Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer.

Loss of BRCA1 p220 function often results in basal-like breast cancer (BLBC), but the underlying disease mechanism is largely opaque. In mammary epithelial cells (MECs), BRCA1 interacts with multiple proteins, including NUMB and HES1, to form complexes that participate in interstrand crosslink (ICL) DNA repair and MEC differentiation control. Unrepaired ICL damage results in aberrant transdifferentiation to a mesenchymal state of cultured, human basal-like MECs and to a basal/mesenchymal state in primary mouse luminal MECs. Loss of BRCA1, NUMB, or HES1 or chemically induced ICL damage in primary murine luminal MECs results in persistent DNA damage that triggers luminal to basal/mesenchymal transdifferentiation. In vivo single-cell analysis revealed a time-dependent evolution from normal luminal MECs to luminal progenitor-like tumor cells with basal/mesenchymal transdifferentiation during murine BRCA1 BLBC development. Growing DNA damage accompanied this malignant transformation.

Polysome collapse and RNA condensation fluidize the cytoplasm.

The cell interior is packed with macromolecules of mesoscale size, and this crowded milieu significantly influences cellular physiology. Cellular stress responses almost universally lead to inhibition of translation, resulting in polysome collapse and release of mRNA. The released mRNA molecules condense with RNA-binding proteins to form ribonucleoprotein (RNP) condensates known as processing bodies and stress granules. Here, we show that polysome collapse and condensation of RNA transiently fluidize the cytoplasm, and coarse-grained molecular dynamic simulations support this as a minimal mechanism for the observed biophysical changes. Increased mesoscale diffusivity correlates with the efficient formation of quality control bodies (Q-bodies), membraneless organelles that compartmentalize misfolded peptides during stress. Synthetic, light-induced RNA condensation also fluidizes the cytoplasm. Together, our study reveals a functional role for stress-induced translation inhibition and formation of RNP condensates in modulating the physical properties of the cytoplasm to enable efficient response of cells to stress conditions.

Mice expressing fluorescent PAR2 reveal that endocytosis mediates colonic inflammation and pain.

G protein-coupled receptors (GPCRs) regulate many pathophysiological processes and are major therapeutic targets. The impact of disease on the subcellular distribution and function of GPCRs is poorly understood. We investigated trafficking and signaling of protease-activated receptor 2 (PAR2) in colitis. To localize PAR2 and assess redistribution during disease, we generated knockin mice expressing PAR2 fused to monomeric ultrastable green fluorescent protein (muGFP). PAR2-muGFP signaled and trafficked normally. PAR2 messenger RNA was detected at similar levels in Par2-mugfp and wild-type mice. Immunostaining with a GFP antibody and RNAScope in situ hybridization using F2rl1 (PAR2) and Gfp probes revealed that PAR2-muGFP was expressed in epithelial cells of the small and large intestine and in subsets of enteric and dorsal root ganglia neurons. In healthy mice, PAR2-muGFP was prominently localized to the basolateral membrane of colonocytes. In mice with colitis, PAR2-muGFP was depleted from the plasma membrane of colonocytes and redistributed to early endosomes, consistent with generation of proinflammatory proteases that activate PAR2 PAR2 agonists stimulated endocytosis of PAR2 and recruitment of Gαq, Gαi, and ß-arrestin to early endosomes of T84 colon carcinoma cells. PAR2 agonists increased paracellular permeability of colonic epithelial cells, induced colonic inflammation and hyperalgesia in mice, and stimulated proinflammatory cytokine release from segments of human colon. Knockdown of dynamin-2 (Dnm2), the major colonocyte isoform, and Dnm inhibition attenuated PAR2 endocytosis, signaling complex assembly and colonic inflammation and hyperalgesia. Thus, PAR2 endocytosis sustains protease-evoked inflammation and nociception and PAR2 in endosomes is a potential therapeutic target for colitis.

Loratadine as an Anti-inflammatory Agent Against Clostridium difficile Toxin B.

BACKGROUND: Clostridium difficile infection (CDI) is a debilitating nosocomial infection. C. difficile produces toxins A and B, which cause inflammation. Existing therapies have issues with recurrence, cost, and safety. We aim to discover a safe, effective, and economical nonmicrobiological therapeutic approach against CDI. METHODS: We included human primary peripheral blood mononuclear cells (PBMCs), fresh human colonic explants, and humanized HuCD34-NCG mice. Toxin A+B+ VPI 10463 and A-B+ ribotype 017 C. difficile strains were used. We used single-cell RNA profiling and high-throughput screening to find actionable toxin B-dependent pathways in PBMCs. RESULTS: Histamine 1 receptor-related drugs were found among the hit compounds that reversed toxin-mediated macrophage inflammatory protein (MIP) 1α expression in PBMCs. We identified loratadine as the safest representative antihistamine for therapeutic development. Loratadine inhibited toxin B-induced MIP-1α secretion in fresh human colonic tissues. Oral loratadine (10 mg/kg/d) maintained survival, inhibited intestinal CCl3 messenger RNA expression, and prevented vancomycin-associated recurrence in the VPI 10463-infected mice and ribotype 017-infected hamsters. Splenocytes from loratadine-treated mice conferred anti-inflammatory effects to the VPI 10463-infected T/B-cell--deficient Rag-/- mice. Oral loratadine suppressed human MIP-1α expression in monocytes/macrophages in toxin B-expressing ribotype 017-infected humanized HuCD34-NCG mice. CONCLUSIONS: Loratadine may be repurposed to optimize existing therapies against CDI.

Loratadine, a Food and Drug Administration­approved antihistamine, inhibits toxin B­mediated proinflammatory macrophage inflammatory protein 1α secretion from immune cells. Its anti-inflammatory effect ameliorates intestinal inflammation in Clostridium difficile­infected animals. Loratadine may be repurposed to optimize existing therapies.

Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells.

BACKGROUND: Dysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC. METHODS: The clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA+ B cells. RESULTS: HCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8+ T lymphocyte activation was enhanced in the absence of IL-21R due to the reduction of immunosuppressive IgA+ B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis was activated in MASH-driven HCC and thus promoted the transcription of Igha, resulting in the induction of IgA+ B cells. CONCLUSIONS: IL-21R plays a cancer-promoting role by inducing IgA+ B cells in MASH-driven hepatocarcinogenesis. Targeting IL-21R signaling represents a potential therapeutic strategy for cancer therapy.

Unveiling the Potential of Sulfur-Containing Gas Signaling Molecules in Acute Lung Injury: A Promising Therapeutic Avenue.

Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), are pulmonary conditions that cause significant morbidity and mortality. The common etiologies of these conditions include pneumonia, pulmonary contusion, fat embolism, smoke inhalation, sepsis, shock, and acute pancreatitis. Inflammation, oxidative stress, apoptosis, and autophagy are key pathophysiological mechanisms underlying ALI. Hydrogen sulfide (H2S) and sulfur dioxide (SO2) are sulfur-containing gas signaling molecules that can mitigate these pathogenic processes by modulating various signaling pathways, such as toll-like receptor 4 (TLR4)/nod-like receptor protein 3 (NLRP3), extracellular signal-regulating protein kinase 1/2 (ERK1/2), mitogen-activated protein kinase (MAPK), phosphatidyl inositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), and nuclear factor kappa B (NF-κB), thereby conferring protection against ALI. Given the limited clinical effectiveness of prevailing ALI treatments, investigation of the modulation of sulfur-containing gas signaling molecules (H2S and SO2) in ALI is imperative. This article presents an overview of the regulatory pathways of sulfur-containing gas signaling molecules in ALI animal models induced by various stimuli, such as lipopolysaccharide, gas inhalation, oleic acid, and ischemia-reperfusion. Furthermore, this study explored the therapeutic prospects of diverse H2S and SO2 donors for ALI, stemming from diverse etiologies. The aim of the present study was to establish a theoretical framework, in order to promote the new treatment of ALI.

Men with nonobstructive coronary disease have higher burden of ischemic heart disease detected by cardiopulmonary exercise test.

BACKGROUND: Nonobstructive coronary artery disease (NOCAD), characterized by the presence of myocardial ischemic symptoms and signs without obstructive coronaries, is a common clinical condition, but it is less well understood. Few studies have analyzed the gender differences in inducible myocardial ischemia assessed by cardiopulmonary exercise test (CPET) in NOCAD. METHODS: We conducted a study of 289 NOCAD patients (mean age 60, 56% women) with ischemic symptoms and confirmed ⫹50% coronaries stenoses by coronary angiography who underwent symptom-limited CPET. We assessed ischemic response using predicted % peak VO2 , O2 pulse trajectory, and exercise ECG test. RESULTS: Men with NOCAD had significantly lower predicted % peak VO2 (62% vs. 73%), higher proportions of flattening pattern (16% vs. 2%), and downward patterns of O2 pulse trajectory (2% vs. 0%) (p < .0001) compared with women. In contrast, women with NOCAD had a higher prevalence of shallow patterns of O2 pulse trajectory (21% vs. 6%, p < .0001). Men with NOCAD had a higher risk ischemic profile (medium risk: 63% vs. 54%, high risk: 18% vs. 4%, p < .0001). After adjustment, men with NOCAD had significantly lower predicted % peak VO2 (ß -27.4, 95% CI -30.74 to -24.07), higher risk for abnormal O2 pulse trajectories (OR 4.21, 95% CI 1.93 to 9.19), and myocardial ischemia risk per CPET parameters (OR 3.14, 95% CI 1.78 to 5.54) (p < .0001). CONCLUSION: Men with NOCAD had a higher risk profile for ischemic heart disease per CPET. Therefore, they should receive rigorous management and follow-up to prevent cardiovascular events.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study.

BACKGROUND: TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese without diabetes. METHODS: In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18-75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103. RESULTS: A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, n = 12 per group) or placebo (n = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 µg*h/mL, and AUC0-inf ranged from 159 to 340 µg*h/mL. TG103 had a half-life of 110-116 h, with a median Tmax of 36-48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with p < 0.05 for all comparisons with placebo. CONCLUSIONS: In this trial, all three doses of once-weekly TG103 were well tolerated with an acceptable safety profile. TG103 demonstrated preliminary 12-week body weight loss without lifestyle interventions, thus showing great potential for the treatment of overweight and obesity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04855292. Registered on April 22, 2021.

A Functional "Key" Amplified Piezoelectric Effect Modulates ROS Storm with an Open Source for Multimodal Synergistic Cancer Therapy.

Chemodynamic therapy (CDT) is a non-invasive strategy for generating reactive oxygen species (ROS) and is promising for cancer treatment. However, increasing ROS in tumor therapy remains challenging. Therefore, exogenous excitation and inhibition of electron-hole pair recombination are attractive for modulating ROS storms in tumors. Herein, a Ce-doped BiFeO3 (CBFO) piezoelectric sonosensitizer to modulate ROS generation and realize a synergistic mechanism of CDT/sonodynamic therapy and piezodynamic therapy (PzDT) is proposed. The mixed Fe2+ and Ce3+ can implement a circular Fenton/Fenton-like reaction in the tumor microenvironment. Abundant ·OH can be generated by ultrasound (US) stimulation to enhance CDT efficacy. As a typical piezoelectric sonosensitizer, CBFO can produce O2 - owing to the enhanced polarization by the US, resulting in the motion of charge carriers. In addition, CBFO can produce a piezoresponse irradiated upon US, which accelerates the migration rate of electrons/holes in opposite directions and results in energy band bending, further achieving toxic ROS production and realizing PzDT. Density functional theory calculations confirmed that Ce doping shortens the diffusion of electrons and improves the conductivity and catalytic activity of CBFO. This distinct US-enhanced strategy emphasizes the effects of doping engineering and piezoelectric-optimized therapy and shows great potential for the treatment of malignant tumors.

Systematic calibration of epitranscriptomic maps using a synthetic modification-free RNA library.

Recent years have witnessed rapid progress in the field of epitranscriptomics. Functional interpretation of the epitranscriptome relies on sequencing technologies that determine the location and stoichiometry of various RNA modifications. However, contradictory results have been reported among studies, bringing the biological impacts of certain RNA modifications into doubt. Here, we develop a synthetic RNA library resembling the endogenous transcriptome but without any RNA modification. By incorporating this modification-free RNA library into established mapping techniques as a negative control, we reveal abundant false positives resulting from sequence bias or RNA structure. After calibration, precise and quantitative mapping expands the understanding of two representative modification types, N6-methyladenosine (m6A) and 5-methylcytosine (m5C). We propose that this approach provides a systematic solution for the calibration of various RNA-modification mappings and holds great promise in epitranscriptomic studies.

Integrating network pharmacology and animal experimental validation to investigate the action mechanism of oleanolic acid in obesity.

BACKGROUND: Obesity, a condition associated with the development of widespread cardiovascular disease, metabolic disorders, and other health complications, has emerged as a significant global health issue. Oleanolic acid (OA), a pentacyclic triterpenoid compound that is widely distributed in various natural plants, has demonstrated potential anti-inflammatory and anti-atherosclerotic properties. However, the mechanism by which OA fights obesity has not been well studied. METHOD: Network pharmacology was utilized to search for potential targets and pathways of OA against obesity. Molecular docking and molecular dynamics simulations were utilized to validate the interaction of OA with core targets, and an animal model of obesity induced by high-fat eating was then employed to confirm the most central of these targets. RESULTS: The network pharmacology study thoroughly examined 42 important OA targets for the treatment of obesity. The key biological processes (BP), cellular components (CC), and molecular functions (MF) of OA for anti-obesity were identified using GO enrichment analysis, including intracellular receptor signaling, intracellular steroid hormone receptor signaling, chromatin, nucleoplasm, receptor complex, endoplasmic reticulum membrane, and RNA polymerase II transcription Factor Activity. The KEGG/DAVID database enrichment study found that metabolic pathways, PPAR signaling pathways, cancer pathways/PPAR signaling pathways, insulin resistance, and ovarian steroidogenesis all play essential roles in the treatment of obesity and OA. The protein-protein interaction (PPI) network was used to screen nine main targets: PPARG, PPARA, MAPK3, NR3C1, PTGS2, CYP19A1, CNR1, HSD11B1, and AGTR1. Using molecular docking technology, the possible binding mechanism and degree of binding between OA and each important target were validated, demonstrating that OA has a good binding potential with each target. The molecular dynamics simulation's Root Mean Square Deviation (RMSD), and Radius of Gyration (Rg) further demonstrated that OA has strong binding stability with each target. Additional animal studies confirmed the significance of the core target PPARG and the core pathway PPAR signaling pathway in OA anti-obesity. CONCLUSION: Overall, our study utilized a multifaceted approach to investigate the value and mechanisms of OA in treating obesity, thereby providing a novel foundation for the identification and development of natural drug treatments.

Integrated lipid metabolomics and proteomics analysis reveal the pathogenesis of polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrinological and metabolic disorder that can lead to female infertility. Lipid metabolomics and proteomics are the new disciplines in systems biology aimed to discover metabolic pathway changes in diseases and diagnosis of biomarkers. This study aims to reveal the features of PCOS to explore its pathogenesis at the protein and metabolic level. METHODS: We collected follicular fluid samples and granulosa cells of women with PCOS and normal women who underwent in vitro fertilization(IVF) and embryo transfer were recruited. The samples were for the lipidomic study and the proteomic study based on the latest metabolomics and proteomics research platform. RESULTS: Lipid metabolomic analysis revealed abnormal metabolism of glycerides, glycerophospholipids, and sphingomyelin in the FF of PCOS. Differential lipids were strongly linked with the rate of high-quality embryos. In total, 144 differentially expressed proteins were screened in ovarian granulosa cells in women with PCOS compared to controls. Go functional enrichment analysis showed that differential proteins were associated with blood coagulation and lead to follicular development disorders. CONCLUSION: The results showed that the differential lipid metabolites and proteins in PCOS were closely related to follicle quality,which can be potential biomarkers for oocyte maturation and ART outcomes.

Nd:YVO4/YVO4 cascaded Raman laser pumped dual-wavelength signal wave MgO:PPLN-OPO with wide range adjustable wavelength interval.

This article presents a dual-wavelength signal wave output system capable of generating a broad range of adjustable wavelength intervals. The setup involved the creation of a dual-wavelength cascaded Raman laser featuring composite cavities operating at 1176 nm and 1313 nm. Experimental investigations were carried out on an external cavity MgO:PPLN-OPO driven by the cascaded Raman laser. By setting the crystal polarization period to 27.6-34.4 µm and the temperature to 50-130°C, adjustable tunable output of dual-wavelength signal wave at 1176 nm-MgO:PPLN-OPO (1550-2294 nm) and 1313 nm-MgO:PPLN-OPO (1768-2189 nm) was achieved with a wavelength interval of 0-218 nm. Under the conditions of a period of 34.4 µm, temperature of 90°C, and an incident Raman power of 2.6 W, the highest conversion efficiency of Raman to dual-wavelength signal wave (2212, 2182 nm) was 34.2%. Furthermore, the maximum output power of dual-wavelength signal wave was recorded at 1.02 W with an incident Raman power of 3.33 W.

Simultaneous assessment of stress hyperglycemia ratio and glycemic variability to predict mortality in patients with coronary artery disease: a retrospective cohort study from the MIMIC-IV database.

BACKGROUND: Stress hyperglycemia and glycemic variability (GV) can reflect dramatic increases and acute fluctuations in blood glucose, which are associated with adverse cardiovascular events. This study aimed to explore whether the combined assessment of the stress hyperglycemia ratio (SHR) and GV provides additional information for prognostic prediction in patients with coronary artery disease (CAD) hospitalized in the intensive care unit (ICU). METHODS: Patients diagnosed with CAD from the Medical Information Mart for Intensive Care-IV database (version 2.2) between 2008 and 2019 were retrospectively included in the analysis. The primary endpoint was 1-year mortality, and the secondary endpoint was in-hospital mortality. Levels of SHR and GV were stratified into tertiles, with the highest tertile classified as high and the lower two tertiles classified as low. The associations of SHR, GV, and their combination with mortality were determined by logistic and Cox regression analyses. RESULTS: A total of 2789 patients were included, with a mean age of 69.6 years, and 30.1% were female. Overall, 138 (4.9%) patients died in the hospital, and 404 (14.5%) patients died at 1 year. The combination of SHR and GV was superior to SHR (in-hospital mortality: 0.710 vs. 0.689, p = 0.012; 1-year mortality: 0.644 vs. 0.615, p = 0.007) and GV (in-hospital mortality: 0.710 vs. 0.632, p = 0.004; 1-year mortality: 0.644 vs. 0.603, p < 0.001) alone for predicting mortality in the receiver operating characteristic analysis. In addition, nondiabetic patients with high SHR levels and high GV were associated with the greatest risk of both in-hospital mortality (odds ratio [OR] = 10.831, 95% confidence interval [CI] 4.494-26.105) and 1-year mortality (hazard ratio [HR] = 5.830, 95% CI 3.175-10.702). However, in the diabetic population, the highest risk of in-hospital mortality (OR = 4.221, 95% CI 1.542-11.558) and 1-year mortality (HR = 2.013, 95% CI 1.224-3.311) was observed in patients with high SHR levels but low GV. CONCLUSIONS: The simultaneous evaluation of SHR and GV provides more information for risk stratification and prognostic prediction than SHR and GV alone, contributing to developing individualized strategies for glucose management in patients with CAD admitted to the ICU.

The additive effect of the triglyceride-glucose index and estimated glucose disposal rate on long-term mortality among individuals with and without diabetes: a population-based study.

BACKGROUND: The triglyceride-glucose (TyG) index and estimated glucose disposal rate (eGDR), which are calculated using different parameters, are widely used as markers of insulin resistance and are associated with cardiovascular diseases and prognosis. However, whether they have an additive effect on the risk of mortality remains unclear. This study aimed to explore whether the combined assessment of the TyG index and eGDR improved the prediction of long-term mortality in individuals with and without diabetes. METHODS: In this cross-sectional and cohort study, data were derived from the National Health and Nutrition Examination Survey (NHANES) 2001-2018, and death record information was obtained from the National Death Index. The associations of the TyG index and eGDR with all-cause and cardiovascular mortality were determined by multivariate Cox regression analysis and restricted cubic splines. RESULTS: Among the 17,787 individuals included in the analysis, there were 1946 (10.9%) all-cause deaths and 649 (3.6%) cardiovascular deaths during a median follow-up of 8.92 years. In individuals with diabetes, the restricted cubic spline curves for the associations of the TyG index and eGDR with mortality followed a J-shape and an L-shape, respectively. The risk of mortality significantly increased after the TyG index was > 9.04 (all-cause mortality) or > 9.30 (cardiovascular mortality), and after eGDR was < 4 mg/kg/min (both all-cause and cardiovascular mortality). In individuals without diabetes, the association between eGDR and mortality followed a negative linear relationship. However, there was no association between the TyG index and mortality. Compared with individuals in the low TyG and high eGDR group, those in the high TyG and low eGDR group (TyG > 9.04 and eGDR < 4) showed the highest risk for all-cause mortality (hazard ratio [HR] = 1.592, 95% confidence interval [CI] 1.284-1.975) and cardiovascular mortality (HR = 1.683, 95% CI 1.179-2.400) in the overall population. Similar results were observed in individuals with and without diabetes. CONCLUSIONS: There was a potential additive effect of the TyG index and eGDR on the risk of long-term mortality in individuals with and without diabetes, which provided additional information for prognostic prediction and contributed to improving risk stratification.

Sliding Dynamics of Current-Driven Skyrmion Crystal and Helix in Chiral Magnets.

The skyrmion crystal (SkX) and helix (HL) phases, present in typical chiral magnets, can each be considered as forms of density waves but with distinct topologies. The SkX exhibits gyrodynamics analogous to electrons under a magnetic field, while the HL state resembles topological trivial spin density waves. However, unlike the charge density waves, the theoretical analysis of the sliding motion of SkX and HL remains unclear, especially regarding the similarities and differences in sliding dynamics between these two spin density waves. In this Letter, we systematically explore the sliding dynamics of SkX and HL in chiral magnets in the limit of large current density. We demonstrate that the sliding dynamics of both SkX and HL can be unified within the same theoretical framework as density waves, despite their distinct microscopic orders. Furthermore, we highlight the significant role of gyrotropic sliding induced by impurity effects in the SkX state, underscoring the impact of nontrivial topology on the sliding motion of density waves. Our theoretical analysis shows that the effect of impurity pinning is much stronger in HL compared with SkX, i.e., χ^{SkX}/χ^{HL}∼α^{2} (χ^{SkX}, χ^{HL}: susceptibility to the impurity potential, α (≪1) is the Gilbert damping). Moreover, the velocity correction is mostly in the transverse direction to the current in SkX. These results are further substantiated by realistic Landau-Lifshitz-Gilbert simulations.

Anomalous h/2e Periodicity and Majorana Zero Modes in Chiral Josephson Junctions.

Recent experiments reported that quantum Hall chiral edge state-mediated Josephson junctions (chiral Josephson junctions) could exhibit Fraunhofer oscillations with a periodicity of either h/e [Vignaud et al., Nature (London) 624, 545 (2023)NATUAS0028-083610.1038/s41586-023-06764-4] or h/2e [Amet et al., Science 352, 966 (2016)SCIEAS0036-807510.1126/science.aad6203]. While the h/e-periodic component of the supercurrent had been anticipated theoretically before, the emergence of the h/2e periodicity is still not fully understood. In this Letter, we systematically study the Fraunhofer oscillations of chiral Josephson junctions. In chiral Josephson junctions, the chiral edge states coupled to the superconductors become chiral Andreev edge states. We find that in short junctions, the coupling of the chiral Andreev edge states can trigger the h/2e-magnetic flux periodicity. Our theory resolves the important puzzle concerning the appearance of the h/2e periodicity in chiral Josephson junctions. Furthermore, we explain that when the chiral Andreev edge states couple, a pair of localized Majorana zero modes appear at the ends of the Josephson junction, which are robust and independent of the phase difference between the two superconductors. As the h/2e periodicity and the Majorana zero modes have the same physical origin in the wide junction limit, the Fraunhofer oscillation period could be useful in identifying the regime with Majorana zero modes.

Predictive factors of medium-giant coronary artery aneurysms in Kawasaki disease.

BACKGROUND: We aimed to examine predictive measures for medium and giant coronary artery aneurysms (CAA) in Kawasaki disease (KD) patients. METHODS: Patients who were diagnosed with KD from 2015 to 2021 were retrospectively reviewed. The clinical and laboratory data were compared between medium-giant group and non-medium-giant group. RESULTS: A total of 1331 KD patients were investigated, of whom 63 patients (4.7%) developed medium-giant CAA including 27 patients (2%) with giant CAA. Sex, age, fever duration, intravenous immunoglobulin (IVIG) resistance, platelet count, and albumin level independently predicted medium or giant CAA by multivariate logistic regression analysis. Male, age, duration of fever, IVIG resistance, platelet count, hemoglobin, and erythrocyte sedimentation rate were independent predictors for giant CAA. The two new scoring systems using these factors in identifying patients with medium-giant CAA and giant CAA had respectively sensitivities of 86.89% and 92.59%, and specificities of 81.65% and 87.93%. Validation in 2021 dataset (193 KD patients) showed comparable sensitivity and specificity to development dataset. CONCLUSIONS: Male, age, fever duration, IVIG resistance, platelet count, albumin, hemoglobin, and erythrocyte sedimentation rate might be significant predictors of medium and giant CAA. The sensitivity and specificity in our risk prediction model were higher than in previous research. IMPACT: This is the first study to search for risk factors and establish a prediction model for the development of medium-giant CAA in the Chinese population using z-scores and absolute inner diameter values based on large sample sizes. The sensitivity and specificity in our model were higher than in previous studies. Our research could help clinicians better predict medium-giant CAA and choose more appropriate treatment.

Correlation Between TRAb and Early Onset Hypothyroidism After 131I Treatment for Graves' Disease.

The aim of the study was to explore the clinical features related to early hypothyroidism and the relationship between the changes of thyrotropin receptor antibodies (TRAb) and early hypothyroidism in the course of 131I treatment for Graves' disease. This study was a retrospective observation, including 226 patients who received the first 131I treatment. The general information and laboratory tests were collected before and after 131I treatment, and the laboratory data affecting the difference in disease outcome were analyzed. According to the changes of antibodies in the third month, whether the changes of antibodies were involved in the occurrence of early-onset hypothyroidism was analyzed. Early onset hypothyroidism occurred in 165 of 226 patients, and the results showed that the incidence of early hypothyroidism was higher in patients with low baseline TRAb level (p=0.03) and increased TRAb after treatment (p=0.007). Both baseline TRAb levels (p<0.001) and the 24-hour iodine uptake rate (p=0.004) are significant factors influencing the changes in TRAb. The likelihood of a rise in TRAb was higher when the baseline TRAb was less than 18.55 U/l and the 24-hour iodine uptake level exceeded 63.61%. Low baseline and elevated post-treatment levels of TRAb were significantly associated with early-onset hypothyroidism after 131I treatment. Monitoring this index during RAI treatment is helpful in identifying early-onset hypothyroidism and mastering the clinical outcome and prognosis of Graves' disease.

Novel nano-drug delivery system for natural products and their application.

The development of natural products for potential new drugs faces obstacles such as unknown mechanisms, poor solubility, and limited bioavailability, which limit the broadened applicability of natural products. Therefore, there is a need for advanced pharmaceutical formulations of active compounds or natural products. In recent years, novel nano-drug delivery systems (NDDS) for natural products, including nanosuspensions, nanoliposomes, micelle, microemulsions/self-microemulsions, nanocapsules, and solid lipid nanoparticles, have been developed to improve solubility, bioavailability, and tissue distribution as well as for prolonged retention and enhanced permeation. Here, we updated the NDDS delivery systems used for natural products with the potential enhancement in therapeutic efficiency observed with nano-delivery systems.