SREBP-1c impairs ULK1 sulfhydration-mediated autophagic flux to promote hepatic steatosis in high-fat-diet-fed mice.

A metabolic imbalance between lipid synthesis and degradation can lead to hepatic lipid accumulation, a characteristic of patients with non-alcoholic fatty liver disease (NAFLD). Here, we report that high-fat-diet-induced sterol regulatory element-binding protein (SREBP)-1c, a key transcription factor that regulates lipid biosynthesis, impairs autophagic lipid catabolism via altered H2S signaling. SREBP-1c reduced cystathionine gamma-lyase (CSE) via miR-216a, which in turn decreased hepatic H2S levels and sulfhydration-dependent activation of Unc-51-like autophagy-activating kinase 1 (ULK1). Furthermore, Cys951Ser mutation of ULK1 decreased autolysosome formation and promoted hepatic lipid accumulation in mice, suggesting that the loss of ULK1 sulfhydration was directly associated with the pathogenesis of NAFLD. Moreover, silencing of CSE in SREBP-1c knockout mice increased liver triglycerides, confirming the connection between CSE, autophagy, and SREBP-1c. Overall, our results uncover a 2-fold mechanism for SREBP-1c-driven hepatic lipid accumulation through reciprocal activation and inhibition of hepatic lipid biosynthesis and degradation, respectively.

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.

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.

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.

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.

Sirtuins as molecular targets, mediators, and protective agents in metal-induced toxicity.

Metal dyshomeostasis, and especially overexposure, is known to cause adverse health effects due to modulation of a variety of metabolic pathways. An increasing body of literature has demonstrated that metal exposure may affect SIRT signaling, although the existing data are insufficient. Therefore, in this review we discuss the available data (PubMed-Medline, Google Scholar) on the influence of metal overload on sirtuin (SIRT) signaling and its association with other mechanisms involved in metal-induced toxicity. The existing data demonstrate that cadmium (Cd), mercury (Hg), arsenic (As), lead (Pb), aluminium (Al), hexavalent chromium (CrVI), manganese (Mn), iron (Fe), and copper (Cu) can inhibit SIRT1 activity. In addition, an inhibitory effect of Cd, Pb, As, and Fe on SIRT3 has been demonstrated. In turn, metal-induced inhibition of SIRT was shown to affect deacetylation of target proteins including FOXO, PGC1α, p53 and NF-kB. Increased acetylation downregulates PGC1α signaling pathway, resulting in cellular altered redox status and increased susceptibility to oxidative stress, as well as decreased mitochondrial biogenesis. Lower rates of LKB1 deacetylation may be responsible for metal-induced decreases in AMPK activity and subsequent metabolic disturbances. A shift to the acetylated FOXO results in increased expression of pro-apoptotic genes which upregulates apoptosis together with increased p53 signaling. Correspondingly, decreased NF-kB deacetylation results in upregulation of target genes of proinflammatory cytokines, enzymes, and cellular adhesion molecules thus promoting inflammation. Therefore, alterations in sirtuin activity may at least partially mediate metal-induced metabolic disturbances that have been implicated in neurotoxicity, nephrotoxicity, cardiotoxicity, and other toxic effects of heavy metals.

A Förster Resonance Energy Transfer-Based Ratiometric Sensor with the Allosteric Transcription Factor TetR.

A recent description of an antibody-free assay is significantly extended for small molecule analytes using allosteric transcription factors (aTFs) and Förster resonance energy transfer (FRET). The FRET signal indicates the differential binding of an aTF-DNA pair with a dose-dependent response to its effector molecule, i.e., the analyte. The new sensors described here, based on the well-characterized aTF TetR, demonstrate several new features of the assay approach: 1) the generalizability of the sensors to additional aTF-DNA-analyte systems, 2) sensitivity modulation through the choice of donor fluorophore (quantum dots or fluorescent proteins, FPs), and 3) sensor tuning using aTF variants with differing aTF-DNA binding affinities. While all of these modular sensors self-assemble, the design reported here based on a recombinant aTF-FP chimera with commercially available dye-labeled DNA uses readily accessible sensor components to facilitate easy adoption of the sensing approach by the broader community.

How to Make Anticancer Drugs Cross the Blood-Brain Barrier to Treat Brain Metastases.

The incidence of brain metastases has increased in the last 10 years. However, the survival of patients with brain metastases remains poor and challenging in daily practice in medical oncology. One of the mechanisms suggested for the persistence of a high incidence of brain metastases is the failure to cross the blood-brain barrier of most chemotherapeutic agents, including the more recent targeted therapies. Therefore, new pharmacological approaches are needed to optimize the efficacy of anticancer drug protocols. In this article, we present recent findings in molecular data on brain metastases. We then discuss published data from pharmacological studies on the crossing of the blood-brain barrier by anticancer agents. We go on to discuss future developments to facilitate drug penetration across the blood-brain barrier for the treatment of brain metastases among cancer patients, using physical methods or physiological transporters.

Event-Based Surveillance at Community and Healthcare Facilities, Vietnam, 2016-2017.

Surveillance and outbreak reporting systems in Vietnam required improvements to function effectively as early warning and response systems. Accordingly, the Ministry of Health of Vietnam, in collaboration with the US Centers for Disease Control and Prevention, launched a pilot project in 2016 focusing on community and hospital event-based surveillance. The pilot was implemented in 4 of Vietnam's 63 provinces. The pilot demonstrated that event-based surveillance resulted in early detection and reporting of outbreaks, improved collaboration between the healthcare facilities and preventive sectors of the ministry, and increased community participation in surveillance and reporting.

Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by tau pathology in neurons and glial cells. Transcriptional regulation has been implicated as a potential mechanism in conferring disease risk and neuropathology for some PSP genetic risk variants. However, the role of transcriptional changes as potential drivers of distinct cell-specific tau lesions has not been explored. In this study, we integrated brain gene expression measurements, quantitative neuropathology traits and genome-wide genotypes from 268 autopsy-confirmed PSP patients to identify transcriptional associations with unique cell-specific tau pathologies. We provide individual transcript and transcriptional network associations for quantitative oligodendroglial (coiled bodies = CB), neuronal (neurofibrillary tangles = NFT), astrocytic (tufted astrocytes = TA) tau pathology, and tau threads and genomic annotations of these findings. We identified divergent patterns of transcriptional associations for the distinct tau lesions, with the neuronal and astrocytic neuropathologies being the most different. We determined that NFT are positively associated with a brain co-expression network enriched for synaptic and PSP candidate risk genes, whereas TA are positively associated with a microglial gene-enriched immune network. In contrast, TA is negatively associated with synaptic and NFT with immune system transcripts. Our findings have implications for the diverse molecular mechanisms that underlie cell-specific vulnerability and disease risk in PSP.

Short communication: Implementation of a breeding value for heat tolerance in Australian dairy cattle.

Excessive ambient temperature and humidity can impair milk production and fertility of dairy cows. Selection for heat-tolerant animals is one possible option to mitigate the effects of heat stress. To enable selection for this trait, we describe the development of a heat tolerance breeding value for Australian dairy cattle. We estimated the direct genomic values of decline in milk, fat, and protein yield per unit increase of temperature-humidity index (THI) using 46,726 single nucleotide polymorphisms and a reference population of 2,236 sires and 11,853 cows for Holsteins and 506 sires and 4,268 cows for Jerseys. This new direct genomic value is the Australian genomic breeding value for heat tolerance (HT ABVg). The components of the HT ABVg are the decline in milk, fat, and protein per unit increase in THI when THI increases above the threshold of 60. These components are weighted by their respective economic values, assumed to be equivalent to the weights applied to milk, fat, and protein yield in the Australian selection indices. Within each breed, the HT ABVg is then standardized to have a mean of 100 and standard deviation (SD) of 5, which is consistent with the presentation of breeding values for many other traits in Australia. The HT ABVg ranged from -4 to +3 SD in Holsteins and -3 to +4 SD in Jerseys. The mean reliabilities of HT ABVg among validation sires, calculated from the prediction error variance and additive genetic variance, were 38% in both breeds. The range in ABVg and their reliability suggests that HT can be improved using genomic selection. There has been a deterioration in the genetic trend of HT, and to moderate the decline it is suggested that the HT ABVg should be included in a multitrait economic index with other traits that contribute to farm profit.

Salivary oxidative stress biomarkers in chronic periodontitis and acute coronary syndrome.

OBJECTIVES: The study aimed at assessing oxidative stress (OS) biomarker levels in the saliva of patients with chronic periodontitis (CP) and acute coronary syndrome (ACS) and establishing their correlation to periodontal parameters and markers for cardiovascular events. MATERIALS AND METHODS: The present study enrolled 24 patients with ACS and CP (the ACSCP group), 24 patients with ACS only (the ACS group), 24 patients with CP only (the CP group), and 24 healthy controls. Plaque index (PI), gingival index, bleeding on probing, probing pocket depth (PPD), and clinical attachment loss were recorded. Markers for cardiovascular events included serum high sensitivity C-reactive protein (hsCRP) and plasma fibrinogen. 8-Hydroxydeoxyguanosine (8-OHdG), protein carbonyl (PC), malondialdehyde (MDA), and total antioxidant capacity (TAOC) were used as OS biomarkers. RESULTS: Salivary 8-OHdG, MDA, and PC levels were significantly higher in the ACSCP, ACS, and CP groups than in healthy controls (p < 0.05). There were significant correlations between salivary PC levels and PI or PPD (p < 0.05) as well as between salivary 8-OHdG levels and all periodontal parameters (p < 0.05). TAOC levels in saliva were correlated to both serum hsCRP and plasma fibrinogen (p < 0.05). Salivary MDA levels were correlated to all periodontal parameters and biomarkers for cardiovascular events (p < 0.05). CONCLUSIONS: Salivary OS biomarker levels were higher in diseased groups compared to control. They also correlated to clinical periodontal parameters and markers for cardiovascular events in ACS patients, with or without CP. CLINICAL RELEVANCE: Salivary OS biomarkers could potentially serve as diagnostic tools for cardiovascular and/or periodontal diseases.

Genomic selection for tolerance to heat stress in Australian dairy cattle.

Temperature and humidity levels above a certain threshold decrease milk production in dairy cattle, and genetic variation is associated with the amount of lost production. To enable selection for improved heat tolerance, the aim of this study was to develop genomic estimated breeding values (GEBV) for heat tolerance in dairy cattle. Heat tolerance was defined as the rate of decline in production under heat stress. We combined herd test-day recording data from 366,835 Holstein and 76,852 Jersey cows with daily temperature and humidity measurements from weather stations closest to the tested herds for test days between 2003 and 2013. We used daily mean values of temperature-humidity index averaged for the day of test and the 4 previous days as the measure of heat stress. Tolerance to heat stress was estimated for each cow using a random regression model with a common threshold of temperature-humidity index=60 for all cows. The slope solutions for cows from this model were used to define the daughter trait deviations of their sires. Genomic best linear unbiased prediction was used to calculate GEBV for heat tolerance for milk, fat, and protein yield. Two reference populations were used, the first consisted of genotyped sires only (2,300 Holstein and 575 Jersey sires), and the other included genotyped sires and cows (2,189 Holstein and 1,188 Jersey cows). The remainder of the genotyped sires were used as a validation set. All animals had genotypes for 632,003 single nucleotide polymorphisms. When using only genotyped sires in the reference set and only the first parity data, the accuracy of GEBV for heat tolerance in relation to changes in milk, fat, and protein yield were 0.48, 0.50, and 0.49 in the Holstein validation sires and 0.44, 0.61, and 0.53 in the Jersey validation sires, respectively. Some slight improvement in the accuracy of prediction was achieved when cows were included in the reference population for Holsteins. No clear improvements in the accuracy of genomic prediction were observed when data from the second and third parities were included. Correlations of GEBV for heat tolerance with Australian Breeding Values for other traits suggested heat tolerance had a favorable genetic correlation with fertility (0.29-0.39 in Holsteins and 0.15-0.27 in Jerseys), but unfavorable correlations for some production traits. Options to improve heat tolerance with genomic selection in Australian dairy cattle are discussed.

Computational and functional analyses of a small-molecule binding site in ROMK.

The renal outer medullary potassium channel (ROMK, or Kir1.1, encoded by KCNJ1) critically regulates renal tubule electrolyte and water transport and hence blood volume and pressure. The discovery of loss-of-function mutations in KCNJ1 underlying renal salt and water wasting and lower blood pressure has sparked interest in developing new classes of antihypertensive diuretics targeting ROMK. The recent development of nanomolar-affinity small-molecule inhibitors of ROMK creates opportunities for exploring the chemical and physical basis of ligand-channel interactions required for selective ROMK inhibition. We previously reported that the bis-nitro-phenyl ROMK inhibitor VU591 exhibits voltage-dependent knock-off at hyperpolarizing potentials, suggesting that the binding site is located within the ion-conduction pore. In this study, comparative molecular modeling and in silico ligand docking were used to interrogate the full-length ROMK pore for energetically favorable VU591 binding sites. Cluster analysis of 2498 low-energy poses resulting from 9900 Monte Carlo docking trajectories on each of 10 conformationally distinct ROMK comparative homology models identified two putative binding sites in the transmembrane pore that were subsequently tested for a role in VU591-dependent inhibition using site-directed mutagenesis and patch-clamp electrophysiology. Introduction of mutations into the lower site had no effect on the sensitivity of the channel to VU591. In contrast, mutations of Val(168) or Asn(171) in the upper site, which are unique to ROMK within the Kir channel family, led to a dramatic reduction in VU591 sensitivity. This study highlights the utility of computational modeling for defining ligand-ROMK interactions and proposes a mechanism for inhibition of ROMK.

Extensive variation between tissues in allele specific expression in an outbred mammal.

BACKGROUND: Allele specific gene expression (ASE), with the paternal allele more expressed than the maternal allele or vice versa, appears to be a common phenomenon in humans and mice. In other species the extent of ASE is unknown, and even in humans and mice there are several outstanding questions. These include; to what extent is ASE tissue specific? how often does the direction of allele expression imbalance reverse between tissues? how often is only one of the two alleles expressed? is there a genome wide bias towards expression of the paternal or maternal allele; and finally do genes that are nearby on a chromosome share the same direction of ASE? Here we use gene expression data (RNASeq) from 18 tissues from a single cow to investigate each of these questions in turn, and then validate some of these findings in two tissues from 20 cows. RESULTS: Between 40 and 100 million sequence reads were generated per tissue across three replicate samples for each of the eighteen tissues from the single cow (the discovery dataset). A bovine gene expression atlas was created (the first from RNASeq data), and differentially expressed genes in each tissue were identified. To analyse ASE, we had access to unambiguously phased genotypes for all heterozygous variants in the cow's whole genome sequence, where these variants were homozygous in the whole genome sequence of her sire, and as a result we were able to map reads to parental genomes, to determine SNP and genes showing ASE in each tissue. In total 25,251 heterozygous SNP within 7985 genes were tested for ASE in at least one tissue. ASE was pervasive, 89 % of genes tested had significant ASE in at least one tissue. This large proportion of genes displaying ASE was confirmed in the two tissues in a validation dataset. For individual tissues the proportion of genes showing significant ASE varied from as low as 8-16 % of those tested in thymus to as high as 71-82 % of those tested in lung. There were a number of cases where the direction of allele expression imbalance reversed between tissues. For example the gene SPTY2D1 showed almost complete paternal allele expression in kidney and thymus, and almost complete maternal allele expression in the brain caudal lobe and brain cerebellum. Mono allelic expression (MAE) was common, with 1349 of 4856 genes (28 %) tested with more than one heterozygous SNP showing MAE. Across all tissues, 54.17 % of all genes with ASE favoured the paternal allele. Genes that are closely linked on the chromosome were more likely to show higher expression of the same allele (paternal or maternal) than expected by chance. We identified several long runs of neighbouring genes that showed either paternal or maternal ASE, one example was five adjacent genes (GIMAP8, GIMAP7 copy1, GIMAP4, GIMAP7 copy 2 and GIMAP5) that showed almost exclusive paternal expression in brain caudal lobe. CONCLUSIONS: Investigating the extent of ASE across 18 bovine tissues in one cow and two tissues in 20 cows demonstrated 1) ASE is pervasive in cattle, 2) the ASE is often MAE but ranges from MAE to slight overexpression of the major allele, 3) the ASE is most often tissue specific and that more than half the time displays divergent allele specific expression patterns across tissues, 4) across all genes there is a slight bias towards expression of the paternal allele and 5) genes expressing the same parental allele are clustered together more than expected by chance, and there are several runs of large numbers of genes expressing the same parental allele.

Enhanced Inactivation of Escherichia coli and MS2 Coliphage by Cupric Ion in the Presence of Hydroxylamine: Dual Microbicidal Effects.

The inactivation of Escherichia coli and MS2 coliphage by Cu(II) is found to be significantly enhanced in the presence of hydroxylamine (HA). The addition of a small amount of HA (i.e., 5-20 µM) increased the inactivation efficacies of E. coli and MS2 coliphage by 5- to 100-fold, depending on the conditions. Dual effects were anticipated to enhance the biocidal activity of Cu(II) by the addition of HA, viz. (i) the accelerated reduction of Cu(II) into Cu(I) (a stronger biocide) and (ii) the production of reactive oxidants from the reaction of Cu(I) with dissolved oxygen (evidenced by the oxidative transformation of methanol into formaldehyde). Deaeration enhanced the inactivation of E. coli but slightly decreased the inactivation efficacy of MS2 coliphage. The addition of 10 µM hydrogen peroxide (H2O2) greatly enhanced the MS2 inactivation, whereas the same concentration of H2O2 did not significantly affect the inactivation efficacy of E. coli Observations collectively indicate that different biocidal actions lead to the inactivation of E. coli and MS2 coliphage. The toxicity of Cu(I) is dominantly responsible for the E. coli inactivation. However, for the MS2 coliphage inactivation, the oxidative damage induced by reactive oxidants is as important as the effect of Cu(I).

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.

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.