Highlights • Astrocytes are the housekeeping cells of the CNS controlling homeostasis and defence. • In ageing, astrocytes undergo complex region-specific remodelling. • In AD, generalised ...astrodegeneration may contribute to synaptic deficits.
Background
Magnetic resonance imaging (MRI) is the most accurate imaging technique for left ventricular ejection fraction (LVEF) quantification, but as yet the prognostic value of LVEF assessment at ...any time after ST‐segment elevation myocardial infarction (STEMI) for subsequent major adverse cardiac event (MACE) prediction is uncertain.
Purpose
To explore the prognostic impact of MRI‐derived LVEF at any time post‐STEMI to predict subsequent MACE (cardiovascular death or re‐admission for acute heart failure).
Study Type
Prospective.
Population
One thousand thirteen STEMI patients were included in a multicenter registry.
Field Strength/Sequence
1.5‐T. Balanced steady‐state free precession (cine imaging) and segmented inversion recovery steady‐state free precession (late gadolinium enhancement) sequences.
Assessment
Post‐infarction MRI‐derived LVEF (reduced r: <40%; mid‐range mr: 40%–49%; preserved p: ≥50%) was sequentially quantified at 1 week and after >3 months of follow‐up.
Statistical Tests
Multi‐state Markov model to determine the prognostic value of each LVEF state (r‐, mr‐ or p‐) at any time point assessed to predict subsequent MACE. A P‐value <0.05 was considered to be statistically significant.
Results
During a 6.2‐year median follow‐up, 105 MACE (10%) were registered. Transitions toward improved LVEF predominated and only r‐LVEF (at any time assessed) was significantly related to a higher incidence of subsequent MACE. The observed transitions from r‐LVEF, mr‐LVEF, and p‐LVEF states to MACE were: 15.3%, 6%, and 6.7%, respectively. Regarding the adjusted transition intensity ratios, patients in r‐LVEF state were 4.52‐fold more likely than those in mr‐LVEF state and 5.01‐fold more likely than those in p‐LVEF state to move to MACE state. Nevertheless, no significant differences were found in transitions from mr‐LVEF and p‐LVEF states to MACE state (P‐value = 0.6).
Data Conclusion
LVEF is an important MRI index for simple and dynamic post‐STEMI risk stratification. Detection of r‐LVEF by MRI at any time during follow‐up identifies a subset of patients at high risk of subsequent events.
Level of Evidence
2
Technical Efficacy Stage
2
In this article, a novel robust data-driven model-free predictive control framework based on the I/O data of the controlled plants, which is performed by incorporating the neural predictor-based ...model-free adaptive control and finite control-set model predictive control, is first proposed. The salient feature of the suggested framework is that the uncertainties, such as unmodeled dynamics and external disturbances, can be explicitly addressed in controlled systems. From a practical standpoint, however, the potential of this proposal is limited by a significantly increased online computational complexity, which makes it difficult to implement. To circumvent this limitation, a supervised imitation learning technique using data labeled is developed to imitate the known suggested controller, which the majority of the online computational burden can be transformed into offline computing by utilizing a trained artificial neural network subject to robustness characteristics. In particular, this development motivates a much simpler robust predictive control solution, which is convenient to implement in applications. Thus, by this proposal, the online implementation of much more complex predictive control strategies is made possible, and it explores a new possibility for future development of the complex control methodology. Finally, extensive simulative and experimental investigations for modular multilevel converter validate the interest and viability of the proposed design methodology.
This article aims to first focus on an improvement of finite control-set model predictive control strategy for power converters that is based on reinforcement learning event-triggered predictive ...control architecture with the help of adaptive dynamic programming technique and event-triggered mechanism subject to system uncertainties. Our development, endowed with the merits of reinforcement learning and event-triggered control as well as predictive control solution, is able to alleviate the issues of parametric uncertainties and high switching frequency inherent in the existing scheme, while retaining the merits of the finite control-set model predictive control. Finally, this proposal is experimentally evaluated, where robust performance tests confirm the interest and applicability of the proposed control methodology.
Adherence to the Mediterranean Diet (MD) has been associated with a reduced incidence of neurodegenerative diseases and better cognitive performance. Virgin olive oil, the main source of lipids in ...the MD, is rich in minor phenolic components, particularly hydroxytyrosol (HT). HT potent antioxidant and anti-inflammatory actions have attracted researchers' attention and may contribute to neuroprotective effects credited to MD. In this review HT bioavailability and pharmacokinetics are presented prior to discussing health beneficial effects. In vitro and in vivo neuroprotective effects together with its multiple mechanisms of action are reviewed. Other microconstituents of olive oil are also considered due to their potential neuroprotective effects (oleocanthal, triterpenic acids). Finally, we discuss the potential role of HT as a therapeutic tool in the prevention of neurodegenerative diseases.
Cranberries have multiple health effects but their impact on gut microbiota has not been examined in randomized controlled feeding trials. We evaluated the relationship between the microbiota and ...cranberries in the context of an animal-based diet. In a randomized, double-blind, cross-over, controlled design trial, 11 healthy adults consumed for 5 days each a control diet (animal-based diet plus 30 g/day placebo powder) and a cranberry diet (animal-based diet plus 30 g/day freeze-dried whole cranberry powder). The animal-based diet included meats, dairy products, and simple sugars. Stool, urine, and blood samples were obtained before and after each intervention phase. As compared to the pre-control diet, control diet modified 46 taxonomic clades, including an increase in the abundance of Firmicutes and decrease in Bacteroidetes. Moreover, it increased bacteria-derived deoxycholic acid and decreased acetate and butyrate in stool. As compared to the post-intervention phase of control diet, the cranberry diet modified 9 taxonomic clades, including a decrease in the abundance of Firmicutes and increase in Bacteroidetes. Further, the cranberry diet attenuated control diet-induced increase in secondary bile acids and decrease in short-chain fatty acids (SCFA), and increased urinary anthocyanins and bacterially derived phenolic acids. No changes were found in fecal trimethylamine and plasma cytokines. In conclusion, an animal-based diet altered the microbiota composition to a less favorable profile, increased carcinogenic bile acids, and decreased beneficial SCFA. Cranberries attenuated the impact of the animal-based diet on microbiota composition, bile acids, and SCFA, evidencing their capacity to modulate the gut microbiota.
Alzheimer’s disease (AD) is the most common cause of dementia. The pathophysiology of this disease is characterized by the accumulation of amyloid-β, leading to the formation of senile plaques, and ...by the intracellular presence of neurofibrillary tangles based on hyperphosphorylated tau protein. In the therapeutic approach to AD, we can identify three important fronts: the approved drugs currently available for the treatment of the disease, which include aducanumab, donepezil, galantamine, rivastigmine, memantine, and a combination of memantine and donepezil; therapies under investigation that work mainly on Aβ pathology and tau pathology, and which include γ-secretase inhibitors, β-secretase inhibitors, α-secretase modulators, aggregation inhibitors, metal interfering drugs, drugs that enhance Aβ clearance, inhibitors of tau protein hyperphosphorylation, tau protein aggregation inhibitors, and drugs that promote the clearance of tau, and finally, other alternative therapies designed to improve lifestyle, thus contributing to the prevention of the disease. Therefore, the aim of this review was to analyze and describe current treatments and possible future alternatives in the therapeutic approach to AD.
Abstract In order to maintain cellular homeostasis, the activity of several thousand proteins needs to be carefully orchestrated in a spatio-temporal manner, and multiple layers of regulation exist ...to ensure that protein function is properly carried out. Critical regulatory mechanisms include trafficking of proteins to specific subcellular compartments and post-translational modifications (PTMs), such as ubiquitylation or sumoylation. These mechanisms often operate in a co-ordinated manner to determine the levels, localization and activity of a protein. In particular, the functional relationships between active nucleocytoplasmic transport and the ubiquitin/SUMO modification pathways are becoming progressively elucidated. In this review, we focus on the interplay between these two processes, and its importance in cancer. We begin by presenting an overview of the processes of protein ubiquitylation and sumoylation, with an emphasis on the cross-regulation that exists between the nuclear transport machinery and the ubiquitin/SUMO modification enzymes. Next, we focus on the regulation of the important tumor proteins p53 and PTEN as examples to illustrate how these processes cooperate to modulate the activity of cancer-related proteins. Importantly, novel drugs are being developed that target proteins playing a role in nuclear transport (e.g. the nuclear export receptor CRM1) and ubiquitin/SUMO modifications (e.g. ubiquitin E3 ligases and deubiquitinases). A deeper understanding of the interplay between these processes may facilitate in the future the rational combination of these novel agents.
Abstract Tauopathies are neurodegenerative diseases, sporadic or familial, mainly characterized by dementia and parkinsonism associated to atrophy of the frontotemporal cortex and the basal ganglia, ...with deposition of abnormal tau in brain. Hereditary tauopathies are related with mutations of the tau gene. Up to the present, these diseases have not been helped by any disease-modifying treatment, and patients die a few years after the onset of symptoms. We have developed and characterized a mouse model of tauopathy with parkinsonism, overexpressing human mutated tau protein with deletion of parkin (PK−/− /TauVLW ). At 3 months of age, these mice present abnormal dopamine-related behavior, severe dropout of dopamine neurons in the ventral midbrain, reduced dopamine levels in the striatum and abundant phosphorylated tau-positive neuritic plaques, neurofibrillary tangles, astrogliosis, and, at 12 months old, plaques of murine β-amyloid in the hippocampus. Trehalose is a natural disaccharide that increases the removal of abnormal proteins through enhancement of autophagy. In this work, we tested if 1% trehalose in the drinking water reverts the PK−/− /TauVLW phenotype. The treatment with trehalose of 3-month-old PK−/− /TauVLW mice for 2.5 months reverted the dropout of dopamine neurons, which takes place in the ventral midbrain of vehicle treated PK−/− /TauVLW and the reduced dopamine-related proteins levels in the midbrain and striatum. The number of phosphorylated tau-positive neuritic plaques and the levels of phosphorylated tau decreased, as well as astrogliosis in brain regions. The autophagy markers in the brain, the autophagic vacuoles isolated from the liver, and the electron microscopy data indicate that these effects of trehalose are mediated by autophagy. The treatment with trehalose for 4 months of 3-month-old PK−/− /TauVLW mice maintained the amelioration of the tau pathology and astrogliosis but failed to revert DA-related pathology in the striatum. Furthermore, the 3-week treatment with trehalose of 14-month-old PK−/− /TauVLW mice, at the limit of their life expectancy, improved the motor behavior and anxiety of these animals, and reduced their levels of phosphorylated tau and the number of murine β-amyloid plaques. Trehalose is neuroprotective in this model of tauopathy. Since trehalose is free of toxic effects at high concentrations, this study opens the way for clinical studies of the effects of trehalose in human tauopathies.
SUMMARY
The common‐bean (Phaseolus vulgaris), a widely consumed legume, originated in Mesoamerica and expanded to South America, resulting in the development of two geographically distinct gene ...pools. Poor soil condition, including metal toxicity, are often constraints to common‐bean crop production. Several P. vulgaris miRNAs, including miR1511, respond to metal toxicity. The MIR1511 gene sequence from the two P. vulgaris model sequenced genotypes revealed that, as opposed to BAT93 (Mesoamerican), the G19833 (Andean) accession displays a 58‐bp deletion, comprising the mature and star miR1511 sequences. Genotyping‐By‐Sequencing data analysis from 87 non‐admixed Phaseolus genotypes, comprising different Phaseolus species and P. vulgaris populations, revealed that all the P. vulgaris Andean genotypes and part of the Mesoamerican (MW1) genotypes analyzed displayed a truncated MIR1511 gene. The geographic origin of genotypes with a complete versus truncated MIR1511 showed a distinct distribution. The P. vulgaris ALS3 (Aluminum Sensitive Protein 3) gene, known to be important for aluminum detoxification in several plants, was experimentally validated as the miR1511 target. Roots from BAT93 plants showed decreased miR1511 and increased ALS3 transcript levels at early stages under aluminum toxicity (AlT), while G19833 plants, lacking mature miR1511, showed higher and earlier ALS3 response. Root architecture analyses evidenced higher tolerance of G19833 plants to AlT. However, G19833 plants engineered for miR1511 overexpression showed lower ALS3 transcript level and increased sensitivity to AlT. Absence of miR1511 in Andean genotypes, resulting in a diminished ALS3 transcript degradation, appears to be an evolutionary advantage to high Al levels in soils with increased drought conditions.
Significance Statement
miR1511 is differentially distributed among Phaseolus species and genotypes, and regulates ALS3 transcript, known to be important for aluminum detoxification in plants. The absence of miR1511 in Andean genotypes, resulting in a diminished ALS3 transcript degradation, appears to be an evolutionary advantage to high Al levels in soils with increased drought conditions.
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