Methods for Monitoring NCOA4-Mediated Ferritinophagy.

Ferritinophagy is a selective form of autophagy in which ferritin, the primary intracellular iron storage protein complex, is targeted by NCOA4 (Nuclear receptor coactivator 4) to the lysosome for degradation. NCOA4-mediated ferritinophagy plays a crucial role in cellular iron metabolism, influencing iron homeostasis, heme synthesis, mitochondrial respiratory function, and ferroptosis, an iron-dependent form of cell death. Targeting ferritinophagy has emerged as a potential anticancer therapeutic strategy. In this context, we provide a flowchart of the procedures and accompanying protocols for monitoring ferritinophagic flux.

Bridging the gap: Multi-omics profiling of brain tissue in Alzheimer's disease and older controls in multi-ethnic populations.

INTRODUCTION: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked Black Americans (BA) and Latin Americans (LA), who are disproportionately affected by AD. METHODS: To bridge this gap, Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTS: We generated multi-omics data and curated and harmonized phenotypic data from BA (n = 306), LA (n = 326), or BA and LA (n = 4) brain donors plus non-Hispanic White (n = 252) and other (n = 20) ethnic groups, to establish a foundational dataset enriched for BA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSION: The inclusion of traditionally underrepresented groups in multi-omics studies is essential to discovering the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD. HIGHLIGHTS: Accelerating Medicines Partnership in Alzheimer's Disease Diversity Initiative led brain tissue profiling in multi-ethnic populations. Brain multi-omics data is generated from Black American, Latin American, and non-Hispanic White donors. RNA, whole genome sequencing and tandem mass tag proteomicsis completed and shared. Multiple brain regions including caudate, temporal and dorsolateral prefrontal cortex were profiled.

New α-glucosidase inhibitory xanthones from the fruits of Garcinia schomburgkiana.

Two previously unreported xanthones, xanthoschomes A and B (1 and 2), along with six known xanthones, α-mangostin (3), ß-mangostin (4), γ-mangostin (5), garcinone C (6), 2-(γ,γ-dimethylallyl)-1,7-dihydroxy-3-methoxyxanthone (7), and dulxanthone D (8), have been isolated from the fruits of Vietnamese Garcinia schomburgkiana. The structures of all isolated compounds were fully characterised using spectroscopic data and comparison with the previous literature. All isolated compounds were evaluated for their in vitro α-glucosidase inhibitory activity. Compounds 1-8 demonstrated effective α-glucosidase inhibition, with the IC50 ranging from 2.91 to 26.0 µM, outperforming the standard acarbose (IC50 179 µM). Among these isolated compounds, compound 8 exhibited the highest inhibitory activity against α-glucosidase, with an IC50 value of 2.91 µM.

Structural basis for the intracellular regulation of ferritin degradation.

The interaction between nuclear receptor coactivator 4 (NCOA4) and the iron storage protein ferritin is a crucial component of cellular iron homeostasis. The binding of NCOA4 to the FTH1 subunits of ferritin initiates ferritinophagy-a ferritin-specific autophagic pathway leading to the release of the iron stored inside ferritin. The dysregulation of NCOA4 is associated with several diseases, including neurodegenerative disorders and cancer, highlighting the NCOA4-ferritin interface as a prime target for drug development. Here, we present the cryo-EM structure of the NCOA4-FTH1 interface, resolving 16 amino acids of NCOA4 that are crucial for the interaction. The characterization of mutants, designed to modulate the NCOA4-FTH1 interaction, is used to validate the significance of the different features of the binding site. Our results explain the role of the large solvent-exposed hydrophobic patch found on the surface of FTH1 and pave the way for the rational development of ferritinophagy modulators.

Bridging the Gap: Multi-Omics Profiling of Brain Tissue in Alzheimer's Disease and Older Controls in Multi-Ethnic Populations.

INTRODUCTION: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD. METHODS: To bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTS: We generated multi-omics data and curated and harmonized phenotypic data from AA (n=306), LA (n=326), or AA and LA (n=4) brain donors plus Non-Hispanic White (n=252) and other (n=20) ethnic groups, to establish a foundational dataset enriched for AA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSION: Inclusion of traditionally underrepresented groups in multi-omics studies is essential to discover the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD.

Hydrogen Sulfide and Liver Health: Insights into Liver Diseases.

Significance: Hydrogen sulfide (H2S) is a recently recognized gasotransmitter involved in physiological and pathological conditions in mammals. It protects organs from oxidative stress, inflammation, hypertension, and cell death. With abundant expression of H2S-production enzymes, the liver is closely linked to H2S signaling. Recent Advances: Hepatic H2S comes from various sources, including gut microbiota, exogenous sulfur salts, and endogenous production. Recent studies highlight the importance of hepatic H2S in liver diseases such as nonalcoholic fatty liver disease (NAFLD), liver injury, and cancer, particularly at advanced stages. Endogenous H2S production deficiency is associated with severe liver disease, while exogenous H2S donors protect against liver dysfunction. Critical Issues: However, the roles of H2S in NAFLD, liver injury, and liver cancer are still debated, and its effects depend on donor type, dosage, treatment duration, and cell type, suggesting a multifaceted role. This review aimed to critically evaluate H2S production, metabolism, mode of action, and roles in liver function and disease. Future Direction: Understanding H2S's precise roles and mechanisms in liver health will advance potential therapeutic applications in preclinical and clinical research. Targeting H2S-producing enzymes and exogenous H2S sources, alone or in combination with other drugs, could be explored. Quantifying endogenous H2S levels may aid in diagnosing and managing liver diseases. Antioxid. Redox Signal. 40, 122-144.

A unique genetic variation with respect to blast (Pyricularia oryzae Cavara) resistance in rice (Oryza sativa L.) varieties in Vietnam.

A unique genetic variation with respect to blast resistance was clarified in 201 rice accessions from Vietnam. These accessions were classified into three clusters-A, B1, and B2-based on their reactions to 26 standard differential blast isolates selected in Vietnam. Cluster A was the dominant cultivar group in Vietnam and the most susceptible of the three clusters. Cluster B1 was the smallest group and the most resistant. Cluster B2 was the second-most dominant group and of intermediate resistance between clusters A and B1. The percentages of accessions comprising each cluster varied by region and area. Accessions in cluster A were distributed widely throughout Vietnam and had the highest frequencies in both the Central and North regions. Accessions in cluster B2 were found with highest frequencies in the mountainous and intermediate areas of the North region. Accessions in cluster B1 were found with highest frequencies in the Central region and Red River Delta area (North region). These results suggest that rice accessions in Vietnam were basically susceptible (cluster A) or of intermediate resistance (cluster B2), and that high-resistance cultivars were mainly distributed in the low altitude areas, such as the Red River Delta area and Central region.

A Rare Presentation of Rhodococcus Equi Bacteremia as a Result of Right Upper Arm Cellulitis: A Case Report and Literature Review.

Rhodococcus equi is an emerging opportunistic pathogen in immunocompromised patients. Owing to its resemblance to Mycobacterium, Nocardia, and Corynebacterium, R. equi is frequently misdiagnosed as a contaminant, which can result in treatment delays. A 65-year-old man with a history of end-stage renal disease (ESRD) presented to the emergency room with pain and increased swelling in his right upper extremity. Shortly after he arrived in the emergency room, his condition deteriorated. Intravenous vancomycin was administered after collecting blood cultures. The blood cultures grew Rhodococcus equi, and oral azithromycin and oral rifampin were added for a 14-day course of treatment. The patient recovered without any further complications and was subsequently discharged home.  R. equi is a partially acid-fast actinomycete that spreads through contact with grazing animals and contaminated soil. R. equi invades macrophages to survive and causes infection within a host. In this particular case, the patient worked on a farm taking care of goats. He was exposed to the bacteria after falling and sustaining multiple lacerations to the right arm. This case is unique due to the development of bacteremia with R. equi, an uncommon cause of bacteremia that led to cardiopulmonary arrest. The treatment with oral azithromycin combined with oral rifampin and intravenous vancomycin was effective for the complete resolution of the infection.

The influence of smoking on oral neutrophils and matrix metalloproteinase-8 in periodontitis patients before and after nonsurgical treatment.

Objective: To evaluate and compare the oral neutrophil numbers (ONN) in saliva, the level of matrix metalloproteinase-8 (MMP-8) in gingival crevicular fluid (GCF) and the periodontal parameters in smokers versus non-smokers with periodontitis, before and after nonsurgical periodontal treatment (NSPT). Materials and method: 40 chronic periodontitis patients including 20 smokers and 20 non-smokers were enrolled in this quasi-experimental study. All patients were received the NSPT included instructing oral hygiene, scaling and root planing. At baseline (T0) and after NSPT 1 month (T1) and 3 months (T3), all patients were assessed for salivary ONN, GCF MMP-8, and clinical parameters like plaque index (PlI), gingival index (GI), bleeding on probing (BOP), probing pocket depth (PPD) and clinical attachment loss (CAL). The differences between the two groups were analyzed using the independent sample t-test and the Mann-Whitney U test; and the differences between T0, T1 and T3 of each group were analyzed with paired-samples t-test and Wilcoxon signed-rank test. The level of significance was set at 0.05. Results: The ONN was significantly less in smokers than in non-smokers although there was no significant difference in other parameters between the two groups at baseline (p > 0.05). All clinical periodontal parameters reduced significantly after 1 month and 3 months of NSPT in both groups (p < 0.01). PPD of non-smokers was significantly lower than those of smokers at T1 and T3. ONN and MMP-8 level showed a significant decrease in non-smoking subjects, while there was no significant difference in smoking ones after NSPT (T1 and T3). At 1 month after treatment, ONN tended to reduce in non-smokers whereas to increase in smokers significantly. Conclusion: Smoking reduced ONN, impaired treatment effect in reducing PPD, and changed the MMP-8 level in gingival crevicular fluid to NSPT. Trial registration: Identifier NCT04974502 in CLinicalTrials.gov.

Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer's disease related proteins.

BACKGROUND: Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aß) plaques and neurofibrillary tangles. The main protein components of these hallmarks include Aß40, Aß42, tau, phosphor-tau, and APOE. We hypothesize that genetic variants influence the levels and solubility of these AD-related proteins in the brain; identifying these may provide key insights into disease pathogenesis. METHODS: Genome-wide genotypes were collected from 441 AD cases, imputed to the haplotype reference consortium (HRC) panel, and filtered for quality and frequency. Temporal cortex levels of five AD-related proteins from three fractions, buffer-soluble (TBS), detergent-soluble (Triton-X = TX), and insoluble (Formic acid = FA), were available for these same individuals. Variants were tested for association with each quantitative biochemical measure using linear regression, and GSA-SNP2 was used to identify enriched Gene Ontology (GO) terms. Implicated variants and genes were further assessed for association with other relevant variables. RESULTS: We identified genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. CONCLUSIONS: Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.

Integration of Interbull's multiple across-country evaluation approach breeding values into the multiple-trait single-step random regression test-day genetic evaluation for yield traits of Australian Red breeds.

Interbull's multiple across-country evaluaftion provides national breeding organizations with breeding values for internationally used bulls, which integrate performance data obtained in different breeding populations, environments, and production systems. However, breeding value-based selection decisions on domestic individuals born to foreign sires can only benefit from Interbull breeding values if they are integrated such that their information can contribute to the breeding values of all related domestic animals. For that purpose, several methods have been proposed which either model Interbull breeding values as prior information in a Bayesian approach, as additional pseudo data points, or as correlated traits, where these methods also differ in their software and parameterization requirements. Further, the complexity of integration also depends on the traits and genetic evaluation models. Especially random regression models require attention because of the dimensionality discrepancy between the number of Interbull breeding values and the number of modeled genetic effects. This paper presents the results from integrating 16,063 Interbull breeding values into the domestic single-step random regression test-day model for milk, fat, and protein yield for Australian Red dairy cattle breeds. Interbull breeding values were modeled as pseudo data points with data point-specific residual variances derived within animal across traits, ignoring relationships between integrated animals. Results suggest that the integration was successful with regard to alignment of Interbull breeding values with their domestic equivalent as well as with regard to the individual and population-wide increase in reliabilities. Depending on the relationship structure between integration candidates, further work is required to account for those relationships in a computationally feasible manner. Other traits with separate parity effects nationally could use a similar approach, even if not modeled with a test-day model.

SMILE Downregulation during Melanogenesis Induces MITF Transcription in B16F10 Cells.

SMILE (small heterodimer partner-interacting leucine zipper protein) is a transcriptional corepressor that potently regulates various cellular processes such as metabolism and growth in numerous tissues. However, its regulatory role in skin tissue remains uncharacterized. Here, we demonstrated that SMILE expression markedly decreased in human melanoma biopsy specimens and was inversely correlated with that of microphthalmia-associated transcription factor (MITF). During melanogenesis, α-melanocyte-stimulating hormone (α-MSH) induction of MITF was mediated by a decrease in SMILE expression in B16F10 mouse melanoma cells. Mechanistically, SMILE was regulated by α-MSH/cAMP/protein kinase A signaling and suppressed MITF promoter activity via corepressing transcriptional activity of the cAMP response element-binding protein. Moreover, SMILE overexpression significantly reduced α-MSH-induced MITF and melanogenic genes, thereby inhibiting melanin production in melanocytes. Conversely, SMILE inhibition increased the transcription of melanogenic genes and melanin contents. These results indicate that SMILE is a downstream effector of cAMP-mediated signaling and is a critical factor in the regulation of melanogenic transcription; in addition, they suggest a potential role of SMILE as a corepressor in skin pigmentation.

A descriptive case report of telesupervision and online case-based learning for speech and language therapy students in Vietnam during the COVID-19 pandemic.

BACKGROUND:  Vietnam's first speech and language therapy (SLT) degrees commenced in 2019 utilising international educators. Continuity of the degrees was impacted by travel restrictions during the coronavirus disease 2019 (COVID-19) pandemic. OBJECTIVES:  This article presents a descriptive case report exploring the viability of online learning to continue clinical education (CE) of SLT students in Vietnam during the pandemic. METHOD:  Students were scheduled for face to face placements throughout 2021. International SLT educators were to travel to Vietnam and work with interpreters and locally trained certificate level therapists to provide placement supervision. When travel became impossible, tele-supervision by international therapists working remotely and in partnership with local therapists and interpreters was arranged. The second wave of Covid-19 excluded students from healthcare settings early in their placements. To conclude these placements, tele-supervisors led online case-based discussions with students. For subsequent placements, Vietnamese and international therapists facilitated two to three weeks of online case-based group discussions for students, using cases with videos or avatars. RESULTS:  Learning outcomes for students, as evidenced in written and oral assessments demonstrated attainment of many of the learning objectives of the placements. Satisfaction for all participants (students, tele-supervisors, online group facilitators) was high. Students will undertake face to face placements in the future; however they will commence these placements with heightened clinical reasoning and planning skills. CONCLUSION:  Online CE is possible in LMIC and, as part of a program which includes face to face placements, can support essential CE outcomes and enhance preparation for subsequent direct experiences with patients.

The Role of miR-29s in Human Cancers-An Update.

MicroRNAs (miRNAs) are small non-coding RNAs that directly bind to the 3' untranslated region (3'-UTR) of the target mRNAs to inhibit their expression. The miRNA-29s (miR-29s) are suggested to be either tumor suppressors or oncogenic miRNAs that are strongly dysregulated in various types of cancer. Their dysregulation alters the expression of their target genes, thereby exerting influence on different cellular pathways including cell proliferation, apoptosis, migration, and invasion, thereby contributing to carcinogenesis. In the present review, we aimed to provide an overview of the current knowledge on the miR-29s biological network and its functions in cancer, as well as its current and potential applications as a diagnostic and prognostic biomarker and/or a therapeutic target in major types of human cancer.

Population-Based Pharmacokinetics and Dose Optimization of Imipenem in Vietnamese Critically-Ill Patients.

Purpose: The purpose of this study was to characterize the population-based pharmacokinetic (POP-PK) profile of imipenem in Vietnamese adult patients and to assess the probability of target attainment (PTA) of the pharmacokinetic/pharmacodynamic (PK/PD) parameter to determine the optimal dose. Patients and Methods: A POP-PK model of imipenem was developed in patients with severe infection from a 1500-bed general hospital in Vietnam, using MONOLIX 2019. After the initial dose infusion, 6 blood samples per patient were collected to measure plasma imipenem levels. Eight covariates (eg, age, weight) were investigated to ascertain their influence on imipenem's PK. Monte Carlo simulations were performed to determine the PTA for the time in which the total steady-state imipenem concentrations remained above the MIC (T>MIC) for 40% and 100% of the dosing interval. Results: The best fit to the PK data was a two-compartment model with inter-individual variability (IIV) in clearance (CL), central volume of distribution (Vc), intercompartmental clearance (Q), and peripheral volume of distribution (Vp). Only creatinine clearance was retained as a covariate on CL in the final model. The typical value of CL and Vc were estimated to be 4.79 L/h and 11.1 L, respectively. The between-subject variability in this population was noted to be high (>38%, especially for IIV on Q at 110%). Prolonged or continuous infusion demonstrated efficacy (40% T>MIC) against bacteria with a MIC of 4mg/L. To achieve 100% T>MIC or bacteria with MIC>4 mg/L, however, the number of doses must be increased while maintaining the same daily dose for the 3-hour prolonged infusion regimen. Conclusion: A population pharmacokinetic model of imipenem was developed for Vietnamese adult patients with severe illness. By using Monte Carlo simulation, the appropriate dose has been suggested based on the bacterial MIC value and the targeted PK/PD goal.

Light-to-Hydrogen Improvement Based on Three-Factored Au@CeO2/Gr Hierarchical Photocatalysts.

Recently, various attempts have been made for light-to-fuels conversion, often with limited performance. Herein we report active and lasting three-factored hierarchical photocatalysts consisting of plasmon Au, ceria semiconductor, and graphene conductor for hydrogen production. The Au@CeO2/Gr2.0 entity (graphene outer shell thickness of 2.0 nm) under visible-light irradiation exhibits a colossal achievement (8.0 µmol mgcat-1 h-1), which is 2.2- and 14.3-fold higher than those of binary Au@CeO2 and free-standing CeO2 species, outperforming the currently available catalysts. Yet, it delivers a high maximum quantum yield efficiency of 38.4% at an incident wavelength of 560 nm. These improvements are unambiguously attributed to three indispensable effects: (1) the plasmon resonant energy is light-excited and transferred to produce hot electrons localizing near the surface of Au@CeO2, where (2) the high-surface-area Gr conductive shell will capture them to direct hydrogen evolution reactions, and (3) the active graphene hybridized on the defect-rich surface of Au@CeO2 favorably adsorbs hydrogen atoms, which all bring up thorough insight into the working of a ternary Au@CeO2/Gr catalyst system in terms of light-to-hydrogen conversion.

Immune-related biomarkers shared by inflammatory bowel disease and liver cancer.

It has been indicated that there is an association between inflammatory bowel disease (IBD) and hepatocellular carcinoma (HCC). However, the molecular mechanism underlying the risk of developing HCC among patients with IBD is not well understood. The current study aimed to identify shared genes and potential pathways and regulators between IBD and HCC using a system biology approach. By performing the different gene expression analyses, we identified 871 common differentially expressed genes (DEGs) between IBD and HCC. Of these, 112 genes overlapped with immune genes were subjected to subsequent bioinformatics analyses. The results revealed four hub genes (CXCL2, MMP9, SPP1 and SRC) and several other key regulators including six transcription factors (FOXC1, FOXL1, GATA2, YY1, ZNF354C and TP53) and five microRNAs (miR-124-3p, miR-34a-5p, miR-1-3p, miR-7-5p and miR-99b-5p) for these disease networks. Protein-drug interaction analysis discovered the interaction of the hub genes with 46 SRC-related and 11 MMP9- related drugs that may have a therapeutic effect on IBD and HCC. In conclusion, this study sheds light on the potential connecting mechanisms of HCC and IBD.

Transcriptional landscape of human microglia implicates age, sex, and APOE-related immunometabolic pathway perturbations.

Microglia have fundamental roles in health and disease; however, effects of age, sex, and genetic factors on human microglia have not been fully explored. We applied bulk and single-cell approaches to comprehensively characterize human microglia transcriptomes and their associations with age, sex, and APOE. We identified a novel microglial signature, characterized its expression in bulk tissue and single-cell microglia transcriptomes. We discovered microglial co-expression network modules associated with age, sex, and APOE-ε4 that are enriched for lipid and carbohydrate metabolism genes. Integrated analyses of modules with single-cell transcriptomes revealed significant overlap between age-associated module genes and both pro-inflammatory and disease-associated microglial clusters. These modules and clusters harbor known neurodegenerative disease genes including APOE, PLCG2, and BIN1. Meta-analyses with published bulk and single-cell microglial datasets further supported our findings. Thus, these data represent a well-characterized human microglial transcriptome resource and highlight age, sex, and APOE-related microglial immunometabolism perturbations with potential relevance in neurodegeneration.

Aortic valve reconstruction surgery using autologous pericardium: The experience in Vietnam.

OBJECTIVE: The study aimed to evaluate the indications and describe the aortic valve reconstruction techniques by Ozaki's procedure in Vietnam and report mid-term outcomes of this technique in Vietnam. METHODS: Between June 2017 and December 2019, 72 patients diagnosed with isolated aortic valve disease, with a mean age of 52.9 (19-79 years old), and a male:female ratio of 3:1 underwent aortic valve reconstruction surgery by Ozaki's technique at Cardiovascular Center, E Hospital, Vietnam. RESULTS: The aortic valve diseases consisted of aortic stenosis (42%), aortic regurgitation (28%), and a combination of both (30%). In addition, the proportion of aortic valves with bicuspid morphology and small annulus (≤21 mm) was 28% and 38.9%, respectively. The mean aortic cross-clamp time was 106 ± 13.8 min, mean cardiopulmonary bypass time was 136.7 ± 18.5 min, and 2.8% of all patients required conversion to prosthetic valve replacement surgery. The mean follow-up time was 26.4 months (12-42 months), the survival rate was 95.8%, the reoperation rate was 2.8%, and rate of postoperative moderate or higher aortic valve regurgitation was 4.2%. Postoperative valvular hemodynamics was favorable, with a peak pressure gradient of 16.1 mmHg and an effective orifice area index of 2.3 cm2 . CONCLUSIONS: This procedure was safe and effective, with favorable valvular hemodynamics and a low rate of valvular degeneration. However, more long-term follow-up data are needed.