Drosophila Ncd proteins are motor proteins that play important roles in spindle organization. Ncd and the tubulin dimer are highly charged. Thus, it is crucial to investigate Ncd-tubulin dimer ...interactions in the presence of ions, especially ions that are bound or restricted at the Ncd-tubulin dimer binding interfaces. To consider the ion effects, widely used implicit solvent models treat ions implicitly in the continuous solvent environment without focusing on the individual ions' effects. But highly charged biomolecules such as the Ncd and tubulin dimer may capture some ions at highly charged regions as bound ions. Such bound ions are restricted to their binding sites; thus, they can be treated as part of the biomolecules. By applying multiscale computational methods, including the machine-learning-based Hybridizing Ions Treatment-2 program, molecular dynamics simulations, DelPhi, and DelPhiForce, we studied the interaction between the Ncd motor domain and the tubulin dimer using a hybrid solvent model, which considers the bound ions explicitly and the other ions implicitly in the solvent environment. To identify the importance of treating bound ions explicitly, we also performed calculations using the implicit solvent model without considering the individual bound ions. We found that the calculations of the electrostatic features differ significantly between those of the hybrid solvent model and the pure implicit solvent model. The analyses show that treating bound ions at highly charged regions explicitly is crucial for electrostatic calculations. This work proposes a machine-learning-based approach to handle the bound ions using the hybrid solvent model. Such an approach is not only capable of handling kinesin-tubulin complexes but is also appropriate for other highly charged biomolecules, such as DNA/RNA, viral capsid proteins, etc.
The syntheses, spectroscopic characterizations, and fluorescence quenching efficiencies of polymers and copolymers containing tetraphenylsilole- or silafluorene-vinylene repeat units are reported. ...These materials were prepared by catalytic hydrosilylation reactions between appropriate monomeric metallole alkynes and hydrides. Trimeric model compounds methyl(tetraphenyl)silole-vinylene trimer (1), methyl(tetraphenyl)silole-silafluorene-vinylene cotrimer (2), and methylsilafluorene-vinylene trimer (3) were synthesized to provide detailed structural and spectroscopic characteristics of the polymer backbone and to assess the extent of delocalization in the luminescent excited state. Poly(tetraphenylsilole-vinylene) (4), poly(tetraphenylsilole-silafluorene-vinylene) (5), and poly(silafluorene-vinylene) (6) maintain a regio-regular trans-vinylene Si−C backbone with possible ground state σ*−π and excited state σ*−π* conjugation through the vinylene bridge between metallole units. Fluorescence spectra of the polymers show an ∼13 nm bathochromic shift in λflu from their respective model compounds. Molecular weights (M n) for these polymers and copolymers are in the range of 4000–4500. Detection of nitroaromatic explosives by solution-phase fluorescence quenching of polymers 4−6 was observed with Stern−Volmer constants in the range of 400−20 000 for TNT, DNT, and picric acid (PA). A surface detection method for the analysis of solid particulates of TNT, DNT, PA, RDX, HMX, Tetryl, TNG, and PETN is also described for silafluorene-containing polymers. Polymer 6 exhibited detection for all the preceding types of explosive residues with a 200 pg cm−2 detection limit for Tetryl. Polymers 4 and 5 exhibited only luminescence quenching with nitroaromatic explosives, revealing that the excited-state energy of the sensor plays a key role in the fluorescence detection of explosives.
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IJS, KILJ, NUK, PNG, UL, UM
Pneumomediastinum (PM) and subcutaneous emphysema are characterized by extra-alveolar air within the mediastinum and subcutaneous tissue. PM may occur spontaneously or due to trauma or an underlying ...airway disease. Spontaneous pneumomediastinum (SPM) may be caused by intractable vomiting, forceful coughing, child birthing, or performing a Valsalva maneuver. However, there are limited studies or case reports that present a combination of influenza A infection and electronic cigarette (e-cigarette)-induced SPM. This case report presents SPM in a previously healthy 20-year-old female with untreated influenza A infection and a history of e-cigarette use who presented to the emergency department with fever, cough, chest pain, dyspnea, and vomiting. Her physical examination was significant for neck tenderness, subcutaneous neck crepitus, and increased respiratory effort. Diagnostic evaluation included a chest X-ray and chest computed tomography that revealed PM with subcutaneous emphysema extending into the neck, as well as a negative Gastrografin study. She was treated conservatively and discharged after two days, with a follow-up scheduled at a pulmonary clinic. This case report highlights the need for a detailed substance use history, particularly e-cigarette use, when determining the etiology of SPM in a previously healthy patient. Management for SPM is conservative and should include addressing underlying etiologies with special attention to cessation and education of e-cigarettes and illicit substances.
Adolescent electronic cigarette (e-cigarettes) use is a major public health concern. However, there is a relative dearth of literature on factors that prevent the use of e-cigarettes for adolescents. ...The purpose of the present study was to focus on five protective factors relevant for the prevention of adolescent e-cigarette use. We tested these factors with a large sample of adolescents within a single anlaytic model that allowed for making comparisons among protective factors as well as replicating findings from prior research. Secondary data analysis was conducted on a large sub-sample (n = 33, 193) of data from students who participated in a school survey in the state of Utah. Results from logistic regression indicated that belief in a moral order (OR = 2.30, p < .001), perceived risk of e-cigarette use (OR = 2.22, p < .001), family management (OR = 1.62, p < .001), and commitment to school (OR = 1.43, p < .001) were significantly associated with abstaining from e-cigarette use in the past 30-days. Implications of the findings are discussed in the context of preventing adolescent e-cigarette use.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Abstract
The family of Janus Kinases (JAKs) associated with the JAK–signal transducers and activators of transcription signaling pathway plays a vital role in the regulation of various cellular ...processes. The conformational change of JAKs is the fundamental steps for activation, affecting multiple intracellular signaling pathways. However, the transitional process from inactive to active kinase is still a mystery. This study is aimed at investigating the electrostatic properties and transitional states of JAK1 to a fully activation to a catalytically active enzyme. To achieve this goal, structures of the inhibited/activated full-length JAK1 were modelled and the energies of JAK1 with Tyrosine Kinase (TK) domain at different positions were calculated, and Dijkstra’s method was applied to find the energetically smoothest path. Through a comparison of the energetically smoothest paths of kinase inactivating P733L and S703I mutations, an evaluation of the reasons why these mutations lead to negative or positive regulation of JAK1 are provided. Our energy analysis suggests that activation of JAK1 is thermodynamically spontaneous, with the inhibition resulting from an energy barrier at the initial steps of activation, specifically the release of the TK domain from the inhibited Four-point-one, Ezrin, Radixin, Moesin-PK cavity. Overall, this work provides insights into the potential pathway for TK translocation and the activation mechanism of JAK1.
Graphical Abstract
Graphical Abstract
Signaling bias is a feature of many G protein-coupled receptor (GPCR) targeting drugs with potential clinical implications. Whether it is therapeutically advantageous for a drug to be G protein ...biased or β-arrestin biased depends on the context of the signaling pathway. Here, we explored GPCR ligands that exhibit biased signaling to gain insights into scaffolds and pharmacophores that lead to bias. More specifically, we considered BiasDB, a database containing information about GPCR biased ligands, and focused our analysis on ligands which show either a G protein or β-arrestin bias. Five different machine learning models were trained on these ligands using 15 different sets of features. Molecular fragments which were important for training the models were analyzed. Two of these fragments (number of secondary amines and number of aromatic amines) were more prevalent in β-arrestin biased ligands. After training a random forest model on HierS scaffolds, we found five scaffolds, which demonstrated G protein or β-arrestin bias. We also conducted t-SNE clustering, observing correspondence between unsupervised and supervised machine learning methods. To increase the applicability of our work, we developed a web implementation of our models, which can predict bias based on user-provided SMILES, drug names, or PubChem CID. Our web implementation is available at: drugdiscovery.utep.edu/biasnet.
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IJS, KILJ, NUK, PNG, UL, UM
Microtubules are key players in several stages of the cell cycle and are also involved in the transportation of cellular organelles. Microtubules are polymerized by α/β tubulin dimers with a highly ...dynamic feature, especially at the plus ends of the microtubules. Therefore, understanding the interactions among tubulins is crucial for characterizing microtubule dynamics. Studying microtubule dynamics can help researchers make advances in the treatment of neurodegenerative diseases and cancer. In this study, we utilize a series of computational approaches to study the electrostatic interactions at the binding interfaces of tubulin monomers. Our study revealed that among all the four types of tubulin-tubulin binding modes, the electrostatic attractive interactions in the α/β tubulin binding are the strongest while the interactions of α/α tubulin binding in the longitudinal direction are the weakest. Our calculations explained that due to the electrostatic interactions, the tubulins always preferred to form α/β tubulin dimers. The interactions between two protofilaments are the weakest. Thus, the protofilaments are easily separated from each other. Furthermore, the important residues involved in the salt bridges at the binding interfaces of the tubulins are identified, which illustrates the details of the interactions in the microtubule. This study elucidates some mechanistic details of microtubule dynamics and also identifies important residues at the binding interfaces as potential drug targets for the inhibition of cancer cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The kidney uses specialized G protein-coupled receptors, including olfactory receptors (ORs), to act as sensors of molecules and metabolites. In the present study, we cloned and studied seven renal ...ORs, which we previously found to be expressed in the murine renal cortex. As most ORs are orphan receptors, our goal was to identify ligands for these ORs in the hope that this will guide future research into their functional roles. We identified novel ligands for two ORs: Olfr558 and Olfr90. For Olfr558, we confirmed activation by previously reported ligands and identified 16 additional carboxylic acids that activated this OR. The strongest activation of Olfr558 was produced by butyric, cyclobutanecarboxylic, isovaleric, 2-methylvaleric, 3-methylvaleric, 4-methylvaleric, and valeric acids. The primary in vivo source of both butyric and isovaleric acids is gut microbial metabolism. We also identified 14 novel ligands that activated Olfr90, the strongest of which were 2-methyl-4-propyl-1,3-oxathiane, 1-octen-3-ol, 2-octanol, and 3-octanol. Interestingly, 8 of these 14 ligands are of fungal origin. We also investigated the tissue distribution of these receptors and found that they are each found in a subset of "nonsensory" tissues. Finally, we examined the putative human orthologs of Olfr558 and Olfr90 and found that the human ortholog of Olfr558 (OR51E1) has a similar ligand profile, indicating that the role of this OR is likely evolutionarily conserved. In summary, we examined seven novel renal ORs and identified new ligands for Olfr558 and Olfr90, which imply that both of these receptors serve to detect metabolites produced by microorganisms.
Electrostatic features are fundamental to protein functions and protein-protein interactions. Studying highly charged biomolecules is challenging given the heterogeneous distribution of the ionic ...cloud around such biomolecules. Here we report a new computational method, Hybridizing Ions Treatment-2 (HIT-2), which is used to model biomolecule-bound ions using the implicit solvation model. By modeling ions, HIT-2 allows the user to calculate important electrostatic features of the biomolecules. HIT-2 applies an efficient algorithm to calculate the position of bound ions from molecular dynamics simulations. Modeling parameters were optimized by machine learning methods from thousands of datasets. The optimized parameters produced results with errors lower than 0.2 Å. The testing results on bound Ca2+ and Zn2+ in NAMD simulations also proved that HIT-2 can effectively identify bound ion types, numbers, and positions. Also, multiple tests performed on HIT-2 suggest the method can handle biomolecules that undergo remarkable conformational changes. HIT-2 can significantly improve electrostatic calculations for many problems in computational biophysics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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