Methylation of histone H3 lysine 4 is linked to active transcription and can be removed by LSD1 or the JmjC domain‐containing proteins by amino‐oxidation or hydroxylation, respectively. Here we ...describe that its deamination can be catalyzed by lysyl oxidase‐like 2 protein (LOXL2), presenting an unconventional chemical mechanism for H3K4 modification. Infrared spectroscopy and mass spectrometry analyses demonstrated that recombinant LOXL2 specifically deaminates trimethylated H3K4. Moreover, by regulating H3K4me3 deamination, LOXL2 activity is linked with the transcriptional control of the CDH1 gene. These results reveal the existence of further H3 modification as well as a novel mechanism for H3K4me3 demethylation.
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The GEO accession number for the data referred to this paper is GSE35600.
Herranz et al. show that trimethylated lysine 4 in histone H3 can be deaminated by LOXL2 revealing the existence of a new modification of H3 as well as a novel mechanism for H3K4me3 demethylation. Moreover, the authors demonstrate how this oxidation of H3 is linked with transcriptional repression of the CDH1 gene.
Chemical descriptors encode the physicochemical and structural properties of small molecules, and they are at the core of chemoinformatics. The broad release of bioactivity data has prompted enriched ...representations of compounds, reaching beyond chemical structures and capturing their known biological properties. Unfortunately, bioactivity descriptors are not available for most small molecules, which limits their applicability to a few thousand well characterized compounds. Here we present a collection of deep neural networks able to infer bioactivity signatures for any compound of interest, even when little or no experimental information is available for them. Our signaturizers relate to bioactivities of 25 different types (including target profiles, cellular response and clinical outcomes) and can be used as drop-in replacements for chemical descriptors in day-to-day chemoinformatics tasks. Indeed, we illustrate how inferred bioactivity signatures are useful to navigate the chemical space in a biologically relevant manner, unveiling higher-order organization in natural product collections, and to enrich mostly uncharacterized chemical libraries for activity against the drug-orphan target Snail1. Moreover, we implement a battery of signature-activity relationship (SigAR) models and show a substantial improvement in performance, with respect to chemistry-based classifiers, across a series of biophysics and physiology activity prediction benchmarks.
Abstract F-box proteins are the key recognition subunit of multimeric E3 ubiquitin ligase complexes that participate in the proteasome degradation of specific substrates. In the last years, a ...discrete number of F-box proteins have been shown to regulate the epithelial-to-mesenchymal transition (EMT), a process defined by a rapid change of cell phenotype, the loss of epithelial characteristics and the acquisition of a more invasive phenotype. Specific EMT transcription factors (EMT-TFs), such as Snail, Slug, Twist and Zeb, control EMT induction both during development and in cancer. These EMT-TFs are short-lived proteins that are targeted to the proteasome system by specific F-box proteins, keeping them at low levels. F-box proteins also indirectly regulate the EMT process by controlling EMT inducers, such as Notch, c-Myc or mTOR. Here we summarize the role that these F-box proteins (Fbxw1, Fbxw7, Fbxl14, Fbxl5, Fbxo11 and Fbxo45) play in controlling EMT during development and cancer progression, a process dependent on post-translational modifications that govern their interaction with target proteins.
Type 2 diabetes is a chronic metabolic disease that affects mitochondrial function. In this context, the rescue mechanisms of mitochondrial health, such as mitophagy and mitochondrial biogenesis, are ...of crucial importance. The gold standard for the treatment of type 2 diabetes is metformin, which has a beneficial impact on the mitochondrial metabolism. In this study, we set out to describe the effect of metformin treatment on mitochondrial function and mitophagy in peripheral blood mononuclear cells (PBMCs) from type 2 diabetic patients. We performed a preliminary cross-sectional observational study complying with CONSORT requirements, for which we recruited 242 subjects, divided into 101 healthy volunteers, 93 metformin-treated type 2 diabetic patients and 48 non-metformin-treated type 2 diabetic patients. Mitochondria from the type 2 diabetic patients not treated with metformin displayed more reactive oxygen species (ROS) than those from healthy or metformin-treated subjects. Protein expression of the electron transport chain (ETC) complexes was lower in PBMCs from type 2 diabetic patients without metformin treatment than in those from the other two groups. Mitophagy was altered in type 2 diabetic patients, evident in a decrease in the protein levels of PINK1 and Parkin in parallel to that of the mitochondrial biogenesis protein PGC1α, both of which effects were reversed by metformin. Analysis of AMPK phosphorylation revealed that its activation was decreased in the PBMCs of type 2 diabetic patients, an effect which was reversed, once again, by metformin. In addition, there was an increase in the serum levels of TNFα and IL-6 in type 2 diabetic patients and this was reversed with metformin treatment. These results demonstrate that metformin improves mitochondrial function, restores the levels of ETC complexes, and enhances AMPK activation and mitophagy, suggesting beneficial clinical implications in the treatment of type 2 diabetes.
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•Metformin promoted electron transport chain expression on type 2 diabetic patients.•Metformin restored mitophagy levels via PINK1 and PARKIN on type 2 diabetic patients.•Mitochondrial biogenesis was enhanced by metformin on type 2 diabetic patients.•Metformin restored AMPK activation on type 2 diabetic patients.
•A practical application of cascade use of geothermal energy in a polygeneration plant is presented.•The polygeneration plant sequentially produces electricity, cooling and dehydrated products.•An ...exergy assessment was performed to identify improvements of polygeneration plant performance.•Critical components influencing the economics of the system were identified by exergoeconomics.•Products costs are 8.54 $/h for electricity, 7.78 $/h for cooling and 3.52 $/h for dehydration.
This paper presents an advanced exergy and exergoeconomic analysis applied to a polygeneration plant operating in a geothermal cascade arrangement. An organic Rankine cycle (ORC), an absorption chiller and a dehydrator are the main components of the plant. The energy and exergy analysis of the polygeneration plant were carried out operating under real, unavoidable and ideal conditions. Considering real conditions, the polygeneration plant is able to reach a power output of 40 kWe, a cooling effect of 175.8 kWf and 30 kWt of useful heat for dehydration. The conventional exergy analysis shows that the component with the highest destruction of exergy of the polygeneration plant is the main heat exchanger (HX-I) having 44.05 kW, followed by the ORC with 38.58 kW. The advanced exergy analysis also indicates that 10.61 kW and 2.28 kW of exergy destruction in the HX-I and in the ORC can be avoided by improving design variables of these components. In this same context, the thermally activated refrigeration (TAR) can avoid destroying endogenously 7.36 kW while interacting with the other components of the plant operating under ideal conditions. On the other hand, the conventional exergoeconomic analysis reveals a cost of electricity production of 8.54 $/h, a cost of cooling production of 7.78 $/h and a cost of useful heat production for dehydration of 3.52 $/h. Finally, the advanced exergoeconomic analysis indicates that the heat exchanger HX-II is the component of the plant where more opportunity for reducing exergy destruction can be found.
The relationship between caloric restriction-mediated weight loss and the generation of ROS and its effects on atherosclerotic markers in obesity is not fully understood. Therefore, we set out to ...investigate whether dietary weight loss intervention improves markers of oxidative stress in leukocytes and subclinical parameters of atherosclerosis.
This was an interventional study of 59 obese subjects (BMI > 35 kg/m
) who underwent 6 months of dietary therapy, including a 6-week very-low-calorie diet (VLCD) followed by an 18-week low-calorie diet (LCD). We determined clinical parameters, inflammatory markers-hsCRP, TNFα and NFκB -, oxidative stress parameters-total superoxide, glutathione, catalase activity and protein carbonyl groups-, soluble cellular adhesion molecules-sICAM, sP-selectin, sPSGL-1 -, myeloperoxidase (MPO), leukocyte-endothelium cell interactions-rolling flux, velocity and adhesion-and LDL subfractions, before and after the dietary intervention.
After losing weight, an improvement was observed in the patients' anthropometric, blood pressure and metabolic parameters, and was associated with reduced inflammatory response (hsCRP, TNFα and NFκB). Oxidative stress parameters improved, since superoxide production and protein carbonyl content were reduced and antioxidant systems were enhanced. In addition, a significant reduction of subclinical markers of atherosclerosis-small and dense LDL particles, MPO, sP-selectin and leukocyte adhesion-and an increase in soluble PSGL-1 were reported.
Our findings reveal that the improvement of subclinical atherosclerotic markers after dietary weight loss intervention is associated with a reduction of oxidative stress in leukocytes and inflammatory pathways, suggesting that these are the underlying mechanisms responsible for the reduced risk of cardiovascular disease in obese subjects after losing weight.
•An application of different power cycles coupled to a geothermal polygeneration plant is presented.•The polygeneration plant sequentially produces electricity, refrigeration and dehydrated products, ...using the cascade concept.•Power cycles considered as feasible are Goswami, Kalina and ORC.•Thermodynamic and economic performance was carried considering energy, exergy and economic indicators.•Among power cycles studied ORC cycle achieved better energy and economic performance.
Low-temperature geothermal energy is an abundant and renewable resource, but with technical and economic limitations for the generation of electricity. Currently, the polygeneration systems are an alternative for effective use of energy resources, geothermal energy included. In this paper a comparative analysis of the thermodynamic and economic performance of Kalina (KAC), Goswami (GOC) and Organic Rankine (ORC) cycles coupled to a polygeneration plant that uses geothermal energy of low-grade temperature to produce electricity, refrigeration and dehydrated products, simultaneously, is presented. It is proposed that the system design operates sequentially at different thermic levels under the concept of cascade utilization. The KAC, GOC and ORC cycles are analyzed as candidates for electricity generation, placed in a first thermal level. In a second thermal level, a cooling technology activated with thermal energy for fresh product conservation is included. Finally, a fresh product dehydrator is included in the last thermal level. To carry out the analysis, a standard structure has been proposed, to which the laws of mass and energy conservation apply. In addition, an exergy analysis is performed to know the performance of the system from the perspective of the second law of thermodynamics. The results indicate that the KAC and ORC cycles are more flexible to integrate, since the systeḿs products can adjust to the predefined needs. However, a better energy and exergetic efficiency of the polygeneration plant is obtained with the ORC, having 30.68 and 27.43%, respectively. From economic perspective the ORC has also the lowest Simple Payback Period (3.36 years) and the highest NPV (1.684 × 106 USD) among power cycles studied.
Outdoor ultrafine particles (UFP, <0.1 μm) and black carbon (BC) vary greatly within cities and may have adverse impacts on human health. In this study, we used a hybrid approach to develop new ...models to estimate within-city spatial variations in outdoor UFP and BC concentrations across Bucaramanga, Colombia. We conducted a mobile monitoring campaign over 20 days in 2019. Regression models were trained on land use data and combined with predictions from convolutional neural networks (CNN) trained to predict UFP and BC concentrations using satellite and street-level images. The combined UFP model (R 2 = 0.54) outperformed the CNN (R 2 = 0.47) and land use regression (LUR) models (R 2 = 0.47) on their own. Similarly, the combined BC model also outperformed the CNN and LUR BC models (R 2 = 0.51 vs 0.43 and 0.45, respectively). Spatial variations in model performance were more stable for the CNN and combined models compared to the LUR models, suggesting that the combined approach may be less likely to contribute to differential exposure measurement error in epidemiological studies. In general, our findings demonstrated that satellite and street-level images can be combined with a traditional LUR modeling approach to improve predictions of within-city spatial variations in outdoor UFP and BC concentrations.
•Performance of four supercritical carbon dioxide Brayton cycles were optimized.•There is an optimal combination of cycle operating conditions.•Intercooled recuperated Brayton cycle produced the ...highest electric power output.•Intercooling and recuperation improved the electric power output by 7.53%.•Impact of pressure drops and auxiliary pumping power was assessed.
The transcritical carbon dioxide Rankine cycle has emerged as an alternative for power generation in low-grade heat applications. However, the low heat rejection temperatures required for condensing the carbon dioxide is almost prohibitive for many locations. A simple solution is the adoption of a supercritical carbon dioxide Brayton cycle which does not need such low temperature heat sinks. This power cycle has been poorly studied previously in low-grade heat applications. Therefore, with the aim of determining the performance and feasibility of the supercritical carbon dioxide Brayton cycle from thermodynamic viewpoint, using a low-grade geothermal heat source, this paper presents a comparative thermodynamic analysis between four different supercritical carbon dioxide Brayton cycles. For this purpose, detailed models were developed and solved by coupling the thermodynamic model with the thermal-hydraulic model of a Printed Circuit Heat Exchanger. Subsequently, simulations of a base case, a parametric analysis, and an optimization using Genetic Algorithms, were carried out. Results show that there is a combination of operating conditions that maximizes the electrical output of the system. Besides, some values of the minimum pressure of the cycles can increase substantially the precooler cooling water pumping power. At the optimum design point, using a 20 kg/s geothermal brine stream at 150 °C as heat source with a minimum allowable reinjection temperature of 70 °C, the Intercooled Recuperated Brayton Cycle achieved the highest electric power output, energy and exergy efficiencies, obtaining values of 779.99 kW, 11.51%, and 52.49%, respectively. The other feasible alternatives were the Recuperated Brayton Cycle, the Simple Brayton Cycle and the Intercooled Brayton Cycle, ranked, in that order.
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