Liver Extracellular Vesicles and Particles Enriched ß-Sitosterol Effectively Promote Liver Regeneration in Mice.

Background: The liver's regenerative capacity allows it to repair itself after injury. Extracellular vesicles and particles (EVPs) in the liver's interstitial space are crucial for signal transduction, metabolism, and immune regulation. Understanding the role and mechanism of liver-derived EVPs in regeneration is significant, particularly after partial hepatectomy, where the mechanisms remain unclear. Methods: A 70% hepatectomy model was established in mice, and EVPs were isolated and characterized using electron microscopy, nanocharacterization, and Western blot analysis. Combined metabolomic and transcriptomic analyses revealed ß-sitosterol enrichment in EVPs and activation of the Hedgehog signaling pathway during regeneration. The role of ß-sitosterol in EVPs on the Hedgehog pathway and its targets were identified using qRT-PCR, Western blot analysis. The regulation of carnitine synthesis by this pathway was determined using a dual luciferase assay. The effect of a ß-sitosterol diet on liver regeneration was verified in mice. Results: After 70% hepatectomy, the liver successfully regenerated without liver failure or death. At 24 hours post-surgery, tissue staining showed transient regeneration-associated steatosis (TRAS), with increased Ki67 positivity at 48 hours. EVPs displayed a spherical lipid bilayer structure with particle sizes of 70-130 nm. CD9, CD63, and CD81 in liver-derived EVPs were confirmed. Transcriptomic and metabolomic analyses showed EVPs supplementation significantly promoted carnitine synthesis and fatty acid oxidation. Tissue staining confirmed accelerated TRAS resolution and enhanced liver regeneration with EVP supplementation. Mass spectrometry identified ß-sitosterol in EVPs, which binds to Smo protein, activating the Hedgehog pathway. This led to the nuclear transport of Gli3, stimulating Setd5 transcription and inducing carnitine synthesis, thereby accelerating fatty acid oxidation. Mice with increased ß-sitosterol intake showed faster TRAS resolution and liver regeneration compared to controls. Conclusion: Liver-derived EVPs promote regeneration after partial hepatectomy. ß-sitosterol from EVPs accelerates fatty acid oxidation and promotes liver regeneration by activating Hedgehog signaling pathway.

QACDes: QoS-aware context-sensitive design of cyber-physical systems.

There is a lot of confusion and ambiguity regarding the quantification of the Quality of Service (QoS) of a system, especially for cyber-physical systems (CPS) involved in automating or controlling the operations in built environments and critical urban infrastructures, such as office buildings, factories, transportation systems, smart cities, etc. In these cases, the QoS, as experienced by human users, depends on the context in which they (i.e., humans) interact with these systems. Traditionally, the QoS of a CPS has been defined in terms of absolute metrics. Such measures are unable to take into account the variations in performance due to contextual factors arising out of different kinds of human interactions. Further, the QoS of a CPS has typically been evaluated by comparing the performance of the actual, fully realized system with the given QoS constraints only after the actual system has been completely developed. In the case of faults in the design exposed by observed deviations from the QoS constraints due to unpredicted variations in the contextual factors, the system needs to be re-designed and re-developed from scratch. Due to the above-mentioned reason, the validation approach associated with the traditional QoS makes the design of CPS systems prohibitively expensive, impractical, as well as infeasible in numerous application areas, such as civil and engineering works, since it may not be possible to modify the system once developed beyond a certain extent. To that end, we propose a context-aware definition of QoS of a CPS which facilitates the design of robust systems as elaborated below. In this paper, we define QoS as a function of contextual factors. A CPS designed according to our QoS specifications would always satisfy the QoS irrespective of any possible changes in contextual factors resulting from many different human interactions that may occur during operation of the system. We also present QACDes - a novel framework that provides a formal mechanism for validating the design of a CPS with respect to the specified QoS constraints at the design phase as well as after the realization of the actual system. QACDes can validate any given CPS, irrespective of its application domain, against a QoS guarantee: (A) as early as even before the design phase by comparing the proposed model with a baseline model, or (B) after the realization of the actual system based on logs collected from running the actual system. We consider a lighting control system that manages the light switches - switching it on/off depending on contextual factors, such as the presence of occupants and time of the day. Using the lighting control system in a building as a use case, we analyze and demonstrate the effectiveness of our QoS definition as well as the QACDes framework against the performance metric measured in an actual fully-realized CPS.

Weight-adjusted waist index as a practical predictor for diabetes, cardiovascular disease, and non-accidental mortality risk.

BACKGROUND AND AIM: Identifying a more suitable marker among various measures of adiposity, demonstrating strong associations and predictive ability for clinical use, remains a topic of debate. Weight-adjusted waist index (WWI) has been proposed as a novel index of adiposity, yet its exploration is limited, especially in Chinese populations. This study seeks to examine the associations between body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHTR), weight-adjusted waist index (WWI), waist circumference divided by body mass to the power of 0.333 (WC/M0.333), visceral adiposity index (VAI), lipid accumulation product (LAP), and the incidence of diabetes, cardiovascular disease, and non-accidental mortality in Chinese populations. Furthermore, our goal is to compare the respective predictive values of these measures for these health outcomes. METHODS AND RESULTS: This prospective cohort study included 21,750 subjects with a 9-year follow-up period. Cox proportional hazard models were used to investigate the relationship between eight anthropometric indexes and the incidence of diabetes, cardiovascular disease, and non-accidental mortality. The predictive value of these eight indexes was compared using the area under the curve metric. Significant positive associations were found between WWI and the risk of diabetes. Using the first quartile (Q1) of WWI as the reference group, hazard ratios with 95% confidence intervals for the risk of diabetes were 1.58 (0.98-2.55) for Q2, 2.18 (1.34-3.35) for Q3, and 2.27 (1.41-3.67) for Q4. Significant associations were observed with the highest quartile of WWI for the risk of cardiovascular disease [Q2: HR 1.45 (95% CI 1.06-1.98); Q3: 1.33 (0.97-1.83); Q4: 1.55 (1.13-2.14)] and risk of non-accidental mortality [Q2: 0.94 (0.80-1.11); Q3: 1.24 (1.04-1.48); Q4: 1.44 (1.16-1.79)]. Receiver operating characteristic analysis revealed that WWI exhibited superior discrimination and accuracy in predicting cardiovascular disease and non-accidental mortality compared to other adiposity indexes (BMI, WC, WHR, WHTR, WC/M0.333, VAI, and LAP). CONCLUSION: WWI exhibited the most robust and consistent association with the incidence of cardiovascular disease and non-accidental mortality. Given its simplicity and widespread use, WWI emerges as a novel and practical predictor of diabetes, cardiovascular disease, and non-accidental mortality among the eight adiposity indexes investigated in this study.

The peptide-based bispecific CAR T cells target EGFR and tumor stroma for effective cancer therapy.

BACKGROUND AND PURPOSE: The efficacy of chimeric antigen receptor (CAR)-T cell for solid tumors is limited partially because of the lack of tumor-specific antigens and off-target effects. Low molecular weight peptides allowed CAR T cell to display several antigen receptors to reduce off-target effects. Here, we develop a peptide-based bispecific CAR for EGFR and tumor stroma, which are expressed in a variety of tumor types. EXPERIMENTAL APPROACH AND KEY RESULTS: The peptide-based CAR T cells show excellent proliferation, cytotoxicity activity and are only activated by tumor cells overexpressing EGFR instead of normal cells with low EGFR expressing. In mouse xenograft models, the peptide bispecific CAR T cells can be delivered into the inner of tumor masses and thus are effective in inhibiting tumor growth. Meanwhile, they show strong expansion capacity and the property of maintaining long-term function in vivo. During treatment, no off-tumor toxicity is observed on healthy organs expressing lower levels of EGFR. CONCLUSIONS & IMPLICATIONS: Our findings demonstrate that peptide-based bispecific CAR T holds great potential in solid tumor therapy due to an excellent targeting ability towards tumors and tumor microenvironment.

Glucocorticoids in lung cancer: Navigating the balance between immunosuppression and therapeutic efficacy.

Glucocorticoids (GCs), a class of hormones secreted by the adrenal glands, are released into the bloodstream to maintain homeostasis and modulate responses to various stressors. These hormones function by binding to the widely expressed GC receptor (GR), thereby regulating a wide range of pathophysiological processes, especially in metabolism and immunity. The role of GCs in the tumor immune microenvironment (TIME) of lung cancer (LC) has been a focal point of research. As immunosuppressive agents, GCs exert a crucial impact on the occurrence, progression, and treatment of LC. In the TIME of LC, GCs act as a constantly swinging pendulum, simultaneously offering tumor-suppressive properties while diminishing the efficacy of immune-based therapies. The present study reviews the role and mechanisms of GCs in the TIME of LC.

Stretchable Iontronic Tactile Sensing Fabric.

The iontronic tactile sensing modality has garnered significant attention due to its exceptional sensitivity, immunity to noise, and versatility in materials. Recently, various formats of iontronic tactile sensors have been developed, including droplets, polymer films, paper, ionic gels, and fabrics. However, the stretchability of the current iontronic pressure sensing fabric is inadequate, hindered by the limited stretchiness of the ionic functional fabric. Incorporating a stretchable tactile sensing implement could enhance the wear comfortability by preventing relative movement and ensuring intimate contact between the sensor and the skin. The research focuses on the development of a stretchable iontronic pressure sensing (SIPS) fabric for monitoring diverse aspects of body health and movement in wearable applications. The tactile sensing structure is generated at the iontronic interface between highly stretchable ionic and conductive fabrics. In particular, the ionic fabric is prepared by coating a layer of polyurethane/ionic liquid gel onto a Spandex fabric. To showcase its remarkable sensitivity, stretchability, and ability to detect diverse body information, several application scenarios have been demonstrated including an elastic wristband for precise pulse wave detection, a flexible belt with multitactile sensing channels for respiration and motion tracking purposes, and a stretchable fabric cuff equipped with a high-resolution sensing array comprising 32 × 32 units for accurate gesture recognition.

Single cell transcriptomic analysis reveals tumor immune infiltration by NK cells gene signature in lung adenocarcinoma.

Background: Natural Killer (NK) cells are vital components of the innate immune system, crucial for combating infections and tumor growth, making them pivotal in cancer prognosis and immunotherapy. We sought to understand the diverse characteristics of NK cells within lung adenocarcinoma (LUAD) by conducting single-cell RNA sequencing analyses. Methods: Using the scRNA-seq dataset for multiple primary lung cancers (MPLCs), we examined two major NK cell groups, NK1 and NK2, comparing the expression profiles of 422 differentially expressed NK signature genes. We identified eight genes (SPON2, PLEKHG3, CAMK2N1, RAB27B, CTBP2, EFHD2, GOLM1, and PLOD1) that distinguish NK1 from NK2 cells. A prognostic signature, the NK gene signature (NKGS) score, was established through LASSO Cox regression. High NKGS scores were linked to poorer overall survival in TCGA-LUAD patients and consistently validated in other datasets (GSE31210 and GSE14814). Results: Functional analysis revealed an enrichment of genes related to the TGF-ß signaling pathway in the high NKGS score group. Moreover, a high NKGS score correlated with an immunosuppressive tumor microenvironment (TME) driven by immune evasion mechanisms. We also observed reduced T-cell receptor (TCR) repertoire diversity in the high-risk NKGS group, indicating a negative association between inflammation and risk score. Conclusion: This study introduced the innovative NKGS score, differentiating NK1 from NK2 cells. High NKGS scores were associated with the TGF-ß pathway and provided insights into LUAD prognosis and immune activities.

The risk of asthma in singletons conceived by ART: a retrospective cohort study.

STUDY QUESTION: Do singleton children conceived by ART have a higher asthma risk than naturally conceived (NC) singletons? SUMMARY ANSWER: The asthma risk was similar for ART-conceived singletons and NC singletons, and there were no clear differences between the various types of ART. WHAT IS KNOWN ALREADY: Whether ART increases asthma risk in offspring is questionable. The evidence is inconsistent and limited by ethnicity, geographic distribution, inadequate confounder adjustment, unsatisfactory control groups, and specific methods of ART. Furthermore, the mediating effects of obstetric and neonatal outcomes on the association between ART and asthma remain unclear. STUDY DESIGN SIZE DURATION: This observational, single-centre study was conducted at a reproductive centre of an affiliated university hospital between September 2009 and April 2023. A total of 3227 singletons aged 3-6 years conceived by IVF versus ICSI or fresh versus frozen embryo transfer were retrospectively enrolled, and a total of 1206 NC singletons of the same age were subsequently recruited. PARTICIPANTS/MATERIALS SETTING METHODS: Asthma was defined as a self-reported physician diagnosis or wheezing in the past 12 months. We performed multivariable logistic regression analyses to examine associations between asthma in offspring and ART use, adjusting for parental characteristics (age, education level, occupation type, BMI, asthma), smoking exposure, residence type, child sex, child age, and year of follow-up. Mediating effects were explored using longitudinal mediation structural equation modelling. MAIN RESULTS AND THE ROLE OF CHANCE: Asthma was reported for 51 (4.2%) of the 1206 NC singletons (median [interquartile range] age 5 [4-5] years; 48.1% females) and 169 (5.2%) of the 3227 ART-conceived singletons (5 [5-5] years; 47.6% females). We found that risks of childhood asthma in singletons conceived by ART were, overall, similar to those of NC singletons before (odds ratio [OR], 1.25 [95% CI, 0.92-1.74]; P = 0.170) and after adjustment (adjusted OR [aOR], 0.66 [95% CI, 0.44-1.03]; P = 0.126). The results were similar in multiple sensitivity analyses, and there were no clear differences in asthma risks according to the method of ART. Mediation analysis revealed a significant positive indirect effect of neonatal intensive care unit (NICU) admission (standard path coefficient, b = 0.025, P < 0.05) and a negative indirect effect of breastfeeding (b = -0.012, P < 0.05) on the association between ART and asthma in singleton offspring. LIMITATIONS REASONS FOR CAUTION: This study is limited to singletons only and cannot be generalized. The study is also limited by its retrospective observational single-centre nature and sample size. Mediation analyses were exploratory. Therefore, the findings need to be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: These findings can help infertile couples undergoing ART be reassured about the risk of childhood asthma in singleton offspring. Breastfeeding is recommended as a potentially feasible intervention to reduce the asthma risks in ART-conceived children who are at increased potential risk of asthma, such as those with NICU admissions. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Key Research and Development Program of Zhejiang Province (2021C03100), the National Key Research and Development Program of China (2021YFC2700603), and the Program for Key Subjects of Zhejiang Province in Medicine and Hygiene to Y. Z., the Zhejiang Province Natural Science Foundation (No. LQ22H040006) and the National Natural Science Foundation of China (No.82101759) to M.T., and the National Natural Science Foundation of China (No. 82201860) to J.Y. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: ChiCTR2300069906.

Particulate Matter (PM) and Parent, Nitrated and Oxygenated Polycyclic Aromatic Hydrocarbon (PAH) Emissions of Emulsified Heavy Fuel Oil in Marine Low-Speed Main Engine.

To understand the influences of emulsified fuel on ship exhaust emissions more comprehensively, the emissions of particulate matter (PM), nitrated, oxygenated and parent polycyclic aromatic hydrocarbons (PAHs) were studied on a ship main engine burning emulsified heavy fuel oil (EHFO) and heavy fuel oil (HFO) as a reference. The results demonstrate that EHFO (emulsified heavy fuel oil) exhibits notable abilities to significantly reduce emissions of particulate matter (PM) and low molecular weight PAHs (polycyclic aromatic hydrocarbons) in the gas phase, particularly showcasing maximum reductions of 13.99% and 40.5%, respectively. Nevertheless, burning EHFO could increase the emission of high molecular weight PAHs in fine particles and pose a consequent higher carcinogenic risk for individual particles. The total average (gaseous plus particulate) ΣBEQ of EHFO exhausts (41.5 µg/m3) was generally higher than that of HFO exhausts (18.7 µg/m3). Additionally, the combustion of EHFO (extra-heavy fuel oil) can significantly alter the emission quantity, composition, and particle-size distribution of PAH derivatives. These changes may be linked to molecular structures, such as zigzag configurations in C=O bonds. Our findings may favor the comprehensive environmental assessments on the onboard application of EHFO.

The impact and inflammatory characteristics of SARS-CoV-2 infection during ovarian stimulation on the outcomes of assisted reproductive treatment.

Introduction: Despite the global prevalence of coronavirus disease 2019 (COVID-19), limited research has been conducted on the effects of SARS-CoV-2 infection on human reproduction. The aims of this study were to investigate the impact of SARS-CoV-2 infection during controlled ovarian stimulation (COS) on the outcomes of assisted reproductive treatment (ART) and the cytokine status of patients. Methods: This retrospective cohort study included 202 couples who received ART treatment, 101 couples infected with SARS-CoV-2 during COS and 101 matched uninfected couples. The parameters of ovarian stimulation and pregnancy outcomes were compared between the two groups. The All-Human Inflammation Array Q3 kit was utilized to measure cytokine levels in both blood and follicular fluid. Results: No difference was found in the number of good-quality embryos (3.3 ± 3.1 vs. 3.0 ± 2.2, P = 0.553) between the infected and uninfected groups. Among couples who received fresh embryo transfers, no difference was observed in clinical pregnancy rate (53.3% vs. 51.5%, P = 0.907). The rates of fertilization, implantation, miscarriage, ectopic pregnancy and live birth were also comparable between the two groups. After adjustments were made for confounders, regression models indicated that the quality of embryos (B = 0.16, P = 0.605) and clinical pregnancy rate (P = 0.206) remained unaffected by SARS-CoV-2 infection. The serum levels of MCP-1, TIMP-1, I-309, TNF-RI and TNF-RII were increased, while that of eotaxin-2 was decreased in COVID-19 patients. No significant difference was found in the levels of cytokines in follicular fluid between the two groups. Conclusion: Asymptomatic or mild COVID-19 during COS had no adverse effects on ART outcomes. Although mild inflammation was present in the serum, it was not detected in the follicular fluid of these patients. The subsequent immune response needs further investigation.

Interleukin-1 increases SERPINE1 expression in human granulosa-lutein cell via P50/P52 signaling pathways.

It has been reported that immune factors are associated with the occurrence of polycystic ovary syndrome (PCOS). Interleukin-1 (IL-1) is a member of the interleukin family that widely participates in the regulation of the inflammatory response in the immune system. In addition, it has been reported that aberrant IL-1 accumulation in serum is associated with the occurrence of PCOS. However, little is known about how IL-1 participates in the pathogenesis of PCOS. In the present study, we demonstrated that the immune microenvironment was altered in follicular fluid from PCOS patients and that the expression levels of two IL-1 cytokines, IL-1α and IL-1ß were increased. Transcriptome analysis revealed that IL-1α and IL-1ß treatment induced primary human granulosa-lutein (hGL) cell inflammatory response and increased the expression of serpin family E member 1 (SERPINE1). Mechanistically, we demonstrated that IL-1α and IL-1ß upregulated SERPINE1 expression through IL-1R1-mediated activation of downstream P50 and P52 signaling pathways in human granulosa cells. Our study highlighted the role of immune state changes in the occurrence of PCOS and provided new insight into the treatment of patients with IL-1-induced ovarian function disorders.

MHC-Fine: Fine-tuned AlphaFold for precise MHC-peptide complex prediction.

The precise prediction of major histocompatibility complex (MHC)-peptide complex structures is pivotal for understanding cellular immune responses and advancing vaccine design. In this study, we enhanced AlphaFold's capabilities by fine-tuning it with a specialized dataset consisting of exclusively high-resolution class I MHC-peptide crystal structures. This tailored approach aimed to address the generalist nature of AlphaFold's original training, which, while broad-ranging, lacked the granularity necessary for the high-precision demands of class I MHC-peptide interaction prediction. A comparative analysis was conducted against the homology-modeling-based method Pandora as well as the AlphaFold multimer model. Our results demonstrate that our fine-tuned model outperforms others in terms of root-mean-square deviation (median value for Cα atoms for peptides is 0.66 Å) and also provides enhanced predicted local distance difference test scores, offering a more reliable assessment of the predicted structures. These advances have substantial implications for computational immunology, potentially accelerating the development of novel therapeutics and vaccines by providing a more precise computational lens through which to view MHC-peptide interactions.

BRCA1 safeguards genome integrity by activating chromosome asynapsis checkpoint to eliminate recombination-defective oocytes.

In the meiotic prophase, programmed DNA double-strand breaks are repaired by meiotic recombination. Recombination-defective meiocytes are eliminated to preserve genome integrity in gametes. BRCA1 is a critical protein in somatic homologous recombination, but studies have suggested that BRCA1 is dispensable for meiotic recombination. Here we show that BRCA1 is essential for meiotic recombination. Interestingly, BRCA1 also has a function in eliminating recombination-defective oocytes. Brca1 knockout (KO) rescues the survival of Dmc1 KO oocytes far more efficiently than removing CHK2, a vital component of the DNA damage checkpoint in oocytes. Mechanistically, BRCA1 activates chromosome asynapsis checkpoint by promoting ATR activity at unsynapsed chromosome axes in Dmc1 KO oocytes. Moreover, Brca1 KO also rescues the survival of asynaptic Spo11 KO oocytes. Collectively, our study not only unveils an unappreciated role of chromosome asynapsis in eliminating recombination-defective oocytes but also reveals the dual functions of BRCA1 in safeguarding oocyte genome integrity.

Moxibustion for declined cardiorespiratory fitness of apparently healthy older adults: A study protocol for a randomized controlled trial.

BACKGROUND: Aging and age-related declines lead to varying degrees of decreased cardiorespiratory fitness (CRF) in apparently healthy older adults. Exercise training, the primary approach for enhancing CRF, encounters several constraints when used with elderly individuals. Existing evidence implies that moxibustion might enhance the CRF of older adults. However, clinical research in this area still needs to be improved. METHODS: This study will employ a randomized, assessor-blinded, controlled trial design involving 126 eligible participants. These participants will be stratified and randomly assigned to one moxibustion group, one sham moxibustion group, and one blank control group. Acupoints of bilateral Zusanli (ST36), Shenque (CV8), and Guanyuan (CV4) are selected for both real and sham moxibustion groups. The treatment will last 60 min per session, 5 sessions a week for 12 weeks. The blank control group will not receive any intervention for CRF improvement. Primary outcomes will be the mean change in peak oxygen uptake (VO2peak), anaerobic threshold (AT), and serum central carbon metabolites (CCB) from the baseline to observation points. Secondary outcome measures involve the six-minute walk distance (6MWD), the Short Form 36 Health Survey (SF-36), and the Qi and Blood Status Questionnaire (QBSQ). Outcome assessments will be conducted at weeks 4, 8, 12, and 24 as part of the follow-up. Adverse events will be assessed at each visit. DISCUSSION: This trial can potentially ascertain moxibustion's effectiveness and safety in enhancing CRF among apparently healthy older adults. TRAIL REGISTRATION: ChiCTR, ChiCTR2300070303. Registered on April 08, 2023.

Recommended Tool Compounds for Modifying the Cystic Fibrosis Transmembrane Conductance Regulator Channel Variants.

Cystic fibrosis (CF) is a genetic disorder arising from variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to multiple organ system defects. CFTR tool compounds are molecules that can modify the activity of the CFTR channel. Especially, patients that are currently not able to benefit from approved CFTR modulators, such as patients with rare CFTR variants, benefit from further research in discovering novel tools to modulate CFTR. This Review explores the development and classification of CFTR tool compounds, including CFTR blockers (CFTRinh-172, GlyH-101), potentiators (VRT-532, Genistein), correctors (VRT-325, Corr-4a), and other approved and unapproved modulators, with detailed descriptions and discussions for each compound. The challenges and future directions in targeting rare variants and optimizing drug delivery, and the potential synergistic effects in combination therapies are outlined. CFTR modulation holds promise not only for CF treatment but also for generating CF models that contribute to CF research and potentially treating other diseases such as secretory diarrhea. Therefore, continued research on CFTR tool compounds is critical.

Trajectories of Body Mass Index and Waist Circumference in Relation to the Risk of Cardiac Arrhythmia: A Prospective Cohort Study.

BACKGROUND: The aim of the current study was to explore the trajectories, variabilities, and cumulative exposures of body mass index (BMI) and waist circumference (WC) with cardiac arrhythmia (CA) risks. METHODS: In total, 35,739 adults from the Kailuan study were included. BMI and WC were measured repeatedly during the 2006-2010 waves. CA was identified via electrocardiogram diagnosis. BMI and WC trajectories were fitted using a group-based trajectory model. The associations were estimated using Cox proportional hazards models. RESULTS: We identified four stable trajectories for BMI and WC, respectively. Neither the BMI trajectories nor the baseline BMI values were associated with the risk of CA. Compared to the low-stable WC group, participants in the high-stable WC group had a higher risk of CA (hazard ratio (HR) = 1.40, 95% confidence interval (CI): 1.06, 1.86). Interestingly, the cumulative exposures of BMI and WC instead of their variabilities were associated with the risk of CA. In the stratified analyses, the positive associations of the high-stable WC group with the risk of CA were found in females only (HR = 1.98, 95% CI: 1.02, 3.83). CONCLUSIONS: A high-stable WC trajectory is associated with a higher risk of CA among Chinese female adults, underscoring the potential of WC rather than BMI to identify adults who are at risk.

Switched Control of HyTAQs: A Framework of Stochastic Hybrid Fuzzy Systems With Variable Dimensions.

This article is concerned with the switched control of hybrid terrestrial and aerial quadrotors (HyTAQs) via stochastic hybrid fuzzy system methodology, in which the terrestrial and aerial mode switching is subject to a Markov process with lower-bounded sojourn time. For the first time, the bimodal nonlinear attitude dynamics of HyTAQs is analyzed and modeled based on the Takagi-Sugeno (T-S) fuzzy model, and switched fuzzy controllers are developed to stabilize the hybrid fuzzy system. The characteristic of state dimension switching caused by ground contact is modeled via the singular system presentation with mode-dependent singularity matrices, based on which numerically testable criteria of stability and stabilization in the stochastic sense are derived. Compared with the previous control approaches based on Markov jump systems, the proposed one is able to describe the deterministic dwelling duration in practice and integrate multiple subsystems with algebraic equations of different dimensions, while achieving lower conservatism. Illustrative examples are provided to demonstrate the effectiveness and potential of the designed variable-dimension fuzzy controllers.

Healthy lifestyle decreases the risk of the first incidence of non-communicable chronic disease and its progression to multimorbidity and its mediating roles of metabolic components: a prospective cohort study in China.

OBJECTIVES: To identify the influence of healthy lifestyles on the incidence of the first NCD (FNCD), multiple chronic conditions (MCCs), and the progression from FNCD to MCCs. DESIGN: cohort study. SETTING: Zhejiang, China PARTICIPANTS: 10566 subjects (55.5 ± 13.5 years, 43.1% male) free of NCDs at baseline from the Zhejiang Metabolic Syndrome prospective cohort. MEASUREMENTS: Healthy lifestyle score (HLS) was developed by 6 common healthy lifestyle factors as smoking, alcohol drinking, physical activity, body mass index (BMI) and waist-to-hip ratio (WHR). Healthy lifestyle data and metabolic biomarkers collected via a face-to-face questionnaire-based interview, clinical health examination and routine biochemical determination. Biochemical variables were determined using biochemical auto-analyzer. Participants were stratified into four group based on the levels of HLS as ≤2, 3, 4 and ≥5. Multiple Cox proportional hazards model was applied to examine the relationship between HLS and the risk of FNCD, MCCs and the progression from FNCD to MCCs. The population-attributable fractions (PAF) were used to assess the attributable role of HLS. Mediating effect was examined by mediation package in R. RESULTS: After a median of 9.92 years of follow-up, 1572 participants (14.9%) developed FNCD, and 149 (1.4%) developed MCCs. In the fully adjusted model, the higher HLS group (≥5) was associated with lower risk of FNCD (HR = 0.68 and 95% CI: 0.56-0.82), MCCs (HR = 0.31 and 95%CI: 0.14-0.69); and the progression from FNCD to MCCs (HR = 0.39 and 95%CI: 0.18-0.85). Metabolic components (TC, TG, HDL-C, LDC-C, FPG, and UA) played the mediating roles with the proportion ranging from 5.02% to 22.2% for FNCD and 5.94% to 20.1% for MCCs. PAFs (95%CI) for poor adherence to the overall healthy lifestyle (HLS ≤ 3) were 17.5% (11.2%, 23.7%) for FNCD, 42.9% (23.4%, 61.0%) for MCCs, and 37.0% (15.5%, 56.3%) for the progression from FNCD to MCCs. CONCLUSIONS: High HLS decreases the risk of FNCD, MCCs, and the progression from FNCD to MCCs. These effects are partially mediated by metabolic components. Maintaining healthy lifestyles might reduce the disease burden of common chronic diseases.

Zygotic Splicing Activation of the Transcriptome is a Crucial Aspect of Maternal-to-Zygotic Transition and Required for the Conversion from Totipotency to Pluripotency.

During maternal-to-zygotic transition (MZT) in the embryo, mRNA undergoes complex post-transcriptional regulatory processes. However, it is unclear whether and how alternative splicing plays a functional role in MZT. By analyzing transcriptome changes in mouse and human early embryos, dynamic changes in alternative splicing during MZT are observed and a previously unnoticed process of zygotic splicing activation (ZSA) following embryonic transcriptional activation is described. As the underlying mechanism of RNA splicing, splicing factors undergo dramatic maternal-to-zygotic conversion. This conversion relies on the key maternal factors BTG4 and PABPN1L and is zygotic-transcription-dependent. CDK11-dependent phosphorylation of the key splicing factor, SF3B1, and its aggregation with SRSF2 in the subnuclear domains of 2-cell embryos are prerequisites for ZSA. Isoforms generated by erroneous splicing, such as full-length Dppa4, hinder normal embryonic development. Moreover, alternative splicing regulates the conversion of early embryonic blastomeres from totipotency to pluripotency, thereby affecting embryonic lineage differentiation. ZSA is an essential post-transcriptional process of MZT and has physiological significance in generating new life. In addition to transcriptional activation, appropriate expression of transcript isoforms is also necessary for preimplantation embryonic development.