Chemistry-informed Machine Learning Explains Calcium-binding Proteins' Fuzzy Shape for Communicating Changes in the Atomic States of Calcium Ions.

Proteins' fuzziness are features for communicating changes in cell signaling instigated by binding with secondary messengers, such as calcium ions, associated with the coordination of muscle contraction, neurotransmitter release, and gene expression. Binding with the disordered parts of a protein, calcium ions must balance their charge states with the shape of calcium-binding proteins and their versatile pool of partners depending on the circumstances they transmit, but it is unclear whether the limited experimental data available can be used to train models to accurately predict the charges of calcium-binding protein variants. Here, we developed a chemistry-informed, machine-learning algorithm that implements a game theoretic approach to explain the output of a machine-learning model without the prerequisite of an excessively large database for high-performance prediction of atomic charges.

A Potential Role for MAGI-1 in the Bi-Directional Relationship Between Major Depressive Disorder and Cardiovascular Disease.

Purpose Of Review: Major Depressive Disorder (MDD) is characterized by persistent symptoms such as fatigue, loss of interest in activities, feelings of sadness and worthlessness. MDD often coexist with cardiovascular disease (CVD), yet the precise link between these conditions remains unclear. This review explores factors underlying the development of MDD and CVD, including genetic, epigenetic, platelet activation, inflammation, hypothalamic-pituitary-adrenal (HPA) axis activation, endothelial cell (EC) dysfunction, and blood-brain barrier (BBB) disruption.

Discovery of YK-029A, a novel mutant EGFR inhibitor targeting both T790 M and exon 20 insertion mutations, as a treatment for NSCLC.

Although traditional EGFR-TKIs have advanced the treatment landscape of NSCLC with sensitive driver mutations (del19 or L858R), some NSCLC patients with EGFR exon 20 insertion mutations have been left with few effective therapies. The development of novel TKIs is still in progress. Herein, we describe the structure-guided design of a novel selective and orally bioavailable inhibitor, YK-029A, which could overcome both the T790 M mutations and exon 20 insertion of EGFR.

A relay velocity model infers cell-dependent RNA velocity.

RNA velocity provides an approach for inferring cellular state transitions from single-cell RNA sequencing (scRNA-seq) data. Conventional RNA velocity models infer universal kinetics from all cells in an scRNA-seq experiment, resulting in unpredictable performance in experiments with multi-stage and/or multi-lineage transition of cell states where the assumption of the same kinetic rates for all cells no longer holds. Here we present cellDancer, a scalable deep neural network that locally infers velocity for each cell from its neighbors and then relays a series of local velocities to provide single-cell resolution inference of velocity kinetics.

Experiment and Simulation Reveal Residue Details for How Target Binding Tunes Calmodulin's Calcium-Binding Properties.

We aim to elucidate the molecular mechanism of the reciprocal relation of calmodulin's (CaM) target binding and its affinity for calcium ions (Ca), which is central to decoding CaM-dependent Ca signaling in a cell. We employed stopped-flow experiments and coarse-grained molecular simulations that learn the coordination chemistry of Ca in CaM from first-principle calculations. The associative memories as part of the coarse-grained force fields built on known protein structures further influence CaM's selection of its polymorphic target peptides in the simulations.

[Relationship between sudden sensorineural hearing loss and facial auditory nerve and anterior inferior cerebellar artery vascular loop in the internal auditory tract MRI].

To investigate the correlation between the facial auditory nerve and anterior inferior cerebellar artery vascular loop in MRI of the internal auditory meatus and idiopathic sudden sensorineural hearing loss. This retrospective study enrolled 144 patients with idiopathic sudden sensorineural hearing loss（SSNHL）（experimental group） and 36 healthy subjects with 72 ears（control group）, who attended the Department of Otolaryngology Head and Neck Surgery, the 940th Hospital of the Joint Logistics Support Unit of the Chinese PLA from January, 2019 to January, 2021. The magnetic resonance imaging（MRI） data of the internal auditory meatus and clinical data were collected and compared between the two groups.

Comprehensive spectral libraries for various rabbit eye tissue proteomes.

Rabbits have been widely used for studying ocular physiology and pathology due to their relatively large eye size and similar structures with human eyes. Various rabbit ocular disease models, such as dry eye, age-related macular degeneration, and glaucoma, have been established. Despite the growing application of proteomics in vision research using rabbit ocular models, there is no spectral assay library for rabbit eye proteome publicly available.

Correlating Interfacial Charge Transfer Rates with Interfacial Molecular Structure in the Tetraphenyldibenzoperiflanthene/C Organic Photovoltaic System.

Organic photovoltaics (OPV) is an emerging solar cell technology that offers vast advantages such as low-cost manufacturing, transparency, and solution processability. However, because the performance of OPV devices is still disappointing compared to their inorganic counterparts, better understanding of how controlling the molecular-level morphology can impact performance is needed. To this end, one has to overcome significant challenges that stem from the complexity and heterogeneity of the underlying electronic structure and molecular morphology.

Coarse-Grained Modeling and Molecular Dynamics Simulations of Ca-Calmodulin.

Calmodulin (CaM) is a calcium-binding protein that transduces signals to downstream proteins through target binding upon calcium binding in a time-dependent manner. Understanding the target binding process that tunes CaM's affinity for the calcium ions (Ca), or vice versa, may provide insight into how Ca-CaM selects its target binding proteins. However, modeling of Ca-CaM in molecular simulations is challenging because of the gross structural changes in its central linker regions while the two lobes are relatively rigid due to tight binding of the Ca to the calcium-binding loops where the loop forms a pentagonal bipyramidal coordination geometry with Ca.

CTRAMER: An open-source software package for correlating interfacial charge transfer rate constants with donor/acceptor geometries in organic photovoltaic materials.

In this paper, we present CTRAMER (Charge-Transfer RAtes from Molecular dynamics, Electronic structure, and Rate theory)-an open-source software package for calculating interfacial charge-transfer (CT) rate constants in organic photovoltaic (OPV) materials based on ab initio calculations and molecular dynamics simulations. The software is based on identifying representative donor/acceptor geometries within interfacial structures obtained from molecular dynamics simulation of donor/acceptor blends and calculating the corresponding Fermi's golden rule CT rate constants within the framework of the linearized-semiclassical approximation. While the methods used are well established, the integration of these state-of-the-art tools originating from different disciplines to study photoinduced CT processes with explicit treatment of the environment, in our opinion, makes this package unique and innovative.

Determining the atomic charge of calcium ion requires the information of its coordination geometry in an EF-hand motif.

It is challenging to parameterize the force field for calcium ions (Ca) in calcium-binding proteins because of their unique coordination chemistry that involves the surrounding atoms required for stability. In this work, we observed a wide variation in Ca binding loop conformations of the Ca-binding protein calmodulin, which adopts the most populated ternary structures determined from the molecular dynamics simulations, followed by ab initio quantum mechanical (QM) calculations on all 12 amino acids in the loop that coordinate Ca in aqueous solution. Ca charges were derived by fitting to the electrostatic potential in the context of a classical or polarizable force field (PFF).

On the Interplay between Electronic Structure and Polarizable Force Fields When Calculating Solution-Phase Charge-Transfer Rates.

We present a comprehensive analysis of the interplay between the choice of an electronic structure method and the effect of using polarizable force fields vs. nonpolarizable force fields when calculating solution-phase charge-transfer (CT) rates. The analysis is based on an integrative approach that combines inputs from electronic structure calculations and molecular dynamics simulations and is performed in the context of the carotenoid-porphyrin-C molecular triad dissolved in an explicit tetrahydrofuran (THF) liquid solvent.

Molecular Dynamics Ensemble Refinement of Intrinsically Disordered Peptides According to Deconvoluted Spectra from Circular Dichroism.

We have developed a computational method of atomistically refining the structural ensemble of intrinsically disordered peptides (IDPs) facilitated by experimental measurements using circular dichroism spectroscopy (CD). A major challenge surrounding this approach stems from the deconvolution of experimental CD spectra into secondary structure features of the IDP ensemble. Currently available algorithms for CD deconvolution were designed to analyze the spectra of proteins with stable secondary structures.

Induced polarization restricts the conformational distribution of a light-harvesting molecular triad in the ground state.

The light-harvesting molecular triad consisting of carotenoid polyene (C), diaryl-porphyrin (P) and pyrrole-fullerene (C) is a donor-acceptor molecule capable of absorbing incident light in the visible range. Its ability to convert solar energy to electrical excitation and charge separation energy suggests a great potential in real-world applications. The ensemble of its conformations under ambient conditions varies widely according to its electronic state.

Opposing Intermolecular Tuning of Ca Affinity for Calmodulin by Neurogranin and CaMKII Peptides.

We investigated the impact of bound calmodulin (CaM)-target compound structure on the affinity of calcium (Ca) by integrating coarse-grained models and all-atomistic simulations with nonequilibrium physics. We focused on binding between CaM and two specific targets, Ca/CaM-dependent protein kinase II (CaMKII) and neurogranin (Ng), as they both regulate CaM-dependent Ca signaling pathways in neurons. It was shown experimentally that Ca/CaM (holoCaM) binds to the CaMKII peptide with overwhelmingly higher affinity than Ca-free CaM (apoCaM); the binding of CaMKII peptide to CaM in return increases the Ca affinity for CaM.

Conformational frustration in calmodulin-target recognition.

Calmodulin (CaM) is a primary calcium (Ca(2+) )-signaling protein that specifically recognizes and activates highly diverse target proteins. We explored the molecular basis of target recognition of CaM with peptides representing the CaM-binding domains from two Ca(2+) -CaM-dependent kinases, CaMKI and CaMKII, by employing experimentally constrained molecular simulations. Detailed binding route analysis revealed that the two CaM target peptides, although similar in length and net charge, follow distinct routes that lead to a higher binding frustration in the CaM-CaMKII complex than in the CaM-CaMKI complex.

Histone deacetylase inhibitor sodium butyrate attenuates gentamicin-induced hearing loss in vivo.

Objective: Although histone deacetylase (HDAC) inhibition has been shown to protect against gentamicin (GM)-induced hearing loss in vitro, its protective effect has not been proven in vivo. In the present study, the aim was to investigate the protective effect of sodium butyrate (NaB), a specific HDAC inhibitor, on GM-induced ototoxicity in vivo.

Methods: Forty 8-week-old albino guinea pigs were divided into two experimental groups.

The role of RIP3 mediated necroptosis in ouabain-induced spiral ganglion neurons injuries.

Spiral ganglion neuron (SGN) injury is a generally accepted precursor of auditory neuropathy. Receptor-interacting protein 3 (RIP3) has been reported as an important necroptosis pathway mediator that can be blocked by necrostatin-1 (Nec-1). In our study, we sought to identify whether necroptosis participated in SGN injury.

Acoustical stimulus changes the expression of stromal cell-derived factor-1 in the spiral ganglion neurons of the rat cochlea.

Neural stem cell (NSC) transplantation into the cochlea has been tested as a treatment for spiral ganglion neuron (SGN) degenerative disease and injury in various animal models. A recent study has shown evidence of functional recovery after transplantation of the stem cells into a degenerated-SGN model. Chemokine stromal cell-derived factor-1 (SDF-1, or known as CXC chemokine ligand-12, CXCL-12) signaling through CXCR4 has previously been identified as a key step in the homing of the stem cells within the injury areas; meanwhile, studies have revealed that the SDF-1/CXCR4 axis is also involved in axon guidance and pathfinding.

Wnt1 from cochlear schwann cells enhances neuronal differentiation of transplanted neural stem cells in a rat spiral ganglion neuron degeneration model.

Although neural stem cell (NSC) transplantation is widely expected to become a therapy for nervous system degenerative diseases and injuries, the low neuronal differentiation rate of NSCs transplanted into the inner ear is a major obstacle for the successful treatment of spiral ganglion neuron (SGN) degeneration. In this study, we validated whether the local microenvironment influences the neuronal differentiation of transplanted NSCs in the inner ear. Using a rat SGN degeneration model, we demonstrated that transplanted NSCs were more likely to differentiate into microtubule-associated protein 2 (MAP2)-positive neurons in SGN-degenerated cochleae than in control cochleae.

MicroRNA-195 chemosensitizes colon cancer cells to the chemotherapeutic drug doxorubicin by targeting the first binding site of BCL2L2 mRNA.

The mechanisms underlying doxorubicin (Dox) resistance in colon cancer cells are not fully understood. MicroRNA (miRNA) play important roles in tumorigenesis and drug resistance. However, the relationship between miRNA and Dox resistance in colon cancer cells has not been previously explored.

Stem cell transplantation via the cochlear lateral wall for replacement of degenerated spiral ganglion neurons.

Spiral ganglion neurons (SGNs) are poorly regenerated in the mammalian inner ear. Because of this, stem cell transplantation has been used to replace injured SGNs, and several studies have addressed this approach. However, the difficulty of delivering stem cells into the cochlea and encouraging their migration to Rosenthal's canal (RC), where the SGNs are located, severely restricts this therapeutic strategy.

Up-regulation of stromal cell-derived factor-1 enhances migration of transplanted neural stem cells to injury region following degeneration of spiral ganglion neurons in the adult rat inner ear.

Neural stem cell (NSC) transplantation into the cochlea is widely used for the treatment of spiral ganglion neuron (SGN) degenerative disease and injury in the animal models, but the migration of the transplanted NSCs to the injury region is difficult and the mechanism is still unclear. In this study, we aimed to validate whether the SGN-degenerated cochlear microenvironment plays a role in the NSC migration and investigated whether stromal cell-derived factor-1 (SDF-1) was involved in the NSCs migration. Using a rat SGN degeneration model, we demonstrated that the transplanted NSCs are more likely to migrate to the injury region during the early post-injury (EPI) than the late post-injury (LPI) stage and the control cochlea.