Liver fibrosis is a reversible wound-healing response involving TGFβ1/SMAD activation of hepatic stellate cells (HSCs). It results from excessive deposition of extracellular matrix components and can ...lead to impairment of liver function. Here, we show that vitamin D receptor (VDR) ligands inhibit HSC activation by TGFβ1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGFβ1 signaling causes a redistribution of genome-wide VDR-binding sites (VDR cistrome) in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGFβ1-dependent chromatin remodeling. In the presence of VDR ligands, VDR binding to the coregulated genes reduces SMAD3 occupancy at these sites, inhibiting fibrosis. These results reveal an intersecting VDR/SMAD genomic circuit that regulates hepatic fibrogenesis and define a role for VDR as an endocrine checkpoint to modulate the wound-healing response in liver. Furthermore, the findings suggest VDR ligands as a potential therapy for liver fibrosis.
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•Vitamin D receptor (VDR) ligands inhibit hepatic stellate cell activation and fibrosis•Vdr knockout mice spontaneously develop liver fibrosis•TGFβ1 signaling shifts the genome-wide binding locations of VDR•VDR antagonizes SMAD3/TGFβ1 activation of profibrotic genes
In the absence of vitamin D receptor (VDR) signaling, SMADs respond to liver injury by activating a set of genes in hepatic stellate cells that cause fibrosis and liver impairment. Paradoxically, SMAD activity also enables repression of fibrosis by making the chromatin around SMAD target sites more accessible to VDR, which, in the presence of ligands, binds and inhibits SMAD activity.
Objectives This study sought to determine the utility of quantitation of right ventricular (RV) function in predicting RV failure in patients undergoing left ventricular assist device (LVAD) ...implantation. Background Clinical evaluation alone seems insufficient for predicting RV failure, an important cause of morbidity and mortality after LVAD implantation. Methods Clinical, hemodynamic, and echocardiographic data were collected on 117 patients undergoing LVAD implantation. Standard pre-procedural echocardiographic RV measurements were supplemented by velocity vector imaging of RV free wall longitudinal strain. RV failure was defined as the need for placement of an RV assist device, or the use of inotropic agents for >14 days. Receiver operating characteristic curves were derived, with resampling to generate valid estimates of prediction accuracy. A net reclassification index was calculated for comparison of risk scores. Results RV failure occurred in 47 of 117 patients (40%). There was a significant difference in peak strain between patients with and without RV failure (–9.0% vs. –12.2%; p < 0.01). A peak strain cutoff of –9.6% predicted RV failure with 76% specificity and 68% sensitivity. In a multivariate logistic regression analysis including variables from the established Michigan RV risk score, peak strain remained an independent predictor of RV failure. RV strain was incremental to the Michigan risk score as a predictor of RV failure (area under the receiver operating characteristic curve: 0.77 vs. 0.66; p < 0.01). The net reclassification index with strain was +10.4%. Conclusions Reduced RV free wall peak longitudinal strain was associated with an increased risk for RV failure among patients undergoing LVAD implantation.
Humans and most animals can learn new tasks without forgetting old ones. However, training artificial neural networks (ANNs) on new tasks typically causes them to forget previously learned tasks. ...This phenomenon is the result of “catastrophic forgetting,” in which training an ANN disrupts connection weights that were important for solving previous tasks, degrading task performance. Several recent studies have proposed methods to stabilize connection weights of ANNs that are deemed most important for solving a task, which helps alleviate catastrophic forgetting. Here, drawing inspiration from algorithms that are believed to be implemented in vivo, we propose a complementary method: adding a context-dependent gating signal, such that only sparse, mostly nonoverlapping patterns of units are active for any one task. This method is easy to implement, requires little computational overhead, and allows ANNs to maintain high performance across large numbers of sequentially presented tasks, particularly when combined with weight stabilization. We show that this method works for both feedforward and recurrent network architectures, trained using either supervised or reinforcement-based learning. This suggests that using multiple, complementary methods, akin to what is believed to occur in the brain, can be a highly effective strategy to support continual learning.
To determine the incidence of major adverse events related to a large volume of image-guided liver biopsies performed at our institution over a 12-year period and to identify risk factors for major ...bleeding events.
A retrospective analysis of an internally maintained biopsy registry was performed. The analysis revealed that 6613 image-guided liver biopsies were performed in 5987 adult patients between December 7, 2001, and December 31, 2013. Liver biopsies were performed using real-time ultrasound guidance and a spring-loaded biopsy device, with rare exceptions. Adverse events considered major and included in this study were hematoma, infection, pneumothorax, hemothorax, and death. Using data from the biopsy registry, we evaluated statistically significant risk factors (P<.05) for hematoma related to image-guided liver biopsy, including coagulation status, biopsy technique, and medications.
A total of 49 acute and delayed major adverse events (0.7%) occurred after 6613 liver biopsy events. The incidence of hematoma requiring transfusion and/or angiographic intervention was 0.5% (34 of 6613). The incidence of infection was 0.1% (8 of 6613), and that of hemothorax was 0.06% (4 of 6613). No patient (0%) incurred a pneumothorax after biopsy. Three patients (0.05%) died within 30 days of liver biopsy, 1 being directly related to biopsy. Thirty-eight of 46 major adverse events (83%) presented acutely (within 24 hours). More than 2 biopsy passes, platelets 50,000/μL or less, and female sex were statistically significant risk factors for postbiopsy hemorrhage.
Image-guided liver biopsy performed by subspecialized interventionalists at a tertiary medical center is safe when the platelet count is greater than 50,000/μL. With appreciation of specific risk factors, safety outcomes of this procedure can be optimized in both general and specialized centers.
Oncometabolites in renal cancer Yong, Cissy; Stewart, Grant D; Frezza, Christian
Nature reviews. Nephrology,
03/2020, Letnik:
16, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The study of cancer metabolism has evolved vastly beyond the remit of tumour proliferation and survival with the identification of the role of 'oncometabolites' in tumorigenesis. Simply defined, ...oncometabolites are conventional metabolites that, when aberrantly accumulated, have pro-oncogenic functions. Their discovery has led researchers to revisit the Warburg hypothesis, first postulated in the 1950s, of aberrant metabolism as an aetiological determinant of cancer. As such, the identification of oncometabolites and their utilization in diagnostics and prognostics, as novel therapeutic targets and as biomarkers of disease, are areas of considerable interest in oncology. To date, fumarate, succinate, L-2-hydroxyglutarate (L-2-HG) and D-2-hydroxyglutarate (D-2-HG) have been characterized as bona fide oncometabolites. Extensive metabolic reprogramming occurs during tumour initiation and progression in renal cell carcinoma (RCC) and three oncometabolites - fumarate, succinate and L-2-HG - have been implicated in this disease process. All of these oncometabolites inhibit a superfamily of enzymes known as α-ketoglutarate-dependent dioxygenases, leading to epigenetic dysregulation and induction of pseudohypoxic phenotypes, and also have specific pro-oncogenic capabilities. Oncometabolites could potentially be exploited for the development of novel targeted therapies and as biomarkers of disease.
Few well-controlled studies have comprehensively examined the effects of very-low-carbohydrate diets on type 2 diabetes (T2D).
We compared the effects of a very-low-carbohydrate, high-unsaturated ...fat, low-saturated fat (LC) diet with a high-carbohydrate, low-fat (HC) diet on glycemic control and cardiovascular disease risk factors in T2D after 52 wk.
In this randomized controlled trial that was conducted in an outpatient research clinic, 115 obese adults with T2D mean ± SD age: 58 ± 7 y; body mass index (in kg/m(2)): 34.6 ± 4.3; glycated hemoglobin (HbA1c): 7.3 ± 1.1%; duration of diabetes: 8 ± 6 y were randomly assigned to consume either a hypocaloric LC diet 14% of energy as carbohydrate (carbohydrate <50 g/d), 28% of energy as protein, and 58% of energy as fat (<10% saturated fat) or an energy-matched HC diet 53% of energy as carbohydrate, 17% of energy as protein, and 30% of energy as fat (<10% saturated fat) combined with supervised aerobic and resistance exercise (60 min; 3 d/wk). Outcomes were glycemic control assessed with use of measurements of HbA1c, fasting blood glucose, glycemic variability assessed with use of 48-h continuous glucose monitoring, diabetes medication, weight, blood pressure, and lipids assessed at baseline, 24, and 52 wk.
Both groups achieved similar completion rates (LC diet: 71%; HC diet: 65%) and mean (95% CI) reductions in weight LC diet: -9.8 kg (-11.7, -7.9 kg); HC diet: -10.1 kg (-12.0, -8.2 kg), blood pressure LC diet: -7.1 (-10.6, -3.7)/-6.2 (-8.2, -4.1) mm Hg; HC diet: -5.8 (-9.4, -2.2)/-6.4 (-8.4, -4.3) mm Hg, HbA1c LC diet: -1.0% (-1.2%, -0.7%); HC diet: -1.0% (-1.3%, -0.8%), fasting glucose LC diet: -0.7 mmol/L (-1.3, -0.1 mmol/L); HC diet: -1.5 mmol/L (-2.1, -0.8 mmol/L), and LDL cholesterol LC diet: -0.1 mmol/L (-0.3, 0.1 mmol/L); HC diet: -0.2 mmol/L (-0.4, 0.03 mmol/L) (P-diet effect ≥ 0.10). Compared with the HC-diet group, the LC-diet group achieved greater mean (95% CI) reductions in the diabetes medication score LC diet: -0.5 arbitrary units (-0.7, -0.4 arbitrary units); HC diet: -0.2 arbitrary units (-0.4, -0.06 arbitrary units); P = 0.02, glycemic variability assessed by measuring the continuous overall net glycemic action-1 LC diet: -0.5 mmol/L (-0.6, -0.3 mmol/L); HC diet: -0.05 mmol/L (-0.2, -0.1 mmol/L); P = 0.003, and triglycerides LC diet: -0.4 mmol/L (-0.5, -0.2 mmol/L); HC diet: -0.01 mmol/L (-0.2, 0.2 mmol/L); P = 0.001 and greater mean (95% CI) increases in HDL cholesterol LC diet: 0.1 mmol/L (0.1, 0.2 mmol/L); HC diet: 0.06 mmol/L (-0.01, 0.1 mmol/L); P = 0.002.
Both diets achieved substantial weight loss and reduced HbA1c and fasting glucose. The LC diet, which was high in unsaturated fat and low in saturated fat, achieved greater improvements in the lipid profile, blood glucose stability, and reductions in diabetes medication requirements, suggesting an effective strategy for the optimization of T2D management. This trial was registered at www.anzctr.org.au as ACTRN12612000369820.
The eukaryotic replicative helicase CMG is a closed ring around double-stranded (ds)DNA at origins yet must transition to single-stranded (ss)DNA for helicase action. CMG must also handle repair ...intermediates, such as reversed forks that lack ssDNA. Here, using correlative single-molecule fluorescence and force microscopy, we show that CMG harbors a ssDNA gate that enables transitions between ss and dsDNA. When coupled to DNA polymerase, CMG remains on ssDNA, but when uncoupled, CMG employs this gate to traverse forked junctions onto dsDNA. Surprisingly, CMG undergoes rapid diffusion on dsDNA and can transition back onto ssDNA to nucleate a functional replisome. The gate—distinct from that between Mcm2/5 used for origin loading—is intrinsic to CMG; however, Mcm10 promotes strand passage by enhancing the affinity of CMG to DNA. This gating process may explain the dsDNA-to-ssDNA transition of CMG at origins and help preserve CMG on dsDNA during fork repair.
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•Eukaryotic CMG helicase employs a gate in its ring to switch between ss and dsDNA•Gating enables CMG to vacate a replication fork when uncoupled from DNA polymerase•CMG diffuses on dsDNA and uses this gate to enter a fork and restart replication•Mcm10, an essential replisome factor, tethers CMG to DNA during the gating process
A “gate” in the eukaryotic CMG helicase allows it to switch between single- and double-stranded DNA, providing an explanation for how replication forks can continue past DNA lesions and restart after stalling
Nucleic acid extraction and sequencing of genes from organisms within environmental samples encompasses a variety of techniques collectively referred to as environmental DNA or ‘eDNA’. The key ...advantages of eDNA analysis include the detection of cryptic or otherwise elusive organisms, large-scale sampling with fewer biases than specimen-based methods, and generation of data for molecular systematics. These are particularly relevant for parasitology because parasites can be difficult to locate and are morphologically intractable and genetically divergent. However, parasites have rarely been the focus of eDNA studies. Focusing on eukaryote parasites, we review the increasing diversity of the ‘eDNA toolbox’. Combining eDNA methods with complementary tools offers much potential to understand parasite communities, disease risk, and parasite roles in broader ecosystem processes such as food web structuring and community assembly.
Transcriptional coregulators control the activity of many transcription factors and are thought to have wide-ranging effects on gene expression patterns. We show here that muscle-specific loss of ...nuclear receptor corepressor 1 (NCoR1) in mice leads to enhanced exercise endurance due to an increase of both muscle mass and of mitochondrial number and activity. The activation of selected transcription factors that control muscle function, such as MEF2, PPARβ/δ, and ERRs, underpins these phenotypic alterations. NCoR1 levels are decreased in conditions that require fat oxidation, resetting transcriptional programs to boost oxidative metabolism. Knockdown of
gei-8, the sole
C. elegans NCoR homolog, also robustly increased muscle mitochondria and respiration, suggesting conservation of NCoR1 function. Collectively, our data suggest that NCoR1 plays an adaptive role in muscle physiology and that interference with NCoR1 action could be used to improve muscle function.
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► Muscle mass and oxidative capacity increase in muscle-specific
NCoR1
−/−
mice ► NCoR1 modulates the activity of transcription factors MEF2, PPARβ/δ, and ERRs ► NCoR1 levels are reduced by physiological conditions that favor fat oxidation ► NCoR1 impact on muscle function is conserved in
C. elegans
Exercise capacity and mitochondrial oxidation are enhanced by the loss of a transcriptional cofactor in muscle cells through modulation of a select set of transcription factors that includes PPARβ/δ.
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