Robust trigger wave speed in Xenopus cytoplasmic extracts.

Self-regenerating trigger waves can spread rapidly through the crowded cytoplasm without diminishing in amplitude or speed, providing consistent, reliable, long-range communication. The macromolecular concentration of the cytoplasm varies in response to physiological and environmental fluctuations, raising the question of how or if trigger waves can robustly operate in the face of such fluctuations. Using Xenopus extracts, we find that mitotic and apoptotic trigger wave speeds are remarkably invariant. We derive a model that accounts for this robustness and for the eventual slowing at extremely high and low cytoplasmic concentrations. The model implies that the positive and negative effects of cytoplasmic concentration (increased reactant concentration vs. increased viscosity) are nearly precisely balanced. Accordingly, artificially maintaining a constant cytoplasmic viscosity during dilution abrogates this robustness. The robustness in trigger wave speeds may contribute to the reliability of the extremely rapid embryonic cell cycle.

Electrochemical Stability of MXenes in Water Based on Constant Potential AIMD Simulations.

MXene has been recently explored as promising electrocatalytic materials to accelerate the electrocatalytic process for hydrogen evolution, but their dynamic stability under electrochemical conditions remains elusive. Here we performed first-principle ab initio molecular dynamics calculations to reveal the electrochemical stability of Ti2CTx MXene in different aqueous environments. The results revealed the high vulnerability of the pure and vacancy-defected Ti2CO2 MXene towards water attack, leading to surface oxidation of MXene under neutral electrochemical condition that formed adsorbed oxygen species to Ti and dissociated proton in solution. The surface oxidation of Ti2CO2 could be prevented in the acid condition or in the neutral condition under the negative potential. Differently, the fully F- or OH-functionalized Ti2CF2 and Ti2C(OH)2 as well as the mixed functionalized Ti2C(O0.5OH0.5)2 and Ti2CO1.12F0.88 are highly stable under various electrochemical conditions, which can effectively prevent close contact between water and surface Ti atoms via electronic repulsion or steric hindrance. These findings provide atomic level understanding of the aqueous stability of MXene and provide useful strategies to prevent degradation and achieve highly stable MXenes.

Surface Termination (-O, -F or -OH) and Metal Doping on the HER Activity of Mo2CTx MXene.

Two-dimensional MXenes have recently garnered significant attention as electrocatalytic materials for hydrogen evolution reaction (HER). However, previous theoretical studies mainly focused on the effect of pure functional groups while neglecting hybrid functional groups that are commonly observed in experiments. Herein, we investigated the hybrid functionalized Mo2CTx MXene (T=-O, -F or -OH) to probe the HER properties. In binary O/F co-functionalization, the presence of F groups would attenuate the H adsorption and lead to the enhanced HER activity than the fully O-terminated Mo2CO2. However, the surface HER activity of ternary O/F/OH functionalized Mo2CTx is not satisfactory owing to the relatively weak H adsorption capacity. To further enhance the catalytic activity, modification was performed by introducing another metal element into its lattice structure. The doped metal (Fe, Co, Ni, Cu) exhibits reduced charge transfer to O compared to Mo atoms, leading to enhanced H adsorption and improved overall activity. The synergistic effect of hybrid functionalization and TM modification provides useful guidance for achieving feasible Mo2CTx candidates with high HER performance, which can be applied to the electrocatalytic applications of other MXenes.

Impaired Meningeal Lymphatics and Glymphatic Pathway in Patients with White Matter Hyperintensity.

White matter hyperintensity (WMH) represents a critical global medical concern linked to cognitive decline and dementia, yet its underlying mechanisms remain poorly understood. Here, humans are directly demonstrated that high WMH burden correlates with delayed drainage of meningeal lymphatic vessels (mLVs) and glymphatic pathway. Additionally, a longitudinal cohort study reveals that glymphatic dysfunction predicts WMH progression. Next, in a rat model of WMH, the presence of impaired lymphangiogenesis and glymphatic drainage is confirmed, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis through adeno-associated virus delivery of vascular endothelial growth factor-C (VEGF-C) mitigates microglial gliosis and white matter demyelination. Conversely, blocking the growth of mLVs with a VEGF-C trap strategy exacerbates these changes. The findings highlight the role of mLVs and glymphatic pathway dysfunction in aggravating brain white matter injury, providing a potential novel strategy for WMH prevention and treatment.

Mitochondrial transplantation: A promising therapy for mitochondrial disorders.

As a vital energy source for cellular metabolism and tissue survival, the mitochondrion can undergo morphological or positional change and even shuttle between cells in response to various stimuli and energy demands. Multiple human diseases are originated from mitochondrial dysfunction, but the curative succusses by traditional treatments are limited. Mitochondrial transplantation therapy (MTT) is an innovative therapeutic approach that is to deliver the healthy mitochondria either derived from normal cells or reassembled through synthetic biology into the cells and tissues suffering from mitochondrial damages and finally replace their defective mitochondria and restore their function. MTT has already been under investigation in clinical trials for cardiac ischemia-reperfusion injury and given an encouraging performance in animal models of numerous fatal critical diseases including central nervous system disorders, cardiovascular diseases, inflammatory conditions, cancer, renal injury, and pulmonary damage. This review article summarizes the mechanisms and strategies of mitochondrial transfer and the MTT application for types of mitochondrial diseases, and discusses the potential challenge in MTT clinical application, aiming to exhibit the good therapeutic prospects of MTTs in clinics.

Photoresponsive Hydrogels for Tissue Engineering.

Hydrophilic and biocompatible hydrogels are widely applied as ideal scaffolds in tissue engineering. The "smart" gelation material can alter its structural, physiochemical, and functional features in answer to various endo/exogenous stimuli to better biomimic the endogenous extracellular matrix for the engineering of cells and tissues. Light irradiation owns a high spatial-temporal resolution, complete biorthogonal reactivity, and fine-tunability and can thus induce physiochemical reactions within the matrix of photoresponsive hydrogels with good precision, efficiency, and safety. Both gel structure (e.g., geometry, porosity, and dimension) and performance (like conductivity and thermogenic or mechanical properties) can hence be programmed on-demand to yield the biochemical and biophysical signals regulating the morphology, growth, motility, and phenotype of engineered cells and tissues. Here we summarize the strategies and mechanisms for encoding light-reactivity into a hydrogel and demonstrate how fantastically such responsive gels change their structure and properties with light irradiation as desired and thus improve their applications in tissue engineering including cargo delivery, dynamic three-dimensional cell culture, and tissue repair and regeneration, aiming to provide a basis for more and better translation of photoresponsive hydrogels in the clinic.

USP25 Elevates SHLD2-Mediated DNA Double-Strand Break Repair and Regulates Chemoresponse in Cancer.

DNA damage plays a significant role in the tumorigenesis and progression of the disease. Abnormal DNA repair affects the therapy and prognosis of cancer. In this study, it is demonstrated that the deubiquitinase USP25 promotes non-homologous end joining (NHEJ), which in turn contributes to chemoresistance in cancer. It is shown that USP25 deubiquitinates SHLD2 at the K64 site, which enhances its binding with REV7 and promotes NHEJ. Furthermore, USP25 deficiency impairs NHEJ-mediated DNA repair and reduces class switch recombination (CSR) in USP25-deficient mice. USP25 is overexpressed in a subset of colon cancers. Depletion of USP25 sensitizes colon cancer cells to IR, 5-Fu, and cisplatin. TRIM25 is also identified, an E3 ligase, as the enzyme responsible for degrading USP25. Downregulation of TRIM25 leads to an increase in USP25 levels, which in turn induces chemoresistance in colon cancer cells. Finally, a peptide that disrupts the USP25-SHLD2 interaction is successfully identified, impairing NHEJ and increasing sensitivity to chemotherapy in PDX model. Overall, these findings reveal USP25 as a critical effector of SHLD2 in regulating the NHEJ repair pathway and suggest its potential as a therapeutic target for cancer therapy.

Experimental study on the antifatigue effect of icariin.

Fatigue is a serious disturbance to human health, especially in people who have a severe disease such as cancer, or have been infected with COVID-19. Our research objective is to evaluate the anti-fatigue effect and mechanism of icariin through a mouse experimental model. Mice were treated with icariin for 30 days and anti-fatigue effects were evaluated by the weight-bearing swimming test, serum urea nitrogen test, lactic acid accumulation and clearance test in blood and the amount of liver glycogen. The protein expression levels of adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1-α) in the skeletal muscle of mice in each group were measured by western blotting. Results showed that icariin prolonged the weight-bearing swimming time of animals, reduced the serum urea nitrogen level after exercise, decreased the blood lactic acid concentration after exercise and increased the liver glycogen content observably. Compared to that in the control group, icariin upregulated AMPK and PGC1-α expression in skeletal muscle. Icariin can improve fatigue resistance in mice and its mechanism may be through improving the AMPK/PGC-1α pathway in skeletal muscle to enhance energy synthesis, decreasing the accumulation of metabolites and slowing glycogen consumption and decomposition.

Efficacy of the induced pluripotent stem cell derived and engineered CD276-targeted CAR-NK cells against human esophageal squamous cell carcinoma.

Introduction: Chimeric antigen receptor natural killer (CAR-NK) cells have been found to be successful in treating hematologic malignancies and present potential for usage in solid tumors. Methods: In this study, we created CD276-targeted CAR-expressing NK cells from pluripotent stem cells (iPSC CD276-targeted CAR-NK cells) and evaluated their cytotoxicity against esophageal squamous cell carcinoma (ESCC) using patient-specific organoid (PSO) models comprising of both CD276-positive and CD276-negative adjacent epithelium PSO models (normal control PSO, NC PSO) as well as primary culture of ESCC cell models. In addition, in vitro and in vivo models such as KYSE-150 were also examined. iPSC NK cells and NK-free media were used as the CAR-free and NK-free controls, respectively. Results: The positive CD276 staining was specifically detected on the ESCC membrane in 51.43% (54/105) of the patients of all stages, and in 51.35% (38/74) of stages III and IV. The iPS CD276-targeted CAR-NK cells, comparing with the iPS NK cells and the NK-free medium, exhibited specific and significant cytotoxic activity against CD276-positive ESCC PSO rather than CD276-negative NC PSO, and exhibited significant cytotoxicity against CD276-expressing cultured ESCC cells, as well as against CD276-expressing KYSE-150 in vitro and in BNDG mouse xenograft. Discussion: The efficacy of the iPSC CD276-targeted CAR-NK cells demonstrated by their successful treatment of CD276-expressing ESCC in a multitude of pre-clinical models implied that they hold tremendous therapeutic potential for treating patients with CD276-expressing ESCC.

USP19 regulates DNA methylation damage repair and confers temozolomide resistance through MGMT stabilization.

OBJECTIVE: To elucidate the relationship between USP19 and O(6)-methylguanine-DNA methyltransferase (MGMT) after temozolomide treatment in glioblastoma (GBM) patients with chemotherapy resistance. METHODS: Screening the deubiquitinase pannel and identifying the deubiquitinase directly interacts with and deubiquitination MGMT. Deubiquitination assay to confirm USP19 deubiquitinates MGMT. The colony formation and tumor growth study in xenograft assess USP19 affects the GBM sensitive to TMZ was performed by T98G, LN18, U251, and U87 cell lines. Immunohistochemistry staining and survival analysis were performed to explore how USP19 is correlated to MGMT in GBM clinical management. RESULTS: USP19 removes the ubiquitination of MGMT to facilitate the DNA methylation damage repair. Depletion of USP19 results in the glioblastoma cell sensitivity to temozolomide, which can be rescued by overexpressing MGMT. USP19 is overexpressed in glioblastoma patient samples, which positively correlates with the level of MGMT protein and poor prognosis in these patients. CONCLUSION: The regulation of MGMT ubiquitination by USP19 plays a critical role in DNA methylation damage repair and GBM patients' temozolomide chemotherapy response.

Hierarchical superstructure aerogels for in situ biofluid metabolomics.

High-throughput biofluid metabolomics analysis for screening life-threatening diseases is urgently needed. However, the high salt content of biofluid samples, which introduces severe interference, can greatly limit the analysis throughput. Here, a new 3-D interconnected hierarchical superstructure, namely a "plasmonic gold-on-silica (Au/SiO2) double-layered aerogel", integrating distinctive features of an upper plasmonic gold aerogel with a lower inert silica aerogel was successfully developed to achieve in situ separation and storage of inorganic salts in the silica aerogel, parallel enrichment of metabolites on the surface of the functionalized gold aerogel, and direct desorption/ionization of enriched metabolites by the photo-excited gold aerogel for rapid, sensitive, and comprehensive metabolomics analysis of human serum/urine samples. By integrating all these unique advantages into the hierarchical aerogel, multifunctional properties were introduced in the SALDI substrate to enable its effective utilization in clinical metabolomics for the discovery of reliable metabolic biomarkers to achieve unambiguous differentiation of early and advanced-stage lung cancer patients from healthy individuals. This study provides insight into the design and application of superstructured nanomaterials for in situ separation, storage, and photoexcitation of multi-components in complex biofluid samples for sensitive analysis.

Identification, diversity, and evolution analysis of Commd gene family in Haliotis discus hannai and immune response to biotic and abiotic stresses.

The Commd (Copper Metabolism gene MURR1 Domain) family genes play crucial roles in various biological processes, including copper and sodium transport regulation, NF-κB activity, and cell cycle progression. Their function in Haliotis discus hannai, however, remains unclear. This study focused on identifying and analyzing the Commd genes in H. discus hannai, including their gene structure, phylogenetic relationships, expression profiles, sequence diversity, and alternative splicing. The results revealed significant homology between H. discus hannai's Commd genes and those of other mollusks. Both transcriptome quantitative analysis and qRT-PCR demonstrated the responsiveness of these genes to heat stress and Vibrio parahaemolyticus infection. Notably, alternative splicing analysis revealed that COMMD2, COMMD4, COMMD5, and COMMD7 produce multiple alternative splice variants. Furthermore, sequence diversity analysis uncovered numerous missense mutations, specifically 9 in COMMD5 and 14 in COMMD10. These findings contribute to expanding knowledge on the function and evolution of the Commd gene family and underscore the potential role of COMMD in the innate immune response of H. discus hannai. This research, therefore, offers a novel perspective on the molecular mechanisms underpinning the involvement of Commd genes in innate immunity, paving the way for further explorations in this field.

High affinity and low PARP-trapping benzimidazole derivatives as a potential warhead for PARP1 degraders.

PARPi have been explored and applied in the treatment of various cancers with remarkable efficacy, especially BRCA1/2 mutated ovarian, breast, prostate, and pancreatic cancers. However, PARPi renders inevitable drug resistance and showed high toxicity because of PARP-Trapping with long-term clinic tracking. To overcome the drug resistance and the high toxicity of PARPi, many novel methods have been developed including PROTACs. Being an event-driven technology, PROTACs needs a high affinity, low toxicity warhead with no steric hindrance in binding process. Veliparib shows the lowest PARP-Trapping effect but could hardly to be the warhead of PROTACs because of the strong steric hindrance. Other PARP1 inhibitors showed less steric hindrance but owns high PARP-Trapping effect. Thus, the development of novel warhead with high PARP1 affinity, low PARP1-Trapping, and no steric hindrance would be valuable. In this work, we reserved benzimidazole as the motif to reserve the low PARP1-Trapping effect and substituted the pyrrole by aromatic ring to avoiding the steric hindrance in PARP1 binding cave. Thus, a series of benzimidazole derivates were designed and synthesized, and some biological activities in vitro were evaluated including the inhibition for PARP1 enzyme and the PARP-Trapping effect using MDA-MB-436 cell line. Results showed that the compound 19A10 has higher PARP1 affinity(IC50 = 4.62 nM)) and similar low PARP-Trapping effect compared with Veliparib(IC50 (MDA-MB-436) >100 µM). Docking study showed that the compound 19A10 could avoiding the steric hindrance which was much better than Veliparib. So, the compound 19A10 could potentially be a perfect warhead for PARP1 degraders. Besides, because of the depletion of the PARP1 and the decreasing of the binding capability, we suppose that the PROTACs using 19A10 as the warhead would be no-PARP-Trapping effect. Furthermore, QSAR study showed that to develop novel compounds with high PARP1 binding affinity and low PARP-Trapping, we can choose the skeleton with substituent R1H, R2 = piperiazine, and R3 with large tPSA. And, if we want to develop the compounds with high PARP1 binding affinity and high PARP-Trapping which can possibly improve the lethality against tumor cells, we can choose the skeleton with substituent R1F, R2 = 3-methy-piperiazine, and R3 with large tPSA.

Viscosity-dependent control of protein synthesis and degradation.

It has been proposed that the concentration of proteins in the cytoplasm maximizes the speed of important biochemical reactions. Here we have used Xenopus egg extracts, which can be diluted or concentrated to yield a range of cytoplasmic protein concentrations, to test the effect of cytoplasmic concentration on mRNA translation and protein degradation. We find that protein synthesis rates are maximal in ~1x cytoplasm, whereas protein degradation continues to rise to a higher optimal concentration of ~1.8x. We show that this difference in optima can be attributed to a greater sensitivity of translation to cytoplasmic viscosity. The different concentration optima could produce a negative feedback homeostatic system, where increasing the cytoplasmic protein concentration above the 1x physiological level increases the viscosity of the cytoplasm, which selectively inhibits translation and drives the system back toward the 1x set point.

LiverRisk score: An accurate, cost-effective tool to predict fibrosis, liver-related, and diabetes-related mortality in the general population.

BACKGROUND: Noninvasive and early assessment of liver fibrosis is of great significance and is challenging. We aimed to evaluate the predictive performance and cost-effectiveness of the LiverRisk score for liver fibrosis and liver-related and diabetes-related mortality in the general population. METHODS: The general population from the NHANES 2017-March 2020, NHANES 1999-2018, and UK Biobank 2006-2010 were included in the cross-sectional cohort (n = 3,770), along with the NHANES follow-up cohort (n = 25,317) and the UK Biobank follow-up cohort (n = 17,259). The cost-effectiveness analysis was performed using TreeAge Pro software. Liver stiffness measurements ≥10 kPa were defined as compensated advanced chronic liver disease (cACLD). FINDINGS: Compared to conventional scores, the LiverRisk score had significantly better accuracy and calibration in predicting liver fibrosis, with an area under the receiver operating characteristic curve (AUC) of 0.76 (0.72-0.79) for cACLD. According to the updated thresholds of LiverRisk score (6 and 10), we reclassified the population into three groups: low, medium, and high risk. The AUCs of LiverRisk score for predicting liver-related and diabetes-related mortality at 5, 10, and 15 years were all above 0.8, with better performance than the Fibrosis-4 score. Furthermore, compared to the low-risk group, the medium-risk and high-risk groups in the two follow-up cohorts had a significantly higher risk of liver-related and diabetes-related mortality. Finally, the cost-effectiveness analysis showed that the incremental cost-effectiveness ratio for LiverRisk score compared to FIB-4 was USD $18,170 per additional quality-adjusted life-year (QALY) gained, below the willingness-to-pay threshold of $50,000/QALY. CONCLUSIONS: The LiverRisk score is an accurate, cost-effective tool to predict liver fibrosis and liver-related and diabetes-related mortality in the general population. FUNDING: The National Natural Science Foundation of China (nos. 82330060, 92059202, and 92359304); the Key Research and Development Program of Jiangsu Province (BE2023767a); the Fundamental Research Fund of Southeast University (3290002303A2); Changjiang Scholars Talent Cultivation Project of Zhongda Hospital of Southeast University (2023YJXYYRCPY03); and the Research Personnel Cultivation Program of Zhongda Hospital Southeast University (CZXM-GSP-RC125).

When and what: A longitudinal study on the role of screen time and activities in adolescent sleep.

OBJECTIVES: Previous research has highlighted a link between electronic media use and sleep outcomes, but the nuanced impacts of screen use at different time of day and activities on adolescent sleep are underexplored. METHODS: 831 participants underwent online assessment three times with interval of three months regarding their screen time and activities at specific times of the day, daytime sleepiness was assessed with the Epworth Sleepiness Scale, and sleep outcomes were assessed with the Pittsburgh Sleep Quality Index and Insomnia Severity Index. The associations between time spent on various screen activities, and sleep outcomes were examined respectively after controlling for inter-individual differences using the Random Intercept Cross-Lagged Panel Model models and LMMs. RESULTS: The RI_CLPM model revealed that both electronic screen time during daytime and after lights off in the evening in Wave1 negatively predicted the sleep quality in Wave2; the nighttime screen time before lights off in Wave1 significantly negatively predicted the seventy of insomnia in Wave2. Whereas no cross-lag and predictive effects of sleep outcomes on screen time were revealed. Moreover, daytime screen exposure, including T.V. watching and social media use, and nighttime music listening were negatively associated with sleep quality. Conversely, nighttime screen time of shopping and working/studying positively influenced sleep quality. Additionally, daytime screen time of T.V. viewing was positively associated with increased insomnia severity, whereas nighttime work/study-related screen time negatively affected insomnia severity. Nighttime screen time of music listening negatively predicted daytime sleepiness. CONCLUSIONS: The current findings contributed to the existing literature suggesting that the effects of electronic screen time on sleep depended on both the time of day and type of screen activities.

The health context paradox in the relationship between victimization, classroom bullying attitudes, and adolescent depression: An analysis based on the hlm model.

From the perspective of the health context paradox, this study examined the relationship between adolescent victimization and depression based on the diathesis-stress model and attribution theory using a nested model. A survey was conducted on 3743 Chinese adolescents using the Bullying & Victimization Scale, Rumination Scale, Beck Depression Inventory, and Bullying Attitude Scale. The results disclosed that victimization had a positive impact on depression, rumination played a mediating role between victimization and depression, and classroom anti-bullying attitudes heightened the correlation between victimization and developing depression as well as between victimization and engaging in rumination thinking. This study provides a new cross-level perspective to reduce the occurrence of depression among bullied adolescents and further validates the health context paradox, expanding its applicability range. It also provides new experimental research references for reducing depression among bullied adolescents from a more comprehensive, cross-level perspective in the future.

The enzymes of serine synthesis pathway in cancer metastasis.

Metastasis, the major cause of cancer mortality, requires cancer cells to reprogram their metabolism to adapt to and thrive in different environments, thereby leaving metastatic cells metabolic characteristics different from their parental cells. Mounting research has revealed that the de novo serine synthesis pathway (SSP), a glycolytic branching pathway that consumes glucose carbons for serine makeup and α-ketoglutarate generation and thus supports the proliferation, survival, and motility of cancer cells, is one such reprogrammed metabolic pathway. During different metastatic cascades, the SSP enzyme proteins or their enzymatic activity are both dynamically altered; manipulating their expression or catalytic activity could effectively prevent the progression of cancer metastasis; and the SSP enzymatic proteins could even conduce to metastasis via their nonenzymatic functions. In this article we overview the SSP dynamics during cancer metastasis and put the focuses on the regulatory role of the SSP in metastasis and the underlying mechanisms that mainly involve cellular anabolism/catabolism, redox balance, and epigenetics, aiming to provide a theoretical basis for the development of therapeutic strategies for targeting metastatic lesions.

Germline Mutations of Holliday Junction Resolvase Genes in Multiple Primary Malignancies Involving Lung Cancer Lead to PARP Inhibitor Sensitization.

PURPOSE: The incidence of multiple primary malignancies (MPM) involving lung cancer has increased in recent decades. There is an urgent need to clarify the genetic profile of such patients and explore more efficacious therapy for them. EXPERIMENTAL DESIGN: Peripheral blood samples from MPM involving patients with lung cancer were assessed by whole-exome sequencing (WES), and the identified variants were referenced for pathogenicity using the public available database. Pathway enrichment analysis of mutated genes was performed to identify the most relevant pathway. Next, the effects of mutations in relevant pathway on function and response to targeted drugs were verified by in vitro and in vivo experiments. RESULTS: Germline exomes of 71 patients diagnosed with MPM involving lung cancer were sequenced. Pathway enrichment analysis shows that the homologous recombination repair (HRR) pathway has the strongest correlation. Moreover, HRR genes, especially key Holliday junction resolvases (HJR) genes (GEN1, BLM, SXL4, and RMI1), were most frequently mutated, unlike the status in the samples from patients with lung cancer only. Next, we identified a total of seven mutations in HJR genes led to homologous recombination DNA repair deficiency and rendered lung cancer cells sensitive to PARP inhibitor treatment, both in vitro and in vivo. CONCLUSIONS: This is the first study to map the profile of germline mutations in patients with MPM involving lung cancer. This study may shed light on early prevention and novel targeted therapies for MPM involving patients with lung cancer with HJR mutations.