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Background/Objectives: Fatty acids are involved in some hepatic disorders. The proprotein convertase subtilisin kexin 9 (PCSK9) inhibits the uptake of low-density lipoproteins (LDLs), which contain lipids, into the liver and may thus be associated with nonalcoholic fatty liver disease (NAFLD), a cardiovascular disorder (CVD) risk. Statins reduce blood LDL–cholesterol (LDL-C) levels and CVD risk and can attenuate the development of NAFLD while increasing blood PCSK9 levels. Methods: We investigated the correlation between PCSK9 and liver conditions in patients with familial hypercholesterolemia (FH), a CVD risk population with elevated blood LDL-C levels, under statin treatment. Blood tests for lipids, PCSK9, and liver function (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) were performed in patients with FH taking statins (n = 25, mean age = 57 years, 12% of males). The ALT:AST ratio was used as a marker of NAFLD risk. Results: The mean LDL-C level was 3.38 mmol/L, and the median PCSK9 level was 312 ng/mL. The median ALT:AST ratio was 0.88. A significant negative correlation was observed between the PCSK9 and ALT:AST ratio (β = −0.67, p < 0.05). Conclusions: Their negative correlation might give a hypothetical insight into the effect of statin treatment on the development of NAFLD, in relation to PCSK9 behavior, in patients with FH. [ABSTRACT FROM AUTHOR]

Transcriptional latency of HIV is a last barrier to viral eradication. Chromatin-remodeling complexes and post-translational histone modifications likely play key roles in HIV-1 reactivation, but the underlying mechanisms are incompletely understood. We performed an RNAi-based screen of human lysine methyltransferases and identified the SET and MYND domain-containing protein 2 (SMYD2) as an enzyme that regulates HIV-1 latency. Knockdown of SMYD2 or its pharmacological inhibition reactivated latent HIV-1 in T cell lines and in primary CD4+ T cells. SMYD2 associated with latent HIV-1 promoter chromatin, which was enriched in monomethylated lysine 20 at histone H4 (H4K20me1), a mark lost in cells lacking SMYD2. Further, we find that lethal 3 malignant brain tumor 1 (L3MBTL1), a reader protein with chromatin-compacting properties that recognizes H4K20me1, was recruited to the latent HIV-1 promoter in a SMYD2-dependent manner. We propose that a SMYD2-H4K20me1-L3MBTL1 axis contributes to HIV-1 latency and can be targeted with small-molecule SMYD2 inhibitors.

BackgroundPrevious reports have shown that lipoprotein lipase (LPL) activity significantly increases in the postprandial plasma associated with the increase of TG-rich lipoproteins. Therefore, we have reexamined those relationships using newly developed LPL assay with the different kinds of food intake.MethodsStandard meal (n=81), 50g of fat (n=54), 75g of glucose (n=25) and cookie (25g fat and 75g carbohydrate fat) (n=28) were administered in generally healthy volunteers. Plasma LPL, HTGL and TC, TG, LDL-C, HDL-C, RLP-C and RLP-TG were determined at subsequent withdrawal after the food intake.ResultsPlasma TG, RLP-C and RLP-TG were significantly increased at 8PM (2h after dinner of standard meal) compared with 8AM before breakfast within the same day. Also those parameters were significantly increased in 2-6h after fat load. However, the concentrations and activities of LPL and HTGL did not significantly increase in association with an increase in the TG and remnant lipoproteins. Also LPL concentration did not significantly increase after glucose and "cookie test" within 4h.ConclusionNo significant increase of LPL activity was found at CM and VLDL overload after different kinds of food intake when reexamined by newly developed assay for LPL activity and concentration.

Background: Supporting smoking cessation at pharmacies can be challenging owing to difficulties in recruiting smokers to participate in cessation programs, insufficient communication skills among pharmacists, and lack of knowledge and self-efficacy in successfully quitting smoking in Japan. Objective: This study evaluates the effectiveness of a smoking cessation training program on community pharmacists' knowledge, attitude, and self-efficacy in supporting smoking cessation. Methods: The study, conducted in Japanese pharmacies with 100 community pharmacists, employed a quasi-experimental design. Two online training programs were implemented. Participants completed a web-based survey assessing their knowledge, attitude, and self-efficacy in supporting smoking cessation before, immediately after, and 1 year after the training program. A two-way analysis of variance with a mixed model was used to examine score changes at each time point. Results: Total knowledge scores significantly increased between baseline and immediately after training and baseline and 1 year after training. The total attitude scores between baseline and immediately after training differed significantly. However, no differences were noted between baseline and 1 year after training. Total self-efficacy scores significantly increased at baseline, immediately after training, and between baseline and 1 year after training. Despite no significant interactions between the programs, there was a partial interaction effect on knowledge, with only the customized program having items whose knowledge levels improved after 1 year. Conclusion and Relevance: The training program improved community pharmacists' knowledge, attitude, and self-efficacy regarding smoking cessation support. The customized program must be reinforced to improve support performance and maintain attitude. [ABSTRACT FROM AUTHOR]

Aims: Oral candidosis is common in patients with end‐of‐life cancer; however, its prognosis is unclear. We aimed to assess oral candidosis and Candida species as prognostic indicators in palliative care for these patients. Methods: We consecutively included palliative care patients, assessed for candidosis via microbiological techniques, and classified into three groups by the extent of oral lesions. The association between oral candidosis and overall survival was assessed using a Cox proportional hazards model adjusted by performance status (PS). Results: We studied 142 patients (median age 77; 52.8% women) with a 76.1% oral candidosis prevalence. Candida albicans (80.6%) was the most common species. Oral lesions were classified as none, grade 1 (28.7%), or ≥ grade 2 (14.8%). During follow‐up, Cox models identified ≥grade 2 lesions (aHR = 2.04; 95% CI: 1.18–3.54; p =.011) and Candida tropicalis (aHR = 2.38; 95% CI: 1.03–5.55; p =.044) as predictors. Conclusion: The extent of oral candidosis lesions or the presence of C. tropicalis may serve as prognostic indicator in patients with end‐of‐life cancer. Therefore, solely concentrating on the prevalence and frequency of fungal species may be insufficient for predicting life prognosis; it is advisable to assess these parameters through both visual examination and culture. [ABSTRACT FROM AUTHOR]

The HIV-1 transactivator protein Tat is a critical regulator of HIV transcription primarily enabling efficient elongation of viral transcripts. Its interactions with RNA and various host factors are regulated by ordered, transient post-translational modifications. Here, we report a novel Tat modification, monomethylation at lysine 71 (K71). We found that Lys-71 monomethylation (K71me) is catalyzed by KMT7, a methyltransferase that also targets lysine 51 (K51) in Tat. Using mass spectrometry, in vitro enzymology, and modification-specific antibodies, we found that KMT7 monomethylates both Lys-71 and Lys-51 in Tat. K71me is important for full Tat transactivation, as KMT7 knockdown impaired the transcriptional activity of wild type (WT) Tat but not a Tat K71R mutant. These findings underscore the role of KMT7 as an important monomethyltransferase regulating HIV transcription through Tat.

Aims: To determine the Oral Health Assessment Tool (OHAT) critical score in palliative care patients and the optimal timing for predicting mortality using time‐dependent receiver operating characteristic (ROC) curves. Methods and Results: A retrospective observational study was conducted on 176 patients treated by the palliative care team of our medical center between April 2017 and March 2020. Oral health was assessed using the OHAT. Prediction accuracy was evaluated using the area under the curve (AUC) analysis, sensitivity, and specificity, using time‐dependent ROC curves. Overall survival (OS) was compared using Kaplan‐Meier curves with the log‐rank test; hazard ratios (HRs) adjusted for covariates were calculated using a Cox proportional hazard model. A OHAT score of 6 was shown to best predict 21‐day OS (AUC 0.681, sensitivity 42.2%, specificity 80.0%). The median OS was significantly shorter in patients with total OHAT scores ≥6 than in patients with scores < 6 (21 days vs. 43 days, p =.017). For individual OHAT items, the unhealthy status of the lips and tongue was associated with decreased OS (HR = 1.91; 95% confidence interval [CI], 1.19–3.05 and adjusted HR = 1.48; 95% CI, 1.00–2.20). Conclusion: Predicting disease prognosis based on patient oral health can enable clinicians to provide timely treatment. [ABSTRACT FROM AUTHOR]

Background: Omega-3 fatty acid supplementation has been shown to help maintain muscle function and reduce muscle soreness after exercise-induced muscle damage. However, the relationship between the dietary and biological status of omega-3 fatty acids in rugby players remains unclear. Objectives: This study aimed to investigate the connection between the dietary and biological status of omega-3 fatty acids in university rugby players. Methods: We conducted a cross-sectional study involving university rugby players and age-matched sedentary controls. We assessed diets, including omega-3 and omega-6 polyunsaturated fatty acids, using self-administered dietary questionnaires. Whole blood lipidomics was performed before and after a single training session. Results: The rugby group (n = 29) had significantly higher intakes of omega-3 and omega-6 fatty acids compared to the control group (n = 31). While the blood omega-6 relative concentration did not differ between the groups, the rugby group had lower omega-3 fatty acid levels than the control group (4.4 ± 1.1 vs. 6.2 ± 1.8%). Approximately 48% of rugby players had an omega-3 index (O3i) considered as high risk for cardiovascular disease, and 52% were classified as intermediate risk. None of the players had a low-risk O3i. A single training session had an impact on the omega-3 and omega-6 metabolic pathways. Conclusions: Despite having a higher omega-3 fatty acid intake than controls, rugby football players may still be deficient in omega-3 fatty acids. Further nutritional interventions are needed to address these issues. [ABSTRACT FROM AUTHOR]

The essential transactivator function of the HIV Tat protein is regulated by multiple posttranslational modifications. Although individual modifications are well characterized, their crosstalk and dynamics of occurrence during the HIV transcription cycle remain unclear.We examine interactions between two critical modifications within the RNA-binding domain of Tat: monomethylation of lysine 51 (K51) mediated by Set7/9/KMT7, an early event in the Tat transactivation cycle that strengthens the interaction of Tat with TAR RNA, and acetylation of lysine 50 (K50) mediated by p300/KAT3B, a later process that dissociates the complex formed by Tat, TAR RNA and the cyclin T1 subunit of the positive transcription elongation factor b (P-TEFb). We find K51 monomethylation inhibited in synthetic Tat peptides carrying an acetyl group at K50 while acetylation can occur in methylated peptides, albeit at a reduced rate. To examine whether Tat is subject to sequential monomethylation and acetylation in cells, we performed mass spectrometry on immunoprecipitated Tat proteins and generated new modification-specific Tat antibodies against monomethylated/acetylated Tat. No bimodified Tat protein was detected in cells pointing to a demethylation step during the Tat transactivation cycle. We identify lysine-specific demethylase 1 (LSD1/KDM1) as a Tat K51-specific demethylase, which is required for the activation of HIV transcription in latently infected T cells. LSD1/KDM1 and its cofactor CoREST associates with the HIV promoter in vivo and activate Tat transcriptional activity in a K51-dependent manner. In addition, small hairpin RNAs directed against LSD1/KDM1 or inhibition of its activity with the monoamine oxidase inhibitor phenelzine suppresses the activation of HIV transcription in latently infected T cells.Our data support the model that a LSD1/KDM1/CoREST complex, normally known as a transcriptional suppressor, acts as a novel activator of HIV transcription through demethylation of K51 in Tat. Small molecule inhibitors of LSD1/KDM1 show therapeutic promise by enforcing HIV latency in infected T cells.

Lifestyle interventions have been shown to prevent or delay the onset of diabetes; however, inter-individual variability in responses to such interventions makes lifestyle recommendations challenging. We analyzed the Japan Diabetes Outcome Intervention Trial-1 (J-DOIT1) study data using a previously published mechanistic simulation model of type 2 diabetes onset and progression to understand the causes of inter-individual variability and to optimize dietary intervention strategies at an individual level. J-DOIT1, a large-scale lifestyle intervention study, involved 2607 subjects with a 4.2-year median follow-up period. We selected 112 individuals from the J-DOIT1 study and calibrated the mechanistic model to each participant's body weight and HbA1c time courses. We evaluated the relationship of physiological (e.g., insulin sensitivity) and lifestyle (e.g., dietary intake) parameters with variability in outcome. Finally, we used simulation analyses to predict individually optimized diets for weight reduction. The model predicted individual body weight and HbA1c time courses with a mean (±SD) prediction error of 1.0 kg (±1.2) and 0.14% (±0.18), respectively. Individuals with the most and least improved biomarkers showed no significant differences in model-estimated energy balance. A wide range of weight changes was observed for similar model-estimated caloric changes, indicating that caloric balance alone may not be a good predictor of body weight. The model suggests that a set of optimal diets exists to achieve a defined weight reduction, and this set of diets is unique to each individual. Our diabetes model can simulate changes in body weight and glycemic control as a result of lifestyle interventions. Moreover, this model could help dieticians and physicians to optimize personalized nutritional strategies according to their patients' goals. [ABSTRACT FROM AUTHOR]