Because of the refractory nature of mutant KRAS lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant KRAS LUAD have proven to be potential molecular targets for therapeutic development. Here we determine the clinical, functional, and mechanistic role of inhibitor of differentiation-1 (Id1) in mutant KRAS LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of Id1 was a marker of poor survival in patients harboring mutant, but not wild-type KRAS. Abrogation of Id1 induced G2-M arrest and apoptosis in mutant KRAS LUAD cells. In vivo, loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the KRAS oncogene through JNK, and loss of Id1 resulted in downregulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the KRAS signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring Id1 as a critical gene in mutant KRAS LUAD and warrants further studies of Id1 as a therapeutic target in patients with LUAD. SIGNIFICANCE: These findings highlight the prognostic significance of the transcriptional regulator Id1 in KRAS-mutant lung adenocarcinoma and provide mechanistic insight into how it controls tumor growth and metastasis.

Although intracellular heme trafficking must occur for heme protein assembly, only a few heme transporters have been unequivocally discovered and nothing is known about their structure or mechanisms. Cytochrome c biogenesis in prokaryotes requires the transport of heme from inside to outside for stereospecific attachment to cytochrome c via two thioether bonds (at CXXCH). The CcsBA integral membrane protein was shown to transport and attach heme (and thus is a cytochrome c synthetase), but the structure and mechanisms underlying these two activities are poorly understood. We employed a new cysteine/heme crosslinking tool that traps endogenous heme in heme binding sites. We combined these data with a comprehensive imidazole correction approach (for heme ligand interrogation) to map heme binding sites. Results illuminate the process of heme transfer through the membrane to an external binding site (called the WWD domain). Using meta-genomic data (GREMLIN) and Rosetta modeling programs, a structural model of the transmembrane (TM) regions in CcsBA were determined. The heme mapping data were then incorporated to model the TM heme binding site (with TM-His1 and TM-His2 as ligands) and the external heme binding WWD domain (with P-His1 and P-His2 as ligands). Other periplasmic structure/function studies facilitated modeling of the full CcsBA protein as a framework for understanding the mechanisms. Mechanisms are proposed for heme transport from TM-His to WWD/P-His and subsequent stereospecific attachment of heme. A ligand exchange of the P-His1 for histidine of CXXCH at the synthetase active site is suggested.IMPORTANCE The movement or trafficking of heme is critical for cellular functions (e.g., oxygen transport and energy production); however, intracellular heme is tightly regulated due to its inherent cytotoxicity. These factors, combined with the transient nature of transport, have resulted in a lack of direct knowledge on the mechanisms of heme binding and trafficking. Here, we used the cytochrome c biogenesis system II pathway as a model to study heme trafficking. System II is composed of two integral membrane proteins (CcsBA) which function to transport heme across the membrane and stereospecifically position it for covalent attachment to apocytochrome c We mapped two heme binding domains in CcsBA and suggest a path for heme trafficking. These data, in combination with metagenomic coevolution data, are used to determine a structural model of CcsBA, leading to increased understanding of the mechanisms for heme transport and the cytochrome c synthetase function of CcsBA.

Bacterial ribosomes frequently translate to the 3' end of an mRNA without terminating at an in-frame stop codon. In all bacteria studied to date, these "nonstop" ribosomes are rescued using trans-translation. Genes required for trans-translation are essential in some species, but other species can survive without trans-translation because they express an alternative ribosome rescue factor, ArfA or ArfB. Francisella tularensis cells lacking trans-translation are viable, but F. tularensis does not encode ArfA or ArfB. Transposon mutagenesis followed by deep sequencing (Tn-seq) identified a new alternative ribosome rescue factor, now named ArfT. arfT can be deleted in wild-type (wt) cells but not in cells that lack trans-translation activity. Overexpression of ArfT suppresses the slow-growth phenotype in cells lacking trans-translation and counteracts growth arrest caused by trans-translation inhibitors, indicating that ArfT rescues nonstop ribosomes in vivo Ribosome rescue assays in vitro show that ArfT promotes hydrolysis of peptidyl-tRNA on nonstop ribosomes in conjunction with F. tularensis release factors. Unlike ArfA, which requires RF2 for activity, ArfT can function with either RF1 or RF2. Overall, these results indicate that ArfT is a new alternative ribosome rescue factor with a distinct mechanism from ArfA and ArfB.IMPORTANCEFrancisella tularensis is a highly infectious intracellular pathogen that kills more than half of infected humans if left untreated. F. tularensis has also been classified as a potential bioterrorism agent with a great risk for deliberate misuse. Recently, compounds that inhibit ribosome rescue have been shown to have antibiotic activity against F. tularensis and other important pathogens. Like all bacteria that have been studied, F. tularensis uses trans-translation as the main pathway to rescue stalled ribosomes. However, unlike most bacteria, F. tularensis can survive without any of the known factors for ribosome rescue. Our work identified a F. tularensis protein, ArfT, that rescues stalled ribosomes in the absence of trans-translation using a new mechanism. These results indicate that ribosome rescue activity is essential in F. tularensis and suggest that ribosome rescue activity might be essential in all bacteria.

Many viruses produce protein-coding and noncoding subgenomic RNAs (sgRNAs) that are critical for infection. A recently discovered pathway for viral sgRNA production uses exoribonuclease-resistant RNAs (xrRNAs), discrete folded RNA elements that block the processive exoribonucleolytic degradation of RNA. xrRNAs are widespread in animal-infecting flaviviruses but had been found only in three members of the plant virus genus Dianthovirus Also, xrRNAs had been found only in the 3' untranslated regions (3'UTRs) of viral RNAs, where they produce noncoding sgRNAs. The degree to which xrRNA elements exist in other viruses, the conservation of their ring-like fold, and the ability of xrRNAs to operate in diverse contexts were unknown. Using computational tools and biochemical assays, we discovered xrRNA elements pervading two large families of plant-infecting RNA viruses, demonstrating their importance and widespread utility. Comparison of the sequences and functional requirements suggests that all adopt the characteristic ring-like fold. Unexpectedly, many of these newly discovered xrRNAs are located in intergenic regions rather than 3´UTRs, and some are associated with the 5' ends of subgenomic RNAs that encode viral proteins. This suggests that xrRNAs are involved in the production of both coding and noncoding subgenomic RNAs and can operate as part of broader mechanisms to regulate RNA levels and protein expression. These discoveries expand the potential roles for xrRNAs and suggest that xrRNAs may represent a more general strategy for RNA maturation and maintenance than previously known.IMPORTANCE During infection, viruses often produce subgenomic RNAs (sgRNAs) that either serve as the template for protein synthesis or act as "riboregulators" that interact with and influence the viral and cellular machinery. Recently, a mechanism for producing sgRNAs was found that depends on the presence of specifically structured RNA elements (xrRNAs). However, the degree to which this mechanism is used, where the elements are found, their structural diversity, and what types of sgRNAs are produced by this pathway were unclear. This article describes the discovery of these structured RNA elements in two large families of plant viruses and shows that they are used to produce both protein-coding sgRNAs and "riboregulatory" RNAs. These discoveries provide evidence that xrRNA-based RNA maturation pathways may be more widespread than previously anticipated and that they are involved in producing a variety of RNAs of diverse functions.

Organohalide compounds are widespread in the environment as a result of both anthropogenic activities and natural production. The marine environment, in particular, is a major reservoir of organohalides, and reductive dehalogenation is thought to be an important process in the overall cycling of these compounds. Deltaproteobacteria are important members of the marine microbiota with diverse metabolic capacities, and reductive dehalogenation has been observed in some Deltaproteobacteria In this study, a comprehensive survey of Deltaproteobacteria genomes revealed that approximately 10% contain reductive dehalogenase (RDase) genes, which are found within a common gene neighborhood. The dehalogenating potential of select RDase A-containing Deltaproteobacteria and their gene expression were experimentally verified. Three Deltaproteobacteria strains isolated from marine environments representing diverse species, Halodesulfovibrio marinisediminis, Desulfuromusa kysingii, and Desulfovibrio bizertensis, were shown to reductively dehalogenate bromophenols and utilize them as terminal electron acceptors in organohalide respiration. Their debrominating activity was not inhibited by sulfate or elemental sulfur, and these species are either sulfate- or sulfur-reducing bacteria. The analysis of RDase A gene transcripts indicated significant upregulation induced by 2,6-dibromophenol. This study extends our knowledge of the phylogenetic diversity of organohalide-respiring bacteria and their functional RDase A gene diversity. The identification of reductive dehalogenase genes in diverse Deltaproteobacteria and confirmation of their organohalide-respiring capability suggest that Deltaproteobacteria play an important role in natural organohalide cycling.IMPORTANCE The marine environment is a major reservoir for both anthropogenic and natural organohalides, and reductive dehalogenation is thought to be an important process in the overall cycling of these compounds. Here we demonstrate that the capacity of organohalide respiration appears to be widely distributed in members of marine Deltaproteobacteria The identification of reductive dehalogenase genes in diverse Deltaproteobacteria and the confirmation of their dehalogenating activity through functional assays and transcript analysis in select isolates extend our knowledge of organohalide-respiring Deltaproteobacteria diversity. The presence of functional reductive dehalogenase genes in diverse Deltaproteobacteria implies that they may play an important role in organohalide respiration in the environment.

Autophagy is an essential process of the eukaryotic cell allowing degradation and recycling of dysfunctional cellular components in response to either physiological or pathological changes. Inhibition of autophagy in combination with chemotherapeutic treatment has emerged as a novel approach in cancer treatment leading to cell cycle arrest, differentiation, and apoptosis. Suberoyl hydroxamic acid (SAHA) is a broad-spectrum histone deacetylase inhibitor (HDACi) suppressing family members in multiple HDAC classes. Increasing evidence indicates that SAHA and other HDACi can, in addition to mitochondria-mediated apoptosis, also promote caspase-independent autophagy. SAHA-induced mTOR inactivation as a major regulator of autophagy activating the remaining autophagic core machinery is by far the most reported pathway in several tumor models. However, the question of which upstream mechanisms regulate SAHA-induced mTOR inactivation that consequently initiate autophagy has been mainly left unexplored. To elucidate this issue, we recently initiated a study clarifying different modes of SAHA-induced cell death in two human uterine sarcoma cell lines which led to the conclusion that the tumor suppressor protein p53 could act as a molecular switch between SAHA-triggered autophagic or apoptotic cell death. In this review, we present current research evidence about HDACi-mediated apoptotic and autophagic pathways, in particular with regard to p53 and its therapeutic implications.

Transcriptional repressor GATA binding 1 (TRPS1), an atypical GATA transcription factor, functions as a transcriptional repressor and is also implicated in human cancers. However, the underlying mechanism of TRPS1 contributing to malignancy remains obscure. In the current study, we report that TRPS1 recognizes both gene proximal and distal transcription start site (TSS) sequences to repress gene expression. Co-IP mass spectrometry and biochemical studies showed that TRPS1 binds to CHD4/NuRD(MTA2). Genome-wide and molecular studies revealed that CHD4/NuRD(MTA2) is required for TRPS1 transcriptional repression. Mechanically, TRPS1 and CHD4/NuRD(MTA2) form precision-guided transcriptional repression machinery in which TRPS1 guides the machinery to specific target sites by recognizing GATA elements, and CHD4/NuRD(MTA2) represses the transcription of target genes. Furthermore, TP63 was identified and validated to be a direct target of TRPS1-CHD4/NuRD(MTA2) complex, which represses TP63 expression by involving decommission of TP63 enhancer in the described precision-guided manner, leading to a reduction of the ΔNp63 level and contributing to migration and invasion of cancer cells.

Structural variation (SV) is associated with inherited diseases. Next-generation sequencing (NGS) is an efficient method for SV detection because of its high-throughput, low cost, and base-pair resolution. However, due to lack of standard NGS protocols and a limited number of clinical samples with pathogenic SVs, comprehensive standards for SV detection, interpretation, and reporting are to be established.

The growing interest reflected in the studies on dental erosion is justified by the severe health problems it entails, i.e. esthetic, phonetic, masticatory disturbances and pulp complications. Most studies investigate the prevalence of dental erosion in adults and children, the severity of lesions and etiopathogenetic factors.

The nutritional disorders are modifiable predisposing factors of the current leading causes of morbidity and premature mortality, such as cardiovascular diseases, diabetes and cancers. An early recognition of appropriate interventions could decrease the burden of medical costs and increase the healthy life expectancy. The aims of our study were the description of nutritional status, its associated factors, and the detection of eating disorders among Romanian medical students of the "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca.

Armadilloofficinalis Duméril, 1816 (Armadillidae) is a widespread terrestrial isopod species in the Mediterranean basin and on the western coasts of the Black Sea. The species is adapted to live in xeric environments and has mainly nocturnal habits. This species is capable of producing stridulations, which is nowadays recognized as a synapomorphy of the genus. In both sexes, these vibrations are produced by a line of scales on the propodus of pereopod 4 and 5. The main goals of this study are: to describe the manca stages of Armadilloofficinalis; to detect the presence of the stridulatory apparatus in the manca stages; to evaluate the differences of such apparatus in the various manca stages. The manca stages (I, II, III) of Armadilloofficinalis are described for the first time showing: i, the shortest duration (known in literature) of the manca stage I (approximately 30 minutes); ii, the presence of a rudimental stridulatory organ that may be of great importance in terms of evolutionary aspects and adaptation to terrestrial life. Notes on the reproductive biology are also reported. Furthermore, some considerations on future perspectives for A.officinalis as a model species in biotremology are also discussed.

Melanconis-like species comprise latent fungal pathogens with a wide range of woody hosts. Taxonomy of these pathogens is difficult due to their uninformative descriptions and similar asexual morphology. Based on molecular phylogenies, many species of this group were placed in various families of Diaporthales. In this study, eight species of melanconis-like fungi were isolated from Betulaalbosinensis, B.platyphylla (Betulaceae), Cornuscontroversa (Cornaceae), Corylusmandshurica (Betulaceae) and Juglansregia (Juglandaceae) in China. These species were phylogenetically placed in three families of Diaporhthales, i.e. Juglanconisjuglandina, J.oblonga (Juglanconidaceae), Melanconiellabetulicola sp. nov., M.corylina sp. nov. (Melanconiellaceae), Melanconisbetulae, Ms.itoana, Ms.stilbostoma (Melanconidaceae) and one new genus, Sheathospora (Melanconiellaceae). Sheathospora is proposed to accommodate Melanconiellacornuta with conical and discrete pycnidia with aseptate, hyaline, cylindrical to ellipsoidal conidia with distinct hyaline sheath on branches of Cornuscontroversa. Combined analyses of ITS, LSU, CAL, RPB2 and TEF1-α sequence data were used to construct the molecular phylogeny. Additionally, we provided separate phylogenetic trees for three families (Juglanconidaceae, Melanconidaceae and Melanconiellaceae) to show the species distribution of melanconis-like fungi in China.

Lithium, a glycogen synthase kinase-3β (GSK-3β) inhibitor, prevents cannabinoid withdrawal syndrome, but there is limited data exploring the interaction between lithium and cannabinoid system on memory processes. The present study aimed to test the interaction between dorsal hippocampal (CA1 region) cannabinoid system and lithium on spatial memory in rats. Spatial memory was assessed in Morris Water Maze (MWM) apparatus by a single training session of eight trials. The results showed that pre-training intra-CA1 microinjection of ACPA, the cannabinoid type 1 receptor (CB1r) agonist, at doses of 0.001, 0.01 or 1 µg/rat, or AM251, the cannabinoid type 1 receptor (CB1r) antagonist, at doses of 1, 10 or 100 ng/rat, increased escape latency and traveled distance to the platform, suggesting a spatial learning impairment, whereas intraperitoneal administration of lithium (0.5, 1 or 5 mg/kg) had no effect on spatial learning. Also, rats that received lithium plus a lower dose of ACPA (0.001 µg/rat) or AM251 (1 ng/rat) had successful performance in the MWM. In the probe test, the results showed that pre-training administration of lithium (5 mg/kg) and ACPA (0.01 or 1 µg/rat) but not AM251 (at all doses used) impaired spatial memory retrieval. Also, lower dose of ACPA (0.001 µg/rat) or AM251 (1 ng/rat) potentiated the effect of ineffective doses of lithium (0.5 and 1 mg/kg) on spatial memory retrieval, while restored the effect of effective dose of lithium (5 mg/kg). In conclusion, cannabinoids may have a dual effect on lithium-induced spatial memory impairment in rats.

Shortly after sarcosine was delineated as a potential biomarker for prostate cancer in 2009, a variety of analytical methods for clinical application were developed. Moreover, higher uptake of glycine in the mitochondria also played a role in cancer proliferation. A major constraint in the accurate quantification of sarcosine was the interference of the two isomers, α-alanine and β-alanine, using chromatographic separation techniques. Accordingly, we aimed to develop an analytical method for determining sarcosine and its related metabolites (α- and β-alanine, glycine and creatinine) under the same conditions by gas chromatography-tandem mass spectrometry (GC-MS/MS). BSTFA + 1 % TMCS was used for silylation, and GC-MS/MS conditions were optimized for the target analytes. The unique transition ions of sarcosine, α- and β-alanine, glycine and creatinine set up in MRM acquisition were m/z 116 → 73, 190 → 147, 176 → 147, 176 → 147 and 100 → 73, respectively. This newly developed method was successfully validated to apply in clinical settings with low limits of detection (0.01 - 0.03 µg•mL-1), high correlations (R2 > 0.99), great accuracy (88 - 110 % recovery), and notable precision (RSD < 10 %). All TMS derivatives were > 80 % stable for up to 2 h after derivatization and analyzing during this period promises to achieve an accurate result. Monitoring the five-substance profile could enhance prospects for early diagnosis of prostate cancer.

Background: Neuro-surgical emergencies are serious (long-term disability and high mortality) and costly to the national health services. Tele-medicine intervention can facilitate to reduce this gap. Our study aims to evaluate the cost-effectiveness of tele-video-consultation intervention for the management of neuro-surgical emergencies in the general hospitals. Methods: We retrieved health service data from the tele-consultation service, online tele-medicine database portal and hospital patient registry, between January 2009 and December 2012 and evaluated cost-effectiveness of the tele-video-consultation intervention from an Italian National Health Service perspective. Results: Seventy-five percent of the tele-consultations were completed within 15 min and 90% within 30 min. The average costs were €2,326 in the intervention group and €4,173 in the care as usual group. The intervention avoided 73% potential transfer (saving of 139,916 km travel distance during a 4-years period). The incremental cost-saving per transfer avoided from the tele-medicine intervention was €365. Conclusions: Tele-medicine intervention could be worth investing from the Italian National Health Service perspective.

Studies on the association between post-traumatic stress disorder (PTSD) and levels of catecholamines have yielded inconsistent results. The aim of this study was to conduct a systematic review and meta-analysis to assess whether concentrations of the catecholamines dopamine, norepinephrine, and epinephrine are associated with PTSD. This study searched relevant articles in the following databases: PubMed, Embase, Web of Science, and Psyc-ARTICLES. Each database was searched from its inception to September, 2018. Data related to catecholamine concentrations were extracted for patients with PTSD and the controls to calculate standardized mean differences and to evaluate effect sizes. A meta-analysis was then performed to compare the concentration of each catecholamine between the two groups in blood and/or urine samples. Heterogeneity was quantified using I 2 and its significance was tested using the Q statistics. Subgroup analyses of the types of controls, PTSD assessment tools, and assayed methods used in the studies were performed to explore sources of heterogeneity among studies. Random-effects models were used to combine results from selected studies. A total of 1,388 articles were identified, of which 27 were included in the final analysis. Heterogeneity was high; hence random-effects models were used to combine results of selected studies. Results revealed significantly higher norepinephrine levels in people with PTSD than in the controls [standardized mean difference (SMD) = 0.35, 95% confidence interval (CI): 0.13 to 0.57, p = 0.002]. No difference was found in dopamine and epinephrine concentrations between the two groups. Elevated norepinephrine levels may be an important indicator for PTSD.

A mounting body of evidence indicates that adolescents are specially more susceptible to alcohol influence than adults. However, the mechanisms underlying this phenomenon remain poorly understood. Astrocyte-mediated gliotransmission is crucial for hippocampal plasticity and recently, the opening of hemichannels and pannexons has been found to participate in both processes. Here, we evaluated whether adolescent rats exposed to ethanol exhibit changes in the activity of astrocyte hemichannels and pannexons in the hippocampus, as well as alterations in astrocyte arborization and cytokine levels. Adolescent rats were subjected to ethanol (3.0 g/kg) for two successive days at 48-h periods over 14 days. The opening of hemichannels and pannexons was examined in hippocampal slices by dye uptake, whereas hippocampal cytokine levels and astroglial arborization were determined by ELISA and Sholl analysis, respectively. We found that adolescent ethanol exposure increased the opening of connexin 43 (Cx43) hemichannels and pannexin-1 (Panx1) channels in astrocytes. Blockade of p38 mitogen-activated protein kinase (MAPK), inducible nitric oxide synthase (iNOS) and cyclooxygenases (COXs), as well as chelation of intracellular Ca2+, drastically reduced the ethanol-induced channel opening in astrocytes. Importantly, ethanol-induced Cx43 hemichannel and Panx1 channel activity was correlated with increased levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6 in the hippocampus, as well as with profound alterations in astrocyte arbor complexity. Thus, we propose that uncontrolled opening of astrocyte hemichannels and pannexons may contribute not only to the glial dysfunction and neurotoxicity caused by adolescent alcohol consumption, but also to the pathogenesis of alcohol use disorders in the adulthood.

Prior knowledge structures (or schemas) confer multiple behavioral benefits. First, when we encounter information that fits with prior knowledge structures, this information is generally better learned and remembered. Second, prior knowledge can support prospective planning. In humans, memory enhancements related to prior knowledge have been suggested to be supported, in part, by computations in prefrontal and medial temporal lobe (MTL) cortex. Moreover, animal studies further implicate a role for the hippocampus in schema-based facilitation and in the emergence of prospective planning signals following new learning. To date, convergence across the schema-enhanced learning and memory literature may be constrained by the predominant use of hippocampally dependent spatial navigation paradigms in rodents, and non-spatial list-based learning paradigms in humans. Here, we targeted this missing link by examining the effects of prior knowledge on human navigational learning in a hippocampally dependent virtual navigation paradigm that closely relates to foundational studies in rodents. Outside the scanner, participants overlearned Old Paired Associates (OPA- item-location associations) in multiple spatial environments, and they subsequently learned New Paired Associates (NPA-new item-location associations) in the environments while undergoing fMRI. We hypothesized that greater OPA knowledge precision would positively affect NPA learning, and that the hippocampus would be instrumental in translating this new learning into prospective planning of navigational paths to NPA locations. Behavioral results revealed that OPA knowledge predicted one-shot learning of NPA locations, and neural results indicated that one-shot learning was predicted by the rapid emergence of performance-predictive prospective planning signals in hippocampus. Prospective memory relationships were not significant in parahippocampal cortex and were marginally dissociable from the primary hippocampal effect. Collectively, these results extend understanding of how schemas impact learning and performance, showing that the precision of prior spatial knowledge is important for future learning in humans, and that the hippocampus is involved in translating this knowledge into new goal-directed behaviors.

The preservation of cognitive abilities with aging is a priority both for individuals and nations given the aging populations of many countries. Recently the gut microbiome has been identified as a new territory to explore in relation to cognition. Experiments using rodents have identified a link between the gut microbiome and cognitive function, particularly that low microbial diversity leads to poor cognition function. Similar studies in humans could identify novel targets to encourage healthy cognition in an aging population. Here, we investigate the association of gut microbiota and cognitive function in a human cohort considering the influence of physical frailty. We analyzed 16S rRNA gene sequence data, derived from fecal samples obtained from 1,551 individuals over the age of 40. Cognitive data was collected using four cognitive tests: verbal fluency (n = 1,368), Deary-Liewald Reaction Time Test (DLRT; n = 873), Mini Mental State Examination (recall; n = 1,374) and Paired Associates Learning from the Cambridge Neuropsychological Test Automated Battery (CANTAB-PAL; n = 405). We use mixed effects models to identify associations with alpha diversity, operational taxonomic units (OTUs) and taxa and performed further analyses adjusting for physical frailty. We then repeated the analyses in a subset of individuals with dietary data, also excluding those using medications shown to influence gut microbiome composition. DLRT and verbal fluency were negatively associated with alpha diversity of the gut microbiota (False-Discovery Rate, FDR, p < 0.05). However, when considering frailty as a covariate, only associations between the DLRT and diversity measures remained. Repeating analyses excluding Proton pump inhibitor (PPI) and antibiotic users and accounting for diet, we similarly observe significant negative associations between the DLRT and alpha diversity measures and a further negative association between DLRT and the abundance of the order Burkholderiales that remains significant after adjusting for host frailty. This highlights the importance of considering concurrent differences in physical health in studies of cognitive performance and suggests that physical health has a relatively larger association with the gut microbiome. However, the frailty independent cognitive-gut microbiota associations that were observed might represent important targets for further research, with potential for use in diagnostic surveillance in cognitive aging and interventions to improve vitality.

The term "metabolic syndrome" (MetS) refers to a combination of diabetes, high blood pressure, and obesity. The origin of MetS includes a combination of multiple factors, such as sedentary lifestyle, unhealthy diet choice, and genetic factors. MetS is highly prevalent and adversely affects the general population by elevating risk of cardiovascular complications, organ failure, and much other pathology associated with late-stage diabetes. Anthocyanins (ANTs) are health-promoting bioactive compounds belonging to the flavonoids subclass of polyphenols. Numerous studies have reported the potential therapeutic benefits on MetS syndrome and diabetes from fruits rich in ANTs. This review summarizes the role of several dietary ANTs on preventing and managing MetS as well as the pharmacological mechanisms and biopharmaceutical features of their action. We also discuss potential nanoformulation and encapsulation approaches that may enhance the bioefficacy of ANTs in MetS. Experiments have demonstrated that ANTs may attenuate the symptoms of MetS via improving insulin resistance, impaired glucose tolerance, dyslipidaemia, cholesterol levels, hypertension, blood glucose, protecting β cells, and preventing free radical production. In brief, the intake of ANT-rich supplements should be considered due to their plausible ability for prevention and management of MetS. Additionally, randomized double-blind clinical trials are obligatory for evaluating the bioefficacy and pharmacological mechanisms of ANTs and their pharmaceutical formulations in patients with MetS.