High-Risk Polymorphisms Associated with the Molecular Function of Human HMGCR Gene Infer the Impedance of Cholesterol Biosynthesis

Background: HMG-CoA reductase or HMGCR (3-Hydroxy-3-methylglutaryl-CoA reductase) is a rate-limiting enzyme involved in cholesterol biosynthesis. HMGCR plays an important role in the possible occurrence of hypercholesterolemia leading to atherosclerosis and coronary heart disease. This enzyme is a major target for cholesterol lowering drugs such as “statins” which blocks the synthesis of mevalonate, a precursor for cholesterol biosynthesis. This study aims to characterize deleterious mutations and classify functional Single Nucleotide Polymorphisms (SNPs) of the HMGCR gene through analysis of functional and structural evaluation, domain association, solvent accessibility, and energy minimization studies. Results: Among 6,815 SNP entries from different databases, approximately 388 SNPs were found to be missense. Analysis showed that seven missense SNPs are more likely to have deleterious effects. A tertiary model of the mutant protein was constructed to determine the functional and structural effects of the HMGCR mutation. In addition, the location of the mutations suggests that they may have deleterious effects because most of the mutations are resides in the functional domain of the protein. The findings from the bunch of bioinformatics tools predicted that rs147043821 and rs193026499 missense SNPs could cause significant structural and functional instability in the mutated proteins of the HMGCR gene. Conclusion: Therefore, the results of the current study would undoubtedly be accommodating in future endeavors concerning drug discovery and therapeutics against hypercholesterolemia.

The fibula and talus position difference in functional and mechanical ankle instability: MRI findings

Purpose: This study aimed to use MRI to evaluate the fibula and talus position difference in functional and mechanical ankle stability patients. Methods: 61 and 68 patients with functional and mechanical instability, and 60 healthy volunteers were involved. Based on the axial MRI images, the rotation of the talus was identified through the Malleolar Talus Index (MTI). The position relative to the talus (Axial Malleolar Index, AMI) and medial malleolus (Intermalleolar Index, IMI) were used to evaluated the displacement of the fibula. Results: Post hoc analysis showed that the values of malleolar talus index was significantly larger among mechanical instability (89.18° ± 2.31°) than that in functional instability patients (86.55° ±61.65°, P < 0.001) and healthy volunteers (85.59° ± 2.42°, P < 0.001). The axial malleolar index of the mechanical instability patients (11.39° ± 1.41°) were significantly larger than healthy volunteers (7.91° ± 0.83°) (P < 0.0001). There were no statistically significant differences in the above three indexes between the functional instability patients and healthy volunteers. Conclusion: The functional instability patients didn’t have a posteriorly positioned fibula and an internally rotated talus. The malleolar talus index was significantly larger among mechanical instability patients than that in functional instability patients. Increased malleolar talus index may become a new indirect MRI sign for identifying functional and mechanical instability patients.

Clade GR and Clade GH Isolates in Asia Show Highest Amount of SNPs

Clades are monophyletic groups composed of a common ancestor and all its lineal descendants. As the propensity of virulence of a disease depends upon the type of clade the virus belongs to and it causes different fatality rates of disease in different countries, so the clade-wise analysis of SARS-CoV-2 isolates collected from different countries can illuminate the actual evolutionary relationships between them. In this study, 1566 SARS-CoV-2 genome sequences across ten Asian countries are collected, clustered, and characterized based on the clade they belong to. The isolates are compared to the Wuhan reference sequence (Accession no:MN996528.1) to identify the mutations that occurred at different protein regions. Structural changes in amino acids due to mutations lead to functional instability of the proteins. Detailed clade-wise functional assessments are carried out to quantify the stability and vulnerability of the mutations occurring in SARS-CoV-2 genomes which can shade light on personalized prevention and treatment of the disease and encourage towards the invention of clade-specific vaccines.

Quantitative Evaluation of Functional Instability Due to Anterior Cruciate Ligament Deficiency

Background: A safe and simple procedure to evaluate functional instability due to anterior cruciate ligament (ACL) deficiency (ACLD) has not been established. The angle of trunk backward tilting, which is known as a posture at risk for ACL injuries, could be used as a parameter to evaluate functional instability due to ACLD. Purpose: To measure the backward tilt angle of the trunk with participants standing upright on 1 leg and to investigate its usefulness to quantitatively evaluate functional instability due to ACLD. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: Our cohort included 50 participants with unilateral ACLD and 40 participants with bilateral healthy knees. The trunk backward tilt (TBT) test was conducted as follows: the participant was asked to maximally tilt the trunk backward in a single-leg standing position, while forward tilt of the index leg was blocked with a custom-made device. The TBT angle was measured using a side-view photograph. Subjective knee instability during the test was recorded using a visual analog scale (VAS). The relative and absolute reliability of the TBT test were verified in a sample of healthy participants and those with ACLD, and comparisons between indicators were performed. Multiple regression analysis was performed with the injured/uninjured side ratio (I/U ratio) of the TBT angle as the dependent variable and the following independent variables: (1) I/U ratio of knee extension muscle strength, (2) I/U ratio of knee flexion muscle strength, (3) side-to-side difference (SSD) of the KT-1000 arthrometer measurement, (4) sex, and (5) SSD of the VAS score. Results: The TBT test had high reliability among healthy participants and those with ACLD. The TBT angle was significantly smaller and the VAS score was significantly higher on the injured side compared with the uninjured side and with healthy knees ( P < .001 for all). Among the independent variables, the SSD of the VAS score had a negative influence on the I/U ratio of the TBT angle ( R 2 = 0.59; P < .001). Conclusion: The TBT test is a simple, safe, and reliable method for quantitatively evaluating functional instability due to ACLD under weightbearing conditions that reflect subjective knee instability. The test will provide an index of treatment outcomes and return to sports through additional objective measurements before and after ACL reconstruction.

Identification of the type of enterprise corporate culture with regard to the perception of changes

The article claims that modern management views enterprise performance as an open socio-economic system, in which personnel play a central role. Employees’ attitude to various processes in management determines success of strategies and tactics. The personnel play a crucial role in implementing changes, because they demonstrate support, neutrality, or resistance. It is noted that the resistance to changes stems from the prevailing corporate culture of the enterprise and depends on its development. The purpose of the research paper is to provide evidence for the dependence of changes on types of corporate culture, and to develop tools of identification of these types. The article examines the concept of corporate culture in relation to management of changes, and determines the connection between corporate culture and resistance to changes based on the indicator of instability of changes. It is found out that resistance to changes in a certain corporate culture is the process of growing unwillingness to change due to the prevalent corporate culture. The tendency to resist changes is defined as functional instability of corporate culture, which is characterized by high frequency of resistance in response to changes and measures taken to overcome such resistance. With regard to management of changes, the author proposes to distinguish between two types of corporate cultures: fiduciary and non-fiduciary, based on employees’ attitude to changes. In fiduciary corporate culture, there is a high level of trust between the management and personnel in a way that the management encourages introducing changes. If resistance arises, it is minimal, and it is quickly overcome through information and motivation measures. In non-fiduciary corporate culture, the management and the team responsible for changes do not show or lack interest in changes, and under these circumstances, resistance, that has a significant impact, is comprehensive and systemic. In fiduciary corporate culture, the role of personnel in the management of changes can be described as linear processes, whereas in non-fiduciary corporate culture, changes can be described as variable flows of changes resulting from unwillingness to introduce changes. The level of corporate culture with regard to changes is proposed to be determined through using the integral indicator calculated as a weighted average of partial indicators (characteristics) of corporate culture: 1) strong – weak; 2) adaptive – not adaptive; 3) ethical – unethical; 4) developed – latent; 5) harmonious – non-harmonic; 6) creative – bureaucratic; 7) controlled – spontaneous; 8) with a high-low level of instability. The approbation of this approach to the identification of corporate culture of the enterprise was carried out on the basis of enterprises that form the basis of the iron ore sub-sector of Ukraine. The approach, discussed in the research, has been applied for identification of corporate culture the mining industry f Ukraine, chosen as an example.

Functional instability allows access to DNA in longer transcription Activator-Like effector (TALE) arrays

Transcription activator-like effectors (TALEs) bind DNA through an array of tandem 34-residue repeats. How TALE repeat domains wrap around DNA, often extending more than 1.5 helical turns, without using external energy is not well understood. Here, we examine the kinetics of DNA binding of TALE arrays with varying numbers of identical repeats. Single molecule fluorescence analysis and deterministic modeling reveal conformational heterogeneity in both the free- and DNA-bound TALE arrays. Our findings, combined with previously identified partly folded states, indicate a TALE instability that is functionally important for DNA binding. For TALEs forming less than one superhelical turn around DNA, partly folded states inhibit DNA binding. In contrast, for TALEs forming more than one turn, partly folded states facilitate DNA binding, demonstrating a mode of ‘functional instability’ that facilitates macromolecular assembly. Increasing repeat number slows down interconversion between the various DNA-free and DNA-bound states.