TP53-related signature for predicting prognosis and tumor microenvironment characteristics in bladder cancer: A multi-omics study

Background: The tumor suppressor gene TP53 is frequently mutated or inactivated in bladder cancer (BLCA), which is implicated in the pathogenesis of tumor. However, the cellular mechanisms of TP53 mutations are complicated, yet well-defined, but their clinical prognostic value in the management of BLCA remains controversial. This study aimed to explore the role of TP53 mutation in regulating the tumor microenvironment (TME), elucidate the effects of TP53 activity on BLCA prognosis and immunotherapy response.Methods: A TP53-related signature based on TP53-induced and TP53-repressed genes was used to construct a TP53 activity-related score and classifier. The abundance of different immune cell types was determined using CIBERSORT to estimate immune cell infiltration. Moreover, the heterogeneity of the tumor immune microenvironment between the high and low TP53 score groups was further evaluated using single-cell mass cytometry (CyTOF) and imaging mass cytometry (IMC). Moreover, pathway enrichment analysis was performed to explore the differential biological functions between tumor epithelial cells with high and low TP53 activity scores. Finally, the receptor–ligand interactions between immune cells and tumor epithelial cells harboring distinct TP53 activity were analyzed by single-cell RNA-sequencing.Results: The TP53 activity-related gene signature differentiated well between TP53 functional retention and inactivation in BLCA. BLCA patients with low TP53 scores had worse survival prognosis, more TP53 mutations, higher grade, and stronger lymph node metastasis than those with high TP53 scores. Additionally, CyTOF and IMC analyses revealed that BLCA patients with low TP53 scores exhibited a potent immunosuppressive TME. Consistently, single-cell sequencing results showed that tumor epithelial cells with low TP53 scores were significantly associated with high cell proliferation and stemness abilities and strongly interacted with immunosuppressive receptor–ligand pairs.Conclusion: BLCA patients with low TP53 scores have a worse prognosis and a more immunosuppressive TME. This TP53 activity-related signature can serve as a potential prognostic signature for predicting the immune response, which may facilitate the development of new strategies for immunotherapy in BLCA

On the structure of the turbulent/non-turbulent interface in a fully developed spatially evolving axisymmetric wake

In this work, we numerically study the structure of the turbulent/nonturbulent (T/NT) interface in a fully developed spatially evolving axisymmetric wake by means of direct numerical simulations. There is a continuous and contorted pure shear layer (PSL) adjacent to the outer edge of the T/NT interface. The local thickness of the PSL δPSL exhibits a wide range of scales (from the Kolmogorov scale to the Taylor microscale) and the conditional mean thickness 〈δPSL〉I/ηc≈6 with ηc being the centerline Kolmogorov scale is the same as the viscous superlayer. In the viscous superlayer, the pure shear motions without rotation are overwhelmingly dominant. It is also demonstrated that the physics of the turbulent sublayer is closely related to the PSL with a large thickness. Another significant finding is that the time averaged area of the rotational region 〈AR〉, and the pure shear region 〈AS〉 at different streamwise locations scale with the square of the wake-width bU2. This study opens an avenue for a better understanding of the structures of the T/NT interface

Clinical features and risk factors of COVID-19-associated liver injury and function: A retrospective analysis of 830 cases

Introduction and objectives: The incidence of liver injury (LI) in hospitalized COVID-19 patients ranged from 14% to 53% based on sole or multiple elevated indexes for LI. The aims of our study were to investigate the changes of parameters (ALT, AST) in LI and determine the risk factors for LI in a cohort of 830 COVID-19 patients. Methods: Demographic information, clinical features, and laboratory testing outcomes on admission were compared between patients with and without liver biochemistry abnormality (LBA). The same comparisons were performed between the LBA and LI groups. The updated RUCAM was used to determine the causality between drugs application and LI. Univariable and multivariable logistic regression analyses were used to explore the potential risk factors associated with LBA and LI. Results: A total of 227 (27.3%) patients exhibited LBA and 32 (3.9%) patients were categorized as having LI based on the diagnostic criteria. 32.6% (74/227) of the LBA patients had RUCAM score >3, whereas the non-LBA patients had a slight lower at rate of 24.2% (146/603) (P?=?0.047). Multivariable regression showed that a higher incidence of LBA was associated with hepatic hypoattenuation on computed tomography (CT) (odds ratio: 2.243, 95% confidence interval: 1.410–3.592, p?=?0.001), lymphocyte proportion 1?mg/dL (2.650, 1.845–3.806, p?1 (2.558, 1.820-3.596, p?1.0?mg/dL, lymphocyte proportion 1.7?mol/L are potential risk factors for LI

Bridging Code Semantic and LLMs: Semantic Chain-of-Thought Prompting for Code Generation

Large language models (LLMs) have showcased remarkable prowess in code generation. However, automated code generation is still challenging since it requires a high-level semantic mapping between natural language requirements and codes. Most existing LLMs-based approaches for code generation rely on decoder-only causal language models often treate codes merely as plain text tokens, i.e., feeding the requirements as a prompt input, and outputing code as flat sequence of tokens, potentially missing the rich semantic features inherent in source code. To bridge this gap, this paper proposes the "Semantic Chain-of-Thought" approach to intruduce semantic information of code, named SeCoT. Our motivation is that the semantic information of the source code (\eg data flow and control flow) describes more precise program execution behavior, intention and function. By guiding LLM consider and integrate semantic information, we can achieve a more granular understanding and representation of code, enhancing code generation accuracy. Meanwhile, while traditional techniques leveraging such semantic information require complex static or dynamic code analysis to obtain features such as data flow and control flow, SeCoT demonstrates that this process can be fully automated via the intrinsic capabilities of LLMs (i.e., in-context learning), while being generalizable and applicable to challenging domains. While SeCoT can be applied with different LLMs, this paper focuses on the powerful GPT-style models: ChatGPT(close-source model) and WizardCoder(open-source model). The experimental study on three popular DL benchmarks (i.e., HumanEval, HumanEval-ET and MBPP) shows that SeCoT can achieves state-of-the-art performance, greatly improving the potential for large models and code generation.Comment: There may be calculation errors in Table 4 of the paper. We need time to verify and supplement, so the manuscript needs to be withdrawn. Thanks

Mechanistic Exploration of Dendrite Growth and Inhibition for Lithium Metal Batteries

Li metal has been considered an ideal anode in lithium batteries due to its high theoretical capacity of 3860 mAh·g−1 and lowest negative reduction potential of −3.040 V among the standard hydrogen electrodes. However, lithium dendrites can easily grow on the surface of the negative electrode during charging, which results in a short circuit of the battery and reduces its efficiency. This paper investigated dendrite growth and inhibition mechanisms in lithium metal batteries to improve battery life. The impacts of the initial nucleation spacing, surface energy anisotropy strength, and interfacial electrochemical driving force on lithium dendrite growth were analyzed with electrochemical experiments and mathematical models. The results showed that the smaller nucleation spacing inhibits the growth of dendrite side branches and reduces the roughness of lithium metal deposition on the negative electrode. A lower interfacial energy anisotropy strength can slow down the growth of dendrite tips and improve the dendrite growth structure. The growth of the dendrites is influenced by the interfacial electrochemical driving force. Reducing the nucleation overpotential can effectively inhibit the growth of lithium dendrites

H3K36 Histone Methyltransferase Setd2 Is Required for Murine Embryonic Stem Cell Differentiation toward Endoderm

Setd2 is known as a histone-H3K36-specific methyltransferase. However, its role in physiological function remains unclear. In this study, we show that Setd2 mainly regulates differentiation of murine embryonic stem cells (mESCs) toward primitive endoderm. Furthermore, we show that downregulated endoderm-related genes in Setd2−/− mESCs are associated with an aberrantly low level of Erk activity and that enforced expression of Fgfr3 can rescue the defective Erk pathway in Setd2−/− mESCs. Interestingly, the transcriptional initiation of Fgfr3 is directly regulated through histone H3K36me3 modification in its distal promoter region by Setd2. These results indicate that Setd2 controls the primitive endoderm differentiation of mESCs by regulating the Fgfr3-Erk signaling

Hypoxia-Inducible Factor-1α: A Potential Factor for the Enhancement of Osseointegration between Dental Implants and Tissue-Engineered Bone

Introduction: Tissue-engineered bones are widely utilized to protect healthy tissue, reduce pain, and increase the success rate of dental implants. one of the most challenging obstacles lies in obtaining effective os-seointegration between dental implants and tissue-engineered structures. Deficiencies in vascularization, osteogenic factors, oxygen, and other nutrients inside the tissue-engineered bone during the early stages following implantation all inhibit effective osseointe-gration. Oxygen is required for aerobic metabolism in bone and blood vessel tissues, but oxygen levels inside tissue-engineered bone are not suf-ficient for cell proliferation. HIF-1α is a pivotal regulator of hypoxic and ischemic vascular responses, driving transcriptional activation of hundreds of genes involved in vascular reactivity, angiogenesis, arteriogenesis, and osteogenesis.The hypothesis: Hypoxia-Inducible Factor-1α seems a potential factor for the enhancement of osseointegration between dental implants and tissue-engineered bone.Evaluation of the hypothesis: Enhancement of HIF-1α protein expression is recognized as the most promising approach for angiogenesis, because it can induce multiple angiogenic targets in a coordinated manner. Therefore, it will be a novel potential therapeutic methods targeting HIF-1α expression to enhance osseointegration be-tween dental implants and tissue-engineered bone

Comparative short-term efficacy and acceptability of a combination of pharmacotherapy and psychotherapy for depressive disorder in children and adolescents: a systematic review and meta-analysis

Background: Although the clinical efficacy and safety of combination of pharmacotherapy and psychotherapy in the treatment of depressive disorders in children and adolescents have been studied, the results remain controversial. This meta-analysis aimed to study the short-term efficacy and acceptability of combined therapy for children and adolescents with depressive disorders. Methods: We conducted a systematic search in multiple databases for randomised controlled trials (RCTs), up to 31 December 2020, that assessed the combination of pharmacotherapy and psychotherapy against other active treatment options (pharmacotherapy, psychotherapy and placebo combined psychotherapy) in children and adolescents (≤ 18 years old) with depressive disorder. This study was registered with PROSPERO (CRD42020196701). Results: A total of 14 RCTs involving 1,325 patients were included. For the primary and secondary outcomes, there were no statistically significant differences between the compared interventions in terms of remission (odds ratios [OR] = 1.37; 95% confidence interval [CI]: 0.93 to 2.04), acceptability (OR = 0.99; 95% CI: 0.72 to 1.38), efficacy (standardised mean differences = -0.07; 95% CI: -0.32 to 0.19), and suicidality (OR = 1.17; 95% CI: 0.67 to 2.06). Limited evidence showed that the combination of fluoxetine (OR = 1.90, 95% CI: 1.10 to 3.29) or non-selective serotonin reuptake inhibitors (non-SSRI) (OR = 2.46, 95% CI: 1.06 to 5.72) with cognitive-behavioural therapy (CBT) was superior to other active treatment options. Most included trials were rated as ‘some concerns’ in terms of risk of bias assessment. Conclusion: There is no evidence from the limited available data that all combined therapies are superior to other active treatment options for the acute treatment of depressive disorder in children and adolescents. However, it showed that fluoxetine or non-SSRI pharmacotherapies combined with CBT might be superior to other therapies in short-term. Mixed characteristics (e.g. age) and small sample size of non-SSRI combined therapy may influence the generalisability of the results

Comparative efficacy and acceptability of psychotherapies for post-traumatic stress disorder in children and adolescents: a systematic review and network meta-analysis

Background: Available evidence on the comparative efficacy and acceptability of psychotherapies for post-traumatic stress disorder (PTSD) in children and adolescents remains uncertain. Objective: We aimed to compare and rank the different types and formats of psychotherapies for PTSD in children and adolescents. Methods: We searched eight databases and other international registers up to 31 December 2020. The pairwise meta-analyses and frequentist network meta-analyses estimated pooled standardised mean differences (SMDs) and ORs with random-effects model. Efficacy at post-treatment and follow-up, acceptability, depressive and anxiety symptoms were measured. Findings: We included 56 randomised controlled trials with 5327 patients comparing 14 different types of psychotherapies and 3 control conditions. For efficacy, cognitive processing therapy (CPT), behavioural therapy (BT), individual trauma-focused cognitive–behavioural therapy (TF-CBT), eye movement desensitisation and reprocessing, and group TF-CBT were significantly superior to all control conditions at post-treatment and follow-up (SMDs between −2.42 and −0.25). Moreover, CPT, BT and individual TF-CBT were more effective than supportive therapy (SMDs between −1.92 and −0.49). Results for depressive and anxiety symptoms were similar to the findings for the primary outcome. Most of the results were rated as ‘moderate’ to ‘very low’ in terms of confidence of evidence. Conclusions: CPT, BT and individual TF-CBT appear to be the best choices of psychotherapy for PTSD in young patients. Other types and different ways of delivering psychological treatment can be alternative options. Clinicians should consider the importance of each outcome and the patients’ preferences in real clinical practice