Discovering Effective Chiral Dipeptides against Aß(1-42) Aggregation by the Computational Screening Strategy.

The ß-sheet-breaker (BSB) peptides inhibiting amyloidogenic aggregation have been extensively studied. However, the inhibition efficacy of ultrashort chiral dipeptides remains inadequately understood. In this study, we proposed a computational screening strategy to identify chiral dipeptides as BSB with optimal antiaggregation performance against Aß(1-42) aggregation. We constructed a complete dipeptide library encompassing all possible chiral sequence arrangements and then filtered the library by cascaded molecular docking-molecular dynamics (MD) simulation. Our screening strategy discovered dipeptide DWDP (superscript for chirality) that displayed strong interactions with Aß fibrils and inhibitory effects on Aß aggregation, validated by subsequent experiments. Mechanistic investigation by both MD and replica-exchange molecular dynamics (REMD) simulations revealed that DWDP interacts with Aß by hydrophobic contacts and hydrogen bonds and thus inhibits Aß intermolecular contacts and salt bridge formation, therefore inhibiting Aß aggregation and disrupting Aß aggregates. Totally, our strategy presents a viable approach to discover potential dipeptides with effective antiaggregation ability as potential therapeutic agents for Alzheimer's disease.

Public awareness of gastric cancer risk factors and screening behaviours in Shijiazhuang, China: A community-based survey.

BACKGROUND: Reducing exposure to risk factors and screening represent 2 major approaches to gastric cancer (GC) prevention, but public knowledge GC risk factors and screening behaviour remain unknown. We aimed to investigate public awareness of GC risk factors, adherence to screening, and barriers hindering screening practices in China. METHODS: This community-based household survey was conducted within Shijiazhuang, China, and 1490 residents were recruited through a multistage stratified cluster random sampling approach. A self-administered questionnaire was completed which consisted of three sections: demographics, awareness of GC risk factors, and personal screening behaviours. Factors associated with knowledge of risk factors and screening behaviours were evaluated using binary logistic regression analysis. RESULTS: The mean risk factor awareness score of 12 (7, 15) revealed insufficient knowledge in 51.1% of participants. Dietary lifestyle factors were better understood than physical activity and weight-related factors. Marital status (OR 1.967; 95% CI 1.415 to 2.734), higher income (OR 1.197; 95% CI 1.010 to 1.418), and a history of upper gastrointestinal problems (OR 0.048; 95% CI 1.002 to 1.311) were associated with higher awareness. Merely 21.5% underwent GC screening, with higher rates linked to older age (OR 1.642; 95% CI 1.418 to 1.902), higher education (OR 1.398; 95% CI 1.176 to 1.662), a history of upper gastrointestinal problems (OR 3.842; 95% CI 2.833 to 5.209), and moderate (OR 2.077; 95% CI 1.352 to 3.191) and high (OR 2.529; 95% CI 1.311 to 4.878) perceived GC risk. Notably, participants commonly refused gastroscopy due to the absence of symptoms or signs. CONCLUSIONS: In Shijiazhuang, more than half of participants demonstrated inadequate knowledge of GC risk factors, and screening participation rates were remarkably low. This emphasizes the need for targeted interventions to enhance GC awareness and significantly improve screening rates.

Rapid detection of HPV16 utilizing recombinase polymerase amplification with the employment of an extremely low concentration of the probe.

Human papillomavirus 16 (HPV16) infection is the leading cause of cervical cancer. The current mainstream method for detecting HPV16 is quantitative real-time PCR (qPCR). However, due to its time-consuming nature and reliance on expensive qPCR instruments, there is growing interest in more convenient, rapid and private approaches such as recombinase polymerase amplification (RPA). In this study, we innovated an effective method for HPV16 detection by integrating a RPA system with lateral flow strip (LFS) detection. Primers with optimal efficiency and specificity were designed, and false positive signals caused by dimers were eliminated by reducing the probe concentration. The RPA-LFS method demonstrates high sensitivity and specificity, capable of detecting 230 copies per reaction of HPV16 within 25 min without cross-reactivity to other subtypes. It exhibits good tolerance, remaining unaffected by 1.0% miconazole, 0.5% tioconazole and 1.0% hemoglobin. The results of clinical samples detected by this method were consistent with those of qPCR. The method provides a practical reference for HPV16 diagnosis and can be valuable in home and resource-limited settings, contributing to the reduction of cervical cancer incidence.

Continuous self-circulating up-flow granular sludge fluidized bed process treating low-strength real municipal wastewater at high hydraulic loads.

Conditions conducive to aerobic granular sludge (AGS) growth and maintenance are very difficult to realize in continuous-flow biological treatment processes. This study conducted a continuous-flow self-circulating up-flow granular sludge fluidized bed (Zier process) treating real urban wastewater approximately one year. The substantial self-circulating multiple times (RSCMT, 8-15 times) and up-flow velocity (8-15 m/h) generated by aeration, the only power equipment in Zier process, facilitated pollutant removal, particle granulation and stabilization. With hydraulic retention time of 5 h, RSCMT of 9.3-14.4 times and chemical oxygen demand (COD)/total nitrogen (TN) ratio of 5.9 ± 1.0, the effluent COD, ammonia nitrogen and TN were 28.6 ± 7.7, 1.1 ± 1.2, and 13.3 ± 1.7 mg/L, respectively. The median particle size was 150-250 µm and effluent suspended solids concentration was 33.4 ± 14.5 mg/L. It is unnecessary to set up sludge reflux which simplifies the subsequent mud-water separation facilities. The Zier process provides a new process structure for implementation of continuous-flow AGS process.

Cepharanthine sensitizes gastric cancer cells to chemotherapy by targeting TRIB3-FOXO3-FOXM1 axis to inhibit autophagy.

BACKGROUND: Gastric cancer is among the common solid tumors. Chemotherapy resistance is the most common issue in gastric cancer treatment. Inhibiting intracellular autophagy may be a feasible method for overcoming chemotherapy resistance. Cepharanthine (CEP), a natural small molecule extracted from the stephania cephalantha Hayata plant, has been demonstrated to significantly inhibit cancer growth and can regulate autophagy. Although CEP can significantly inhibit cancer growth, it remains unclear whether CEP can regulate autophagy in gastric cancer. This study aimed to investigate whether CEP can enhance the sensitivity of gastric cancer to chemotherapy and elucidate its molecular mechanism. METHODS: Three gastric cancer cell lines (AGS, SGC7901, and MFC) and one normal gastric mucosal epithelial cell line (GES-1) were used for in vitro experiments. The characterization of autophagy in gastric cancer cells included the detection of autophagy markers and autophagy flux through immunofluorescence staining and Western blotting, as well as the assessment of lysosomal function using fluorescence staining (LysoTracker Red DND-99, Acridine Orange staining) and Western blotting. The cytotoxicity of CEP, autophagy inhibitors (chloroquine [CQ] and 3-methyladenine [3MA]), and chemotherapy drugs (doxorubicin [DOX] and cisplatin [CIS]) was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell colony formation, and fluorescence staining techniques (H2DCFDA, Dihydroethidium, and JC-1 staining). The interaction between CEP and autophagy inhibitors was tested in a 615 mice model, and changes in the gut microbiota were determined through accurate 16S absolute quantification sequencing. The signaling pathway and autophagy regulatory target TRIB3-FOXO3-FOXM1 were confirmed through molecular docking, RNA sequencing, bioinformatic analysis, transfection techniques, and Western blotting. RESULTS: CEP blocked autophagic flux in gastric cancer cells without affecting lysosomal function. As a novel autophagy inhibitor, CEP could combine with conventional autophagy inhibitors (CQ and 3MA) to block intracellular autophagy, thereby inhibiting gastric cancer growth. During this process, changes in the gut microbiota were observed, including low-level changes in Odoribacterium, Erysipelatoclostridium, and ParaPrevotella and high-level changes in Ileibacterium, Enterorhabdus, and Bifidobacterium. Additionally, CEP synergistically inhibited the growth of gastric cancer when combined with chemotherapy drugs. Mechanistically, the TRIB3-FOXO3-FOXM1 signaling axis was found to be involved in the inhibition of gastric cancer by CEP combined with autophagy inhibitors and chemotherapy drugs, thereby mediating cell apoptosis. CONCLUSION: This study links the TRIB3-FOXO3-FOXM1 axis with chemotherapy efficacy. Our findings demonstrated that CEP inhibits autophagy by modulating the FOXO3-FOXM1 axis. When combined with chemotherapy drugs (DOX and CIS), CEP, as an autophagy inhibitor, can limit TRIB3 protein expression, thereby regulating the FOXO3-FOXM1 axis and enhancing its ability to prevent gastric cancer growth. These findings may contribute to improving the prognosis of patients with gastric cancer. Furthermore, these results enrich the fundamental understanding of how autophagy inhibition can enhance clinical cancer treatment efficacy and provide insights into the potential mechanisms by which CEP functions as an anti-tumor drug, thereby exploring its value for clinical application.

Correction: Indoor air pollution by solid fuel usages for cooking is longitudinally associated with possible sarcopenia in middle-aged Chinese population.

[This corrects the article DOI: 10.1007/s40201-024-00911-3.].

Toripalimab combined with definitive chemoradiotherapy for locally advanced cervical squamous cell carcinoma patients (TRACE): A single-arm, phase I/II trial.

PURPOSE: This phase I/II trial (ChiCTR2000032879) assessed the safety and efficacy of toripalimab combined with chemoradiotherapy for locally advanced cervical squamous cell carcinoma. METHODS AND MATERIALS: Twenty-two patients, regardless of their programmed death ligand-1 (PD-L1) status, received toripalimab combined with concurrent chemoradiotherapy (CCRT). CCRT included cisplatin (40 mg/m2, once weekly for 5 weeks), radiotherapy (45-50.4 Gy/25-28 Fx, 5 fractions weekly), followed by brachytherapy (24-30 Gy/3-5 Fx) and toripalimab (240 mg, intravenous) on days 1, 22 and 43 during CCRT. The primary endpoints were safety and 2-year progression-free survival (PFS). The secondary endpoints included 2-year local control (LC), local regional control and overall survival (OS). RESULTS: All patients successfully completed CCRT and toripalimab treatment. Grade III and higher adverse events (AEs) were observed in 11 patients (11/22, 50%), and no patient experienced grade V AEs. The objective response rate (ORR) was 100%. At the data cutoff (June 30, 2023), the median follow-up was 31.8 months (9.5 to 37.8 months). The 2-year PFS rate was 81.8%. The 2-year LC and local regional control rates were both 95.5%, and the 2-year OS rate was 90.9%. CONCLUSIONS: Toripalimab combined with CCRT achieved good tolerance and showed promising anti-tumor effects in patients with locally advanced cervical cancer.

Indoor air pollution by solid fuel usages for cooking is longitudinally associated with possible sarcopenia in middle-aged Chinese population.

Objectives: The Asia Working Group of Sarcopenia (AWGS) 2019 consensus proposed a new concept named "possible sarcopenia". The present study was to estimate the association between indoor air pollution by solid fuel usages for cooking and possible sarcopenia among middle-aged and older Chinese population. Methods: A longitudinal cohort analysis was carried out using nationally representative data from the China Health and Retirement Longitudinal Study (CHARLS). A total of 17,708 participants were recruited and followed up in the CHARLS. Cox proportional hazards models were used to estimate the effects of cooking fuel usages on the new onset of possible sarcopenia. Stratified analyses were performed according to gender and age, and sensitivity analyses were performed using the complete dataset. Results: A total of 4,653 participants were included in the final cohort analysis. During the follow-up of 4 years (2011-2015), a total of 1,532 (32.92%) participants developed new-onset possible sarcopenia. Compared with clean fuel usages for cooking, solid fuel usages were associated with a higher risk of possible sarcopenia (HR = 1.37, 95% CI = 1.23-1.52, p-value < 0.001). After adjusting for potential confounders, there was a trend for association between solid fuel usages and an increased risk of possible sarcopenia. Stratified analyses by gender and age demonstrated a stronger association of the solid fuel usages with possible sarcopenia in the middle-aged female participants (Model 1: HR = 1.83, 95% CI = 1.24-2.69, p-value = 0.002; Model 2: HR = 1.65, 95% CI = 1.10-2.47, p-value = 0.016). Sensitivity analyses indicated that the results were robust. Conclusion: Indoor air pollution from solid fuel usages for cooking was a modifiable risk factor for sarcopenia, especially in middle-aged female population. These findings provide a new prevention strategy to reduce the growing burden of sarcopenia, especially for middle-aged female individuals using solid fuels for cooking.

Exploring Physicians' Perceptions of Digital Health's Impact on the Patient-Physician Relationship in the Primary Health Care Setting: Qualitative Descriptive Study.

BACKGROUND: Digital health has become essential for effective clinical practice. However, the successful adoption of digital health is dependent on the strength of the patient-physician relationship. The patient-physician relationship shapes the quality of care and impacts health care outcomes, especially in primary care. However, the impact of the increasing use of digital health on the patient-physician relationship is uncertain. OBJECTIVE: This study aims to explore the types of digital health primary care physicians use and understand their impact on the patient-physician relationship from their perspective. METHODS: This exploratory qualitative descriptive study used individual in-depth interviews guided by a semistructured topic guide. We purposively sampled physicians from 6 general primary care clinics in Singapore and used thematic analysis to identify emergent themes. RESULTS: We conducted 12 interviews. We found that primary care physicians in Singapore had minimal exposure to digital health beyond the scope of institutional implementation. The three key themes that emerged were as follows: (1) evolving roles of both physicians and patients; (2) impact on trust, knowledge acquisition, and longitudinal care; and (3) adoption and use factors of digital health impacting patient-physician relationships. The adoption and use factors comprised "social and personal," "technical and material," and "organization and policy" factors. CONCLUSIONS: The study identified that, while primary care physicians held mostly positive views on adopting digital health in improving the patient-physician relationship, they were concerned that digital health might erode trust, hinder proper knowledge acquisition, and reduce humanistic interaction. These concerns called for a nuanced approach to ensure that digital health would not compromise the patient-physician relationship. This could be achieved by ensuring that physicians possess the necessary skills, knowledge, and positive attitude, while health care organizations would provide robust IT capabilities and support. We recommend that education be refined and government policies on digital health adoption and use be revised to align with the goal of strengthening the patient-physician relationship.

Enhancement of Single-Molecule Magnet Properties by Manipulating Intramolecular Dipolar Interactions.

A new single-molecule magnet (SMM) complex [K(18-crown-6)][(COT)Er(µ-Cl)3Er(COT)] (Er2Cl3, COT = cyclooctatetraenide dianion) is obtained by the reaction of [(COT)Er(µ-Cl)(THF)]2 (Er2Cl2, THF = tetrahydrofuran) with an equivalent of KCl in the presence of 18-crown-6. The two COT-Er units in the newly formed complex are triply bridged by µ-Cl ligands, leading to the "head-to-tail" alignment of the magnetic easy axes distinctly different from the "staggered" arrangement in the precursor complex. This structural transformation has led to significantly enhanced intramolecular dipolar interactions and a reduced transverse component of the crystal fields, increasing the energy barrier from 150(8) K for Er2Cl2 to 264(4) K for Er2Cl3 and extending its magnetic relaxation time at 2 K by 2500 times with respect to Er2Cl2. More importantly, the blocking temperature increased from lower than 2 K for Er2Cl2 to 8 K for Er2Cl3, and the magnetic hysteresis loops at 2 K changed from butterfly-shaped for Er2Cl2 to open hysteresis loop with coercive force of 7 kOe for Er2Cl3. These results suggest that the properties of SMMs can be effectively tuned and improved by rationally arranging magnetic spins via molecular engineering.

Risk factors for cancer-related cognitive impairment among individuals with lung cancer: a systematic review and meta-analysis.

OBJECTIVES: Cancer-related cognitive impairment (CRCI) exerts a negative impact on the quality of life in lung cancer survivors. Risk factors for CRCI in lung cancer patients remain unclear.This study aimed to identify risk factors for CRCI in lung cancer patients. METHODS: A comprehensive literature search was conducted across PubMed, CINAHL, Web of Science, Wanfang, VIP Database, Embase, and China National Knowledge Infrastructure (CNKI) from their inception until March 10, 2024. Studies were screened, data extracted, and quality assessed using the Agency for Healthcare Research and Quality and Newcastle-Ottawa Scale. Meta-analysis was performed using RevMan 5.4, assessing risk factors through odds ratios (OR) with 95% confidence intervals (CIs). RESULTS: The analysis was comprised of nine studies, including 1,305 patients. Seven studies were high quality, and two were moderate quality. Identified risk factors for CRCI in lung cancer patients included advanced age (OR = 3.51, 95%CI: 2.14-5.74, I2 = 0.0%), cranial irradiation (OR = 2.12, 95% CI: 1.39-3.22, I2 = 0.0%), anxiety (OR = 2.92, 95% CI: 1.65-5.25, I2 = 37%), and symptom cluster burden (OR = 4.85, 95% CI: 2.99-7.87, I2 = 0.0%). Physical activity (OR = 0.37, 95% CI; 0.23-0.58, I2 = 9.0%) was identified as a protective factor. CONCLUSION: Advanced age, cranial irradiation, anxiety, and symptom cluster burden are significant risk factors for CRCI, while physical activity serves as a protective factor. These insights provide healthcare professionals with an evidence-based framework for managing CRCI in lung cancer patients.

PPARγ and C/EBPα enable adipocyte differentiation upon inhibition of histone methyltransferase PRC2 in malignant tumors.

Loss of terminal differentiation is a hallmark of cancer and offers a potential mechanism for differentiation therapy. Polycomb repressive complex 2 (PRC2) serves as the methyltransferase for K27 of histone H3 that is crucial in development. While PRC2 inhibitors show promise in treating various cancers, the underlying mechanisms remain incompletely understood. Here, we demonstrated that the inhibition or depletion of PRC2 enhanced adipocyte differentiation in malignant rhabdoid tumors and mesenchymal stem cells, through upregulation of peroxisome proliferator-activated receptor gamma (PPARG) and CEBPA. Mechanistically, PRC2 directly represses their transcription through H3K27 methylation, as both genes exhibit a bivalent state in mesenchymal stem cells. KO of PPARG compromised C/EBPα expression and impeded the PRC2 inhibitor-induced differentiation into adipocytes. Furthermore, the combination of the PPARγ agonist rosiglitazone and the PRC2 inhibitor MAK683 exhibited a higher inhibition on Ki67 positivity in tumor xenograft compared to MAK683 alone. High CEBPA, PLIN1, and FABP4 levels positively correlated with favorable prognosis in sarcoma patients in The Cancer Genome Atlas cohort. Together, these findings unveil an epigenetic regulatory mechanism for PPARG and highlight the essential role of PPARγ and C/EBPα in the adipocyte differentiation of malignant rhabdoid tumors and sarcomas with a potential clinical implication.

Fucoxanthin Attenuates Angiogenesis by Blocking the VEGFR2-Mediated Signaling Pathway through Binding the Vascular Endothelial Growth Factor.

Fucoxanthin, a dietary carotenoid, is predominantly found in edible brown algae and is commonly consumed worldwide. Fucoxanthin has been shown to possess beneficial health activities such as antidiabetic, anti-inflammatory, antimutagenic, and antiobesity; however, the effects of fucoxanthin on VEGF-mediated angiogenesis and its possible binding with VEGF are unknown. Here, different lines of evidence supported the suppressive roles of fucoxanthin in VEGF-mediated angiogenesis. In human umbilical vein endothelial cells, fucoxanthin remarkedly suppressed VEGF-mediated cell proliferative, migration, and invasive abilities, as well as tube formation, without cytotoxicity. In addition, fucoxanthin inhibited the subintestinal vessel formation of zebrafish in vivo. In signaling cascades, fucoxanthin was proposed to interact with VEGF, thus attenuating VEGF's functions in activating the VEGF receptor and its related downstream signaling, i.e., phosphorylations of MEK and Erk. Fucoxanthin also significantly blocked VEGF-triggered ROS formation. Furthermore, the outcomes of applying fucoxanthin in cancer cells were identified, which included (i) inhibiting VEGF-mediated cell proliferation and migration and (ii) inhibiting NF-κB translocation via limiting MMP2 expression. These lines of investigations supported the antiangiogenic roles of fucoxanthin, as well as reviewing its signaling mechanisms, in blocking the VEGF-triggered responses. The results would benefit the potential development of fucoxanthin for the prevention and treatment of angiogenesis-related diseases.

High terephthalic acid purity: Effective polyethylene terephthalate degradation process based on pH regulation with dual-function hydrolase.

Eco-friendly enzymatic-recycling has been widely utilized in tackling plastic pollution. However, the limited activity on the polyethylene terephthalate (PET) degradation product mono-hydroxyethyl terephthalate (MHET) leads to the formation of heterogeneous hydrolysis products, resulting in PET downcycling. Herein, by applying a dual-function PET hydrolase IsPETasePA with balanced PET and MHET degradation efficiency, an effective PET hydrolysis process was developed to enhance the terephthalic acid (TPA) product purity. Firstly, the impact of pH on the catalytic activity of IsPETasePA revealed that the pH reduction caused by TPA generation hindered the complete conversion of MHET to TPA. Further investigation of the catalytic mechanism showed that the pH-induced protonation of His208 in the catalytic triad destabilized the interaction between IsPETasePA and MHET. Thus, by introducing pH regulation strategy on the bifunctional IsPETasePA, the single-enzyme process could achieve high-purity TPA recovery (>99 %). Overall, this work ensured the high-quality PET enzymatic-recycling for effectively addressing plastic pollution.

Application of earthworm can enhance biological power generation and accelerate sulfamethoxazole removal in agricultural soils.

Microbial degradation plays a crucial role in removing sulfonamides from soil, enhancing sulfamethoxazole (SMX) remediation. To further augment SMX removal efficiency and mitigate the transmission risk associated with antibiotic resistance genes (ARGs), this study proposes a novel approach that integrates micro-animals, microorganisms, and microbial fuel cell (MFC) technology. The results showed that earthworm-MFC synergy substantially reduces SMX content and ARGs abundance in soil. The introduction of earthworms enhances humus content, facilitating electron transfer within MFC and consequently improving current generation. Furthermore, electrical stimulation applied to earthworms led to increased protein secretion and enhanced antioxidant system activity, thereby accelerating SMX degradation. Earthworms also foster MFC-associated bacterial growth and SMX-degrading bacteria proliferation, augmenting MFC treatment efficacy. This synergistic effect significantly augmented the overall efficacy of MFC treatment for antibiotics. Overall, integrating earthworm activity with MFC technology effectively optimizes electricity generation and enhances pollutant removal.

Screening of herbal extracts binding with vascular endothelial growth factor by applying HerboChip platform.

BACKGROUND: Traditional Chinese medicine (TCM) has been hailed as a rich source of medicine, but many types of herbs and their functions still need to be rapidly discovered and elucidated. HerboChip, a target-based drug screening platform, is an array of different fractions deriving from herbal extracts. This study was designed to identify effective components from TCM that interact with vascular endothelial growth factor (VEGF) as a target using HerboChip. METHODS: Selected TCMs that are traditionally used as remedies for cancer prevention and wound healing were determined and extracted with 50% ethanol. Biotinylated-VEGF was hybridized with over 500 chips coated with different HPLC-separated fractions from TCM extracts and straptavidin-Cy5 was applied to identify plant extracts containing VEGF-binding fractions. Cytotoxicity of selected herbal extracts and their activities on VEGF-mediated angiogenic functions were evaluated. RESULTS: Over 500 chips were screened within a week, and ten positive hits were identified. The interaction of the identified herbal extracts with VEGF was confirmed in cultured endothelial cells. The identified herbs promoted or inhibited VEGF-mediated cell proliferation, migration and tube formation. Results from western blotting analysis demonstrated the identified herbal extracts significantly affected VEGF-triggered phosphorylations of eNOS, Akt and Erk. Five TCMs demonstrated potentiating activities on the VEGF response and five TCMs revealed suppressive activities. CONCLUSIONS: The current results demonstrated the applicability of the HerboChip platform and systematically elucidated the activity of selected TCMs on angiogenesis and its related signal transduction mechanisms.

Achieving optical transparency in live animals with absorbing molecules.

Optical imaging plays a central role in biology and medicine but is hindered by light scattering in live tissue. We report the counterintuitive observation that strongly absorbing molecules can achieve optical transparency in live animals. We explored the physics behind this observation and found that when strongly absorbing molecules dissolve in water, they can modify the refractive index of the aqueous medium through the Kramers-Kronig relations to match that of high-index tissue components such as lipids. We have demonstrated that our straightforward approach can reversibly render a live mouse body transparent to allow visualization of a wide range of deep-seated structures and activities. This work suggests that the search for high-performance optical clearing agents should focus on strongly absorbing molecules.

Mitochondria-encoded peptide MOTS-c participates in plasma membrane repair by facilitating the translocation of TRIM72 to membrane.

Rationale: An impairment of plasma membrane repair has been implicated in various diseases such as muscular dystrophy and ischemia/reperfusion injury. MOTS-c, a short peptide encoded by mitochondria, has been shown to pass through the plasma membrane into the bloodstream. This study determined whether this biological behavior was involved in membrane repair and its underlying mechanism. Methods and Results: In human participants, the level of MOTS-c was positively correlated with the abundance of mitochondria, and the membrane repair molecule TRIM72. In contrast to high-intensity eccentric exercise, moderate-intensity exercise improved sarcolemma integrity and physical performance, accompanied by an increase of mitochondria beneath the damaged sarcolemma and secretion of MOTS-c. Furthermore, moderate-intensity exercise increased the interaction between MOTS-c and TRIM72, and MOTS-c facilitated the trafficking of TRIM72 to the sarcolemma. In vitro studies demonstrated that MOTS-c attenuated membrane damage induced by hypotonic solution, which could be blocked by siRNA-TRIM72, but not AMPK inhibitor. Co-immunoprecipitation study showed that MOTS-c interacted with TRIM72 C-terminus, but not N-terminus. The dynamic membrane repair assay revealed that MOTS-c boosted the trafficking of TRIM72 to the injured membrane. However, MOTS-c itself had negligible effects on membrane repair, which was recapitulated in TRIM72-/- mice. Unexpectedly, MOTS-c still increased the fusion of vesicles with the membrane in TRIM72-/- mice, and dot blot analysis revealed an interaction between MOTS-c and phosphatidylinositol (4,5) bisphosphate [PtdIns (4,5) P2]. Finally, MOTS-c blunted ischemia/reperfusion-induced membrane disruption, and preserved heart function. Conclusions: MOTS-c/TRIM72-mediated membrane integrity improvement participates in mitochondria-triggered membrane repair. An interaction between MOTS-c and plasma lipid contributes to the fusion of vesicles with membrane. Our data provide a novel therapeutic strategy for rescuing organ function by facilitating membrane repair with MOTS-c.

Establishing a risk stratification model to identify clinically high-risk N0 breast cancer who could benefit from regional nodal irradiation: a single institute analysis.

Background: The purpose of this real-world study was to investigate the risk factors for developing recurrence among patients with pathological T1-3N0 breast cancer (BC) treated with breast-conserving surgery (BCS) followed by whole breast irradiation alone (WBI) and identify those clinically high-risk BCs who could benefit from regional nodal irradiation (RNI). Materials and methods: Female BC patients treated at Shanghai Ruijin hospital from 2009 to 2016 were retrospectively reviewed. The disease-free survival (DFS), breast cancer specific survival (BCSS) and overall survival (OS) were estimated by the Kaplan-Meier method, and survival differences were compared with the log-rank test. Univariate and multivariate analysis was performed using Cox proportional hazards regression analysis. An external validation was conducted by using SEER database. Results: A total of 622 BC patients treated with BCS+WBI alone were included. With a median follow-up of 82 months, the 7-year OS, BCSS and DFS for the entire cohort was 97%, 99% and 91%, respectively. Multivariable Cox analysis indicated that tumor size (p=0.006), tumor location (p=0.033), lymphovascular invasion (LVI) status (p=0.0028) and Ki-67 index (p=0.051) were independent risk factors for DFS. A scoring system was developed using these four factors and the 7-year DFS and OS were 97% and 96% for patients with 0-1 risk factors, 95% and 82% for patients with ≥2 risk factors (p<0.0001 for DFS, and p=0.0063 for OS). Based on tumor size and tumor location, an external validation by demonstrated that the 7-year OS was 90% and 88% for patients with 0-1 risk factor, which was significantly better than those defined as high-risk BC patients (82%, p<0.0001). Conclusion: By using our institute database, we establish a risk stratification system for identifying sub-group of pN0 BC patients, who are at high risk for developing recurrence. The results of our study support tailored RT decision-making according to individual risks, which needed to be confirmed in further studies.

Mixed effectiveness of global protected areas in resisting habitat loss.

Protected areas are the cornerstones of conservation efforts to mitigate the anthropogenic pressures driving biodiversity loss. Nations aim to protect 30% of Earth's land and water by 2030, yet the effectiveness of protected areas remains unclear. Here we analyze the performance of over 160,000 protected areas in resisting habitat loss at different spatial and temporal scales, using high-resolution data. We find that 1.14 million km2 of habitat, equivalent to three times the size of Japan, across 73% of protected areas, had been altered between 2003 and 2019. These protected areas experienced habitat loss due to the expansion of built-up land, cropland, pastureland, or deforestation. Larger and stricter protected areas generally had lower rates of habitat loss. While most protected areas effectively halted the expansion of built-up areas, they were less successful in preventing deforestation and agricultural conversion. Protected areas were 33% more effective in reducing habitat loss compared to unprotected areas, though their ability to mitigate nearby human pressures was limited and varied spatially. Our findings indicate that, beyond establishing new protected areas, there is an urgent need to enhance the effectiveness of existing ones to better prevent habitat loss and achieve the post-2020 global biodiversity goals.