Molecular mechanisms involved in epidermal growth factor receptor-mediated inhibition of dopamine D3 receptor signaling.

The phenomenon wherein the signaling by a given receptor is regulated by a different class of receptors is termed transactivation or crosstalk. Crosstalk between receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) is highly diverse and has unique functional implications because of the distinct structural features of the receptors and the signaling pathways involved. The present study used the epidermal growth factor receptor (EGFR) and dopamine D3 receptor (D3R), which are both associated with schizophrenia, as the model system to study crosstalk between RTKs and GPCRs. Loss-of-function approaches were used to identify the cellular components involved in the tyrosine phosphorylation of G protein-coupled receptor kinase 2 (GRK2), which is responsible for EGFR-induced regulation of the functions of D3R. SRC proto-oncogene (Src, non-receptor tyrosine kinase), heterotrimeric G protein Gßγ subunit, and endocytosis of EGFR were involved in the tyrosine phosphorylation of GRK2. In response to EGF treatment, Src interacted with EGFR in a Gßγ-dependent manner, resulting in the endocytosis of EGFR. Internalized EGFR in the cytosol mediated Src/Gßγ-dependent tyrosine phosphorylation of GRK2. The binding of tyrosine-phosphorylated GRK2 to the T142 residue of D3R resulted in uncoupling from G proteins, endocytosis, and lysosomal downregulation. This study identified the molecular mechanisms involved in the EGFR-mediated regulation of the functions of D3R, which can be extended to the crosstalk between other RTKs and GPCRs.

Palmitoylation on the carboxyl terminus tail is required for the selective regulation of dopamine D2 versus D3 receptors.

Dopamine D2 receptor (D2R) and D3 receptor (D3R) possess highly conserved amino acid sequences but this study showed that D3R was more extensively palmitoylated than D2R. Based on this finding, the molecular basis of this selective palmitoylation of D3R was determined and the roles of palmitoylation in the regulation of D3R functions were investigated. D3R was palmitoylated on the cysteine residue on its carboxyl terminus tail, the last amino acid residue of D3R, and an exchange of the carboxyl terminus tail between D2R and D3R (D2R-D3C and D3R-D2C) resulted in the switching of the palmitoylation phenotype. When the consensus site for palmitoylation was mutated or the palmitoylation of D3R was inhibited by treatment with 2-bromopalmitate (2BP), a palmitoylation blocker, cell-surface expression, PKC-mediated endocytosis, agonist affinity, and agonist-induced tolerance of D3R were all inhibited. However, these changes were not observed when D3R palmitoylation was inhibited by replacing its carboxyl tail with that of D2R (D3R-D2C) or when the palmitoylation of D2R-D3C was inhibited by treatment with 2BP. Overall, this study shows that D3R is palmitoylated more extensively than D2R even though the carboxyl terminus tails of D2R and D3R are highly homologous, and thus provides a new clue regarding the consensus sequence for palmitoylation. This study also shows that palmitoylation controls various functionalities of D3R only when the receptor is in the intact D3R configuration.

An efficient procedure for the expression and purification of HIV-1 protease from inclusion bodies.

Several studies have focused on HIV-1 protease for developing drugs for treating AIDS. Recombinant HIV-1 protease is used to screen new drugs from synthetic compounds or natural substances. However, large-scale expression and purification of this enzyme is difficult mainly because of its low expression and solubility. In this study, we constructed 9 recombinant plasmids containing a sequence encoding HIV-1 protease along with different fusion tags and examined the expression of the enzyme from these plasmids. Of the 9 plasmids, pET32a(+) plasmid containing the HIV-1 protease-encoding sequence along with sequences encoding an autocleavage site GTVSFNF at the N-terminus and TEV plus 6× His tag at the C-terminus showed the highest expression of the enzyme and was selected for further analysis. The recombinant protein was isolated from inclusion bodies by using 2 tandem Q- and Ni-Sepharose columns. SDS-PAGE of the obtained HIV-1 protease produced a single band of approximately 13 kDa. The enzyme was recovered efficiently (4 mg protein/L of cell culture) and had high specific activity of 1190 nmol min(-1) mg(-1) at an optimal pH of 4.7 and optimal temperature of 37 °C. This procedure for expressing and purifying HIV-1 protease is now being scaled up to produce the enzyme on a large scale for its application.

Asbestos dust concentrations and health conditions of workers at asbestos-cement corrugated sheet production manufacturers in Vietnam: a nationwide assessment.

This study examined contemporary concentrations of asbestos dust during production and the health conditions of workers at asbestos-cement corrugated sheet production manufacturers in Vietnam. A nationwide survey was conducted on 28 factories (with 206 air samples) and 2459 workers. Asbestos fiber dust and the health status of workers were assessed. Results showed that 108/206 (52.4%) samples had asbestos fiber dust. The average concentration of asbestos fibers was 0.19 ± 0.14 fibers/ml. The percentage of workers with thickened pleural lesions/pleural calcification nodules was low. More studies are needed to evaluate the effectiveness of biomarkers in preventing the onset of lung cancer and mesothelioma in workers.

MetaAttention model: a new approach for skin lesion diagnosis using AB features and attention mechanism.

Ozone depletion has always been a hot crisis around the globe. Its consequence is the increase in ultraviolet radiation at the surface in many regions and countries, which then causes danger to the human immune system, eyes, and especially skin - the part that is directly exposed most to the sunlight. According to the World Health Organization, the number of cases of skin cancer is higher than that of breast, prostate, and lung cancer combined. Therefore, there has been a lot of research to apply deep learning models in solving the problem of skin cancer classification. This paper proposes a novel approach, named MetaAttention, aimed at improving the performance of transfer learning models for skin lesion classification. The method combines image features with patients' metadata features using the attention mechanism, incorporating clinical knowledge related to ABCD signals to better distinguish melanoma cell carcinoma disease, which has long been a significant challenge for researchers. The experimental results indicate that the proposed approach outperforms the state-of-the-art method, EfficientNet-B4, achieving an accuracy of 89.9% with Scale-dot product MetaAttention and 90.63% with Additive MetaAttention. The method has the potential to support dermatologists in diagnosing skin lesions effectively and efficiently. Furthermore, with larger datasets, our method could be further fine-tuned to achieve even better performance on a broader range of labels.

Non-communicable diseases prevention in remote areas of Vietnam: Limited roles of health education and community workers.

OBJECTIVE: This study aimed to measure the exposure of residents to health education messages about non-communicable diseases (NCD)-related risk factors, and activities of village health workers (VHWs) in NCDs prevention and control in the mountainous setting of Vietnam. METHOD: A cross-sectional study was performed in Dap Thanh commune (Ba Che, Quang Ninh province, Vietnam), a mountainous area. There were 151 residents aged 18 years or above recruited for this study. Information regarding exposure to messages about risk factors of NCDs, and activities of VHWs was collected via face-to-face interviews using a structured questionnaire. Multivariate logistic regression was employed to identify associated factors with exposing messages about NCD-related risk factors. RESULTS: The majority of participants heard about messages related to risk factors of NCDs in the last 30 days, from 56.3% (physical inactivity message), 59.6% (diet message), 75.5% (alcohol use message) to 79.5% (smoking message). Radio/television was the most common source of the messages (from 91.8% to 95.8%) and the majority of participants heard these messages from one source (from 77.1% to 80.9%). Most of sample reported the unavailability of VHWs in their locals (53.6%). Among locals having VHWs, health communication and education was the most common service provided (54.3%); however, only 30% received NCD management services. Participants who had other jobs were less likely to hear about diet-related messages (OR = 0.32; 95%CI = 0.11-0.92), and those ever smoking were more likely to hear these messages in the last 30 days (OR = 6.86; 95%CI = 1.06-44.51). People who had diabetes mellitus were more likely to hear physical activity-related messages in the last 30 days (OR = 2.55; 95%CI = 1.20-5.41). CONCLUSION: Our findings indicated that health communication regarding risk factors of NCDs in mountainous areas in Vietnam was insufficient, and the role of health workers as formal information source was not recognized. Efforts should be made to increase the capacity and involvement of VHWs in health education and NCD prevention in mountainous regions.

Mental health among Vietnamese urban late adolescents: The association of parenting styles.

The aim of this study was to explore the correlation between parental styles and mental problems among Vietnamese high school students. In total, 16.4 percent of 757 eligible participants reported mental difficulties. Findings showed that being female and in grade 12 were risk factors to mental problems while living in Hue city was likely as a protective factor. The father's warmth reduced the risk of having mental problems among adolescents, while an overprotective mother increased the risk. There was no correlation between authoritarianism of both mother and father and mental difficulties. These results suggest that a parenting program for parents might reduce the risk of mental problems among Vietnamese youth.

Increased risk of preterm birth among non- smoking, non- alcohol drinking women with maternal periodontitis.

The aim of this case-control study was to examine the association between periodontitis and preterm birth among non-smoking, non-alcohol drinking women. The cases were 130 women who delivered a live singleton newborn before 37 weeks gestation. A random sample of 260 women who delivered a normal child on the same day as the cases were selected as controls. Periodontal examinations were performed during 24-hour period postpartum at bedside. Other related information was collected by structured questionnaire and medical records. Multiple logistic regression analysis was performed controlling for age, ethnicity, place of residence, education, occupation, income, pre-pregnancy body mass index (BMI), weight gain, antenatal care (ANC), parity, systematic infections, genitourinary infections, antibiotics used, and history of periodontal treatment. Periodontitis (defined as presence of at least 4 teeth having > or = 1 site with a probing depth (PD) > or = 4 mm, clinical attachment loss (CAL) > or = 3 mm and bleeding on probing (BOP) after 10 seconds at the same site) was diagnosed in 33.9% of cases and 10.4% of controls. Periodontitis was significantly associated with preterm birth (adjusted OR = 4.47, 95%Cl= 2.43, 8.20). These findings suggest that periodontitis may increase the risk of preterm delivery even among women who do not smoke or drink.

Dual regulation of mast cell degranulation through IgE receptor-mediated modulation of M2-type pyruvate kinase.

It was reported that mast cell degranulation is inversely related to the enzymatic activity of M2-type pyruvate kinase (M2PK). This study shows that activation of high-affinity IgE receptor (FcεRI) evokes a sequential dual regulation of M2PK, i.e., an immediate decrement followed by slow phase increment of enzymatic activities. Changes in the activities of M2PK and mast cell degranulation showed similar time course after antigenic stimulation of FcεRI. The immediate inhibition of M2PK involved tyrosine phosphorylation, and subsequently led to a cellular accumulation of glycolytic intermediates, including fructose 1,6-biphosphate (FBP), a feedforward activator of M2PK. As the cellular levels of FBP were increased, both the enzymatic acitivity of M2PK and mast cell degranulation slowly returned to near basal levels. A-Raf, when exogenously introduced into RBL-2H3 cells, phosphorylated M2PK on the serine residues, elevated enzyme activities of M2PK, and resulted in the inhibition of degranulation. These results suggest that dual regulation of M2PK which involves the phosphorylation of M2PK and accumulation of a feedforward activator of M2PK plays important roles in the control of mast cell degranulation.