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In contrast to austenitic and martensitic stainless steels, ferritic stainless steels have a lower hardness and wear resistance but exhibit excellent corrosion resistance. Due to this fact, their use in the aerospace, automobile, and house construction industries is restricted. Several methods have been utilized to enhance the tribological characteristics of ferritic stainless steels. In this work, titanium nitride coating has been carried out by using a cathodic cage of titanium material, and later on, the titanium cathodic cage is replaced by an AISI-304 cathodic cage in a CCPN chamber to form iron nitride coating on AISI-430 ferritic stainless steel coupons through a plasma nitriding process for 4 h at a fixed temperature of 400 °C. The microstructures and mechanical traits of all processed and control coupons were analyzed using scanning electron microscopy, X-ray diffraction, ball-on-disc wear tester, and microhardness tester techniques. The results showed that hardness increased up to 1489 HV with the titanium cage, which is much higher than the hardness of the base material (270 HV). The titanium cage-treated coupons have high layer thickness, smooth surface morphology, and a minimum crystallite size of 2.2 nm. The wear rate was reduced up to 50% over the base material after the titanium cage plasma treatment. The base coupon exhibited severe abrasive wear, whereas nitrided coupons exhibited dominant adhesive wear. In the iron nitride coatings, this effect is also important, owing to the more influential cleaning process in a glow discharge, and the better adhesion with enhanced interlayer thickness is attributed to the fact that the compliance of the interlayer minimizes shear stresses at the coating–substrate interface. The use of a graded interface improves adhesion compared with the case where no interlayer is used but a titanium interlayer of comparable thickness provides a significant increase in measured adhesion. For both titanium and iron nitride films, there is a reduction in wear volume which is a function of interlayer thickness; this will have a substantial effect on wear lifetime. Thus by careful control of the interlayer thickness and composition, it should be possible to improve coating performance in tribological applications. [ABSTRACT FROM AUTHOR]

Cancer research has advanced tremendously with the identification of causative genes, proteins, and signaling pathways. Numerous antitumor drugs have been designed and screened for cancer therapeutics; however, designing target-specific drugs for malignant cells with minimal side effects is challenging. Recently, energy-sensing- and homeostasis-associated molecules and signaling pathways playing a role in proliferation, apoptosis, autophagy, and angiogenesis have received increasing attention. Energy-metabolism-based studies have shown the contribution of energetics to cancer development, where tumor cells show increased glycolytic activity and decreased oxidative phosphorylation (the Warburg effect) in order to obtain the required additional energy for rapid division. The role of energy homeostasis in the survival of normal as well as malignant cells is critical; therefore, fuel intake and expenditure must be balanced within acceptable limits. Thus, energy-sensing enzymes detecting the disruption of glycolysis, AMP, ATP, or GTP levels are promising anticancer therapeutic targets. Here, we review the common energy mediators and energy sensors and their metabolic properties, mechanisms, and associated signaling pathways involved in carcinogenesis, and explore the possibility of identifying drugs for inhibiting the energy metabolism of tumor cells. Furthermore, to corroborate our hypothesis, we performed meta-analysis based on transcriptomic profiling to search for energy-associated biomarkers and canonical pathways.

Acute myeloid leukemia (AML) is hallmarked by the clonal proliferation of myeloid blasts. Mutations that result in the constitutive activation of the fms-like tyrosine kinase 3 ( FLT3 ) gene, coding for a class III receptor tyrosine kinase, are significantly associated with this heterogeneous hematologic malignancy. The fms-related tyrosine kinase 3 ligand binds to the extracellular domain of the FLT3 receptor, inducing homodimer formation in the plasma membrane, leading to autophosphorylation and activation of apoptosis, proliferation, and differentiation of hematopoietic cells in bone marrow. In the present study, we evaluated the association of FLT3 as a significant biomarker for AML and tried to comprehend the effects of specific variations on the FLT3 protein's structure and function. We also examined the effects of I836 variants on binding affinity to sorafenib using molecular docking. We integrated multiple bioinformatics tools, databases, and resources such as OncoDB, UniProt, COSMIC, UALCAN, PyMOL, ProSA, Missense3D, InterProScan, SIFT, PolyPhen, and PredictSNP to annotate the structural, functional, and phenotypic impact of the known variations associated with FLT3 . Twenty-nine FLT3 variants were analyzed using in silico approaches such as DynaMut, CUPSAT, AutoDock, and Discovery Studio for their impact on protein stability, flexibility, function, and binding affinity. The OncoDB and UALCAN portals confirmed the association of FLT3 gene expression and its mutational status with AML. A computational structural analysis of the deleterious variants of FLT3 revealed I863F mutants as destabilizers of the protein structure, possibly leading to functional changes. Many single-nucleotide variations in FLT3 have an impact on its structure and function. Thus, the annotation of FLT3 SNVs and the prediction of their deleterious pathogenic impact will facilitate an insight into the tumorigenesis process and guide experimental studies and clinical implications.

India is a large middle-income country and has surpassed China in overall population, comprising 20% of the global population (over 1.43 billion people). India is experiencing a major demographic shift in its aging population. Chronic diseases are common among older adults and can be persistent over the life course, lead to the onset of disability, and be costly. Among older adults in India, the existence of multiple comorbid chronic conditions (i.e., multimorbidity) is rapidly growing and represents a burgeoning public health burden. Prior research identified greater rates of multimorbidity (e.g., overweight/obesity diabetes, hypertension, cardiovascular disease, stroke, and malignancies) in minority populations in the United States (U.S.); however, limited studies have attempted to characterize multimorbidity among older adult sub-populations residing in India. To address this gap, we conducted a narrative review of studies on multimorbidity using the data from the Longitudinal Aging Study of India (LASI), the largest nationally representative longitudinal survey study of adults in India. Our definition of multimorbidity was the presence of more than two conditions in the same person. Our findings, based on 15 reviewed studies, aim to (1) characterize the definition and measurement of multimorbidity and to ascertain its prevalence in ethnically and culturally diverse sub-populations in India; (2) identify adverse outcomes associated with multimorbidity in the Indian adult population; and (3) identify gaps, opportunities, and future directions.

Background: Breast cancer (BC) is one of the most common female cancers. Clinical and histopathological information is collectively used for diagnosis, but is often not precise. We applied machine learning (ML) methods to identify the valuable gene signature model based on differentially expressed genes (DEGs) for BC diagnosis and prognosis., Methods: A cohort of 701 samples from 11 GEO BC microarray datasets was used for the identification of significant DEGs. Seven ML methods, including RFECV-LR, RFECV-SVM, LR-L1, SVC-L1, RF, and Extra-Trees were applied for gene reduction and the construction of a diagnostic model for cancer classification. Kaplan-Meier survival analysis was performed for prognostic signature construction. The potential biomarkers were confirmed via qRT-PCR and validated by another set of ML methods including GBDT, XGBoost, AdaBoost, KNN, and MLP., Results: We identified 355 DEGs and predicted BC-associated pathways, including kinetochore metaphase signaling, PTEN, senescence, and phagosome-formation pathways. A hub of 28 DEGs and a novel diagnostic nine-gene signature ( COL10A, S100P, ADAMTS5 , WISP1 , COMP , CXCL10 , LYVE1 , COL11A1 , and INHBA ) were identified using stringent filter conditions. Similarly, a novel prognostic model consisting of eight-gene signatures ( CCNE2 , NUSAP1 , TPX2 , S100P , ITM2A , LIFR , TNXA , and ZBTB16 ) was also identified using disease-free survival and overall survival analysis. Gene signatures were validated by another set of ML methods. Finally, qRT-PCR results confirmed the expression of the identified gene signatures in BC., Conclusion: The ML approach helped construct novel diagnostic and prognostic models based on the expression profiling of BC. The identified nine-gene signature and eight-gene signatures showed excellent potential in BC diagnosis and prognosis, respectively.

Identifying cancer biomarkers is imperative, as upregulated genes offer a better microenvironment for the tumor; hence, targeted inhibition is preferred. The theme of our study is to predict molecular interactions between cancer biomarker proteins and selected natural compounds. We identified an overexpressed potential molecular target (AKT1) and computationally evaluated its inhibition by four dietary ligands (isoliquiritigenin, shogaol, tehranolide, and theophylline). The three-dimensional structures of protein and phytochemicals were retrieved from the RCSB PDB database (4EKL) and NCBI's PubChem, respectively. Rational structure-based docking studies were performed using AutoDock. Results were analyzed based primarily on the estimated free binding energy (kcal/mol), hydrogen bonds, and inhibition constant, Ki, to identify the most effective anti-cancer phytomolecule. Toxicity and drug-likeliness prediction were performed using OSIRIS and SwissADME. Amongst the four phytocompounds, tehranolide has better potential to suppress the expression of AKT1 and could be used for anti-cancer drug development, as inhibition of AKT1 is directly associated with the inhibition of growth, progression, and metastasis of the tumor. Docking analyses reveal that tehranolide has the most efficiency in inhibiting AKT1 and has the potential to be used for the therapeutic management of cancer. Natural compounds targeting cancer biomarkers offer less rejection, minimal toxicity, and fewer side effects.

Terpenes and essential oils are materials of great commercial use due to their broad spectra of antibacterial, antifungal, membrane permeation enhancement and antioxidant biological properties, as well as for their use as flavors and fragrances. Yeast particles (YPs) are 3-5 µm hollow and porous microspheres, a byproduct of some food-grade yeast ( Saccharomyces cerevisiae) extract manufacturing processes, that have been used for the encapsulation of terpenes and essential oils with high payload loading capacity (up to 500% weight) and efficiency, providing stability and sustained-release properties. This review focuses on encapsulation approaches for the preparation of YP-terpene and essential oil materials that have a wide range of potential agricultural, food and pharmaceutical applications.

Atherosclerosis is a chronic inflammation characterized by macrophage infiltration, lipid deposition, and arterial wall thickening. Prevention of atherosclerosis by nutraceuticals is gaining attention. Myricetin, a dietary flavonol, is claimed to possess anti-atherosclerosis properties. We studied myricetin's effect on the atherosclerosis-associated molecular mechanism. Cytotoxicity and proliferation testing to check the viability of myricetin-treated THP-1 macrophages and monocyte migration study in the presence and absence of myricetin was performed. The whole transcriptome analysis was conducted using the Affymetrix microarray platform. The Partek genomics suite for detecting differentially expressed genes (DEGs) and ingenuity pathway analysis was used to identify canonical pathways. Cytotoxicity assays exhibited no significant toxicity in THP-1 macrophages treated with different myricetin concentrations (10-200 μM). Genome-wide expression profiling revealed 58 DEGs (53 upregulated and 5 downregulated) in myricetin-treated THP-1 macrophages. Pathway analysis revealed inhibition of LXR/RXR activation and angiogenesis inhibition by thrombospondin-1 and activated phagocytosis in myricetin-treated THP-1 macrophages. The cytotoxicity assay shows myricetin as a safe phytochemical. In vitro and in silico pathway studies on THP-1 macrophages showed that they can inhibit THP-1 monocyte migration and alter the cholesterol efflux mediated via LXR/RXR signaling. Therefore, myricetin could help in the prevention of cell infiltration in atherosclerotic plaque with reduced risk of stroke or brain damage.

Several diseases, including atherosclerosis, are characterized by inflammation, which is initiated by leukocyte migration to the inflamed lesion. Hence, genes implicated in the early stages of inflammation are potential therapeutic targets to effectively reduce atherogenesis. Algal-derived polysaccharides are one of the most promising sources for pharmaceutical application, although their mechanism of action is still poorly understood. The present study uses a computational method to anticipate the effect of fucoidan and alginate on interactions with adhesion molecules and chemokine, followed by an assessment of the cytotoxicity of the best-predicted bioactive compound for human monocytic THP-1 macrophages by lactate dehydrogenase and crystal violet assay. Moreover, an in vitro pharmacodynamics evaluation was performed. Molecular docking results indicate that fucoidan has a greater affinity for L-and E-selectin, monocyte chemoattractant protein 1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) as compared to alginate. Interestingly, there was no fucoidan cytotoxicity on THP-1 macrophages, even at 200 µg/mL for 24 h. The strong interaction between fucoidan and L-selectin in silico explained its ability to inhibit the THP-1 monocytes migration in vitro. MCP-1 and ICAM-1 expression levels in THP-1 macrophages treated with 50 µg/mL fucoidan for 24 h, followed by induction by IFN-γ, were shown to be significantly suppressed as eight- and four-fold changes, respectively, relative to cells treated only with IFN-γ. These results indicate that the electrostatic interaction of fucoidan improves its binding affinity to inflammatory markers in silico and reduces their expression in THP-1 cells in vitro, thus making fucoidan a good candidate to prevent inflammation.

Background: Chronic myeloid leukemia (CML) is initiated in bone marrow due to chromosomal translocation t(9;22) leading to fusion oncogene BCR-ABL. Targeting BCR-ABL by tyrosine kinase inhibitors (TKIs) has changed fatal CML into an almost curable disease. Despite that, TKIs lose their effectiveness due to disease progression. Unfortunately, the mechanism of CML progression is poorly understood and common biomarkers for CML progression are unavailable. This study was conducted to find novel biomarkers of CML progression by employing whole-exome sequencing (WES). Materials and Methods : WES of accelerated phase (AP) and blast crisis (BC) CML patients was carried out, with chronic-phase CML (CP-CML) patients as control. After DNA library preparation and exome enrichment, clustering and sequencing were carried out using Illumina platforms. Statistical analysis was carried out using SAS/STAT software version 9.4, and R package was employed to find mutations shared exclusively by all AP-/BC-CML patients. Confirmation of mutations was carried out using Sanger sequencing and protein structure modeling using I-TASSER followed by mutant generation and visualization using PyMOL. Results : Three novel genes (ANKRD36, ANKRD36B and PRSS3) were mutated exclusively in all AP-/BC-CML patients. Only ANKRD36 gene mutations (c.1183_1184 delGC and c.1187_1185 dupTT) were confirmed by Sanger sequencing. Protein modeling studies showed that mutations induce structural changes in ANKRD36 protein. Conclusions : Our studies show that ANKRD36 is a potential common biomarker and drug target of early CML progression. ANKRD36 is yet uncharacterized in humans. It has the highest expression in bone marrow, specifically myeloid cells. We recommend carrying out further studies to explore the role of ANKRD36 in the biology and progression of CML.

MERS-CoV was identified for the first time in Jeddah, Saudi Arabia in 2012 in a hospitalized patient. This virus subsequently spread to 27 countries with a total of 939 deaths and 2586 confirmed cases and now has become a serious concern globally. Camels are well known for the transmission of the virus to the human population. In this report, we have discussed the prediction, designing, and evaluation of potential siRNA targeting the ORF1ab gene for the inhibition of MERS-CoV replication. The online software, siDirect 2.0 was used to predict and design the siRNAs, their secondary structure and their target accessibility. ORF1ab gene folding was performed by RNAxs and RNAfold software. A total of twenty-one siRNAs were selected from 462 siRNAs according to their scoring and specificity. siRNAs were evaluated in vitro for their cytotoxicity and antiviral efficacy in Huh7 cell line. No significant cytotoxicity was observed for all siRNAs in Huh7 cells. The in vitro study showed the inhibition of viral replication by three siRNAs. The data generated in this study provide preliminary and encouraging information to evaluate the siRNAs separately as well as in combination against MERS-CoV replication in other cell lines. The prediction of siRNAs using online software resulted in the filtration and selection of potential siRNAs with high accuracy and strength. This computational approach resulted in three effective siRNAs that can be taken further to in vivo animal studies and can be used to develop safe and effective antiviral therapies for other prevalent disease-causing viruses.

Soil-transmitted nematodes (STN) infect 1-2 billion of the poorest people worldwide. Only benzimidazoles are currently used in mass drug administration, with many instances of reduced activity. Terpenes are a class of compounds with anthelmintic activity. Thymol, a natural monoterpene phenol, was used to help eradicate hookworms in the U.S. South circa 1910. However, the use of terpenes as anthelmintics was discontinued because of adverse side effects associated with high doses and premature stomach absorption. Furthermore, the dose-response activity of specific terpenes against STNs has been understudied. Here we used hollow, porous yeast particles (YPs) to efficiently encapsulate (>95%) high levels of terpenes (52% w/w ) and evaluated their anthelmintic activity on hookworms ( Ancylostoma ceylanicum) , a rodent parasite ( Nippostrongylus brasiliensis ), and whipworm ( Trichuris muris) . We identified YP-terpenes that were effective against all three parasites. Further, YP-terpenes overcame albendazole-resistant Caenorhabditis elegans . These results demonstrate that terpenes are broad-acting anthelmintics. Terpenes are predicted to be extremely difficult for parasites to resist, and YP encapsulation provides water-suspendable terpene materials without surfactants and sustained terpene release that could lead to the development of formulations for oral delivery that overcome fast absorption in the stomach, thus reducing dosage and toxic side effects.

Toxicity induced by radiation therapy is a curse for cancer patients undergoing treatment. It is imperative to understand and define an ideal condition where the positive effects notably outweigh the negative. We used a microarray meta-analysis approach to measure global gene-expression before and after radiation exposure. Bioinformatic tools were used for pathways, network, gene ontology and toxicity related studies. We found 429 differentially expressed genes at fold change >2 and p-value <0.05. The most significantly upregulated genes were synuclein alpha (SNCA), carbonic anhydrase I (CA1), X-linked Kx blood group (XK), glycophorin A and B (GYPA and GYPB), and hemogen (HEMGN), while downregulated ones were membrane-spanning 4-domains, subfamily A member 1 (MS4A1), immunoglobulin heavy constant mu (IGHM), chemokine (C-C motif) receptor 7 (CCR7), BTB and CNC homology 1 transcription factor 2 (BACH2), and B-cell CLL/lymphoma 11B (BCL11B). Pathway analysis revealed calcium-induced T lymphocyte apoptosis and the role of nuclear factor of activated T-cells (NFAT) in regulation of the immune response as the most inhibited pathways, while apoptosis signaling was significantly activated. Most of the normal biofunctions were significantly decreased while cell death and survival process were activated. Gene ontology enrichment analysis revealed the immune system process as the most overrepresented group under the biological process category. Toxicity function analysis identified liver, kidney and heart to be the most affected organs during and after radiation therapy. The identified biomarkers and alterations in molecular pathways induced by radiation therapy should be further investigated to reduce the cytotoxicity and development of fatigue.

Alzheimer's disease (AD) is one of the most significant social and health burdens of the present century. Plaques formed by extracellular deposits of amyloid β (Aβ) are the prime player of AD's neuropathology. Studies have implicated the varied role of phospholipase A2 (PLA2) in brain where it contributes to neuronal growth and inflammatory response. Overall contour and chemical nature of the substrate-binding channel in the low molecular weight PLA2s are similar. This study involves the reductionist fragment-based approach to understand the structure adopted by N-terminal fragment of Alzheimer's Aβ peptide in its complex with PLA2. In the current communication, we report the structure determined by X-ray crystallography of N-terminal sequence Asp-Ala-Glu-Phe-Arg-His-Asp-Ser (DAEFRHDS) of Aβ-peptide with a Group I PLA2 purified from venom of Andaman Cobra sub-species Naja naja sagittifera at 2.0 Å resolution (Protein Data Bank (PDB) Code: 3JQ5). This is probably the first attempt to structurally establish interaction between amyloid-β peptide fragment and hydrophobic substrate binding site of PLA2 involving H bond and van der Waals interactions. We speculate that higher affinity between Aβ and PLA2 has the therapeutic potential of decreasing the Aβ-Aβ interaction, thereby reducing the amyloid aggregation and plaque formation in AD.