Optimization and mechanisms of proteolytic enzyme immobilization onto large-pore mesoporous silica nanoparticles: Enhanced tumor penetration.

Immobilization of proteolytic enzymes onto nanocarriers is effective to improve drug diffusion in tumors through degrading the dense extracellular matrix (ECM). Herein, immobilization and release behaviors of hyaluronidase, bromelain, and collagenase (Coll) on mesoporous silica nanoparticles (MSNs) were explored. A series of cationic MSNs (CMSNs) with large and adjustable pore sizes were synthesized, and investigated together with two anionic MSNs of different pore sizes. CMSNs4.0 exhibited the highest enzyme loading capacity for hyaluronidase and bromelain, and CMSNs4.5 was the best for Coll. High electrostatic interaction, matched pore size, and large pore volume and surface area favor the immobilization. Changes of the enzyme conformations and surface charges with pH, existence of a space around the immobilized enzymes, and the depth of the pore structures, affect the release ratio and tunability. The optimal CMSNs-enzyme complexes exhibited deep and homogeneous penetration into pancreatic tumors, a tumor model with the densest ECM, with CMSNs4.5-Coll as the best. Upon loading with doxorubicin (DOX), the CMSNs-enzyme complexes induced high anti-tumor efficiencies. Conceivably, the DOX/CMSNs4.5-NH2-Coll nanodrug exhibited the most effective tumor therapy, with a tumor growth inhibition ratio of 86.1 %. The study provides excellent nanocarrier-enzyme complexes, and offers instructive theories for enhanced tumor penetration and therapy.

BMSC-derived Exosomes Ameliorate Peritoneal Dialysis-associated Peritoneal Fibrosis via the Mir-27a-3p/TP53 Pathway.

OBJECTIVE: Peritoneal fibrosis (PF) is the main cause of declining efficiency and ultrafiltration failure of the peritoneum, which restricts the long-term application of peritoneal dialysis (PD). This study aimed to investigate the therapeutic effects and mechanisms of bone marrow mesenchymal stem cells-derived exosomes (BMSC-Exos) on PF in response to PD. METHODS: Small RNA sequencing analysis of BMSC-Exos was performed by second-generation sequencing. C57BL/6J mice were infused with 4.25% glucose-based peritoneal dialysis fluid (PDF) for 6 consecutive weeks to establish a PF model. A total of 36 mice were randomly divided into 6 groups: control group, 1.5% PDF group, 2.5% PDF group, 4.25% PDF group, BMSC-Exos treatment group, and BMSC-Exos+TP53 treatment group. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to measure the expression level of miR-27a-3p in BMSC-Exos and peritoneum of mice treated with different concentrations of PDF. HE and Masson staining were performed to evaluate the extent of PF. The therapeutic potential of BMSC-Exos for PF was examined through pathological examination, RT-qPCR, Western blotting, and peritoneal function analyses. Epithelial-mesenchymal transition (EMT) of HMrSV5 was induced with 4.25% PDF. Cells were divided into control group, 4.25% PDF group, BMSC-Exos treatment group, and BMSC-Exos+TP53 treatment group. Cell Counting Kit-8 assay was used to measure cell viability, and transwell migration assay was used to verify the capacity of BMSC-Exos to inhibit EMT in HMrSV5 cells. RESULTS: Small RNA sequencing analysis showed that miR-27a-3p was highly expressed in BMSC-derived exosomes compared to BMSCs. The RT-qPCR results showed that the expression of miR-27a-3p was upregulated in BMSC-Exos, but decreased in PD mice. We found that PF was glucose concentration-dependently enhanced in the peritoneum of the PD mice. Compared with the control mice, the PD mice showed high solute transport and decreased ultrafiltration volume as well as an obvious fibroproliferative response, with markedly increased peritoneal thickness and higher expression of α-SMA, collagen-I, fibronectin, and ECM1. The mice with PD showed decreased miR-27a-3p. Peritoneal structural and functional damage was significantly attenuated after BMSC-Exos treatment, while PF and mesothelial damage were significantly ameliorated. Additionally, markers of fibrosis (α-SMA, collagen-I, fibronectin, ECM1) and profibrotic cytokines (TGF-ß1, PDGF) were downregulated at the mRNA and protein levels after BMSC-Exos treatment. In HMrSV5 cells, BMSC-Exos reversed the decrease in cell viability and the increase in cell migratory capacity caused by high-glucose PDF. Western blotting and RT-qPCR analysis revealed that BMSC-Exos treatment resulted in increased expression of E-cadherin (epithelial marker) and decreased expression of α-SMA, Snail, and vimentin (mesenchymal markers) compared to those of the 4.25% PDF-treated cells. Importantly, a dual-luciferase reporter assay showed that TP53 was a target gene of miR-27a-3p. TP53 overexpression significantly reversed the decreases in PF and EMT progression induced by BMSC-Exos. CONCLUSION: The present results demonstrate that BMSC-Exos showed an obvious protective effect on PD-related PF and suggest that BMSC-derived exosomal miR-27a-3p may exert its inhibitory effect on PF and EMT progression by targeting TP53.

Chemoproteomic Profiling Maps Zinc-Dependent Cysteine Reactivity.

As a vital micronutrient, zinc is integral to the structure, function, and signaling networks of diverse proteins. Dysregulated zinc levels, due to either excess intake or deficiency, are associated with a spectrum of health disorders. In this context, understanding zinc-regulated biological processes at the molecular level holds significant relevance to public health and clinical practice. Identifying and characterizing zinc-regulated proteins in their diverse proteoforms, however, remain a difficult task in advancing zinc biology. Herein, we address this challenge by developing a quantitative chemical proteomics platform that globally profiles the reactivities of proteinaceous cysteines upon cellular zinc depletion. Exploiting a protein-conjugated resin for the selective removal of Zn2+ from culture media, we identify an array of zinc-sensitive cysteines on proteins with diverse functions based on their increased reactivity upon zinc depletion. Notably, we find that zinc regulates the enzymatic activities, post-translational modifications, and subcellular distributions of selected target proteins such as peroxiredoxin 6 (PRDX6), platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3), and phosphoglycerate kinase (PGK1).

pH-Sensitive Biomimetic Nanosystem Based on Large-Pore Mesoporous Silica Nanoparticles with High Hyaluronidase Loading for Tumor Deep Penetration.

Loading hyaluronidase (Hyal) in a nanocarrier is a potent strategy to degrade the tumor extracellular matrix for tumor deep penetration and enhanced tumor therapy. Herein, a pH-sensitive biomimicking nanosystem with high Hyal loading, effective tumor targeting, and controllable release is constructed. Specifically, cationic mesoporous silica nanoparticles (CMSNs) with large pores 13.52 nm in diameter were synthesized in a one-pot manner by adding N-[3-trimethoxysilylpropyl]-N,N,N-trimethylammonium to a reversed microemulsion reaction system. The Hyal loading rate was as high as 19.47% owing to matched pore size and the cationic surface charge. Subsequently, a pH-sensitive biomimetic hybrid membrane (pHH) composed of pH-sensitive liposome (pHL), red blood cell membrane, and pancreatic cancer cell membrane was camouflaged on the pHL-coated and doxorubicin/Hyal-loaded CMSNs (shortened as DHCM). The DHCM@pHL@pHH is stable at neutral pH while it releases the payloads smoothly in the tumor acidic microenvironment. Consequently, it can escape from macrophage clearance, be specifically taken up by pancreatic cancer cells, and efficiently accumulate at the tumor site. More importantly, it can penetrate deeply in pancreatic tumors with a tumor growth inhibition ratio of 80.46%. The nanosystem is biocompatible and has potential for clinical transformation, and the nanocarrier is promisingly applicable as a platform for encapsulation of various macromolecules for smart and tumor-targeted delivery.

Little engagement of attention by salient distractors defined in a different dimension or modality to the visual search target.

Singleton distractors may inadvertently capture attention, interfering with the task at hand. The underlying neural mechanisms of how we prevent or handle distractor interference remain elusive. Here, we varied the type of salient distractor introduced in a visual search task: the distractor could be defined in the same (shape) dimension as the target, a different (color) dimension, or a different (tactile) modality (intra-dimensional, cross-dimensional, and, respectively, cross-modal distractor, all matched for physical salience); and besides behavioral interference, we measured lateralized electrophysiological indicators of attentional selectivity (the N2pc, Ppc, PD , CCN/CCP, CDA, and cCDA). The results revealed the intra-dimensional distractor to produce the strongest reaction-time interference, associated with the smallest target-elicited N2pc. In contrast, the cross-dimensional and cross-modal distractors did not engender any significant interference, and the target-elicited N2pc was comparable to the condition in which the search display contained only the target singleton, thus ruling out early attentional capture. Moreover, the cross-modal distractor elicited a significant early CCN/CCP, but did not influence the target-elicited N2pc, suggesting that the tactile distractor is registered by the somatosensory system (rather than being proactively suppressed), without, however, engaging attention. Together, our findings indicate that, in contrast to distractors defined in the same dimension as the target, distractors singled out in a different dimension or modality can be effectively prevented to engage attention, consistent with dimension- or modality-weighting accounts of attentional priority computation.

Long-term (statistically learnt) and short-term (inter-trial) distractor-location effects arise at different pre- and post-selective processing stages.

A salient distractor interferes less with visual search if it appears at a location where it is likely to occur, referred to as distractor-location probability cueing. Conversely, if the current target appears at the same location as a distractor on the preceding trial, search is impeded. While these two location-specific "suppression" effects reflect long-term, statistically learnt and short-term, inter-trial adaptations of the system to distractors, it is unclear at what stage(s) of processing they arise. Here, we adopted the additional-singleton paradigm and examined lateralized event-related potentials (L-ERPs) and lateralized alpha (8-12 Hz) power to track the temporal dynamics of these effects. Behaviorally, we confirmed both effects: reaction times (RTs) interference was reduced for distractors at frequent versus rare (distractor) locations, and RTs were delayed for targets that appeared at previous distractor versus non-distractor locations. Electrophysiologically, the statistical-learning effect was not associated with lateralized alpha power during the pre-stimulus period. Rather, it was seen in an early N1pc referenced to the frequent distractor location (whether or not a distractor or a target occurred there), indicative of a learnt top-down prioritization of this location. This early top-down influence was systematically modulated by (competing) target- and distractor-generated bottom-up saliency signals in the display. In contrast, the inter-trial effect was reflected in an enhanced SPCN when the target was preceded by a distractor at its location. This suggests that establishing that an attentionally selected item is a task-relevant target, rather than an irrelevant distractor, is more demanding at a previously "rejected" distractor location.

Dynamic evaluation of the cervical spine by kinematic MRI in patients with cervical spinal cord injury without fracture and dislocation.

BACKGROUND: The pattern of changes in the cervical spine and the spinal cord and their dynamic characteristics in patients with cervical spinal cord injury without fracture and dislocation remain unclear. This study aimed to evaluate the dynamic changes in the cervical spine and spinal cord from C2/3 to C7/T1 in different positions by using kinematic magnetic resonance imaging in patients with cervical spinal cord injury without fracture and dislocation. This study was approved by the ethics committee of Yuebei People's Hospital. METHODS: Using median sagittal T2-weighted images for 16 patients with cervical spinal cord injury without fracture and dislocation who underwent cervical kinematic MRI, the anterior space available for the cord, spinal cord diameter, posterior space available for the cord from C2/3 to C7/T1, and Muhle's grade were determined. The spinal canal diameter was calculated by adding the anterior space available for the cord, spinal cord diameter, and posterior space available for the cord. RESULTS: The anterior space available for the cord, posterior space available for the cord, and spinal canal diameters at C2/3 and C7/T1 were significantly higher than those from C3/4 to C6/7. Muhle's grades at C2/3 and C7/T1 were significantly lower than those at the other levels. Spinal canal diameter was lower in extension than in the neutral and flexion positions. In the operated segments, significantly lesser space was available for the cord (anterior space available for the cord + posterior space available for the cord), and the spinal cord diameter/spinal canal diameter ratio was higher than those in the C2/3, C7/T1, and non-operated segments. CONCLUSION: Kinematic MRI demonstrated dynamic pathoanatomical changes, such as canal stenosis in different positions, in patients with cervical spinal cord injury without fracture and dislocation. The injured segment had a small canal diameter, high Muhle's grade, low space available for the cord, and high spinal cord diameter/spinal canal diameter ratio.

[Comparison of the predictive value of the modified CADILLAC, GRACE and TIMI risk scores for the risk of short-term death in patients with acute ST segment elevation myocardial infarction after percutaneous coronary intervention].

OBJECTIVE: To establish a modified controlled abciximab and device investigation to lower late angioplasty complication (CADILLAC) score, and to compare the predictive value of modified CADILLAC score, the global registry of acute coronary event (GRACE) score and the thrombolysis in myocardial infarction (TIMI) score in predicting the risk of short-term death after percutaneous coronary intervention (PCI) in patients with acute ST segment elevation myocardial infarction (STEMI). METHODS: A retrospective study was conducted. The clinical data of 169 STEMI patients under going PCI admitted to the department of cardiology of Guizhou Provincial People's Hospital from September 2019 to December 2020 through emergency chest pain fast track were enrolled. A multivariate Logistic regression analysis was used to screen the factors closely related to the mortality risk within 30 days of STEMI, and a modified CADILLAC scoring system was established by referring to CADILLAC scoring settings. The score of modified CADILLAC, GRACE and TIMI scores of patients were calculated after admission, and the number of deaths due to cardiovascular disease (CVD) within 30 days after onset was recorded. The receiver operating characteristic curve (ROC curve) was used to evaluate the predictive value of three scoring systems on the risk of death within 30 days after PCI in patients with STEMI. RESULTS: In 169 STEMI patients, 16 patients died of CVD within 30 days after PCI, and the actual case mortality was 9.47%. Multivariate Logistic regression analysis showed that age > 75 years old, cardiac function Killip ≥ Grade III, ventricular arrhythmia, ST segment elevation ≥ 0.2 mV, cardiac troponin I (cTnI) increase, systolic blood pressure (SBP) < 90 mmHg (1 mmHg ≈ 0.133 kPa) were all independent predictors of death after PCI in STEMI patients. The improved CADILLAC scoring system was constructed based on the above predictive factors combined with left ventricular ejection fraction (LVEF) less than 0.40. The GRACE, TIMI and modified CADILLAC scores of dead patients were significantly higher than those of survival patients (GRACE score: 197.60±31.83 vs. 149.81±36.72, TIMI score: 11.21±2.13 vs. 7.27±1.97, modified CADILLAC score: 12.60±2.52 vs. 6.96±2.17, all P < 0.05). The higher the risk stratification of the three scores, the higher the mortality of patients with CVD within 30 days after PCI [the mortality of patients with low, medium and high risk in GRACE score were 2.41% (2/83), 9.61% (5/52) and 26.47% (9/34); the mortality of patients with low, medium and high risk in TIMI score were 3.12% (3/96), 12.82% (5/39) and 23.53% (8/34); and the mortality of patients with low, medium and high risk in modified CADILLAC score were 3.19% (3/94), 7.69% (4/52) and 39.13% (9/23), respectively, all P < 0.01]. The area under the ROC curve (AUC) of the GRACE, TIMI and the modified CADILLAC scores predicting the risk of death 30 days after PCI in STEMI patients were 0.855 [95% confidence interval (95%CI) was 0.702-0.923], 0.725 (95%CI was 0.666-0.812) and 0.882 (95%CI was 0.732-0.936), respectively, all P = 0.000; the sensitivity of its prediction accuracy were 81.59%, 78.65% and 89.26%, and the specificity were 78.62%, 57.12% and 75.54%, respectively. CONCLUSIONS: The GRACE and the modified CADILLAC scores have predictive value for the short-term mortality risk of STEMI patients after PCI, and the modified CADILLAC score is more accurate. But the TIMI score has a poor predictive effect on the short-term mortality risk of STEMI patients after PCI.

Dermoscopy in Mycobacterium marinum infection and its correlation with clinical and histopathological features: a prospective observational study.

BACKGROUND: Mycobacterium marinum is a nontuberculous mycobacterium and a conditional pathogen to humans, which can be inoculated directly and cause chronic skin granulomas. Dermoscopy has been applied to other granulomatous skin diseases, but not to M. marinum infection. AIM: To explore the dermoscopic features of M. marinum infection, and its correlation with clinical and histopathological features. METHODS: In total, 27 lesions from 27 patients (19 women, 8 men, age range 28-71 years) diagnosed with M. marinum infection were identified by clinical examination, histopathological results, PCR sequencing and mycobacterial culture in the dermatology outpatient department of our hospital from March 2020 to February 2022. The dermoscopy images and pathological characteristics were analysed. RESULTS: Lesions were located on the hands, forearms and upper arms. The following dermoscopic features were observed: yellowish-orange structureless areas (85·2%), white striped structures (59·3%), follicular plugs (29·6%), yellowish oval clods (14·8%) and reddish or pinkish areas (14·8%). Vessel structures were visible in all cases: long hairpin vessels (81·5%), corkscrew vessels (25·9%), comma-shaped vessels (22·2%) and linear vessels (22·2%). CONCLUSION: Yellowish-orange structureless areas, white striped structures and long hairpin vessels are the most common dermoscopic features of M. marinum infection. Thus, dermoscopy could be used as a noninvasive auxiliary diagnostic method to provide a diagnostic basis for this disease.

Engineering crystal water in potassium ammonium vanadate for fast Zn-ion storage.

The effect of different annealing temperatures on the electrochemical performance of potassium ammonium vanadate (KNVO) was investigated, and the annealed KNVO regained H2O from the aqueous electrolyte to achieve an optimal structural water content during activation. In addition, the accompanying oxygen vacancies further promoted Zn2+ diffusion kinetics of the KNVO cathode in AZIBs and achieved excellent rate performance (344 mA h g-1 at 10 A g-1).

Parental Support Is Associated with Moderate to Vigorous Physical Activity among Chinese Adolescents through the Availability of Physical Activity Resources in the Home Environment and Autonomous Motivation.

This study aimed to use a structural equation model (SEM) to determine the association between parental support and moderate to vigorous physical activity (MVPA) among Chinese adolescents and whether the availability of physical activity (PA) resources in the home environment and autonomous motivation of adolescents mediated the association. Data were collected using questionnaires extracted from the Family Life, Activity, Sun, Health, and Eating (FLASHE) study. A final analytical sample of 3738 adolescents was enrolled. A SEM was performed to evaluate the hypothesized associations. It was found that parental support was not only positively directly but also indirectly associated with MVPA in Chinese boys through the home environment (i.e., availability of PA resources) and the autonomous motivation of adolescents. It is worth noting that the above relationships also exist in Chinese girls, except for the regulatory role of autonomous motivation. These findings suggest that future interventions for increasing adolescents' MVPA should focus on health education for parents to provide more PA resources in the home environment and adequately mobilize children's autonomous motivation.

Association of Body Mass Index and Plant-Based Diet with Cognitive Impairment among Older Chinese Adults: A Prospective, Nationwide Cohort Study.

To examine the association of body mass index (BMI) and a plant-based diet (PBD) with cognitive impairment in older adults, this cohort study used data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), a national, community-based, longitudinal, prospective study in China. Cognitive function was evaluated via the Mini-Mental State Examination (MMSE). Diet was assessed using a simplified food frequency questionnaire (FFQ), and PBD patterns were estimated using the overall plant-based diet index (PDI), the healthful plant-based diet index (hPDI), and the unhealthful plant-based diet index (uPDI). BMI was measured objectively during the physical examination. Cox proportional hazard models and restricted cubic spline analyses were used. A total of 4792 participants with normal cognition at baseline were included, and 1077 participants were identified as having developed cognitive impairment during the 24,156 person-years of follow-up. A reverse J-shaped association was observed between BMI and cognitive impairment (p = 0.005 for nonlinearity). Participants who were overweight (HR = 0.79; 95% CI 0.66-0.95) and obese (HR = 0.72; 95% CI 0.54-0.96) had a decreased risk of cognitive impairment, while those who were underweight (HR = 1.42; 95% CI 1.21-1.66) had an increased risk. Lower PDI, lower hPDI, and higher uPDI were associated with an increased risk of cognitive impairment (HR = 1.32; 95% CI 1.16-1.50 for PDI; HR = 1.46; 95% CI 1.29-1.66 for hPDI; HR = 1.21; 95% CI 1.06-1.38 for uPDI). The protective effect of being overweight on cognitive impairment was more pronounced among participants with a higher PDI (HR = 0.74; 95% CI 0.57-0.95) than those with a lower PDI (HR = 0.87; 95% CI 0.67-1.12), among participants with a higher hPDI (HR = 0.73; 95% CI 0.57-0.94) than those with a lower hPDI (HR = 0.93; 95% CI 0.72-1.10), and among participants with a lower uPDI (HR = 0.61; 95% CI 0.46-0.80) than those with a higher uPDI (HR = 1.01; 95% CI 0.80-1.27). Our results support the positive associations of overweight status, obesity, an overall PBD, and a healthful PBD with cognitive function in older adults. A lower adherence to an overall PBD, a healthful PBD, and a higher adherence to an unhealthful PBD may attenuate the protective effect of being overweight on cognitive function.

Corrosion Behavior of Alx(CrFeNi)1-x HEA under Simulated PWR Primary Water.

High-entropy alloys (HEAs) have great potential as accident-tolerant fuel (ATF) cladding. Aluminum-forming duplex (BCC and FCC) stainless-steel (ADSS) is a candidate for ATF cladding, but the multiphase composition is detrimental to its corrosion resistance. In this paper, two single-phase HEAs were prepared by adjusting the content of each element in the ADSS alloy. The two HEAs were designed as Al0.05(CrFeNi)0.95(FCC) and Al0.25(FeCrNi)0.75(BCC). Their corrosion behavior under simulated pressurized water reactor (PWR) primary water was investigated. The corrosion products and corrosion mechanisms of these two HEAs were explored. The results show that the corrosion resistance of HEA alloys containing FCC is better than that of BCC and ADSS alloys. At the same time, the reason why the BCC structure composed of these four elements is not resistant to corrosion is revealed.

Associations of Social Jetlag with Dietary Behavior, Physical Activity and Obesity among Chinese Adolescents.

This study aimed to investigate the associations between social jetlag (SJL), dietary behavior, physical activity, and weight status in Chinese youth. Data were derived from a cross-sectional survey in Wuhan, China in 2019. Information on SJL, the frequency of food and beverage consumption, physical activity, and BMI category were collected via a self-reported questionnaire. The Kruskal-Wallis test and ANOVA were conducted to determine differences in daily consumption frequency of food and beverage groups, BMI category, and physical activity among SJL groups. Logistic regressions and restricted cubic splines were performed to test the association between SJL and the incidence of overweight or obesity. A final sample of 3567 Chinese adolescents [mean (SD) age, 14.67 (1.72) years; 47.41% (1691) female] were included. Our findings demonstrated that adolescents with SJL may consume more unhealthy foods and fewer beneficial foods, while engaging in less moderate to vigorous physical activity (MVPA) and reporting higher BMIs. In addition, adolescents who experience more than 2 h of SJL had significant greater risk of overweight or obesity. Our findings on SJL of Chinese adolescents confirm the harmful effects of SJL and also provide insights into the etiology of obesity in Chinese adolescents.

Photocurrent, humidity sensitivity and proton conductivity properties of a new sulfide semiconductor CsCuS4.

Copper chalcogenides have drawn considerable attention due to their prominent semiconducting properties. A new Cu-containing semiconductor, namely, CsCuS4 (1), was obtained by a halide salt flux method. Its structure featured 1D infinite ∞1[CuS4] - chains, where the polysulfide anion S42- was relatively rare in Cu chalcogenides. The compound was multifunctional and exhibited significant photocurrent, humidity sensitivity, and proton conductivity properties. Specifically, it exhibits an "on" state photocurrent response of 0.95 µA cm-2 and an "off" state photocurrent response of 0.55 µA cm-2 with good reversibility. The humidity-sensitive resistance in dry air (10% RH) could reach up to six orders of magnitude higher than that in wet air (100% RH). Compound 1 showed an activation energy of 0.19 eV and may have potential electrochemical applications.

Body Mass Index, Waist Circumference, and Cognitive Decline Among Chinese Older Adults: A Nationwide Retrospective Cohort Study.

Background: The reported associations between body mass index (BMI), waist circumference (WC), and cognitive decline are not consistent, especially in older adults. Objective: This study aims to investigate the longitudinal associations of BMI, WC, and their change values with cognitive decline among Chinese adults aged 60 years and older and to examine the potential moderating effect of sex on these relationships. Methods: The participants in this study were from waves one to four (2011-2018) of the China Health and Retirement Longitudinal Study (CHARLS). Cognition function, BMI, and WC were measured at four examinations over 7 years. The interview-based cognitive assessments of memory, orientation and attention, and visuospatial ability were recorded. Standardized global cognitive scores were generated. BMI and WC were objectively measured. Mixed-effects models were performed to evaluate the associations. Results: A final sample of 3,035 Chinese older adults [mean (SD) age, 66.94 (5.43) years; 40.16% (n = 1,219) women] were included. Higher BMI (estimate = 0.0107; SE = 0.0024; p < 0.0001) and WC (estimate = 0.0019; SE = 0.0006; p = 0.0037) were associated with slower cognition score decline over a 7-year follow-up, while greater BMI variability (estimate = -0.0365; SE = 0.0116; p = 0.0017) was related to faster cognition score decline. The results were not modified by sex. BMI-defined overweight (estimate = 0.0094; SE = 0.0043; p = 0.0298) was associated with a slower cognition score decline, and both large weight gain (estimate = -0.0266; SE = 0.0074; p = 0.0003) and large WC loss (estimate = -0.0668; SE = 0.0329; p = 0.0426) were associated with faster cognition score decline. Conclusion: Among Chinese older adults, higher BMI, higher WC, and overweight are related to slower cognitive decline, while greater BMI variability, large weight gain, and large WC loss are associated with faster cognitive decline.

Artemisinin inhibits NRas palmitoylation by targeting the protein acyltransferase ZDHHC6.

Protein S-palmitoylation is a post-translational modification that plays a crucial role in cancer cells by regulating the function and localization of oncoproteins and tumor suppressor proteins. Here, we identify artemisinin (ART), a clinically approved antimalarial endoperoxide natural product with promising anticancer activities, as an inhibitor of the ER-residing palmitoyl transferase ZDHHC6 in cancer cells using a chemoproteomic approach. We show that ART covalently binds and inhibits ZDHHC6 to reduce palmitoylation of the oncogenic protein NRas, disrupt NRas subcellular localization, and attenuate the downstream pro-proliferative signaling cascades. Our study identifies artemisinin as a non-lipid-based palmitoylation inhibitor targeting a specific palmitoyl acyltransferase and provides valuable mechanistic insights into the anticancer activity of artemisinins that are currently being studied in human clinical trials for different cancers.

Modeling Parental Influence on Food Consumption among Chinese Adolescents through Self-Efficacy: A Path Analysis.

This study aimed to investigate the associations between perceived parental control, perceived parental modeling and parent-teen co-decision making, and fruit and vegetable (F&V) and sugar-sweetened beverage and junk food (S&J) consumption among Chinese adolescents, and examine whether self-efficacy mediates the associations. Data were collected in a cross-sectional survey of Chinese adolescents carried out in the fall of 2019. The questionnaires were adapted from the Family Life, Activity, Sun, Health, and Eating (FLASHE) Study. Ordinary least-squares regressions and a path analysis were performed to evaluate the hypothesized associations. The final sample included 3595 Chinese adolescents (mean (SD) age, 14.67 (1.73) years; 52.82% (n = 1899) males). Perceived parental control was positively associated with adolescents' F&V consumption, and was negatively associated with adolescents' S&J consumption. Perceived parental modeling and parent-teen co-decision making were both positively associated with adolescents' F&V consumption and negatively associated with their S&J consumption. Adolescents' self-efficacy was positively associated with F&V consumption and negatively associated with S&J consumption. These results suggest that serving as a positive role model, having adolescents participate in the decision-making process, and increasing adolescents' self-efficacy can be feasible and efficacious strategies to improve the nutritional quality of Chinese adolescents' diets.

MICU3 regulates mitochondrial Ca2+-dependent antioxidant response in skeletal muscle aging.

Age-related loss of skeletal muscle mass and function, termed sarcopenia, could impair the quality of life in the elderly. The mechanisms involved in skeletal muscle aging are intricate and largely unknown. However, more and more evidence demonstrated that mitochondrial dysfunction and apoptosis also play an important role in skeletal muscle aging. Recent studies have shown that mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium affects skeletal muscle mass and function by affecting mitochondrial function. During aging, we observed downregulated expression of mitochondrial calcium uptake family member3 (MICU3) in skeletal muscle, a regulator of MCU, which resulted in a significant reduction in mitochondrial calcium uptake. However, the role of MICU3 in skeletal muscle aging remains poorly understood. Therefore, we investigated the effect of MICU3 on the skeletal muscle of aged mice and senescent C2C12 cells induced by D-gal. Downregulation of MICU3 was associated with decreased myogenesis but increased oxidative stress and apoptosis. Reconstitution of MICU3 enhanced antioxidants, prevented the accumulation of mitochondrial ROS, decreased apoptosis, and increased myogenesis. These findings indicate that MICU3 might promote mitochondrial Ca2+ homeostasis and function, attenuate oxidative stress and apoptosis, and restore skeletal muscle mass and function. Therefore, MICU3 may be a potential therapeutic target in skeletal muscle aging.

Chemoproteomic Profiling by Cysteine Fluoroalkylation Reveals Myrocin G as an Inhibitor of the Nonhomologous End Joining DNA Repair Pathway.

Chemoproteomic profiling of cysteines has emerged as a powerful method for screening the proteome-wide targets of cysteine-reactive fragments, drugs, and natural products. Herein, we report the development and an in-depth evaluation of a tetrafluoroalkyl benziodoxole (TFBX) as a cysteine-selective chemoproteomic probe. We show that this probe features numerous key improvements compared to the traditionally used cysteine-reactive probes, including a superior target occupancy, faster labeling kinetics, and broader proteomic coverage, thus enabling profiling of cysteines directly in live cells. In addition, the fluorine "signature" of probe 7 constitutes an additional advantage resulting in a more confident adduct-amino acid site assignment in mass-spectrometry-based identification workflows. We demonstrate the utility of our new probe for proteome-wide target profiling by identifying the cellular targets of (-)-myrocin G, an antiproliferative fungal natural product with a to-date unknown mechanism of action. We show that this natural product and a simplified analogue target the X-ray repair cross-complementing protein 5 (XRCC5), an ATP-dependent DNA helicase that primes DNA repair machinery for nonhomologous end joining (NHEJ) upon DNA double-strand breaks, making them the first reported inhibitors of this biomedically highly important protein. We further demonstrate that myrocins disrupt the interaction of XRCC5 with DNA leading to sensitization of cancer cells to the chemotherapeutic agent etoposide as well as UV-light-induced DNA damage. Altogether, our next-generation cysteine-reactive probe enables broader and deeper profiling of the cysteinome, rendering it a highly attractive tool for elucidation of targets of electrophilic small molecules.