Thermal Titration Molecular Dynamics: The Revenge of the Fragments.

During the last 20 years, the fragment-based drug discovery approach gained popularity in both industrial and academic settings due to its efficient exploration of the chemical space. This bottom-up approach relies on identifying high-efficiency small ligands (fragments) that bind to a target binding site and then rationally evolve them into mature druglike compounds. To achieve such a task, researchers rely on accurate information about the ligand binding mode, usually obtained through experimental techniques, such as X-ray crystallography or computer simulations.

Post-Docking Refinement of Peptide or Protein-RNA Complexes Using Thermal Titration Molecular Dynamics (TTMD): A Stability Insight.

RNA-protein interactions drive and regulate fundamental cellular processes like transcription and translation. Despite being still limited, the growing body of structural data significantly contributes to the characterization of these interactions. However, RNA complexes involving proteins or peptides are not always available due to the structural determination challenges that this biopolymer entails.

Factors inhibiting social activities among adult daycare users.

[Purpose] This study aimed to identify factors that inhibit the social activities of adult daycare users. [Participants and Methods] Based on participation in social activities, we categorized adult daycare users into two groups; socially active and inactive. Using a questionnaire, the socially inactive group were surveyed for their reasons for non-participation in social activities.

Pck2 association with the plasma membrane and efficient response of the cell integrity pathway require regulation of PI4P homeostasis by exomer.

Exomer is a protein complex that facilitates trafficking between the Golgi and the plasma membrane (PM). exomer is composed of Cfr1 and Bch1, and we have found that full activation of the cell integrity pathway (CIP) in response to osmotic stress requires exomer. In the wild-type, the CIP activators Rgf1 (Rho1 GEF) and Pck2 (PKC homologue) and the MEK kinase Mkh1 localize in the PM, internalize after osmotic shock and re-localize after adaptation.

A comprehensive study of SARS-CoV-2 main protease (Mpro) inhibitor-resistant mutants selected in a VSV-based system.

Nirmatrelvir was the first protease inhibitor specifically developed against the SARS-CoV-2 main protease (3CLpro/Mpro) and licensed for clinical use. As SARS-CoV-2 continues to spread, variants resistant to nirmatrelvir and other currently available treatments are likely to arise. This study aimed to identify and characterize mutations that confer resistance to nirmatrelvir.

Perpendicular crossing chains enable high mobility in a noncrystalline conjugated polymer.

The nature of interchain π-system contacts, and their relationship to hole transport, are elucidated for the high-mobility, noncrystalline conjugated polymer C16-IDTBT by the application of scanning tunneling microscopy, molecular dynamics, and quantum chemical calculations. The microstructure is shown to favor an unusual packing motif in which paired chains cross-over one another at near-perpendicular angles. By linking to mesoscale microstructural features, revealed by coarse-grained molecular dynamics and previous studies, and performing simulations of charge transport, it is demonstrated that the high mobility of C16-IDTBT can be explained by the promotion of a highly interconnected transport network, stemming from the adoption of perpendicular contacts at the nanoscale, in combination with fast intrachain transport.

7-Amino-[1,2,4]triazolo[1,5-a][1,3,5]triazines as CK1δ inhibitors: Exploring substitutions at the 2 and 5-positions.

CK1δ is a serine-threonine kinase involved in several pathological conditions including neuroinflammation and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Specifically, it seems that an inhibition of CK1δ could have a neuroprotective effect in these conditions. Here, a series of [1,2,4]triazolo[1,5-a][1,3,5]triazines were developed as ATP-competitive CK1δ inhibitors.

TumFlow: An AI Model for Predicting New Anticancer Molecules.

Melanoma is the fifth most common cancer in the United States. Conventional drug discovery methods are inherently time-consuming and costly, which imposes significant limitations. However, the advent of Artificial Intelligence (AI) has opened up new possibilities for simulating and evaluating numerous drug candidates, thereby mitigating the requisite time and resources.

Analyzing hate speech dynamics on Twitter/X: Insights from conversational data and the impact of user interaction patterns.

This paper investigates the pervasive issue of hate speech within Twitter/X Portuguese network conversations, offering a multifaceted analysis of its characteristics. This study utilizes a mixed-method approach, combining several methodologies of network analysis (triad census and participation shifts) over the network of interaction between users. Qualitative manual content annotation was applied to the dataset to dissect different patterns of hate speech on the platform.

Crosstalk between Regnase-1 and -3 shapes mast cell survival and cytokine expression.

Post-transcriptional regulation of immune-related transcripts by RNA-binding proteins (RBPs) impacts immune cell responses, including mast cell functionality. Despite their importance in immune regulation, the functional role of most RBPs remains to be understood. By manipulating the expression of specific RBPs in murine mast cells, coupled with mass spectrometry and transcriptomic analyses, we found that the Regnase family of proteins acts as a potent regulator of mast cell physiology.

Smartphone use and well-being of adolescent girls: a population-based study.

Background And Objectives: Recent studies have reported an increasing incidence of anxiety among adolescent girls, and associated this with self-reported social media use. This study aimed to measure smartphone and social media use objectively and to evaluate its associations with measures of mental health and well-being.

Methods: In autumn 2022, we recruited a cohort of 1164 first-year female students from 21 socioeconomically diverse high schools.

Dynamics and thermal stability of the bypass polymerase, DinB homolog (Dbh).

The DinB homolog polymerase (Dbh) is a member of the Y-family of translesion DNA polymerases that can synthesize using a damaged DNA template. Since Dbh comes from the thermophilic archaeon it is capable of functioning over a wide range of temperatures. Existing X-ray structures were determined at temperatures where the protein is least active.

Structural Investigations on 2-Amidobenzimidazole Derivatives as New Inhibitors of Protein Kinase CK1 Delta.

Protein kinase CK1δ (CK1δ) is a serine-threonine/kinase that modulates different physiological processes, including the cell cycle, DNA repair, and apoptosis. CK1δ overexpression, and the consequent hyperphosphorylation of specific proteins, can lead to sleep disorders, cancer, and neurodegenerative diseases. CK1δ inhibitors showed anticancer properties as well as neuroprotective effects in cellular and animal models of Parkinson's and Alzheimer's diseases and amyotrophic lateral sclerosis.

Molecular-Scale Imaging Enables Direct Visualization of Molecular Defects and Chain Structure of Conjugated Polymers.

Conjugated polymers have become materials of choice for applications ranging from flexible optoelectronics to neuromorphic computing, but their polydispersity and tendency to aggregate pose severe challenges to their precise characterization. Here, the combination of vacuum electrospray deposition (ESD) with scanning tunneling microscopy (STM) is used to acquire, within the same experiment, assembly patterns, full mass distributions, exact sequencing, and quantification of polymerization defects. In a first step, the ESD-STM results are successfully benchmarked against NMR for low molecular mass polymers, where this technique is still applicable.

Platelet function testing: Update on determinant variables and permissive windows using a platelet-count-based device.

While there are various aspects of platelet biology that can be studied in the lab (i.e. adhesion, degranulation, integrin activation), the master test for platelet function is that which gives a measure of the platelet aggregation capacity upon stimulation with an agonist.

The Role of Side Chains and Hydration on Mixed Charge Transport in n-Type Polymer Films.

Introducing ethylene glycol (EG) side chains to a conjugated polymer backbone is a well-established synthetic strategy for designing organic mixed ion-electron conductors (OMIECs). However, the impact that film swelling has on mixed conduction properties has yet to be scoped, particularly for electron-transporting (n-type) OMIECs. Here, the authors investigate the effect of the length of branched EG chains on mixed charge transport of n-type OMIECs based on a naphthalene-1,4,5,8-tetracarboxylic-diimide-bithiophene backbone.

The bacterial lysate OM-85 engages Toll-like receptors 2 and 4 triggering an immunomodulatory gene signature in human myeloid cells.

OM-85 is a bacterial lysate used in clinical practice to reduce duration and frequency of recurrent respiratory tract infections. Whereas knowledge of its regulatory effects in vivo has substantially advanced, the mechanisms of OM-85 sensing remain inadequately addressed. Here, we show that the immune response to OM-85 in the mouse is largely mediated by myeloid immune cells through Toll-like receptor (TLR) 4 in vitro and in vivo.

Girls referred for amenorrhea: analysis of a patient series from a specialist center.

Objective: Among adolescents, amenorrhea is a common reason for medical consultation. Despite the variety of underlying etiologies, the prevalence of the causes is incompletely understood. This study aimed to assess the demographic and etiological factors among patients with amenorrhea treated in a single specialist unit of adolescent gynecology.

Thermal titration molecular dynamics (TTMD): shedding light on the stability of RNA-small molecule complexes.

Ribonucleic acids are gradually becoming relevant players among putative drug targets, thanks to the increasing amount of structural data exploitable for the rational design of selective and potent binders that can modulate their activity. Mainly, this information allows employing different computational techniques for predicting how well would a ribonucleic-targeting agent fit within the active site of its target macromolecule. Due to some intrinsic peculiarities of complexes involving nucleic acids, such as structural plasticity, surface charge distribution, and solvent-mediated interactions, the application of routinely adopted methodologies like molecular docking is challenged by scoring inaccuracies, while more physically rigorous methods such as molecular dynamics require long simulation times which hamper their conformational sampling capabilities.

Pyrazolo-triazolo-pyrimidine Scaffold as a Molecular Passepartout for the Pan-Recognition of Human Adenosine Receptors.

Adenosine receptors are largely distributed in our organism and are promising therapeutic targets for the treatment of many pathologies. In this perspective, investigating the structural features of the ligands leading to affinity and/or selectivity is of great interest. In this work, we have focused on a small series of pyrazolo-triazolo-pyrimidine antagonists substituted in positions 2, 5, and N8, where bulky acyl moieties at the N5 position and small alkyl groups at the N8 position are associated with affinity and selectivity at the A adenosine receptor even if a good affinity toward the A adenosine receptor has also been observed.

2-Pentadecyl-2-oxazoline inhibits lipopolysaccharide-induced microglia activation interfering with TLR4 signaling.

Aim: 2-Pentadecyl-2-oxazoline (PEA-OXA), the oxazoline derivative of N-palmitoylethanolamine, exerts anti-inflammatory activity; however, very little is known about the molecular mechanisms underlying this effect. Here, we tested the anti-neuroinflammatory effect of PEA-OXA in primary microglia and we also investigated the possible interaction of the molecule with the Toll-like receptor 4 (TLR4)-myeloid differentiation protein-2 (MD-2) complex.

Main Methods: The anti-inflammatory effect of PEA-OXA was analyzed by measuring the expression and release of pro-inflammatory mediators in primary microglia by real-time PCR and ELISA, respectively.