Exploratory data analysis of physicochemical parameters of natural antimicrobial and anticancer peptides: Unraveling the patterns and trends for the rational design of novel peptides.

Introduction: Peptide-based research has attained new avenues in the antibiotics and cancer drug resistance era. The basis of peptide design research lies in playing with or altering physicochemical parameters. Here in this work, we have done exploratory data analysis (EDA) of physicochemical parameters of antimicrobial peptides (AMPs) and anticancer peptides (ACPs), two promising therapeutics for microbial and cancer drug resistance to deduce patterns and trends. Methods: Briefly, we have captured the natural AMPs and ACPs data from the APD3 database. After cleaning the data manually and by CD-HIT web server, further data analysis has been done using Python-based packages, modlAMP and Pandas. We have extracted the descriptive statistics of 10 physicochemical parameters of AMPs and ACPs to build a comprehensive dataset containing all major parameters. The global analysis of datasets has been done using modlAMP to find the initial patterns in global data. The subsets of AMPs and ACPs were curated based on the length of the peptides and were analyzed by Pandas package to deduce the graphical profile of AMPs and ACPs. Results: EDA of AMPs and ACPs shows selectivity in the length and amino acid compositions. The distribution of physicochemical parameters in defined quartile ranges was observed in the descriptive statistical and graphical analysis. The preferred length range of AMPs and ACPs was found to be 21-30 amino acids, whereas few outliers in each parameter were evident after EDA analysis. Conclusion: The derived patterns from natural AMPs and ACPs can be used for the rational design of novel peptides. The statistical and graphical data distribution findings will help in combining the different parameters for potent design of novel AMPs and ACPs.

In silico analysis of genomic landscape of SARS-CoV-2 and its variant of concerns (Delta and Omicron) reveals changes in the coding potential of miRNAs and their target genes.

COVID-19 related morbidities and mortalities are still continued due to the emergence of new variants of SARS-CoV-2. In the last few years, viral miRNAs have been the centre of study to understand the disease pathophysiology. In this work, we aimed to predict the change in coding potential of the viral miRNAs in SARS-CoV-2's VOCs, Delta and Omicron compared to the Reference (Wuhan origin) strain using bioinformatics tools. After ab-intio based screening by the Vmir tool and validation, we retrieved 22, 6, and 6 pre-miRNAs for Reference, Delta, and Omicron. Most of the predicted unique pre-miRNAs of Delta and Omicron were found to be encoded from the terminal and origin of the genomic sequence, respectively. Mature miRNAs identified by MatureBayes from the unique pre-miRNAs were used for target identification using miRDB. A total of 1786, 216, and 143 high-confidence target genes were captured for GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis. The GO and KEGG pathways terms analysis revealed the involvement of Delta miRNAs targeted genes in the pathways such as Human cytomegalovirus infection, Breast cancer, Apoptosis, Neurotrophin signaling, and Axon guidance whereas the Sphingolipid signaling pathway was found for the Omicron. Furthermore, we focussed our analysis on target genes that were validated through GEO's (Gene Expression Omnibus) DEGs (Differentially Expressed Genes) dataset, in which FGL2, TNSF12, OGN, GDF11, and BMP11 target genes were found to be down-regulated by Reference miRNAs and YAE1 and RSU1 by Delta. Few genes were also observed to be validated among in up-regulated gene set of the GEO dataset, in which MMP14, TNFRSF21, SGMS1, and TMEM192 were related to Reference whereas ZEB2 was detected in all three strains. This study thus provides an in-silico based analysis that deciphered the unique pre-miRNAs in Delta and Omicron compared to Reference. However, the findings need future wet lab studies for validation.

Elucidation of Increased Cervical Cancer Risk Due to Polymorphisms in XRCC1 (R399Q and R194W), ERCC5 (D1104H), and NQO1 (P187S).

Genetic variations like single nucleotide polymorphisms (SNPs) are associated with cervical carcinogenesis. In this study, SNPs have been identified that contribute toward changes in the function and stability of the proteins and show association with cervical cancer. Initially, literature mining identified 114 protein-coding polymorphisms with population-based evidence in cervical cancer. Subsequently, the functional assessment was performed using sequence-dependent tools, and thereafter, protein stability was analyzed using sequence and structural data. Twenty-three non-synonymous SNPs (nsSNPs) found to be damaging and destabilizing were then analyzed to check their risk association at the population level. The meta-analysis indicated that polymorphisms in DNA damage repair genes XRCC1 (rs25487 and rs1799782), ERCC5 (rs17655), and oxidative stress-related gene NQO1 (rs1800566) are significantly associated with increased cervical cancer risk. The XRCC1 rs25487 and rs1799782 polymorphisms showed the highest risk of cervical cancer in the homozygous model having odds ratio (OR) = 1.85, 95% confidence interval (CI) = 1.17-2.92, p = 0.01, and recessive model with OR = 1.81, 95% CI = 1.01-3.24, and p = 0.04 respectively. Similarly, rs17655 polymorphism of ERCC5 and rs1800566 polymorphism of NQO1 showed the highest pooled OR in the homozygous (OR = 1.70, 95% CI = 1.32-2.19, p = 0.00004) and heterozygous model (OR = 1.3, 95% CI = 1.06-1.58, p = 0.01) respectively. Thus, in this study, a comprehensive collection of nsSNPs was collated and assessed, leading to the identification of polymorphisms in DNA damage repair and oxidative stress-related genes, that destabilize the protein and shows increased risk associated with cervical cancer.

In silico functional and structural characterization revealed virulent proteins of Francisella tularensis strain SCHU4.

Francisella tularensis is a pathogenic, aerobic gram-negative coccobacillus bacterium. It is the causative agent of tularemia, a rare infectious disease that can attack skin, lungs, eyes, and lymph nodes. The genome of F. tularensis has been sequenced, and ~16% of the proteome is still uncharacterized. Characterizations of these proteins are essential to find new drug targets for better therapeutics. In silico characterization of proteins has become an extremely important approach to determine the functionality of proteins as experimental functional elucidation is unable to keep pace with the current growth of the sequence database. Initially, we have annotated 577 Hypothetical Proteins (HPs) of F. tularensis strain SCHU4 with seven bioinformatics tools which characterized them based on the family, domain and motif. Out of 577 HPs, 119 HPs were annotated by five or more tools and are further screened to predict their virulence properties, subcellular localization, transmembrane helices as well as physicochemical parameters. VirulentPred predicted 66 HPs out of 119 as virulent. These virulent proteins were annotated to find the interacting partner using STRING, and proteins with high confidence interaction scores were used to predict their 3D structures using Phyre2. The three virulent proteins Q5NH99 (phosphoserine phosphatase), Q5NG42 (Cystathionine beta-synthase) and Q5NG83 (Rrf2-type helix turn helix domain) were predicted to involve in modulation of cytoskeletal and innate immunity of host, H2S (hydrogen sulfide) based antibiotic tolerance and nitrite and iron metabolism of bacteria. The above predicted virulent proteins can serve as novel drug targets in the era of antibiotic resistance.

Chyluria Associated With Nephrotic-Range Proteinuria.

Chyluria is the presence of chyle in the urine and is associated with some degree of proteinuria. We report two patients with chyluria who presented with milky urine, weight loss, and edema and were found to have nephrotic-range proteinuria. Although filarial antigen was detected in only one of the patients, flexible cystoscopy could demonstrate chyle efflux from the left ureter in first patient and from both the ureters in the second patient. Both patients received endoscopic sclerotherapy with 0.2% povidone-iodine, which resulted in the clearance of milky urine in three to five days and complete resolution of nephrotic-range proteinuria on follow-up. They remained symptom-free until the six-month follow-up. We deferred renal biopsy in both patients, as proteinuria was confirmed to be non-glomerular in origin.

A comprehensive meta-analysis of non-coding polymorphisms associated with precancerous lesions and cervical cancer.

OBJECTIVES: To study the risk of polymorphisms present in the non-coding regions of genes related with cervical cancer. METHODS: The PubMed database was extensively searched using text-mining techniques to identify literature containing the association of single nucleotide polymorphisms and cervical cancer. Case-control studies published till June 2020 were considered for the meta-analysis if they fulfilled the selection criteria. The polymorphisms within each case-control study were checked for the presence of genotype data and then divided into groups based on the precancerous and cancerous conditions of the cervix. Odds ratio and 95% confidence intervals (CI) were used to study the effects of polymorphisms with the help of different genetic models (allele, dominant, recessive, heterozygous and homozygous). Also checked heterogeneity along with publication bias and statistical significance using the p-value. RESULTS: 120 papers covering 48 unique non-coding SNPs having 37,123 cases and 39,641 control data was considered for the meta-analysis. The genotype data was categorised into Cancer, Precancer and "Cancer + Precancer" groups, for 43, 8 and 11 SNPs respectively. The meta-analysis identified 21 and 1 SNPs as significant in the Cancer and "Cancer + Precancer" groups. Among all the polymorphisms, rs1143627 (IL1B), rs1800795 (IL6), rs1800871 (IL10), rs568408 (IL12A), rs3312227 (IL12B), rs2275913 (IL17A), rs5742909 (CTLA4), rs1800629 (TNFα), and rs4646903 (CYP1A1) were found to increase risk of cervical cancer in at least three of the five genetic models. CONCLUSION: We identified potential non-coding SNPs corresponding to various cytokines like interleukins (ILs), tumor necrosis factor (TNF), interferon (IFN) and other immune related genes like toll like receptor (TLR), cytotoxic T-lymphocyte associated protein (CTLA) and matrix metalloproteinase (MMP), as significant with increased pooled OR in this meta-analysis pointing to risk association of the immune-related genes in cervical carcinogenesis.

A Novel Association Between Coronavirus Disease 2019 and Normocomplementemic Rapidly Progressive Glomerulonephritis-Crescentic Immunoglobulin A Nephropathy: A Report of Two Pediatric Cases.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been predominately associated with respiratory illness. Acute kidney injury (AKI) is the most common reported kidney involvement. Kidney complications, including proteinuria, hematuria, and rarely collapsing glomerulopathy (CG), a form of focal segmental glomerulosclerosis (FSGS), are also well known now and are frequently documented in the literature published so far. We present two cases of glomerulonephritis (GN) in the setting of AKI in COVID-19 infection in children. Kidney biopsy specimens showed immunoglobulin A nephropathy (IgAN) with crescentic GN (CGN) with acute tubular injury with focal medium artery vasculitis. The patients exhibited a severe presentation and rapid progression to end-stage renal disease (ESRD). This report attempts to add a bit to the evolving information on COVID-19 disease, especially in children as far as kidney involvement is concerned.

Deciphering the functional role of hypothetical proteins from Chloroflexus aurantiacs J-10-f1 using bioinformatics approach.

Chloroflexus aurantiacus J-10-f1 is an anoxygenic, photosynthetic, facultative autotrophic gram negative bacterium found from hot spring at a temperature range of 50-60°C. It can sustain itself in dark only if oxygen is available thereby exhibiting a dark orange color, however display a dark green color when grown in sunlight. Genome of the organism contains total of 3853 proteins out of which 785 (~20%) proteins are uncharacterised or hypothetical proteins (HPs). Therefore in this work we have characterized the 785 hypothetical proteins of Chloroflexus aurantiacus J-10-f1 using bioinformatics tools and databases. HPs annotated by more than five domain prediction tools were filtered and named high confidence-hypothetical proteins (HC-HPs). These HC-HPs were further annotated by calculating their physiochemical properties, homologous, subcellular locations, signal peptides and transmembrane regions. We found most of the HC-HPs were involved in photosynthesis, carbohydrate metabolism, biofuel production and cellulose synthesis processes. Furthermore, few of these HC-HPs could provide resistance to bacteria at high temperature due to their thermophilic nature. Hence these HC-HPs have the potential to be used in industrial as well as in biomedical needs. To conclude, the bioinformatics approach used in this study provides an insight to better understand the nature and role of Chloroflexus aurantiacus J-10-f1 hypothetical proteins.

Genome-wide computational prediction of miRNAs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed target genes involved in pulmonary vasculature and antiviral innate immunity.

The current outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China threatened humankind worldwide. The coronaviruses contains the largest RNA genome among all other known RNA viruses, therefore the disease etiology can be understood by analyzing the genome sequence of SARS-CoV-2. In this study, we used an ab-intio based computational tool VMir to scan the complete genome of SARS-CoV-2 to predict pre-miRNAs. The potential pre-miRNAs were identified by ViralMir and mature miRNAs were recognized by Mature Bayes. Additionally, predicted mature miRNAs were analysed against human genome by miRDB server to retrieve target genes. Besides that we also retrieved GO (Gene Ontology) terms for pathways, functions and cellular components. We predicted 26 mature miRNAs from genome of SARS-CoV-2 that targets human genes involved in pathways like EGF receptor signaling, apoptosis signaling, VEGF signaling, FGF receptor signaling. Gene enrichment tool analysis and substantial literature evidences suggests role of genes like BMPR2 and p53 in pulmonary vasculature and antiviral innate immunity respectively. Our findings may help research community to understand virus pathogenesis.

The changing face of pregnancy-related acute kidney injury from eastern part of India: A hospital-based, prospective, observational study.

This study was initiated to look into the etiologies, prevalence, and outcome of pregnancy-related acute kidney injury (PRAKI) in a tertiary care hospital. Women admitted with PRAKI from January 2015 to December 2016 were included in the study. All patients were investigated and treated and followed up for the next six months.. For statistical analysis, Chi- square test and analysis of variance were performed to analyze the data. Multivariate analysis was applied to compare the risk of nonrecovery of renal function in different etiologies of PRAKI. During the study period, 81 patients were admitted with PRAKI, of whom 68 (84%) received hemodialysis (HD). A total of 449 patients including all cases of AKI underwent HD from January 2015 to June 2016. The incidence of dialysis requiring PRAKI was 68 out of the 449 patients (15%). Sixty-eight (84%) patients required dialysis support while the most common cause was sepsis (49%), with the second being pregnancy-associated atypical hemolytic-uremic syndrome (P-aHUS) (17%) followed by obstetric hemorrhages (16%). There was a significant reduction of first-trimester AKI (8.6%) compared to a previous study published from this institute (19.3%). The maternal mortality (25%) and fetal mortality (23.5%) were high. Nearly 39% of the patients had complete recovery of renal function. This study revealed significant PRAKI burden due to a largely preventable cause, puerperal sepsis. Renal survival was poor in P- aHUS. The gaps in the obstetric care may be identified for the improvement of fetomaternal outcome.

Language Learnability Analysis of Hindi: A Comparison with Ideal and Constrained Learning Approaches.

Native language acquisition is one of the initial processes undertaken by the human brain in the infant stage of life. The linguist community has always been interested in finding the method, which is adopted by the human brain to acquire the native language. Word segmentation in one of the most important tasks in acquiring the language. Statistical learning has been employed to be one of the earliest strategies that mimic the way an infant can adapt to segment a lot of different words. It is desired that the language learnability theories be universal in nature and work on most, if not all the languages. In the present work, we have analyzed the learnability of Hindi, the most popular Indian language, using ideal (universal) and constrained Bayesian learner models. We have analyzed the learnability of the language using unigram and bigram approaches by considering word, syllables, and phonemes as the smallest unit of the language. We demonstrate that Bayesian inference is indeed a viable cross-linguistic strategy and works well for Hindi also.

Computational prediction of miRNAs in Nipah virus genome reveals possible interaction with human genes involved in encephalitis.

Current re-emergence of Nipah virus (NiV) in India caused 11 deaths so far and many patients were kept in quarantine. A thorough study of previous outbreaks occurred in Malaysia, Bangladesh and India represents cases with high rate of fatality due to acute encephalitis. Our work involves genome analysis of NiV for prediction of miRNAs and their targeted genes in human in order to understand encephalitis origin. Ab-intio program-VMir was used for initial screening of genome, obtained nine pre-miRNAs was analyzed by ViralMir to check for any pseudo pre-miRNAs. Eighteen functional mature miRNAs were extracted from pre-miRNAs by using Mature-Bayes tool, which targets 669 genes in human genome as retrieved by miRDB. Gene ontology terms by PANTHER provide important pathways in which target genes were involved like Axon guidance, T cell activation, and nicotinic acetylcholine receptor signaling. Significant outcome was obtained after NCBI Gene and OMIM database mining and literature search for predicted target genes. TLR3, TJP1, NOTCH2, FHL1, and GRIA3 target genes obtained showed their involvement in host defense, blood brain barrier, neurogenesis, mental retardation and encephalitis. To conclude, we predicted significant genes in human that can be inhibited by miRNAs of NiV and results in etiology of encephalitis.

In silico mutational analysis and identification of stability centers in human interleukin-4.

Interleukin-4 (IL-4) is a multifunctional cytokine that plays a critical role in apoptosis, differentiation and proliferation. The intensity of IL4 response depends upon binding to its receptor, IL-4R. The therapeutic efficiency of interleukins can be increased by generating structural mutants having greater stability. In the present work, attempts were made to increase the stability of human IL-4 using in-silico site directed mutagenesis. Different orthologous sequences of IL4 from Pan troglodytes, Aotusnigriceps, Macacamulatta, Papiohamadryas, Chlorocebusaethiops, Vicugnapacos, Susscrofa and Homo sapiens were aligned using Clustal Omega that revealed the conserved and non-conserved positions. For each non-conserved position, possible favorable and stabilizing mutations were found using CUPSAT with predicted ΔΔG (kcal/mol). The one with highest ΔΔG (kcal/mol) among all possible mutations, for each non-conserved position was selected and introduced manually in human IL-4 sequence resulting in multiple mutants of IL-4. Mutant proteins were modeled using structure of IL4 (PDB ID: 2B8U) as a template by SWISS MODEL. The mutants A49L and Q106T were identified to have stability centre using SCide. Molecular dynamics and docking analysis also confirmed the mutants stability and binding respectively. Mutants A49L and Q106T had -7.580079 kcal/mol and -39.418124 kcal/mol respectively lesser energy value than the wild type IL4. The result suggested that, the stability of human IL-4 has been increased by mutation.

Characterization of an antifungal compound produced by Bacillus sp. strain A(5) F that inhibits Sclerotinia sclerotiorum.

A potential antagonist, Bacillus sp. strain A(5) F was isolated from soybean rhizosphere following in vitro dual plate screening. The bacterium displayed strong inhibitory activity in vitro against soybean stem rot pathogen, Sclerotinia sclerotiorum. The culture supernatant of strain A(5) F completely suppressed the mycelial growth of the pathogen, indicating that suppression was due to the presence of antifungal compounds in the culture filtrate. The culture filtrate also suppressed other phytopathogenic fungi including Fusarium oxysporum and Macrophomina phaseolina, in vitro suggesting a broad spectrum antagonistic activity against fungal pathogens. Chemical extraction followed by chromatographic analysis resulted in two antifungal fractions. The high resolution-electron spin ionization-mass spectrometry (HR-ESI-MS) and Nuclear Magnetic Resonance (1D and 2D(1) H) spectra of these antifungal fractions revealed the presence of antifungal compounds, one of which showed similarity to bacillomycin D.

Measurement of CO2-laser-irradiation-induced refractive index modulation in single-mode fiber toward long-period fiber grating design and fabrication.

We report a new method to measure the CO(2)-laser-irradiation-induced refractive index modulation in the core of a single-mode optical fiber for the purpose of design and fabrication of long-period fiber gratings (LPFGs) without applying tension. Using an optical fiber Fabry-Perot interferometer, the laser-induced axial refractive index perturbation was measured. We found that the CO(2)-laser-irradiation-induced refractive index change in the fiber core had a negative value and that the magnitude was a sensitive function of the laser exposure time following almost a linear relation. Under the assumption of a Gaussian-shaped refractive index modulation profile and based on the first two terms of Fourier series approximation, the measured refractive index perturbations were used to simulate the LPFG transmission spectra. LPFGs with the same laser exposure parameters were fabricated without applying tension, and their spectra were compared with those obtained by simulations.