between online information exchange and app usage frequency among actual online populations remains unclear and deserves additional study. Therefore, we evaluated the factors affecting the frequency of app usage in the online glucose management population, with a particular emphasis on the connection between online information exchange and app use frequency, contributing to the expansion of the research of diabetes management models. Method: This cross-sectional study was conducted by disseminating questionnaires in blood glucose management-related forums and WeChat groups and included 1586 online users concerned about blood glucose management. Information exchange and app usage frequency were considered as independent and dependent variables, respectively. We performed stratified and single factor analysis, multiple equation regression analysis, smooth curve fitting, and threshold effect and saturation effect analysis. R (version 4.1.3, http://www.Rproject.org) and EmpowerStats were used for data analysis. Result: After adjusting for other covariates, information exchange was independently and positively associated with app use frequency (ß = 8.6, 95% CI: 6.5 to 11.2, p < 0.001). Through interaction analysis, the most significant interaction factors influencing the relationship between information exchange and app usage frequency were identified as health insurance status, whether living with parents, glycated hemoglobin status in the previous month, and self-monitoring of blood glucose (SMBG). The association between information exchange and app usage frequency is U-shaped, with information exchange inflection points of 3.0 and 4.2. Information exchange and app usage frequency are negatively correlated when the average information exchange score is less than 3.0, and for every point increase in the average information exchange score, the likelihood of the app high usage frequency group compared to the app low usage frequency group decreases by 70%. The relationship between information exchange and app usage frequency is strongest when it is greater than or equal to 3.0 and less than or equal to 4.2. The probability of the app high usage frequency group occurring compared to the app low usage frequency group rises 17.3 times for every 1 point increase in the average information exchange score. The probability of the app high usage frequency group occurring in comparison to the app low usage frequency group increased by 1.8 times for every 1 point rise in information exchange when the average information exchange score was higher than 4.2. Conclusion: Age, body mass index, married, living with parents, hemoglobin level, SMBG, and information exchange were positively connected with app usage frequency in our study of online blood glucose management population. The link between information exchange and app use frequency was significantly U-shaped. The app usage frequency changed the most with the rise in information exchange when the information exchange score was greater than or equal to 3.0 and less than or equal to 4.2. Therefore, we ought to offer effort to concentrate on and increase the health-related behaviors and activities of those in this score interval.

Evaluation of Triglyceride Glucose Index and Homeostasis Model of Insulin Resistance in Patients with Polycystic Ovary Syndrome.

Purpose: To use the triglyceride glucose (TyG) index to evaluate insulin resistance (IR) in patients with polycystic ovary syndrome (PCOS) and to explore alternative indicators for early identification of IR. Patients and Methods: This study included 114 patients with PCOS and 61 healthy volunteers. Pearson or Spearman correlations were calculated to compare the association between the TyG index and triglyceride glucose body mass index (TyG-BMI) with homeostatic model assessment for IR (HOMA-IR), homeostasis model assessment for ß-cell function (HOMA-ß), quantitative insulin sensitivity check index (QUICKI), and fasting glucose-to-insulin ratio (FG-IR). The receiver operating characteristic (ROC) curve was used to evaluate the sensitivity and specificity of the TyG index and TyG-BMI in identifying IR (defined as HOMA-IR ≥2.5) in patients with PCOS. Results: Correlation analyses revealed that the TyG index of the PCOS group was positively correlated with HOMA-IR (r=0.515, P<0.01) and HOMA-ß (r=0.348, P<0.01), but negatively correlated with QUICKI (r=-0.532, P<0.01) and FG-IR (r=-0.394, P<0.01). The ROC curve of IR defined by HOMA-IR showed that the AUC value of TyG-BMI was the highest, at 0.796 (95% confidence interval (CI): 0.710-0.866, P<0.001) when the cut-off point was 191.53, with 85.3% sensitivity and 73.9% specificity values. For the TyG index, the AUC was 0.781 (95% CI: 0.693-0.853, P<0.001) when 8.51 was the cut-off point, with a sensitivity of 63.2% and specificity of 87.0%. Conclusion: This study found that the TyG index and TyG-BMI performed better than traditional lipid ratios, such as triglycerides/high density lipoprotein cholesterol (TG/HDL-C), in predicting IR and may be used as markers of IR in Chinese patients with PCOS.

Diffusion of Thin Nanorods in Polymer Melts.

The diffusion of monomerically thin nanorods in polymer melts is studied by molecular dynamics simulations. We focus on the systems where chains are long enough to screen the hydrodynamic interactions such that the diffusion coefficient D ∥ for the direction parallel to the rod decreases linearly with increasing rod length l. In unentangled polymers, the diffusion coefficient for the direction normal to the rod exhibits a crossover from D ⊥ ~ l -2 to D ⊥ ~ l -1 with increasing l, corresponding to a progressive coupling of nanorod motion to the polymers. Accordingly, the rotational diffusion coefficient D R ≈ D ⊥ l -2 ~ l -4 and then D R ~ l -3 as l increases. In entangled polymers, D ⊥ and D R are suppressed for l larger than the entanglement mesh size a. D ⊥ ~ l -3 and D R ~ l -5 for l sufficiently above a in agreement with de Gennes' rod reptation model.

Ion-mediated interactions between like-charged polyelectrolytes with bending flexibility.

Ion-mediated interactions between polyelectrolytes (PEs) are crucial to the properties of flexible biopolymers such as nucleic acids and proteins but the effect of PE flexibility on such interactions has not been explicitly addressed until now. In this work, the potentials of mean force (PMFs) between like-charged PEs with different bending flexibility have been investigated by Monte Carlo simulations and a cylindrical confinement around each PE was involved to model two PEs in an array. We found that in the absence of trivalent salt, the PMFs between like-charged PEs in an array are apparently repulsive while the bending flexibility can visibly decrease the repulsive PMFs. With the addition of high trivalent salt, the PMFs become significantly attractive whereas the attractive PMFs can be apparently weakened by the bending flexibility. Our analyses reveal that the effect of bending flexibility is attributed to the increased PE conformational space, which allows the PEs to fluctuate away to decrease the monovalent ion-mediated repulsion or to weaken the trivalent ion-mediated attraction through disrupting trivalent ion-bridging configuration. Additionally, our further calculations show that the effect of bending flexibility on the ion-mediated interactions is less apparent for PEs without cylindrical confinement.

Cellular Toxicity Study of Silicon Nanowires.

The objective of this study was to achieve the practical bioapplications of silicon nanowires (SiNWs). In this study, the tumor and normal cell lines were used as models to systematically investigate the cytotoxicity of SiNWs synthesized by HF-assisted etching methods. Morphology observation, Cell Counting Kit 8, real-time polymerase chain reaction, and flow cytometry analysis were used to elucidate the cytotoxicity of SiNWs. The results showed that the cytotoxicity of SiNWs is greatly dependent on cell lines, SiNWs concentration, and incubation time. Particularly, SiNWs show better biocompatibility with tumor cell lines (eg, human epithelial cervical cancer [Hela] cells and human hepatocellular liver carcinoma [HepG2] cells) than normal cell lines (eg, human normal liver [HL-7702] cells and human embryonic kidney [HEK293T] cells). The reasons may be that SiNWs could tightly attach to the cell membrane in the cell medium, which obviously affects cell adhesion and inhibits their cell viability, especially for normal cell lines. From systematical analysis and comparison, we obtain the concentration limits of SiNWs, which may advance SiNWs applications and its toxicological study in vitro.

Effect of hENT1 polymorphism G-706C on clinical outcomes of gemcitabine-containing chemotherapy for Chinese non-small-cell lung cancer patients.

AIM: To identify the single-nucleotide polymorphism (SNP) of hENT1 G-706C that is associated with response to gemcitabine-containing chemotherapy, and to determine the prognosis in patients with non-small-cell lung cancer (NSCLC). METHODS: Patients with stage III (A+B) or IV NSCLC were recruited for this study (n=225). Each subject received gemcitabine-containing chemotherapy. The association between human equilibrative nucleoside transporter 1 (hENT1) polymorphism G-706C (rs61758845) and therapeutic effect was evaluated. The SNP hENT1 G-706C was genotyped by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) assays. RESULTS: The polymorphic genotype and the allele frequency of hENT1 G-706C was significantly different between chemotherapy responders and non-responders; to be specific, the response rate of patients carrying an hENT1-706 GG allele was higher than that of patients with a GC or CC genotype. Logistic regression analysis showed that having the GC or CC genotypes was associated with a higher risk of being a non-responder compared with having the GG genotype (OR=2.34, 95% CI: 1.14-4.80; P=0.02). The overall survival in patients with the GG genotype was significantly longer than in those with GC or CC genotype (19.0 versus 15.1 months, P<0.001). The hazard ratio for the (GC+CC) genotype was 1.89 (95% CI: 1.23-2.90) compared with GG carriers (P=0.004). CONCLUSIONS: The hENT1 genetic polymorphism of hENT1 G-706C was associated with response to the gemcitabine-containing chemotherapy and prognosis of NSCLC. Moreover, assaying this SNP in blood cells may represent a valuable biomarker for individualized treatment for NSCLC patients.

Galectin-3 genetic variants are associated with platinum-based chemotherapy response and prognosis in patients with NSCLC.

AIM: To explore the association between the galectin-3 genetic polymorphisms and Platinum-based chemotherapy response as well as the prognosis of non-small cell lung cancer (NSCLC). METHOD: Three hundred twenty patients with Stage III (A+B) or IV NSCLC were enrolled. A Platinum-based chemotherapy was given to each subjects and therapeutic effect was evaluated. The two galectin-3 genetic polymorphisms, namely, galectin-3 +191 A>C and +292 A>C, were genotyped. RESULTS: The polymorphic genotypes and the allele frequency of galectin-3 +191 A>C were not significantly different between responders and non-responders to chemotherapy. For galectin-3 +292 A>C, the AA genotype and A allele distribution were significantly higher in responders than in non-responders. Logistic regression analysis showed CC genotype of galectin-3 +292 presented higher risk of being non-responders compared with the AA genotype (OR = 2.96, 95 % CI: 1.55-5.47; P < 0.001). The overall survival in patients with AA genotype of galectin-3 +292 were significantly longer than in those with CC genotype (25.6 vs. 19.5 months, P = 0.013). The hazard ratio for CC genotype of galectin-3 +292 was 2.43 (95 % CI: 2.03-3.98, compared with AA carriers, P = 0.003). CONCLUSION: The galectin-3 genetic polymorphisms of galectin-3 +292, rather than galectin-3 +191, were associated with the chemotherapy response and prognosis of NSCLC.

[Clinical results of advanced gastric cancer patients treated with oxaliplatin-containing regimen].

BACKGROUND & OBJECTIVE: In vitro clinical research showed oxaliplatin (L-OHP) could obviously suppress the growth of gastric cancer cells in combination with most anti-cancer drugs and help these drugs to kill the tumor cells. This study was designed to evaluate the response and tolerance of oxaliplatin,leucovorin (LV), 5-fluorouracil (5-FU),and etoposide (VP-16) as first-line regimen in advanced gastric cancer, and compare with traditional chemotherapy regimen. METHODS: Forty-eight patients with advanced gastric cancer were divided into treatment group (L-OHP+LV+5-FU+VP-16) and control group(DDP+LV+5-FU+VP-16) using non-randomized method. L-OHP:135 mg/m(2), iv infusion 2 hours, d1(or DDP 20 mg, iv infusion, d1-5); LV:200 mg,iv infusion,d1-5; 5-FU:500 mg/m(2) CI 6 hours on d1-5; VP-16: 100 mg, iv infusion d1-5. Every course lasted 3-4 weeks. RESULTS: The response rate was 64% (16/25) in treatment group (25 cases) and 34.8% (8/23) in control group (23 cases). The statistic difference was seen in two groups (P< 0.05, Chi-square test). The median survival and 1-year survival rate were 11.5 months and 45.6% for treatment group versus 10.5 months and 36.5% for control group. There was no statistical difference in two groups for overall survival (P >0.05, log-rank test). The main side effects were sensory neuritis in treatment group and nausea vomiting in control group. There were significant statistically differences in two groups (P< 0.05, Wilcoxon rank sum test). The other side effects were similar. CONCLUSION: L-OHP + VP-16 + LV + 5-FU regimen is effective and well tolerable for advanced gastric carcinoma.