In-silico identification of deleterious non-synonymous SNPs of TBX1 gene: Functional and structural impact towards 22q11.2DS.

The TBX1 gene plays a critical role in the development of 22q11.2 deletion syndrome (22q11.2DS), a complex genetic disorder associated with various phenotypic manifestations. In this study, we performed in-silico analysis to identify potentially deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) within the TBX1 gene and evaluate their functional and structural impact on 22q11.2DS. A comprehensive analysis pipeline involving multiple computational tools was employed to predict the pathogenicity of nsSNPs. This study assessed protein stability and explored potential alterations in protein-protein interactions. The results revealed the rs751339103(C>A), rs780800634(G>A), rs1936727304(T>C), rs1223320618(G>A), rs1248532217(T>C), rs1294927055 (C>T), rs1331240435 (A>G, rs1601289406 (A>C), rs1936726164 (G>A), and rs911796187(G>A) with a high-risk potential for affecting protein function and stability. These nsSNPs were further analyzed for their impact on post-translational modifications and structural characteristics, indicating their potential disruption of molecular pathways associated with TBX1 and its interacting partners. These findings provide a foundation for further experimental studies and elucidation of potential therapeutic targets and personalized treatment approaches for individuals affected by 22q11.2DS.

Aflatoxin Contamination: An Overview on Health Issues, Detection and Management Strategies.

Aflatoxins (AFs) represent one of the main mycotoxins produced by Aspergillus flavus and Aspergillus parasiticus, with the most prevalent and lethal subtypes being AFB1, AFB2, AFG1, and AFG2. AFs are responsible for causing significant public health issues and economic concerns that affect consumers and farmers globally. Chronic exposure to AFs has been linked to liver cancer, oxidative stress, and fetal growth abnormalities among other health-related risks. Although there are various technologies, such as physical, chemical, and biological controls that have been employed to alleviate the toxic effects of AF, there is still no clearly elucidated universal method available to reduce AF levels in food and feed; the only mitigation is early detection of the toxin in the management of AF contamination. Numerous detection methods, including cultures, molecular techniques, immunochemical, electrochemical immunosensor, chromatographic, and spectroscopic means, are used to determine AF contamination in agricultural products. Recent research has shown that incorporating crops with higher resistance, such as sorghum, into animal feed can reduce the risk of AF contamination in milk and cheese. This review provides a current overview of the health-related risks of chronic dietary AF exposure, recent detection techniques, and management strategies to guide future researchers in developing better detection and management strategies for this toxin.

Identification of NRAS Diagnostic Biomarkers and Drug Targets for Endometrial Cancer-An Integrated in Silico Approach.

The diagnosis of endometrial cancer involves sequential, invasive tests to assess the thickness of the endometrium by a transvaginal ultrasound scan. In 6−33% of cases, endometrial biopsy results in inadequate tissue for a conclusive pathological diagnosis and 6% of postmenopausal women with non-diagnostic specimens are later discovered to have severe endometrial lesions. Thus, identifying diagnostic biomarkers could offer a non-invasive diagnosis for community or home-based triage of symptomatic or asymptomatic women. Herein, this study identified high-risk pathogenic nsSNPs in the NRAS gene. The nsSNPs of NRAS were retrieved from the NCBI database. PROVEAN, SIFT, PolyPhen-2, SNPs&GO, PhD-SNP and PANTHER were used to predict the pathogenicity of the nsSNPs. Eleven nsSNPs were identified as "damaging", and further stability analysis using I-Mutant 2.0 and MutPred 2 indicated eight nsSNPs to cause decreased stability (DDG scores < −0.5). Post-translational modification and protein−protein interactions (PPI) analysis showed putative phosphorylation sites. The PPI network indicated a GFR-MAPK signalling pathway with higher node degrees that were further evaluated for drug targets. The P34L, G12C and Y64D showed significantly lower binding affinity towards GTP than wild-type. Furthermore, the Kaplan−Meier bioinformatics analyses indicated that the NRAS gene deregulation affected the overall survival rate of patients with endometrial cancer, leading to prognostic significance. Findings from this could be considered novel diagnostic and therapeutic markers.

MgrB Mutations and Altered Cell Permeability in Colistin Resistance in Klebsiella pneumoniae.

There has been a resurgence in the clinical use of polymyxin antibiotics such as colistin due to the limited treatment options for infections caused by carbapenem-resistant Enterobacterales (CRE). However, this last-resort antibiotic is currently confronted with challenges which include the emergence of chromosomal and plasmid-borne colistin resistance. Colistin resistance in Klebsiella pneumoniae is commonly caused by the mutations in the chromosomal gene mgrB. MgrB spans the inner membrane and negatively regulates PhoP phosphorylation, which is essential for bacterial outer membrane lipid biosynthesis. The present review intends to draw attention to the role of mgrB chromosomal mutations in membrane permeability in K. pneumoniae that confer colistin resistance. With growing concern regarding the global emergence of colistin resistance, deciphering physical changes of the resistant membrane mediated by mgrB inactivation may provide new insights for the discovery of novel antimicrobials that are highly effective at membrane penetration, in addition to finding out how this can help in alleviating the resistance situation.

A Metal-Containing NP Approach to Treat Methicillin-Resistant Staphylococcus aureus (MRSA): Prospects and Challenges.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of pneumonia in humans, and it is associated with high morbidity and mortality rates, especially in immunocompromised patients. Its high rate of multidrug resistance led to an exploration of novel antimicrobials. Metal nanoparticles have shown potent antibacterial activity, thus instigating their application in MRSA. This review summarizes current insights of Metal-Containing NPs in treating MRSA. This review also provides an in-depth appraisal of opportunities and challenges in utilizing metal-NPs to treat MRSA.

Anti- and Pro-Oxidant Properties of Essential Oils against Antimicrobial Resistance.

The rapid evolution of antimicrobial resistance (AMR) has remained a major public health issue, reducing the efficacy of antibiotics and increasing the difficulty of treating infections. The discovery of novel antimicrobial agents is urgently needed to overcome the challenges created by AMR. Natural products such as plant extracts and essential oils (EOs) have been viewed as potential candidates to combat AMR due to their complex chemistry that carries inherent pro-oxidant and antioxidant properties. EOs and their constituents that hold pro-oxidant properties can induce oxidative stress by producing reactive oxygen species (ROS), leading to biological damage in target cells. In contrast, the antioxidant properties scavenge free radicals through offsetting ROS. Both pro-oxidant and antioxidant activities in EOs represent a promising strategy to tackle AMR. Thus, this review aimed to discuss how pro-oxidants and antioxidants in EOs may contribute to the mitigation of AMR and provided a detailed description of the challenges and limitations of utilizing them as a means to combat AMR.

miRNA in Ischemic Heart Disease and Its Potential as Biomarkers: A Comprehensive Review.

Ischemic heart disease (IHD) constitutes the leading global cause of mortality and morbidity. Although significant progress has been achieved in the diagnosis, treatment, and prognosis of IHD, more robust diagnostic biomarkers and therapeutic interventions are still needed to circumvent the increasing incidence of IHD. MicroRNAs (miRNAs) are critical regulators of cardiovascular function and are involved in various facets of cardiovascular biology. While the knowledge of the role of miRNAs in IHD as diagnostic biomarkers has improved, research emphasis on how miRNAs can be effectively used for diagnosis and prognosis of IHD is crucial. This review provides an overview of the biology, therapeutic and diagnostic potential, as well as the caveats of using miRNAs in IHD based on existing research.

Host-Bacterial Interactions: Outcomes of Antimicrobial Peptide Applications.

The bacterial membrane is part of a secretion system which plays an integral role to secrete proteins responsible for cell viability and pathogenicity; pathogenic bacteria, for example, secrete virulence factors and other membrane-associated proteins to invade the host cells through various types of secretion systems (Type I to Type IX). The bacterial membrane can also mediate microbial communities' communication through quorum sensing (QS), by secreting auto-stimulants to coordinate gene expression. QS plays an important role in regulating various physiological processes, including bacterial biofilm formation while providing increased virulence, subsequently leading to antimicrobial resistance. Multi-drug resistant (MDR) bacteria have emerged as a threat to global health, and various strategies targeting QS and biofilm formation have been explored by researchers worldwide. Since the bacterial secretion systems play such a crucial role in host-bacterial interactions, this review intends to outline current understanding of bacterial membrane systems, which may provide new insights for designing approaches aimed at antimicrobials discovery. Various mechanisms pertaining interaction of the bacterial membrane with host cells and antimicrobial agents will be highlighted, as well as the evolution of bacterial membranes in evasion of antimicrobial agents. Finally, the use of antimicrobial peptides (AMPs) as a cellular device for bacterial secretion systems will be discussed as emerging potential candidates for the treatment of multidrug resistance infections.

Contribution of Aldehydes and Their Derivatives to Antimicrobial and Immunomodulatory Activities.

Essential oils (EOs) are intricate combinations of evaporative compounds produced by aromatic plants and extracted by distillation or expression. EOs are natural secondary metabolites derived from plants and have been found to be useful in food and nutraceutical manufacturing, perfumery and cosmetics; they have also been found to alleviate the phenomenon of antimicrobial resistance (AMR) in addition to functioning as antibacterial and antifungal agents, balancing menstrual cycles and being efficacious as an immune system booster. Several main aldehyde constituents can be found in different types of EOs, and thus, aldehydes and their derivatives will be the main focus of this study with regard to their antimicrobial, antioxidative, anti-inflammatory and immunomodulatory effects. This brief study also explores the activity of aldehydes and their derivatives against pathogenic bacteria for future use in the clinical setting.

A Review on Tradescantia: Phytochemical Constituents, Biological Activities and Health-Promoting Effects.

Tradescantia is a genus of herbaceous and perennial plants belonging to the Commelinaceae family and organized into three infrageneric classifications and 12 sections. More than 80 species within the genus have been used for centuries for medicinal purposes. Phytochemical compounds (from various species of the genus) such as coumarins, alkaloids, saponins, flavonoids, phenolics, tannins, steroids and terpenoids have recently been characterized and described with antioxidant, cytotoxic, anti-inflammatory, anticancer or antimicrobial properties. The objective of this review is to describe the different aspects of the genus Tradescantia, including its botanical characteristics, traditional uses, phytochemical composition, biological activities, and safety aspects.

Oxidative Stress Parameters as Biomarkers of Cardiovascular Disease towards the Development and Progression.

Cardiovascular disease (CVD) remains the leading cause of death globally, with unhealthy lifestyles today greatly increasing the risk. Over the decades, scientific investigation has been carried out on reactive oxygen species (ROS) and their resultant oxidative stress based on their changes made on biological targets such as lipids, proteins, and DNA. Since the existing clinical studies with antioxidants failed to provide relevant findings on CVD prediction, the focus has shifted towards recognition of oxidised targets as biomarkers to predict prognosis and response to accurate treatment. The identification of redox markers could help clinicians in providing risk stratification for CVD events beyond the traditional prognostic and diagnostic targets. This review will focus on how oxidant-related parameters can be applied as biomarkers for CVD based on recent clinical evidence.

Phylogenetic analyses on Marek's disease virus circulating in Iranian backyard and commercial poultry indicate viruses of different origin.

As neoplastic viruses have been affecting Iranian chicken farms more frequently in recent years, the first step in prevention may therefore be to genetically characterize and systematically identify their source and origin. Recently, we published a phylogenetic analysis based on the meq gene of Gallid alphaherpesvirus 2, commonly known as serotype 1 Marek's disease virus (MDV-1), that circulated in Iranian backyard and commercial chickens. In the current study, we are reporting for the first time the identification of a 298 aa meq protein containing only two PPPP motifs from an MDV-1-infected unvaccinated backyard turkey. This protein length has never been reported from any turkey species before. According to phylogenetic analysis, a close genetic relationship (0.68%) to several chicken-origin isolates such as the American vv + 648A strain was found. In addition, we identified a standard meq protein from a MDV-1-infected commercial chicken farm. In corroboration with our previous finding from other Iranian provinces, it is likely that the highly identical MDV-1 viruses currently circulating in Iranian chicken farms, which may be indicative of human role in the spread of the virus, have similar Eurasian origin. Our data suggest that regardless of the meq size, MDV-1 circulating in Iran are from different origins. On the other hand, meq sequences from bird species other than chicken have been reported but are very few. Our investigation suggests MDV-1 circulating in turkey do not have species-specific sequences.

Phytocompounds as an Alternative Antimicrobial Approach in Aquaculture.

Despite culturing the fastest-growing animal in animal husbandry, fish farmers are often adversely economically affected by pathogenic disease outbreaks across the world. Although there are available solutions such as the application of antibiotics to mitigate this phenomenon, the excessive and injudicious use of antibiotics has brought with it major concerns to the community at large, mainly due to the rapid development of resistant bacteria. At present, the use of natural compounds such as phytocompounds that can be an alternative to antibiotics is being explored to address the issue of antimicrobial resistance (AMR). These phytocompounds are bioactive agents that can be found in many species of plants and hold much potential. In this review, we will discuss phytocompounds extracted from plants that have been evidenced to contain antimicrobial, antifungal, antiviral and antiparasitic activities. Further, it has also been found that compounds such as terpenes, phenolics, saponins and alkaloids can be beneficial to the aquaculture industry when applied. This review will focus mainly on compounds that have been identified between 2000 and 2021. It is hoped this review will shed light on promising phytocompounds that can potentially and effectively mitigate AMR.

Lactococcus lactis secreting phage lysins as a potential antimicrobial against multi-drug resistant Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus is an opportunistic Gram-positive bacterium that can form biofilm and become resistant to many types of antibiotics. The treatment of multi-drug resistant Staphylococcus aureus (MDRSA) infection is difficult since it possesses multiple antibiotic-resistant mechanisms. Endolysin and virion-associated peptidoglycan hydrolases (VAPGH) enzymes from bacteriophage have been identified as potential alternative antimicrobial agents. This study aimed to assess the ability of Lactococcus lactis NZ9000 secreting endolysin and VAPGH from S. aureus bacteriophage 88 to inhibit the growth of S. aureus PS 88, a MDRSA. METHOD: Endolysin and VAPGH genes were cloned and expressed in L. lactis NZ9000 after fusion with the SPK1 signal peptide for secretion. The recombinant proteins were expressed and purified, then analyzed for antimicrobial activity using plate assay and turbidity reduction assay. In addition, the spent media of the recombinant lactococcal culture was analyzed for its ability to inhibit the growth of the S. aureus PS 88. RESULTS: Extracellular recombinant endolysin (Endo88) and VAPGH (VAH88) was successfully expressed and secreted from L. lactis which was able to inhibit S. aureus PS 88, as shown by halozone formation on plate assays as well as inhibition of growth in the turbidity reduction assay. Moreover, it was observed that the spent media from L. lactis NZ9000 expressing Endo88 and VAH88 reduced the viability of PS 88 by up to 3.5-log reduction with Endo88 being more efficacious than VAH88. In addition, Endo88 was able to lyse all MRSA strains tested and Staphylococcus epidermidis but not the other bacteria while VAH88 could only lyse S. aureus PS 88. CONCLUSION: Recombinant L. lactisNZ9000 expressing phage 88 endolysin may be potentially developed into a new antimicrobial agent for the treatment of MDRSA infection.

Antimicrobial activity and mode of action of 1,8-cineol against carbapenemase-producing Klebsiella pneumoniae.

Antimicrobial resistance remains one of the most challenging issues that threatens the health of people around the world. Plant-derived natural compounds have received considerable attention for their potential role to mitigate antibiotic resistance. This study was carried out to assess the antimicrobial activity and mode of action of a monoterpene, 1,8-cineol (CN) against carbapenemase-producing Klebsiella pneumoniae (KPC-KP). Results showed that resazurin microplate assay and time-kill analysis revealed bactericidal effects of CN at 28.83 mg/mL. Zeta potential showed that CN increased the surface charge of bacteria and an increase of outer membrane permeability was also detected. CN was able to cause leakage of proteins and nucleic acids in KPC-KP cells upon exposure to CN and ethidium bromide influx/efflux experiment showed the uptake of ethidium bromide into the cell; this was attributed to membrane damage. CN was also found to induce oxidative stress in CN-treated KPC-KP cells through generation of reactive oxygen species which initiated lipid peroxidation and thus damaging the bacterial cell membrane. Scanning and transmission electron microscopies further confirmed the disruption of bacterial cell membrane and loss of intracellular materials. In this study, we demonstrated that CN induced oxidative stress and membrane damage resulting in KPC-KP cell death.

Predominance of Fourth Panzootic Newcastle Disease Virus Subgenotype VII.1.1 in Iran and Its Relation to the Genotypes Circulating in the Region.

Following recent Newcastle disease virus (NDV) outbreaks in Iranian poultry farms which were mostly associated with lesions of the avian gastrointestinal tract, it was speculated that the scale of the outbreaks could be attributed in part to co-circulating infectious agents or a new NDV genotype/subgenotype. This speculation was due to the isolation of a few 5th panzootic subgenotype VII.2 viruses from Iranian poultry farms in 2017. Samples from different species of commercial and domestic birds were collected from different provinces of Iran, 19 of which were selected for the current study. Phylogenetic analyses showed that the recent outbreaks have been caused by only one agent, i.e. the distinctive NDV subgenotype VII.1.1 (previously known VIIl) viruses that seem to be circulating predominantly in Iran, but have also been sporadically reported from Iraq among neighbouring countries. At most, 96.3-96.7% BLAST identity to non-Iranian VII.1.1 isolates was observed. Genetic distance values of <1% were indicative of high similarity between the isolates, but the values were approaximately 2% when the current isolates were compared to the earliest recorded Iranian VII.1.1 viruses isolated in 2010. Using Bayesian analysis, annual mutation rates of 1.7156E-3 (strict) and 1.9902E-3 (relaxed) over 11 years were obtained. In addition, we report that our laboratories have not detected any genotype XIII strains since 2011. Following up on previous reports, we concluded that currently, and except in Columbiforms, subgenotype VII.1.1 may likely be the predominant subgenotype in many bird species in Iran despite the subgenotype VII.2 being predominant in neighbouring countries.

Circulation of at Least Six Distinct Groups of Pigeon-Derived Newcastle Disease Virus in Iran Between 1996 and 2019.

According to the latest Newcastle disease virus (NDV) classification system, Iranian PPMV-1 isolates were classified as either XXI.1.1 or XXI.2 subgenotypes only. However, a few recent studies have suggested the possible existence of other Iranian PPMV-1 genotypes/subgenotypes. Recently, we isolated a PPMV-1 closely related to the African origin subgenotype VI.2.1.2 from an ill captive pigeon in a park aviary in central Tehran (Pg/IR/AMMM160/2019). This subgenotype had never been reported from Iran or neighboring countries. We also isolated a subgenotype VII.1.1 NDV (Pg/IR/AMMM117/2018), usually reported from non-pigeon birds in Iran. The nucleotide distance of AMMM117 was 1.0-2.5% compared to other Iranian subgenotypes VII.1.1 isolates. However, usually the same year VII.1.1 viruses that we isolate from Iranian poultry farms show negligible distances (0.0-0.5%). More isolates are required to study if this difference is due to subgenotype VII.1.1 being circulated and mutated in pigeons. Here, we also characterized two other isolates, namely Pg/IR/AMMM168/2019 and Pg/IR/MAM39/2017. The latter is the first Iranian subgenotype XXI.1.1 to be featured in the NDV datasets of the international NDV consortium. We also investigated the phylogenetic relation of all the published Iranian pigeon-derived NDV to date and updated the grouping according to the latest classification system. We have concluded that at least six different groups of pigeon-derived NDV have been circulating in Iran since 1996, four of which have been reported from just one city over the last seven years. This study suggests that the Iranian pigeon-origin NDV have been more diverse than the Iranian poultry-derived NDV in recent years.

Antimicrobial activity and mode of action of terpene linalyl anthranilate against carbapenemase-producing Klebsiella pneumoniae.

Mining of plant-derived antimicrobials is the major focus at current to counter antibiotic resistance. This study was conducted to characterize the antimicrobial activity and mode of action of linalyl anthranilate (LNA) against carbapenemase-producing Klebsiella pneumoniae (KPC-KP). LNA alone exhibited bactericidal activity at 2.5% (V/V), and in combination with meropenem (MPM) at 1.25% (V/V). Comparative proteomic analysis showed a significant reduction in the number of cytoplasmic and membrane proteins, indicating membrane damage in LNA-treated KPC-KP cells. Up-regulation of oxidative stress regulator proteins and down-regulation of oxidative stress-sensitive proteins indicated oxidative stress. Zeta potential measurement and outer membrane permeability assay revealed that LNA increases both bacterial surface charge and membrane permeability. Ethidium bromide influx/efflux assay showed increased uptake of ethidium bromide in LNA-treated cells, inferring membrane damage. Furthermore, intracellular leakage of nucleic acid and proteins was detected upon LNA treatment. Scanning and transmission electron microscopies again revealed the breakage of bacterial membrane and loss of intracellular materials. LNA was found to induce oxidative stress by generating reactive oxygen species (ROS) that initiate lipid peroxidation and damage the bacterial membrane. In conclusion, LNA generates ROS, initiates lipid peroxidation, and damages the bacterial membrane, resulting in intracellular leakage and eventually killing the KPC-KP cells.