Computational insights into NIMA-related kinase 6: unraveling mutational effects on structure and function.

The NEK6 (NIMA-related kinase 6) serine/threonine kinase is a pivotal player in a multitude of cellular processes, including the regulation of the cell cycle and the response to DNA damage. Its significance extends to disease pathogenesis, as changes in NEK6 activity have been linked to the development of cancer. Non-synonymous single nucleotide polymorphisms (nsSNPs) in NEK6 have been linked to cancer as they alter the protein's native structure and function. The association between NEK6 activity and cancer development has prompted researchers to explore the effects of genetic variations within the NEK6 gene. Therefore, we utilized advanced computational tools to analyze 155 high-confidence nsSNPs in the NEK6 gene. From this analysis, 21 nsSNPs were identified as potentially harmful, raising concerns about their impact on NEK6 activity and cancer risk. These 21 mutations were then examined for structural alterations, and eight of nsSNPs (I51M, V76A, I134N, Y152D, R171Q, V186G, L237R, and C285S) were found to destabilize the protein. Among the destabilizing mutations screened, a specific mutation, R171Q, stood out due to its conserved nature. To understand its impact on the protein and conformation, all-atom molecular dynamics simulations (MDS) for 100 ns were performed for both Wildtype NEK6 (WT-NEK6) and R171Q. The simulations revealed that the R171Q variant was unstable and led to significant conformational changes in NEK6. This study provides valuable insights into NEK6 dysfunction caused by single amino acid alterations, offering a novel understanding of the molecular mechanisms underlying NEK6-related cancer progression.

NIMA-related kinase-6 (NEK6) as an executable target in cancer

Cancer is a disease that develops when cells begin to divide uncontrollably and spreads to other parts of the body. Proliferation and invasion of cancerous cells are generally known to be influenced by cell cycle-related proteins in human malignancies. Therefore, in this review, we have emphasized on the serine/threonine kinase named NEK6. NEK6 is been deliberated to play a critical role in mitosis progression that includes mitotic spindle formation, metaphase to anaphase transition, and centrosome separation. Moreover, it has a mechanistic role in DNA repair and can cause apoptosis when inhibited. Past studies have connected NEK6 protein expression to cancer cell senescence. Besides, there are reports relating NEK6 to a range of malignancies including breast, lung, ovarian, prostate, kidney, liver, and others. Given its significance, this review attempts to describe the structural and functional aspects of NEK6 in various cellular processes, as well as how it is linked to different forms of cancer. Lastly, we have accentuated, on some of the plausible inhibitors that have been explored against NEK6 overexpression (AU)

NIMA-related kinase-6 (NEK6) as an executable target in cancer.

Cancer is a disease that develops when cells begin to divide uncontrollably and spreads to other parts of the body. Proliferation and invasion of cancerous cells are generally known to be influenced by cell cycle-related proteins in human malignancies. Therefore, in this review, we have emphasized on the serine/threonine kinase named NEK6. NEK6 is been deliberated to play a critical role in mitosis progression that includes mitotic spindle formation, metaphase to anaphase transition, and centrosome separation. Moreover, it has a mechanistic role in DNA repair and can cause apoptosis when inhibited. Past studies have connected NEK6 protein expression to cancer cell senescence. Besides, there are reports relating NEK6 to a range of malignancies including breast, lung, ovarian, prostate, kidney, liver, and others. Given its significance, this review attempts to describe the structural and functional aspects of NEK6 in various cellular processes, as well as how it is linked to different forms of cancer. Lastly, we have accentuated, on some of the plausible inhibitors that have been explored against NEK6 overexpression.

Guiding Conventional Protein-Ligand Docking Software with Convolutional Neural Networks.

The high-performance computational techniques have brought significant benefits for drug discovery efforts in recent decades. One of the most challenging problems in drug discovery is the protein-ligand binding pose prediction. To predict the most stable structure of the complex, the performance of conventional structure-based molecular docking methods heavily depends on the accuracy of scoring or energy functions (as an approximation of affinity) for each pose of the protein-ligand docking complex to effectively guide the search in an exponentially large solution space. However, due to the heterogeneity of molecular structures, the existing scoring calculation methods are either tailored to a particular data set or fail to exhibit high accuracy. In this paper, we propose a convolutional neural network (CNN)-based model that learns to predict the stability factor of the protein-ligand complex and exhibits the ability of CNNs to improve the existing docking software. Evaluated results on PDBbind data set indicate that our approach reduces the execution time of the traditional docking-based method while improving the accuracy. Our code, experiment scripts, and pretrained models are available at https://github.com/j9650/MedusaNet.

Association of Angiotensin converting enzyme gene insertion / deletion polymorphism with risk of ischemic heart disease in a population of smokers in southern India.

BACKGROUND: Ischemic heart disease (IHD) remains a major public health problem nationally and internationally. Smoking is a major risk factor for IHD.The deletion (D) allele of the angiotensin converting enzyme (ACE) gene polymorphism has been associated with hypertension, ischemic stroke and myocardial infarction. The present study was carried out to determine the association of the ACE gene insertion/deletion (I/D) polymorphism in IHD patients with and without smoking. MATERIALS AND METHODS: One hundred seven male IHD patients admitted consecutively in the Cardiology unit of a Government Hospital and 100 age and sex matched healthy controls were enrolled in this study.The patients were further divided into smokers and nonsmokers. All the subjects were checked for I/D polymorphism of ACE gene, which is mapped to 17q23.3 with OMIM no 106180, by polymerase chain reaction (PCR). The subjects were also investigated for lipid profile and ejection fraction (EF). RESULTS: We found significant difference in the distribution of D allele between patients and controls (p=0.009, OR 1.69, 95% CI 1.139 to 2.517).The significantly lower EF (p<0.001) was suggestive of greater cardiovascular compromise in smokers. The frequency of ID genotype was significantly associated with cases compared to controls (p=0.012, OR 2.054, 95% CI 1.1694-3.624) but was not significantly associated with smokers as compared to nonsmokers. CONCLUSION: We infer significant association of D allele with IHD. The smokers with ID genotype should be put on prophylactic ACE inhibitor therapy to prevent the morbidity and mortality associated with IHD.

Importance of Serum Copper and Vascular Endothelial Growth Factor (VEGF-A) Levels in Postmenopausal Bleeding.

The main aim of this study is association of serum copper and vascular endothelial growth factor (VEGF-A) in postmenopausal bleeding (PMB) patients. Blood samples were collected from female patients suffering with postmenopausal bleeding (n = 50) as well as healthy females as controls (n = 50). Serum copper levels were estimated by spectrophotometric method and serum VEGF-A by ELISA technique and compared with ultrasonographic measurement of endometrial thickness in both patients and controls. A significant increase in serum copper levels and an almost twofold increase in serum VEGF-A was observed in DUB patients when compared with controls. Correlation (r) between serum VEGF-A levels and endometrial thickness was 0.96. Odds ratio for copper, VEGF-A and combination of copper and VEGF-A was 0.0426, 0.0947 and 0.0313 respectively, in all these cases odds ratio was <1. The abnormal angiogenesis in PMB could be due to increased serum copper levels,which in turn stimulates factors like VEGF-A, thereby causing an increase in endometrial growth.

An epidemiological study on fluorosis in an urban slum area of Nalgonda, Andhra Pradesh, India.

Fluorosis is an important public health problem in certain parts of India. Nalgonda is one of the fluorosis endemic districts of Andhra Pradesh. A cross-sectional study was undertaken to assess the prevalence of dental and skeletal fluorosis in Panagal, one of the urban slum areas of Nalgonda town of Andhra Pradesh. 265 individuals residing in 92 households of five colonies of Panagal were selected by multi-stage random sampling. Fluorosis was assessed by standard clinical methods and water samples were tested for fluoride level. It was observed that mean fluoride level in ground water samples in the area was 4.01 mg/l and that of Nagarjunsagar water was 0.74 mg/l. The mean age of the study subjects in the area was 34.73 years. The overall prevalence of skeletal fluorosis was 24.9% and that of dental fluorosis was 30.6%. The prevalence increased with age. Skeletal and dental fluorosis is endemic in the study area.

Serum anti - TPO levels in benign and malignant breast tumors.

Breast cancer is a hormone dependent neoplasm. Conflicting results regarding the clinical correlation between breast cancer and thyroid diseases have been reported. The objective of this study was to determine the association of anti - TPO levels in patients having complaints of a lump in breast. Serum samples and Fine needle aspiration cytology (FNAC) samples were collected from 31 female patients with a lump in breast between the age group of 20-75 years. 31 age matched normal healthy controls were also examined for the same parameters. Serum samples were analyzed for its anti - TPO levels. FNAC reports confirmed patients as having duct cell carcinoma. They had raised serum anti - TPO levels compared to controls. FNAC results of others (n=26) were reported as fibroadenoma whose anti - TPO levels were less than the controls.

Association of hyperhomocysteinemia to alcohol withdrawal in chronic alcoholics.

This study is conducted in chronic alcoholics to assess the association of an Individual's level of serum homocysteine with the success of achieving alcohol deaddiction in the patient. The patients' nutrition status is also assessed. 50 chronic alcoholics admitted to a deaddiction center were inducted into the study. Patients underwent an 8 weeks holistic program to promote rehabilitation from alcoholism. All the patients were addicted to alcohol for 8 - 10 years. Of the 50 patients enrolled, 39 of them completed the 8 weeks program including complete abstinence from alcohol during this period. Fasting blood samples were collected on admission and again after 8 weeks of alcohol abstinence for analyses of serum homocysteine and serum prealbumin, transferrin, total proteins and albumin, gammaglutamyl transferase (GGT) and alanine transaminase (ALT). Of the 50 patients enrolled in the study, 39 completed the 8 weeks rehabilitation program. 11 patients discontinued within 2 weeks of admission. During the 8 weeks of complete alcohol abstinence, patients were given a balanced diet and multivitamin supplements. A significant improvement in their nutritional status was noted by the elevation of serum levels of prealbumin, transferrin, total proteins and albumin. Serum homocysteine levels decreased significantly (p<0.002) to normal levels from previous hyperhomocytenemia. This was accompanied by decrease in serum GGT and ALT levels indicating improved liver functions. Serum estimation of homocysteine in chronic alcoholics is important to assess whether the patient will have a successful rehabilitation. Normal homocysteine levels are achieved after dietary changes and abstinence from alcohol. Timely correction of hyperhomocysteinemia also provides successful rehabilitation.

Diagnostic strategies for subclinical hypothyroidism.

The aim of this study is to delineate laboratory diagnostic strategies for subclinical hypothyroidism in patients who are clinically symptomatic but may have a normal thyroid profile. Tri - iodothyronine (T(3)), thyroxine (T(4)), thyroid stimulating hormone (TSH) and anti thyroid peroxidase antibodies (anti-TPO) were estimated on fasting blood samples from 99 patients using electrochemiluminescence methods on ELECSYS 1010 (Roche). 74% of study subjects had elevated anti-TPO levels.61% patients had subclinical hypothyroidism. 45 of the 61 subclinical hypothyroid patients had elevated anti-TPO levels (73%). This is an important finding suggesting an autoimmune etiology for subclinical thyroid dysfunction with a higher risk of developing overt hypothyroidism.

Serum lipids and malondialdehyde levels in primiparous patients with pregnancy induced hypertension.

BACKGROUND: Pregnancy induced hypertension (PIH) contributes to 15.6% maternal mortality in India. In Behrampur, Orissa, maternal deaths due to PIH was 32%, which is twice the national incidence. Hence in this population, some factors associated with severity of PIH were studied. Serum lipid concentrations and malondialdehyde (MDA) levels were correlated with severity of PIH and birth weight of the neonate. PATIENTS #ENTITYSTARTX00026; METHODS: 70 primiparous PIH patients and 20 healthy controls were studied. Serum lipids and MDA were estimated. Maternal blood pressures and birth weights of the neonate were recorded. RESULTS AND CONCLUSION: Serum cholesterol, triglyceride, LDL, VLDL and MDA were significantly elevated in primiparous PIH patients when compared to control subjects. Average birth weight of babies born to mothers with PIH was less than those born to control subjects. The most significant factor was that in this geographical area, 26% of the primiparous patients with PIH were below 20 years of age while only 15% of the controls were less than 20 years, indicating that younger maternal age was a contributing factor to PIH.