Closely related to causes of various diseases such as rheumatoid arthritis, septic shock, and coeliac disease; tyrosine nitration is considered as one of the most important post-translational ...modification in proteins. Inside a cell, protein modifications occur accurately by the action of sophisticated cellular machinery. Specific enzymes present in endoplasmic reticulum accomplish this task. The identification of potential tyrosine residues in a protein primary sequence, which can be nitrated, is a challenging task.
To counter the prevailing, laborious and time-consuming experimental approaches, a novel computational model is introduced in the present study. Based on data collected from experimentally verified tyrosine nitration sites feature vectors are formed. Later, an adaptive training algorithm is used to train a back propagation neural network for prediction purposes. To objectively measure the accuracy of the proposed model, rigorous verification and validation tests are carried out.
Through verification and validation, a promising accuracy of 88%, a sensitivity of 85%, a specificity of 89.18% and Mathew's Correlation Coefficient of 0.627 is achieved.
It is concluded that the proposed computational model provides the foundation for further investigation and be used for the identification of nitrotyrosine sites in proteins.
Dryopteris cycadina has diverse traditional uses in the treatment of various human disorders which are supported by pharmacological studies. Similarly, the phytochemical studies of this plant led to ...the isolation of numerous compounds.
The present study deals with α-glucosidase inhibition of various kaempferol derivates including kaempferol-3, 4/-di-O-α- L-rhamnopyranoside 1, kaempferol-3, 5-di-O-α-L-rhamnoside 2 and kaempferol-3,7-di-O-α- L-rhamnopyranoside 3.
The results showed marked concentration-dependent inhibition of the enzyme when assayed at different concentrations and the IC50 values of compounds 1-3 were 137±9.01, 110±7.33, and 136±1.10 mM, respectively far better than standard compound, acarbose 290±0.54 mM. The computational studies revealed strong docking scores of these compounds and augmented the in vitro assay.
In conclusion, the isolated kaempferol derivatives 1-3 from D. cycadina exhibited potent α- glucosidase inhibition.
Background: In various biological processes and cell functions, Post Translational Modifications (PTMs) bear critical significance. Hydroxylation of proline residue is one kind of PTM, which occurs ...following protein synthesis. The experimental determination of hydroxyproline sites in an uncharacterized protein sequence requires extensive, time-consuming and expensive tests.
Methods: With the torrential slide of protein sequences produced in the post-genomic age, certain remarkable computational strategies are desired to overwhelm the issue. Keeping in view the composition and sequence order effect within polypeptide chains, an innovative in-silico predictor via a mathematical model is proposed.
Results: Later, it was stringently verified using self-consistency, cross-validation and jackknife tests on benchmark datasets. It was established after a rigorous jackknife test that the new predictor values are superior to the values predicted by previous methodologies.
Conclusion: This new mathematical technique is the most appropriate and encouraging as compared with the existing models.
Background
Congenital ichthyosis is a diverse group of keratinization disorders associated with generalized scaling of skin of varying severity. The non‐syndromic forms of congenital ichthyosis are ...further grouped into common ichthyosis (ichthyosis vulgaris and X‐linked ichthyosis), autosomal recessive congenital ichthyosis, and keratopathic ichthyosis.
Objective
To identify sequence variants involved in different forms of hereditary ichthyoses.
Methods
We studied eight families with different types of ichthyosis including four families with autosomal recessive congenital ichthyosis and four families with common ichthyosis. Whole exome sequencing and PCR based genotyping was carried out to find out the molecular basis of disease.
Results
In one family, a novel duplication sequence variant NM_002016.2:c.2767dupT; NP_002007.1:p.Ser923PhefsTer2 was identified in FLG gene; in four families a previously reported nonsense sequence variant NM_000359.3:c.232C>T; NP_002007.1:p.Arg78Ter was identified in TGM1 gene, while, in three families of X‐linked recessive ichthyosis, the whole STS gene (NM_001320752.2; NP_001307681.2) regions were deleted.
Study limitation
Gene expression studies have not been performed that would have strengthened the findings of computational analysis.
Conclusion
This study highlights the significance of the c.232C>T variant in the TGM1 gene as a possible founder mutation, complete STS gene deletion as reported previously in Pakistani population, while novel sequence variant in the FLG gene expands the spectrum of variations in this gene. These findings may be used for genetic counseling of the studied families.
Abstract
Background
Coccidioidomycosis (CM) is a common cause of community-acquired pneumonia where CM is endemic. Manifestations include self-limited pulmonary infection, chronic fibrocavitary ...pulmonary disease, and disseminated coccidioidomycosis. Most infections are identified by serological assays including enzyme-linked immunoassay (EIA), complement fixation, and immunodiffusion. These are time-consuming and take days to result, impeding early diagnosis. A new lateral flow assay (LFA; Sōna; IMMY, Norman, OK) improves time-to-result to 1 hour.
Methods
We prospectively enrolled 392 patients with suspected CM, compared the LFA with standard EIA and included procalcitonin evaluation.
Results
Compared with standard EIA, LFA demonstrates 31% sensitivity (95% confidence interval CI, 20–44%) and 92% specificity (95% CI, 88–95%). Acute pulmonary disease (74%) was the most common clinical syndrome. Hospitalized patients constituted 75% of subjects, and compared with outpatients, they more frequently had ≥3 previous healthcare facility visits (P = .05), received antibacterials (P < .01), and had >3 antibacterial courses (P < .01). Procalcitonin (PCT) was <0.25 ng/mL in 52 (83%) EIA-positive patients, suggesting infection was not bacterial.
Conclusions
When CM is a possible diagnosis, LFA identified nearly one-third of EIA-positive infections. Combined with PCT <0.25 ng/mL, LFA could reduce unnecessary antibacterial use by 77%.
Coccidioidomycosis commonly causes community-acquired pneumonia in endemic southwest United States. It is routinely diagnosed by enzyme immunoassay, complement fixation, and immunodiffusion. A novel rapid lateral flow assay (Sōna; IMMY), when combined with procalcitonin, could reduce unnecessary antibacterial utilization by 77%.
Background
Autosomal recessive wooly hair/hypotrichosis is an inherited disorder of hair characterized by less dense, short, and tightly curled hair on the scalp and sometimes less dense to complete ...absence of eyebrows and eyelashes. Autosomal recessive wooly hair/hypotrichosis phenotypes are mostly associated with pathogenic sequence variants in LIPH and LPAR6 genes.
Methods
To find out the molecular basis of the disease, five families with autosomal recessive wooly hair/hypotrichosis were recruited for genetic analysis. Direct Sanger sequencing of LIPH and LPAR6 genes was carried out using BigDye chain termination chemistry. P2RY5 protein homology models were developed to study the effect of mutation on protein structure in a family having novel mutation.
Results
Sanger sequencing revealed a novel homozygous missense mutation (c.47A>T) in the LPAR6 gene in family A, while recurrent mutation (c.436G>A) was detected in the rest of the four families (B‐E). Protein homology models for both native and mutant P2RY5 protein were developed to study the difference in subtle structural features because of Lys16Met (K16M) mutation. We observed that P2RY5K16M mutation results decrease in the number of ionic interactions detrimental to the protein stability. Protein modeling studies revealed that the novel mutation identified here decreased the number of ionic interactions by affecting physicochemical parameters of the protein, leading to an overall decrease in protein stability with no major secondary structural changes.
Conclusion
The molecular analysis further confirms the frequent involvement of LPAR6 in autosomal recessive wooly hair/hypotrichosis, while the bioinformatic study revealed that the missense mutation destabilizes the overall structure of P2RY5 protein.
Liver fibrosis is initial stage of any chronic liver disease and its end stage is develops into cirrhosis. Chronic liver diseases are a crucial global health issue and the cause of approximately 2 ...million deaths per year worldwide. Cirrhosis is currently the 11th most common cause of death globally. Mesenchymal stem cell (MSCs) treatment is the best way to treat acute and chronic liver disease. The aim of this study is to improve the therapeutic potential of MSCs combined with melatonin (MLT) to overcome CCl4-induced liver fibrosis and also investigate the individual impact of melatonin and MSCs against CCl4-induced liver impairment in animal model. Female BALB/c mice were used as CCL4-induced liver fibrotic animal model. Five groups of animal model were made; negative control, Positive control, CCl4+MSCs treated group, CCl4+MLT treated group and CCl4+MSCs+MLT treated group. Cultured MSCs from mice bone marrow were transplanted to CCl4-induced liver injured mice model, individually as well as together with melatonin. Two weeks after MSCs and MLT administration, all groups of mice were sacrificed for examination. Morphological and Histopathological results showed that combined therapy of MSCs+MLT showed substantial beneficial impact on CCl4-induced liver injured model, compared with MSCs and MLT individually. Biochemically, considerable reduction was observed in serum bilirubin and ALT levels of MLT+MSC treated mice, compared to other groups. PCR results shown down-regulation of Bax and up-regulation of Bcl-xl and Albumin, confirm a significant therapeutic effect of MSCs+MLT on CCI4-induced liver fibrosis. From the results, it is concluded that combined therapy of MSCs and MLT show strong therapeutic effect on CCL4-induced liver fibrosis, compared with MSCs and MLT individually.
12‐Oxophytodienoic acid (OPDA), a well‐known phytohormone of the jasmonate family, has a reactive α,β‐unsaturated carbonyl structure which easily adds cellular nucleophiles (Michael addition), making ...OPDA potentially toxic for herbivores. The glutathione S‐transferase GST16 inactivates 12‐OPDA in the insect gut by isomerization to inactive iso‐OPDA. Quantitative tissue expression analysis showed that HarmGST16 transcripts were present in most larval tissues, including those of the midgut, fatbody and Malpighian tubules. Activity assays confirmed the presence of an active enzyme. Interestingly, feeding different diets to Helicoverpa armigera influenced gst16 expression levels in various tissues, and larvae fed wild‐type tobacco leaves had reduced gst16 mRNA levels. The temporal expression of HarmGST16 during larval development was high in the second instar and reduced during the third, fourth and fifth instars. Plant‐mediated RNA interference silencing of HarmGST16 retarded larval growth of H. armigera. Injecting cis‐OPDA into the hemolymph of larvae caused premature pupation. This result, as well as the finding that GST16 influenced the growth of insects, suggests that GST16 may play an important role in larval development.
12‐oxophytodienoic acid (12‐OPDA), a phytohormone of the jasmonate family, has a reactive α,β‐unsaturated carbonyl structure which easily adds cellular nucleophiles, making OPDA potentially toxic for herbivores. The glutathione S‐transferase GST16 inactivates 12‐OPDA in the insect gut by isomerization to inactive iso‐OPDA. We find that GST16 has multiple roles in insects. Apart from detoxification; it may play an important role in larval development.
Aminoacyl‐tRNA synthetases (ARSs) are essential enzymes for faithful assignment of amino acids to their cognate tRNA. Variants in ARS genes are frequently associated with clinically heterogeneous ...phenotypes in humans and follow both autosomal dominant or recessive inheritance patterns in many instances. Variants in tryptophanyl‐tRNA synthetase 1 (WARS1) cause autosomal dominantly inherited distal hereditary motor neuropathy and Charcot‐Marie‐Tooth disease. Presently, only one family with biallelic WARS1 variants has been described. We present three affected individuals from two families with biallelic variants (p.Met1? and p.(Asp419Asn)) in WARS1, showing varying severities of developmental delay and intellectual disability. Hearing impairment and microcephaly, as well as abnormalities of the brain, skeletal system, movement/gait, and behavior were variable features. Phenotyping of knocked down wars‐1 in a Caenorhabditis elegans model showed depletion is associated with defects in germ cell development. A wars1 knockout vertebrate model recapitulates the human clinical phenotypes, confirms variant pathogenicity, and uncovers evidence implicating the p.Met1? variant as potentially impacting an exon critical for normal hearing. Together, our findings provide consolidating evidence for biallelic disruption of WARS1 as causal for an autosomal recessive neurodevelopmental syndrome and present a vertebrate model that recapitulates key phenotypes observed in patients.
Homozygous WARS1 variants have been identified in individuals with syndromic neurodevelopmental and hearing phenotypes. Here, we performed functional studies in Caenorhabditis elegans and zebrafish.
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