Thermally Oxidized Memristor and 1T1R Integration for Selector Function and Low-Power Memory.

Resistive switching memories have garnered significant attention due to their high-density integration and rapid in-memory computing beyond von Neumann's architecture. However, significant challenges are posed in practical applications with respect to their manufacturing process complexity, a leakage current of high resistance state (HRS), and the sneak-path current problem that limits their scalability. Here, a mild-temperature thermal oxidation technique for the fabrication of low-power and ultra-steep memristor based on Ag/TiOx/SnOx/SnSe2/Au architecture is developed. Benefiting from a self-assembled oxidation layer and the formation/rupture of oxygen vacancy conductive filaments, the device exhibits an exceptional threshold switching behavior with high switch ratio exceeding 106, low threshold voltage of ≈1 V, long-term retention of >104 s, an ultra-small subthreshold swing of 2.5 mV decade-1 and high air-stability surpassing 4 months. By decreasing temperature, the device undergoes a transition from unipolar volatile to bipolar nonvolatile characteristics, elucidating the role of oxygen vacancies migration on the resistive switching process. Further, the 1T1R structure is established between a memristor and a 2H-MoTe2 transistor by the van der Waals (vdW) stacking approach, achieving the functionality of selector and multi-value memory with lower power consumption. This work provides a mild-thermal oxidation technology for the low-cost production of high-performance memristors toward future in-memory computing applications.

Multilayer Core-Shell Fiber Device for Improved Strain Sensing and Supercapacitor Applications.

1D fiber devices, known for their exceptional flexibility and seamless integration capabilities, often face trade-offs between desired wearable application characteristics and actual performance. In this study, a multilayer device composed of carbon nanotube (CNT), transition metal carbides/nitrides (MXenes), and cotton fibers, fabricated using a dry spinning method is presented, which significantly enhances both strain sensing and supercapacitor functionality. This core-shell fiber design achieves a record-high sensitivity (GF ≈ 4500) and maintains robust durability under various environmental conditions. Furthermore, the design approach markedly influences capacitance, correlating with the percentage of active material used. Through systematic optimization, the fiber device exhibited a capacitance 26-fold greater than that of a standard neat CNT fiber, emphasizing the crucial role of innovative design and high active material loading in improving device performance.

Nucleic acid-based wearable and implantable electrochemical sensors.

The rapid advancements in nucleic acid-based electrochemical sensors for implantable and wearable applications have marked a significant leap forward in the domain of personal healthcare over the last decade. This technology promises to revolutionize personalized healthcare by facilitating the early diagnosis of diseases, monitoring of disease progression, and tailoring of individual treatment plans. This review navigates through the latest developments in this field, focusing on the strategies for nucleic acid sensing that enable real-time and continuous biomarker analysis directly in various biofluids, such as blood, interstitial fluid, sweat, and saliva. The review delves into various nucleic acid sensing strategies, emphasizing the innovative designs of biorecognition elements and signal transduction mechanisms that enable implantable and wearable applications. Special perspective is given to enhance nucleic acid-based sensor selectivity and sensitivity, which are crucial for the accurate detection of low-level biomarkers. The integration of such sensors into implantable and wearable platforms, including microneedle arrays and flexible electronic systems, actualizes their use in on-body devices for health monitoring. We also tackle the technical challenges encountered in the development of these sensors, such as ensuring long-term stability, managing the complexity of biofluid dynamics, and fulfilling the need for real-time, continuous, and reagentless detection. In conclusion, the review highlights the importance of these sensors in the future of medical engineering, offering insights into design considerations and future research directions to overcome existing limitations and fully realize the potential of nucleic acid-based electrochemical sensors for healthcare applications.

Insulator Polymer Matrix Construction on All-Small-Molecule Photoactive Blend Towards Extrapolated 15000 Hour T80 Stable Devices.

To boost the stability of all-small-molecule (ASM) organic photovoltaic (OPV) blends, an insulator polymer called styrene-ethylene-butylene-styrene (SEBS) as morphology stabilizer is applied into the host system of small molecules BM-ClEH:BO-4Cl. Minor addition of SEBS (1 mg/ml in host solution) provides a significantly enhanced T80 value of 15000 hours (extrapolated), surpassing doping-free (0 mg/ml) and heavy doping (10 mg/ml) counterparts (900 hours, 30 hours). The material reproducibility and cost-effectiveness of the active layer will not be affected by this industrially available polymer, where the power conversion efficiency (PCE) can be well maintained at 15.02%, which is still a decent value for non-halogen solvent-treated ASM OPV. Morphological and photophysical characterizations clearly demonstrate SEBS's pivotal effect on suppressing the degradation of donor molecules and blend film's crystallization/aggregation reorganization, which protects the exciton dynamics effectively. This work pays meaningful attention to the ASM system stability, performs a smart strategy to suppress the film morphology degradation, and releases a comprehensive understanding of the mechanism of device performance reduction.

Association between advanced lung cancer inflammation index and in-hospital mortality in ICU patients with community-acquired pneumonia: A retrospective analysis of the MIMIC-IV database.

Objective: The objective of the present study was to explore the correlation between the advanced lung cancer inflammation index (ALI) and in-hospital mortality among patients diagnosed with community-acquired pneumonia (CAP). Methods: Data from the Medical Information Mart for Intensive Care-IV database were adopted to analyze the in-hospital mortality of ICU patients with CAP. Upon admission to the ICU, fundamental data including vital signs, critical illness scores, comorbidities, and laboratory results, were collected. The in-hospital mortality of all CAP patients was documented. Multivariate logistic regression (MLR) models and restricted cubic spline (RCS) analysis together with subgroup analyses were conducted. Results: This study includes 311 CAP individuals, involving 218 survivors as well as 93 nonsurvivors. The participants had an average age of 63.57 years, and the females accounted for approximately 45.33%. The in-hospital mortality was documented to be 29.90%. MLR analysis found that ALI was identified as an independent predictor for in-hospital mortality among patients with CAP solely in the Q1 group with ALI ≤ 39.38 (HR: 2.227, 95% CI: 1.026-4.831, P = 0.043). RCS analysis showed a nonlinear relationship between the ALI and in-hospital mortality, with a turning point at 81, and on the left side of the inflection point, a negative correlation was observed between ALI and in-hospital mortality (HR: 0.984, 95% CI: 0.975-0.994, P = 0.002). The subgroup with high blood pressure showed significant interaction with the ALI. Conclusion: The present study demonstrated a nonlinear correlation of the ALI with in-hospital mortality among individuals with CAP. Additional confirmation of these findings requires conducting larger prospective investigations.

2D Reconfigurable van der Waals Heterojunction for Logic Gate Circuits and Wide-Spectrum Photodetectors via Sulfur Substitution and Band Matching.

The attractive physical properties of two-dimensional (2D) semiconductors in group IVA-VIA have been fully revealed in recent years. Combining them with 2D ambipolar materials to construct van der Waals heterojunctions (vdWHs) can offer tremendous opportunities for designing multifunctional electronic and optoelectronic devices, such as logic switching circuits, half-wave rectifiers, and broad-spectrum photodetectors. Here, an optimized SnSe0.75S0.25 is grown to design a SnSe0.75S0.25/MoTe2 vdWH for logic operation and wide-spectrum photodetection. Benefiting from the excellent gate modulation under the appropriate sulfur substitution and type-II band alignment, the device exhibits reconfigurable antiambipolar and ambipolar transfer behaviors at positive and negative source-drain voltage (Vds), enabling stable XNOR logic operation. It also features a gate-modulated positive and negative rectifying behavior with rectification ratios of 265:1 and 1:196, confirming its potential as half-wave logic rectifiers. Besides, the device can respond from visible to infrared wavelength up to 1400 nm. Under 635 nm illumination, the maximum responsivity of 1.16 A/W and response time of 657/500 µs are achieved at the Vds of -2 V. Furthermore, due to the strong in-plane anisotropic structure of SnSe0.75S0.25-alloyed nanosheet and narrow bandgap of 2H-MoTe2, it shows a broadband polarization-sensitive function with impressive photocurrent anisotropic ratios of 15.6 (635 nm), 7.0 (808 nm), and 3.7 (1310 nm). The direction along the maximum photocurrent can be reconfigurable depending on the wavelengths. These results indicate that our designed alloyed SnSe0.75S0.25/MoTe2 vdWH has reconfigurable logic operation and broadband photodetection capabilities in 2D multifunctional integrated circuits.

Equality of healthcare resource allocation between impoverished counties and non-impoverished counties in Northwest China: a longitudinal study.

BACKGROUND: The Health and Medical Assistance Program for Poverty Alleviation is part of China's targeted poverty elimination strategy, which aims to protect poor people's right to health and prevent them from becoming trapped in or returning to poverty because of illness. Many tasks have been defined in this program, including raising the medical insurance level, providing a triage system, improving medical and health services, and enhancing people's health. One pivotal aspect of this initiative involves equitable health resource allocation, a key measure aimed at bolstering medical and health services. This study aimed to analyze and compare health resource allocations in different counties in Northwest China after the implementation of the program. METHODS: The Gini coefficient quantifies the level of distributional equality, the Theil index assesses the sources of inequality, and the Health Resource Agglomeration Degree gauges the accessibility of health resources. RESULTS: 1) The health resource allocation distributed based on population(Gini Coefficient < 0.45) was more equitable than that distributed based on area(Gini Coefficient > 0.35) among counties in Northwest China. 2) The contribution rate within non-impoverished counties is higher than that of impoverished counties, which means the inequality within non-impoverished counties. 3) The allocation of beds in medical institutions by area in non-impoverished counties was better than that in impoverished counties, and accessibility to health services for residents in non-impoverished counties was better than that in impoverished counties. CONCLUSION: The analysis of health resource allocation among the five provinces in Northwest China revealed significant differences in equality among the five provinces in Northwest China, and the differences were mainly derived from the non-impoverished counties. Although the equality is gradually improving, the number of health resources in impoverished counties remain lower than that in non-impoverished counties.Subsequently, it is essential to ensure equitable distribution of healthcare resources while also taking into account their utilization and quality.

Diet-derived circulating antioxidants and risk of epilepsy: a Mendelian randomization study.

Background: Previous studies suggest a link between diet-derived circulating antioxidants and epilepsy, but the causal relationship is unclear. This study aims to investigate the causal effect of these antioxidants on epilepsy. Methods: To assess the causal link between dietary antioxidants and epilepsy risk, we conducted a two-sample Mendelian randomization (MR) analysis. This involved examining antioxidants such as zinc, selenium, α- and γ-tocopherol, vitamin A (retinol), vitamin C (ascorbate), and vitamin E (α-tocopherol). We utilized instrumental variables (IVs) which were genetic variations highly associated with these commonly used antioxidants. Exposure data were sourced from a comprehensive genome-wide association study (GWAS). We aggregated data from the International League Against Epilepsy (ILAE) Consortium sample, which included various types of epilepsy, as an outcome variable. Finally, we applied the inverse variance weighting method and conducted sensitivity analyses for further validation. Results: Based on the primary MR estimates and subsequent sensitivity analyses, the inverse variance weighting (IVW) method revealed that a genetically predicted increase in zinc per standard deviation was positively associated with three types of epilepsy. This includes all types of epilepsy (OR = 1.06, 95% CI: 1.02-1.11, p = 0.008), generalized epilepsy (OR = 1.13, 95% CI: 1.01-1.25, p = 0.030), and focal epilepsy (documented hippocampal sclerosis) (OR = 1.01, 95% CI: 1.00-1.02, p = 0.025). However, there is no evidence indicating that other antioxidants obtained from the diet affect the increase of epilepsy either positively or negatively. Conclusion: Our research indicates that the risk of developing epilepsy may be directly linked to the genetic prediction of zinc, whereas no such association was found for other antioxidants.

[Different levels and clinical significance of growth differentiation factor-15 in patients with atrial fibrillation].

OBJECTIVE: To measure the concentration of growth differentiation factor-15 (GDF-15) in the serum of patients with atrial fibrillation (AF), to study the correlations between the levels of GDF-15 and different factors including basic clinical information, biochemical examinations, and atrial structure, and further to explore the association between GDF-15 and AF types and structural remodeling. METHODS: AF patients who were admitted to the ward of the Department of Cardiology at Peking University Third Hospital between October 2017 and October 2019 were prospectively enrolled. Patients admitted to the ward at the same time with sinus rhythm and no prior AF history were enrolled in the control group. Clinical information and blood samples of the patients were collected. Enzyme-linked immunosorbent assay was used to measure the concentration of GDF-15. SPSS 23.0 was used for statistical analysis. RESULTS: In the study, 156 AF patients (64 persistent AF and 92 paroxysmal AF) and 38 patients of the control group were included. Serum GDF-15 levels in the AF group were significantly higher than in the control group [1 112 (723, 1 525) ng/L vs. 697 (499, 825) ng/L, P < 0.001]. Serum GDF-15 levels in the persistent AF group were significantly higher than in the paroxysmal AF group [1 140 (858, 1 708) ng/L vs. 1 090 (662, 1 374) ng/L, P=0.047]. The area under the curve (AUC) of serum GDF-15 levels for prediction of AF was 0.736 (95%CI: 0.651-0.822, P < 0.001). The cut-off value was 843.2 ng/L with a sensitivity of 68.2% and a specificity of 78.9%. The AUC of serum GDF-15 levels for prediction of persistent AF was 0.594 (95%CI: 0.504-0.684, P=0.047). The cut-off va-lue was 771.5 ng/L with a sensitivity of 82.8% and a specificity of 35.9%. Spearman rank correlation analysis showed that the serum GDF-15 levels were positively correlated with age (r=0.480, P < 0.001), left atrial pressure (LAP, r=0.300, P < 0.001), and also negatively correlated with left atrial appendage flow velocity (LAAV, r=-0.252, P=0.002). Multiple linear regression analysis showed that age and LAP affected the GDF-15 levels significantly (P < 0.05). Logistic regression analysis suggested GDF-15 (OR=1.002, 95%CI: 1.001-1.003, P=0.004) and left atrial diameter (LAD, OR=1.400, 95%CI: 1.214-1.616, P < 0.001) were independent predictors of AF. CONCLUSIONS: Serum GDF-15 levels are higher in AF patients. Meanwhile, serum GDF-15 levels are higher in persistent AF patients than paroxysmal AF patients. GDF-15 is associated with AF and atrial structural remodeling.

[Relationship between lipid metabolism molecules in plasma and carotid atheroscle-rotic plaques, traditional cardiovascular risk factors, and dietary factors].

OBJECTIVE: To explore the relationship between lipid metabolism molecules in plasma and carotid atherosclerotic plaques, traditional cardiovascular risk factors and possible dietary related factors. METHODS: Firstly, among 1 312 community people from those who participated in a 10-year follow-up study of subclinical atherosclerosis cohort in Shijingshan District, Beijing, 85 individuals with 2 or more carotid soft plaques or mixed plaques and 89 healthy individuals without plaques were selected according to the inclusive and the exclusive criteria (< 70 years, not having clinical cardiovascular disease and other diseases, etc.). Secondly, 10 cases and 10 controls were randomly selected in the above 85 and 89 individuals respectively. Carotid plaques were detected using GE Vivid i Ultrasound Machine with 8L detector. Lipid metabolism molecules were detected by high performance liquid chromatography-mass spectrometry. The detection indexes included 113 lipid metabolism molecules. Traditional cardiovascular risk factors were collected by unified standard questionnaires, and dietary related factors were collected by main dietary frequency and weight scale. The difference of lipid metabolism molecules between the case group and the control group was analyzed by Wilcoxin rank test. In the control group, the Spearman correlation method was used to analyze the correlation between statistically significant lipid metabolism molecules and traditional cardiovascular risk factors and dietary factors. RESULTS: Among the 113 lipid metabolism molecules, 53 lipid metabolism molecules were detected. C24:0 sphingomyelin (SM), C22:0/ C24:0 ceramide molecules, C18:0 phosphoethanolamine (PE) molecules, and C18:0/C18:2 (Cis) phosphatidylcholine (PC) were significantly higher in the carotid atherosclerotic plaque group than in the control group. The correlation analysis showed that C24:0 SM was significantly positively correlated with low density lipoprotein cholesterol (LDL-C, r=0.636, P < 0.05), C18:2 (Cis) PC (DLPC) was significantly positively correlated with systolic pressure (r=0.733, P < 0.05), C18:0 PE was significantly positively correlated with high sensitivity C-response protein (r=0.782, P < 0.01), C22:0, C24:0 ceramide and C18:0 PE were negatively correlated with vegetable intake (r=-0.679, P < 0.05;r=-0.711, P < 0.05;r=-0.808, P < 0.01), C24:0 ceramide was also negatively correlated with beans food intake (r=-0.736, P < 0.05) in the control group. CONCLUSIONS: The increase of plasma C24:0 SM, C22:0, C24:0 ceramide, C18:0 PE, C18:2 (Cis) PC (DLPC), C18:0 PC (DSPC) may be new risk factors for human atherosclerotic plaques. These molecules may be related to blood lipid, blood pressure or inflammatory level and the intake of vegetables and soy products, but the nature of the association needs to be verified in a larger sample population.

The emerging roles of hydrogen sulfide in ferroptosis.

SIGNIFICANCE: Ferroptosis, a form of regulated cell death characterized by a large amount of lipid peroxidation-mediated membrane damage, joins the evolution of multisystem diseases. For instance, neurodegenerative diseases, chronic obstructive pulmonary disease and acute respiratory distress syndrome, osteoporosis and osteoarthritis, and so on. Since being identified as the third gasotransmitter in living organisms, the intricate role of hydrogen sulfide (H2S) in ferroptosis has emerged at the forefront of research. RECENT ADVANCES: The discovery of novel targets in the relevant metabolic pathways, including transferrin receptor 1, cystine/glutamate antiporter, and others, coupled with the exploration of new signaling pathways, particularly the p53 signaling pathway and the nitric oxide / nuclear factor erythroid 2-related factor 2 signaling pathway, and so on. Many diseases such as emphysema and airway inflammation, myocardial diseases, endothelial dysfunction in aging arteries, and traumatic brain injury have recently been found to be alleviated directly by H2S inhibition of ferroptosis. Safe, effective, and tolerable novel H2S donors have been developed and have shown promising results in phase I clinical trials. CRITICAL ISSUES: Complicated crosstalk between ferroptosis signaling pathway and oncogenic factors results in the risk of cancer when inhibiting ferroptosis. Notably, targeted delivery of H2S is still a challenging task. FUTURE DIRECTIONS: Discovering more reliable and stable novel H2S donors and achieving their targeted delivery will enable further clinical trials for diseases associated with ferroptosis inhibition by H2S, determining their safety, efficacy, and tolerance.

Ultrasound Shear Wave Elastography Evaluation of the Liver and Implications for Perioperative Medicine.

Ultrasound shear wave elastography (SWE) is a non-invasive, low risk technology allowing the assessment of tissue stiffness. Used clinically for nearly two decades to diagnose and stage liver fibrosis and cirrhosis, it has recently been appreciated for its ability to differentiate between more subtle forms of liver dysfunction. In this review, we will discuss the principle of ultrasound shear wave elastography, its traditional utilization in grading liver cirrhosis, as well as its evolving role in identifying more subtle degrees of liver injury. Finally, we will show how this capacity to distinguish nuanced changes may provide an opportunity for its use in perioperative risk stratification.

Comparative analysis of the short and medium-term efficacy of the Da Vinci robot versus laparoscopic total mesangectomy for rectal cancer.

BACKGROUND: The Da Vinci robot-assisted surgery technique has been widely used in laparoscopic mesangectomy for rectal cancer. However, the short-term efficacy of these procedures compared to traditional laparoscopic surgery remains controversial. The purpose of this study was to compare and analyze the short- and medium-term efficacy of Da Vinci robot and laparoscopic surgery in total mesangectomy (TME) for rectal cancer, so as to provide guidance and reference for clinical practice. AIM: To investigate the safety and long-term efficacy of robotic and laparoscopic total mesorectal resection for the treatment of rectal cancer. METHODS: The clinicopathologic data of 240 patients who underwent TME for rectal cancer in the Anorectal Department of People's Hospital of Xinjiang Uygur Autonomous Region from August 2018 to March 2023 were retrospectively analyzed. Among them, 112 patients underwent laparoscopic TME (L-TME) group, and 128 patients underwent robotic TME (R-TME) group. The intraoperative, postoperative, and follow-up conditions of the two groups were compared. RESULTS: The conversion rate of the L-TME group was greater than that of the R-TME group (5.4% vs 0.8%, χ 2 = 4.417, P = 0.036). The complication rate of the L-TME group was greater than that of the R-TME group (32.1% vs 17.2%, χ 2 = 7.290, P = 0.007). The percentage of positive annular margins in the L-TME group was greater than that in the R-TME group (7.1% vs 1.6%, χ 2 = 4.658, P = 0.031). The 3-year disease-free survival (DFS) rate and overall survival (OS) rate of the L-TME group were lower than those of the R-TME group (74.1% vs 85.2%, χ 2 = 4.962, P = 0.026; 81.3% vs 91.4%, χ 2 = 5.494, P = 0.019); in patients with American Joint Committee on Cancer stage III DFS rate and OS rate in the L-TME group were significantly lower than those in the R-TME group (52.5% vs 76.1%, χ 2 = 5.799, P = 0.016; 65.0% vs 84.8%, χ 2 = 4.787, P = 0.029). CONCLUSION: Compared with the L-TME group, the R-TME group had a better tumor prognosis and was more favorable for patients with rectal cancer, especially for patients with stage III rectal cancer.

Role of hydrogen sulfide in dermatological diseases.

Hydrogen sulfide (H2S), together with carbon monoxide (CO) and nitric oxide (NO), is recognized as a vital gasotransmitter. H2S is biosynthesized by enzymatic pathways in the skin and exerts significant physiological effects on a variety of biological processes, such as apoptosis, modulation of inflammation, cellular proliferation, and regulation of vasodilation. As a major health problem, dermatological diseases affect a large proportion of the population every day. It is urgent to design and develop effective drugs to deal with dermatological diseases. Dermatological diseases can arise from a multitude of etiologies, including neoplastic growth, infectious agents, and inflammatory processes. The abnormal metabolism of H2S is associated with many dermatological diseases, such as melanoma, fibrotic diseases, and psoriasis, suggesting its therapeutic potential in the treatment of these diseases. In addition, therapies based on H2S donors are being developed to treat some of these conditions. In the review, we discuss recent advances in the function of H2S in normal skin, the role of altering H2S metabolism in dermatological diseases, and the therapeutic potential of diverse H2S donors for the treatment of dermatological diseases.

Simple Genomic Traits Predict Rates of Polysaccharide Biodegradation.

Natural and chemically modified polysaccharides are extensively employed across a wide array of industries, leading to their prevalence in the waste streams of industrialized societies. With projected increasing demand, a pressing challenge is to swiftly assess and predict their biodegradability to inform the development of new sustainable materials. In this study, we developed a scalable method to evaluate polysaccharide breakdown by measuring microbial growth and analyzing microbial genomes. Our approach, applied to polysaccharides with various structures, correlates strongly with well-established regulatory methods based on oxygen demand. We show that modifications to the polysaccharide structure decreased degradability and favored the growth of microbes adapted to break down chemically modified sugars. More broadly, we discovered two main types of microbial communities associated with different polysaccharide structures─one dominated by fast-growing microbes and another by specialized degraders. Surprisingly, we were able to predict biodegradation rates based only on two genomic features that define these communities: the abundance of genes related to rRNA (indicating fast growth) and the abundance of glycoside hydrolases (enzymes that break down polysaccharides), which together predict nearly 70% of the variation in polysaccharide breakdown. This suggests a trade-off, whereby microbes are either adapted for fast growth or for degrading complex polysaccharide chains, but not both. Finally, we observe that viral elements (prophages) encoded in the genomes of degrading microbes are induced in easily degradable polysaccharides, leading to complex dynamics in biomass accumulation during degradation. In summary, our work provides a practical approach for efficiently assessing polymer degradability and offers genomic insights into how microbes break down polysaccharides.

PKMYT1 knockdown inhibits cholesterol biosynthesis and promotes the drug sensitivity of triple-negative breast cancer cells to atorvastatin.

Triple negative breast cancer (TNBC) as the most aggressive molecular subtype of breast cancer is characterized by high cancer cell proliferation and poor patient prognosis. Abnormal lipid metabolism contributes to the malignant process of cancers. Study observed significantly enhanced cholesterol biosynthesis in TNBC. However, the mechanisms underlying the abnormal increase of cholesterol biosynthesis in TNBC are still unclear. Hence, we identified a member of the serine/threonine protein kinase family PKMYT1 as a key driver of cholesterol synthesis in TNBC cells. Aberrantly high-expressed PKMYT1 in TNBC was indicative of unfavorable prognostic outcomes. In addition, PKMYT1 promoted sterol regulatory element-binding protein 2 (SREBP2)-mediated expression of enzymes related to cholesterol biosynthesis through activating the TNF/ TNF receptor-associated factor 1 (TRAF1)/AKT pathway. Notably, downregulation of PKMYT1 significantly inhibited the feedback upregulation of statin-mediated cholesterol biosynthesis, whereas knockdown of PKMYT1 promoted the drug sensitivity of atorvastatin in TNBC cells. Overall, our study revealed a novel function of PKMYT1 in TNBC cholesterol biosynthesis, providing a new target for targeting tumor metabolic reprogramming in the cancer.

Targeting SOX4/PCK2 signaling suppresses neuroendocrine trans-differentiation of castration-resistant prostate cancer.

BACKGROUND: Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer (PCa), is characterized by loss of AR signaling and resistance to AR-targeted therapy. While it is well reported that second-generation AR blockers induce neuroendocrine (NE) trans-differentiation of castration-resistant prostate cancer (CRPC) to promote the occurrence of NEPC, and pluripotent transcription factors might be potential regulators, the underlying molecular mechanisms remain unclear. METHODS: We analyzed the data from public databsets to screen candidate genes and then focused on SOX4, a regulator of NE trans-differentiation. The expression changes of SOX4 and its relationship with tumor progression were validated in clinical tumor tissues. We evaluated malignant characteristics related to NEPC in prostate cancer cell lines with stable overexpression or knockdown of SOX4 in vitro. Tumor xenografts were analyzed after inoculating the relevant cell lines into nude mice. RNA-seq, ATAC-seq, non-targeted metabolomics analysis, as well as molecular and biochemical assays were carried out to determine the mechanism. RESULTS: We screened public datasets and identified that expression of SOX4 was significantly elevated in NEPC. Overexpressing SOX4 in C4-2B cells increased cell proliferation and migration, upregulated the expression of NE marker genes, and inhibited AR expression. Consistently, inhibition of SOX4 expression in DU-145 and PC-3 cells reduced the above malignant phenotypes and repressed the expression of NE marker genes. For the in vivo assay, we found that knockdown of SOX4 inhibited tumor growth of subcutaneous xenografts in castrated nude mice which were concomitantly treated with enzalutamide (ENZ). Mechanically, we identified that one of the key enzymes in gluconeogenesis, PCK2, was a novel target of SOX4. The activation of carbohydrate metabolism reprogramming by SOX4 could promote NE trans-differentiation via the SOX4/PCK2 pathway. CONCLUSIONS: Our findings reveal that SOX4 promotes NE trans-differentiation both in vitro and in vivo via directly enhancing PCK2 activity to activate carbohydrate metabolism reprogramming. The SOX4/PCK2 pathway and its downstream changes might be novel targets for blocking NE trans-differentiation.

Detection of Bordetella spp. in children with pertussis-like illness from 2018 to 2024 in China.

OBJECTIVE: To evaluate the role of Bordetella pertussis (B. pertussis), B. parapertussis, B. holmesii, and B. bronchiseptica on pertussis resurgence in China, particularly the sharp rise since the latest winter. METHODS: Nasopharyngeal swabs collected from children with pertussis-like illness from January 2018 to March 2024 were cultured to detect B. pertussis, B. parapertussis, B. holmesii, and B. bronchiseptica, and tested for all of these except for B. bronchiseptica using a pooled real-time polymerase chain reaction (PCR) kit targeting insertion sequences ptxS1, IS481, IS1001, and hIS1001. RESULTS: Out of the collected 7732 nasopharyngeal swabs, 1531 cases tested positive for B. pertussis (19.8%, 1531/7732), and 10 cases were positive for B. parapertussis (0.1%, 10/7732). B. holmesii and B.bronchiseptica were not detected. The number of specimens and the detection rate of B. pertussis were 1709 and 26.9% (459/1709) in 2018, 1936 and 20.7% (400/1936) in 2019, which sharply declined to 308 and 11.4% (35/308) in 2020, 306 and 4.2% (13/306) in 2021, and then notably increased to 754 and 17.6% (133/754) in 2022, 1842 and 16.0% (295/1842) in 2023, 877 and 22.3% (196/877) in the first quarter of 2024. The proportion of children aged 3 to less than 6 years (preschool age) and 6 to 16 years (school age) in pertussis cases increased significantly during the study period, especially the proportion of school-aged children increased from 2.0% (9/459) in 2018 to 40.8% (80/196) in 2024. CONCLUSIONS: B. pertussis was the predominant pathogen among children with pertussis-like illness in China, with sporadic detection of B. parapertussis and no detection of B. holmesii or B.bronchiseptica. The preschool and school-age children are increasingly prevalent in B. pertussis infection cases, which may be associated with the latest rapid escalation of pertussis outbreak.

RBP4 promotes denervation-induced muscle atrophy through STRA6-dependent pathway.

BACKGROUNDS: Fat infiltration of skeletal muscle has been recognized as a common feature of many degenerative muscle disorders. Retinol binding protein 4 (RBP4) is an adipokine that has been demonstrated to be correlated with the presence and severity of sarcopenia in the elderly. However, the exact role and the underlying mechanism of RBP4 in muscle atrophy remains unclear. METHODS: Denervation-induced muscle atrophy model was constructed in wild-type and RBP4 knockout mice. To modify the expression of RBP4, mice were received intramuscular injection of retinol-free RBP4 (apo-RBP4), retinol-bound RBP4 (holo-RBP4) or oral gavage of RBP4 inhibitor A1120. Holo-RBP4-stimulated C2C12 myotubes were treated with siRNAs or specific inhibitors targeting signalling receptor and transporter of retinol 6 (STRA6)/Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) pathway. Fat accumulation, myofibre cross-sectional area, myotube diameter and the expression of muscle atrophy markers and myogenesis markers were analysed. RESULTS: The expression levels of RBP4 in skeletal muscles were significantly up-regulated more than 2-fold from 7 days and sustained for 28 days after denervation. Immunofluorescence analysis indicated that increased RBP4 was localized in the infiltrated fatty region in denervated skeletal muscles. Knockout of RBP4 alleviated denervation-induced fatty infiltration and muscle atrophy together with decreased expression of atrophy marker Atrogin-1 and MuRF1 as well as increased expression of myogenesis regulators MyoD and MyoG. By contrast, injection of retinol-bound holo-RBP4 aggregated denervation-induced ectopic fat accumulation and muscle atrophy. Consistently, holo-RBP4 stimulation also had a dose-dependent effect on the reduction of C2C12 myotube diameter and myofibre cross-sectional area, as well as on the increase of Atrogin-1and MuRF1 expression and decrease of MyoD and MyoG expression. Mechanistically, holo-RBP4 treatment increased the expression of its membrane receptor STRA6 (>3-fold) and promoted the phosphorylation of downstream JAK2 and STAT3. Inhibition of STRA6/JAK2/STAT3 pathway either by specific siRNAs or inhibitors could decrease the expression of Atrogin-1 and MuRF1 (>50%) and decrease the expression of MyoD and MyoG (>3-fold) in holo-RBP4-treated C2C12 myotube. RBP4 specific pharmacological antagonist A1120 significantly inhibited the activation of STRA6/JAK2/STAT3 pathway, ameliorated ectopic fat infiltration and protected against denervation-induced muscle atrophy (30% increased myofibre cross-sectional area) in mice. CONCLUSIONS: In conclusion, our data reveal that RBP4 promotes fat infiltration and muscle atrophy through a STRA6-dependent and JAK2/STAT3 pathway-mediated mechanism in denervated skeletal muscle. Our results suggest that lowering RBP4 levels might serve as a promising therapeutic approach for prevention and treatment of muscle atrophy.

Bacterial outer membrane vesicle nanorobot.

Autonomous nanorobots represent an advanced tool for precision therapy to improve therapeutic efficacy. However, current nanorobotic designs primarily rely on inorganic materials with compromised biocompatibility and limited biological functions. Here, we introduce enzyme-powered bacterial outer membrane vesicle (OMV) nanorobots. The immobilized urease on the OMV membrane catalyzes the decomposition of bioavailable urea, generating effective propulsion for nanorobots. This OMV nanorobot preserves the unique features of OMVs, including intrinsic biocompatibility, immunogenicity, versatile surface bioengineering for desired biofunctionalities, capability of cargo loading and protection. We present OMV-based nanorobots designed for effective tumor therapy by leveraging the membrane properties of OMVs. These involve surface bioengineering of robotic body with cell-penetrating peptide for tumor targeting and penetration, which is further enhanced by active propulsion of nanorobots. Additionally, OMV nanorobots can effectively safeguard the loaded gene silencing tool, small interfering RNA (siRNA), from enzymatic degradation. Through systematic in vitro and in vivo studies using a rodent model, we demonstrate that these OMV nanorobots substantially enhanced siRNA delivery and immune stimulation, resulting in the utmost effectiveness in tumor suppression when juxtaposed with static groups, particularly evident in the orthotopic bladder tumor model. This OMV nanorobot opens an inspiring avenue to design advanced medical robots with expanded versatility and adaptability, broadening their operation scope in practical biomedical domains.