Clinical and functional characterization of a novel KCNJ11 (c.101G > A, p.R34H) mutation associated with maturity-onset diabetes mellitus of the young type 13.

PURPOSE: This study aimed to describe the clinical features, diagnostic and therapeutic course of a patient with MODY13 caused by KCNJ11 (c.101G > A, p.R34H) and how it contributes to the pathogenesis of MODY13, and to explore new therapeutic targets. METHODS: Whole-exome sequencing was used to screen prediagnosed individuals and family members with clinically suspected KCNJ11 mutations. Real-time fluorescence quantitative PCR, western blotting, thallium flux of potassium channels, glucose-stimulated insulin secretion (GSIS), and immunofluorescence assays were used to analyze the regulation of insulin secretion by the KCNJ11 mutant in MIN6 cells. Daily blood glucose levels were continuously monitored for 14 days in the proband using the ambulatory blood glucose meter (SIBIONICS). RESULTS: Mutation screening of the entire exon of the gene identified a heterozygous KCNJ11 (c.101G > A, p.R34H) mutation in the proband and his mother. Cell-based GSIS assays after transfection of MIN6 using wild-type and mutant plasmids revealed that this mutation impaired insulin secretory function. Furthermore, we found that this impaired secretory function is associated with reduced functional activity of the mutant KCNJ11 protein and reduced expression of the insulin secretion-associated exocytosis proteins STXBP1 and SNAP25. CONCLUSION: For the first time, we revealed the pathogenic mechanism of KCNJ11 (c.101G > A, p.R34H) associated with MODY13. This mutant can cause alterations in KATP channel activity, reduce sensitivity to glucose stimulation, and impair pancreatic ß-cell secretory function by downregulating insulin secretion-associated exocytosis proteins. Therefore, oral sulfonylurea drugs can lower blood glucose levels through pro-insulinotropic effects and are more favorable for patients with this mutation.

Emotion regulation goals and strategies among individuals with varying levels of sensory processing sensitivity: a latent profile analysis.

Background: Emotion regulation (ER) has emerged as a significant factor influencing the well-being of individuals with high sensory processing sensitivity (SPS). However, the interaction between SPS and the underlying mechanisms of ER remains largely unexplored. Objective: This study aimed to (a) identify profiles of SPS and ER competency using a latent profile analysis (LPA), and (b) investigate the ER goals and strategy use among each profile to better understand ER patterns in highly sensitive individuals with lower ER proficiency. Methods: A total of 813 Chinese college students (mean age = 21.53 ± 2.48; 74.41% female) completed the Highly Sensitive Person Scale, 16-item Difficulties in Emotion Regulation Scale, Emotion Regulation Goals Scale, Emotion Regulation Questionnaire, and the rumination subscale from the Cognitive Emotion Regulation Questionnaire. Results: The LPA identified three profiles: "Low SPS - High ER Competency" (41%), "Moderate SPS - ER Competency" (41%), and "High SPS - Low ER Competency" (18%). ER goals varied significantly among these groups. The "High SPS - Low ER Competency" group predominantly pursued contra-hedonic goals and impression management goals, while the "Low SPS - High ER Competency" group focused on pro-hedonic goals. In terms of strategies, the "Low SPS - High ER Competency" group mainly used cognitive reappraisal, the "Moderate SPS - ER Competency" group leaned towards suppression, and the "High SPS - Low ER Competency" group preferred rumination and suppression. Conclusion: These findings indicate that higher SPS combined with lower ER proficiency is linked to an increased pursuit of contra-hedonic goals and impression management goals, and a reliance on response-focused strategies. This pattern offers new insights for developing psychological support strategies for highly sensitive individuals experiencing mental distress.

Assessment of secular trends of three major gynecologic cancers burden and attributable risk factors from 1990 to 2019: an age period cohort analysis.

BACKGROUND: This study aims to assess the long-term trends in the burden of three major gynecologic cancers(GCs) stratified by social-demographic status across the world from 1990 to 2019. To assess the trends of risk factor attributed mortality, and to examine the specific effects of age, period, cohort behind them in different regions. METHODS: We extracted data on the mortality, disability-adjusted life years(DALYs), and age-standardized rates(ASRs) of cervical cancer(CC), uterine cancer(UC), and ovarian cancer(OC) related to risks from 1990 to 2019, as GCs burden measures. Age-period-cohort analysis was used to analyze trends in attributable mortality rates. RESULTS: The number of deaths and DALYs for CC, UC and OC increased since 1990 worldwide, while the ASDRs decreased. Regionally, the ASDR of CC was the highest in low SDI region at 15.05(11.92, 18.46) per 100,000 in 2019, while the ASDRs of UC and OC were highest in high SDI region at 2.52(2.32,2.64), and 5.67(5.16,6.09). The risk of CC death caused by unsafe sex increased with age and then gradually stabilized, with regional differences. The period effect of CC death attributed to smoking showed a downward trend. The cohort effect of UC death attributed to high BMI decreased in each region, especially in the early period in middle, low-middle and low SDI areas. CONCLUSIONS: Global secular trends of attributed mortality for the three GCs and their age, period, and cohort effects may reflect the diagnosis and treatment progress, rapid socioeconomic transitions, concomitant changes in lifestyle and behavioral patterns in different developing regions. Prevention and controllable measures should be carried out according to the epidemic status in different countries, raising awareness of risk factors to reduce future burden.

Metabolic and Bioprocess Engineering of Clostridium tyrobutyricum for Butyl Butyrate Production on Xylose and Shrimp Shell Waste.

Microbial conversion of agri-food waste to valuable compounds offers a sustainable route to develop the bioeconomy and contribute to sustainable biorefinery. Clostridium tyrobutyricum displays a series of native traits suitable for high productivity conversion of agri-food waste, which make it a promising host for the production of various compounds, such as the short-chain fatty acids and their derivative esters products. In this study, a butanol synthetic pathway was constructed in C. tyrobutyricum, and then efficient butyl butyrate production through in situ esterification was achieved by the supplementation of lipase into the fermentation. The butyryl-CoA/acyl-CoA transferase (cat1) was overexpressed to balance the ratio between precursors butyrate and butanol. Then, a suitable fermentation medium for butyl butyrate production was obtained with xylose as the sole carbon source and shrimp shell waste as the sole nitrogen source. Ultimately, 5.9 g/L of butyl butyrate with a selectivity of 100%, and a productivity of 0.03 g/L·h was achieved under xylose and shrimp shell waste with batch fermentation in a 5 L bioreactor. Transcriptome analyses exhibited an increase in the expression of genes related to the xylose metabolism, nitrogen metabolism, and amino acid metabolism and transport, which reveal the mechanism for the synergistic utilization of xylose and shrimp shell waste. This study presents a novel approach for utilizing xylose and shrimp shell waste to produce butyl butyrate by using an anaerobic fermentative platform based on C. tyrobutyricum. This innovative fermentation medium could save the cost of nitrogen sources (~97%) and open up possibilities for converting agri-food waste into other high-value products.

Combination of miR159 Mimics and Irinotecan Utilizing Lipid Nanoparticles for Enhanced Treatment of Colorectal Cancer.

Colorectal cancer (CRC) ranks as the third most prevalent global malignancy, marked by significant metastasis and post-surgical recurrence, posing formidable challenges to treatment efficacy. The integration of oligonucleotides with chemotherapeutic drugs emerges as a promising strategy for synergistic CRC therapy. The nanoformulation, lipid nanoparticle (LNP), presents the capability to achieve co-delivery of oligonucleotides and chemotherapeutic drugs for cancer therapy. In this study, we constructed lipid nanoparticles, termed as LNP-I-V by microfluidics to co-deliver oligonucleotides miR159 mimics (VDX05001SI) and irinotecan (IRT), demonstrating effective treatment of CRC both in vitro and in vivo. The LNP-I-V exhibited a particle size of 118.67 ± 1.27 nm, ensuring excellent stability and targeting delivery to tumor tissues, where it was internalized and escaped from the endosome with a pH-sensitive profile. Ultimately, LNP-I-V significantly inhibited CRC growth, extended the survival of tumor-bearing mice, and displayed favorable safety profiles. Thus, LNP-I-V held promise as an innovative platform to combine gene therapy and chemotherapy for improving CRC treatment.

Efficacy of botanical lozenges in the treatment of chronic pharyngitis: a randomized controlled trial.

Background: In clinical practice, antibiotics and/or inhaled or oral hormone preparations are the first line of treatment for chronic pharyngitis. However, this therapeutic regimen is not satisfactory enough. At present, medicinal plants as dietary supplements or functional foods are widely recognized for the treatment and prevention of different diseases. Purpose: This study aimed to evaluate the efficacy of the botanical lozenge made from several medicinal plant extracts in the treatment of chronic pharyngitis and its effects on patients' illness perception and adherence to treatment. Methods: Patients with chronic pharyngitis were randomly assigned to the experimental group (n = 52) or the control group (n = 51). Patients were given botanical lozenges prepared from the extracts of medicinal plants such as Siraitia grosvenorii (Swingle) C. Jeffrey ex A.M.Lu and Zhi Y. Zhang [Cucurbitaceae; Siraitiae fructus], Lonicera japonica Thunb [Caprifoliaceae; Lonicerae japonicae flos], Platycodon grandiflorus (Jacq.) A. DC [Campanulaceae; Platycodon radix], and Glycyrrhiza uralensis Fisch. ex DC [Fabaceae; Glycyrrhizae radix et rhizoma] or placebos made of starch for 15 days. The improvement of pharyngeal symptoms and signs, illness perception, and adherence to treatment were evaluated at the end of the intervention. Results: The total score of pharyngeal symptoms of patients in the experimental group (3.33 ± 2.33) was significantly lower than that in the control group (5.20 ± 2.93) (p < 0.01). In comparison to the control group (3.43 ± 1.43), the total pharyngeal signs score of patients in the experimental group (2.69 ± 1.59) was considerably lower (p < 0.01). The improvement rates of pharyngeal itching, dry throat, pharyngeal foreign body sensation, aggravation due to excessive speaking, and congestion of pharyngeal mucosa in the experimental group were 73.81%, 67.50%, 67.57%, 65.22% and 44%, respectively, which were significantly higher than those in the control group (p < 0.05). In addition, patients taking botanical lozenges had better illness perception and adherence to treatment than those taking placebos (p < 0.05). Patients with low adherence to treatment showed less personal control, concerns, and understanding of chronic pharyngitis (p < 0.05). Conclusion: Botanical lozenges not only aided patients in recovering from chronic pharyngitis but also improved their positive perceptions of the disease, which helped them adhere to their treatment regimen. Clinical Trial Registration: [https://www.chictr.org.cn/], identifier [ChiCTR2200062139].

Photoisomerization and thermal reconstruction induced supramolecular chirality inversion in nanofiber determined by minority isomer.

Here, amphiphile GCH based on glutamide-cyanostilbene is designed and synthesized, it is found that it can assembly in acetonitrile, and shows circular dichroism signals. After Z-E isomerizaition by UV irradiation, the CD signal of the assembly can be inverted. Unexpectedly, after another heating and cooling process, the circular dichroism signals can be totally inverted even though the E-isomers are in minority. Finally, the molecular dynamics (MD) simulations deeply elucidate the supramolecuar chirality inversion mechanism. This work brings some new insights into the control of chirality inversion, which may provide a perspective for the smart chiroptical materials construction.

Bearing fault detection by using graph autoencoder and ensemble learning.

The research and application of bearing fault diagnosis techniques are crucial for enhancing equipment reliability, extending bearing lifespan, and reducing maintenance expenses. Nevertheless, most existing methods encounter challenges in discriminating between signals from machines operating under normal and faulty conditions, leading to unstable detection results. To tackle this issue, the present study proposes a novel approach for bearing fault detection based on graph neural networks and ensemble learning. Our key contribution is a novel stochasticity-based compositional method that transforms Euclidean-structured data into a graph format for processing by graph neural networks, with feature fusion and a newly proposed ensemble learning strategy for outlier detection specifically designed for bearing fault diagnosis. This approach marks a significant advancement in accurately identifying bearing faults, highlighting our study's pivotal role in enhancing diagnostic methodologies.

The Effect of Pushing Rate on Foam Stability in the Tessari Method.

BACKGROUND: The Tessari method is commonly used in sclerotherapy for producing foam, involving 2 syringes pushed back and forth 20 times with the use of a 3-way connector. Many factors affect the foam stability which is crucial for clinical efficacy. OBJECTIVE: This study aimed to identify the optimal pushing rate which may impact the foam stability. MATERIALS AND METHODS: Polidocanol (POL) solution (1% and 3%) was used to make sclerosant foam via the Tessari method, with a total of 20 pushes performed at different time durations: 10, 15, 20, 25, 30, 35, and 40 seconds. The foam stability was recorded using foam half-life time (FHT), and the pushing pressure to the syringe was recorded using a self-made electric device. Both FHT and the pressure among different groups were compared respectively. RESULTS: The FHT was decreased as pushing duration exceeding 20 seconds in POL 1% and 15 seconds in POL 3%. Both the highest FHT and pressure point were located in the 10-second group. CONCLUSION: It is recommended to complete 20 back-and-forth passages within 10 seconds to create stable foam.

Reminiscence therapy relieves anxiety, depression and boosts spiritual well-being in both stroke patients and their spouse caregivers: a randomized, controlled study : Reminiscence therapy in stroke patients/caregivers.

AIMS: Reminiscence therapy (RT) is a common nursing care program to ameliorate psychological disorders, while its application in stroke patients and their spouse caregivers is rare. Thus, this randomized, controlled study intended to investigate the influence of RT on anxiety, depression, and spiritual well-being in these individuals. METHODS: Totally, 162 couples of stroke patients and their spouse caregivers were randomly assigned to receive RT (N = 81) and control care (CC) (N = 81) by pairs 4 times per month for 6 months. Hospital Anxiety and Depression Scale for anxiety (HADS-A) and depression (HADS-D), Functional Assessment of Chronic Illness Therapy - Spiritual Well-being scale (FACIT-Sp) were evaluated at month (M)0, M1, M3, and M6. RESULTS: In stroke patients, RT reduced HADS-A score at M3 (P = 0.043) and M6 (P = 0.020), and HADS-D score at M6 (P = 0.034), while increased FACIT-Sp score at M1 (P = 0.023), M3 (P = 0.010), and M6 (P = 0.004) compared to CC. Meanwhile, RT induced greater ameliorations in HADS-A (P = 0.049) and FACIT-Sp (P < 0.001) scores from M0 to M6 versus CC, but less in HADS-D score (P = 0.076). In the aspect of spouse caregivers, RT deceased HADS-A score at M1 (P = 0.042), M3 (P = 0.001), and M6 (P < 0.001), lowered HADS-D score at M3 (P = 0.015) and M6 (P = 0.001), but elevated FACIT-Sp score at M1 (P = 0.042), M3 (P < 0.001), and M6 (P < 0.001) compared to CC. Noteworthily, RT facilitated the improvements of HADS-A (P < 0.001), HADS-D (P = 0.010), and FACIT-Sp (P < 0.001) scores from M0 to M6 versus CC. CONCLUSIONS: RT relieves anxiety, depression and boosts spiritual well-being in both stroke patients and their spouse caregivers.

Associations of Various Physical Activities with Mortality and Life Expectancy are Mediated by Telomere Length.

OBJECTIVES: Physical activity (PA) and telomeres both contribute to healthy aging and longevity. To investigate the optimal dosage of various PA for longevity and the role of telomere length in PA and mortality. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: A total of 333,865 adults (mean age of 56 years) from the UK Biobank were analyzed. METHODS: Walking, moderate PA (MPA), and vigorous PA (VPA) were self-reported via questionnaire, and leukocyte telomere length (LTL) was measured. Cox proportional hazards regression was used to predict all-cause mortality risk. A flexible parametric Royston-Parmar survival model was used to estimate life expectancy. RESULTS: During a median follow-up of 13.8 years, 19,789 deaths were recorded. Compared with the no-walking group, 90 to 720 minutes/week of walking was similarly associated with 27% to 31% of lower mortality and about 6 years of additional life expectancy. We observed nearly major benefits for mortality and life expectancy among those meeting the PA guidelines [151-300 minutes/wk for MPA: hazard ratio (HR) 0.80, 95% CI 0.75-0.85, 3.40-3.42 additional life years; 76-150 minutes/wk for VPA: HR 0.78, 95% CI 0.75-0.82, 2.61 years (2.33-2.89)] vs the no-PA group. Similar benefits were also observed at 76-150 and 301-375 minutes/wk of MPA (18%-19% lower mortality, 3.20-3.42 gained years) or 151-300 minutes/wk of VPA (20%-26% lower mortality, 2.41-2.61 gained years). The associations between MPA, VPA, and mortality risk were slightly mediated by LTL (≈1% mediation proportion, both P < .001). CONCLUSIONS AND IMPLICATIONS: Our study suggests a more flexible range of PA than the current PA guidelines, which could gain similar benefits and is easier to achieve: 90 to 720 minutes/wk of walking, 75 to 375 minutes/wk of MPA, and 75 to 300 minutes/wk of VPA. Telomeres might be a potential mechanism by which PA promotes longevity.

The Stability of Physician-Compounded Foam is Influenced by the Angle of Connector.

BACKGROUND: Foam sclerotherapy is an effective treatment for varicose veins and venous malformations, with its efficacy influenced by foam stability. The methods for preparing physician-compounded foam (PCF) are the double syringe system (DSS) and Tessari method. Few studies have been performed to compare the PCF stability produced by the 2 methods and their mechanisms. We aim to compare the stability of PCF produced by 2 two methods in the same connector and explore the reasons for the difference. METHODS: Foam was generated by the 2 methods under different circumstances. In the Tessari method, 2 syringes were connected at right angles (90°) by a 3-way tap. In the DSS method, 2 syringes were connected by the same 3-way tap in a straight line (180°). The stability and uniformity of foam produced by the 2 methods were compared using foam half-time and optical microscopy, respectively. Assuming that the difference in foam stability between the 2 methods was related to the angles of a connector, we compared the foam stability when 2 syringes were connected with a plastic connector bent to different angles. RESULTS: The DSS method could produce more uniform foam with longer foam half-time than the Tessari method, which was related to the angle of the connector. CONCLUSIONS: The stability of PCF is influenced by the angle of the connector.

Identification of the consistently differential expressed hub mRNAs and proteins in lung adenocarcinoma and construction of the prognostic signature: a multidimensional analysis.

BACKGROUND: This study aimed to elucidate the consistency of differentially expressed hub mRNAs and proteins in lung adenocarcinoma (LUAD) across populations and to construct a comprehensive LUAD prognostic signature. METHODS: The transcriptomic and proteomics data from different populations were standardized and analyzed using the same criteria to identify the consistently differential expressed mRNAs and proteins across genders and races. We then integrated prognosis-related mRNAs with clinical, pathological, and EGFR (epidermal growth factor receptor) mutation data to construct a survival model, subsequently validating it across populations. Through plasma proteomics, plasma proteins that consistently differential expressed with LUAD tissues were screened and validated, with their associations discerned by measuring expressions in tumor tissues and tumor vascular normalization. RESULTS: The consistency rate of differentially expressed mRNAs and proteins was ~20-40%, with ethnic factors leading to about 40-60% consistency of differentially expressed mRNA or protein across populations. The survival model based on the identified eight hub mRNAs as well as stage, smoking status, and EGFR mutations, demonstrated good prognostic prediction capabilities in both Western and East Asian populations, with a higher number of unfavorable variables indicating poorer LUAD prognosis. Notably, GPI expression in tumor tissues was inversely correlated with vascular normalization and positively correlated with plasma GPI expression. CONCLUSION: Our study underscores the significance of integrating transcriptomics and proteomics data, emphasizing the need to account for genetic diversity among ethnic groups. The developed survival model may offer a holistic perspective on LUAD progression, enhancing prognosis and therapeutic strategies.

The Protective Effect of Chronic Intermittent Hypobaric Hypoxia on Preventing the Destruction of CD34+ Haematopoietic Stem Cells in Aplastic Anaemia by Modulating the Th1/Th2 Balance.

Aplastic anaemia (AA) is a haematopoietic disorder caused by immune-mediated attack on haematopoietic stem cells (HSCs). Stem cell transplantation and immunosuppressive therapy remain the major treatment choice for AA patients but have limited benefits and undesired side effects. The aim of our study was to clarify the protective role of immunity of chronic intermittent hypobaric hypoxia (CIHH) and the underlying mechanism in AA. Our integrative analysis demonstrated that CIHH pre-treatment significantly improved haematopoiesis and survival in an AA rat model. We further confirmed that CIHH pre-treatment was closely associated with the Th1/Th2 balance and a large number of negative regulatory haematopoietic factors, such as TNF-α and IFN-γ, produced by hyperactive Th1 lymphocytes released in AA rats, which induced the death program in a large number of CD34+ HSCs by activating the Fas/FasL apoptosis pathway, while CIHH pre-treatment effectively downregulated the expression of TNF-α and IFN-γ, resulting in a reduction in Fas antigen expression in CD34+ HSCs. In summary, this study provides evidence that CIHH has good protective effect against AA by modulating immune balance in Th1/Th2 cells and may provide a new therapeutic strategy.

The potential health effects associated with electronic-cigarette.

A good old gateway theory that electronic-cigarettes (e-cigarettes) are widely recognized as safer tobacco substitutes. In actuality, demographics also show that vaping cannibalizes smoking, the best explanation of the data is the "common liability". However, the utilization of e-cigarette products remains a controversial topic at present. Currently, there has been a widespread and substantial growth in e-cigarette use worldwide owing to their endless new flavors and customizable characteristics. Furthermore, e-cigarette has grown widespread among smokers as well as non-smokers, including adolescents and young adults. And some studies have shown that e-cigarette users are at greater risk to start using combustible cigarettes while e-cigarettes use was also observed the potential benefits to people who want to quit smoking or not. Although it is true that e-cigarettes generally contain fewer toxic substances than combustible cigarettes, this does not mean that the chemical composition in e-cigarettes aerosols poses absolutely no risks. While concerns about toxic substances in e-cigarettes and their widespread use in the population are reasonable, it is also crucial to consider that e-cigarettes have been associated with the potential for promoting smoking cessation and the clinically relevant improvements in users with smoking-related pathologies. Meanwhile, there is still short of understanding of the health impacts associated with e-cigarette use. Therefore, in this review, we discussed the health impacts of e-cigarette exposure on oral, nasal, pulmonary, cardiovascular systems and brain. We aspire for this review to change people's previous perceptions of e-cigarettes and provide them with a more balanced perspective. Additionally, we suggest appropriate adjustments on regulation and policy for e-cigarette to gain greater public health benefits.

Characteristics of vaginal microbiota in various cervical intraepithelial neoplasia: a cross-sectional study.

BACKGROUND: Precancerous lesions of cervical cancer exhibit characteristics indicative of natural progression. To prevent overtreatment of patients whose cervical intraepithelial neoplasia (CIN) in regression and to predict the onset of invasive cervical cancer at an early stage, we've identified the vaginal microbiome as a potential key factor, which is associated with both HPV infection and the various cervical intraepithelial neoplasia. This study aims to investigate the microbiome characteristics of patients with various cervical intraepithelial neoplasia. METHODS: Utilizing high-throughput 16S ribosomal RNA (16S rRNA) sequencing technology, a description of the characteristics and community composition of Vaginal Microbiota (VMB) was conducted among 692 Chinese women infected with the High-risk Human Papillomavirus (HR-HPV). RESULTS: As the grade of the lesions increased, the proportions of Lactobacillus and Pseudomonas demonstrated a significant declining trend, while the proportions of Gardnerella, Dialister, and Prevotella significantly increased. The diversity of the VMB was more significant in high-grade CIN. Furthermore, KEGG pathway enrichment analysis indicates that high-grade cervical intraepithelial neoplasia can inhibit various pathways, including those of phosphotransferase system, transcription factors, Fructose and mannose metabolism, amino sugar and nucleotide sugar metabolism, and galactose metabolism, which may contribute to the development of early cervical cancer symptoms. CONCLUSION: Patients with CIN exhibit a distinct vaginal microbial profile characterized by a decrease in Lactobacillus and Pseudomonas, and an increase in Gardnerella, Prevotella, and Dialister. The proliferation and diminution of these two types of microbial communities are interrelated, suggesting a mutual restraint and balance among them. Disruption of this regulatory balance could potentially lead to the onset of cervical lesions and carcinogenesis. Retrospectively registered: This study was approved by the Ethics Committee of the Beijing Chaoyang Hospital affiliated with the Capital Medical University (NO.2023-S-415).

Effect of Anisotropic Structural Depth on Orientation and Differentiation Behavior of Skeletal Muscle Cells.

Extensive research has been conducted to examine how substrate topological factors are involved in modulating the cell behavior. Among numerous topological factors, the vital influence of the touchable depth of substrates on cell behaviors has already been extensively characterized, but the response of cells to the topological structure at untouchable depth is still elusive. Herein, the influences of substrate depth on myoblast behaviors are systematically investigated using substrates with depths ranging from touchable depth (microgrooved) to untouchable depth (microbridges). The results show that an increase in microgroove depth is accompanied by an inhibited cell spreading, an enhanced elongation, and a more obvious orientation along microgrooves. Interestingly, myoblasts located on microbridges show a more pronounced elongation with increasing culture time but a position-dependent orientation. Myoblasts on the center and parallel boundary of microbridges orient along the bridges, while myoblasts on the vertical boundary align perpendicular to the microbridges. Moreover, the differentiation results of the myoblasts indicate that the differentiated myotubes can maintain this position-dependent orientation. The simulation of the stress field in cell monolayers suggests that the position-dependent orientation is caused by the comprehensive response of myoblasts to the substrate discontinuity and substrate depth. These findings provide valuable insights into the mechanism of cell depth sensing and could inform the design of tissue engineering scaffolds for skeletal muscle and biohybrid actuation.

STING in tumors: a focus on non-innate immune pathways.

Cyclic GMP-AMP synthase (cGAS) and downstream stimulator of interferon genes (STING) are involved in mediating innate immunity by promoting the release of interferon and other inflammatory factors. Mitochondrial DNA (mtDNA) with a double-stranded structure has greater efficiency and sensitivity in being detected by DNA sensors and thus has an important role in the activation of the cGAS-STING pathway. Many previous findings suggest that the cGAS-STING pathway-mediated innate immune regulation is the most important aspect affecting tumor survival, not only in its anti-tumor role but also in shaping the immunosuppressive tumor microenvironment (TME) through a variety of pathways. However, recent studies have shown that STING regulation of non-immune pathways is equally profound and also involved in tumor cell progression. In this paper, we will focus on the non-innate immune system pathways, in which the cGAS-STING pathway also plays an important role in cancer.