Adeno-associated virus serotype rh.10 displays strong muscle tropism following intraperitoneal delivery

Recombinant adeno-associated virus (rAAV) is an attractive tool for basic science and translational medicine including gene therapy, due to the versatility in its cell and organ transduction. Previous work indicates that rAAV transduction patterns are highly dependent on route of administration. Based on this relationship, we hypothesized that intraperitoneal (IP) administration of rAAV produces unique patterns of tissue tropism. To test this hypothesis, we investigated the transduction efficiency of 12 rAAV serotypes carrying an enhanced green fluorescent protein (EGFP) reporter gene in a panel of 12 organs after IP injection. Our data suggest that IP administration emphasizes transduction patterns that are different from previously reported intravascular delivery methods. Using this approach, rAAV efficiently transduces the liver, pancreas, skeletal muscle, heart and diaphragm without causing significant histopathological changes. Of note, rAAVrh.10 showed excellent muscle transduction following IP administration, highlighting its potential as a new muscle-targeting vector

Experimental treatment efficacy of dmrFABP5 on prostate cancer singly or in combination with drugs in use.

Enzalutamide is a drug used to treat prostate cancer (PC) and docetaxel is a drug for chemotherapeutic treatment of diverse cancer types, including PC. The effectiveness of these drugs in treating castration-resistant prostate cancer (CRPC) is poor and therefore CRPC is still largely incurable. However, the bio-inhibitor of fatty acid-binding protein 5 (FABP5), dmrFABP5, which is a mutant form of FABP5 incapable of binding to fatty acids, has been shown recently to be able to suppress the tumorigenicity and metastasis of cultured CRPC cells. The present study investigated the possible synergistic effect of dmrFABP5 combined with either enzalutamide or docetaxel on suppressing the tumorigenic properties of PC cells, including cell viability, migration, invasion and colony proliferation in soft agar. A highly significant synergistic inhibitory effect on these properties was observed when dmrFABP5 was used in combination with enzalutamide on androgen-responsive PC 22RV1 cells. Moreover, a highly significant synergistic inhibitory effect was also observed when dmrFABP5 was combined with docetaxel, and added to 22RV1 cells and to the highly malignant, androgen-receptor (AR)-negative Du145 cells. DmrFABP5 alone failed to produce any suppressive effect when added to the FABP5-negative cell line LNCaP, although enzalutamide could significantly suppress LNCaP cells when used as a single agent. These synergistic inhibitory effects of dmrFABP5 were produced by interrupting the FABP5-related signal transduction pathway in PC cells. Thus, dmrFABP5 appears to be not only a potential single therapeutic agent, but it may also be used in combination with existing drugs to suppress both AR-positive and AR-negative PC

NADPH Oxidase 2-Derived Reactive Oxygen Species Mediate FFAs-Induced Dysfunction and Apoptosis of β-Cells via JNK, p38 MAPK and p53 Pathways

Dysfunction of β-cell is one of major characteristics in the pathogenesis of type 2 diabetes. The combination of obesity and type 2 diabetes, characterized as ‘diabesity’, is associated with elevated plasma free fatty acids (FFAs). Oxidative stress has been implicated in the pathogenesis of FFA-induced β-cell dysfunction. However, molecular mechanisms linking between reactive oxygen species (ROS) and FFA-induced β-cell dysfunction and apoptosis are less clear. In the present study, we test the hypothesis that NOX2-derived ROS may play a critical role in dysfunction and apoptosis of β-cells induced by FFA. Our results show that palmitate and oleate (0.5 mmol/L, 48 h) induced JNK activation and AKT inhibition which resulted in decreased phosphorylation of FOXO1 following nuclear localization and the nucleocytoplasmic translocation of PDX-1, leading to the reducing of insulin and ultimately dysfunction of pancreatic NIT-1 cells. We also found that palmitate and oleate stimulated apoptosis of NIT-1 cells through p38MAPK, p53 and NF-κB pathway. More interestingly, our data suggest that suppression of NOX2 may restore FFA-induced dysfunction and apoptosis of NIT-1 cells. Our findings provide a new insight of the NOX2 as a potential new therapeutic target for preservation of β-cell mass and function

DeepSeek LLM: Scaling Open-Source Language Models with Longtermism

The rapid development of open-source large language models (LLMs) has been truly remarkable. However, the scaling law described in previous literature presents varying conclusions, which casts a dark cloud over scaling LLMs. We delve into the study of scaling laws and present our distinctive findings that facilitate scaling of large scale models in two commonly used open-source configurations, 7B and 67B. Guided by the scaling laws, we introduce DeepSeek LLM, a project dedicated to advancing open-source language models with a long-term perspective. To support the pre-training phase, we have developed a dataset that currently consists of 2 trillion tokens and is continuously expanding. We further conduct supervised fine-tuning (SFT) and Direct Preference Optimization (DPO) on DeepSeek LLM Base models, resulting in the creation of DeepSeek Chat models. Our evaluation results demonstrate that DeepSeek LLM 67B surpasses LLaMA-2 70B on various benchmarks, particularly in the domains of code, mathematics, and reasoning. Furthermore, open-ended evaluations reveal that DeepSeek LLM 67B Chat exhibits superior performance compared to GPT-3.5

Broaden Horizons: The Advancement of Interstitial Cystitis/Bladder Pain Syndrome

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating disease that induces mental stress, lower urinary symptoms, and pelvic pain, therefore resulting in a decline in quality of life. The present diagnoses and treatments still lead to unsatisfactory outcomes, and novel diagnostic and therapeutic modalities are needed. Although our understanding of the etiology and pathophysiology of IC/BPS is growing, the altered permeability of the impaired urothelium, the sensitized nerves on the bladder wall, and the chronic or intermittent sensory pain with inaccurate location, as well as pathologic angiogenesis, fibrosis, and Hunner lesions, all act as barriers to better diagnoses and treatments. This study aimed to summarize the comprehensive information on IC/BPS research, thereby promoting the progress of IC/BPS in the aspects of diagnosis, treatment, and prognosis. According to diverse international guidelines, the etiology of IC/BPS is associated with multiple factors, while the presence of Hunner lesions could largely distinguish the pathology, diagnosis, and treatment of non-Hunner lesions in IC/BPS patients. On the basis of the diagnosis of exclusion, the diverse present diagnostic and therapeutic procedures are undergoing a transition from a single approach to multimodal strategies targeting different potential phenotypes recommended by different guidelines. Investigations into the mechanisms involved in urinary symptoms, pain sensation, and bladder fibrosis indicate the pathophysiology of IC/BPS for further potential strategies, both in diagnosis and treatment. An overview of IC/BPS in terms of epidemiology, etiology, pathology, diagnosis, treatment, and fundamental research is provided with the latest evidence. On the basis of shared decision-making, a multimodal strategy of diagnosis and treatment targeting potential phenotypes for individual patients with IC/BPS would be of great benefit for the entire process of management. The complexity and emerging evidence on IC/BPS elicit more relevant studies and research and could optimize the management of IC/BPS patients

mTORC1-Dependent Protein and Parkinson’s Disease: A Mendelian Randomization Study

Background: The mTOR pathway is crucial in controlling the growth, differentiation, and survival of neurons, and its pharmacological targeting has promising potential as a treatment for Parkinson’s disease. However, the function of mTORC1 downstream proteins, such as RPS6K, EIF4EBP, EIF-4E, EIF-4G, and EIF4A, in PD development remains unclear. Methods: We performed a Mendelian randomization study to evaluate the causal relationship between mTORC1 downstream proteins and Parkinson’s disease. We utilized various MR methods, including inverse-variance-weighted, weighted median, MR–Egger, MR-PRESSO, and MR-RAPS, and conducted sensitivity analyses to identify potential pleiotropy and heterogeneity. Results: The genetic proxy EIF4EBP was found to be inversely related to PD risk (OR = 0.79, 95% CI = 0.67–0.92, p = 0.003), with the results from WM, MR-PRESSO, and MR-RAPS being consistent. The plasma protein levels of EIF4G were also observed to show a suggestive protective effect on PD (OR = 0.85, 95% CI = 0.75–0.97, p = 0.014). No clear causal effect was found for the genetically predicted RP-S6K, EIF-4E, and EIF-4A on PD risk. Sensitivity analyses showed no significant imbalanced pleiotropy or heterogeneity, indicating that the MR estimates were robust and independent. Conclusion: Our unbiased MR study highlights the protective role of serum EIF4EBP levels in PD, suggesting that the pharmacological activation of EIF4EBP activity could be a promising treatment option for PD

Comparative Proteomics Uncovers Correlated Signaling Network and Potential Biomarkers for Progression of Prostate Cancer

Background/Aims: Prostate cancer is one of the most common cancers for males worldwide, and it is prone to show the metastatic foci in lymph node and bone with high mortality. To date, the potential mechanism and the corresponding biomarkers for metastatic prostate cancer are still lacking. Hence, our study aims to clarify the mechanism of prostate cancer progression and identify the useful biomarkers for metastatic prostate cancer. Methods: The proteins and network tightly associated with tumor metastasis were identified using quantitative proteomics. Furthermore, the mRNA level of differential expressed proteins were confirmed using qRT-PCR, and the functional cluster analysis was performed using String and Cytoscape. Results: Totally, our study identified 203 differential proteins closely associated with tumor cell migration, and the mRNA expression of those proteins were verified by qPCR. Moreover, the migration associated molecular network was established using bioinformatics analysis. Conclusion: These data raveled the critical proteins for the cell migration of prostate cancer, and identified the potential markers for diagnosing the metastasis of prostate cancer

Dynamic Warning Method for Structural Health Monitoring Data Based on ARIMA: Case Study of Hong Kong–Zhuhai–Macao Bridge Immersed Tunnel

Structural health monitoring (SHM) is gradually replacing traditional manual detection and is becoming a focus of the research devoted to the operation and maintenance of tunnel structures. However, in the face of massive SHM data, the autonomous early warning method is still required to further reduce the burden of manual analysis. Thus, this study proposed a dynamic warning method for SHM data based on ARIMA and applied it to the concrete strain data of the Hong Kong–Zhuhai–Macao Bridge (HZMB) immersed tunnel. First, wavelet threshold denoising was applied to filter noise from the SHM data. Then, the feasibility and accuracy of establishing an ARIMA model were verified, and it was adopted to predict future time series of SHM data. After that, an anomaly detection scheme was proposed based on the dynamic model and dynamic threshold value, which set the confidence interval of detected anomalies based on the statistical characteristics of the historical series. Finally, a hierarchical warning system was defined to classify anomalies according to their detection threshold and enable hierarchical treatments. The illustrative example of the HZMB immersed tunnel verified that a three-level (5.5 σ, 6.5 σ, and 7.5 σ) dynamic warning schematic can give good results of anomalies detection and greatly improves the efficiency of SHM data management of the tunnel