Chemistry-Enabled Intercellular Enzymatic Labeling for Monitoring the Immune Effects of Cytotoxic T Lymphocytes In Vivo.

Monitoring the effector function of cytotoxic T lymphocytes (CTLs) in vivo remains a great challenge. Here, we develop a chemistry-enabled enzymatic labeling approach to evaluate the tumor-specific immune response of CTLs by precisely monitoring the interaction between CTLs and tumor cells. Staphylococcus aureus sortase A (SrtA) is linked to the CTL surface through bioconjugate chemistry and then catalyzes the transfer of fluorescent-labeled substrate, 5-Tamra-LPETG, to CTLs. Meanwhile, the tumor cells are specifically decorated with N-terminal glycine residues (G5 peptide) through the inherent glycolmetabolism of cathepsin B-specific cleavable triacetylated N-azidoacetyl-d-mannosamine (CB-Ac3ManNAz) and click chemistry. After the infiltration of engineered CTLs into the tumor tissues, the immune-synapse-mediated specific interaction of CTLs and tumor cells leads to the accurate fluorescent labeling of tumor cells through the SrtA-catalyzed 5-Tamra-LPETG transfer. Therefore, the immune effect of CTLs as well as the performance of immune drugs can be determined, providing a novel strategy for pushing ahead immunotherapy.

Intravitreal indocyanine green is toxic to the retinal cells.

BACKGROUND: Indocyanine green (ICG) is widely used to stain the epiretinal membranes and internal limiting membranes during the pars plana vitrectomy (PPV). This study aims to evaluate the effect of ICG on rat retinas and various retinal cell lines, including ARPE-19 cells, rMC-1 cells, BV2 cells, HRMECs and R28 cells. METHODS: ICG solutions were prepared and diluted with glucose solution (GS) according to the standard clinical protocols. The retinal cell lines, including ARPE-19 cells, rMC-1 cells, BV2 cells, HRMECs and R28 cells, were treated with the following solutions: normal glucose (NG, 5 mM), GS-1 (92.5 mM glucose), GS-2 (185.02 mM glucose), ICG-1 (92.5 mM glucose + 0.43 mM ICG), or ICG-2 (185.02 mM glucose + 0.86 mM ICG) for durations of 15 or 30 min. In vivo, the right eyes of the rats were intravitreally injected with ICG-1 or ICG-2 (2 µL), while the left eyes were intravitreally injected with GS-1 or GS-2, served as the osmotic controls, for 30 min or 60 min. The rats intravitreally injected with an equivalent volume of NG or 1x phosphate-buffered saline (1x PBS) were served as the normal control or vehicle control. The cell viability was measured with the Cell Counting Kit-8 (CCK-8), while the cell death in retinal cryosections was detected with the TUNEL assay. RESULTS: The viabilities of the different retinal cell lines involved in this study were significantly reduced by both ICG-1 and ICG-2 treatments at both time points, with ICG-2 resulting in lower cell viability compared to the NG group and the osmotic control group. Additionally, GS-2 treatment also exhibited a decrease in retinal cell viabilities in vitro. To further confirm these results, intravitreal injection of ICG or GS induced more apoptotic cell death in rat retinas as evidenced by the TUNEL assay. CONCLUSIONS: The exposure of ICG or its solvent leads to an augmented retinal cell death, which is directly proportional to the concentration and duration of exposure, both in vivo and in vitro. Caution should be exercised during vitrectomy procedures involving ICG administration during clinical practice. It is recommended to advocate for lower concentrations of ICG with reduced exposure time during ocular surgeries.

Wnt5a/ß-catenin-mediated epithelial-mesenchymal transition: a key driver of subretinal fibrosis in neovascular age-related macular degeneration.

BACKGROUND: Neovascular age-related macular degeneration (nAMD), accounts for up to 90% of AMD-associated vision loss, ultimately resulting in the formation of fibrotic scar in the macular region. The pathogenesis of subretinal fibrosis in nAMD involves the process of epithelial-mesenchymal transition (EMT) occurring in retinal pigment epithelium (RPE). Here, we aim to investigate the underlying mechanisms involved in the Wnt signaling during the EMT of RPE cells and in the pathological process of subretinal fibrosis secondary to nAMD. METHODS: In vivo, the induction of subretinal fibrosis was performed in male C57BL/6J mice through laser photocoagulation. Either FH535 (a ß-catenin inhibitor) or Box5 (a Wnt5a inhibitor) was intravitreally administered on the same day or 14 days following laser induction. The RPE-Bruch's membrane-choriocapillaris complex (RBCC) tissues were collected and subjected to Western blot analysis and immunofluorescence to examine fibrovascular and Wnt-related markers. In vitro, transforming growth factor beta 1 (TGFß1)-treated ARPE-19 cells were co-incubated with or without FH535, Foxy-5 (a Wnt5a-mimicking peptide), Box5, or Wnt5a shRNA, respectively. The changes in EMT- and Wnt-related signaling molecules, as well as cell functions were assessed using qRT-PCR, nuclear-cytoplasmic fractionation assay, Western blot, immunofluorescence, scratch assay or transwell migration assay. The cell viability of ARPE-19 cells was determined using Cell Counting Kit (CCK)-8. RESULTS: The in vivo analysis demonstrated Wnt5a/ROR1, but not Wnt3a, was upregulated in the RBCCs of the laser-induced CNV mice compared to the normal control group. Intravitreal injection of FH535 effectively reduced Wnt5a protein expression. Both FH535 and Box5 effectively attenuated subretinal fibrosis and EMT, as well as the activation of ß-catenin in laser-induced CNV mice, as evidenced by the significant reduction in areas positive for fibronectin, alpha-smooth muscle actin (α-SMA), collagen I, and active ß-catenin labeling. In vitro, Wnt5a/ROR1, active ß-catenin, and some other Wnt signaling molecules were upregulated in the TGFß1-induced EMT cell model using ARPE-19 cells. Co-treatment with FH535, Box5, or Wnt5a shRNA markedly suppressed the activation of Wnt5a, nuclear translocation of active ß-catenin, as well as the EMT in TGFß1-treated ARPE-19 cells. Conversely, treatment with Foxy-5 independently resulted in the activation of abovementioned molecules and subsequent induction of EMT in ARPE-19 cells. CONCLUSIONS: Our study reveals a reciprocal activation between Wnt5a and ß-catenin to mediate EMT as a pivotal driver of subretinal fibrosis in nAMD. This positive feedback loop provides valuable insights into potential therapeutic strategies to treat subretinal fibrosis in nAMD patients.

T3SS protein EsrC binds to the lacI-like operator of type 1 fimbrial operon to suppress adhesion of Edwardsiella piscicida.

Type 1 fimbria, the short hair-like appendage assembled on the bacterial surface, plays a pivotal role in adhesion and invasion in Edwardsiella piscicida. The type III secretion system (T3SS), another bacterial surface appendage, facilitates E. piscicida's replication in vivo by delivering effectors into host cells. Our previous research demonstrated that E. piscicida T3SS protein EseJ inhibits adhesion and invasion of E. piscicida by suppressing type 1 fimbria. However, how EseJ suppresses type 1 fimbria remains elusive. In this study, a lacI-like operator (nt -245 to -1 of fimA) upstream of type 1 fimbrial operon in E. piscicida was identified, and EseJ inhibits type 1 fimbria through the lacI-like operator. Moreover, through DNA pull-down and electrophoretic mobility shift assay, an AraC-type T3SS regulator, EsrC, was screened and verified to bind to nt -145 to -126 and nt -50 to -1 of fimA, suppressing type 1 fimbria. EseJ is almost abolished upon the depletion of EsrC. EsrC and EseJ impede type 1 fimbria expression. Intriguingly, nutrition and microbiota-derived indole activate type 1 fimbria through downregulating T3SS, alleviating EsrC or EseJ's inhibitory effect on lacI-like operator of type 1 fimbrial operon. By this study, it is revealed that upon entering the gastrointestinal tract, rich nutrients and indole downregulate T3SS and thereof upregulate type 1 fimbria, stimulating efficient adhesion and invasion; upon being internalized into epithelium, the limit in indole and nutrition switches on T3SS and thereof switches off type 1 fimbria, facilitating effector delivery to guarantee E. piscicida's survival/replication in vivo.IMPORTANCEIn this work, we identified the lacI-like operator of type 1 fimbrial operon in E. piscicida, which was suppressed by the repressors-T3SS protein EseJ and EsrC. We unveiled that E. piscicida upregulates type 1 fimbria upon sensing rich nutrition and the microbiota-derived indole, thereof promoting the adhesion of E. piscicida. The increase of indole and nutrition promotes type 1 fimbria by downregulating T3SS. The decrease in EseJ and EsrC alleviates their suppression on type 1 fimbria, and vice versa.

The Prognostic Utility of the Triceps Skinfold Thickness Albumin Index in Colorectal Cancer Patients with Cachexia.

PURPOSE: To develop a simple and convenient inflammation-nutrition-adiposity biomarker to complement the TNM staging system, further assess the prognosis of patients with colorectal cancer cachexia. METHODS: This study was a multi-centre cohort study. The triceps skinfold thickness-albumin index (TA) was calculated by combining the triceps skinfold thickness (TSF) and serum albumin levels. Kaplan-Meier analysis and Cox proportional risk regression models were used to assess the relationship between the TA and all-cause mortality. Internal validation was carried out. RESULTS: We included 1025 patients with colorectal cancer cachexia, 61.2% of whom were male, with a mean age of 58.91 (12.45) years. As the TA increased, overall mortality decreased in female patients (hazard ratio [HR], 0.95) but not in male patients (HR, 0.99). Multivariate Cox analysis showed that patients in the normal TA group had a significantly lower risk of death than those in the low TA group (HR, 0.53, 95% CI, 0.40-0.72). Patients with a normal TA had a lower risk of malnutrition, poor quality of life, and poor short-term prognosis than those with a low TA. CONCLUSIONS: TA index enables clinicians to assess the prognosis of patients as early as possible to improve the survival of patients with colorectal cancer cachexia.

Geriatric Nutritional Risk Index Combined with Calf Circumference Can be a Good Predictor of Prognosis in Patients Undergoing Surgery for Gastric or Colorectal Cancer.

OBJECTIVES: To explore the effect of combined hematological and physical measurement indicators on the prognosis of patients undergoing surgery for gastric or colorectal cancer and to screen for the best prognostic indicators. INTRODUCTION: Gastric and colorectal cancer is a widespread health concern worldwide and one of the major contributors to cancer-related death. The hematological and physical measurement indicators have been shown to associate with the prognosis of patients undergoing surgery for gastric or colorectal cancer, respectively, but it is still unclear whether the combination of the two can reflect the prognosis more effectively. METHODS: Thirteen hematological indicators and 5 physical measurement indicators were selected in this study, and the most promising ones were screened using LASSO regression. Then, the best prognostic indicators were selected by time-ROC curves. Survival curves were constructed using the Kaplan-Meier method, and the effects of hematological and physical measurement indicators on the prognosis of patients undergoing surgery for gastric or colorectal cancers were evaluated by Cox proportional risk regression analysis. In addition, the relationship between hematological and physical measurement indicators on secondary outcomes, including length of stay, hospitalization costs, intensive care unit (ICU) admission, and patients' subjective global assessment scores (PGSGA), was explored. RESULTS: After initial screening, among the hematological indicators, the geriatric nutritional risk index (GNRI) showed the highest mean area under the curve (AUC) values. Among body measures, calf circumference (CC) showed the highest mean AUC value. Further analyses showed that the combination of combined nutritional prognostic index (GNRI) and calf circumference (CC) (GNRI-CC) had the best performance in predicting the prognosis of patients undergoing surgery for gastric or colorectal cancers. Low GNRI, low CC, and low GNRI-low CC increased the risk of death by 44%, 48%, and 104%, respectively. Sensitivity analyses showed the same trend. In addition, low GNRI-low CC increased the risk of malnutrition by 17%. CONCLUSION: This study emphasizes that a combination of blood measures and body measures is essential to accurately assess the prognosis of patients undergoing surgery for gastric or colorectal cancers. The GNRI-CC is a good prognostic indicator and can also assess the risk of possible malnutrition.

Prevalence, Trends and Correlates of HIV, Syphilis and HCV Infection Among Chinese Local and Cross-border Migrant Female Sex Workers in the Sino-Vietnam Border Area of Guangxi, 2016-2021.

Female sex workers (FSWs) are considered a high-risk group for sexually transmitted infections (STIs). However, limited data exist on the prevalence and trends of HIV, syphilis and HCV among FSWs in the Sino-Vietnam border area. To determine the prevalence, trends and correlates of STIs among Chinese local FSWs (CL-FSWs) and cross-border migrant FSWs (CM-FSWs), we conducted consecutive cross-sectional surveys from 2016 to 2021, recruiting 7747 CL-FSWs and 932 CM-FSWs. The overall HIV, syphilis and HCV prevalence declined from 1.0%, 8.8% and 1.7% to 0.1%, 0.9% and 0.3%, respectively. There was no significant downward trend in the overall HIV and syphilis prevalence. However, HCV prevalence showed a decreasing trend among CL-FSWs. CM-FSWs had higher HIV prevalence (2.5% vs. 0.6%). Similarities and differences in STIs-related factors existed between CM-FSWs and CL-FSWs. For instance, receiving HIV-related services in the last year reduced the risk of HIV infection (for CM-FSWs: aOR = 0.234, 95% CI: 0.055-0.993; for CL-FSWs: aOR = 0.182, 95% CI: 0.058-0.567). Serving male clients at least 50 years old increased the risk of syphilis infection (for CM-FSWs: aOR = 4.277, 95% CI: 1.535-11.917; for CL-FSWs: aOR = 1.404, 95% CI: 1.087-1.815). Moreover, CM-FSWs with past-year STIs history had a higher risk of HIV (aOR = 34.976, 95% CI: 5.338-229.176) and HCV infection (aOR = 17.649, 95% CI: 1.846-168.846), both of which were associated with multiple factors in CL-FSWs. It is therefore necessary to develop effective, accessible, high-quality and targeted interventions for CM-FSWs and CL-FSWs.

Causal relationships between vitamin E and multiple kidney diseases: evidence from trans-ethnic Mendelian randomization study.

PURPOSE: The association between vitamin E and the risk of kidney disease is well documented in observational studies, but the role of vitamin E in kidney disease remain inconclusive. Here, we evaluated the causal effect of vitamin E on the risk of multiple kidney diseases, including chronic kidney disease, membranous nephropathy, diabetic nephropathy, IgA nephropathy, and dialysis. METHODS: We conducted a two-sample Mendelian randomization analysis from large-scale trans-ancestry genome-wide association studies to determine whether there was a significant causal relationship between vitamin E and multiple kidney diseases in European, American, and Asian ancestry. Instrumental genetic variants associated with vitamin E were selected, and summary statistic-based methods of inverse variance weighted, MR Egger, weighted median, simple mode, and weighted mode methods were conducted. Pleiotropy and sensitivity were assessed. RESULTS: We obtained 87 instrumental genetic variants in European ancestry and found no causal relationship between vitamin E and chronic kidney disease, membranous nephropathy, diabetic nephropathy, IgA nephropathy, and dialysis with no heterogeneity and pleiotropy. We obtained 18 instrumental genetic variants in Asian ancestry and vitamin E had no causal relationship with membranous nephropathy, diabetic nephropathy, and IgA nephropathy with no heterogeneity and pleiotropy. In African ancestry, 25 instrumental genetic variants were obtained and no causal relationship was identified with no heterogeneity and pleiotropy. CONCLUSION: Our study first suggested plausible non-causal associations between vitamin E and multiple kidney diseases among different ancestry.

Exploring the impact of women-specific reproductive factors on phenotypic aging and the role of life's essential 8.

BACKGROUND: Aging is an inevitable biological process. Accelerated aging renders adults more susceptible to chronic diseases and increases their mortality rates. Previous studies have reported the relationship between lifestyle factors and phenotypic aging. However, the relationship between intrinsic factors, such as reproductive factors, and phenotypic aging remains unclear. METHODS: This study utilized data from the National Health and Nutrition Examination Survey (NHANES), spanning from 1999 to 2010 and 2015-2018, with 14,736 adult women. Random forest imputation was used to handle missing covariate values in the final cohort. Weighted linear regression was utilized to analyze the relationship between women-specific reproductive factors and PhenoAgeAccel. Considering the potential impact of menopausal status on the results, additional analyses were conducted on premenopausal and postmenopausal participants. Additionally, the Life's Essential 8 (LE8) was used to investigate the impact of healthy lifestyle and other factors on the relationship between women-specific reproductive factors and PhenoAgeAccel. Stratified analyses were conducted based on significant interaction p-values. RESULTS: In the fully adjusted models, delayed menarche and gynecological surgery were associated with increased PhenoAgeAccel, whereas pregnancy history were associated with a decrease. Additionally, early or late ages of menopause, first live birth, and last live birth can all negatively impact PhenoAgeAccel. The relationship between women-specific reproductive factors and PhenoAgeAccel differs between premenopausal and postmenopausal women. High LE8 scores positively impacted the relationship between certain reproductive factors (age at menarche, age at menopause, age at first live birth, and age at last live birth) and phenotypic age acceleration. Stratified analysis showed significant interactions for the following variables: BMI with age at menarche, pregnancy history, and age at menopause; ethnicity with age at menopause, age at first live birth, and parity; smoking status with use of contraceptive pills and gynecologic surgery; hypertension with use of contraceptive pills, pregnancy history, and age at menopause. CONCLUSION: Delayed menarche, gynecological surgery, and early or late ages of menopause, first live birth, and last live birth are associated with accelerated phenotypic aging. High LE8 score may alleviate the adverse effects of reproductive factors on phenotypic aging.

The application of Chinese version of SARC-F and SARC-CalF in sarcopenia screening against five definitions: a diagnostic test accuracy study.

BACKGROUND: SARC-F questionnaire is a simple and convenient tool for sarcopenia screening, and SARC-CalF is a modified version of it. The developments of their Chinese versions are warranted for the clinical use for Chinese population. This study aimed to culturally adapt the SARC-F questionnaire into Chinese using standardized methods, validate the reliability and diagnostic accuracy of the Chinese version SARC-F and SARC-CalF against five sarcopenia diagnosis criteria, and determine optimal cut-off values for clinical practice in Chinese population. METHODS: The translation and cross-cultural adaptation of SARC-F into Chinese were conducted following the methodological report from European Union Geriatric Medicine Society Sarcopenia Special Interest Group. The Chinese version of SARC-F was validated through a diagnostic test, using diagnostic criteria of sarcopenia recommended by the revised 2019 European Working Group on Sarcopenia in Older People (EWGSOP2) consensus, Asian Working Group for Sarcopenia (AWGS2019) consensus, the International Working Group on Sarcopenia (IWGS), the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium and the Sarcopenia Definition and Outcomes Consortium (SDOC). Additional analysis was done against the criteria of severe sarcopenia according to the revised EWGSOP2 and AWGS2019. RESULTS: The Chinese version of SARC-F was well translated and demonstrated good reliability and acceptability. The diagnostic test included 1859 community-dwelling older individuals from two medical centers. Against five different definitions of sarcopenia, the Chinese version of SARC-F showed reasonable diagnostic accuracy for sarcopenia screening (AUC 0.614-0.821), and was demonstrated low sensitivity (13.7-37.9%) but high specificity (94.8-97.7%) with a cut-off value of ≥ 4. SARC-CalF significantly enhanced the diagnostic accuracy of SARC-F when using definitions of EWGSOP2, AWGS2019 and IWGS (all P ≤ 0.001). A score of ≥ 2 for SARC-F and ≥ 7 for SARC-CalF were established as optimal cut-off points for identifying older individuals as at risk of sarcopenia in Chinese population. CONCLUSIONS: The Chinese version SARC-F is of reasonable reliability and validity for sarcopenia screening. Despite its low sensitivity, it proves to be a useful tool to identify severe cases in community taking advantage of its simplicity. SARC-CalF appears to be a more suitable screening tool for clinical use in detecting sarcopenia.

Expression and Clinical Significance of MAGE-A Proteins and mRNA in Lung Cancer Patients: A Retrospective Study.

Objective: This study investigated the expression and clinical significance of Melanoma Associated Antigen (MAGE)-A proteins and mRNA in patients with non-small cell lung cancer (NSCLC). Methods: A retrospective study was conducted, and we selected a cohort of 88 NSCLC patients treated at our hospital from January 2015 to January 2020. Adjacent tissues were chosen as controls. The expression of MAGE-A proteins in lung cancer and adjacent tissues was assessed via Western blot, while MAGE-As mRNA expression was measured using RT-PCR. Results: The relative expression levels of MAGE-A proteins and mRNA in NSCLC tissues were significantly higher than those in adjacent tissues (P < .05), with values of (0.343 ± 0.101) and (0.728 ± 0.112), respectively. Furthermore, MAGE-As protein expression was significantly higher in stage III - IV lung cancer compared to stage I - II (P < .05). No significant differences were observed in MAGE-A protein expression concerning gender, age, tumor diameter, pathological type, and differentiation degree (P > .05). The relative expression of MAGE-As mRNA was significantly higher in clinical stage III - IV and moderately differentiated lung cancer tissues compared to stage I - II and well-differentiated tissues (P < .05). No significant differences were found in MAGE-As mRNA expression concerning gender, age, tumor diameter, and pathological type (P > .05). Patients with high MAGE-As mRNA expression had a significantly shorter median overall survival of 33 months (95% CI: 31.64-34.36) compared to those with low MAGE-As mRNA expression (P < .05). However, no significant difference was observed in median overall survival between patients with high and low MAGE-As protein expression (P > .05). Conclusions: In NSCLC, the up-regulation of MAGE-A proteins and mRNA is associated with clinical stage and differentiation degree, warranting further investigation.

Baicalin protects against hepatocyte injury caused by aflatoxin B1 via the TP53-related ferroptosis Pathway.

OBJECTIVE: Baicalin has antioxidative, antiviral, and anti-inflammatory properties. However, its ability to alleviate oxidative stress (OS) and DNA damage in liver cells exposed to aflatoxin B1 (AFB1), a highly hepatotoxic compound, remains uncertain. In this study, the protective effects of baicalin on AFB1-induced hepatocyte injury and the mechanisms underlying those effects were investigated. METHODS: Stable cell lines expressing CYP3A4 were established using lentiviral vectors to assess oxidative stress levels by conducting assays to determine the content of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Additionally, DNA damage was evaluated by 8-hydroxy-2-deoxyguanosine (8-OHdG) and comet assays. Transcriptome sequencing, molecular docking, and in vitro experiments were conducted to determine the mechanisms underlying the effects of baicalin on AFB1-induced hepatocyte injury. In vivo, a rat model of hepatocyte injury induced by AFB1 was used to evaluate the effects of baicalin. RESULTS: In vitro, baicalin significantly attenuated AFB1-induced injury caused due to OS, as determined by a decrease in ROS, MDA, and SOD levels. Baicalin also considerably decreased AFB1-induced DNA damage in hepatocytes. This protective effect of baicalin was found to be closely associated with the TP53-mediated ferroptosis pathway. To elaborate, baicalin physically interacts with P53, leading to the suppression of the expression of GPX4 and SLC7A11, which in turn inhibits ferroptosis. In vivo findings showed that baicalin decreased DNA damage and ferroptosis in AFB1-treated rat liver tissues, as determined by a decrease in the expression of γ-H2AX and an increase in GPX4 and SLC7A11 levels. Overexpression of TP53 weakened the protective effects of baicalin. CONCLUSIONS: Baicalin can alleviate AFB1-induced OS and DNA damage in liver cells via the TP53-mediated ferroptosis pathway. In this study, a theoretical foundation was established for the use of baicalin in protecting the liver from the toxic effects of AFB1.

Measuring Human Auditory Evoked Fields with a Flexible Multi-Channel OPM-Based MEG System.

BACKGROUND: Magnetoencephalography (MEG) is a non-invasive imaging technique for directly measuring the external magnetic field generated from synchronously activated pyramidal neurons in the brain. The optically pumped magnetometer (OPM) is known for its less expensive, non-cryogenic, movable and user-friendly custom-design provides the potential for a change in functional neuroimaging based on MEG. METHODS: An array of OPMs covering the opposite sides of a subject's head is placed inside a magnetically shielded room (MSR) and responses evoked from the auditory cortices are measured. RESULTS: High signal-to-noise ratio auditory evoked response fields (AEFs) were detected by a wearable OPM-MEG system in a MSR, for which a flexible helmet was specially designed to minimize the sensor-to-head distance, along with a set of bi-planar coils developed for background field and gradient nulling. Neuronal current sources activated in AEF experiments were localized and the auditory cortices showed the highest activities. Performance of the hybrid optically pumped magnetometer-magnetoencephalography/electroencephalography (OPM-MEG/EEG) system was also assessed. CONCLUSIONS: The multi-channel OPM-MEG system performs well in a custom built MSR equipped with bi-planar coils and detects human AEFs with a flexible helmet. Moreover, the similarities and differences of auditory evoked potentials (AEPs) and AEFs are discussed, while the operation of OPM-MEG sensors in conjunction with EEG electrodes provides an encouraging combination for the exploration of hybrid OPM-MEG/EEG systems.

Nanoprobe-based molecular imaging for tumor stratification.

The responses of patients to tumor therapies vary due to tumor heterogeneity. Tumor stratification has been attracting increasing attention for accurately distinguishing between responders to treatment and non-responders. Nanoprobes with unique physical and chemical properties have great potential for patient stratification. This review begins by describing the features and design principles of nanoprobes that can visualize specific cell types and biomarkers and release inflammatory factors during or before tumor treatment. Then, we focus on the recent advancements in using nanoprobes to stratify various therapeutic modalities, including chemotherapy, radiotherapy (RT), photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), ferroptosis, and immunotherapy. The main challenges and perspectives of nanoprobes in cancer stratification are also discussed to facilitate probe development and clinical applications.

Validity of the modified versions of SARC-F+EBM for sarcopenia screening and diagnosis in China: the PPLSS study.

BACKGROUND AND OBJECTIVES: It is recommended by Asian Working Group for Sarcopenia to early identify people at risk for sarcopenia using simple screening tools like SARC-F. The modified version SARC-F+EBM showed higher diagnostic performance. However, this cut-off value of body mass index (BMI) remained uncertain to be used in Chinese population. In this study, we used appropriate BMI recommended for Chinese older population and further modified SARC-F+EBM by combining calf circumference. METHODS AND STUDY DESIGN: Diagnostic tests were performed and the receiver operating characteristics analyses were conducted between the SARC-F, SARC-F+EBM (cut-off of BMI: ≤ 21 kg/m2), SARC-F+EBM (CN) (cut-off of BMI: ≤ 22 kg/m2), SARC-CalF and SARC-CalF+EBM (CN) (cut-off of BMI: ≤ 22 kg/m2) in 1660 community-dwelling participants aged ≥ 65 years from China. RESULTS: The participants had an average age of 71.7±5.1 years, of which 56.8% were women. All the modified models could enhance the areas under the receiver operating characteristic curve (AUC) of original SARC-F (all p<0.001). The SARC-F+EBM (CN) also showed a significantly higher sensitivity of 47.4% (p<0.001) and an AUC of 0.809 (p=0.005) than SARC-F+EBM. SARC-CalF+EBM (CN) was validated to be of great diagnostic value of the highest AUC of 0.88 among these sarcopenia screening tools, including SARC-F, SARC-CalF and SARC-F+EBM (CN) (all p<0.001). Using this study population as a reference, the optimal cut-off value of SARC-CalF+EBM (CN) is ≥12 points, with a sensitivity of 79.3% and a specificity of 80.7%. CONCLUSIONS: The SARC-F+EBM (CN) and SARC-CalF+EBM (CN) could enhance the diagnostic performance of SARC-F and SARC-F+EBM and are suitable sarcopenia screening tools for Chinese population.

Biomimetic Nanovesicle with Mitochondria-Synthesized Sonosensitizer and Mitophagy Inhibition for Cancer Sono-Immunotherapy.

Mitochondria are crucial for both sonodynamic therapy and antitumor immunity. However, how to accurately damage mitochondria and meanwhile prevent the mitophagy and immune checkpoint inhibition is still a great challenge. Herein, hexyl 5-aminolevulinate hydrochloride (HAL) and 3-methyladenine (3MA) are loaded into the tumor cell-derived microparticle (X-MP), which can direct the target delivery of the prepared HAL/3MA@X-MP to the tumor cells. HAL induces the confined biosynthesis and accumulation of sonosensitizer PpIX in mitochondria, leading to the localized generation of reactive oxygen species (ROS) upon ultrasound irradiation and, thus, the efficient mitochondrial damage. Meanwhile, 3MA not only inhibits mitophagy but also down-regulates the PD-L1 expression, promoting the immunogenic cell death (ICD) while blocking the immune checkpoint recognition. The smart synergism of precise mitochondrial damage, mitophagy inhibition and antitumor immunity results in potent therapeutic efficacy without obvious side effects.

Fused-Ring Pyrrole-Based Near-Infrared Emissive Organic RTP Material for Persistent Afterglow Bioimaging.

Organic near-infrared room temperature phosphorescence (RTP) materials offer remarkable advantages in bioimaging due to their characteristic time scales and background noise elimination. However, developing near-infrared RTP materials for deep tissue imaging still faces challenges since the small band gap may increase the non-radiative decay, resulting in weak emission and short phosphorescence lifetime. In this study, fused-ring pyrrole-based structures were employed as the guest molecules for the construction of long wavelength emissive RTP materials. Compared to the decrease of the singlet energy level, the triplet energy level showed a more effectively decrease with the increase of the conjugation of the substituent groups. Moreover, the sufficient conjugation of fused ring structures in the guest molecule suppresses the non-radiative decay of triplet excitons. Therefore, a near-infrared RTP material (764 nm) was achieved for deep penetration bioimaging. Tumor cell membrane is used to coat RTP nanoparticles (NPs) to avoid decreasing the RTP performance compared to traditional coating by amphiphilic surfactants. RTP NPs with tumor-targeting properties show favorable phosphorescent properties, superior stability, and excellent biocompatibility. These NPs are applied for time-resolved luminescence imaging to eliminate background interference with excellent tissue penetration. This study provides a practical solution to prepare long-wavelength and long-lifetime organic RTP materials and their applications in bioimaging.

African Suid Genomes Provide Insights into the Local Adaptation to Diverse African Environments.

African wild suids consist of several endemic species that represent ancient members of the family Suidae and have colonized diverse habitats on the African continent. However, limited genomic resources for African wild suids hinder our understanding of their evolution and genetic diversity. In this study, we assembled high-quality genomes of a common warthog (Phacochoerus africanus), a red river hog (Potamochoerus porcus), as well as an East Asian Diannan small-ear pig (Sus scrofa). Phylogenetic analysis showed that common warthog and red river hog diverged from their common ancestor around the Miocene/Pliocene boundary, putatively predating their entry into Africa. We detected species-specific selective signals associated with sensory perception and interferon signaling pathways in common warthog and red river hog, respectively, which contributed to their local adaptation to savannah and tropical rainforest environments, respectively. The structural variation and evolving signals in genes involved in T-cell immunity, viral infection, and lymphoid development were identified in their ancestral lineage. Our results provide new insights into the evolutionary histories and divergent genetic adaptations of African suids.

Muscle distribution in relation to all-cause and cause-specific mortality in young and middle-aged adults.

BACKGROUND: The relationship between muscle and prognosis, especially that between muscle distribution across different body parts, and the related prognosis is not well established. OBJECTIVE: To investigate the relationship between muscle distribution and all-cause and cause-specific mortality and their potential modifiers. DESIGN: Longitudinal cohort study. C-index, IDI, and NRI were used to determine the best indicator of prognosis. COX regression analysis was performed to explore the relationship between variables and outcomes. Interaction and subgroup analyses were applied to identify the potential modifiers. PARTICIPANTS: A total of 5052 participants (weighted: 124,841,420) extracted from the NHANES 2003-2006 of median age 45 years and constituting 50.3% men were assessed. For validation, we included 3040 patients from the INSCOC cohort in China. MAIN MEASURES: Muscle mass and distribution. KEY RESULTS: COX regression analysis revealed that upper limbs (HR = 0.41, 95% CI 0.33-0.51), lower limbs (HR = 0.54, 95% CI 0.47-0.64), trunk (HR = 0.71, 95% CI, 0.59-0.85), gynoid (HR = 0.47, 95% CI 0.38-0.58), and total lean mass (HR = 0.55, 95% CI 0.45-0.66) were all associated with the better survival of participants (P trend < 0.001). The changes in the lean mass ratio of the upper and lower limbs and the lean mass ratio of the android and gynoid attenuated the protective effect of lean mass. Age and sex acted as potential modifiers, and the relationship between lean mass and the prognosis was more significant in men and middle-aged participants when compared to that in other age groups. Sensitive analyses depicted that despite lean mass having a long-term impact on prognosis (15 years), it has a more substantial effect on near-term survival (5 years). CONCLUSION: Muscle mass and its distribution affect the prognosis with a more significant impact on the near-term than that on the long-term prognosis. Age and sex acted as vital modifiers.

Aquaporin 11 alleviates retinal Müller intracellular edema through water efflux in diabetic retinopathy.

Retinal Müller glial dysfunction and intracellular edema are important mechanisms leading to diabetic macular edema (DME). Aquaporin 11 (AQP11) is primarily expressed in Müller glia with unclear functions. This study aims to explore the role of AQP11 in the pathogenesis of intracellular edema of Müller glia in diabetic retinopathy (DR). Here, we found that AQP11 expression, primarily located at the endfeet of Müller glia, was down-regulated with diabetes progression, accompanied by intracellular edema, which was alleviated by intravitreal injection of lentivirus-mediated AQP11 overexpression. Similarly, intracellular edema of hypoxia-treated rat Müller cell line (rMC-1) was aggravated by AQP11 inhibition, while attenuated by AQP11 overexpression, accompanied by enhanced function in glutamate metabolism and reduced cell death. The down-regulation of AQP11 was also verified in the Müller glia from the epiretinal membranes (ERMs) of proliferative DR (PDR) patients. Mechanistically, down-regulation of AQP11 in DR was mediated by the HIF-1α-dependent and independent miRNA-AQP11 axis. Overall, we deciphered the AQP11 down-regulation, mediated by miRNA-AQP11 axis, resulted in Müller drainage dysfunction and subsequent intracellular edema in DR, which was partially reversed by AQP11 overexpression. Our findings propose a novel mechanism for the pathogenesis of DME, thus targeting AQP11 regulation provides a new therapeutic strategy for DME.