Genetically engineered pre-microRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children, and microRNA-34a (miR-34a) replacement therapy represents a new treatment strategy. This study was to define the effectiveness and safety profiles of a novel bioengineered miR-34a prodrug in orthotopic OS xenograft tumor mouse model. Highly purified pre-miR-34a prodrug significantly inhibited the proliferation of human 143B and MG-63 cells in a dose dependent manner and to much greater degrees than controls, which was attributed to induction of apoptosis and G2 cell cycle arrest. Inhibition of OS cell growth and invasion were associated with release of high levels of mature miR-34a from pre-miR-34a prodrug and consequently reduction of protein levels of many miR-34a target genes including SIRT1, BCL2, c-MET, and CDK6. Furthermore, intravenous administration of in vivo-jetPEI formulated miR-34a prodrug significantly reduced OS tumor growth in orthotopic xenograft mouse models. In addition, mouse blood chemistry profiles indicated that therapeutic doses of bioengineered miR-34a prodrug were well tolerated in these animals. The results demonstrated that bioengineered miR-34a prodrug was effective to control OS tumor growth which involved the induction of apoptosis and cell cycle arrest, supporting the development of bioengineered RNAs as a novel class of large molecule therapeutic agents

Prevalence of COPD and its association with socioeconomic status in China: Findings from China Chronic Disease Risk Factor Surveillance 2007

<p>Abstract</p> <p>Background</p> <p>Socioeconomic status is likely an independent risk factor for Chronic Obstructive Pulmonary Disease (COPD), but little research has been done in China to study this association in a nationwide sample.</p> <p>Methods</p> <p>We used data from the 2007 China Chronic Disease Risk Factor Surveillance of 49,363 Chinese men and women aged 15-69 years to examine the association between the prevalence of self-reported physician diagnosed COPD and socioeconomic status defined by both educational level and annual household income. Multivariable logistic regression modelling was performed with adjustement for potential confounders.</p> <p>Results</p> <p>Both low educational attainment and low household income were independently associated with higher risk of physician-diagnosed COPD. Compared to subjects with high educational level, subjects with low educational level had a significantly increased risk of COPD (OR 1.67, 95%CI 1.32-2.13, p for trend< 0.001 for urban, OR 1.76, 95%CI 1.34-2.30, p for trend < 0.001 for rural) after adjusting for age, sex, smoking status, passive smoking and geographic regions. Similarly increased risk was observed for household income and COPD in urban (OR 1.64, 95%CI 1.28-2.09, P for trend< 0.001) but not rural areas. Among never smokers, low educational level and household income were still associated with a significant higher prevalence of COPD (OR 1.77, 95%CI 1.40-2.25, OR 1.31, 95%CI 1.05-1.62). Removal of those with asthma diagnosis did not alter the observed associations.</p> <p>Conclusions</p> <p>Socioeconomic status is a risk factor for self-reported physician-diagnosed COPD independently of current or passive smoking. Prospective studies are needed in China to better understand the association between socioeconomic status and COPD.</p

Recording sympathetic nerve activity from the skin

Sympathetic tone is important in cardiac arrhythmogenesis; however, methods to estimate sympathetic tone are either invasive or require proper sinus node function that may be abnormal in disease states. Because of the direct and extensive connections among various nerve structures, it is possible for the sympathetic nerves in the various structures to activate simultaneously. Therefore, we hypothesized that nerve activity can be recorded from the skin and it can be used to estimate the cardiac sympathetic tone. Preclinical studies in canines demonstrated that nerve activity is detectable using conventional ECG electrodes and can be used to estimate cardiac sympathetic tone. Subsequent clinical studies further supported this concept. In addition to studying the autonomic mechanisms of cardiac arrhythmia, these new methods may have broad application in studying both cardiac and non-cardiac diseases

Mechanism underlying synergic activation of Tyrosinase promoter by MITF and IRF4

Background: The transcription factor interferon regulatory factor 4 (IRF4) was identified to be involved in human pigmentation by genome-wide association studies (GWASs). The rs12203592-[T/C], which is located in intron 4 of IRF4, shows the strongest link to these pigmentation phenotypes including freckling, sun sensitivity, eye and hair color. Previous studies indicated a functional cooperation of IRF4 with Microphthalmia-associated transcription factor (MITF), a causing gene of Waardenburg syndrome (WS), to synergistically trans-activate Tyrosinase (TYR). However, the underlying mechanism is still unknown. Methods: To investigate the importance of DNA binding in the synergic effect of IRF4. Reporter plasmids with mutant TYR promoters was generated to locate the IRF4 DNA binding sites in the Tyrosinase minimal promoter. By building MITF and IRF4 truncated mutations plasmids, the necessary regions of the synergy functions of these two proteins were also located. Results: The cooperative effect between MITF and IRF4 was specific for TYR promoter. The DNA-binding of IRF4 was critical for the synergic function. IRF4 DNA binding sites in TYR promoter were identified. The Trans-activation domains in IRF4 (aa134-207, aa300-420) were both important for the synergic function, whereas the auto-mask domain (aa207-300) appeared to mask the synergic effect. Mutational analysis in MITF indicated that both DNA-binding and transcriptional activation domains were both required for this synergic effect. Conclusions: Here we showed that IRF4 potently synergized with MITF to activate the TYR promoter, which was dependent on DNA binding of IRF4. The synergic domains in both IRF4 and MITF were identified by mutational analysis. This identification of IRF4 as a partner for MITF in regulation of TYR may provide an important molecular function for IRF4 in the genesis of melanocytes and the pathogenic mechanism in WS

Paternal Origin of Mongolic-Speaking Populations: A Review of Studies from Recent Decades (1999–2019) and their Implications for Multidisciplinary Research in the Future

The activities of Mongolic-speaking populations, a large group of people in eastern Eurasia, have important impact on the history of East Asia and other parts of Eurasia. Most previous genetic research of East Asian populations, including ancient DNA studies, have involved samples from Mongolic-speaking populations or their ancient relatives. Here, we summarized frequency data of paternal Y-chromosome haplogroups from all available literature about Mongolic-speaking populations from 1999 to 2019. Fourteen paternal components were identified and six of them were proposed as major and common components in ancestor groups of Mongolic-speaking populations. We thoroughly discussed the possible origin, migration patterns, and the roles of these six components in the evolution history of Mongolic-speaking populations. Meanwhile, we discussed the implications of the present achievements of human genetics for multidisciplinary research in ethnology, history, archaeology and linguistics in the future

Construction of a large-scale maritime element semantic schema based on knowledge graph models for unmanned automated decision-making

In maritime logistics optimization, considerable research efforts are focused on the extraction of deep behavioral characteristics from comprehensive shipping data to discern patterns in maritime vessel behavior. The effective linkage of these characteristics with maritime infrastructure, such as berths, is critical for the enhancement of ship navigation systems. This endeavor is paramount not only as a research focus within maritime information science but also for the progression of intelligent maritime systems. Traditional methodologies have primarily emphasized the analysis of navigational paths of vessels without an extensive consideration of the geographical dynamics between ships and port infrastructure. However, the introduction of knowledge graphs has enabled the integration of disparate data sources, facilitating new insights that propel the development of intelligent maritime systems. This manuscript presents a novel framework using knowledge graph technology for profound analysis of maritime data. Utilizing automatic identification system (AIS) data alongside spatial information from port facilities, the framework forms semantic triplet connections among ships, anchorages, berths, and waterways. This enables the semantic modeling of maritime behaviors, offering precise identification of ships through their diverse semantic information. Moreover, by exploiting the semantic relations between ships and berths, a reverse semantic knowledge graph for berths is constructed, which is specifically tailored to ship type, size, and category. The manuscript critically evaluates a range of graph embedding techniques, dimensionality reduction methods, and classification strategies through experimental frameworks to determine the most efficacious methodologies. The findings reveal that the maritime knowledge graph significantly enhances the semantic understanding of unmanned maritime equipment, thereby improving decision-making capabilities. Additionally, it establishes a semantic foundation for the development of expansive maritime models, illustrating the potential of knowledge graph technology in advancing intelligent maritime systems

Prognostic significance of the neutrophil to lymphocyte ratio in patients with non-small cell lung cancer: a systemic review and metaanalysis,”

Abstract: Neutrophil to Lymphocyte Ratio (NLR) was recently demonstrated as a useful index in predicting the prognosis of Non-Small Cell Lung Cancer (NSCLC). Thus, a meta-analysis was performed to demonstrate the relationship between NLR and overall survival (OS), progress-free survival (PFS) or disease free survival (DFS) in patients with NSCLC. We searched for relevant literatures in PubMed, EMBASE and Cochrane library and pooled the eligible studies and synthesized hazard ratios (HRs) using Stata 12.0. Final analysis of NSCLC patients from 12 eligible studies was performed. Combined HR suggested that high NLR had an unfavorable effect on patients&apos; OS (n=1700 in 11 studies; HR= 1.43, 95% CI: 1.25-1.64; I^2=80.2%, P&lt;0.01) and PFS (n=664 in 5 studies, HR=1.37, 95% CI: 1.07-1.74; I^2=70.8%, P=0.004). Subgroup analysis based on cutoff shown that, compared with other subgroups, the subgroup with a cutoff of 5 had a significantly poorer survival (HR=1.87, 95% CI 1.49-2.34) with less heterogeneity (I^2=21.3%, P=0.28). However, subgroup analysis based on treatment method indicated that the &quot;surgery&quot; subgroup seemed to have not a significant impact on survival (HR=1.32, 95% CI 0.99-1.77; I^2=80.0%, P=0.063) compared with the chemotherapy subgroup (HR=1.61, 95% CI 1.24-2.10; I^2=82.6%, P&lt;0.01). Additionally, combined odds ratio (OR) suggested high NLR was associated inversely with response to treatment (n = 276 in 2 studies; OR = 1.73, 95% CI: 1.04-2.88; I^2=0%, P=0.40). This study suggests high NLR (especially with a cutoff of 5) seems to be associated with a worse prognosis in patients with NSCLC as well as a worse response to treatments

Effects of Stepwise Denervation of the Stellate Ganglion: Novel Insights from an Acute Canine Study

Background The stellate ganglion (SG) is important for cardiac autonomic control. SG modification is an option for treating refractory ventricular tachyarrhythmias. The optimal extent of left- and right-sided SG denervation necessary for antiarrhythmic effect, however, remains to be learned. Objective The purpose of this study was to evaluate the effects of stepwise SG denervation on hemodynamic and electrophysiological parameters in dogs. Methods After sequential left and right thoracotomy in 8 healthy dogs, the SG was exposed by dissection. Two pacing wires were placed in the upper SG to deliver high-frequency stimulation. The lower SG, ansae subclaviae, and upper SG were removed in a stepwise manner. The same protocol was performed on the right side. Blood pressure (BP), heart rate, and electrophysiological parameters were recorded at baseline and after 5 minutes of stimulation. Results Systolic and diastolic BP significantly increased during stimulation of the upper left SG. The mean increase in systolic BP from baseline was 49.4 ± 26.6 mm Hg (P = .007), 25.5 ± 14.1 mm Hg after the lower SG was removed (P = .02), and 8.6 ± 3.4 mm Hg after resection of the ipsilateral ansae subclaviae (P = .048). Heart rate and other electrophysiological parameters did not change significantly. After the complete removal of the left SG, systolic BP increased by 34.0 ± 17.6 mm Hg (P = .005) after stimulation of the right SG. Conclusion Sympathetic output remains after the lower SG is removed, and sympathetic output from the right SG remains after the complete resection of the left SG and ansae subclaviae. Thus, some patients who undergo left SG denervation can still have significant sympathetic response via right SG regulation