Influence of Tau on Neurotoxicity and Cerebral Vasculature Impairment Associated with Alzheimer's Disease.

Alzheimer's disease is a fatal chronic neurodegenerative condition marked by a gradual decline in cognitive abilities and impaired vascular function within the central nervous system. This affliction initiates its insidious progression with the accumulation of two aberrant protein entities including Aß plaques and neurofibrillary tangles. These chronic elements target distinct brain regions, steadily erasing the functionality of the hippocampus and triggering the erosion of memory and neuronal integrity. Several assumptions are anticipated for AD as genetic alterations, the occurrence of Aß plaques, altered processing of amyloid precursor protein, mitochondrial damage, and discrepancy of neurotropic factors. In addition to Aß oligomers, the deposition of tau hyper-phosphorylates also plays an indispensable part in AD etiology. The brain comprises a complex network of capillaries that is crucial for maintaining proper function. Tau is expressed in cerebral blood vessels, where it helps to regulate blood flow and sustain the blood-brain barrier's integrity. In AD, tau pathology can disrupt cerebral blood supply and deteriorate the BBB, leading to neuronal neurodegeneration. Neuroinflammation, deficits in the microvasculature and endothelial functions, and Aß deposition are characteristically detected in the initial phases of AD. These variations trigger neuronal malfunction and cognitive impairment. Intracellular tau accumulation in microglia and astrocytes triggers deleterious effects on the integrity of endothelium and cerebral blood supply resulting in further advancement of the ailment and cerebral instability. In this review, we will discuss the impact of tau on neurovascular impairment, mitochondrial dysfunction, oxidative stress, and the role of hyperphosphorylated tau in neuron excitotoxicity and inflammation.

Identification of TBK1 inhibitors against breast cancer using a computational approach supported by machine learning.

Introduction: The cytosolic Ser/Thr kinase TBK1 is of utmost importance in facilitating signals that facilitate tumor migration and growth. TBK1-related signaling plays important role in tumor progression, and there is need to work on new methods and workflows to identify new molecules for potential treatments for TBK1-affecting oncologies such as breast cancer. Methods: Here, we propose the machine learning assisted computational drug discovery approach to identify TBK1 inhibitors. Through our computational ML-integrated approach, we identified four novel inhibitors that could be used as new hit molecules for TBK1 inhibition. Results and Discussion: All these four molecules displayed solvent based free energy values of -48.78, -47.56, -46.78 and -45.47 Kcal/mol and glide docking score of -10.4, -9.84, -10.03, -10.06 Kcal/mol respectively. The molecules displayed highly stable RMSD plots, hydrogen bond patterns and MMPBSA score close to or higher than BX795 molecule. In future, all these compounds can be further refined or validated by in vitro as well as in vivo activity. Also, we have found two novel groups that have the potential to be utilized in a fragment-based design strategy for the discovery and development of novel inhibitors targeting TBK1. Our method for identifying small molecule inhibitors can be used to make fundamental advances in drug design methods for the TBK1 protein which will further help to reduce breast cancer incidence.

A protein-miRNA biomic analysis approach to explore neuroprotective potential of nobiletin in human neural progenitor cells (hNPCs).

Chemical-induced neurotoxicity is increasingly recognized to accelerate the development of neurodegenerative disorders (NDs), which pose an increasing health burden to society. Attempts are being made to develop drugs that can cross the blood-brain barrier and have minimal or no side effects. Nobiletin (NOB), a polymethoxylated flavonoid with anti-oxidative and anti-inflammatory effects, has been demonstrated to be a promising compound to treat a variety of NDs. Here, we investigated the potential role of NOB in sodium arsenate (NA)-induced deregulated miRNAs and target proteins in human neural progenitor cells (hNPCs). The proteomics and microRNA (miRNA) profiling was done for different groups, namely, unexposed control, NA-exposed, NA + NOB, and NOB groups. Following the correlation analysis between deregulated miRNAs and target proteins, RT-PCR analysis was used to validate the selected genes. The proteomic analysis showed that significantly deregulated proteins were associated with neurodegeneration pathways, response to oxidative stress, RNA processing, DNA repair, and apoptotic process following exposure to NA. The OpenArray analysis confirmed that NA exposure significantly altered miRNAs that regulate P53 signaling, Wnt signaling, cell death, and cell cycle pathways. The RT-PCR validation studies concur with proteomic data as marker genes associated with autophagy and apoptosis (HO-1, SQSTM1, LC-3, Cas3, Apaf1, HSP70, and SNCA1) were altered following NA exposure. It was observed that the treatment of NOB significantly restored the deregulated miRNAs and proteins to their basal levels. Hence, it may be considered one of its neuroprotective mechanisms. Together, the findings are promising to demonstrate the potential applicability of NOB as a neuroprotectant against chemical-induced neurotoxicity.

Silver Nanoparticles Derived from Probiotic Lactobacillus casei-a Novel Approach for Combating Bacterial Infections and Cancer.

In the face of rising antibiotic resistance and the need for novel therapeutic approaches against cancer, the present study delves into the various facets of biosynthesized silver nanoparticles (AgNPs) derived from the probiotic strain Lactobacillus casei (AgNPs-LC), assessing their efficacy in combating bacterial infections, disrupting biofilm formation, interfering with quorum sensing mechanisms, and exhibiting anti-cancer properties. The results showed that the AgNPs-LC had a spherical shape with an average size of 15 nm. The biosynthesized AgNPs-LC showed a symmetrical absorption spectrum with a peak at 458 nm with a diameter of 5-20 nm. AgNPs-LC exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria and inhibited the biofilm formation (> 50% at sub-MIC) and quorum sensing-mediated virulence factors, such as the production of violacein in C. violaceum (> 80% at sub-MIC), pyocyanin in P. aeruginosa (> 70% at sub-MIC), and prodigiosin in S. marcescens (> 80% at sub-MIC). The exopolysaccharides (EPS) were also found to reduce in the presence of AgNPs-LC. Furthermore, the AgNPs-LC showed anti-cancer and anti-metastasis activity via inhibiting cell migration and invasion of human lung cancer (A-549) cells. Overall, the present study brings out the multifaceted therapeutic capabilities of AgNPs-LC which offer exciting prospects for the development of innovative biomedical and pharmaceutical interventions, making AgNPs-LC a versatile and promising candidate for a wide range of applications in healthcare and medicine. However, further research is essential to fully harness their therapeutic potential.

Pharmacophore-Based Screening, Molecular Docking, and Dynamic Simulation of Fungal Metabolites as Inhibitors of Multi-Targets in Neurodegenerative Disorders.

Neurodegenerative disorders, such as Alzheimer's disease (AD), negatively affect the economic and psychological system. For AD, there is still a lack of disease-altering treatments and promising cures due to its complex pathophysiology. In this study, we computationally screened the natural database of fungal metabolites against three known therapeutic target proteins of AD. Initially, a pharmacophore-based, drug-likeness category was employed for screening, and it filtered the 14 (A-N) best hits out of 17,544 fungal metabolites. The 14 best hits were docked individually against GSK-3ß, the NMDA receptor, and BACE-1 to investigate the potential of finding a multitarget inhibitor. We found that compounds B, F, and L were immuno-toxic, whereas E, H, I, and J had a higher LD50 dose (5000 mg/kg). Among the examined metabolites, the Bisacremine-C (compound I) was found to be the most active molecule against GSK-3ß (ΔG: -8.7 ± 0.2 Kcal/mol, Ki: 2.4 × 106 M-1), NMDA (ΔG: -9.5 ± 0.1 Kcal/mol, Ki: 9.2 × 106 M-1), and BACE-1 (ΔG: -9.1 ± 0.2 Kcal/mol, Ki: 4.7 × 106 M-1). It showed a 25-fold higher affinity with GSK-3ß, 6.3-fold higher affinity with NMDA, and 9.04-fold higher affinity with BACE-1 than their native ligands, respectively. Molecular dynamic simulation parameters, such as RMSD, RMSF, Rg, and SASA, all confirmed that the overall structures of the targeted enzymes did not change significantly after binding with Bisacremine-C, and the ligand remained inside the binding cavity in a stable conformation for most of the simulation time. The most significant hydrophobic contacts for the GSK-3ß-Bisacremine-C complex are with ILE62, VAL70, ALA83, and LEU188, whereas GLN185 is significant for H-bonds. In terms of hydrophobic contacts, TYR184 and PHE246 are the most important, while SER180 is vital for H-bonds in NMDA-Bisacremine-C. THR232 is the most crucial for H-bonds in BACE-1-Bisacremine-C and ILE110-produced hydrophobic contacts. This study laid a foundation for further experimental validation and clinical trials regarding the biopotency of Bisacremine-C.

Targeting NMDA receptor in Alzheimer's disease: identifying novel inhibitors using computational approaches.

The glutamate-gated ion channels known as N-methyl-d-aspartate receptors (NMDARs) are important for both normal and pathological brain function. Subunit-selective antagonists have high therapeutic promise since many pathological conditions involve NMDAR over activation, although few clinical successes have been reported. Allosteric inhibitors of GluN2B-containing receptors are among the most potential NMDAR targeting drugs. Since the discovery of ifenprodil, a variety of GluN2B-selective compounds have been discovered, each with remarkably unique structural motifs. These results expand the allosteric and pharmacolog-ical spectrum of NMDARs and provide a new structural basis for the development of next-generation GluN2B antagonists that have therapeutic potential in brain diseases. Small molecule therapeutic inhibitors targeting NMDA have recently been developed to target CNS disorders such as Alzheimer's disease. In the current study, a cheminformatics method was used to discover potential antagonists and to identify the structural requirements for Gly/NMDA antagonism. In this case we have created a useful pharmacophore model with solid statistical values. Through pharmacophore mapping, the verified model was used to filter out virtual matches from the ZINC database. Assessing receptor-ligand binding mechanisms and affinities used molecular docking. To find the best hits, the GlideScore and the interaction of molecules with important amino acids were considered essential features. We found some molecular inhibitors, namely, ZINC13729211, ZINC07430424, ZINC08614951, ZINC60927204, ZINC12447511, and ZINC18889258 with high binding affinity using computational methods. The molecules in our studies showed characteristics such as good stability, hydrogen bonding and higher binding affinities in the solvation-based assessment method than ifenprodil with acceptable ADMET profile. Moreover, these six leads have been proposed as potential new perspectives for exploring potent Gly/NMDA receptor antagonists. In addition, it can be tested in the laboratory for potential therapeutic strategies for both in vitro and in vivo research.

TRP channels: Role in neurodegenerative diseases and therapeutic targets.

TRP (Transient receptor potential) channels are integral membrane proteins consisting of a superfamily of cation channels that allow permeability of both monovalent and divalent cations. TRP channels are subdivided into six subfamilies: TRPC, TRPV, TRPM, TRPP, TRPML, and TRPA, and are expressed in almost every cell and tissue. TRPs play an instrumental role in the regulation of various physiological processes. TRP channels are extensively represented in brain tissues and are present in both prokaryotes and eukaryotes, exhibiting responses to several mechanisms, including physical, chemical, and thermal stimuli. TRP channels are involved in the perturbation of Ca2+ homeostasis in intracellular calcium stores, both in neuronal and non-neuronal cells, and its discrepancy leads to several neuronal disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). TRPs participate in neurite outgrowth, receptor signaling, and excitotoxic cell death in the central nervous system. Understanding the mechanism of TRP channels in neurodegenerative diseases may extend to developing novel therapies. Thus, this review articulates TRP channels' physiological and pathological role in exploring new therapeutic interventions in neurodegenerative diseases.

Myco-Synthesis of Silver Nanoparticles and Their Bioactive Role against Pathogenic Microbes.

Nanotechnology based on nanoscale materials is rapidly being used in clinical settings, particularly as a new approach for infectious illnesses. Recently, many physical/chemical approaches utilized to produce nanoparticles are expensive and highly unsafe to biological species and ecosystems. This study demonstrated an environmentally friendly mode of producing nanoparticles (NPs) where Fusarium oxysporum has been employed for generation of silver nanoparticles (AgNPs), which were further tested for their antimicrobial potentials against a variety of pathogenic microorganisms. The characterization of NPs was completed by UV-Vis spectroscopy, DLS and TEM, where it has been found that the NPs were mostly globular, with the size range of 50 to 100 nm. The myco-synthesized AgNPs showed prominent antibacterial potency observed as zone of inhibition of 2.6 mm, 1.8 mm, 1.5 mm, and 1.8 mm against Vibrio cholerae, Streptococcus pneumoniae, Klebsiella pneumoniae and Bacillus anthracis, respectively, at 100 µM. Similarly, at 200 µM for A. alternata, A. flavus and Trichoderma have shown zone of inhibition as 2.6 mm, 2.4 mm, and 2.1 mm, respectively. Moreover, SEM analysis of A. alternata confirmed the hyphal damage where the layers of membranes were torn off, and further EDX data analysis showed the presence of silver NPs, which might be responsible for hyphal damage. The potency of NPs may be related with the capping of fungal proteins that are produced extracellularly. Thus, these AgNPs may be used against pathogenic microbes and play a beneficial role against multi-drug resistance.

A Critical Review on Human Malaria and Schistosomiasis Vaccines: Current State, Recent Advancements, and Developments.

Malaria and schistosomiasis are two major parasitic diseases that remain leading causes of morbidity and mortality worldwide. Co-infections of these two parasites are common in the tropics, where both diseases are endemic. The clinical consequences of schistosomiasis and malaria are determined by a variety of host, parasitic, and environmental variables. Chronic schistosomiasis causes malnutrition and cognitive impairments in children, while malaria can cause fatal acute infections. There are effective drugs available to treat malaria and schistosomiasis. However, the occurrence of allelic polymorphisms and the rapid selection of parasites with genetic mutations can confer reduced susceptibility and lead to the emergence of drug resistance. Moreover, the successful elimination and complete management of these parasites are difficult due to the lack of effective vaccines against Plasmodium and Schistosoma infections. Therefore, it is important to highlight all current vaccine candidates undergoing clinical trials, such as pre-erythrocytic and erythrocytic stage malaria, as well as a next-generation RTS,S-like vaccine, the R21/Matrix-M vaccine, that conferred 77% protection against clinical malaria in a Phase 2b trial. Moreover, this review also discusses the progress and development of schistosomiasis vaccines. Furthermore, significant information is provided through this review on the effectiveness and progress of schistosomiasis vaccines currently under clinical trials, such as Sh28GST, Sm-14, and Sm-p80. Overall, this review provides insights into recent progress in malarial and schistosomiasis vaccines and their developmental approaches.

Therapeutic Role of ELOVL in Neurological Diseases.

Fatty acids play an important role in controlling the energy balance of mammals. De novo lipogenesis also generates a significant amount of lipids that are endogenously produced in addition to their ingestion. Fatty acid elongation beyond 16 carbons (palmitic acid), which can lead to the production of very long chain fatty acids (VLCFA), can be caused by the rate-limiting condensation process. Seven elongases, ELOVL1-7, have been identified in mammals and each has a unique substrate specificity. Researchers have recently developed a keen interest in the elongation of very long chain fatty acids protein 1 (ELOVL1) enzyme as a potential treatment for a variety of diseases. A number of neurological disorders directly or indirectly related to ELOVL1 involve the elongation of monounsaturated (C20:1 and C22:1) and saturated (C18:0-C26:0) acyl-CoAs. VLCFAs and ELOVL1 have a direct impact on the neurological disease. Other neurological symptoms such as ichthyotic keratoderma, spasticity, and hypomyelination have also been linked to the major enzyme (ELOVL1). Recently, ELOVL1 has also been heavily used to treat a number of diseases. The current review focuses on in-depth unique insights regarding the role of ELOVL1 as a therapeutic target and associated neurological disorders.

Computational insight into structural basis of human ELOVL1 inhibition.

Very long-chain fatty acids (VLCFAs) play a direct role in the development of a neurological disorder, X-linked adrenoleukodystrophy (X-ALD). Since ELOVL1 catalyzes the rate-limiting step of the synthesis of VLCFAs, it has emerged as an attractive target for the treatment of X-ALD. Recently two potent inhibitors, compound 22 (C22) and compound 27 (C27) have been reported to specifically inhibit human ELOVL1 but their structural basis of inhibition has not been explored. In the present study, we have used a homology model of human ELOVL1 to deduce the binding site and binding modes of C22 and C27. We have employed computational approaches to characterize the binding of C22 and C27. Initially, binding of hexacosanoyl-CoA (C26:0-CoA) to ELOVL1 was modelled and further validated by molecular dynamics (MD) simulation. We observed that the fatty acid tail of C26: CoA protrudes from a unique opening located at the occluded end of ELOVL1. Structural comparison of ELOVL1 with the crystal structure of ELOVL7 revealed that the unique opening was not present in human ELOVL7. Combined blind and focused molecular docking approaches revealed that C22 and C27 exhibit favourable binding in the same unique opening. Further, MD simulations and free binding energy calculations confirmed that C22 and C27 maintain the favourable binding in the unique opening of ELOVL1. Overall, our findings suggest that selective human ELOVL1 inhibitors block the binding of long tails of VLCFAs near the occluded end of ELOVL1. Present study will be helpful in the discovery and design of novel, selective and potent inhibitors of human ELOVL1.

Reversal of Azole Resistance in Candida albicans by Human Neutrophil Peptide.

With the spread of AIDS and the increase in immunocompromised patients, multi-drug-resistant fungal infections have become a serious concern among clinicians, predominantly in the developing world. Therefore, developing novel strategies and new drugs is essential to overcome drug resistance in fungal pathogens. Antimicrobial peptides of human origin have been investigated as a potential treatment against Candida infections. In this study, human neutrophil peptide (HNP) was tested for its antifungal activity alone and in combination with fluconazole (FLC) against azole-susceptible and resistant C. albicans isolates, following CLSI guidelines. Susceptibility and combination interactions were also confirmed by MUSE cell viability assay and isobolograms for synergistic combinations, respectively. The effect of HNP on biofilm inhibition was determined spectrophotometrically and microscopically. Drug susceptibility testing showed minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) ranging from 7.813 to 62.5 µg/mL and 15.625 to 250 µg/mL against all the tested C. albicans strains. The combination activity of FLC with HNP exhibited synergistic and additive interactions in 43% of each and indifferent interaction in 14%, and none of the combinations showed antagonistic interaction. Furthermore, HNB inhibited biofilm formation in all the tested C. albicans isolates. At the respective MICs, HNP exhibited inhibitory effects on the activity of the drug efflux pumps and their genes. These results warrant the application of HNP as a mono- or combination therapy with FLC to treat azole-resistant C. albicans.

Bacteriocin-Nanoconjugates (Bac10307-AgNPs) Biosynthesized from Lactobacillus acidophilus-Derived Bacteriocins Exhibit Enhanced and Promising Biological Activities.

The proteinaceous compounds produced by lactic acid bacteria are called bacteriocins and have a wide variety of bioactive properties. However, bacteriocin's commercial availability is limited due to short stability periods and low yields. Therefore, the objective of this study was to synthesize bacteriocin-derived silver nanoparticles (Bac10307-AgNPs) extracted from Lactobacillus acidophilus (L. acidophilus), which may have the potential to increase the bioactivity of bacteriocins and overcome the hurdles. It was found that extracted and purified Bac10307 had a broad range of stability for both temperature (20-100 °C) and pH (3-12). Further, based on Sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis, its molecular weight was estimated to be 4.2 kDa. The synthesized Bac10307-AgNPs showed a peak of surface plasmon resonance at 430 nm λmax. Fourier transform infrared (FTIR) confirmed the presence of biological moieties, and transmission electron microscopy (TEM) coupled with Energy dispersive X-Ray (EDX) confirmed that AgNPs were spherical and irregularly shaped, with a size range of 9-20 nm. As a result, the Bac10307-AgNPs displayed very strong antibacterial activity with MIC values as low as 8 µg/mL for Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa), when compared to Bac10307 alone. In addition, Bac10307-AgNPs demonstrated promising in vitro antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) (IC50 = 116.04 µg/mL) and in vitro cytotoxicity against human liver cancer cells (HepG2) (IC50 = 135.63 µg/mL), more than Bac10307 alone (IC50 = 139.82 µg/mL against DPPH and 158.20 µg/mL against HepG2). Furthermore, a protein-protein molecular docking simulation study of bacteriocins with target proteins of different biological functions was also carried out in order to ascertain the interactions between bacteriocins and target proteins.

Identifying novel and potent inhibitors of EGFR protein for the drug development against the breast cancer.

The epidermal growth factor receptor (EGFR) has been shown to be extremely important in numerous signaling pathways, particularly those involved in cancer progression. Many therapeutic inhibitors, consisting of both small molecules and monoclonal antibodies, have been developed to target inflammatory, triple-negative and metastatic breast cancer. With the emergence of resistance in breast cancer treatment strategies, there is a need to develop novel drug targets that not only overcome resistance, but also exhibit low toxicity and high specificity. The work presented here focuses on the identification of new inhibitors against the EGFR protein using combined computational approaches. Using a comprehensive machine learning-based virtual screening approach complemented by other computational approaches, we identified six new molecules from the ZINC database. The gold docking score of these six novel molecules is 125.95, 125.38, 123.13, 119.71, 115.64 and 113.73, respectively, while the gold score of the control group is 120.74. In addition, we also analyzed the FEC value of these compounds and found that the values of compounds 1, 2, 3 and 4 (-61.82, -63.98, -67.98 and -63.32, respectively) were higher are than those of the control group (-61.05). Furthermore, these molecules showed highly stable RMSD plots and good interaction of hydrogen bonds. The identified inhibitors provided interesting insights for understanding the electronic, hydrophobic, steric and structural requirements for EGFR inhibitory activity. Distinguishing these novel molecules could lead to the development of new drugs useful in treating breast cancer.Communicated by Ramaswamy H. Sarma.

BTYNB, an inhibitor of RNA binding protein IGF2BP1 reduces proliferation and induces differentiation of leukemic cancer cells.

Leukemia is a group of diseases characterized by altered growth and differentiation of lymphoid or myeloid progenitors of blood. The existence of specific clusters of cells with stemness-like characteristics like differentiation, self-renewal, detoxification, and resistance to apoptosis in Leukemia makes them difficult to treat. It was recently reported that an oncofetal RNA binding protein, insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), maintains leukemic stem cell properties. BTYNB is an inhibitor of IGF2BP1 that was shown to affect the biological functions of IGF2BP1 however, the effect of BTYNB in Leukemia is not properly established. In this study, we assessed the effect of BTYNB on leukemic cell differentiation and proliferation. We performed cell viability assay to assess the effect of BTYNB in leukemic cells. We then assessed cell morphology of the leukemic cells treated with BTYNB. Further, we conducted an apoptosis assay and cell cycle assay. We found the cell viability of leukemic cells was significantly decreased post treatment with BTYNBs. Further, a noticeable morphological change was observed in BTYNB treated leukemic cells. BTYNB treated leukemic cells showed increased cell death and cell cycle arrest at S-phase. Evidence from the upregulation of BAK and p21 further confirmed apoptosis and cycle arrest. The gene expression of differentiation genes such as CD11B, ZFPM1, and KLF5 were significantly upregulated in BTYNB treated leukemic cells, therefore, confirming cell differentiation. Collectively, our study showed inhibition of IGF2BP1 function using BTYNB promotes differentiation in leukemic cells.

Mucormycosis: A hidden mystery of fungal infection, possible diagnosis, treatment and development of new therapeutic agents.

Mucormycosis is a fungal infection which got worsens with time if not diagnosed and treated. The current COVID-19 pandemic has association with fungal infection specifically with mucormycosis. Already immunocompromised patients are easy target for COVID-19 and mucormycosis as well. COVID-19 infection imparts in weak immune system so chances of infection is comparatively high in COVID-19 patients. Furthermore, diabetes, corticosteroid medicines, and a weakened immune system are the most prevalent risk factors for this infection as we discussed in case studies here. The steroid therapy for COVID-19 patients sometimes have negative impact on the patient health and this state encounters many infections including mucormycosis. There are treatments available but less promising and less effective. So, researchers are focusing on the promising agents against mucormycosis. It is reported that early treatment with liposomal amphotericin B (AmB), manogepix, echinocandins isavuconazole, posacanazole and other promising therapeutic agents have overcome the burden of mucormycosis. Lipid formulations of AmB have become the standard treatment for mucormycosis due to their greater safety and efficacy. In this review article, we have discussed case studies with the infection of mucormycosis in COVID-19 patients. Furthermore, we focused on anti-mucormycosis agents with mechanism of action of various therapeutics, including coverage of new antifungal agents being investigated as part of the urgent global response to control and combat this lethal infection, especially those with established risk factors.

Prevalence of rheumatoid arthritis and diagnostic validity of a prediction score, in patients visiting orthropedic clinics in the Madinah region of Saudi Arabia: a retrospective cross-sectional study.

Introduction: In Saudi Arabia, the epidemiology of rheumatoid arthritis (RA) is not well studied and is marked by inconsistencies in clinical diagnosis. Therefore, in this study, we explored the prevalence, clinical characteristics, and diagnostic validity of a prediction score based upon disease markers in orthropedic clinics' patients in the Madinah region of Saudi Arabia. Method: The clinical data for this retrospective cross-sectional study were retrieved from the database registry of orthopedic clinics in selected hospitals of the Medinah province of Saudi Arabia. Sociodemographic features, disease markers and the clinical characteristics were collected for a period of 6 months, from December 1, 2020, to May 31, 2021. The prediction score was generated from the sum of disease markers, coded as dichotomous variables. Results: The total sample size of our study was 401. The prevalence of RA in the study subjects (n = 401) was 14.46% (n = 58). Among RA patients, the majority were females (60.3%). Painful joints (69%) and swollen joints (51.7%) were the most common clinical complaints among RA patients. RA patients suffered from arthritis (51.7%) and experienced fatigue (46.6%), weight loss (44.8%), and loss of appetite (41.4%). Diabetes (55.2%) was the most common comorbidity in the RA patients. The sensitivity and specificity of the prediction score at the criterion score of 2.5 were 67.3% and 63.0%, respectively. The area under the curve was 0.69 (95% CI [0.62-0.76]). Conclusion: There was a moderately high prevalence of RA in patients visiting the orthropedic clinics of the selected hospitals of Madinah region of Saudi Arabia. The diagnostic validity of the prediction score, though promising, was slightly lower than the acceptable range.

A Subtraction Genomics-Based Approach to Identify and Characterize New Drug Targets in Bordetella pertussis: Whooping Cough.

Bordetella pertussis is a Gram-negative bacterium known to cause pertussis or whooping cough. The disease affects the respiratory system and is contagious. Pertussis causes high mortality among infants aged less than one-year-old, although it can affect anyone of any age. Globally, 16 million cases of pertussis were reported in 2008, 95% of which were in developing nations, and approximately 195,000 children died from the disease. Under a computational subtractive genomics approach, the total proteome of a pathogen is gently trimmed down to a few potential drug targets. First, from NCBI, we obtained the pathogen proteins followed by CD hit for removal of duplicate proteins. The BLAST step was applied to find non-similar proteins, and then, we applied BLAST to these non-similar bacterial proteins with DEG to find essential bacterial proteins. After this, to find the location, these vital proteins were screened via PSORTb; the majority of proteins were in cytoplasm. The KASS server was used to determine the involvement of these proteins in the metabolic pathways of bacteria, and KEGG was applied to find the unique metabolic pathways of the pathogen. Finally, we applied BLAST to these vital, unique, and non-similar proteins with FDA-approved drug targets, and four proteins of the B. pertussis strain B1917 were identified that might be powerful drug targets. A variety of therapeutic molecules could be designed to target these proteins in order to treat infections caused by bacteria.

Whole-Exome Sequencing Reveals Migraine-Associated Novel Functional Variants in Arab Ancestry Females: A Pilot Study.

Migraine, as the seventh most disabling neurological disease with 26.9% prevalence in Saudi females, lacks studies on identifying associated genes and pathways with migraines in the Arab population. This case control study aims to identify the migraine-associated novel genes and risk variants. More than 1900 Arab ancestry young female college students were screened: 103 fulfilled the ICHD-3 criteria for migraine and 20 cases confirmed in the neurology clinic were included for the study with age-matched healthy controls. DNA from blood samples were subjected to paired-end whole-exome sequencing. After quality control, 3365343 missense, frameshift, missense splice region variants and insertion-deletion (indels) polymorphisms were tested for association with migraine. Significant variants were validated using Sanger sequencing. A total of 17 (p-value 9.091 × 10-05) functional variants in 12 genes (RETNLB, SCAI, ADH4, ESPL1, CPT2, FLG, PPP4R1, SERPINB5, ZNF66, ETAA1, EXO1 and CPA6) were associated with higher migraine risk, including a stop-gained frameshift (-13-14*SX) variant in the gene RETNLB (rs5851607; p-value 3.446 × 10-06). Gene analysis revealed that half of the significant novel migraine risk genes were expressed in the temporal lobe (p-value 0.0058) of the cerebral cortex. This is the first study exploring the migraine risk of 17 functional variants in 12 genes among Saudi female migraineurs of Arab ancestry using whole-exome sequencing. Half of the significant genes were expressed in the temporal lobe, which expands migraine pathophysiology and early identification using biomarkers for research possibilities on personalised genetics.

Understanding Acquired Brain Injury: A Review.

Any type of brain injury that transpires post-birth is referred to as Acquired Brain Injury (ABI). In general, ABI does not result from congenital disorders, degenerative diseases, or by brain trauma at birth. Although the human brain is protected from the external world by layers of tissues and bone, floating in nutrient-rich cerebrospinal fluid (CSF); it remains susceptible to harm and impairment. Brain damage resulting from ABI leads to changes in the normal neuronal tissue activity and/or structure in one or multiple areas of the brain, which can often affect normal brain functions. Impairment sustained from an ABI can last anywhere from days to a lifetime depending on the severity of the injury; however, many patients face trouble integrating themselves back into the community due to possible psychological and physiological outcomes. In this review, we discuss ABI pathologies, their types, and cellular mechanisms and summarize the therapeutic approaches for a better understanding of the subject and to create awareness among the public.