Plasma GPI and PGD are associated with vascular normalization and may serve as novel prognostic biomarkers for lung adenocarcinoma: Multi-omics and multi-dimensional analysis.

The aim of this study was to explore potential novel plasma protein biomarkers for lung adenocarcinoma (LUAD). A plasma proteomics analysis was carried out and candidate protein biomarkers were validated in 102 LUAD cases and 102 matched healthy controls. The same LUAD tumor tissues were detected to explore the correlation between the expression of candidate proteins in tissues and plasma and vascular normalization. A LUAD active metastasis mice model was constructed to explore the role of candidate proteins for lung metastasis. GPI and PGD were verified to be upregulated in plasma from LUAD patients, and the expression of GPI in tumor tissue was positively correlated with the expression of GPI in plasma and negatively correlated with the normalization of tumor blood vessels. Meanwhile, a negative correlation between the expression of GPI and PGD in plasma and tumor vascular normalization was discovered. In the LUAD active metastasis model, the lowest levels of vascular normalization and the highest expression of GPI and PGD were found in mice with lung metastases. This study found that GPI and PGD may be potential plasma biomarkers for LUAD, and monitoring those may infer the risk of metastasis and malignancy of the tumor. SIGNIFICANT: We identified GPI and PGD as potential novel diagnostic and prognostic biomarkers for LUAD. PGD and GPI can be used as diagnostic biomarkers in combination with other available strategies to assist in the screening and diagnosis of LUAD, and as prognostic biomarkers aid in predict the risk of tumor metastasis and malignancy in patients with LUAD.

Specific CD4+ T cell phenotypes associate with bacterial control in people who 'resist' infection with Mycobacterium tuberculosis.

A subset of individuals exposed to Mycobacterium tuberculosis (Mtb) that we refer to as 'resisters' (RSTR) show evidence of IFN-γ- T cell responses to Mtb-specific antigens despite serially negative results on clinical testing. Here we found that Mtb-specific T cells in RSTR were clonally expanded, confirming the priming of adaptive immune responses following Mtb exposure. RSTR CD4+ T cells showed enrichment of TH17 and regulatory T cell-like functional programs compared to Mtb-specific T cells from individuals with latent Mtb infection. Using public datasets, we showed that these TH17 cell-like functional programs were associated with lack of progression to active tuberculosis among South African adolescents with latent Mtb infection and with bacterial control in nonhuman primates. Our findings suggested that RSTR may successfully control Mtb following exposure and immune priming and established a set of T cell biomarkers to facilitate further study of this clinical phenotype.

LDHA contributes to nicotine induced cardiac fibrosis through autophagy flux impairment.

Cardiac fibrosis is a typical feature of cardiac pathological remodeling, which is associated with adverse clinical outcomes and has no effective therapy. Nicotine is an important risk factor for cardiac fibrosis, yet its underlying molecular mechanism remains poorly understood. This study aimed to identify its potential molecular mechanism in nicotine-induced cardiac fibrosis. Our results showed nicotine exposure led to the proliferation and transformation of cardiac fibroblasts (CFs) into myofibroblasts (MFs) by impairing autophagy flux. Through the use of drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) technology, it was discovered that nicotine directly increased the stability and protein levels of lactate dehydrogenase A (LDHA) by binding to it. Nicotine treatment impaired autophagy flux by regulating the AMPK/mTOR signaling pathway, impeding the nuclear translocation of transcription factor EB (TFEB), and reducing the activity of cathepsin B (CTSB). In vivo, nicotine treatment exacerbated cardiac fibrosis induced in spontaneously hypertensive rats (SHR) and worsened cardiac function. Interestingly, the absence of LDHA reversed these effects both in vitro and in vivo. Our study identified LDHA as a novel nicotine-binding protein that plays a crucial role in mediating cardiac fibrosis by blocking autophagy flux. The findings suggest that LDHA could potentially serve as a promising target for the treatment of cardiac fibrosis.

Effect of catheter needle caliber on polidocanol foam stability in foam sclerotherapy.

Background: Although sclerotherapy is widely used to treat vascular malformations (VMs), it is associated with several challenges. One significant issue is the insufficient understanding of the influence of various factors on the stability of polidocanol (POL) foam used in sclerotherapy. Objective: This study aimed to explore the effect of the catheter needle caliber on foam stability when using POL with or without hyaluronic acid (HA) for the treatment of VMs. Methods and materials: The Tessari method generated sclerosant foam using POL both with and without HA. We used catheters and syringe needles of various calibers, and the resulting foam was transferred into new syringes to facilitate a comparison of foam stability. Foam half-life (FHT) was utilized as a metric to assess foam stability. Results: The study found that narrower needle calibers produced a more stable foam when POL was used alone; however, no significant effect was observed when HA was added. Furthermore, when the foam was expelled using catheters and syringe needles of the same size, no noticeable changes in the stability were observed. Conclusion: When choosing needles of varying calibers, their effect on foam stability should be carefully considered, particularly when the foam contains HA.

Analysis of potential diagnostic markers and therapeutic targets for rheumatoid arthritis with comorbid depression immunologic indicators.

OBJECTIVE: Depression can impact the severity of rheumatoid arthritis (RA). This study aimed to investigate the relationship between Th1, Th2, Th17, Treg cell subsets, and their associated cytokines (e.g., IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ, and TNF-α), and the occurrence of RA both with and without comorbid depression. The objective is to identify potential biological markers, therapeutic targets, and the therapeutic effects of RA with comorbid depression. RESULTS: 53 RA patients,46 RA with comorbid depression patients and 51 healthy subjects were included in the RA,RD and HC group from August 2021 and October 2022. Among RA patients, 46.46 % were comorbid with depression. IL-6 concentrations were significantly higher in RD group than in RA group.Comparison between the HC and RA and RD groups revealed that Th1 %, Th17 %, Th1, Th17, Th1/Th2, Th17/Treg and Th1/Treg were significantly higher in the RA and RD groups, and conversely, Th2 %, Treg%, Th2 and Treg were significantly lower than in the HC group.The RA group compared to the RD group found that Th17 %, Th17 and Th17/Treg were significantly higher in the RD group than in the RA group, however, Th1 %, Treg and Th2/Treg were significantly lower than in the RA group. The total HAMD score had a medium strength positive correlation with IL-6. CONCLUSION: These findings suggest that elevated the autoimmunity status was overactivated in RA with or without depression activates patients, IL-6 may be a predictor of the severity of RA with comorbid depression, IL-6 concentrations and an imbalance in the Th17/Treg may underlie the comorbidity of RA and depression, offering potential targets for therapeutic intervention, prompting further evaluation of the role of indirect inflammatory markers in RA with comorbid depression, highlighting the need for additional research to clarify the complex relationship between inflammation and psychological health.

NEDD4L mediates ITGB4 ubiquitination and degradation to suppress esophageal carcinoma progression.

The ubiquitination-mediated protein degradation exerts a vital role in the progression of multiple tumors. NEDD4L, which belongs to the E3 ubiquitin ligase NEDD4 family, is related to tumor genesis, metastasis and drug resistance. However, the anti-tumor role of NEDD4L in esophageal carcinoma, and the potential specific recognition substrate remain unclear. Based on public esophageal carcinoma database and clinical sample data, it was discovered in this study that the expression of NEDD4L in esophageal carcinoma was apparently lower than that in atypical hyperplastic esophageal tissue and esophageal squamous epithelium. Besides, patients with high expression of NEDD4L in esophageal carcinoma tissue had longer progression-free survival than those with low expression. Experiments in vivo and in vitro also verified that NEDD4L suppressed the growth and metastasis of esophageal carcinoma. Based on co-immunoprecipitation and proteome analysis, the NEDD4L ubiquitination-degraded protein ITGB4 was obtained. In terms of the mechanism, the HECT domain of NEDD4L specifically bound to the Galx-ß domain of ITGB4, which modified the K915 site of ITGB4 in an ubiquitination manner, and promoted the ubiquitination degradation of ITGB4, thus suppressing the malignant phenotype of esophageal carcinoma.

Cognitive Function and Medication Adherence in Older Adults With H-Type Hypertension: The Mediating Effect of Metamemory.

PURPOSE: Medication adherence in adults with H-type hypertension plays a crucial role in lowering blood pressure and treating complications. Cognitive function has been identified as a significant influencing factor for medication adherence, whereas excessive levels of homocysteine can impair cognitive function. Metamemory, which is influenced by cognitive function, also affects medication adherence. However, the complex relationship among these factors remains poorly understood among adults with H-type hypertension. Therefore, we hypothesize that metamemory serves as a mediator for the impact of cognitive function on medication adherence. METHOD: A total of 232 adults with H-type hypertension were enrolled to provide cognitive function scores, metamemory scores, and medication adherence rates. RESULTS: A pairwise correlation exists among cognitive function, metamemory, and medication adherence. Metamemory partially mediates (57.5%) the relationship between cognitive function and medication adherence. CONCLUSION: Our findings suggest that interventions targeting improvements in metamemory may enhance medication adherence among individuals with H-type hypertension. [Journal of Gerontological Nursing, 50(6), 44-52.].

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.

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.

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.

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.

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.