Identification of 6-methyladenosine sites using novel feature encoding methods and ensemble models.

N6-methyladenosine (6 mA) is the most common internal modification in eukaryotic mRNA. Mass spectrometry and site-directed mutagenesis, two of the most common conventional approaches, have been shown to be laborious and challenging. In recent years, there has been a rising interest in analyzing RNA sequences to systematically investigate mutated locations. Using novel methods for feature development, the current work aimed to identify 6 mA locations in RNA sequences. Following the generation of these novel features, they were used to train an ensemble of models using methods such as stacking, boosting, and bagging. The trained ensemble models were assessed using an independent test set and k-fold cross validation. When compared to baseline predictors, the suggested model performed better and showed improved ratings across the board for key measures of accuracy.

H2AX: A key player in DNA damage response and a promising target for cancer therapy.

Cancer is caused by a complex interaction of factors that interrupt the normal growth and division of cells. At the center of this process is the intricate relationship between DNA damage and the cellular mechanisms responsible for maintaining genomic stability. When DNA damage is not repaired, it can cause genetic mutations that contribute to the initiation and progression of cancer. On the other hand, the DNA damage response system, which involves the phosphorylation of the histone variant H2AX (γH2AX), is crucial in preserving genomic integrity by signaling and facilitating the repair of DNA double-strand breaks. This review provides an explanation of the molecular dynamics of H2AX in the context of DNA damage response. It emphasizes the crucial role of H2AX in recruiting and localizing repair machinery at sites of chromatin damage. The review explains how H2AX phosphorylation, facilitated by the master kinases ATM and ATR, acts as a signal for DNA damage, triggering downstream pathways that govern cell cycle checkpoints, apoptosis, and the cellular fate decision between repair and cell death. The phosphorylation of H2AX is a critical regulatory point, ensuring cell survival by promoting repair or steering cells towards apoptosis in cases of catastrophic genomic damage. Moreover, we explore the therapeutic potential of targeting H2AX in cancer treatment, leveraging its dual function as a biomarker of DNA integrity and a therapeutic target. By delineating the pathways that lead to H2AX phosphorylation and its roles in apoptosis and cell cycle control, we highlight the significance of H2AX as both a prognostic tool and a focal point for therapeutic intervention, offering insights into its utility in enhancing the efficacy of cancer treatments.

Network-base approaches to identify therapeutic biomarkers in hepatocellular carcinoma and search for drug hunting utilizing molecular dynamics simulations.

The presence of conditions like Alpha-1 antitrypsin deficiency, hemochromatosis, non-alcoholic fatty liver diseases and metabolic syndrome can elevate the susceptibility to hepatic cellular carcinoma (HCC). Utilizing network-based gene expression profiling via network analyst tools, presents a novel approach for drug target discovery. The significance level (p-score) obtained through Cytoscape in the intended center gene survival assessment confirms the identification of all target center genes, which play a fundamental role in disease formation and progression in HCC. A total of 1064 deferential expression genes were found. These include MCM2 with the highest degree, followed by 4917 MCM6 and MCM4 with a 3944-degree score. We investigated the regulatory kinases involved in establishing the protein-protein interactions network using X2K web tool. The docking approach yields a favorable binding affinity of -8.7 kcal/mol against the target MCM2 using Auto-Dock Vina. Interestingly after simulating the complex system via AMBER16 package, results showed that the root mean square deviation values remained within 4.74 Å for a protein and remains stable throughout the time intervals. Additionally, the ligand's fit to the protein exhibited fluctuations at some intervals but remains stable. Finally, Gibbs free energy was found to be at its lowest at 1 kcal/mol which presents the real time interactive binding of the atomic residues among inhibitor and protein. The displacement of the ligand was measured showing stable movement and displacement along the active site. These findings increased our understanding for potential biomarkers in hepatocellular carcinoma and an experimental approach will further enhance our outcomes in future.Communicated by Ramaswamy H. Sarma.

Structural vaccinology, molecular simulation and immune simulation approaches to design multi-epitopes vaccine against John Cunningham virus.

The JCV (John Cunningham Virus) is known to cause progressive multifocal leukoencephalopathy, a condition that results in the formation of tumors. Symptoms of this condition such as sensory defects, cognitive dysfunction, muscle weakness, homonosapobia, difficulties with coordination, and aphasia. To date, there is no specific and effective treatment to completely cure or prevent John Cunningham polyomavirus infections. Since the best way to control the disease is vaccination. In this study, the immunoinformatic tools were used to predict the high immunogenic and non-allergenic B cells, helper T cells (HTL), and cytotoxic T cells (CTL) epitopes from capsid, major capsid, and T antigen proteins of JC virus to design the highly efficient subunit vaccines. The specific immunogenic linkers were used to link together the predicted epitopes and subjected to 3D modeling by using the Robetta server. MD simulation was used to confirm that the newly constructed vaccines are stable and properly fold. Additionally, the molecular docking approach revealed that the vaccines have a strong binding affinity with human TLR-7. The codon adaptation index (CAI) and GC content values verified that the constructed vaccines would be highly expressed in E. coli pET28a (+) plasmid. The immune simulation analysis indicated that the human immune system would have a strong response to the vaccines, with a high titer of IgM and IgG antibodies being produced. In conclusion, this study will provide a pre-clinical concept to construct an effective, highly antigenic, non-allergenic, and thermostable vaccine to combat the infection of the John Cunningham virus.

Analysis of E2F1 single-nucleotide polymorphisms reveals deleterious non-synonymous substitutions that disrupt E2F1-RB protein interaction in cancer.

Cancer is a medical condition that is caused by the abnormal growth and division of cells, leading to the formation of tumors. The E2F1 and RB pathways are critical in regulating cell cycle, and their dysregulation can contribute to the development of cancer. In this study, we analyzed experimentally reported SNPs in E2F1 and assessed their effects on the binding affinity with RB. Out of 46, nine mutations were predicted as deleterious, and further analysis revealed four highly destabilizing mutations (L206W, R232C, I254T, A267T) that significantly altered the protein structure. Molecular docking of wild-type and mutant E2F1 with RB revealed a docking score of -242 kcal/mol for wild-type, while the mutant complexes had scores ranging from -217 to -220 kcal/mol. Molecular simulation analysis revealed variations in the dynamics features of both mutant and wild-type complexes due to the acquired mutations. Furthermore, the total binding free energy for the wild-type E2F1-RB complex was -64.89 kcal/mol, while those of the L206W, R232C, I254T, and A267T E2F1-RB mutants were -45.90 kcal/mol, -53.52 kcal/mol, -55.67 kcal/mol, and -61.22 kcal/mol, respectively. Our study is the first to extensively analyze E2F1 gene mutations and identifies candidate mutations for further validation and potential targeting for cancer therapeutics.

Hemophilia Healing with AAV: Navigating the Frontier of Gene Therapy.

Gene therapy for hemophilia has advanced tremendously after thirty years of continual study and development. Advancements in medical science have facilitated attaining normal levels of Factor VIII (FVIII) or Factor IX (FIX) in individuals with haemophilia, thereby offering the potential for their complete recovery. Despite the notable advancements in various countries, there is significant scope for further enhancement in haemophilia gene therapy. Adeno-associated virus (AAV) currently serves as the primary vehicle for gene therapy in clinical trials targeting haemophilia. Subsequent investigations will prioritize enhancing viral capsid structures, transgene compositions, and promoters to achieve heightened transduction efficacy, diminished immunogenicity, and more predictable therapeutic results. The present study indicates that whereas animal models have transduction efficiency that is over 100% high, human hepatocytes are unable to express clotting factors and transduction efficiency to comparable levels. According to the current study, achieving high transduction efficiency and high levels of clotting factor expression in human hepatocytes is still insufficient. It is also crucial to reduce the risk of cellular stress caused by protein overload. Despite encountering various hurdles, the field of haemophilia gene therapy holds promise for the future. As technology continues to advance and mature, it is anticipated that a personalized therapeutic approach will be developed to cure haemophilia effectively.

Surveillance of pesticide residues in tomato and eggplant and assessment of acute and chronic health risks to the consumers in Pakistan.

Pesticide application has become a mandatory requirement of the modern agricultural system, resulting in the objectionable levels of pesticide residues in the treated food commodities and posing health threats to the consumers. This study aimed at optimization and validation of an analytical method which can be reliably applied for routine monitoring of the selected eighteen widely reported pesticides in tomato and eggplant. The principle of quick, easy, cheap, effective, rugged, and safe, i.e., QuEChERS, involving the acetate-buffered extraction followed by cleanup using the primary secondary amines (PSA) was employed. The analytical method was validated at three spiking levels (0.05, 0.01, 0.005 mg/kg) using gas chromatograph-micro electron capture detector (GC-µECD). Gas chromatograph-mass spectrometric detector (GC-MSD) was also used for confirmation and quantification using selective ion monitoring (SIM) mode. The method was applied on fresh samples of tomato (n = 33) and eggplant (n = 27) collected from local markets of Khyber Pakhtunkhwa, Pakistan, in the crop season 2020-2021. Twenty-five (76%) tomato samples and fifteen (56%) eggplant samples were found positive for one or more pesticides. Though the chronic and acute health risk assessments indicate that both of these vegetables are unlikely to pose any unacceptable health threat to their consumers, yet the risks from regular intake of pesticides-contaminated food commodities should be regularly addressed for possible protection of the public health and assurance of safe and consistent agro-trade, alike.

Pirin Inhibits FAS-Mediated Apoptosis to Support Colorectal Cancer Survival.

Resistance to immunotherapy in colorectal cancer (CRC) is associated with obstruction of FAS (Apo-1 or CD95)-dependent apoptosis, a hallmark of cancer. Here it is demonstrated that the upregulation of pirin (PIR) protein in colon cancers promotes tumorigenesis. Knockout or inhibition of PIR dramatically increases FAS expression, FAS-dependent apoptosis and attenuates colorectal tumor formation in mice. Specifically, NFκB2 is a direct transcriptional activator of FAS and robustly suppressed by PIR in dual mechanisms. One is the disruption of NFκB2 complex (p52-RELB) association with FAS promoter, the other is the inhibition of NIK-mediated NFκB2 activation and nuclear translocation, leading to the inability of active NFκB2 complex toward the transcription of FAS. Furthermore, PIR interacts with FAS and recruits it in cytosol, preventing its membrane translocation and assembling. Importantly, knockdown or knockout of PIR dramatically sensitizes cells to FAS mAb- or active CD8+ T cells-triggered cell death. Taken together, a PIR-NIK-NFκB2-FAS survival pathway is established, which plays a key role in supporting CRC survival.

Novel echocardiographic markers for left ventricular filling pressure prediction in heart failure with preserved ejection fraction (ECHO-PREDICT): a prospective cross-sectional study.

Heart failure with preserved ejection fraction is a complex clinical syndrome associated with a high level of morbidity and mortality, constituting 56% of heart failure cases and showing an increasing prevalence. The E/Ea ratio, used for echocardiographic assessment of left ventricular (LV) filling pressure, has been commonly recommended as a noninvasive measure. However, its validity lacks robust prospective validation in patients with preserved LV ejection fraction, and its accuracy has been questioned in comparison to patients with reduced LV ejection fraction. The objective of this study was to evaluate the accuracy of novel echocardiographic markers incorporating peak E velocity, left atrial volume index (LAVi), and pulmonary artery systolic pressure (PAP) for noninvasive estimation of LV end-diastolic pressure (LVEDP) against invasive measurement. In this cross-sectional study conducted at a tertiary care hospital, a sample size of 122 participants was utilized. Statistical analyses including independent samples t-test, χ2 test, and linear regression analysis were employed to explore correlations and predict outcomes. The results indicated that Group 1 (LVEDP <20 mmHg) had a mean age of 59.25 years, while Group 2 (LVEDP >20 mmHg) had a mean age of 56.93 years. Mitral E velocity positively predicted LVEDP, while Mitral E/A ratio showed a negative association. Notably, (E+PAP)/2, (E+LAVi)/2, and Mitral E exhibited good discriminative ability, with respective area under the curve values of 0.840, 0.900, and 0.854. (E+LAVi)/2 demonstrated the highest discriminatory power, with a threshold of 40.100, yielding high sensitivity (0.971) but relatively low specificity (0.302) in predicting LVEDP greater than 20. These findings emphasize the accuracy and utility of combining diastolic variables and peak E velocity as markers for left ventricular filling pressure in patients with a high burden of cardiac disease. Additionally, the study highlights the importance of these parameters in assessing cardiac abnormalities and supports the potential of novel echocardiographic parameters, particularly (E+LAVi)/2, in predicting LVEDP greater than 20. Further research is warranted to validate and explore the prognostic implications of these parameters in larger patient populations, ultimately improving the diagnosis and management of cardiac disease and enhancing clinical outcomes.

Lansoprazole plus levosulpiride versus esomeprazole in participants with gastroesophageal reflux disease and erosive esophagitis: a double blinded randomized control trial.

Aim: The aim was to compare the efficacy and safety of lansoprazole plus levosulpiride over esomeprazole. Methodology: This randomized control trial recruited 1000 participants having symptomatic gastroesophageal reflux disease (GERD) and erosive esophagitis and they were blindly randomized into two groups in a 1:1 ratio with appropriate concealment. Group 1 was given lansoprazole plus levosulpiride combination twice daily whereas group 2 was prescribed only esomeprazole twice daily. The primary efficacy endpoint was the healing of erosive esophagitis and GERD at week 49. Secondary assessments included improvement in quality of life. Participants' quality of life was assessed before starting the treatment and post-treatment using a short-form health survey questionnaire (SF-36). Results: The lansoprazole plus levosulpiride group had significantly lower rates of positive postintervention GERD and erosive esophagitis status, and higher rates of sustained resolution of heartburn compared to the esomeprazole alone group. However, the lansoprazole plus levosulpiride group also had a higher risk of nausea. Conclusion: Lansoprazole plus levosulpiride is a more effective and safe treatment for GERD than esomeprazole alone. Participants in the lansoprazole plus levosulpiride group showed a significantly higher rate of sustained resolution of GERD, lower rates of postintervention GERD and erosive esophagitis status, and a higher incidence of nausea compared to the esomeprazole alone group. Although quality of life worsened in both groups, adverse effects did not significantly differ. These findings strongly support the use of lansoprazole plus levosulpiride as a preferred treatment option for GERD and erosive esophagitis, which could have significant clinical implications for managing this common condition.

Potential anticancer and antioxidant lauric acid-based hydrazone synthesis and computational study toward the electronic properties.

The modification of natural products is one of the key areas of synthetic organic chemistry for obtaining valuable chemical building blocks that have medicinal significance. In this study, lauric acid-based hydrazones, namely (E)-N'-(2-nitrobenzylidene)dodecanehydrazide (NBDH), (E)-N'-(naphthalen-1-ylmethylene)dodecanehydrazide (NMDH), and (E)-N'-(4-fluorobenzylidene)dodecanehydrazide (FBDH), were synthesized and characterized using spectroscopic techniques. The newly synthesized lauric acid-based hydrazones were screened for their anticancer and antioxidant potential. The antioxidants showed their activity by inhibiting the oxidative chain reactions that produce reactive oxygen species. The antioxidant activity showed that NBDH exhibited the maximum DPPH inhibitory activity when compared with that of NMDH and FBDH, whereas the anticancer activity showed that FBDH exhibited maximum percent viability when compared to that of NBDH and NMDH. The reactivity and biological needs of the synthesized compounds NBDH, NMDH, and FBDH were met by performing geometrical, FT-IR vibrational, UV-visible, global reactivity parameters (GRP), MEP, FMO, NBO, ELF, LOL, and nonlinear optical (NLO) analysis at the DFT/B3LYP/6-311+G(d,p) level. NBO analysis confirmed the existence of extended conjugation and intramolecular charge transfer among NBDH, NMDH, and FBDH, which have the lowest gap in π → π*, which are in line with the FMO results where successful charge transfer occurred from the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO). GRP analysis confirmed the potential of NBDH, NMDH, and FBDH for biological, electronic, and NLO applications. It is clear from the comparative analysis of the urea molecule that NBDH, NMDH, and FBDH all comprise fine NLO properties.

PseU-Pred: An ensemble model for accurate identification of pseudouridine sites.

Pseudouridine (ψ) is reported to occur frequently in all types of RNA. This uridine modification has been shown to be essential for processes such as RNA stability and stress response. Also, it is linked to a few human diseases, such as prostate cancer, anemia, etc. A few laboratory techniques, such as Pseudo-seq and N3-CMC-enriched Pseudouridine sequencing (CeU-Seq) are used for detecting ψ sites. However, these are laborious and drawn-out methods. The convenience of sequencing data has enabled the development of computationally intelligent models for improving ψ site identification methods. The proposed work provides a prediction model for the identification of ψ sites through popular ensemble methods such as stacking, bagging, and boosting. Features were obtained through a novel feature extraction mechanism with the assimilation of statistical moments, which were used to train ensemble models. The cross-validation test and independent set test were used to evaluate the precision of the trained models. The proposed model outperformed the preexisting predictors and revealed 87% accuracy, 0.90 specificity, 0.85 sensitivity, and a 0.75 Matthews correlation coefficient. A web server has been built and is available publicly for the researchers at https://taseersuleman-y-test-pseu-pred-c2wmtj.streamlit.app/.

Use of eradication therapy in adjunction to periodontal therapy versus alone for treatment of Helicobacter pylori infections: a mini review.

Approximately 50% of the human population on the Earth is estimated to be affected by the bacterium Helicobacter pylori. which causes disease manifestations ranging from peptic ulcer disease to chronic gastritis to gastric cancer. It has been a struggle to contain this bacterium using conventional antibiotics due to rising antimicrobial resistance, which has made its eradication an even bigger challenge. Due to this major issue, scientists have ventured to use alternative approaches to bring about the eradication of H. pylori colonization. Aim: The main aim of this review was to update previous studies that investigated periodontal therapy's effect on H. pylori eradication. Method: A systematic electronic search of the currently available research was conducted to identify all the relevant trials and original studies that compared the clinical effect of periodontal therapy in conjunction with eradication therapy. Results: The newly updated review of the literature did not change the conclusion previously reached and instead reinforced the fact with more power and more recent studies that the addition of periodontal therapy to eradication therapy for H. pylori is superior to the use of eradication therapy alone for H. pylori. Core Tip: The addition of periodontal therapy to the standard eradication therapy may be a clinically viable option and pave the way for tackling the H. pylori burden as well as aiding in the prevention of antimicrobial resistance to an extent, along with immensely increasing the efficacy of the standard eradication therapy for H. pylori that is currently in use around the world.

Designing a multi-epitopes subunit vaccine against human herpes virus 6A based on molecular dynamics and immune stimulation.

Human Herpesvirus 6A (HHV-6A) is a prevalent virus associated with various clinical manifestations, including neurological disorders, autoimmune diseases, and promotes tumor cell growth. HHV-6A is an enveloped, double-stranded DNA virus with a genome of approximately 160-170 kb containing a hundred open-reading frames. An immunoinformatics approach was applied to predict high immunogenic and non-allergenic CTL, HTL, and B cell epitopes and design a multi-epitope subunit vaccine based on HHV-6A glycoprotein B (gB), glycoprotein H (gH), and glycoprotein Q (gQ). The stability and correct folding of the modeled vaccines were confirmed through molecular dynamics simulation. Molecular docking found that the designed vaccines have a strong binding network with human TLR3, with Kd values of 1.5E-11 mol/L, 2.6E-12 mol/L, 6.5E-13 mol/L, and 7.1E-11 mol/L for gB-TLR3, gH-TLR3, gQ-TLR3, and the combined vaccine-TLR3, respectively. The codon adaptation index values of the vaccines were above 0.8, and their GC content was around 67 % (normal range 30-70 %), indicating their potential for high expression. Immune simulation analysis demonstrated robust immune responses against the vaccine, with approximately 650,000/ml combined IgG and IgM antibody titer. This study lays a strong foundation for developing a safe and effective vaccine against HHV-6A, with significant implications for treating associated conditions.

iDHU-Ensem: Identification of dihydrouridine sites through ensemble learning models.

Background: Dihydrouridine (D) is one of the most significant uridine modifications that have a prominent occurrence in eukaryotes. The folding and conformational flexibility of transfer RNA (tRNA) can be attained through this modification. Objective: The modification also triggers lung cancer in humans. The identification of D sites was carried out through conventional laboratory methods; however, those were costly and time-consuming. The readiness of RNA sequences helps in the identification of D sites through computationally intelligent models. However, the most challenging part is turning these biological sequences into distinct vectors. Methods: The current research proposed novel feature extraction mechanisms and the identification of D sites in tRNA sequences using ensemble models. The ensemble models were then subjected to evaluation using k-fold cross-validation and independent testing. Results: The results revealed that the stacking ensemble model outperformed all the ensemble models by revealing 0.98 accuracy, 0.98 specificity, 0.97 sensitivity, and 0.92 Matthews Correlation Coefficient. The proposed model, iDHU-Ensem, was also compared with pre-existing predictors using an independent test. The accuracy scores have shown that the proposed model in this research study performed better than the available predictors. Conclusion: The current research contributed towards the enhancement of D site identification capabilities through computationally intelligent methods. A web-based server, iDHU-Ensem, was also made available for the researchers at https://taseersuleman-idhu-ensem-idhu-ensem.streamlit.app/.

Efficacy and tolerability of isocitrate dehydrogenase inhibitors in patients with acute myeloid leukemia: A systematic review of clinical trials.

BACKGROUND: Acute myeloid leukemia (AML) is a hematological malignancy due to anomalous differentiation and proliferation of hematopoietic stem cells with myeloid blast buildup. Induction chemotherapy is considered the first line of treatment in most patients with AML. However, targeted therapy in the form of FLT-3, IDH, BCL-2, and immune checkpoint inhibitors, can be considered as the first line depending on their molecular profile, resistance to chemotherapy, comorbidities, etc. This review aims to assess the tolerability and efficacy of isocitrate dehydrogenase (IDH) inhibitors in AML. METHODS: We searched Medline, WOS, Embase, and clinicaltrials.gov. PRISMA guidelines were followed in this systematic review. 3327 articles were screened, and 9 clinical trials (N = 1119) were included. RESULTS: In randomized clinical trials (RCTs), objective response (OR) was reported in 63-74% of the patients with IDH inhibitors + azacitidine as compared to 19-36 % of the patients with azacitidine monotherapy in newly diagnosed (ND) medically unfit patients. Survival rates were significantly improved with the use of ivosidenib. OR was reported in 39.1-46 % of the patients who relapsed/refractory to chemotherapy. ≥Grade 3 IDH differentiation syndrome and QT prolongation were reported in 3.9-10 % and 2-10 % of the patients, respectively. CONCLUSION: IDH inhibitors (ivosidenib for IDH-1 and enasidenib for IDH-2) are safe and effective in treating ND medically unfit or relapsed refractory patients with IDH mutation. However, no survival benefit was reported with enasidenib. More randomized multicenter double-blinded clinical studies are needed to confirm these results and compare them with other targeting agents.

Repositioning of experimentally validated anti-breast cancer peptides to target FAK-PAX complex to halt the breast cancer progression: a biomolecular simulation approach.

FAK (focal adhesin kinase), a tyrosine kinase, plays an imperative role in cell-cell communication, particularly in cell signaling systems. It is a multi-functional signaling protein, which integrates and transduces signals into cancer cells through growth factor receptors or integrin and its interaction with Paxillin (PAX). The molecular processes by which FAK promotes the development and progression of cancer have progressively established the possible relationship between FAK-PAX complex in many types of cancer. The interaction of FAX and PAX is very important in breast cancer and thus acts as an essential biomarker for drugs, vaccines or peptide inhibitor designing. In this regard, computational approaches, particularly peptide designing to target the binding interface of the interacting partners, would greatly assist the design of peptide inhibitors against various cancer. Accordingly, in this present study, we screened 236 experimentally validated anti-breast cancer peptides using computational drugs repositioning approach to design peptides targeting the FAK-PAX complex. Using protein-peptide docking the binding site for the HP1 was confirmed and a total of 236 anti-breast cancer peptides were screened. Among the 236, only 12 peptides reported a docking score better than the control. From these 12, Magainin with the docking score - 103.8 ± 10.3 kcal/mol, NRC-07 with the docking score - 100.8 ± 16.5 kcal/mol, and Indolicidin with the docking score - 101.7 ± 3.9 kcal/mol, peptides potentially inhibit the FAX-PAX binding. Calculation of protein's motion and FEL revealed the binding and inhibitory behavior. Moreover, binding free energy (MM/GBSA) confirmed that Magainin exhibited the total binding energy - 53.28 kcal/mol, NRC-07 possessed the TBE - 44.16 kcal/mol, and Indolicidin reported the TBE of - 40.48 kcal/mol, thus explaining the inhibitory potential of these peptides. In conclusion, these peptides exhibit strong inhibitory potential and could abrogate the FAK-PAX complex in in vitro models and thus may relieve the burden of breast cancer.

DHU-Pred: accurate prediction of dihydrouridine sites using position and composition variant features on diverse classifiers.

Background: Dihydrouridine (D) is a modified transfer RNA post-transcriptional modification (PTM) that occurs abundantly in bacteria, eukaryotes, and archaea. The D modification assists in the stability and conformational flexibility of tRNA. The D modification is also responsible for pulmonary carcinogenesis in humans. Objective: For the detection of D sites, mass spectrometry and site-directed mutagenesis have been developed. However, both are labor-intensive and time-consuming methods. The availability of sequence data has provided the opportunity to build computational models for enhancing the identification of D sites. Based on the sequence data, the DHU-Pred model was proposed in this study to find possible D sites. Methodology: The model was built by employing comprehensive machine learning and feature extraction approaches. It was then validated using in-demand evaluation metrics and rigorous experimentation and testing approaches. Results: The DHU-Pred revealed an accuracy score of 96.9%, which was considerably higher compared to the existing D site predictors. Availability and Implementation: A user-friendly web server for the proposed model was also developed and is freely available for the researchers.

Sequence-structure functional implications and molecular simulation of high deleterious nonsynonymous substitutions in IDH1 revealed the mechanism of drug resistance in glioma.

In the past few years, various somatic point mutations of isocitrate dehydrogenase (IDH) encoding genes (IDH1 and IDH2) have been identified in a broad range of cancers, including glioma. Despite the important function of IDH1 in tumorigenesis and its very polymorphic nature, it is not yet clear how different nsSNPs affect the structure and function of IDH1. In the present study, we employed different machine learning algorithms to screen nsSNPs in the IDH1 gene that are highly deleterious. From a total of 207 SNPs, all of the servers classified 80 mutations as deleterious. Among the 80 deleterious mutations, 14 were reported to be highly destabilizing using structure-based prediction methods. Three highly destabilizing mutations G15E, W92G, and I333S were further subjected to molecular docking and simulation validation. The docking results and molecular simulation analysis further displayed variation in dynamics features. The results from molecular docking and binding free energy demonstrated reduced binding of the drug in contrast to the wild type. This, consequently, shows the impact of these deleterious substitutions on the binding of the small molecule. PCA (principal component analysis) and FEL (free energy landscape) analysis revealed that these mutations had caused different arrangements to bind small molecules than the wild type where the total internal motion is decreased, thus consequently producing minimal binding effects. This study is the first extensive in silico analysis of the IDH1 gene that can narrow down the candidate mutations for further validation and targeting for therapeutic purposes.

m1A-pred: Prediction of Modified 1-methyladenosine Sites in RNA Sequences through Artificial Intelligence.

BACKGROUND: The process of nucleotides modification or methyl groups addition to nucleotides is known as post-transcriptional modification (PTM). 1-methyladenosine (m1A) is a type of PTM formed by adding a methyl group to the nitrogen at the 1st position of the adenosine base. Many human disorders are associated with m1A, which is widely found in ribosomal RNA and transfer RNA. OBJECTIVE: The conventional methods such as mass spectrometry and site-directed mutagenesis proved to be laborious and burdensome. Systematic identification of modified sites from RNA sequences is gaining much attention nowadays. Consequently, an extreme gradient boost predictor, m1A-Pred, is developed in this study for the prediction of modified m1A sites. METHODS: The current study involves the extraction of position and composition-based properties within nucleotide sequences. The extraction of features helps in the development of the features vector. Statistical moments were endorsed for dimensionality reduction in the obtained features. RESULTS: Through a series of experiments using different computational models and evaluation methods, it was revealed that the proposed predictor, m1A-pred, proved to be the most robust and accurate model for the identification of modified sites. AVAILABILITY AND IMPLEMENTATION: To enhance the research on m1A sites, a friendly server was also developed, which was the final phase of this research.