The Davydov model was conjectured to describe how an amide I excitation created during ATP hydrolysis in myosin might be significant in providing energy to drive myosin\'s chemomechanical cycle. The free energy surfaces of the myosin relay helix peptide dissolved in 2,2,2-trifluoroethanol (TFE), determined by metadynamics simulations, demonstrate local minima differing in free energy by only ~2 kT, corresponding to broken and stabilized hydrogen bonds, respectively. Experimental pump-probe and 2D infrared spectroscopy were performed on the peptide dissolved in TFE. The relative heights of two peaks seen in the pump-probe data and the corresponding relative volumes of diagonal peaks seen in the 2D-IR spectra at time delays between 0.5 ps and 1 ps differ noticeably from what is seen at earlier or later time delays or in the linear spectrum, indicating that a vibrational excitation may influence the conformational state of this helix. Thus, it is possible that the presence of an amide I excitation may be a direct factor in the conformational state taken on by the myosin relay helix following ATP hydrolysis in myosin.

UNASSIGNED: We investigated the natural history of retinal dystrophy owing to variants in the MYO7A gene.
UNASSIGNED: Fifty-three patients (mean age, 33.6 ± 16.7 years) with Usher syndrome owing to biallelic, mostly pathogenic, variants in MYO7A underwent baseline and two annual follow-up visits. Best-corrected visual acuity (BCVA), semiautomatic kinetic visual field, full-field electroretinogram, color fundus imaging, microperimetry, spectral-domain optical coherence tomography, and fundus autofluorescence were assessed.
UNASSIGNED: At baseline, all patients presented with decreased BCVA (66.4 ± 17.9 Early Treatment Diabetic Retinopathy score and 59.5 ± 21.7 Early Treatment Diabetic Retinopathy score, in the better- and worse-seeing eyes, respectively), restricted semiautomatic kinetic visual field (III4e area, 3365.8 ± 4142.1°2; 4176.4 ± 4400.3°2) and decreased macular sensitivity (9.7 ± 9.9 dB; 9.0 ± 10.2 dB). Spectral-domain optical coherence tomography revealed reduced central macular thickness (259.6 ± 63.0 µm; 250.7 ± 63.3 µm) and narrowed ellipsoid zone band width (2807.5 ± 2374.6 µm; 2615.5 ± 2370.4 µm). Longitudinal analyses (50 patients) showed a significant decrease of BCVA in better-seeing eyes, whereas no changes were observed in worse-seeing eyes for any parameter. BCVA, semiautomatic kinetic visual field (III4e and V4e) and macular sensitivity were related significantly to age at baseline. Hyperautofluorescent foveal patch (16 eyes [31.4%]) and abnormal central hypoautofluorescence (9 eyes [17.6%]) were significantly associated with worse morphological and functional read-outs compared with the hyperautofluorescent ring pattern (22 eyes [43.1%]).
UNASSIGNED: Our European multicentric study offers the first prospective longitudinal analysis in one of the largest cohorts of MYO7A patients described to date, confirming the slow disease progression. More important, this study emphasizes the key role of fundus autofluorescence patterns in retinal impairment staging and advocates its adoption as an objective biomarker in patient selection for future gene therapy clinical trials.

UNASSIGNED: Mental disorders are largely socially determined, yet the combined impact of multidimensional social factors on the two most common mental disorders, depression and anxiety, remains unclear.
UNASSIGNED: We constructed a polysocial risk score (PsRS), a multidimensional social risk indicator including components from three domains: socioeconomic status, neighborhood and living environment and psychosocial factors. Supported by the UK Biobank cohort, we randomly divided 110 332 participants into the discovery cohort (60%; n = 66 200) and the replication cohort (40%; n = 44 134). We tested the associations between 13 single social factors with Patient Health Questionnaire (PHQ) score, Generalized Anxiety Disorder Scale (GAD) score and self-reported depression and anxiety. The significant social factors were used to calculate PsRS for each mental disorder by considering weights from the multivariable linear model. Generalized linear models were applied to explore the association between PsRS and depression and anxiety. Genome-wide environmental interaction study (GWEIS) was further performed to test the effect of interactions between PsRS and SNPs on the risk of mental phenotypes.
UNASSIGNED: In the discovery cohort, PsRS was positively associated with PHQ score (β = 0.37; 95% CI = 0.35-0.38), GAD score (β = 0.27; 95% CI = 0.25-0.28), risk of self-reported depression (OR = 1.29; 95% CI = 1.28-1.31) and anxiety (OR = 1.19; 95% CI = 1.19-1.23). Similar results were observed in the replication cohort. Emotional stress, lack of social support and low household income were significantly associated with the development of depression and anxiety. GWEIS identified multiple candidate loci for PHQ score, such as rs149137169 (ST18) (Pdiscovery = 1.08 × 10-8, Preplication = 3.25 × 10-6) and rs3759812 (MYO9A) (Pdiscovery = 3.87 × 10-9, Preplication = 6.21 × 10-5). Additionally, seven loci were detected for GAD score, such as rs114006170 (TMPRSS11D) (Pdiscovery = 1.14 × 10-9, Preplication = 7.36 × 10-5) and rs77927903 (PIP4K2A) (Pdiscovery = 2.40 × 10-9, Preplication = 0.002).
UNASSIGNED: Our findings reveal the positive effects of multidimensional social factors on the risk of depression and anxiety. It is important to address key social disadvantage in mental health promotion and treatment.

Unconventional myosins are a superfamily of actin-based motor proteins that perform a number of roles in fundamental cellular processes, including (but not limited to) intracellular trafficking, cell motility, endocytosis, exocytosis and cytokinesis. 40 myosins genes have been identified in humans, which belong to different 12 classes based on their domain structure and organisation. These genes are widely expressed in different tissues, and mutations leading to loss of function are associated with a wide variety of pathologies while over-expression often results in cancer. Caenorhabditis elegans (C. elegans) is a small, free-living, non-parasitic nematode. ~38% of the genome of C. elegans has predicted orthologues in the human genome, making it a valuable tool to study the function of human counterparts and human diseases. To date, 8 unconventional myosin genes have been identified in the nematode, from 6 different classes with high homology to human paralogues. The hum-1 and hum-5 (heavy chain of an unconventional myosin) genes encode myosin of class I, hum-2 of class V, hum-3 and hum-8 of class VI, hum-6 of class VII and hum-7 of class IX. The hum-4 gene encodes a high molecular mass myosin (307 kDa) that is one of the most highly divergent myosins and is a member of class XII. Mutations in many of the human orthologues are lethal, indicating their essential properties. However, a functional characterisation for many of these genes in C. elegans has not yet been performed. This article reviews the current knowledge of unconventional myosin genes in C. elegans and explores the potential use of the nematode to study the function and regulation of myosin motors to provide valuable insights into their role in diseases.

OBJECTIVE: This study investigated the new splice site mutations of Myosin VIIA (MYO7A) in patients with Usher syndrome type 1 (USH1) from a three-generation Chinese consanguineous family.
METHODS: All subjects underwent comprehensive ophthalmic examinations and an audiometric test. Demographic data, family history, and peripheral blood leukocytes were collected. We performed whole exome sequencing (WES) to analyze the genomic DNA of the family. DNA sequence and restriction fragment length polymorphism (RFLP) analyses were also done. The identified genetic variants were validated by conducting polymerase chain reaction (PCR) in 100 healthy control subjects and comparing with the NCBI VARIANT database and the 1000 Genomes Project. The functional consequences were further analyzed.
RESULTS: WES identified two new splice site mutations (c.5648G > A(rs111033215) and c.6238-1G > C) in MYO7A in two patients with USH1, i.e., the proband and her elder brother. DNA sequence and RFLP analyses showed that other members without USH1 carried only one of the two mutations. In the analysis of healthy controls, neither mutation existed. Both mutations were predicted to be damaging and were most likely associated with USH1.
CONCLUSIONS: In the three-generation Chinese consanguineous family with USH1, c.5648G > A(rs111033215) and c.6238-1G > C mutations in MYO7A are most likely associated with the disease. Our findings expand the mutational spectrum of MYO7A, which will enhance the understanding of the genetic abnormalities in USH1 and provide more evidence for future investigations on therapeutic strategies such as precise gene replacement or gene editing.

The development of small molecule myosin modulators has seen an increased effort in recent years due to their possible use in the treatment of cardiac and skeletal myopathies. Omecamtiv mecarbil (OM) is the first-in-class cardiac myotrope and the first to enter clinical trials. Its selectivity toward slow/beta-cardiac myosin lies at the heart of its function; however, little is known about the underlying reasons for selectivity to this isoform as opposed to other closely related ones such as fast-type skeletal myosins. In this work, we compared the structure and dynamics of the OM binding site in cardiac and in fasttype IIa skeletal myosin to identify possible reasons for OM selectivity. We found that the different shape, size, and composition of the binding pocket in skeletal myosin directly affects the binding mode and related affinity of OM, which is potentially a result of weaker interactions and less optimal molecular recognition. Moreover, we identified a side pocket adjacent to the OM binding site that shows increased accessibility in skeletal myosin compared with the cardiac isoform. These findings could pave the way to the development of skeletal-selective compounds that can target this region of the protein and potentially be used to treat congenital myopathies where muscle weakness is related to myosin loss of function.

Critical illness myopathy (CIM) is a consequence of modern critical care resulting in general muscle wasting and paralyses of all limb and trunk muscles, resulting in prolonged weaning from the ventilator, intensive care unit (ICU) treatment and rehabilitation. CIM is associated with severe morbidity/mortality and significant negative socioeconomic consequences, which has become increasingly evident during the current COVID-19 pandemic, but underlying mechanisms remain elusive.
Ten neuro-ICU patients exposed to long-term controlled mechanical ventilation were followed with repeated muscle biopsies, electrophysiology and plasma collection three times per week for up to 12 days. Single muscle fibre contractile recordings were conducted on the first and final biopsy, and a multiomics approach was taken to analyse gene and protein expression in muscle and plasma at all collection time points.
(i) A progressive preferential myosin loss, the hallmark of CIM, was observed in all neuro-ICU patients during the observation period (myosin:actin ratio decreased from 2.0 in the first to 0.9 in the final biopsy, P < 0.001). The myosin loss was coupled to a general transcriptional downregulation of myofibrillar proteins (P < 0.05; absolute fold change >2) and activation of protein degradation pathways (false discovery rate [FDR] <0.1), resulting in significant muscle fibre atrophy and loss in force generation capacity, which declined >65% during the 12 day observation period (muscle fibre cross-sectional area [CSA] and maximum single muscle fibre force normalized to CSA [specific force] declined 30% [P < 0.007] and 50% [P < 0.0001], respectively). (ii) Membrane excitability was not affected as indicated by the maintained compound muscle action potential amplitude upon supramaximal stimulation of upper and lower extremity motor nerves. (iii) Analyses of plasma revealed early activation of inflammatory and proinflammatory pathways (FDR < 0.1), as well as a redistribution of zinc ions from plasma.
The mechanical ventilation-induced lung injury with release of cytokines/chemokines and the complete mechanical silencing uniquely observed in immobilized ICU patients affecting skeletal muscle gene/protein expression are forwarded as the dominant factors triggering CIM.

The poor water solubility of myofibrillar proteins (MPs) limits their application in food industry, and is directly related to the molecular behavior associated with myosin assembly into filaments. This study aims to explore the effect of high-intensity ultrasound (HIU) combined with nonenzymatic glycation on the solubility, structural characteristics, and filament-forming behavior of MPs in low ionic strength media. The results showed that the HIU (200-400 W) application could promote the subsequent glycation reaction between MPs and dextran (DX) and interfere with the electrostatic balance between myosin rods, suppressing the formation of filamentous myosin polymers. Glycated MPs pretreated by 400 W HIU had the highest solubility, which corresponded to the smallest particle size, highest zeta potential, and optimum storage stability (P < 0.05). Structure analysis and microscopic morphology observations suggested that the loss of the MP superhelix and the depolymerization of filamentous polymers were the main mechanisms for MP solubilization. In conclusion, HIU combined with glycation can effectively improve the water solubility of MPs by destroying or suppressing the assembly of myosin molecules.

The denaturation of proteins (particularly myosin) due to freezing can lead to the deterioration of Penaeus vannamei. The purpose of this study was to verify the antifreeze protective effects of polyphenols screened by a molecular docking technique, and to explore their interactions with myosin after freezing treatment. It was found that the screened polyphenols could significantly increase the freezing rate and unfreezable water content of shrimp paste. The results of fluorescence spectra indicated that the hesperetin to myosin quenching process included both dynamic and static quenching, and it was primarily bound to myosin through hydrophobic interactions; The quenching of myosin by both dihydroquercetin and mangiferin was static quenching, and they were bound to myosin mainly by hydrogen bonds and van der Waals forces; All three of these polyphenols had only one binding site on myosin. Surface hydrophobicity indicated that all four polyphenols were engaged in non-covalent binding (hydrophobic interactions) with myosin. Infrared spectra demonstrated that the addition of these four polyphenols significantly increased the α-helix content of myosin. They also reduced the myosin particle size, zeta potential, and protein degeneration degree. Scanning electron microscopy revealed that the four polyphenols reduced the degree of aggregation, while more uniformly distributing the myosin particles. These observations provide a basis for the screening of polyphenols and further research into the protective mechanism of polyphenols on frozen myosin.

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