A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics.

The enzyme kynurenine 3-monooxygenase (KMO) operates at a critical branch-point in the kynurenine pathway (KP), the major route of tryptophan metabolism. As the KP has been implicated in the pathogenesis of several human diseases, KMO and other enzymes that control metabolic flux through the pathway are potential therapeutic targets for these disorders. While KMO is localized to the outer mitochondrial membrane in eukaryotic organisms, no mitochondrial role for KMO has been described. In this study, KMO deficient Drosophila melanogaster were investigated for mitochondrial phenotypes in vitro and in vivo. We find that a loss of function allele or RNAi knockdown of the Drosophila KMO ortholog (cinnabar) causes a range of morphological and functional alterations to mitochondria, which are independent of changes to levels of KP metabolites. Notably, cinnabar genetically interacts with the Parkinson’s disease associated genes Pink1 and parkin, as well as the mitochondrial fission gene Drp1, implicating KMO in mitochondrial dynamics and mitophagy, mechanisms which govern the maintenance of a healthy mitochondrial network. Overexpression of human KMO in mammalian cells finds that KMO plays a role in the post-translational regulation of DRP1. These findings reveal a novel mitochondrial role for KMO, independent from its enzymatic role in the kynurenine pathway

Scans per day as predictors of optimal glycemic control in people with type 1 diabetes mellitus using flash glucose monitoring: What number of scans per day should raise a red flag?

Aims: This study aimed to determine the minimum frequency of flash glucose monitoring (FGM) scans necessary for optimal glycemic control in patients with type 1 diabetes (T1D). Methods: Data were collected from 692 patients (47.5% female, with a median age of 47.4 years) who used FGM systems daily and recorded their clinical variables and device data. Results: Logistic regression models showed that performing more than 12 scans per day was associated with improved T1D control (OR = 4.22, p < 0.001) and a reduction in HbA1c (7.6 vs 7.0%, 60–53 mmol/mol p < 0.001). However, those performing less than 6 scans showed no improvement in HbA1c (7.9 vs 7.8%, 63–61 mmol/mol p = 0.514). Thirteen daily scans were determined as the optimal cutoff point for predicting optimal glycemic control using a maximally selected rank algorithm. Significant reductions were observed in mean glucose (< 0.001), coefficient of variation (< 0.001), HbA1c (< 0.001), and an increase in TIR (< 0.001) in patients who performed more than 12 daily scans. Conclusions: The results suggest that a higher frequency of daily scans by T1D patients using FGM systems leads to improved chronic glycemic control. The minimum recommended frequency for optimal control is 13 scans per day, and more than 6 daily scans are needed to improve HbA1

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.info:eu-repo/semantics/publishedVersio

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Exploiting Quantitative Trait Analysis in Yeast to Identify Genetic Modifiers of Huntington’s and Parkinson’s Disease

Huntington’s disease (HD) and Parkinson’s disease (PD) are neurodegenerative diseases (NDs) in which protein misfolding/accumulation are associated with neuronal dysfunction and loss. HD is a hereditary disease caused by the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. Although the number of repeats correlates with the severity of the disease, there is still variability amongst individuals with the same number of repeats. PD is the second most common ND and, although there are familial forms, most PD cases are sporadic, caused by a combination of environmental and genetic risk factors, one of which is the SNCA gene that encodes α-Synuclein (αSyn). To find candidate genetic modifiers responsible for the variability in severity/risk in HD and PD, quantitative trait loci (QTL) analysis was performed in yeast. The effect of mutant HTT (mHTT) and αSyn on growth was assessed in 14 genetically diverse natural isolates using PHENOS - a software that allows the analysis of yeast growth on solid media -. The strains that showed the most extreme phenotypes (SX1, HN6 and BJ20) were intercrossed to generate a large population of stains with new combinations of alleles. The QTL analysis was performed using the effect on growth of mHTT and αSyn separately, and the possible modifier genes that were present in both lists were further validated in yeast and fruit flies by overexpressing or downregulating them. Through this work we identified four genes whose deletion enhanced the toxicity of the proteins: PPM1 and TIF6 enhanced both mHTT and αSyn toxicity, while PER1 and GIN4 only enhanced αSyn toxicity. The overexpression (OE) of TIF6 was protective against mHTT and αSyn toxicity in yeast. In conclusion, these four genes, specially TIF6, are interesting therapeutic targets for HD and PD and should be validated in more complex models.</p

A new pachyrukhine (Notoungulata: Typotheria) from the late Early Miocene of south-central Chile

Here, we studied several Pachyrukhinae (Mammalia: Notoungulata: Typotheria: Hegetotheriidae) fossils recovered from the late Early Miocene (Santacrucian SALMA) beds of the Cura-Mallín Formation at the Laguna del Laja (Biobío Region, Chile). The specimens are referred to a new species of the genus Pachyrukhos Ameghino, 1885, P. ngenwinkul sp. nov. The holotype of this taxon is a relatively well-preserved articulated skull and mandibles, which was investigated using 3D X-ray Microscopy. The new taxon is distinguished from other Pachyrukhos species by having a p2 smaller than p3, M3 mesiodistally shorter (around 30%) than M1, and upper premolars of a rather subtriangular contour. Pachyrukhos ngenwinkul is the most common mammal and the smallest-sized (with ~2 kg of body mass) notoungulate found in the Santacrucian assemblage at the Laguna del Laja. The discovery of this new taxon improves our understanding of the Neogene pachyrukhine diversity in southern South America and highlights the potential of the Chilean Andean Cenozoic deposits in revealing a hidden diversity of extinct continental mammals.Fil: Solórzano, Andrés. Universidad Católica de Maule; ChileFil: Encinas, Alfonso. Universidad de Concepción; ChileFil: Kramarz, Alejandro Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; ArgentinaFil: Carrasco, Gabriel. Servicios Científicos Educativos y Turismo Científico Chile; ChileFil: Núñez Flores, Mónica. Universidad de Antofagasta;Fil: Bobe, René. University of Oxford; Reino Unid

A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics.

The enzyme kynurenine 3-monooxygenase (KMO) operates at a critical branch-point in the kynurenine pathway (KP), the major route of tryptophan metabolism. As the KP has been implicated in the pathogenesis of several human diseases, KMO and other enzymes that control metabolic flux through the pathway are potential therapeutic targets for these disorders. While KMO is localized to the outer mitochondrial membrane in eukaryotic organisms, no mitochondrial role for KMO has been described. In this study, KMO deficient Drosophila melanogaster were investigated for mitochondrial phenotypes in vitro and in vivo. We find that a loss of function allele or RNAi knockdown of the Drosophila KMO ortholog (cinnabar) causes a range of morphological and functional alterations to mitochondria, which are independent of changes to levels of KP metabolites. Notably, cinnabar genetically interacts with the Parkinson's disease associated genes Pink1 and parkin, as well as the mitochondrial fission gene Drp1, implicating KMO in mitochondrial dynamics and mitophagy, mechanisms which govern the maintenance of a healthy mitochondrial network. Overexpression of human KMO in mammalian cells finds that KMO plays a role in the post-translational regulation of DRP1. These findings reveal a novel mitochondrial role for KMO, independent from its enzymatic role in the kynurenine pathway

Engineering a Pro-Osteogenic Secretome through the Transient Silencing of the Gene Encoding Secreted Frizzled Related Protein 1

The evidence sustaining the regenerative properties of mesenchymal stem cells' (MSCs) secretome has prompted a paradigm change, where MSCs have shifted from being considered direct contributors to tissue regeneration toward being seen as cell factories for producing biotech medicines. We have previously designed a method to prime MSCs towards osteogenic differentiation by silencing the Wnt/β-Catenin inhibitor Sfpr1. This approach produces a significant increase in bone formation in osteoporotic mice. In this current work, we set to investigate the contribution of the secretome from the MSCs where Sfrp1 has been silenced, to the positive effect seen on bone regeneration in vivo. The conditioned media (CM) of the murine MSCs line C3H10T1/2, where Sfrp1 has been transiently silenced (CM-Sfrp1), was found to induce, in vitro, an increase in the osteogenic differentiation of this same cell line, as well as a decrease of the expression of the Wnt inhibitor Dkk1 in murine osteocytes ex vivo. A reduction in the RANKL/OPG ratio was also detected ex vivo, suggesting a negative effect of CM-Sfrp1 on osteoclastogenesis. Moreover, this CM significantly increases the mineralization of human primary MSCs isolated from osteoportotic patients in vitro. Proteomic analysis identified enrichment of proteins involved in osteogenesis within the soluble and vesicular fractions of this secretome. Altogether, we demonstrate the pro-osteogenic potential of the secretome of MSCs primmed in this fashion, suggesting that this is a valid approach to enhance the osteo-regenerative properties of MSCs' secretomeFunding: This research was funded by a grant from the Spanish Ministerio de Economía y competitividad (Project PID2021-127493OB-C21), one grant from the Instituto de Salud Carlos III (PI22/0264) and two grants from the National Institutes of Health (R37-CA251763, R01-CA209882) To J.D.-C., D.G.-S. and A.G.-G. were funded by two grants from the Instituto de Investigación Marqués de Valdecilla-IDIVAL (PREVAL19/02 and PREVAL 20/01). M.DD was funded by the “Investigo Program”, part of the “Plan Nacional de Recuperación, Transformación y Resiliencia” from The Spanish Governmen

Discovering HIV related information by means of association rules and machine learning

Acquired immunodeficiency syndrome (AIDS) is still one of the main health problems worldwide. It is therefore essential to keep making progress in improving the prognosis and quality of life of affected patients. One way to advance along this pathway is to uncover connections between other disorders associated with HIV/AIDS-so that they can be anticipated and possibly mitigated. We propose to achieve this by using Association Rules (ARs). They allow us to represent the dependencies between a number of diseases and other specific diseases. However, classical techniques systematically generate every AR meeting some minimal conditions on data frequency, hence generating a vast amount of uninteresting ARs, which need to be filtered out. The lack of manually annotated ARs has favored unsupervised filtering, even though they produce limited results. In this paper, we propose a semi-supervised system, able to identify relevant ARs among HIV-related diseases with a minimal amount of annotated training data. Our system has been able to extract a good number of relationships between HIV-related diseases that have been previously detected in the literature but are scattered and are often little known. Furthermore, a number of plausible new relationships have shown up which deserve further investigation by qualified medical experts