Compressive Mechanical Behavior and Corresponding Failure Mechanism of Polymethacrylimide Foam Induced by Thermo-Mechanical Coupling.

Thermal-mechanical coupling during the molding process can cause compressive yield in the polymer foam core and then affect the molding quality of the sandwich structure. This work investigates the compressive mechanical properties and failure mechanism of polymethacrylimide (PMI) foam in the molding temperature range of 20-120 °C. First, the DMA result indicates that PMI foam has minimal mechanical loss in the 20~120 °C range and can be regarded as an elastoplastic material, and the TGA curve further proves that the PMI foam is thermally stable within 120 °C. Then, the compression results show that compared with 20 °C, the yield stress and elastic modulus of PMI foam decrease by 22.0% and 17.5% at 80 °C and 35.2% and 31.4% at 120 °C, respectively. Meanwhile, the failure mode changes from brittle fracture to plastic yield at about 80 °C. Moreover, a real representative volume element (rRVE) of PMI foam is established by using Micro-CT and Avizo 3D reconstruction methods, and the simulation results indicate that PMI foam mainly shows brittle fractures at 20 °C, while both brittle fractures and plastic yield occur at 80 °C, and most foam cells undergo plastic yield at 120 °C. Finally, the simulation based on a single-cell RVE reveals that the air pressure inside the foam has an obvious influence of about 6.7% on the yield stress of PMI foam at 80 °C (brittle-plastic transition zone).

Sleep deprivation reduces the baroreflex sensitivity through elevated angiotensin (Ang) II subtype 1 receptor expression in the nucleus tractus solitarii.

Introduction: Sleep insufficiency has been linked to an increased risk of high blood pressure and cardiovascular diseases. Emerging studies have demonstrated that impaired baroreflex sensitivity (BRS) is involved in the adverse cardiovascular effects caused by sleep deprivation, however, the underlying mechanisms remain unknown. Therefore, the present study aims to clarify the role of abnormal renin-angiotensin system in the nucleus tractus solitarii (NTS) in impaired BRS induced by sleep deprivation. Methods: Rats were randomly divided into two groups: normal sleep (Ctrl) and chronic sleep deprivation (CSD) group. Rats were sleep deprived by an automated sleep deprivation system. The blood pressure, heart rate, BRS, the number of c-Fos positive cells and the expression of angiotensin (Ang) II subtype 1 receptors (AT1R) in the NTS of rats were assessed. Results: Compared to Ctrl group, CSD group exhibited a higher blood pressure, heart rate, and reduced BRS. Moreover, the number of c-Fos positive cells and local field potential in the NTS in CSD group were increased compared with the Ctrl group. It was shown that the expression of the AT1R and the content of Ang II and the ratio of Ang II to Ang-(1-7) were increased in the NTS of rats in CSD group compared to Ctrl group. In addition, microinjection of losartan into the NTS significantly improved the impaired BRS caused by sleep deprivation. Discussion: In conclusion, these data suggest that the elevated AT1R expression in the NTS mediates the reduced BRS induced by chronic sleep deprivation.

Decrypting the skeletal toxicity of vertebrates caused by environmental pollutants from an evolutionary perspective: From fish to mammals.

The rapid development of modern society has led to an increasing severity in the generation of new pollutants and the significant emission of old pollutants, exerting considerable pressure on the ecological environment and posing a serious threat to both biological survival and human health. The skeletal system, as a vital supportive structure and functional unit in organisms, is pivotal in maintaining body shape, safeguarding internal organs, storing minerals, and facilitating blood cell production. Although previous studies have uncovered the toxic effects of pollutants on vertebrate skeletal systems, there is a lack of comprehensive literature reviews in this field. Hence, this paper systematically summarizes the toxic effects and mechanisms of environmental pollutants on the skeletons of vertebrates based on the evolutionary context from fish to mammals. Our findings reveal that current research mainly focuses on fish and mammals, and the identified impact mechanisms mainly involve the regulation of bone signaling pathways, oxidative stress response, endocrine system disorders, and immune system dysfunction. This study aims to provide a comprehensive and systematic understanding of research on skeletal toxicity, while also promoting further research and development in related fields.

Identification of Susceptibility Genes Underlying Bovine Respiratory Disease in Xinjiang Brown Cattle Based on DNA Methylation.

DNA methylation is a form of epigenetic regulation, having pivotal parts in controlling cellular expansion and expression levels within genes. Although blood DNA methylation has been studied in humans and other species, its prominence in cattle is largely unknown. This study aimed to methodically probe the genomic methylation map of Xinjiang brown (XJB) cattle suffering from bovine respiratory disease (BRD), consequently widening cattle blood methylome ranges. Genome-wide DNA methylation profiling of the XJB blood was investigated through whole-genome bisulfite sequencing (WGBS). Many differentially methylated regions (DMRs) obtained by comparing the cases and controls groups were found within the CG, CHG, and CHH (where H is A, T, or C) sequences (16,765, 7502, and 2656, respectively), encompassing 4334 differentially methylated genes (DMGs). Furthermore, GO/KEGG analyses showed that some DMGs were involved within immune response pathways. Combining WGBS-Seq data and existing RNA-Seq data, we identified 71 significantly differentially methylated (DMGs) and expressed (DEGs) genes (p < 0.05). Next, complementary analyses identified nine DMGs (LTA, STAT3, IKBKG, IRAK1, NOD2, TLR2, TNFRSF1A, and IKBKB) that might be involved in the immune response of XJB cattle infected with respiratory diseases. Although further investigations are needed to confirm their exact implication in the involved immune processes, these genes could potentially be used for a marker-assisted selection of animals resistant to BRD. This study also provides new knowledge regarding epigenetic control for the bovine respiratory immune process.

The absence of the ribosomal protein Rpl2702 elicits the MAPK-mTOR signaling to modulate mitochondrial morphology and functions.

Ribosomes mediate protein synthesis, which is one of the most energy-demanding activities within the cell, and mitochondria are one of the main sources generating energy. How mitochondrial morphology and functions are adjusted to cope with ribosomal defects, which can impair protein synthesis and affect cell viability, is poorly understood. Here, we used the fission yeast Schizosaccharomyces Pombe as a model organism to investigate the interplay between ribosome and mitochondria. We found that a ribosomal insult, caused by the absence of Rpl2702, activates a signaling pathway involving Sty1/MAPK and mTOR to modulate mitochondrial morphology and functions. Specifically, we demonstrated that Sty1/MAPK induces mitochondrial fragmentation in a mTOR-independent manner while both Sty1/MAPK and mTOR increases the levels of mitochondrial membrane potential and mitochondrial reactive oxygen species (mROS). Moreover, we demonstrated that Sty1/MAPK acts upstream of Tor1/TORC2 and Tor1/TORC2 and is required to activate Tor2/TORC1. The enhancements of mitochondrial membrane potential and mROS function to promote proliferation of cells bearing ribosomal defects. Hence, our study reveals a previously uncharacterized Sty1/MAPK-mTOR signaling axis that regulates mitochondrial morphology and functions in response to ribosomal insults and provides new insights into the molecular and physiological adaptations of cells to impaired protein synthesis.

Prevalence and contributing factors of anemia in patients with gynecological cancer: a retrospective cohort study.

This retrospective cohort study aimed to determine the prevalence of anemia among patients with gynecological cancer prior to any treatment and to identify contributing factors associated with anemia in this group. We retrospectively analyzed data from female patients aged 18 and above, diagnosed with various forms of gynecological cancer at The Affiliated Hospital of Southwest Medical University between February 2016 and March 2021. Anemia was assessed based on the most recent CBC results before any cancer treatment. Eligibility was based on a definitive histopathological diagnosis. Key variables included demographic details, clinical characteristics, and blood counts, focusing on hemoglobin levels. Statistical analysis was conducted using logistic regression models, and anemia was defined as hemoglobin levels below 12 g/dL for women, according to WHO criteria. Of the 320 participants, a significant prevalence of anemia was found. Correlations between anemia and factors like age, educational level, and biological markers (iron, folic acid, and vitamin B12 levels) were identified. In our study, we found that the prevalence of anemia among patients with gynecological cancer prior to any treatment was 59.06%, indicating a significant health concern within this population. The study highlights a significant prevalence of anemia in patients with gynecological cancer, emphasizing the need for regular hemoglobin screening and individualized management. These findings suggest the importance of considering various characteristics and clinical variables in anemia management among this patient group. Further studies are needed to explore the long-term effects of these factors on patient outcomes and to develop targeted interventions.

P3N-PIPO but not P3 is the avirulence determinant in melon carrying the Wmr resistance against watermelon mosaic virus, although they contain a common genetic determinant.

Viruses employ a series of diverse translational strategies to expand their coding capacity, which produces viral proteins with common domains and entangles virus-host interactions. P3N-PIPO, which is a transcriptional slippage product from the P3 cistron, is a potyviral protein dedicated to intercellular movement. Here, we show that P3N-PIPO from watermelon mosaic virus (WMV) triggers cell death when transiently expressed in Cucumis melo accession PI 414723 carrying the Wmr resistance gene. Surprisingly, expression of the P3N domain, shared by both P3N-PIPO and P3, can alone induce cell death, whereas expression of P3 fails to activate cell death in PI 414723. Confocal microscopy analysis revealed that P3N-PIPO targets plasmodesmata (PD) and P3N associates with PD, while P3 localizes in endoplasmic reticulum in melon cells. We also found that mutations in residues L35, L38, P41, and I43 of the P3N domain individually disrupt the cell death induced by P3N-PIPO, but do not affect the PD localization of P3N-PIPO. Furthermore, WMV mutants with L35A or I43A can systemically infect PI 414723 plants. These key residues guide us to discover some WMV isolates potentially breaking the Wmr resistance. Through searching the NCBI database, we discovered some WMV isolates with variations in these key sites, and one naturally occurring I43V variation enables WMV to systemically infect PI 414723 plants. Taken together, these results demonstrate that P3N-PIPO, but not P3, is the avirulence determinant recognized by Wmr, although the shared N terminal P3N domain can alone trigger cell death.IMPORTANCEThis work reveals a novel viral avirulence (Avr) gene recognized by a resistance (R) gene. This novel viral Avr gene is special because it is a transcriptional slippage product from another virus gene, which means that their encoding proteins share the common N-terminal domain but have distinct C-terminal domains. Amazingly, we found that it is the common N-terminal domain that determines the Avr-R recognition, but only one of the viral proteins can be recognized by the R protein to induce cell death. Next, we found that these two viral proteins target different subcellular compartments. In addition, we discovered some virus isolates with variations in the common N-terminal domain and one naturally occurring variation that enables the virus to overcome the resistance. These results show how viral proteins with common domains interact with a host resistance protein and provide new evidence for the arms race between plants and viruses.

Knowledge, attitudes, and practices towards urinary system stones among the Chengdu population.

This cross-sectional study aimed to explore the knowledge, attitudes, and practices (KAP) regarding urinary system stones among the general public in Chengdu, China. Conducted between January and June 2023, this research targeted individuals undergoing physical examinations at the Health Management Center of Sichuan Provincial People's Hospital. Structured questionnaires were administered to collect demographic information and assess KAP related to urinary system stones. Following meticulous scrutiny, 1014 valid questionnaires were retained for analysis. The computed scores for knowledge, attitude, and practice were 9.36 ± 4.23 (possible score range 0-17), 37.75 ± 7.20 (possible score range 11-55), and 30.77 ± 4.00 (possible score range 10-50), respectively. These outcomes suggested insufficient knowledge and moderately positive attitudes and practices among the participants. Structural Equation Modeling (SEM) analysis revealed a direct impact of knowledge on attitude (ß = 0.967, P < 0.001), with attitude subsequently exerting a direct influence on practice (ß = 0.167, P < 0.001). This indicated an indirect impact of knowledge on practice. Additionally, there was a direct effect of knowledge on practice (ß = 0.167, P < 0.001). In conclusion, the general populace in Chengdu exhibited insufficient knowledge and moderate attitudes and practices concerning urinary stones. These findings underscore the imperative for targeted educational interventions aimed at enhancing public awareness and fostering positive attitudes and practices toward urinary stone prevention and management.

WDR61 ablation triggers R-loop accumulation and suppresses breast cancer progression.

Although, superkiller complex protein 8 (SKI8), previously known as WDR61 has been identified and mapped in breast tumor, little is currently known about its function. This study aims to elucidate the role of WDR61 in breast tumor development and its potential as a therapeutic target. Here, we show that tamoxifen-induced knockout of Wdr61 reduces the risk of breast tumors, resulting in smaller tumor size and weight, and improved overall survival. Furthermore, we show that knockdown of WDR61 compromises the proliferation of breast tumor cells with reduced colony-forming capacity. Further investigations demonstrate that the protective effect of WDR61 loss on breast tumor development is due to genomic instability. Mechanistic studies reveal that WDR61 interacts with the R-loop, and loss of WDR61 leads to R-loops accumulation in breast tumor cells, causing DNA damage and subsequent inhibition of cell proliferation. In summary, this study highlights the critical dependence of breast tumors on WDR61, which suppresses R-loop and counteracts endogenous DNA damage in tumor cells.

Zebrafish cobll1a regulates lipid homeostasis via the RA signaling pathway.

Background: The COBLL1 gene has been implicated in human central obesity, fasting insulin levels, type 2 diabetes, and blood lipid profiles. However, its molecular mechanisms remain largely unexplored. Methods: In this study, we established cobll1a mutant lines using the CRISPR/Cas9-mediated gene knockout technique. To further dissect the molecular underpinnings of cobll1a during early development, transcriptome sequencing and bioinformatics analysis was employed. Results: Our study showed that compared to the control, cobll1a -/- zebrafish embryos exhibited impaired development of digestive organs, including the liver, intestine, and pancreas, at 4 days post-fertilization (dpf). Transcriptome sequencing and bioinformatics analysis results showed that in cobll1a knockout group, the expression level of genes in the Retinoic Acid (RA) signaling pathway was affected, and the expression level of lipid metabolism-related genes (fasn, scd, elovl2, elovl6, dgat1a, srebf1 and srebf2) were significantly changed (p < 0.01), leading to increased lipid synthesis and decreased lipid catabolism. The expression level of apolipoprotein genes (apoa1a, apoa1b, apoa2, apoa4a, apoa4b, and apoea) genes were downregulated. Conclusion: Our study suggest that the loss of cobll1a resulted in disrupted RA metabolism, reduced lipoprotein expression, and abnormal lipid transport, therefore contributing to lipid accumulation and deleterious effects on early liver development.

Mechanical protein polycystin-1 directly regulates osteoclastogenesis and bone resorption.

Mechanical loading is required for bone homeostasis, but the underlying mechanism is still unclear. Our previous studies revealed that the mechanical protein polycystin-1 (PC1, encoded by Pkd1) is critical for bone formation. However, the role of PC1 in bone resorption is unknown. Here, we found that PC1 directly regulates osteoclastogenesis and bone resorption. The conditional deletion of Pkd1 in the osteoclast lineage resulted in a reduced number of osteoclasts, decreased bone resorption, and increased bone mass. A cohort study of 32,500 patients further revealed that autosomal dominant polycystic kidney disease, which is mainly caused by loss-of-function mutation of the PKD1 gene, is associated with a lower risk of hip fracture than those with other chronic kidney diseases. Moreover, mice with osteoclast-specific knockout of Pkd1 showed complete resistance to unloading-induced bone loss. A mechanistic study revealed that PC1 facilitated TAZ nuclear translocation via the C-terminal tail-TAZ complex and that conditional deletion of Taz in the osteoclast lineage resulted in reduced osteoclastogenesis and increased bone mass. Pharmacological regulation of the PC1-TAZ axis alleviated unloading- and estrogen deficiency- induced bone loss. Thus, the PC1-TAZ axis may be a potential therapeutic target for osteoclast-related osteoporosis.

CK2-HTATSF1-TOPBP1 signaling axis modulates tumor chemotherapy response.

Homologous recombination (HR) plays a key role in maintaining genomic stability, and the efficiency of the HR system is closely associated with tumor response to chemotherapy. Our previous work reported that CK2 kinase phosphorylates HTATSF1 Ser748 (pS748) to facilitate HTATSF1 interaction with TOPBP1, which in turn, promotes RAD51 recruitment and HR repair. However, the clinical implication of the CK2-HTATSF1-TOPBP1 pathway in tumorigenesis and chemotherapeutic response remains to be elucidated. Here, we report that the CK2-HTATSF1-TOPBP1 axis is generally hyperactivated in multiple malignancies and renders breast tumors less responsive to chemotherapy. In contrast, deletion mutations of each gene in this axis, which also occur in breast and lung tumor samples, predict higher HR deficiency (HRD) scores, and tumor cells bearing a loss-of-function mutation of HTATSF1 are vulnerable to PARP inhibitors (PARPis) or platinum drugs. Taken together, our study suggests that the integrity of the CK2-HTATSF1-TOPBP1 axis is closely linked to tumorigenesis, and serves as an indicator of tumor HR status and modulates chemotherapy response.

The in vitro mechanism of Vaspinregulates the proliferation and steroidogenesis of rat lutein cells.

OBJECTIVE: Stable luteal cell function is an important prerequisite for reproductive ability and embryonic development. However, luteal insufficiency seriously harms couples who have the desire to have a pregnancy, and the most important thing is that there is no complete solution. In addition, Vaspin has been shown to have regulatory effects on luteal cells, but the complex mechanisms involved have not been fully elucidated. Therefore, this study aimed to explore the effect of Vaspin on rat luteal cells and its mechanism. METHODS: Granulosa lutein cells separated from the ovary of female rats were incubated for 24h with gradient concentrations of Vaspin, and granulosa lutein cells incubated with 0.5% bovine serum albumin were used as controls. The proliferation, apoptosis, angiogenesis, progesterone (P4) and estradiol (E2) were detected by CCK-8, Anneixn-FITC/PI staining, angiogenesis experiment and ELISA. Western blot was applied to observe the expression levels of proteins related to cell proliferation, apoptosis, angiogenesis and MEK/MAPK signaling pathway. RESULTS: Compared with the Control group, Vaspin could significantly up-regulate the proliferation of granulosa lutein cells and reduce the apoptosis. Moreover, Vaspin promoted the angiogenesis of granulosa lutein cells and the production of P4 and E2 in a concentration-dependent manner. Furthermore, Vaspin up-regulated the CyclinD1, CyclinB1, Bcl2, VEGFA and FGF-2 expression in granulosa lutein cells, and down-regulated the level of Bax. Also, Vaspin increased the p-MEK1 and p-p38 levels. CONCLUSION: Vaspin can up-regulate the proliferation and steroidogenesis of rat luteal cells and reduce apoptosis, which may be related to the influence of MEK/MAPK activity.

Mechanism for Fe(III) to decrease cadmium uptake of wheat plant: Rhizosphere passivation, competitive absorption and physiological regulation.

The presence of dissolved Fe(III) and Fe(III)-containing minerals has been found to alleviate cadmium (Cd) accumulation in wheat plants grown in Cd-contaminated soils, but the specific mechanism remains elusive. In this work, hydroponic experiments were conducted to dissect the mechanism for dissolved Fe(III) (0-2000 µmol L-1) to decrease Cd uptake of wheat plants and study the influence of Fe(III) concentration and Cd(II) pollution level (0-20 µmol L-1) on the Cd uptake process. The results indicated that dissolved Fe(III) significantly decreased Cd uptake through rhizosphere passivation, competitive absorption, and physiological regulation. The formation of poorly crystalline Fe(III) oxides facilitated the adsorption and immobilization of Cd(II) on the rhizoplane (over 80.4 %). In wheat rhizosphere, the content of CaCl2-extractable Cd decreased by 52.7 % when Fe(III) concentration was controlled at 2000 µmol L-1, and the presence of Fe(III) may reduce the formation of Cd(II)-organic acid complexes (including malic acid and succinic acid secreted by wheat roots), which could be attributed to competitive reactions. Down-regulation of Cd uptake genes (TaNramp5-a and TaNramp5-b) and transport genes (TaHMA3-a, TaHMA3-b and TaHMA2), along with up-regulation of the Cd efflux gene TaPDR8-4A7A, contributed much to the reduction of Cd accumulation in wheat plants in the presence of Fe(III). The inhibitory effect of Fe(III) on Cd uptake and transport in wheat plants declined with increasing Cd(II) concentration, particularly at 20 µmol L-1. This work provides important implications for remediating Cd-contaminated farmland soil and ensuring the safe production of wheat by using dissolved Fe(III) and Fe(III)-containing minerals.

Systematic profiling of Taxol resistance and sensitivity to tubulin missence mutations at molecular and cellular levels.

Taxol (paclitaxel) is the first approved microtubule-stabilizing agent (MSA) by binding stoichiometrically to tubulin, which is considered to be one of the most significant advances in first-line chemotherapy against diverse tumors. However, a large number of residue missence mutations harboring in the tubulin have been observed to cause acquired drug resistance, largely limiting the clinical application of Taxol and its analogs in chemotherapy. A systematic investigation of the intermolecular interactions between the Taxol and various tubulin mutants would help to establish a comprehensive picture of drug response to tubulin mutations in clinical treatment of cancer, and to design new MSA agents with high potency and selectivity to overcome drug resistance. In this study, we described an integration of in silico analysis and in vitro assay (iSiV) to profile Taxol against a panel of 149 clinically observed, cancer-associated missence mutations in ß-tubulin at molecular and cellular levels, aiming to a systematic understanding of molecular mechanism and biological implication underlying drug resistance and sensitivity conferring from tubulin mutations. It is revealed that the Taxol-resistant mutations can be classified into three types: (I) nonbonded interaction broken due to mutation, (II) steric hindrance caused by mutation, and (III) conformational change upon mutation. In addition, we identified three new Taxol-resistant mutations (C239Y, T274I, and R320P) that can largely reduce the binding affinity of Taxol to tubulin at molecular level, in which the T274I and R320P were observed to considerably impair the antitumor activity of Taxol at cellular level. Moreover, a novel drug-susceptible mutation (M363T) was also identified, which improves Taxol affinity by 2.6-fold and decreases Taxol antitumor EC50 values from 29.4 to 18.7 µM.

Are children with IgA nephropathy different from adult patients?

BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.

Optimal dose of fenfluramine in adjuvant treatment of drug-resistant epilepsy: evidence from randomized controlled trials.

Objective: Several clinical trials have suggested that fenfluramine (FFA) is effective for the treatment of epilepsy in Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). However, the exploration of its optimal target dose is ongoing. This study aimed to summarize the best evidence to inform this clinical issue. Materials and methods: We searched PubMed, Embase (via Ovid), and Web of Science for relevant literature published before December 1st, 2023. Randomized, double-blind, placebo-controlled studies that evaluated the efficacy, safety, and tolerability of FFA in DS and LGS were identified and meta-analysis was performed according to doses. The study was registered with PROSPERO (CRD42023392454). Results: Six hundred and twelve patients from four randomized controlled trials were enrolled. The results demonstrated that FFA at 0.2, 0.4, or 0.7 mg/kg/d showed significantly greater efficacy compared to placebo in terms of at least 50% reduction (p < 0.001, p < 0.001, p < 0.001) and at least 75% reduction (p < 0.001, p = 0.007, p < 0.001) in monthly seizure frequency from baseline. Moreover, significantly more patients receiving FFA than placebo were rated as much improved or very much improved in CGI-I by both caregivers/parents and investigators (p < 0.001). The most common treatment-emergent adverse events were decreased appetite, diarrhea, fatigue, and weight loss, with no valvular heart disease or pulmonary hypertension observed in any participant. For dose comparison, 0.7 mg/kg/d group presented higher efficacy on at least 75% reduction in seizure (p = 0.006) but not on at least 50% reduction. Weight loss (p = 0.002), decreased appetite (p = 0.04), and all-cause withdrawal (p = 0.036) were more common in 0.7 mg/kg/d group than 0.2 mg/kg/d. There was no statistical difference in other safety parameters between these two groups. Conclusion: The higher range of the licensed dose achieves the optimal balance between efficacy, safety, and tolerability in patients with DS and LGS. Clinical trial registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023392454.

Triglyceride glucose index is associated with functional coronary artery stenosis in hypertensive patients.

Background: The triglyceride glucose (TyG) index is an effective method for determining insulin resistance (IR). Limited research has explored the connection between the TyG index and functionally significant stenosis in hypertensive patients. Furthermore, the connections between the TyG index, fat attenuation index (FAI) and atherosclerotic plaque characteristics are also worth exploring. Methods: The study screened 1622 hypertensive participants without coronary artery disease history who underwent coronary computed tomography angiography. The TyG index was calculated as ln (fasting glucose [mg/dL] * fasting TG [mg/dL]/2). Adverse plaque characteristics (HRPCs), high-risk plaques (HRPs), FAI, and CT-derived fractional flow reserve (FFRCT) were analyzed and measured for all patients. Functionally significant stenosis causing ischemia is defined as FFRCT ≤ 0.80. Two patient groups were created based on the FFRCT: the FFRCT < 0.80 group and the FFRCT > 0.80 group. In hypertensive patients, the association between the TyG index and FFRCT was examined applying a logistic regression model. Results: The TyG index was higher for people with FFRCT ≤ 0.80 contrast to those with FFRCT > 0.80. After controlling for additional confounding factors, the logistic regression model revealed a clear connection between the TyG index and FFRCT ≤ 0.80 (OR = 1.718, 95% CI 1.097-2.690, p = 0.018). The restricted cubic spline analysis displayed a nonlinear connection between the TyG index and FFRCT ≤ 0.80 (p for nonlinear = 0.001). The TyG index increased the fraction of individuals with HRPs and HRPCs, FAI raised, and FFRCT decreased (p < 0.05). The multivariate linear regression analysis illustrated a powerfulcorrelation between high TyG index levels and FAI, FFRCT, positive remodeling (PR), and low-attenuation plaque (LAPs) (standardized regression coefficients: 0.029 [p = 0.007], -0.051 [p < 0.001], 0.029 [p = 0.027], and 0.026 [p = 0.046], separately). Conclusion: In hypertensive patients, the TyG index showed an excellent association with a risk of FFRCT ≤ 0.80. Additionally, the TyG index was also linked to FAI, FFRCT, PR, and LAPs.

Reducing target binding affinity improves the therapeutic index of anti-MET antibody-drug conjugate in tumor bearing animals.

Many oncology antibody-drug conjugates (ADCs) have failed to demonstrate efficacy in clinic because of dose-limiting toxicity caused by uptake into healthy tissues. We developed an approach that harnesses ADC affinity to broaden the therapeutic index (TI) using two anti-mesenchymal-epithelial transition factor (MET) monoclonal antibodies (mAbs) with high affinity (HAV) or low affinity (LAV) conjugated to monomethyl auristatin E (MMAE). The estimated TI for LAV-ADC was at least 3 times greater than the HAV-ADC. The LAV- and HAV-ADCs showed similar levels of anti-tumor activity in the xenograft model, while the 111In-DTPA studies showed similar amounts of the ADCs in HT29 tumors. Although the LAV-ADC has ~2-fold slower blood clearance than the HAV-ADC, higher liver toxicity was observed with HAV-ADC. While the SPECT/CT 111In- and 124I- DTPA findings showed HAV-ADC has higher accumulation and rapid clearance in normal tissues, intravital microscopy (IVM) studies confirmed HAV mAb accumulates within hepatic sinusoidal endothelial cells while the LAV mAb does not. These results demonstrated that lowering the MET binding affinity provides a larger TI for MET-ADC. Decreasing the affinity of the ADC reduces the target mediated drug disposition (TMDD) to MET expressed in normal tissues while maintaining uptake/delivery to the tumor. This approach can be applied to multiple ADCs to improve the clinical outcomes.

In Vivo Toxicology of Metabolizable Atomically Precise Au25 Clusters at Ultrahigh Doses.

Ultrasmall Au25(MPA)18 clusters show great potential in biocatalysts and bioimaging due to their well-defined, tunable structure and properties. Hence, in vivo pharmacokinetics and toxicity of Au nanoclusters (Au NCs) are very important for clinical translation, especially at high dosages. Herein, the in vivo hematological, tissue, and neurological effects following exposure to Au NCs (300 and 500 mg kg-1) were investigated, in which the concentration is 10 times higher than in therapeutic use. The biochemical and hematological parameters of the injected Au NCs were within normal limits, even at the ultrahigh level of 500 mg kg-1. Meanwhile, no histopathological changes were observed in the Au NC group, and immunofluorescence staining showed no obvious lesions in the major organs. Furthermore, real-time near-infrared-II (NIR-II) imaging showed that most of the Au25(MPA)18 and Au24Zn1(MPA)18 can be metabolized via the kidney. The results demonstrated that Au NCs exhibit good biosafety by evaluating the manifestation of toxic effects on major organs at ultrahigh doses, providing reliable data for their application in biomedicine.