Improving normothermic machine perfusion and blood transfusion through biocompatible blood silicification.

The growing world population and increasing life expectancy are driving the need to improve the quality of blood transfusion, organ transplantation, and preservation. Here, to improve the ability of red blood cells (RBCs) for normothermic machine perfusion, a biocompatible blood silicification approach termed "shielding-augmenting RBC-in-nanoscale amorphous silica (SARNAS)" has been developed. The key to RBC surface engineering and structure augmentation is the precise control of the hydrolysis form of silicic acid to realize stabilization of RBC within conformal nanoscale silica-based exoskeletons. The formed silicified RBCs (Si-RBCs) maintain membrane/structural integrity, normal cellular functions (e.g., metabolism, oxygen-carrying capability), and enhance resistance to external stressors as well as tunable mechanical properties, resulting in nearly 100% RBC cryoprotection. In vivo experiments confirm their excellent biocompatibility. By shielding RBC surface antigens, the Si-RBCs provide universal blood compatibility, the ability for allogeneic mechanical perfusion, and more importantly, the possibility for cross-species transfusion. Being simple, reliable, and easily scalable, the SARNAS strategy holds great promise to revolutionize the use of engineered blood for future clinical applications.

Pan-cancer scRNA-seq analysis reveals immunological and diagnostic significance of the peripheral blood mononuclear cells.

Peripheral blood mononuclear cells (PBMCs) reflect systemic immune response during cancer progression. However, a comprehensive understanding of the composition and function of PBMCs in cancer patients is lacking, and the potential of these features to assist cancer diagnosis is also unclear. Here, the compositional and status differences between cancer patients and healthy donors in PBMCs were investigated by single-cell RNA sequencing (scRNA-seq), involving 262,025 PBMCs from 68 cancer samples and 14 healthy samples. We observed an enhanced activation and differentiation of most immune subsets in cancer patients, along with reduction of naïve T cells, expansion of macrophages, impairment of NK cells and myeloid cells, as well as tumor promotion and immunosuppression. Based on characteristics including differential cell type abundances and/or hub genes identified from weight gene co-expression network analysis (WGCNA) modules of each major cell type, we applied logistic regression to construct cancer diagnosis models. Furthermore, we found that the above models can distinguish cancer patients and healthy donors with high sensitivity. Our study provided new insights into using the features of PBMCs in non-invasive cancer diagnosis.

Ribbon-Ordered Superlattice Enables Reversible Anion Redox and Stable High-Voltage Na-Ion Battery Cathodes.

High-voltage layered oxide cathodes attract great attention for sodium-ion batteries (SIBs) due to the potential high energy density, but high voltage usually leads to rapid capacity decay. Herein, a stable high-voltage NaLi0.1Ni0.35Mn0.3Ti0.25O2 cathode with a ribbon-ordered superlattice is reported, and the intrinsic coupling mechanism between structure evolution and the anion redox reaction (ARR) is revealed. Li introduction constructs a special Li-O-Na configuration activating reversible nonbonded O 2p (|O2p)-type ARR and regulates the structure evolution way, enabling the reversible Li ions out-of-layer migration instead of the irreversible transition metal ions out-of-layer migration. The reversible structure evolution enhances the reversibility of the bonded O 2p (O2p)-type ARR and inhibits the generation of oxygen dimers, thus suppressing the irreversible molecular oxygen (O2)-type ARR. After the structure regulation, the structure evolution becomes reversible, |O2p-type ARR is activated, O2p-type ARR becomes stable, and O2-type ARR is inhibited, which largely suppresses the capacity degradation and voltage decay. The discharge capacity is increased from 154 to 168 mA h g-1, the capacity retention after 200 cycles significantly increases from 35 to 84%, and the voltage retention increases from 78 to 93%. This study presents some guidance for the design of high-voltage, O3-type oxide cathodes for high-performance SIBs.

N-acetylgalactosaminyltransferase GALNT6 is a potential therapeutic target of clear cell renal cell carcinoma progression.

High expression of truncated O-glycans Tn antigen predicts adverse clinical outcome in patients with clear cell renal cell carcinoma (ccRCC). To understand the biosynthetic underpinnings of Tn antigen changes in ccRCC, we focused on N-acetylgalactosaminyltransferases (GALNTs, also known as GalNAcTs) known to be involved in Tn antigen synthesis. Data from GSE15641 profile and local cohort showed that GALNT6 was significantly upregulated in ccRCC tissues. The current study aimed to determine the role of GALNT6 in ccRCC, and whether GALNT6-mediated O-glycosylation aggravates malignant behaviors. Gain- and loss-of-function experiments showed that overexpression of GALNT6 accelerated ccRCC cell proliferation, migration, and invasion, as well as promoted ccRCC-derived xenograft tumor growth and lung metastasis. In line with this, silencing of GALNT6 yielded the opposite results. Mechanically, high expression of GALNT6 led to the accumulation of Tn antigen in ccRCC cells. By undertaking immunoprecipitation coupled with liquid chromatography/mass spectrometry, vicia villosa agglutinin blot, and site-directed mutagenesis assays, we found that O-glycosylation of prohibitin 2 (PHB2) at Ser161 was required for the GALNT6-induced ccRCC cell proliferation, migration, and invasion. Additionally, we identified lens epithelium-derived growth factor (LEDGF) as a key regulator of GALNT6 transcriptional induction in ccRCC growth and an upstream contributor to ccRCC aggressive behavior. Collectively, our findings indicate that GALNT6-mediated abnormal O-glycosylation promotes ccRCC progression, which provides a potential therapeutic target in ccRCC development.

Identification, characterization and complete genome analysis of a Vibrio anguillarum isolated from Sebastes schlegelii.

Vibrio anguillarum is an important fish pathogen in mariculture, which can infect fish with great economic losses. In this study, a Vibrio anguillarum isolated from Sebastes schlegelii was named VA1 and was identified and characterized from aspects of morphology, physiological and biochemical characteristics, 16SRNA, virulence genes, drug sensitivity, and extracellular enzyme activity. At the same time, The VA1 was investigated at the genomic level. The results showed that a Gram-negative was isolated from the diseased fish. The VA1 was characterized with uneven surface and visible flagella wrapped in a sheath and microbubble structures. The VA1 was identified as Vibrio anguillarum based on the 16S RNA sequence and physiological and biochemical characteristics. The VA1 carried most of the virulence genes (24/29) and was resistant to penicillin, oxacillin, ampicillin, cefradine, neomycin, pipemidic acid, ofloxacin, and norfloxacin. The pathogenicity of the isolated strain was confirmed by an experimental analysis, and its LD50 was 6.43 × 106 CFU/ml. The VA1 had the ability to secrete gelatinase, protease, and amylase, and it had α-hemolysis. The whole genome size of the VA1 was 4232328bp and the G + C content was 44.95 %, consisting of two circular chromosomes, Chromosome1 and Chromosome2, with no plasmid. There were 1006 predicted protein coding sequences (CDSs). A total of 526 genes were predicted as virulence-related genes which could be classified as type IV pili, flagella, hemolysin, siderophore, and type VI secretion system. Virulence genes and correlation data were supported with the histopathological examination of the affected organs and tissues. 194 genes were predicted as antibiotic resistance genes, including fluoroquinolone antibiotic, aminoglycoside antibiotic, and beta-lactam resistant genes, which agreed with the results of the above drug sensitivity, indicating VA1 to be a multidrug-resistant bacterium. This study provided a theoretical basis for a better understanding of pathogenicity and antibiotic resistance, which might contribute to the prevention of V. anguillarum in the future.

Recent advances of 3-fucosyllactose in health effects and production.

Human milk oligosaccharides (HMOs) have been recognized as gold standard for infant development. 3-Fucosyllactose (3-FL), being one of the Generally Recognized as Safe HMOs, represents a core trisaccharide within the realm of HMOs; however, it has received comparatively less attention in contrast to extensively studied 2'-fucosyllactose. The objective of this review is to comprehensively summarize the health effects of 3-FL, including its impact on gut microbiota proliferation, antimicrobial effects, immune regulation, antiviral protection, and brain maturation. Additionally, the discussion also covers the commercial application and regulatory approval status of 3-FL. Lastly, an organized presentation of large-scale production methods for 3-FL aims to provide a comprehensive guide that highlights current strategies and challenges in optimization.

Associations of cord serum polybrominated diphenyl ether (PBDE) mixture with birth outcomes and mediating role of thyroid function: Evidence from the Sheyang Mini Birth Cohort Study.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs), a series of worldwide applied flame retardants, may influence fetal growth and interfere with thyroid function. The study intended to explore the relationship between in-utero exposure to PBDE mixture and newborn anthropometric indexes and to further examine the potential mediating role of thyroid function. METHODS: Demographics and laboratory measures of 924 mother-infant pairs were obtained from the database of the Sheyang Mini Birth Cohort Study. We applied gas chromatography-mass spectrometry (GC-MS) and electrochemiluminescence immunoassay to measure nine PBDE congeners and seven thyroid function parameters in umbilical cord serum samples, respectively. We fitted generalized linear models and Bayesian kernel machine regression (BKMR) to evaluate associations of lipid-adjusted cord serum PBDEs, as individuals and as a mixture, with newborn anthropometric and cord serum thyroid function parameters. We applied causal mediation analysis to test our hypothesis that thyroid function parameters act as a mediator between PBDEs and birth outcomes. RESULTS: The molarity of cord serum ∑9PBDE had a median value of 31.23 nmol/g lipid (IQR 19.14 nmol/g lipid, 54.77 nmol/g lipid). BDE-209 was the most dominant congener. Birth length was positively associated with both single exposure to BDE-28 and cumulative exposure to PBDEs. Correspondingly, ponderal index (PI) was negatively associated with BDE-28 and the total effects of PBDE mixture. Free triiodothyronine had a negative trend with BDE-209 and PBDE mixture. In the sex-stratified analysis, BDE-153 concentrations were positively correlated with PI among males (ß = 0.03; 95%CI: 0.01, 0.05; P = 0.01) but not among females. Cord serum thyrotropin mediated 14.92% of the estimated effect of BDE-153 on PI. CONCLUSIONS: In-utero mixture exposure to PBDEs was associated with birth outcomes and thyroid function. Thyroid function might act as a mediator in the process in which PBDEs impact the growth of the fetus.

U-shaped association between serum 25-hydroxyvitamin D concentrations and urinary leakage among adult females aged 45 years and over in the United States: a cross-sectional study.

BACKGROUND: The relationship between serum vitamin D status and urinary leakage (UL) among middle-aged females needs to be further studied. The aim of this study was to evaluate the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with UL among American females ages 45 years and over. METHODS: Seven cycles of the National Health and Nutrition Examination Survey (NHANES) with self-report UL data, were used. A total of 9525 women aged 45 years and older were enrolled in this study. Univariate and multivariate logistic regression models and the smooth curve fitting were utilized to analyze the association between clinical UL and serum 25-hydroxyvitamin D [25(OH)D] concentrations. RESULTS: A non-linear relationship between serum 25(OH)D concentrations and clinical ULwas observed. When serum 25(OH)D concentration was higher than the inflection point 63.5 nmol/L, a positive correlation was observed between serum 25(OH)D concentrations and clinical UL ([OR]: 1.007, 95%CI: 1.005-1.009, P < 0.01). However, when serum 25(OH)D concentration was below the inflection point 63.5 nmol/L, a negative correlation was observed between serum 25(OH)D concentrations and clinical UL ([OR]: 0.993, 95%CI: 0.989-0.996, P < 0.01). CONCLUSIONS: The association between serum vitamin D and the risk of UL exhibited a U-shaped pattern among US middle-aged females, with an inflection point occurring at a serum 25(OH)D concentration of 63.5 nmol/L.

Clinical study on freehand of bicortical sacral screw fixation with the assistance of torque measurement device.

BACKGROUND: Sacral screw loosening is a typical complication after internal fixation surgery through the vertebral arch system. Bicortical fixation can successfully prevent screw loosening, and how improving the rate of bicortical fixation is a challenging clinical investigation. OBJECTIVE: To investigate the feasibility of improving the double corticality of sacral screws and the optimal fixation depth to achieve double cortical fixation by combining the torque measurement method with bare hands. METHODS: Ninety-seven cases of posterior lumbar internal fixation with pedicle root system were included in this study. Based on the tactile feedback of the surgeon indicating the expected penetration of the screw into the contralateral cortex of the sacrum, the screws were further rotated by 180°, 360°, or 720°, categorized into the bicortical 180° group, bicortical 360° group, and bicortical 720° group, respectively. Intraoperatively, the torque during screw insertion was recorded. Postoperatively, the rate of double-cortex engagement was evaluated at 7 days, and screw loosening was assessed at 1 year follow-up. RESULTS: The bicortical rates of the 180° group, 360° group, and 720° group were 66.13%, 91.18% and 93.75%, respectively. There were statistically significant differences between the 180° group and both the 360° and 720° groups (P < 0.05). However, there was no statistically significant difference between the 360° group and the 720° group (P > 0.05).The rates of loosening of sacral screws in the 180° group, 360° group, and 720° group were 20.97%, 7.35% and 7.81%, respectively. There were statistically significant differences between the 180° group and both the 360° and 720° groups (P < 0.05). However, there was no statistically significant difference between the 360° group and the 720° group (P > 0.05). The bicortical 360° group achieved a relatively satisfactory rate of dual cortical purchase while maintaining a lower rate of screw loosening. CONCLUSION: Manual insertion of sacral screws with the assistance of a torque measurement device can achieve a relatively satisfactory dual cortical purchase rate while reducing patient hospitalization costs.

A modified method for precise anastomosis during laparoscopic low anterior resection for rectal cancer: the first clinical experience and application.

BACKGROUND: There is no criterion to guide and evaluate the anastomosis of laparoscopic low anterior resection (LAR). We developed a new technique for precise anastomosis. This study endeavored to evaluate the effectiveness and safety of this new technology. METHODS: Patients with mid-low rectal cancer who underwent laparoscopic LAR in our department were enrolled retrospectively between January 1, 2021 and July 1, 2023. During the LAR, the distance between the sacral promontory and the rectal stump was measured and used to determine the length of the sigmoid colon, which was preserved for anastomose. The demographic characteristics and short-term outcomes were analyzed. RESULTS: Forty-nine patients (26 men, 23 women) with low and middle rectal cancer were retrospectively enrolled in the study. The distance of the tumor from the anal verge was 6.4 ± 2.7 cm. The operative time was 193 ± 42 min. All patients underwent precise anastomosis, among which 12 patients underwent freeing of the splenic flexure of the colon. According to our criteria, there was no redundant or tense state of the colon anterior to the sacrum after the anastomosis. Only one patient had a postoperative anastomotic leak (Grade B). All 15 patients receiving neoadjuvant chemoradiotherapy underwent terminal ileostomy. No postoperative death occurred within 30 days of the surgery. The median follow-up time in our study was 12 months. One patient developed a single metastasis in the right lobe of the liver in the eighth month after surgery and underwent microwave radiofrequency ablation, which did not recur in the four months of postoperative follow-up, and the rest of the patients survived disease-free without recurrence of metastasis. CONCLUSIONS: Precise measurement of the proximal colon of the anastomosis can ensure accurate and convenient colorectal anastomosis and this may be a technique worthy of clinical application. However, its effectiveness needs to be further verified in a multicenter clinical trial.

Effect of total solids content on anaerobic digestion of waste activated sludge enhanced by high-temperature thermal hydrolysis.

Total solids (TS) content may provide a regulatory strategy for optimizing anaerobic digestion enhanced by high-temperature thermal hydrolysis, but the role of TS content is not yet clear. In this study, the effect of TS content on the high-temperature thermal hydrolysis and anaerobic digestion of sludge and its mechanism were investigated. The results showed that increasing the TS content from 2% to 8% increased the sludge solubility and methane production potential, reaching peak values of 26.6% and 336 ± 6 mL/g volatile solids (VS), respectively. With a further increase in TS content to 12%, the strong Maillard reaction increased the aromaticity and structural stability of extracellular polymer substances, decreasing sludge solubility to 18.6%. Furthermore, the decrease in sludge biodegradability and the formation of inhibitory by-products resulted in a reduction in methane production to 272 ± 4 mL/g VS. This article provides a new perspective to understand the role of TS content in the thermal hydrolysis of sludge and a novel approach to regulate the Maillard reaction.

Study on the Anti-Inflammatory Mechanism of Coumarins in Peucedanum decursivum Based on Spatial Metabolomics Combined with Network Pharmacology.

Peucedanum decursivum (Miq.) Maxim (P. decursivum) is a traditional Chinese medicinal plant with pharmacological effects such as anti-inflammatory and anti-tumor effects, the root of which is widely used as medicine. Determining the spatial distribution and pharmacological mechanisms of metabolites is necessary when studying the effective substances of medicinal plants. As a means of obtaining spatial distribution information of metabolites, mass spectrometry imaging has high sensitivity and allows for molecule visualization. In this study, matrix-assisted laser desorption mass spectrometry (MALDI-TOF-MSI) and network pharmacology were used for the first time to visually study the spatial distribution and anti-inflammatory mechanism of coumarins, which are metabolites of P. decursivum, to determine their tissue localization and mechanism of action. A total of 27 coumarins were identified by MALDI-TOF-MSI, which mainly concentrated in the cortex, periderm, and phloem of the root of P. decursivum. Network pharmacology studies have identified key targets for the anti-inflammatory effect of P. decursivum, such as TNF, PTGS2, and PRAKA. GO enrichment and KEGG pathway analyses indicated that coumarins in P. decursivum mainly participated in biological processes such as inflammatory response, positive regulation of protein kinase B signaling, chemical carcinogenesis receptor activation, pathways in cancer, and other biological pathways. The molecular docking results indicated that there was good binding between components and targets. This study provides a basis for understanding the spatial distribution and anti-inflammatory mechanism of coumarins in P. decursivum.

Chiral Star-Shaped [CoIII3LnIII] Clusters with Enantiopure Schiff Bases: Synthesis, Structure, and Magnetism.

Two enantiomeric pairs of new 3d-4f heterometallic clusters have been synthesized from two enantiomer Schiff base derivatives: (R/S)-2-[(2-hydroxy-1-phenylethylimino)methyl] phenol (R-/S-H2L). The formulae of the series clusters are Co3Ln(R-L)6 (Ln = Dy (1R), Gd (2R)), Co3Ln (S-L)6 (Ln = Dy (1S), Gd (2S)), whose crystal structures and magnetic properties have been characterized. Structural analysis indicated that the above clusters crystallize in the chiral P213 group space. The central lanthanide ion has a coordination geometry of D3 surrounded by three [CoIII(L)2]- anions using six aliphatic oxygen atoms of L2- featuring a star-shaped [CoIII3LnIII] configuration. Magnetic measurements showed the presence of slow magnetic relaxation with an effective energy barrier of 22.33 K in the DyIII derivatives under a zero-dc field. Furthermore, the circular dichroism (CD) spectra of 1R and 1S confirmed their enantiomeric nature.

Liquid biopsy at the frontier in renal cell carcinoma: recent analysis of techniques and clinical application.

Renal cell carcinoma (RCC) is a major pathological type of kidney cancer and is one of the most common malignancies worldwide. The unremarkable symptoms of early stages, proneness to postoperative metastasis or recurrence, and low sensitivity to radiotherapy and chemotherapy pose a challenge for the diagnosis and treatment of RCC. Liquid biopsy is an emerging test that measures patient biomarkers, including circulating tumor cells, cell-free DNA/cell-free tumor DNA, cell-free RNA, exosomes, and tumor-derived metabolites and proteins. Owing to its non-invasiveness, liquid biopsy enables continuous and real-time collection of patient information for diagnosis, prognostic assessment, treatment monitoring, and response evaluation. Therefore, the selection of appropriate biomarkers for liquid biopsy is crucial for identifying high-risk patients, developing personalized therapeutic plans, and practicing precision medicine. In recent years, owing to the rapid development and iteration of extraction and analysis technologies, liquid biopsy has emerged as a low cost, high efficiency, and high accuracy clinical detection method. Here, we comprehensively review liquid biopsy components and their clinical applications over the past 5 years. Additionally, we discuss its limitations and predict its future prospects.

J-shape relationship between normal fasting plasma glucose and risk of type 2 diabetes in the general population: results from two cohort studies.

BACKGROUND: Previous studies have reported that high fasting plasma glucose (FPG), even that within the normal range, is associated with the risk of type 2 diabetes (T2D). Nevertheless, these findings are limited to specific populations. Thus, studies in the general population are imperative. METHODS: This study included two cohorts comprising 204 640 individuals who underwent physical examinations at the Rich Healthcare Group present at 32 locations in 11 cities of China from 2010 to 2016 and 15 464 individuals who underwent physical tests at the Murakami Memorial Hospital in Japan. Cox regression, restricted cubic spline (RCS), Kaplan-Meier (KM) curves, and subgroup analysis were used to determine the relationship between FPG and T2D. Receiver operating characteristic (ROC) curves were used to evaluate the predictive power of FPG for T2D. RESULTS: The mean age of the 220 104 participants (204 640 Chinese and 15 464 Japanese participants) was 41.8 years (41.7 years for the Chinese and 43.7 years for the Japanese participants). During follow-up, 2611 individuals developed T2D (2238 Chinese and 373 Japanese participants). The RCS demonstrated a J-shaped relationship between FPG and T2D risk, with inflexion points of 4.5 and 5.2 for the Chinese and Japanese populations, respectively. Multivariate-adjusted hazard ratio (HR) was 7.75 for FPG and T2D risk after the inflexion point (7.3 for Chinese and 21.13 for Japanese participants). CONCLUSIONS: In general Chinese and Japanese populations, the normal baseline FPG range showed a J-shaped relationship with the risk of T2D. Baseline FPG levels help identify individuals at high risk of T2D and may enable early primary prevention to improve their outcomes.

Developing a Model to Predict High Health Care Utilization Among Patients in a New York City Safety Net System.

BACKGROUND: Health care facilities use predictive models to identify patients at risk of high future health care utilization who may benefit from tailored interventions. Previous predictive models that have focused solely on inpatient readmission risk, relied on commercial insurance claims data, or failed to incorporate social determinants of health may not be generalizable to safety net hospital populations. To address these limitations, we developed a payer-agnostic risk model for patients receiving care at the largest US safety net hospital system. METHODS: We transformed electronic health record and administrative data from 833,969 adult patients who received care during July 2016-July 2017 into demographic, utilization, diagnosis, medication, and social determinant variables (including homelessness and incarceration history) to predict health care utilization during the following year.We selected the final model by developing and validating multiple classification and regression models predicting 10+ acute days, 5+ acute days, or continuous acute days. We compared a portfolio of performance metrics while prioritizing positive predictive value for patients whose predicted utilization was among the top 1% to maximize clinical utility. RESULTS: The final model predicted continuous number of acute days and included 17 variables. For the top 1% of high acute care utilizers, the model had a positive predictive value of 47.6% and sensitivity of 17.3%. Previous health care utilization and psychosocial factors were the strongest predictors of future high acute care utilization. CONCLUSIONS: We demonstrated a feasible approach to predictive high acute care utilization in a safety net hospital using electronic health record data while incorporating social risk factors.

Occurrence, functional properties, and preparation of 3-fucosyllactose, one of the smallest human milk oligosaccharides.

Human milk oligosaccharides (HMOs) are receiving wide interest and high attention due to their health benefits, especially for newborns. The HMOs-fortified products are expected to mimic human milk not only in the kinds of added oligosaccharides components but also the appropriate proportion between these components, and further provide the nutrition and physiological effects of human milk to newborns as closely as possible. In comparison to intensively studied 2'-fucosyllactose (2'-FL), 3-fucosyllactose (3-FL) has less attention in almost all respects. Nerveless, 3-FL naturally occurs in breast milk and increases roughly over the course of lactation with a nonnegligible content, and plays an irreplaceable role in human milk and delivers functional properties to newborns. According to the safety evaluation, 3-FL shows no acute oral toxicity, genetic toxicity, and subchronic toxicity. It has been approved as generally recognized as safe (GRAS). Biological production of 3-FL can be realized by enzymatic and cell factory approaches. The α1,3- or α1,3/4-fucosyltransferase is the key enzyme for 3-FL biosynthesis. Various metabolic engineering strategies have been applied to enhance 3-FL yield using cell factory approach. In conclusion, this review gives an overview of the recent scientific literatures regarding occurrence, bioactive properties, safety evaluation, and biotechnological preparation of 3-FL.

SZC-6, a small-molecule activator of SIRT3, attenuates cardiac hypertrophy in mice.

Sirtuin3 (SIRT3), a class III histone deacetylase, is implicated in various cardiovascular diseases as a novel therapeutic target. SIRT3 has been proven to be cardioprotective in a model of Ang II-induced cardiac hypertrophy. However, a few small-molecule compounds targeting deacetylases could activate SIRT3. In this study, we generated a novel SIRT3 activator, 3-(2-bromo-4-hydroxyphenyl)-7-hydroxy-2H-chromen-2-one (SZC-6), through structural optimization of the first SIRT3 agonist C12. We demonstrated that SZC-6 directly bound to SIRT3 with Kd value of 15 µM, and increased SIRT3 deacetylation activity with EC50 value of 23.2 ± 3.3 µM. In neonatal rat cardiomyocytes (NRCMs), pretreatment with SZC-6 (10, 20, 40 µM) dose-dependently attenuated isoproterenol (ISO)-induced hypertrophic responses. Administration of SZC-6 (20, 40 and 60 mg·kg-1·d-1, s.c.) for 2 weeks starting from one week prior ISO treatment dose-dependently reversed ISO-induced impairment of diastolic and systolic cardiac function in wild-type mice, but not in SIRT3 knockdown mice. We showed that SZC-6 (10, 20, 40 µM) dose-dependently inhibited cardiac fibroblast proliferation and differentiation into myofibroblasts, which was abolished in SIRT3-knockdown mice. We further revealed that activation of SIRT3 by SZC-6 increased ATP production and rate of mitochondrial oxygen consumption, and reduced ROS, improving mitochondrial function in ISO-treated NRCMs. We also found that SZC-6 dose-dependently enhanced LKB1 phosphorylation, thereby promoting AMPK activation to inhibit Drp1-dependent mitochondrial fragmentation. Taken together, these results demonstrate that SZC-6 is a novel SIRT3 agonist with potential value in the treatment of cardiac hypertrophy partly through activation of the LKB1-AMPK pathway.

DeePMD-kit v2: A software package for deep potential models.

DeePMD-kit is a powerful open-source software package that facilitates molecular dynamics simulations using machine learning potentials known as Deep Potential (DP) models. This package, which was released in 2017, has been widely used in the fields of physics, chemistry, biology, and material science for studying atomistic systems. The current version of DeePMD-kit offers numerous advanced features, such as DeepPot-SE, attention-based and hybrid descriptors, the ability to fit tensile properties, type embedding, model deviation, DP-range correction, DP long range, graphics processing unit support for customized operators, model compression, non-von Neumann molecular dynamics, and improved usability, including documentation, compiled binary packages, graphical user interfaces, and application programming interfaces. This article presents an overview of the current major version of the DeePMD-kit package, highlighting its features and technical details. Additionally, this article presents a comprehensive procedure for conducting molecular dynamics as a representative application, benchmarks the accuracy and efficiency of different models, and discusses ongoing developments.

Blood-based liquid biopsy: insights into early detection, prediction, and treatment monitoring of bladder cancer.

Bladder cancer (BC) is a clinical challenge worldwide with late clinical presentation, poor prognosis, and low survival rates. Traditional cystoscopy and tissue biopsy are routine methods for the diagnosis, prognosis, and monitoring of BC. However, due to the heterogeneity and limitations of tumors, such as aggressiveness, high cost, and limited applicability of longitudinal surveillance, the identification of tumor markers has attracted significant attention in BC. Over the past decade, liquid biopsies (e.g., blood) have proven to be highly efficient methods for the discovery of BC biomarkers. This noninvasive sampling method is used to analyze unique tumor components released into the peripheral circulation and allows serial sampling and longitudinal monitoring of tumor progression. Several liquid biopsy biomarkers are being extensively studied and have shown promising results in clinical applications of BC, including early detection, detection of microscopic residual disease, prediction of recurrence, and response to therapy. Therefore, in this review, we aim to provide an update on various novel blood-based liquid biopsy markers and review the advantages and current limitations of liquid biopsy in BC therapy. The role of blood-based circulating tumor cells, circulating tumor DNA, cell-free RNA, exosomes, metabolomics, and proteomics in diagnosis, prognosis, and treatment monitoring, and their applicability to the personalized management of BC, are highlighted.