Aficamten vs Metoprolol for Obstructive Hypertrophic Cardiomyopathy: MAPLE-HCM Rationale, Study Design, and Baseline Characteristics.

Beta-blockers and nondihydropyridine calcium-channel blockers have been standard-of-care (SOC) medications for patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM), even though these agents do not directly affect the underlying pathophysiology of the disease. Cardiac myosin inhibitors act by decreasing the number of myosin heads binding to actin, reducing the pathologic hypercontractility of HCM, and have been shown to improve exercise capacity and alleviate symptoms in oHCM when added to SOC medications. Cardiac myosin inhibitors are currently considered as second-line therapy in the absence of head-to-head comparison studies vs SOC medications.

Discovery of novel microsomal prostaglandin E synthase 1 (mPGES-1) inhibitors by a structurally inspired virtual screening study.

Prostaglandin (PG) E is a pro-inflammatory lipid mediator derived from the metabolism of arachidonic acid (AA) by cyclooxygenases (COX) and PGE synthases. Nonsteroidal anti-inflammatory drugs (NSAIDs), commonly used in the treatment of inflammation, nonselectively inhibit COX activity and decrease PGE production. However, these drugs cause gastrointestinal bleeding and several cardiovascular complications.

Molecular dynamics simulations to decipher the hotspots at the allosteric site of human 5-lipoxygenase.

Human 5-lipoxygenase (LOX) is a non-heme, Fe-containing LOX which catalyses the conversion of arachidonic acid (AA) to leukotriene A (LTA). LTA is subsequently converted to cysteinyl-LTs and LTB that cause bronchoconstriction and act as chemotactic and chemokinetic agent on human leukocytes, respectively. Leukotrienes play significant roles in inflammation in asthma, cardiovascular diseases, allergic rhinitis, atopic dermatitis, inflammatory bowel disease, rheumatoid arthritis, psoriasis and many more.

Targeting protein kinase C-α prolongs survival and restores liver function in sepsis: Evidence from preclinical models.

Sepsis is a life-threatening organ failure resulting from a poorly regulated infection response. Organ dysfunction includes hepatic involvement, weakening the immune system due to excretory liver failure, and metabolic dysfunction, increasing the death risk. Although experimental studies correlated excretory liver functionality with immune performance and survival rates in sepsis, the proteins and pathways involved remain unclear.

Role of amino acid substitutions on proteolytic stability of histatin 5 in the presence of secreted aspartyl proteases and salivary proteases.

Histatin 5 (Hst5) is a 24-amino-acid peptide naturally present in human saliva that has been proposed as a potential antifungal therapeutic. However, Hst5 is susceptible to degradation by secreted aspartyl proteases (Saps) produced by Candida albicans, which could limit its efficacy as a therapeutic. To better understand the role of the lysine residues of Hst5 in proteolysis by C.

Design of a Duplex-to-Complex Structure-Switching Approach for the Homogeneous Determination of Marine Biotoxins in Water.

In this report, we describe a fluorescent assay for the detection of six marine toxins in water. The mechanism of detection is based on a duplex-to-complex structure-switching approach. The six aptamers specific to the targeted cyanotoxins were conjugated to a fluorescent dye, carboxyfluorescein (FAM).

Optimized psilocybin production in tryptophan catabolism-repressed fungi.

The high therapeutic potential of psilocybin, a prodrug of the psychotropic psilocin, holds great promise for the treatment of mental disorders such as therapy-refractory depression, alcohol use disorder and anorexia nervosa. Psilocybin has been designated a 'Breakthrough Therapy' by the US Food and Drug Administration, and therefore a sustainable production process must be established to meet future market demands. Here, we present the development of an in vivo psilocybin production chassis based on repression of l-tryptophan catabolism.

Design of an innovative aptasensor for the detection of chemotherapeutic drug Fludarabine phosphate.

Monitoring the concentration of Fludarabine phosphate, a standard chemotherapeutic drug widely used in cancer treatment, is vital for ensuring the drug's safety and effectiveness, tailoring treatments to individual needs, and consequently improving overall patient outcomes. Regarding the limitations of conventional techniques in terms of complexity, large time measurements, and a high cost, there is an urgent need to develop simple, rapid, and cost-effective devices. In this paper, we report the design of an aptasensor for the specific and selective detection of Fludarabine.

Synthesis and Biological Activity Assessment of 2-Styrylbenzothiazoles as Potential Multifunctional Therapeutic Agents.

A current trend in healthcare research is to discover multifunctional compounds, able to interact with multiple biological targets, in order to simplify multi-drug therapies and improve patient compliance. The aim of this work was to outline the growing demand for innovative multifunctional compounds, achieved through the synthesis, characterisation and SAR evaluation of a series of 2-styrylbenzothiazole derivatives. The six synthesised compounds were studied for their potential as photoprotective, antioxidant, antiproliferative, and anti-inflammatory agents.

The Second Methylation in Psilocybin Biosynthesis Is Enabled by a Hydrogen Bonding Network Extending into the Secondary Sphere Surrounding the Methyltransferase Active Site.

The Psilocybe cubensis SAM-dependent methyltransferase, PsiM, catalyzes the last step in the biosynthesis of psilocybin. Likely evolved from monomethylating RNA methyltransferases, PsiM acquired a key amino acid exchange in the secondary sphere of the active site, M247 N, which is responsible for its capacity to dimethylate. Two variants, PsiM and PsiM, were generated to further examine the role of Asn247 for mono- and dimethylation in PsiM.

Facilitating accessible, rapid, and appropriate processing of ancient metagenomic data with AMDirT.

Background: Access to sample-level metadata is important when selecting public metagenomic sequencing datasets for reuse in new biological analyses. The Standards, Precautions, and Advances in Ancient Metagenomics community (SPAAM, https://spaam-community.org) has previously published AncientMetagenomeDir, a collection of curated and standardised sample metadata tables for metagenomic and microbial genome datasets generated from ancient samples.

The effectiveness of coronary computed tomography angiography and functional testing for the diagnosis of obstructive coronary artery disease: results from the individual patient data Collaborative Meta-Analysis of Cardiac CT (COME-CCT).

Aim: To determine the effectiveness of functional stress testing and computed tomography angiography (CTA) for diagnosis of obstructive coronary artery disease (CAD).

Methods And Results: Two-thousand nine-hundred twenty symptomatic stable chest pain patients were included in the international Collaborative Meta-Analysis of Cardiac CT consortium to compare CTA with exercise electrocardiography (exercise-ECG) and single-photon emission computed tomography (SPECT) for diagnosis of CAD defined as ≥ 50% diameter stenosis by invasive coronary angiography (ICA) as reference standard. Generalised linear mixed models were used for calculating the diagnostic accuracy of each diagnostic test including non-diagnostic results as dependent variables in a logistic regression model with random intercepts and slopes.

An automated calculation pipeline for differential pair interaction energies with molecular force fields using the Tinker Molecular Modeling Package.

An automated pipeline for comprehensive calculation of intermolecular interaction energies based on molecular force-fields using the Tinker molecular modelling package is presented. Starting with non-optimized chemically intuitive monomer structures, the pipeline allows the approximation of global minimum energy monomers and dimers, configuration sampling for various monomer-monomer distances, estimation of coordination numbers by molecular dynamics simulations, and the evaluation of differential pair interaction energies. The latter are used to derive Flory-Huggins parameters and isotropic particle-particle repulsions for Dissipative Particle Dynamics (DPD).

The isoprenyl chain length of coenzyme Q mediates the nutritional resistance of fungi to amoeba predation.

Unlabelled: Amoebae are environmental predators feeding on bacteria, fungi, and other eukaryotic microbes. Predatory interactions alter microbial communities and impose selective pressure toward phagocytic resistance or escape which may, in turn, foster virulence attributes. The ubiquitous fungivorous amoeba has a wide prey spectrum in the fungal kingdom but discriminates against members of the clade, such as and .

mNFE: microbiome network flow entropy for detecting pre-disease states of type 1 diabetes.

In the development of Type 1 diabetes (T1D), there are critical states just before drastic changes, and identifying these pre-disease states may predict T1D or provide crucial early-warning signals. Unlike gene expression data, gut microbiome data can be collected noninvasively from stool samples. Gut microbiome sequencing data contain different levels of phylogenetic information that can be utilized to detect the tipping point or critical state in a reliable manner, thereby providing accurate and effective early-warning signals.

Efficient heterogeneous synthesis of nucleophilic carboxymethyl hydrazides of polysaccharides.

Nucleophilic moieties in polysaccharides (PS) with distinct higher reactivity compared with the hydroxy group are interesting for sustainable applications in chemistry, medicine, and pharmacy. An efficient heterogeneous method for the formation of such nucleophilic PS is described. Employing alcohols as slurry medium, protonated carboxymethyl (CM) PS and hydrazine hydrate are allowed to react at elevated temperatures.

Valuing Negative Affect Weakens Affect-Health Linkages: Similarities and Differences Across Affect Valuation Measures.

Negative affect (NA) has been robustly linked to poorer psychological health, including greater depressive symptoms, personal burnout, and perceived stress. These associations, known as , have been postulated by our research team to vary with different levels of (NAV), such that people who NA states as more pleasant, helpful, appropriate, and/or meaningful may show weaker affect-health links. Another affect valuation construct is , which is the degree to which people ideally want to experience NA states (i.

Integrated data-driven cross-disciplinary framework to prevent chemical water pollution.

Access to a clean and healthy environment is a human right and a prerequisite for maintaining a sustainable ecosystem. Experts across domains along the chemical life cycle have traditionally operated in isolation, leading to limited connectivity between upstream chemical innovation to downstream development of water-treatment technologies. This fragmented and historically reactive approach to managing emerging contaminants has resulted in significant externalized societal costs.

Arachidonic acid-derived lipid mediators in multiple sclerosis pathogenesis: fueling or dampening disease progression?

Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by neuroinflammation, demyelination, and neurodegeneration. Considering the increasing prevalence among young adults worldwide and the disabling phenotype of the disease, a deeper understanding of the complexity of the disease pathogenesis is needed to ultimately improve diagnosis and personalize treatment opportunities. Recent findings suggest that bioactive lipid mediators (LM) derived from ω-3/-6 polyunsaturated fatty acids (PUFA), also termed eicosanoids, may contribute to MS pathogenesis.

Poly(dehydroalanine)-Based Hydrogels as Efficient Soft Matter Matrices for Light-Driven Catalysis.

Soft matter integration of photosensitizers and catalysts provides promising solutions to developing sustainable materials for energy conversion. Particularly, hydrogels bring unique benefits, such as spatial control and 3D-accessibility of molecular units, as well as recyclability. Herein, the preparation of polyampholyte hydrogels based on poly(dehydroalanine) (PDha) is reported.

From 'mental fog' to post-acute COVID-19 syndrome's executive function alteration: Implications for clinical approach.

A common symptom of the neuropsychiatric Post-Acute COVID-19 syndrome (neuro-PACS) is the so called 'brain fog'. Patients describe the brain fog as problems with attention, memory and mental fatigue. Brain fog is experienced by 9-55% of people for months after having contracted SARS-CoV-2 virus.

Differential impact of 5-lipoxygenase-activating protein antagonists on the biosynthesis of leukotrienes and of specialized pro-resolving mediators.

Lipoxygenases (LOX) transform arachidonic acid (AA, C20:4) and docosahexaenoic acid (DHA, C22:6) into bioactive lipid mediators (LMs) that comprise not only pro-inflammatory leukotrienes (LTs) but also the specialized pro-resolving mediators (SPMs) that promote inflammation resolution and tissue regeneration. The 5-LOX-activating protein (FLAP) is known to provide AA as a substrate to 5-LOX for generating LTs, such as LTB, a potent chemoattractant and activator of phagocytes. Notably, 5-LOX is also involved in the biosynthesis of certain SPMs, namely, lipoxins and D-resolvins, implying a role of FLAP in SPM formation.

Substituted 1,2,4-Triazoles as Novel and Selective Inhibitors of Leukotriene Biosynthesis Targeting 5-Lipoxygenase-Activating Protein.

5-Lipoxygenase-activating protein (FLAP) is a regulator of cellular leukotriene biosynthesis, which governs the transfer of arachidonic acid (AA) to 5-lipoxygenase for efficient metabolism. Here, the synthesis and FLAP-antagonistic potential of fast synthetically accessible 1,2,4-triazole derivatives based on a previously discovered virtual screening hit compound is described. Our findings reveal that simple structural variations on 4,5-diaryl moieties and the 3-thioether side chain of the 1,2,4-triazole scaffold markedly influence the inhibitory potential, highlighting the significant chemical features necessary for FLAP antagonism.

Hyperthermia Influences the Secretion Signature of Tumor Cells and Affects Endothelial Cell Sprouting.

Tumors are a highly heterogeneous mass of tissue showing distinct therapy responses. In particular, the therapeutic outcome of tumor hyperthermia treatments has been inconsistent, presumably due to tumor versus endothelial cell cross-talks related to the treatment temperature and the tumor tissue environment. Here, we investigated the impact of the average or strong hyperthermic treatment (43 °C or 47 °C for 1 h) of the human pancreatic adenocarcinoma cell line (PANC-1 and BxPC-3) on endothelial cells (HUVECs) under post-treatment normoxic or hypoxic conditions.