P53 is a recognized tumor suppressor gene, which mainly depends on the activity of its transfer factor to realize the tumor suppressor effect. Mouse two-minute 2 (MDM2) is an important inhibitor of ...p53. When combined with MDM2, the activity of p53 will be reduced, and the anti-cancer effect will be weakened. According to the mechanism between p53 and MDM2, researchers focus on the inhibitors to inhibit their binding. Through a large number of drug screening methods and means, this article has found many new inhibitors of p53-MDM2 interaction, most of which are still in the clinical research stage. Specifically, we classify the drugs based on their different action mechanisms. Firstly, some drugs combine with MDM2 to inhibit the p53-MDM2 interaction. They are Siremadlin (NVP-HDM201), RG7112, and NVP-CGM09. While some act on p53, they rely on their induction of p53 signalling and inhibition of tumour cell proliferation in p53 wild-type tumor cell lines, like MK-8242 and KRT-232(AMG-232). What’s more, one inhibitor’s action bases on P53 and MDM2 in T cells is APG-115. And last but not least, there are also several drugs that stable tumor suppressor TP53, leading to p53 activation and inducing cell cycle arrest and apoptosis, they are Idasanutlin (RG7388) and Milademetan (DS-3032/RAIN-32). Furthermore, clinical studies are finding that monotherapy does not deliver a powerful therapeutic effect. Various combination strategies are being explored with MDM2 inhibitors preclinically and in the clinic. This article will talk about some specific combinations: APG-115 combine with immune checkpoint inhibitor PD-1/PD-L1, MDM2 inhibitors combine with BCL-2 inhibitors, anti-CD20 therapeutic antibodies, and the last, combine with alkylating agents.
Adolescence represents a pivotal stage in the development of healthy behaviors, where establishing positive physical activity habits can have enduring effects on an individual's overall wellbeing. ...The ecological model highlights the influence of environmental factors on human behavior, with the family environment playing a significant role in shaping the physical activity habits of adolescents.
The aim of this scale is to develop a reliable and effective tool, customized for the unique societal context of China, to assess how family factors influence the physical activity habits of Chinese adolescents. Participants were recruited through stratified cluster sampling from 24 secondary schools in six Chinese provinces between October and November 2021, resulting in 1,061 participants. Analysis was conducted on 1,004 valid questionnaires, divided into two samples. Sample 1, consisting of 502 students (248 males and 254 females; M
= 15.5), underwent item analysis and exploratory factor analysis. Sample 2, comprising 502 students (267 males and 235 females; M
= 16.5), underwent confirmatory factor analysis and internal consistency reliability analysis.
Through exploratory factor analysis, we extracted three factors comprising 15 items: "Family Environment Construction" (4 items), "Family Action Support" (6 items), and "Family Health Awareness" (5 items). The Cronbach's alpha values for these factors ranged from 0.890 to 0.894. Confirmatory factor analysis confirmed a satisfactory model fit (CMIN/DF = 1.45, SRMR = 0.027, GFI = 0.991, TLI = 0.989, RMSEA = 0.03).
The scale demonstrated strong internal consistency and test-retest reliability, confirming its effectiveness in empirical research. This study holds significant implications for enhancing the physical activity levels of adolescents, promoting their physical and mental wellbeing, enriching their developmental experiences, and contributing to their overall sense of happiness.
Abstract
Removing phosphate from wastewater can help alleviate eutrophication. Therefore, in this study, lanthanum and magnesium were loaded onto the thermally modified palygorskite (PAL) using a ...coprecipitation method, and a composite material was prepared for phosphate recovery. In the pH range of 2–7, the material can effectively adsorb the phosphate. In the kinetic experiment, the material was able to rapidly adsorb phosphate within 4 h of the beginning of the reaction. The adsorption isotherm result of the material was in accordance with Freundlich isotherm model. When pH was 7, the theoretical maximum adsorption capacity was 20.4 mg P/g. When phosphate coexisted with CO32− and HCO3−, the adsorption was significantly inhibited. In the adsorption–desorption experiment, the material can be reused at least five times after elution with 1 mol/L of sodium hydroxide solution. The equilibrium adsorption capacity of the material for total phosphorus in piggery wastewater was 7.25 mg P/g, achieving a total phosphorus removal rate of 95.3%. The characterization of XRD, FT-IR and XPS suggested that phosphate was mainly exchanged with La–OH in the material, forming an amorphous LaPO4 complex.
It has been widely reported that plasmonic effects of metallic nanomaterials can enhance light-harvesting in polymer solar cells (PSCs). However, the improved light trapping degree is closely related ...to the shape of the nanoparticles (NPs), which inevitably limits the efficiency enhancement for PSCs. In this paper, we demonstrate that the incorporation of Au arrowhead nanorods (AHNRs) into the active layer of inverted PSCs can dramatically lead to a 28.7% efficiency enhancement as compared to preoptimize control PSCs. Both theoretical and experimental results show that the origin of the improved power conversion efficiency (PCE) can be attributed to not only the optical absorption enhancement but also charge transport capacity improvement. The metal tip of AHNRs can lead to a significant enhancement of local field and long-range scattering. In addition, a wide-band absorption improvement is observed, and charge carrier mobilities increase by an order of magnitude. These results offer an effective approach to enhance the efficiency for PSCs.
Twenty-Five Wei'er Tea Pills (TFP), a traditional Tibetan medicine, has shown to have a promising therapeutic effect in patients with Rheumatoid arthritis (RA), as well as being safe. Nonetheless, ...there have been limited pharmacological studies that have explored this therapeutic option. As gut microbiota has been proven to have a critical role in the pathogenesis of RA, this study aims to explore and reveal relevant ways by which TFP interacts with the chemical crosstalk between the gut microbiome and its host. 16S rRNA sequencing, combined with un-targeted metabolomics, were conducted on collagen-induced arthritis (CIA) rats. CIA model rats treated with TFP showed significant improvement in weight gain, pathological phenomena in joints, as well as decreased serum levels of TNF-α, IL-6 and increased level of IL-4 and IL-10. Significant dysfunction in the gut microbiome and alteration in serum metabolites were observed in CIA model rats, which were restored by TFP treatment. Coherence analysis indicated that TFP modulated the pathways of histidine metabolism, phenylalanine metabolism, alanine, aspartate, glutamate metabolism, amino sugar and nucleotide sugar metabolism owing to the abundances of
,
, Prevotellaceae
and Christensenellaceae
in the gut microflora. The corresponding metabolites involved L-histidine, histamine, phenylethylamine, asparagine, L-aspartic acid, D-fructose 1-phosphate, D-Mannose 6-phosphate, D-Glucose 6-phosphate, and Glucose 1-phosphate. In conclusion, this study reveals the ameliorative effects of TFP on RA through the chemical crosstalk that exists between the gut microbiota and its host, and also further enriches our understandings of the pathogenesis of RA.
Abstract
Age is closely related to human health and disease risks. However, chronologically defined age often disagrees with biological age, primarily due to genetic and environmental variables. ...Identifying effective indicators for biological age in clinical practice and self-monitoring is important but currently lacking. The human lens accumulates age-related changes that are amenable to rapid and objective assessment. Here, using lens photographs from 20 to 96-year-olds, we develop LensAge to reflect lens aging via deep learning. LensAge is closely correlated with chronological age of relatively healthy individuals (R
2
> 0.80, mean absolute errors of 4.25 to 4.82 years). Among the general population, we calculate the LensAge index by contrasting LensAge and chronological age to reflect the aging rate relative to peers. The LensAge index effectively reveals the risks of age-related eye and systemic disease occurrence, as well as all-cause mortality. It outperforms chronological age in reflecting age-related disease risks (
p
< 0.001). More importantly, our models can conveniently work based on smartphone photographs, suggesting suitability for routine self-examination of aging status. Overall, our study demonstrates that the LensAge index may serve as an ideal quantitative indicator for clinically assessing and self-monitoring biological age in humans.
Tacrolimus has been widely applied to prevent organ rejection after transplantation. However, the conventional pharmaceutical formulation of tacrolimus limits its applications in ocular therapy due ...to its hydrophobicity and low corneal penetrability. We optimized tacrolimus-loaded methoxy poly (ethylene glycol-block-poly (d, l)-lactic-co-glycolic acid) nanoparticles (TAC-NPs) by simple and effective nanotechnology as a drug delivery system for corneal graft rejection to overcome these drawbacks. The prepared TAC-NPs were 82.9 ± 1.3 nm in size, and the drug loading and encapsulation efficiency were 8.01 ± 0.23% and 80.10 ± 2.33%. Furthermore, New Zealand rabbits were used to analyze the single-dose pharmacokinetics of the TAC-NPs using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). In rats with allogenic penetrating keratoplasty, the administration of TAC-NPs dispersion drops improved the TAC concentrations in the aqueous humor and cornea, consistent with a significantly higher effective inhibition of IL-2, IL-17, and VEGF expression compared with conventional 0.1% tacrolimus drops. Meanwhile, we also compared two different topical administration methods (including eye drop and subconjunctival injection) of TAC-NPs to maximize the sustained release characteristic of NPs. In summary, the small-sized TAC-NPs enhanced transcorneal permeation and absorption of TAC and more effectively inhibited corneal allograft rejection, which indicated that biodegradable polymeric nanomaterials-based drug delivery system had great potential for improving the clinical therapy efficacy of hydrophobic drugs.
Cranio-lenticulo-sutural dysplasia (CLSD) is a rare dysmorphic syndrome characterized by skeletal dysmorphism, late-closing fontanels, and cataracts. CLSD is caused by mutations in the SEC23A gene ...(OMIM# 607812) and can be inherited in either an autosomal dominant or autosomal recessive pattern. To date, only four mutations have been reported to cause CLSD. This study aims to identify the disease-causing variants in a large cohort of congenital cataract patients, to expand the genotypic and phenotypic spectrum of CLSD, and to confirm the association between SEC23A and autosomal recessive CLSD (ARCLSD).
We collected detailed medical records and performed comprehensive ocular examinations and whole-exome sequencing (WES) on 115 patients with congenital cataracts. After suspecting that a patient may have CLSD based on the sequencing results, we proceeded to conduct transmission electron microscopy (TEM) on the cultured skin fibroblasts. The clinical validity of the reported gene-disease relationships for the gene and the disease was evaluated using the ClinGen gene curation framework.
Two novel compound heterozygous variants (c.710A > C p.Asp237Ala, c.1946T > C p.Leu649Pro) of the SEC23A gene, classified as variant of uncertain significance, were identified in the proband with skeletal, cardiac, ocular, and hearing defects. The observation of typical distended endoplasmic reticulum cisternae further supported the diagnosis of CLSD. Application of the ClinGen gene curation framework confirmed the association between SEC23A and ARCLSD.
This study expands the genotypic and phenotypic spectrum of CLSD, proposes TEM as a supplemental diagnostic method, and indicates that congenital cataracts are a typical sign of ARCLSD.
Recent advances in the interfacial modification of inverted-type polymer solar cells (PSCs) have resulted from controlling the surface energy of the cathode-modified layer (TiO2 or ZnO) to enhance ...the short-circuit current (J sc) or optimizing the contact morphology of the cathode (indium tin oxide or fluorine-doped tin oxide) and active layer to increase the fill factor. Herein, we report that the performance enhancement of PSCs is achieved by incorporating a donor macromolecule copper phthalocyanine (CuPc) as an anode modification layer. Using the approach based on orienting the microstructure evolution, uniformly dispersed island-shaped CuPc spot accumulations are built on the top of PTB7:PC71BM blend film, leading to an efficient spectral absorption and photogenerated exciton splitting. The best power conversion efficiency of PSCs is increased up to 9.726%. In addition to the enhanced light absorption, the tailored anode energy level alignment and optimized boundary morphology by incorporating the CuPc interlayer boost charge extraction efficiency and suppress the interfacial molecular recombination. These results demonstrate that surface morphology induction through molecular deposition is an effective method to improve the performance of PSCs, which reveals the potential implications of the interlayer between the organic active layer and the electrode buffer layer.
Congenital cataracts (CCs) have significant genotypic and phenotypic heterogeneity. The major intrinsic protein (MIP) gene, one of the causative genes of CCs, plays a vital role in maintaining the ...homeostasis and transparency of the lens. In this study, we identified a unique phenotype of anterior umbilication of the lens in a four-generation pedigree with CCs. All patients in the observed family had nystagmus, nuclear cataracts, and elongated axial lengths compared with their healthy counterparts except for patient I:2, whose axial length was unavailable, and patientII:4, who had total cataracts. We confirmed, using Sanger sequencing based on whole-exon sequencing (WES) data, that all patients carried a heterozygous variant NM_012064.4:c.97C > T (NP_036196.1:p.R33C) in their MIP gene. To our knowledge, 29 variants of the human MIP gene and the relative phenotypes associated with CCs have been identified. Nevertheless, this is the first report on the anterior umbilication of the lens with nuclear or total opacity caused by the c.97C > T (p.R33C) variant in the MIP gene. These results also provide evidence that the elongated axial length might be associated with this variant. This study further confirms the phenotypic heterogeneity of CCs.
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