BindingSiteDTI: differential-scale binding site modelling for drug-target interaction prediction.

MOTIVATION: Enhanced by contemporary computational advances, the prediction of drug-target interactions (DTIs) has become crucial in developing de novo and effective drugs. Existing deep learning approaches to DTI prediction are frequently beleaguered by a tendency to overfit specific molecular representations, which significantly impedes their predictive reliability and utility in novel drug discovery contexts. Furthermore, existing DTI networks often disregard the molecular size variance between macro molecules (targets) and micro molecules (drugs) by treating them at an equivalent scale that undermines the accurate elucidation of their interaction. RESULTS: We propose a novel DTI network with a differential-scale scheme to model the binding site for enhancing DTI prediction, which is named as BindingSiteDTI. It explicitly extracts multiscale substructures from targets with different scales of molecular size and fixed-scale substructures from drugs, facilitating the identification of structurally similar substructural tokens, and models the concealed relationships at the substructural level to construct interaction feature. Experiments conducted on popular benchmarks, including DUD-E, human, and BindingDB, shown that BindingSiteDTI contains significant improvements compared with recent DTI prediction methods. AVAILABILITY AND IMPLEMENTATION: The source code of BindingSiteDTI can be accessed at https://github.com/MagicPF/BindingSiteDTI.

MicroRNA-23a Curbs Necrosis during Early T Cell Activation by Enforcing Intracellular Reactive Oxygen Species Equilibrium.

Upon antigen engagement, augmented cytosolic reactive oxygen species (ROS) are needed to achieve optimal T cell receptor (TCR) signaling. However, uncontrolled ROS production is a prominent cause of necrosis, which elicits hyper-inflammation and tissue damage. Hence, it is critical to program activated T cells to achieve ROS equilibrium. Here, we determined that miR-23a is indispensable for effector CD4(+) T cell expansion, particularly by providing early protection from excessive necrosis. Mechanistically, miR-23a targeted PPIF, gatekeeper of the mitochondria permeability transition pore, thereby restricting ROS flux and maintaining mitochondrial integrity. Upon acute Listeria monocytogenes infection, deleting miR-23a in T cells resulted in excessive inflammation, massive liver damage, and a marked mortality increase, which highlights the essential role of miR-23a in maintaining immune homeostasis.

A Bibliometric Analysis of the Spatial Transcriptomics Literature from 2006 to 2023.

In recent years, spatial transcriptomics (ST) research has become a popular field of study and has shown great potential in medicine. However, there are few bibliometric analyses in this field. Thus, in this study, we aimed to find and analyze the frontiers and trends of this medical research field based on the available literature. A computerized search was applied to the WoSCC (Web of Science Core Collection) Database for literature published from 2006 to 2023. Complete records of all literature and cited references were extracted and screened. The bibliometric analysis and visualization were performed using CiteSpace, VOSviewer, Bibliometrix R Package software, and Scimago Graphica. A total of 1467 papers and reviews were included. The analysis revealed that the ST publication and citation results have shown a rapid upward trend over the last 3 years. Nature Communications and Nature were the most productive and most co-cited journals, respectively. In the comprehensive global collaborative network, the United States is the country with the most organizations and publications, followed closely by China and the United Kingdom. The author Joakim Lundeberg published the most cited paper, while Patrik L. Ståhl ranked first among co-cited authors. The hot topics in ST are tissue recognition, cancer, heterogeneity, immunotherapy, differentiation, and models. ST technologies have greatly contributed to in-depth research in medical fields such as oncology and neuroscience, opening up new possibilities for the diagnosis and treatment of diseases. Moreover, artificial intelligence and big data drive additional development in ST fields.

Dual External Field Strategy in Regulating the Superhalogen Characteristics of the Non-Noble Metal Constituted Tantalum Oxide Clusters.

The identification of the non-noble metal constituted TaO cluster as a potential analogue to the noble metal Au is significant for the development of tailored materials. It leverages the superatom concept to engineer properties with precision. However, the impact of incrementally integrating TaO units on the electronic configurations and properties within larger TaO-based clusters remains to be elucidated. By employing the density functional theory calculations, the global minima and low-lying isomers of the TanOn (n = 2-5) clusters were determined, and their structural evolution was disclosed. In the cluster series, Ta5O5 was found to possess the highest electron affinity (EA) with a value of 2.14 eV, based on which a dual external field (DEF) strategy was applied to regulate the electronic property of the cluster. Initially, the electron-withdrawing CO ligand was affixed to Ta5O5, followed by the application of an oriented external electric field (OEEF). The CO ligation was found to be able to enhance the Ta5O5 cluster's electron capture capability by adjusting its electron energy levels, with the EA of Ta5O5(CO)4 peaking at 2.58 eV. Subsequently, the introduction of OEEF further elevated the EA of the CO-ligated cluster. Notably, OEEF, when applied along the +x axis, was observed to sharply increase the EA to 3.26 eV, meeting the criteria for superhalogens. The enhancement of EA in response to OEEF intensity can be quantified as a functional relationship. This finding highlights the advantage of OEEF over conventional methods, demonstrating its capacity for precise and continuous modulation of cluster EAs. Consequently, this research has adeptly transformed tantalum oxide clusters into superhalogen structures, underscoring the effectiveness of the DEF strategy in augmenting cluster EAs and its promise as a viable tool for the creation of superhalogens.

An electrochemiluminescence aptasensor based on highly luminescent silver-based MOF and biotin-streptavidin system for mercury ion detection.

In this study, for the first time, a silver-based metal-organic framework (Ag-MOF) was synthesized and used as the electrochemiluminescence (ECL) emitter for building an ECL sensor. After modification with chitosan (CS) and gold nanoparticles (Au NPs), the ECL stability of Ag-MOF was improved. To detect mercury ions, a biosensor was constructed using the mercury ion aptamer and steric effect of streptavidin. First, the capture strand (cDNA) with terminal-modified sulfhydryl group was attached to the electrode surface by the Au-S bond. Then, the mercury-ion aptamer (Apt-Hg) modified with biotin was anchored to the electrode by complementary pairing with cDNA. Streptavidin (SA) could be fixed on the electrode by linking with biotin, thereby reducing the ECL signal. However, in the presence of mercury ions, the aptamer was removed and streptavidin could not be immobilized on the electrode. Hence, the ECL signal of the sensor increased with the concentration of mercury ions, which was linear in the range from 1 µM to 300 fM. The detection limit could reach 66 fM (S/N = 3). The sensor provided a new method for the detection of mercury ions.

Association between diagnostic delay and prognosis of pulmonary tuberculosis in Shandong, China: a retrospective study.

BACKGROUND: Tuberculosis (TB) is one of the main infectious diseases that seriously threatens global health, while diagnostic delay (DD) and treatment dramatically threaten TB control. METHODS: Between 2005 and 2017 in Shandong, China, we enrolled pulmonary tuberculosis (PTB) patients with DD. DD trends were evaluated by Joinpoint regression, and associations between PTB patient characteristics and DD were estimated by univariate and multivariate logistic regression. The influence of DD duration on prognosis and sputum smear results were assessed by Spearman correlation coefficients. RESULTS: We identified 208,822 PTB cases with a median DD of 33 days (interquartile range (IQR) 18-63). The trend of PTB with DD declined significantly between 2009 and 2017 (annual percent change (APC): - 4.0%, P = 0.047, 2009-2013; APC: - 6.6%, P = 0.001, 2013-2017). Patients aged > 45 years old (adjusted odds ratio (aOR): 1.223, 95% confidence interval (CI) 1.189-1.257, 46-65 years; aOR: 1.306, 95% CI 1.267-1.346, > 65 years), farmers (aOR: 1.520, 95% CI 1.447-1.596), and those with a previous treatment history (aOR: 1.759, 95% CI 1.699-1.821) were prone to developing long DD (> 30 days, P < 0.05). An unfavorable outcome was negatively associated with a short DD (OR: 0.876, 95% CI 0.843-0.910, P < 0.001). Sputum smear positive rate and unfavorable outcomes were positively correlated with DD duration (Spearman correlation coefficients (rs) = 1, P < 0.001). CONCLUSIONS: The DD situation remains serious; more efficient and comprehensive strategies are urgently required to minimize DD, especially for high-risk patients.

Illuminating Key Microbial Players and Metabolic Processes Involved in the Remineralization of Particulate Organic Carbon in the Ocean's Twilight Zone by Metaproteomics.

The twilight zone (from the base of the euphotic zone to the depth of 1,000 m) is the major area of particulate organic carbon (POC) remineralization in the ocean, and heterotrophic microbes contribute to more than 70% of the estimated remineralization. However, little is known about the microbial community and metabolic activity directly associated with POC remineralization in this chronically understudied realm. Here, we characterized the microbial community proteomes of POC samples collected from the twilight zone of three contrasting sites in the Northwest Pacific Ocean using a metaproteomic approach. The particle-attached bacteria from Alteromonadales, Rhodobacterales, and Enterobacterales were the primary POC remineralizers. Hydrolytic enzymes, including proteases and hydrolases, that degrade proteinaceous components and polysaccharides, the main constituents of POC, were abundant and taxonomically associated with these bacterial groups. Furthermore, identification of diverse species-specific transporters and metabolic enzymes implied niche specialization for nutrient acquisition among these bacterial groups. Temperature was the main environmental factor driving the active bacterial groups and metabolic processes, and Enterobacterales replaced Alteromonadales as the predominant group under low temperature. This study provides insight into the key bacteria and metabolic processes involved in POC remineralization, and niche complementarity and species substitution among bacterial groups are critical for efficient POC remineralization in the twilight zone. IMPORTANCE The ocean's twilight zone is a critical zone where more than 70% of the sinking particulate organic carbon (POC) is remineralized. Therefore, the twilight zone determines the size of biological carbon storage in the ocean and regulates the global climate. Prokaryotes are major players that govern remineralization of POC in this region. However, knowledge of microbial community structure and metabolic activity is still lacking. This study unveiled microbial communities and metabolic activities of POC samples collected from the twilight zone of three contrasting environments in the Northwest Pacific Ocean using a metaproteomic approach. Alteromonadales, Rhodobacterales, and Enterobacterales were the major remineralizers of POC. They excreted diverse species-specific hydrolytic enzymes to split POC into solubilized POC or dissolved organic carbon. Temperature played a crucial role in regulating the community composition and metabolism. Furthermore, niche complementarity or species substitution among bacterial groups guaranteed the efficient remineralization of POC in the twilight zone.

Population aging and trends of pulmonary tuberculosis incidence in the elderly.

BACKGROUND: To explore population aging and the epidemic trend of pulmonary tuberculosis (PTB) in the elderly, and provide a basis for the prevention and control of pulmonary tuberculosis among the elderly. METHODS: We collected clinical information of 239,707 newly active PTB patients in Shandong Province from 2005 to 2017. We analyzed and compared the clinical characteristics, reported incidence and temporal trend of PTB among the elderly group (≥60 years) and the non-elderly group (< 60 years) through logistic model and Join-point regression model. RESULTS: Among the total PTB cases, 77,192(32.2%) were elderly. Compared with non-elderly patients, newly active elderly PTB patients account for a greater proportion of male cases (OR 1.688, 95% CI 1.656-1.722), rural population cases (OR 3.411, 95% CI 3.320-3.505) and bacteriologically confirmed PTB cases (OR 1.213, 95%CI 1.193-1.234). The annual reported incidence of total, elderly, pulmonary bacteriologically confirmed cases were 35.21, 68.84, 35.63 (per 100,000), respectively. The annual reported incidence of PTB in the whole population, the elderly group and the non-elderly group has shown a slow downward trend since 2008. The joinpoint regression model showed that the overall reported incidence of PTB in the elderly significantly decreased from 2007 to 2017 (APC = -5.3, P < 0.05). The reported incidence of bacteriologically confirmed PTB among elderly patients declined rapidly from 2005 to 2014(2005-2010 APC = -7.2%, P < 0.05; 2010-2014 APC = -22.6%, P < 0.05; 2014-2017 APC = -9.0%, P = 0.1). The reported incidence of clinically diagnosed PTB among elderly patients from 2005 to 2017 (11.48-38.42/100,000) increased by about 235%. It rose significantly from 2007 to 2014 (APC = 9.4, P<0.05). CONCLUSIONS: Compared with the non-elderly population, the reported incidence of PTB in the elderly population is higher. The main burden of PTB will shift to the elderly, men, rural population, and clinically diagnosed patients. With the intensification of aging, more researches on elderly PTB prevention and treatment will facilitate the realization of the global tuberculosis (TB) control targets.

Association between body mass index and newly diagnosed drug-resistant pulmonary tuberculosis in Shandong, China from 2004 to 2019.

BACKGROUND: Drug-resistant tuberculosis (DR-TB), obesity, and malnutrition are growing public health problems in the world. However, little has discussed the impact of different BMI status on the emergence of TB drug resistance. We aimed to explore the drug-resistant profiles of DR-TB and its clinical predictors among underweight, overweight or obesity population. METHODS: 8957 newly diagnosed TB cases with drug susceptibility results and BMI data in Shandong China, from 2004 to 2019 were enrolled. Multivariable and univariable logistic regression models were applied to investigate the impact of BMI on different drug-resistance. Clinical predicators and drug-resistant profiles of DR-TB among obesity, underweight, normal TB group were also described. RESULTS: Among 8957 TB cases, 6417 (71.64%) were normal weight, 2121 (23.68%) were underweight, 373 (4.16%) were overweight, and 46 (0.51%) were obese. The proportion of drug resistance and co-morbidity among normal weight, underweight, overweight, obese TB groups were 18.86%/18.25%/20.38%/23.91% (DR-TB), 11.19%/11.74%/9.65%/17.39% (mono-resistant tuberculosis, MR-TB), 3.41%/3.06%/5.36%/0.00% (multidrug resistant tuberculosis, MDR-TB), 4.21%/3.39%/5.36%/6.52% (polydrug resistant tuberculosis, PDR-TB), 10.57%/8.44%/19.57%/23.91% (co-morbidity), respectively. Compared with normal weight group, underweight were associated with lower risk of streptomycin-related resistance (OR 0.844, 95% CI 0.726-0.982), but contributed to a higher risk of MR-TB (isoniazid) (odds ratio (OR) 1.347, 95% CI 1.049-1.730; adjusted OR (aOR) 1.31, 95% CI 1.017-1.686), P < 0.05. In addition, overweight were positively associated with MDR-TB (OR 1.603, 95% CI 1.002-2.566; aOR 1.639, 95% CI 1.02-2.633), isoniazid + rifampicin + streptomycin resistance (OR 1.948, 95% confidence interval (CI): 1.061-3.577; aOR 2.113, 95% CI 1.141-3.912), Any isoniazid + streptomycin resistance (OR 1.472, 95% CI 1.013-2.14; aOR 1.483, 95% CI 1.017-2.164), P < 0.05. CONCLUSIONS: The higher risk of MDR-TB, isoniazid + rifampicin + streptomycin resistance, Any isoniazid + streptomycin resistance, and co-morbidity among overweight population implies that routine screening for drug sensitivity and more attention on co-morbidity among overweight TB cases may be necessary. In addition, underweight TB cases have a higher risk of isoniazid resistance. Our study suggests that an in-depth study of the interaction between host metabolic activity and infection of DR-TB may contribute more to novel treatment options or preventive measures, and accelerate the implementation of the STOP TB strategy.

Dynamic transcriptome landscape of Paragonimus proliferus developmental stages in the rat lungs.

Paragonimus proliferus, a lung fluke of the genus Paragonimus, was first reported in Yunnan province, China. P. proliferus can infect Sprague-Dawley (SD) rats and cause lung damage, but there is still no direct evidence of human infection. Until now, there has been a lack of studies on P. proliferus parasitism and development in mammalian lung tissue. The aim of this study was to perform transcriptomic profiling of P. proliferus at different developmental stages. SD rats were infected with P. proliferus metacercariae obtained from crabs; worms isolated from the lungs at different time points as well as metacercariae were subjected to whole transcriptome sequencing. Overall, 34,403 transcripts with the total length of 33,223,828 bp, average length of 965 bp, and N50 of 1833 bp were assembled. Comparative analysis indicated that P. proliferus, similar to other Paragonimus spp., expressed genes related to catabolism, whereas P. proliferus-specific transcripts were related to the maintenance of cellular redox homeostasis, sensitivity to bacteria, and immune response. Transcriptional dynamics analysis revealed that genes involved in the regulation of catabolism and apoptosis had stable expression over the P. proliferus life cycle, whereas those involved in development and immune response showed time-dependent changes. High expression of genes associated with immune response corresponded to that of genes regulating the sensitivity to bacteria and immune protection. We constructed a P. proliferus developmental model, including the development of the body, suckers, blood cells, reproductive and tracheal systems, lymph, skin, cartilage, and other tissues and organs, and an immune response model, which mainly involved T cells and macrophages. Our study provides a foundation for further research into the molecular biology and infection mechanism of P. proliferus.

Ambient air pollutants, diabetes and risk of newly diagnosed drug-resistant tuberculosis.

BACKGROUND: Drug-resistant tuberculosis (DR-TB), diabetes and exposure to air pollution are thought to be important threat to human health, but no studies have explored the effects of ambient air pollutants on DR-TB when adjusting diabetes status so far. METHODS: We performed a study among 3759 newly diagnosed TB cases with drug-susceptibility testing results, diabetes status, and individual air pollution data in Shandong from 2015 to 2019. Generalized linear mixed models (GLMM) including three models (Model 1: without covariates, Model 2: adjusted by diabetes status only, Model 3: with all covariates) were applied. RESULTS: Of 3759 TB patients enrolled, 716 (19.05%) were DR-TB, and 333 (8.86%) had diabetes. High exposure to O3 was associated with an increased risk of RFP-resistance (Model 2 or 3: odds ratio (OR) = 1.008, 95% confidence intervals (CI): 1.002-1.014), ethambutol-resistance (Model 3: OR = 1.015, 95%CI: 1.004-1.027) and any rifampicin+streptomycin resistance (Model 1,2,3: OR = 1.01, 95%CI: 1.002-1.018) at 90 days. In contrast, NO2 was associated with a reduced risk of DR-TB (Model 3: OR = 0.99, 95%CI: 0.981-0.999) and multidrug-resistant TB (MDR-TB) (Model 3: OR = 0.977, 95%CI: 0.96-0.994) at 360 days. Additionally, SO2 (Model 1, 2, 3: OR = 0.987, 95%CI: 0.977-0.998) showed a protective effect on MDR-TB at 90 days. PM2.5 (90 days, Model 2: OR = 0.991, 95%CI: 0.983-0.999), PM10 (360 days, Model 2: OR = 0.992, 95%CI: 0.985-0.999) had protective effects on any RFP+SM resistance. CONCLUSIONS: O3 contributed to an elevated risk of TB resistance but PM2.5, PM10, SO2, NO2 showed an inverse effect. Air pollutants may affect the development of drug resistance among TB cases by adjusting the status of diabetes.

AUXIN RESPONSE FACTOR17 Directly Regulates MYB108 for Anther Dehiscence.

The timely release of mature pollen following anther dehiscence is essential for reproduction in flowering plants. AUXIN RESPONSE FACTOR17 (ARF17) plays a crucial role in pollen wall pattern formation, tapetum development, and auxin signal transduction in anthers. Here, we showed that ARF17 is also involved in anther dehiscence. The Arabidopsis (Arabidopsis thaliana) arf17 mutant exhibits defective endothecium lignification, which leads to defects in anther dehiscence. The expression of MYB108, which encodes a transcription factor important for anther dehiscence, was dramatically down-regulated in the flower buds of arf17 Chromatin immunoprecipitation assays and electrophoretic mobility shift assays showed ARF17 directly binds to the MYB108 promoter. In an ARF17-GFP transgenic line, in which ARF17-GFP fully complements the arf17 phenotype, ARF17-GFP was observed in the endothecia at anther stage 11. The GUS signal driven by the MYB108 promoter was also detected in endothecia at late anther stages in transgenic plants expressing promoterMYB108::GUS Thus, the expression pattern of both ARF17 and MYB108 is consistent with the function of these genes in anther dehiscence. Furthermore, the expression of MYB108 driven by the ARF17 promoter successfully restored the defects in anther dehiscence of arf17 These results demonstrated that ARF17 regulates the expression of MYB108 for anther dehiscence. Together with its function in microcytes and tapeta, ARF17 likely coordinates the development of different sporophytic cell layers in anthers. The ARF17-MYB108 pathway involved in regulating anther dehiscence is also discussed.

Downregulation of DLGAP1-Antisense RNA 1 Alleviates Vascular Endothelial Cell Injury Via Activation of the Phosphoinositide 3-kinase/Akt Pathway Results from an Acute Limb Ischemia Rat Model.

OBJECTIVE: This study aimed to investigate the effect of long non-coding RNA (lncRNA) DLGAP1 antisense RNA 1 (DLGAP1-AS1) on vascular endothelial cell (VEC) injury via the phosphoinositide 3-kinase (PI3K)/Akt pathway in rat models of acute lower limb ischaemia-reperfusion (I/R). METHODS: Differentially expressed lncRNAs related to I/R were screened using the gene expression omnibus database. Acute lower limb I/R models were induced in male Wistar rats, in which the regulatory mechanisms of DLGAP1-AS1 silencing were analysed after the treatment of small interfering RNA (siRNA) against DLGAP1-AS1 or an inhibitor of the PI3K/Akt pathway. The relationship between DLGAP1-AS1 and the PI3K/Akt pathway was analysed. The levels of tumour necrosis factor (TNF)-α and vascular cell adhesion molecule-1 (VCAM-1), as well as malondialdehyde (MDA) concentration and creatine kinase (CK) activity, were measured. The number of circulating endothelial cells (CECs) and apoptosis of VECs were identified. RESULTS: Microarray based analysis indicated that DLGAP1-AS1 was highly expressed in I/R, which was further confirmed by detection of expression in rat models of acute lower limb I/R. Notably, the treatment of siRNA against DLGAP1-AS1 led to the activation of the PI3K/Akt pathway. In response to siRNA against DLGAP1-AS1, the levels of TNF-α and VCAM-1 were decreased, and MDA concentration and CK activity was downregulated. Reduced CEC numbers and suppressed VEC apoptosis were also observed. CONCLUSION: DLGAP1-AS1 silencing could further suppress the oxidative stress, exert an anti-apoptosis effect, and reduce inflammatory reaction, whereby VEC injury is alleviated by activation of the PI3K/Akt pathway in rats with acute lower limb I/R.

Association between economic development level and tuberculosis registered incidence in Shandong, China.

BACKGROUND: Tuberculosis (TB) is one of the major infectious diseases that seriously endanger people's health. In Shandong province, the relationship between the level of economic development and TB incidence has not been studied. This study aims to provide more research basis for the government to prevent and control TB by exploring the impact of different economic factors on TB incidence. METHODS: By constructing threshold regression model (TRM), we described the extent to which different economic factors contribute to TB registered incidence and differences in TB registered incidence among seventeen cities with different levels of economic development in Shandong province, China, during 2006-2017. Data were retrieved from the China Information System for Disease Control and Prevention. RESULTS: Per capita medical expenditure (regression coefficient, -0.0314462; SD, 0.0079305; P > |t|, 0.000) and per capita savings (regression coefficient, 0.0001924; SD, 0.0000566; P > |t|, 0.001) passed the significance test at the level of 1%.They are the two economic indicators that have the greatest impact on TB registered incidence. Through the threshold test, we selected the per capita savings as the threshold variable. In the three stages of per capita savings (<9772.8086 China Yuan(CNY); 9772.8086-33,835.5391 CNY; >33,835.5391 CNY), rural per capita income always has a significant negative impact on the TB registered incidence (The regression coefficients are - 0.0015682, - 0.0028132 and - 0.0022253 respectively. P is 0.007,0.000 and 0.000 respectively.).In cities with good economies, TB registered incidence was 38.30% in 2006 and dropped to 25.10% by 2017. In cities with moderate economies, TB registered incidence peaked in 2008 at 43.10% and dropped to 27.1% by 2017.In poorer cities, TB registered incidence peaked in 2008 at 56.30% and dropped to 28.9% in 2017. CONCLUSION: We found that per capita savings and per capita medical expenditure are most closely related to the TB incidence. Therefore, relevant departments should formulate a more complete medical system and medical insurance policy to effectively solve the problem of "difficult and expensive medical treatment". In order to further reduce the TB incidence, in addition to timely and accurate diagnosis and treatment, it is more important for governments to increase investment in medicine and health care.

Hypoglycemic Effects of Oat Oligopeptides in High-Calorie Diet/STZ-Induced Diabetic Rats.

The study was aimed to determine whether treatment with oat oligopeptides (OOPs) could modulate hyperglycemia related to type 2 diabetes mellitus (T2DM) in Sprague⁻Dawley (SD) rats. Diabetic SD rats modeling by a joint effect of high-calorie diet for 45 days and twice intraperitoneal injection of 30 mg/kg streptozotocin at one-week interval were observed with or without OOPs administration (0.25, 0.50, 1.00, and 2.00 g/kg Body Weight) for 12 weeks. Fasting blood glucose (FBG), oral glucose test tolerance (OGTT), serum insulin, level of antioxidant, and hepatic enzymes were measured. In addition, frequency of micturition was recorded in this study for the first time. It was observed that the administration of OOPs (2.00 g/kg Body Weight) resulted in a significant decrease (p < 0.05) in FBG since 6th week and a significant decrease (p < 0.05) in the OGTT-AUC on 6th and 10th week. In addition, the administration of OOPs (2.00 g/kg Body Weight) reduced HOMA-IR index and 24-h urine volume significantly (p < 0.05) whereas increased SOD activity significantly (p < 0.05). These results suggested that OOPs may have a hypoglycemic effect in diabetic rats.

Overexpression of microRNA-138 alleviates human coronary artery endothelial cell injury and inflammatory response by inhibiting the PI3K/Akt/eNOS pathway.

This study aimed to investigate the role of miR-138 in human coronary artery endothelial cell (HCAEC) injury and inflammatory response and the involvement of the PI3K/Akt/eNOS signalling pathway. Oxidized low-density lipoprotein (OX-LDL)-induced HCAEC injury models were established and assigned to blank, miR-138 mimic, miR-138 inhibitor, LY294002 (an inhibitor of the PI3K/Akt/eNOS pathway), miR-138 inhibitor + LY294002 and negative control (NC) groups. qRT-PCR and Western blotting were performed to detect the miR-138, PI3K, Akt and eNOS levels and the protein expressions of PI3K, Akt, eNOS, p-Akt, p-eNOS, Bcl-2, Bax and caspase-3. ELISAs were employed to measure the expressions of TNF-α, IL-4, IL-6, IL-8, IL-10 and nitric oxide (NO) and the activities of lactate dehydrogenase (LDH) and eNOS. MTT and flow cytometry were performed to assess the proliferation and apoptosis of HCAECs. Compared to the blank group, PI3K, Akt and eNOS were down-regulated in the miR-138 mimic and LY294002 groups but were up-regulated in the miR-138 inhibitor group. The miR-138 mimic and LY294002 groups showed decreased concentrations of TNF-α, IL-6, IL-8 and NO and reduced activities of LDH and eNOS, while opposite trends were observed in the miR-138 inhibitor group. The concentrations of IL-4 and IL-10 increased in the miR-138 mimic and LY294002 groups but decreased in the miR-138 inhibitor group. The miR-138 mimic and LY294002 groups had significantly decreased cell proliferation and increased cell apoptosis compared to the blank group. These findings indicate that up-regulation of miR-138 alleviates HCAEC injury and inflammatory response by inhibiting the PI3K/Akt/eNOS signalling pathway.

Fine regulation of ARF17 for anther development and pollen formation.

BACKGROUND: In Arabidopsis, the tapetum and microsporocytes are critical for pollen formation. Previous studies have shown that ARF17 is expressed in microsporocytes and tetrads and directly regulates tetrad wall synthesis for pollen formation. ARF17 is the direct target of miR160, and promoterARF17::5mARF17 (5mARF17/WT) transgenic plants, which have five silent mutations within the miR160-complementary domain, are sterile. RESULTS: Here, we found that ARF17 is also expressed in the tapetum, which was defective in arf17 mutants. Compared with arf17 mutants, 5mARF17/WT plants had abnormal tapetal cells and tetrads but were less vacuolated in the tapetum. Immunocytochemical assays showed that the ARF17 protein over-accumulated in tapetum, microsporocytes and tetrads of 5mARF17/WT plants at early anther stages, but its expression pattern was not affected during anther development. 5mARF17 driven by its native promoter did not rescue the arf17 male-sterile phenotype. The expression of 5mARF17 driven by the tapetum-specific promoter A9 led to a defective tapetum and male sterility in transgenic plants. These results suggest that the overexpression of ARF17 in the tapetum and microsporocytes of 5mARF17/WT plants leads to male sterility. Microarray data revealed that an abundance of genes involved in transcription and translation are ectopically expressed in 5mARF17/WT plants. CONCLUSIONS: Our work shows that ARF17 plays an essential role in anther development and pollen formation, and ARF17 expression under miR160 regulation is critical for its function during anther development.

MeCP2 enforces Foxp3 expression to promote regulatory T cells' resilience to inflammation.

Forkhead box P3(+) (Foxp3(+)) regulatory T cells (Tregs) are crucial for peripheral tolerance. During inflammation, steady Foxp3 expression in Tregs is essential for maintaining their lineage identity and suppressive function. However, the molecular machinery governing Tregs' resilience to inflammation-induced Foxp3 destabilization remains elusive. Here, we demonstrate that methyl-CpG binding protein 2 (MeCP2), an eminent epigenetic regulator known primarily as the etiological factor of Rett syndrome, is critical to sustain Foxp3 expression in Tregs during inflammation. In response to inflammatory stimuli, MeCP2 is specifically recruited to the Conserved Non-Coding sequence 2 region of the foxp3 locus, where it collaborates with cAMP responsive element binding protein 1 to promote local histone H3 acetylation, thereby counteracting inflammation-induced epigenetic silencing of foxp3. Consequently, Treg-specific deletion of MeCP2 causes spontaneous immune activation in mice and failure in protection against autoimmunity. Furthermore, we demonstrate that Foxp3 expression in MeCP2-deficient Tregs diminishes with time, resulting in their failure to suppress effector T-cell-mediated colitis. Thus, MeCP2 serves as a critical safeguard that confers Tregs with resilience against inflammation.

miR-17-92 cluster targets phosphatase and tensin homology and Ikaros Family Zinc Finger 4 to promote TH17-mediated inflammation.

The miR-17-92 cluster regulates a broad spectrum of biological processes of T cell immunity. This cluster was found to facilitate T cell proliferation, enhance antitumor activities and promote T cell-dependent antibody responses. However, little is known about the role of this miRNA cluster in the development of autoimmune diseases. Multiple sclerosis is a neuro-destructive autoimmune disease caused by the pathogenicity of TH17 cells, whose differentiation is tightly controlled by a variety of transcriptional and post-transcriptional regulators. Our study unveils the critical role of miR-17-92 in TH17 differentiation: T cell-specific miR-17-92 deficiency reduced TH17 differentiation and ameliorated experimental autoimmune encephalomyelitis (EAE) symptoms. We demonstrated that miR-17 and miR-19b are the two miRNAs in this cluster responsible for promoting TH17 responses. MiR-19b represses the expression of Phosphatase and Tensin Homology (PTEN), thereby augmenting the PI3K-AKT-mTOR axis essential for proper TH17 differentiation. Meanwhile, miR-17 enhances TH17 polarization by inhibiting a novel target, Ikaros Family Zinc Finger 4 (IKZF4). By establishing the miR-17-92 cluster as a key driver of TH17 responses, our data identify this miRNA cluster as a potential therapeutic target for the clinical intervention of multiple sclerosis.

[Validation of subjective and objective evaluation methods for orthodontic treatment outcome].

OBJECTIVE: To assess the correlations between objective measurements of 108 finished orthodontic cases and subjective assessments made by 69 orthodontic specialists, to explore the statistically significant measuring categories of cast and cephalogram and to validate the regression model. METHODS: A stratified random sample of 108 cases was drawn from the large sample of 2 383 patients who finished orthodontic treatment between July 2006 and August 2008 in six orthodontic treatment centers around China. For each patient, the post-treatment information sources evaluated in this study included standardized plaster study casts and a lateral cephalometric X-ray image. These information sources were evaluated both singly and in combination by a panel of 69 orthodontic specialists. The average subjective grading scores of 69 orthodontists were regarded as the gold standard. Six examiners used the peer assessment rating (PAR) index and American board of orthodontics-objective grading system (ABO-OGS) to measure all the study casts respectively and three other examiners measured all the lateral cephalometric X-ray images by using customized software. The objective measuring data were correlated with the gold standard. The correlations between the objective measurement and the subjective evaluation were assessed, the statistically significant measuring categories of cast and cephalogram were explored and the regression model was validated. RESULTS: The ABO-OGS scores of "occlusal relationship" correlated most strongly with the subjective scores of cast (r=0.655, P<0.01), and the secondarily correlated category with those were the PAR scores of "overjet" (r=0.525, P<0.01). The proclination of the lower incisors correlated most strongly with the subjective scores of cephalogram (r=0.446, P<0.01), and the secondarily correlated category with those was the protrusion of the lower lips (r=0.436, P<0.01). Nine components were predictive for the post-treatment model and lateral ephalometric film (Post-M+C) outcome: alignment (ABO-OGS), occlusal relationship (ABO-OGS), interproximal contact(ABO-OGS), L1/NB°, overjet (PAR), SNB°, occlusal contacts (ABO-OGS), U1/SN2° and centerline (PAR). These 9 components accounted for 72% of the variability in the average subjective grading scores. CONCLUSION: The objective regression model could replace the averaged opinion of Chinese orthodontic experts effectively, making objective assessment of orthodontic treatment outcome for Chinese patients.