Probabilistic weather forecasting with machine learning.

Weather forecasts are fundamentally uncertain, so predicting the range of probable weather scenarios is crucial for important decisions, from warning the public about hazardous weather to planning renewable energy use. Traditionally, weather forecasts have been based on numerical weather prediction (NWP), which relies on physics-based simulations of the atmosphere. Recent advances in machine learning (ML)-based weather prediction (MLWP) have produced ML-based models with less forecast error than single NWP simulations.

Arsenic Trioxide (ATO) Induces NAD(P)H Quinone Oxidoreductase 1 (NQO1) Expression in Hepatic and Extrahepatic Tissues of C57BL/6 Mice.

Arsenic trioxide (ATO) has emerged as a potent therapeutic agent for acute promyelocytic leukemia (APL), yet its clinical application is often limited by significant adverse effects. This study investigates the molecular mechanisms underlying ATO's impact on cellular detoxification pathways, focusing on the regulation of NAD(P)H/quinone oxidoreductase (NQO1), a crucial enzyme in maintaining cellular homeostasis and cancer prevention. We explored ATO's effects on NQO1 expression in C57BL/6 mice and Hepa-1c1c7 cells, both independently and in combination with 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD), a known NQO1 inducer.

Quantification of Epoxyeicosatrienoic acids Enantiomers: The development of reliable and practical liquid chromatography mass Spectrometry assay.

Epoxyeicosatrienoic acids (EETs) are increasingly recognized as key metabolites in the arachidonic acid (AA) metabolic pathway. EETs are epoxy derivatives of AA with two chiral centers formed by cytochrome P450 (CYP) enzymes. EETs have reported biological activities as racemates; however, knowledge on specific optical isomers of EET is lacking.

Effect of Cannabistilbene I in Attenuating Angiotensin II-Induced Cardiac Hypertrophy: Insights into Cytochrome P450s and Arachidonic Acid Metabolites Modulation.

This research investigated the impact of Cannabistilbene I on Angiotensin II (Ang II)-induced cardiac hypertrophy and its potential role in cytochrome P450 (CYP) enzymes and arachidonic acid (AA) metabolic pathways. Cardiac hypertrophy, a response to increased stress on the heart, can lead to severe cardiovascular diseases if not managed effectively. CYP enzymes and AA metabolites play critical roles in cardiac function and hypertrophy, making them important targets for therapeutic intervention.

The role of nuclear factor erythroid 2-related factor 2 (NRF2) in arsenic toxicity.

Arsenic, a naturally occurring toxic element, manifests in various chemical forms and is widespread in the environment. Exposure to arsenic is a well-established risk factor for an elevated incidence of various cancers and chronic diseases. The crux of arsenic-mediated toxicity lies in its ability to induce oxidative stress, characterized by an unsettling imbalance between oxidants and antioxidants, accompanied by the rampant generation of reactive oxygen species and free radicals.

11-Hydroxyeicosatetraenoics induces cellular hypertrophy in an enantioselective manner.

Background: R/S enantiomers of 11-hydroxyeicosatertraenoic acid (11-HETE) are formed from arachidonic acid by enzymatic and non-enzymatic pathways. 11-HETE is predominately formed by the cytochrome P450 1B1 (CYP1B1). The role of CYP1B1 in the development of cardiovascular diseases is well established.

Identification of aryl hydrocarbon receptor allosteric antagonists from clinically approved drugs.

The human aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, plays a pivotal role in a diverse array of pathways in biological and pathophysiological events. This position AhR as a promising target for both carcinogenesis and antitumor strategies. In this study we utilized computational modeling to screen and identify FDA-approved drugs binding to the allosteric site between α2 of bHLH and PAS-A domains of AhR, with the aim of inhibiting its canonical pathway activity.

Modulation of aryl hydrocarbon receptor activity by tyrosine kinase inhibitors (ponatinib and tofacitinib).

Ponatinib and tofacitinib, established kinase inhibitors and FDA-approved for chronic myeloid leukemia and rheumatoid arthritis, are recently undergoing investigation in diverse clinical trials for potential repurposing. The aryl hydrocarbon receptor (AhR), a transcription factor influencing a spectrum of physiological and pathophysiological activities, stands as a therapeutic target for numerous diseases. This study employs molecular modelling tools and in vitro assays to identify ponatinib and tofacitinib as AhR ligands, elucidating their binding and molecular interactions in the AhR PAS-B domain.

Modulation of Angiotensin II-Induced Cellular Hypertrophy by Cannflavin-C: Unveiling the Impact on Cytochrome P450 1B1 and Arachidonic Acid Metabolites.

This research aimed to clarify the impacts of cannflavin-C on angiotensin II (Ang II)-induced cardiac hypertrophy and their potential role in modulating cytochrome P450 1B1 (CYP1B1) and arachidonic acid (AA) metabolites. Currently there is no evidence to suggest that cannflavin-C, a prenylated flavonoid, has any significant effects on the heart or cardiac hypertrophy. The metabolism of arachidonic acid (AA) into midchain hydroxyeicosatetraenoic acids (HETEs), facilitated by CYP1B1 enzyme, plays a role in the development of cardiac hypertrophy, which is marked by enlarged cardiac cells.

Alteration of Hepatic Cytochrome P450 Expression and Arachidonic Acid Metabolism by Arsenic Trioxide (ATO) in C57BL/6 Mice.

The success of arsenic trioxide (ATO) in acute promyelocytic leukemia has driven a plethora studies to investigate its efficacy in other malignancies. However, the inherent toxicity of ATO limits the expansion of its clinical applications. Such toxicity may be linked to ATO-induced metabolic derangements of endogenous substrates.

Changes in cardiovascular arachidonic acid metabolism in experimental models of menopause and implications on postmenopausal cardiac hypertrophy.

Menopause is a normal stage in the human female aging process characterized by the cessation of menstruation and the ovarian production of estrogen and progesterone hormones. Menopause is associated with an increased risk of several different diseases. Cardiovascular diseases are generally less common in females than in age-matched males.

Cytochrome P450 1B1 is critical in the development of TNF-α, IL-6, and LPS-induced cellular hypertrophy.

Heart failure (HF) is preceded by cellular hypertrophy (CeH) which alters expression of cytochrome P450 enzymes (CYPs) and arachidonic acid (AA) metabolism. Inflammation is involved in CeH pathophysiology, but mechanisms remain elusive. This study investigates the impacts of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and lipopolysaccharides (LPS) on the development of CeH and the role of CYP1B1.

Identifying novel aryl hydrocarbon receptor (AhR) modulators from clinically approved drugs: In silico screening and In vitro validation.

The aryl hydrocarbon receptor (AhR) functions as a vital ligand-activated transcription factor, governing both physiological and pathophysiological processes. Notably, it responds to xenobiotics, leading to a diverse array of outcomes. In the context of drug repurposing, we present here a combined approach of utilizing structure-based virtual screening and molecular dynamics simulations.

Comparing the oxidative functions of neutrophil myeloperoxidase and cytochrome P450 enzymes in drug metabolism.

Drug metabolism is an essential process that chemically alters xenobiotic substrates to activate or terminate drug activity. Myeloperoxidase (MPO) is a neutrophil-derived haem-containing enzyme that is involved in killing invading pathogens, although consequentially, this same oxidative activity can produce metabolites that damage host tissue and play a role in various human pathologies. Cytochrome P450s (CYPs) are a superfamily of haem-containing enzymes that are significantly involved in the metabolism of drugs by functioning as monooxygenases and can be induced or inhibited, resulting in significant drug-drug interactions that lead to unanticipated adverse drug reactions.

Investigating the Aryl Hydrocarbon Receptor Agonist/Antagonist Conformational Switch Using Well-Tempered Metadynamics Simulations.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates biological signals to control various complicated cellular functions. It plays a crucial role in environmental sensing and xenobiotic metabolism. Dysregulation of AhR is associated with health concerns, including cancer and immune system disorders.

Dimethylmonothioarsinic acid (DMMTA) differentially modulates the expression of AHR-regulated cytochrome P450 1A enzymes in vivo and in vitro.

Dimethylmonothioarsinic acid (DMMTA), a pentavalent thio-arsenic derivative, has been found in bodily fluids and tissues including urine, liver, kidney homogenates, plasma, and red blood cells. Although DMMTA is a minor metabolite in humans and animals, its substantial toxicity raises concerns about potential carcinogenic effects. This toxicity could be attributed to arsenicals' ability to regulate cytochrome P450 1 A (CYP1A) enzymes, pivotal in procarcinogen activation or detoxification.

Optimizing the superstructure configuration of highway bridges for cost-effective construction.

The structural progress of bridges in conjunction with efficiency has gained researchers' attention in the last few decades. Structures optimization applying mathematical analysis is utilized to achieve sustainability in the design and construction of bridges. Despite the extensive research in this area of knowledge, further structural optimization development needs to be developed.

Enantioselectivity in some physiological and pathophysiological roles of hydroxyeicosatetraenoic acids.

The phenomenon of chirality has been shown to greatly impact drug activities and effects. Different enantiomers may exhibit different effects in a certain biological condition or disease state. Cytochrome P450 (CYP) enzymes metabolize arachidonic acid (AA) into a large variety of metabolites with a wide range of activities.

Differential Modulatory Effects of Methylmercury (MeHg) on Ahr-regulated Genes in Extrahepatic Tissues of C57BL/6 Mice.

Methylmercury (MeHg) and 2,3,7,8-tetrachlorodibenzodioxin (TCDD) are potent environmental pollutants implicated in the modulation of xenobiotic-metabolizing enzymes, particularly the cytochrome P450 1 family (CYP1) which is regulated by the aryl hydrocarbon receptor (AHR). However, the co-exposure to MeHg and TCDD raises concerns about their potential combined effects, necessitating thorough investigation. The primary objective of this study was to investigate the individual and combined effects of MeHg and TCDD on AHR-regulated CYP1 enzymes in mouse extrahepatic tissues.

The Effects of 16-HETE Enantiomers on Hypertrophic Markers in Human Fetal Ventricular Cardiomyocytes, RL-14 Cells.

Background: Cytochrome P450 (CYP) metabolizes arachidonic acid to produce bioactive metabolites such as EETs and HETEs: mid-chain, subterminal, and terminal HETEs. Recent studies have revealed the role of CYP1B1 and its associated cardiotoxic mid-chain HETE metabolites in developing cardiac hypertrophy and heart failure. Subterminal HETEs have also been involved in various physiological and pathophysiological processes; however, their role in cardiac hypertrophy has not been fully defined.

Methylmercury (MeHg) transcriptionally regulates NAD(P)H:quinone oxidoreductase 1 (NQO1) in Hepa-1c1c7 cells.

The detoxification of quinones through NAD(P)H:quinone oxidoreductase (NQO1) is a crucial mechanism to maintain cellular homeostasis. The exposure to heavy metals, specifically methylmercury (MeHg), induces several antioxidant enzymes, including NQO1. The nuclear factor erythroid 2-related factor-2 (NRF2) is known to regulate the expression of gene and also the aryl hydrocarbon receptor (AHR) is another gene regulator.

Differential modulation of cytochrome P450 enzymes by arsenicals in non-human experimental models.

Arsenic is a hazardous heavy metalloid that imposes threats to human health globally. It is widely spread throughout the environment in various forms. Arsenic-based compounds are either inorganic compounds (iAs) or organoarsenicals (oAs), where the latter are biotically generated from the former.

Arsenic trioxide (ATO) up-regulates cytochrome P450 1A (CYP1A) enzymes in murine hepatoma Hepa-1c1c7 cell line.

Arsenic trioxide (ATO) is a highly toxic arsenical which has been successfully exploited for treating acute promyelocytic leukemia (APL). Unfortunately, its therapeutic efficacy is accompanied by serious toxicities with undeciphered mechanisms. Cytochrome P450 1A (CYP1A) enzymes undergo modulation by arsenicals, with ensuing critical consequences regarding drug clearance or procarcinogen activation.

Physiological and pathophysiological roles of hepoxilins and their analogs.

The metabolism of arachidonic acid (AA) occurs different pathways leading to the production of a great number of metabolites with a wide range of biological effects. Hepoxilins (HXs) are physiologically active AA metabolites produced through the lipoxygenase pathway. Since their discovery, several researchers have investigated their biological effects.