Development of Receptor Desolvation Scoring and Covalent Sampling in DOCK 6: Methods Evaluated on a RAS Test Set.

Molecular docking methods are widely used in drug discovery efforts. RAS proteins are important cancer drug targets, and are useful systems for evaluating docking methods, including accounting for solvation effects and covalent small molecule binding. Water often plays a key role in small molecule binding to RAS proteins, and many inhibitors─including FDA-approved drugs─covalently bind to oncogenic RAS proteins.

Intraspecific variability of rice root knot nematodes across diverse agroecosystems for sustainable management.

In the rice agroecosystems of Southeast Asia, rice root knot nematode (Meloidogyne graminicola) significantly impairs yield, representing a major species within the 'graminis-group' known for its morphological similarities with other root knot nematodes (RKNs). This study delves into the variations in reproductive potential, morphology, morphometrics, and genetic diversity among thirty RKN populations in rice across three distinct agroecological zones in Jharkhand, India. Despite notable differences in reproductive potential among the populations, morphological and morphometric correlations to reproductive potential were inconclusive.

Cryo-EM Structure of AAA + ATPase Thorase Reveals Novel Helical Filament Formation.

The AAA+ (ATPases associated with a variety of cellular activities) ATPase, Thorase, also known as ATAD1, plays multiple roles in synaptic plasticity, mitochondrial quality control and mTOR signaling through disassembling protein complexes like AMPAR and mTORC1 in an ATP-dependent manner. The Oligomerization of Thorase is crucial for its disassembly and remodeling functions. We show that wild-type Thorase forms long helical filaments , dependent on ATP binding but not hydrolysis.

Control of inflammatory lung injury and repair by metabolic signaling in endothelial cells.

Purpose Of Review: Sepsis-induced inflammatory lung injury includes acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). There are currently no effective treatments for ALI/ARDS, but clinical outcomes could be improved by inhibiting lung injury and/or promoting post-sepsis vascular repair. In this review, we describe studies of endothelial cell metabolic pathways in sepsis-induced ALI/ARDS and vascular repair and identify areas of research that deserve attention in future studies.

Dehydrin Client Proteins Identified Using Phage Display Affinity Selected Libraries Processed With Paired-End Phage Sequencing.

The late embryogenesis abundant proteins (LEAPs) are a class of noncatalytic, intrinsically disordered proteins with a malleable structure. Some LEAPs exhibit a protein and/or membrane binding capacity and LEAP binding to various targets has been positively correlated with abiotic stress tolerance. Regarding the LEAPs' presumptive role in protein protection, identifying client proteins (CtPs) to which LEAPs bind is one practicable means of revealing the mechanism by which they exert their function.

Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial.

Background: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD).

Effect of an Autotaxin Inhibitor, 2-(4-Chlorophenyl)-7-methyl-8-pentylimidazo[1,2-] Pyrimidin-5(8)-one (CBT-295), on Bile Duct Ligation-Induced Chronic Liver Disease and Associated Hepatic Encephalopathy in Rats.

The role of autotaxin (ATX)-lysophosphatidic acid (LPA) is yet to be explored in the context of liver cirrhosis and associated encephalopathy. Our objective of this study was to evaluate the role of an ATX inhibitor in biliary cirrhosis and associated hepatic encephalopathy in rats. The preliminary investigation revealed significant impairment in liver function, which eventually led to the development of hepatic encephalopathy.

Considerations Around Structure-Based Drug Discovery for KRAS Using DOCK.

Molecular docking is a popular computational tool in drug discovery. Leveraging structural information, docking software predicts binding poses of small molecules to cavities on the surfaces of proteins. Virtual screening for ligand discovery is a useful application of docking software.

Structural dynamics of RAF1-HSP90-CDC37 and HSP90 complexes reveal asymmetric client interactions and key structural elements.

RAF kinases are integral to the RAS-MAPK signaling pathway, and proper RAF1 folding relies on its interaction with the chaperone HSP90 and the cochaperone CDC37. Understanding the intricate molecular interactions governing RAF1 folding is crucial for comprehending this process. Here, we present a cryo-EM structure of the closed-state RAF1-HSP90-CDC37 complex, where the C-lobe of the RAF1 kinase domain binds to one side of the HSP90 dimer, and an unfolded N-lobe segment of the RAF1 kinase domain threads through the center of the HSP90 dimer.

Editorial Commentary: Suture Button Fixation for the Latarjet Procedure Is Superior to Screw Fixation.

An increasing body of evidence suggests that suture button fixation is comparable with screw fixation in Latarjet and potentially associated with reduced graft resorption. Suture button fixation may facilitate performing the Latarjet procedure, particularly when done in an arthroscopic manner. The use of suture button fixation technique theoretically facilitates improved positioning of the graft on the glenoid, as it frees the surgeon from the potential of the soft-tissue envelope to impact positioning of the graft, which can occur with screw-based guides.

Effects of Mars Global Simulant (MGS-1) on Growth and Physiology of Sweet Potato: A Space Model Plant.

Growing food autonomously on Mars is challenging due to the Martian soil's low nutrient content and high salinity. Understanding how plants adapt and evaluating their nutritional attributes are pivotal for sustained Mars missions. This research delves into the regeneration, stress tolerance, and dietary metrics of sweet potato () across different Mars Global Simulant (MGS-1) concentrations (0, 25, 50, and 75%).

Hippo Signaling Mediates TGFβ-Dependent Transcriptional Inputs in Cardiac Cushion Mesenchymal Cells to Regulate Extracellular Matrix Remodeling.

The transforming growth factor beta (TGFβ) and Hippo signaling pathways are evolutionarily conserved pathways that play a critical role in cardiac fibroblasts during embryonic development, tissue repair, and fibrosis. TGFβ signaling and Hippo signaling are also important for cardiac cushion remodeling and septation during embryonic development. Loss of TGFβ2 in mice causes cardiac cushion remodeling defects resulting in congenital heart disease.

DOCK 6: Incorporating hierarchical traversal through precomputed ligand conformations to enable large-scale docking.

To allow DOCK 6 access to unprecedented chemical space for screening billions of small molecules, we have implemented features from DOCK 3.7 into DOCK 6, including a search routine that traverses precomputed ligand conformations stored in a hierarchical database. We tested them on the DUDE-Z and SB2012 test sets.

Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen.

Specificity remains a major challenge to current therapeutic strategies for cancer. Mutation associated neoantigens (MANAs) are products of genetic alterations, making them highly specific therapeutic targets. MANAs are HLA-presented (pHLA) peptides derived from intracellular mutant proteins that are otherwise inaccessible to antibody-based therapeutics.

Role of EIN2-mediated ethylene signaling in regulating petal senescence, abscission, reproductive development, and hormonal crosstalk in tobacco.

Ethylene plays a pivotal role in a wide range of developmental, physiological, and defense processes in plants. EIN2 (ETHYLENE INSENSITIVE2) is a key player in the ethylene signaling pathway. To characterize the role of EIN2 in processes, such as petal senescence, where it has been found to play important roles along with various other developmental and physiological processes, the tobacco (Nicotiana tabacum) ortholog of EIN2 (NtEIN2) was isolated and NtEIN2 silenced transgenic lines were generated using RNA interference (RNAi).

Sodium/Iodide Symporter Metastable Intermediates Provide Insights into Conformational Transition between Principal Thermodynamic States.

The Sodium/Iodide Symporter (NIS), a 13-helix transmembrane protein found in the thyroid and other tissues, transports iodide, a required constituent of thyroid hormones T3 and T4. Despite extensive experimental information and clinical data, structural details of the intermediate microstates comprising the conformational transition of NIS between its inwardly and outwardly open states remain unresolved. We present data from a combination of enhanced sampling and transition path molecular dynamics (MD) simulations that elucidate the principal intermediate states comprising the inwardly to outwardly open transition of fully bound and apo NIS under an enforced ionic gradient.

Evaluation of Osteochondral Allograft Transplant Using In-Office Needle Arthroscopy.

In-office needle arthroscopy (IONA) has been available in various iterations for decades. Studies have described it as comparable if not superior to magnetic resonance imaging for identifying intra-articular pathology with associated cost savings per patient. A new IONA system has been brought to market with a modernized user interface and disposable handpieces offering the opportunity to address intra-articular pathology.

Prohibitin1 maintains mitochondrial quality in isoproterenol-induced cardiac hypertrophy in H9C2 cells.

Background Information: Various types of stress initially induce a state of cardiac hypertrophy (CH) in the heart. But, persistent escalation of cardiac stress leads to progression from an adaptive physiological to a maladaptive pathological state. So, elucidating molecular mechanisms that can attenuate CH is imperative in developing cardiac therapies.

Identification of 5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine as novel orally bioavailable and metabolically stable antimalarial compound for further exploration.

Malaria continues to be a significant public health problem threatened by the emergence and spread of resistance to artemisinin-based combination therapies and marked half a million deaths in 2016. A new imidazopyridine chemotype has been envisaged through scaffold-hopping approach combined with docking studies for putative-binding interactions with Plasmodium falciparum phosphatidylinositol-4-kinase (PfPI4K) target. The docking results steered to the synthesis of compound 1 [5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine] followed by the in vitro screening for antiplasmodial activity and ADME-PK studies.

Class I PI3K Biology.

This chapter is an introduction to phosphoinositide 3-kinases (PI3K), with class I PI3Ks as the central focus. First, the various PI3K isoforms in class I are presented with emphasis on their overall structure, subunits, subunit constitutive domains, domain-domain interactions, and functional relevance. This structural analysis is followed by a comprehensive history of seminal investigations into PI3K activity.

Inhibition of Autotaxin Ameliorates LPA-Mediated Neuroinflammation and Alleviates Neurological Dysfunction in Acute Hepatic Encephalopathy.

Growing evidence suggests an essential role of neuroinflammation in behavioral abnormalities associated with hepatic encephalopathy (HE). Here, we report the involvement of autotaxin-lysophosphatidic acid (LPA) signaling in HE's pathogenesis. We demonstrate that the autotaxin (ATX) inhibitor PF-8380 attenuates neuroinflammation and improves neurological dysfunction in the mouse model of HE.