Influence of matrix metalloproteinase 9 variant rs17576 on ischemic stroke risk and severity in acute coronary syndrome.

BACKGROUND: Ischemic injury is a common mechanism in both ischemic stroke (IS) and acute coronary syndrome (ACS). Matrix metalloproteinase 9 (MMP-9), an endopeptidase that degrades extracellular matrix, is important in the pathogenesis of IS. The purpose of this study is to evaluate the association between the SNP rs17576 in MMP-9 gene with (1) the risk and severity of acute ischemic stroke in Saudi Arab individuals with recent acute coronary syndrome, and (2) the risk of acute coronary syndrome in Saudi Arab individuals without ischemic stroke. METHODS: A case control study of 200 IS patients, 520 ACS patients (without IS), and 500 aged-matched healthy controls were genotyped to detect the MMP-9 polymorphism rs17156. RESULTS: Our study demonstrated a non-significant difference in the genotype and allele frequencies of the MMP9 rs17576 polymorphism between the patients with IS and patients with ACS without IS (P = 0.31 for the GA genotype, 0.25 for the AA genotype and P = 0.20 for the A allele). AA genotype was found to be statistically significant between IS and control groups; [OR=1.84, 95 % CI (1.08-3.14), p =0.015]. A allele showed a significant difference between the two groups [OR=1.28, 95 % CI (1.00-1.64), p =0.028]. By comparing ACS without IS and controls, AA genotype was significant [OR=1.46, 95 % CI (1.01-2.12), p =0.029]. Stratification by NIHSS score revealed higher mortality and early neurologic deterioration in IS patients with NIHSS score ≥ 16 (p < 0.001, 0.044 respectively). CONCLUSION: We deduced the lack of association either with allele or genotype frequencies (p>0.05) between the IS cases and the cases of ACS without IS. In contrast there was a significant association of mutant genotype AA between either the IS group or ACS (without IS) group, and the control group. In addition, different rs17576 genotypes were not associated with raised mortality or a tendency to develop early neurologic deterioration.

LRRK2 kinase inhibition protects against Parkinson's disease-associated environmental toxicants.

Idiopathic Parkinson's disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that pollute our environment. While most are structurally distinct, a common cellular target for their toxicity is mitochondrial dysfunction, a key pathological trigger involved in the selective vulnerability of dopaminergic neurons. We and others have shown that environmental mitochondrial toxicants such as the pesticides rotenone and paraquat, and the organic solvent trichloroethylene (TCE) appear to be influenced by the protein LRRK2, a genetic risk factor for PD. As LRRK2 mediates vesicular trafficking and influences endolysosomal function, we postulated that LRRK2 kinase activity may inhibit the autophagic removal of toxicant damaged mitochondria, resulting in elevated oxidative stress. Conversely, we suspected that inhibition of LRRK2, which has been shown to be protective against dopaminergic neurodegeneration caused by mitochondrial toxicants, would reduce the intracellular production of reactive oxygen species (ROS) and prevent mitochondrial toxicity from inducing cell death. To do this, we tested in vitro if genetic or pharmacologic inhibition of LRRK2 (MLi2) protected against ROS caused by four toxicants associated with PD risk - rotenone, paraquat, TCE, and tetrachloroethylene (PERC). In parallel, we assessed if LRRK2 inhibition with MLi2 could protect against TCE-induced toxicity in vivo, in a follow up study from our observation that TCE elevated LRRK2 kinase activity in the nigrostriatal tract of rats prior to dopaminergic neurodegeneration. We found that LRRK2 inhibition blocked toxicant-induced ROS and promoted mitophagy in vitro, and protected against dopaminergic neurodegeneration, neuroinflammation, and mitochondrial damage caused by TCE in vivo. We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant-induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.

Treatment Perception and Utilization of Dental Care During Pregnancy Among Women Visiting Antenatal Clinics in King Abdulaziz Medical City & Primary Healthcare, National Guard, Jeddah, Saudi Arabia.

Objectives To identify how readily accessible dental care is to a sample of pregnant women in King Abdulaziz Medical City (KAMC), Jeddah, and to determine any potential obstacles to receiving dental care while pregnant. Methodology Female patients visiting antenatal clinics in KAMC in Jeddah, Saudi Arabia were the target group for this cross-sectional study. The age range was limited to childbearing age (18-48 years old). Both pregnant and non-pregnant women were established in obstetrics and gynecology clinics. The pattern of dental service use and attitude toward dental treatment during pregnancy were assessed using a self-administered questionnaire. Other data were gathered, such as demographics, education, employment status, and the number of live births. Results This study included 361 participants in the survey with an 80% response rate. A large proportion of participants was in the age group of 19 to 35 years old (75.07%; p-value < 0.0001), holding undergraduate degrees (58.17%; p-value < 0.0001), housewives (77.56%; p-value < 0.0001), married (99.45%; p-value < 0.0001), non-pregnant women (75.07%; p-value < 0.0001), and have three or more children (42.94%; p-value < 0.0001). About two-thirds of the participants reported using private hospitals for their dental services (65.37%; p-value < 0.0001), while 22.03% (p-value < 0.0001) of the participants reported visiting a dentist in the last six months and 7.2% (p-value < 0.0001) visited a dentist during pregnancy. In terms of awareness questions, 72.02% (p-value < 0.0001) reported that if the mother did not eat well, the baby takes calcium from the mother's teeth, 43.77% (p-value < 0.0001) reported brushing teeth at least three times a day, and 42.94% (p-value < 0.0001) of women reported that they do not have an idea about what they need to do if a pregnant woman needs treatment that requires taking X-rays. Similar patterns were observed in other awareness answers. Conclusion Based on the study's findings, there is a significantly low rate of dental care utilization in the sample of pregnant women. We conclude that educated women are more likely to maintain good oral hygiene and are more satisfied with their oral health. However, a large proportion of participants reported dental problems during their pregnancy. In general, a lack of knowledge about the safety of dental care during pregnancy is the main obstacle to seeking dental care. Limitations The selected sample was from antenatal clinics in KAMC & Primary Healthcare, National Guard, Jeddah, Saudi Arabia. As a result, the findings of this study cannot be applied to the total female population of Jeddah, Saudi Arabia. Because the information was self-reported, which is a common issue with self-administered questionnaires, and because participation in the study was voluntary and participant confidentiality was maintained, there is a low chance that the data may be subject to recall or response bias.

Bioactivity of Myrtus communis from the Montenegro coastline / Bioactividad de Myrtus communis del litoral de Montenegro

Although numerous studies have demonstrated the biomedical potential of Myrtus communis L., (Myrtaceae) data on myrt le from Montenegro are scarce. T o evaluate antioxidant, antimutagenic and antibacterial activity of myrtle methanolic extracts. Antioxidant activity was evaluated by measuring free radicals scavenging activity, reducing power and enzyme inhibition. The strongest scavenging activity was towards DPPH radical ( 2,2 - diphenyl - 1 - picry lhydrazyl) (IC 50 1.69 - 2.25 mg/mL) and superoxide anion (IC 50 0.56 to 0.88 mg/mL), followed by high reducing power (428 - 472 mgAA/g.DE) and inhibition of XOD (IC 50 0.308 - 0.6261mg/mL). Antimutagenic activity was evaluated in reverse mutation assays with Esche richia coli WP2 oxyR mutant IC202 and deficient in the induction of antioxidant enzymes. The myrtle extracts strongly inhibited mutagenesis induced by t - BOOH, reaching 70% at the highest concentration applied. Antimicrobial activity was examined on eight different bacterial strains. Gram - positive bacteria, S. epidermis , S. aureus and M. flavus demonstrated the highest sensitivity towards extracts (MICs 4.5 - 9 mg/mL), but significantly lower towards essential oil (MIC 0.42 - 3.32 mg/mL).

Aunque numerosos estudios han demostrado el potencial biomédico de Myrtus communis L., (Myrtaceae), los datos sobre el mirto de Montenegro son escasos. E valuar la actividad antioxidante, antimutagéni ca y antibacteriana de extractos metanólicos de mirto. La actividad antioxidante se evaluó midiendo la actividad de eliminación de radicales libres, el poder reductor y la inhibición enzimática. La actividad secuestrante más fuerte fue hacia DPPH radical ( IC 50 1.69 - 2.25 mg/mL) y radicales de anión superóxido (IC 50 0.56 a 0.88 mg/mL), seguido de alto poder reductor (428 - 472 m gAA/g.DE) e inhibición de XOD (I C 50 0,308 - 0,6261 mg/m L ). La actividad antimutagénica se evaluó en ensayos de mutación inversa con Esche richia coli WP2 oxyR mutante IC202 y deficiente en la inducción de enzimas antioxidantes. Los extractos de mirto inhibieron fuertemente la mutagénesis inducida por t - BOOH, alcanzando el 70% a la mayor concentración aplicada. La actividad antimicrobiana se examinó en octo cepas bacterianas diferentes. Las bacterias grampositivas, S. epidermis , S. aureus y M. flavus demostraron la sensibilidad más alta hacia los extractos (MIC 4.5 - 9 mg/mL), pero significativamente más baja hacia el aceite esencial (MIC 0.42 - 3 .32 mg/mL). Los resultados muestran la gran perspectiva nutrafarmacéutica de la especie montenegrina Myrtus communis .

Corrigendum to "Anti- E. coli immunoglobulin yolk (IgY): Reduction of pathogen receptors and inflammation factors could be caused by decrease in E. coli load" [Heliyon 9(3) (February 21, 2023) e13876]>.

[This corrects the article DOI: 10.1016/j.heliyon.2023.e13876.].

Novel LDLR Variant in Familial Hypercholesterolemia: NGS-Based Identification, In Silico Characterization, and Pharmacogenetic Insights.

BACKGROUND: Familial Hypercholesterolemia (FH) is a hereditary condition that causes a rise in blood cholesterol throughout a person's life. FH can result in myocardial infarction and even sudden death if not treated. FH is thought to be caused mainly by variants in the gene for the low-density lipoprotein receptor (LDLR). This study aimed to investigate the genetic variants in FH patients, verify their pathogenicity, and comprehend the relationships between genotype and phenotype. Also, review studies assessed the relationship between the LDLR null variants and the reaction to lipid-lowering therapy. METHODS: The study utilised high-throughput next-generation sequencing for genetic screening of FH-associated genes and capillary sequencing for cascade screening. Furthermore, bioinformatic analysis was employed to describe the pathogenic effects of the revealed novel variant on the structural features of the corresponding RNA molecule. RESULTS: We studied the clinical signs of hypercholesterolemia in a Saudi family with three generations of FH. We discovered a novel frameshift variant (c.666_670dup, p.(Asp224Alafs*43) in the LDLR and a known single nucleotide variant (c.9835A > G, p.(Ser3279Gly) in the APOB gene. It is thought that the LDLR variant causes a protein to be prematurely truncated, likely through nonsense-mediated protein decay. The LDLR variant is strongly predicted to be pathogenic in accordance with ACMG guidelines and co-segregated with the FH clinical characteristics of the family. This LDLR variant exhibited severe clinical FH phenotypes and was restricted to the LDLR protein's ligand-binding domain. According to computational functional characterization, this LDLR variant was predicted to change the free energy dynamics of the RNA molecule, thereby affecting its stability. This frameshift variant is thought to eliminate important functional domains in LDLR that are required for receptor recycling and LDL particle binding. We provide insight into how FH patients with a null variant in the LDLR gene respond to lipid-lowering therapy. CONCLUSIONS: The findings expand the range of FH variants and assist coronary artery disease preventive efforts by improving diagnosis, understanding the genotype-phenotype relationship, prognosis, and personalised therapy for patients with FH.

Low-dose inhalation exposure to trichloroethylene induces dopaminergic neurodegeneration in rodents.

Trichloroethylene (TCE) is one of the most pervasive environmental contaminants in the world and is associated with Parkinson disease (PD) risk. Experimental models in rodents show that TCE is selectively toxic to dopaminergic neurons at high doses of ingestion, however, TCE is a highly volatile toxicant, and the primary pathway of human exposure is inhalation. As TCE is a highly lipophilic, volatile organic contaminant (VOC), inhalation exposure results in rapid diffusion throughout the brain, avoiding first-pass hepatic metabolism that necessitated high doses to recapitulate exposure conditions observed in human populations. We hypothesized that inhalation of TCE would induce significantly more potent neurodegeneration than ingestion and better recapitulate environmental conditions of vapor intrusion or off gassing from liquid TCE. To this end, we developed a novel, whole-body passive exposure inhalation chamber in which we exposed 10-month-old male and female Lewis rats to 50 ppm TCE (time weighted average, TWA) or filtered room air (control) over 8 weeks. In addition, we exposed 12-month-old male and female C57Bl/6 mice to 100 ppm TCE (TWA) or control over 12 weeks. Both rats and mice exposed to chronic TCE inhalation showed significant degeneration of nigrostriatal dopaminergic neurons as well as motor and gait impairments. TCE exposure also induced accumulation of pSer129-αSyn in dopaminergic neurons as well as microglial activation within the substantia nigra of rats. Collectively, these data indicate that TCE inhalation causes highly potent dopaminergic neurodegeneration and recapitulates some of the observed neuropathology associated with PD, providing a future platform for insight into the mechanisms and environmental conditions that influence PD risk from TCE exposure.

Flexural Properties in Edgewise Bending of LVL Reinforced with Woven Carbon Fibers.

This paper presents the results of experimental testing of the bending strength and modulus of elasticity in edgewise bending of unreinforced and reinforced seven-layer LVL (laminated veneer lumber) poplar veneer panels. The aim of the research is to determine the influence of woven carbon fibers on the improvement of the bending properties and modulus of elasticity of LVL bending in the plane of the plate, as well as the influence of adhesives on the bending properties of the composite product, in order to test the potential of using this newly obtained material as a structural element. Bending was performed on small-scale samples. The main research task is the examination of three types of reinforcement, which differ from each other in position, orientation, and number of layers of reinforcement, using two different types of adhesives: epoxy adhesive and Melamine Urea Formaldehyde Resins (MUF). The composite material was produced in four different combinations in relation to the orientation and position of the reinforcement in the layup. The applied reinforcement is defined through three different configurations (EK1, EK2, and EK3) and a fourth control sample (EK4). Each configuration was produced by applying the two previously mentioned types of adhesives. The research findings showed that in the case of samples produced by applying CFRP (carbon fiber reinforced polymer) using epoxy adhesive, it significantly affected the increase in bending strength and flexural modulus of elasticity. The average improvement in bending strength is 32.9%, 33.2%, and 38.7%, i.e., the flexural modulus of elasticity is 54.1%, 50.7%, and 54.7%, respectively, for configurations EK1, EK2, and EK3, compared to control sample EK4. During the testing, the test samples from reinforced panels EK1 and EK2 showed partly plastic behavior up to the fracture point, while the diagram for the test samples from reinforced panels EK3 shows elastic behavior to a considerable extent, with a significantly smaller plastic behavior zone. This research proved the impossibility of using melamine-urea formaldehyde adhesive to form a composite product based on veneer and carbon fabric. The greatest contribution of this work is the experimentally verified and confirmed result of the possibility of applying poplar veneer to design structural elements in LVL using epoxy adhesive.

Anti-E. coli Immunoglobulin Yolk (IgY): Reduction of pathogen receptors and inflammation factors could be caused by decrease in E. coli load.

Graft versus host disease (GVHD) remains the major cause of morbidity and mortality after allogeneic stem cell transplantation, especially for intestinal GVHD, as steroid resistant GVHD results in high mortality. For this reason, new treatments of GVHD are needed. One approach is the reduction of pathogenic bacteria using anti-E. coli Immunoglobulin Yolk (IgY). In a haploidentical murine model, B6D2F1 mice conditioned with total body irradiation (TBI), received bone marrow cells (BM) and splenocytes (SC) from either syngeneic (Syn = B6D2F1) or allogeneic (Allo = C57BL/6) donors. Following this, animals received from day -2 until day +28 chow contained IgY or control chow. Thereafter the incidence and severity of aGVHD, the cytokines, chemokines, IDO1 and different pathogen-recognition receptors (PRR) were analyzed and compared to control animals (received chow without IgY). We found that animals receiving chow with IgY antibody showed reduced GVHD severity compared to control animals. On day28 after alloBMT, IDO, NOD2, TLR2, TLR4 and the inflammatory chemokine CCL3, were reduced in the colon and correlated with a significant decrease in E. coli bacteria. In summary chow containing chicken antibodies (IgY) improved GVHD via decrease in bacterial load of E coli conducting to reduction of pathogen receptors (NOD2, TLR2 and 4), IDO, chemokines and cytokines.

The rate of microtubule breaking increases exponentially with curvature.

Microtubules, cylindrical assemblies of tubulin proteins with a 25 nm diameter and micrometer lengths, are a central part of the cytoskeleton and also serve as building blocks for nanobiodevices. Microtubule breaking can result from the activity of severing enzymes and mechanical stress. Breaking can lead to a loss of structural integrity, or an increase in the numbers of microtubules. We observed breaking of taxol-stabilized microtubules in a gliding motility assay where microtubules are propelled by surface-adhered kinesin-1 motor proteins. We find that over 95% of all breaking events are associated with the strong bending following pinning events (where the leading tip of the microtubule becomes stuck). Furthermore, the breaking rate increased exponentially with increasing curvature. These observations are explained by a model accounting for the complex mechanochemistry of a microtubule. The presence of severing enzymes is not required to observe breaking at rates comparable to those measured previously in cells.

Oral ingestion of the environmental toxicant trichloroethylene in rats induces alterations in the gut microbiome: Relevance to idiopathic Parkinson's disease.

Microbial alterations within the gut microbiome appear to be a common feature of individuals with Parkinson's disease (PD), providing further evidence for the role of the gut-brain axis in PD development. As a major site of contact with the environment, questions have emerged surrounding the cause and effect of alterations to the gut microbiome by environmental contaminants associated with PD risk, such as pesticides, metals, and organic solvents. Recent data from our lab shows that ingestion of the industrial byproduct and environmental pollutant trichloroethylene (TCE) induces key Parkinsonian pathology within aged rats, including the degeneration of dopaminergic neurons, α-synuclein accumulation, neuroinflammation, and endolysosomal deficits. As TCE is the most common organic contaminant within drinking water, we postulated that ingestion of TCE associated with PD-related neurodegeneration may alter the gut microbiome to a similar extent as observed in persons with PD. To assess this, we collected fecal samples from adult rats treated with 200 mg/kg TCE over 6 weeks via oral gavage - the dose that produced nigrostriatal neurodegeneration - and analyzed the gut microbiome via whole genome shotgun sequencing. Our results showed changes in gut microorganisms reflective of the microbial signatures observed in individuals with idiopathic PD, such as decreased abundance of short-chain fatty acid producing Blautia and elevated lactic-acid producing Bifidobacteria, as well as genera who contain species previously reported as opportunistic pathogens such as Clostridium. From these experimental data, we postulate that TCE exposure within contaminated drinking water could induce alterations of the gut microbiome that contributes to chronic disease risk, including idiopathic PD.

Coronary Artery Disease: Association Study of 5 Loci with Angiographic Indices of Disease Severity.

BACKGROUND: Different common gene variants were related to coronary artery disease (CAD) in many studies. Yet, the relation of these loci to the severity of CAD is not completely elucidated. METHODS: We enrolled 520 subjects (315 CAD cases and 205 controls). CAD presence and extension were assessed by coronary angiography (CAG). Genotyping of five SNPs (namely, rs2230806 (1051G > A) in ABCA1 on chromosome 9, rs2075291 (553G > T) in ApoA5 on chromosome 11, rs320 in LPL on chromosome 8 intron (T → G at position 481), rs10757278 (c.22114477A > G), and rs2383206 (c.22115026 A > G) on chromosome 9p21 locus) was performed by allele-specific PCR. The degree and site of arterial lesions were used to classify patients, tested for association with CAD severity, and related to allele dosage. RESULTS: The polymorphisms rs2383206 and rs10757278 showed significant associations with 2- and 3-vessel coronary disease (p =0.003 and 0.006, respectively). The homozygous GG genotypes of rs10757278 was associated with higher frequency of left anterior descending (LAD), right coronary artery (RCA) and left circumflex (LCX) diseases (p =0.002, 0.016 and 0.002, respectively). The GG genotypes of rs2383206 were found in higher percentage in patients with left main (LM) trunk and left circumflex (LCX) diseases (p = 0.013 and 0.002, respectively). CONCLUSION: SNPs rs10757278 and rs2383206 allele dosage could predict CAD severity in the Saudi Arab population.

Compound A Increases Cell Infiltration in Target Organs of Acute Graft-versus-Host Disease (aGVHD) in a Mouse Model.

Systemic steroids are used to treat acute graft-versus-host disease (aGVHD) caused by allogenic bone marrow transplantation (allo-BMT); however, their prolonged use results in complications. Hence, new agents for treating aGVHD are required. Recently, a new compound A (CpdA), with anti-inflammatory activity and reduced side effects compared to steroids, has been identified. Here, we aimed to determine whether CpdA can improve the outcome of aGVHD when administered after transplantation in a mouse model (C57BL/6 in B6D2F1). After conditioning with 9Gy total body irradiation, mice were infused with bone marrow (BM) cells and splenocytes from either syngeneic (B6D2F1) or allogeneic (C57BL/6) donors. The animals were subsequently treated (3 days/week) with 7.5 mg/kg CpdA from day +15 to day +28; the controls received 0.9% NaCl. Thereafter, the incidence and severity of aGVHD in aGVHD target organs were analyzed. Survival and clinical scores did not differ significantly; however, CpdA-treated animals showed high cell infiltration in the target organs. In bulk mixed lymphocyte reactions, CpdA treatment reduced the cell proliferation and expression of inflammatory cytokines and chemokines compared to controls, whereas levels of TNF, IL-23, chemokines, and chemokine receptors increased. CpdA significantly reduced proliferation in vitro but increased T cell infiltration in target organs.

Targeted next-generation sequencing reveals novel and known variants of thrombophilia associated genes in Saudi patients with venous thromboembolism.

BACKGROUND: Thrombophilia is a substantial source of indisposition and mortality in several countries, including Arab populations. Deep venous thrombosis (DVT) with or without pulmonary embolism (PE) is the prevalent clinical manifestation of thrombophilia. While many genetic risk factors for DVT are known, almost all associated with hemostasis, many genetic factors remain unexplained. Nowadays, Next Generation Sequencing (NGS) offers a potential solution that allows several candidate genes to be analyzed simultaneously at a reasonable expense. METHODS: We performed variant screening in the thrombophilia associated genes in Factor V Leiden (FVL) mutation-negative patients using Ion Torrent Next-generation sequencing (NGS). Ion AmpliSeq panel for 18 genes was designed. Twenty-nine unrelated patients with idiopathic VTE were recruited for NGS. RESULTS: We were able to identify 19 variants (1 novel and 18 previously reported) in 10 out of 18 targeted genes. Pathogenic variants were identified in 22 patients demonstrating mutation detection rates of 76%. Previously reported variants in the F5, MTHFR, PROS1, PROC, F8, F9, SERPINA10, SERPIND1, and HRG genes were recognized in 21 patients. More than one variant in the targeted genes was detected in some of the patients with VTE. We identified SERPINA10 recurrent variant p.(R88*) in seven patients representing 32% of VTE cases. Additionally, we report one novel variant c.356G > T, p.(G119V) in the F7 gene, considered to be pathogenic in this study. CONCLUSIONS: Our studies finding illustrates the ability of targeted next-generation sequencing to uncover uncommon/unknown genetic variants that may predispose to thrombophilia. The finding of the novel variant in the F7 gene extends the spectrum of variants affecting thrombosis. While a comparatively small number of subjects have been included in our cohort, the findings summarize the possible genetic features of thrombophilia.

Early decreases in cortical mid-gamma peaks coincide with the onset of motor deficits and precede exaggerated beta build-up in rat models for Parkinson's disease.

Evidence suggests that exaggerated beta range local field potentials (LFP) in basal ganglia-thalamocortical circuits constitute an important biomarker for feedback for deep brain stimulation in Parkinson's disease patients, although the role of this phenomenon in triggering parkinsonian motor symptoms remains unclear. A useful model for probing the causal role of motor circuit LFP synchronization in motor dysfunction is the unilateral dopamine cell-lesioned rat, which shows dramatic motor deficits walking contralaterally to the lesion but can walk steadily ipsilaterally on a circular treadmill. Within hours after 6-OHDA injection, rats show marked deficits in ipsilateral walking with early loss of significant motor cortex (MCx) LFP peaks in the mid-gamma 41-45 Hz range in the lesioned hemisphere; both effects were reversed by dopamine agonist administration. Increases in MCx and substantia nigra pars reticulata (SNpr) coherence and LFP power in the 29-40 Hz range emerged more gradually over 7 days, although without further progression of walking deficits. Twice-daily chronic dopamine antagonist treatment induced rapid onset of catalepsy and also reduced MCx 41-45 Hz LFP activity at 1 h, with increases in MCx and SNpr 29-40 Hz power/coherence emerging over 7 days, as assessed during periods of walking before the morning treatments. Thus, increases in high beta power in these parkinsonian models emerge gradually and are not linearly correlated with motor deficits. Earlier changes in cortical circuits, reflected in the rapid decreases in MCx LFP mid-gamma LFP activity, may contribute to evolving plasticity supporting increased beta range synchronized activity in basal ganglia-thalamocortical circuits after loss of dopamine receptor stimulation.

Next Generation Exome Sequencing of Pediatric Asthma Identifies Rare and Novel Variants in Candidate Genes.

Multiple genes have been implicated to have a role in asthma predisposition by association studies. Pediatric patients often manifest a more extensive form of this disease and a particularly severe disease course. It is likely that genetic predisposition could play a more substantial role in this group. This study is aimed at identifying the spectrum of rare and novel variation in known pediatric asthma susceptibility genes using whole exome sequencing analysis in nine individual cases of childhood onset allergic asthma. DNA samples from the nine children with a history of bronchial asthma diagnosis underwent whole exome sequencing on Ion Proton. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. The analysis showed 21 variants in the subjects, 13 had been previously identified, and 8 were novel. Also, among of which, nineteen were nonsynonymous and 2 were nonsense. With regard to the novel variants, the 2 nonsynonymous variants in the PRKG1 gene (PRKG1: p.C519W and PRKG1: p.G520W) were presented in 4 cases, and a nonsynonymous variant in the MAVS gene (MAVS: p.A45V) was identified in 3 cases. The variants we found in this study will enrich the variant spectrum and build up the database in the Saudi population. Novel eight variants were identified in the study which provides more evidence in the genetic susceptibility in asthma among Saudi children, providing a genetic screening map for the molecular genetic determinants of allergic disease in Saudi children, with the goal of reducing the impact of chronic diseases on the health and the economy. We believe that the advanced specified statistical filtration/annotation programs used in this study succeeded to release such results in a preliminary study, exploring the genetic map of that disease in Saudi children.

Strategies for Vaccination: Conventional Vaccine Approaches Versus New-Generation Strategies in Combination with Adjuvants.

The current COVID-19 pandemic, caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), has raised significant economic, social, and psychological concerns. The rapid spread of the virus, coupled with the absence of vaccines and antiviral treatments for SARS-CoV-2, has galvanized a major global endeavor to develop effective vaccines. Within a matter of just a few months of the initial outbreak, research teams worldwide, adopting a range of different strategies, embarked on a quest to develop effective vaccine that could be effectively used to suppress this virulent pathogen. In this review, we describe conventional approaches to vaccine development, including strategies employing proteins, peptides, and attenuated or inactivated pathogens in combination with adjuvants (including genetic adjuvants). We also present details of the novel strategies that were adopted by different research groups to successfully transfer recombinantly expressed antigens while using viral vectors (adenoviral and retroviral) and non-viral delivery systems, and how recently developed methods have been applied in order to produce vaccines that are based on mRNA, self-amplifying RNA (saRNA), and trans-amplifying RNA (taRNA). Moreover, we discuss the methods that are being used to enhance mRNA stability and protein production, the advantages and disadvantages of different methods, and the challenges that are encountered during the development of effective vaccines.

Assessment of genetic polymorphism associated with ATP-binding cassette transporter A1 (ABCA1) gene and fluctuations in serum lipid profile levels in patients with coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is one of the common genetic and clinical risk factors associated with cardiovascular and multifactorial disorder. ATP-binding cassette transporter A1 (ABCA1) gene plays an important role in lipid metabolism and in multiple studies associated with CAD. However, more studies are needed to identify the exact role of single nucleotide polymorphisms which may cause CAD. OBJECTIVES: The aim of this study is to investigate the genetic association of polymorphism g.1051G > A in the ABCA1 gene with CAD patients in the Saudi population. METHODS: We included 315 confirmed CAD cases, and 205 non-CAD or control subjects in this case-control study. DNA isolation was carried out for all registered participants and the polymorphism g.1051G > A was genotyped with Polymerase Chain Reaction followed by Restriction Fragment Length Polymorphism analysis with EcoNI restriction enzyme. RESULTS: Modifiable risk factors such as Body Mass Index, smoking and diabetes were strongly associated and non-modifiable risk factors such as hypertension (Systolic Blood Pressure and Diastolic Blood Pressure) and serum analysis such as Fasting Blood Glucose, Total cholesterol (TC), Triglyceride (TG) and LDL-c were significantly associated in CAD cases (p < 0.05). Allele (OR-1.73;95% CI:1.33-2.26; p = 0.0004), GA vs GG (OR-2.26; 95% CI: 1.53-3.35; p = 0.0003 and dominant inheritance pattern (OR-2.23; 95% CI:1.56-3.20; p = 0.00009 was strongly associated with CAD cases and control subjects. The frequency level of use of atorvastatin was significantly different among GG, GA and AA subjects. Additionally, TC and TG levels were influenced by the presence of g.1051G > A polymorphism. CONCLUSION: The polymorphism g.1051G > A in the gene ABCA1 is closely associated with the existence of the CAD subjects. This polymorphism could also affect the serum levels of the lipid profile, suggesting a possible occurrence of CAD in the Saudi population.

EGFRvIII expression and isocitrate dehydrogenase mutations in patients with glioma.

Molecular pathology and personalized medicine are still being evolved in Saudi Arabia, and genetic testing for the detection of mutations as cancer markers have not been established in the diagnostics laboratories in Saudi Arabia. The aim of the present study was to determine the prevalence of isocitrate dehydrogenase (IDH1 and IDH2) mutations and epidermal growth factor receptor variant (EGFRv)III transcript expression in Saudi Arabian patients with glioma. Out of 117 brain tumors tested by reverse transcription-quantitative PCR for EGFRvIII, 41 cases tested positive. In the glioblastoma (GBM) category, 28/55 tumors were positive, in astrocytoma tumors 5/22, and in oligodendrogliomas 4/13 cases were positive respectively. EGFRvIII transcript was sequenced by capillary electrophoresis to demonstrate the presence of EGFRvIII-specific junction where exons 2-7 were deleted. In the present study 106 tumors were sequenced for IDH1 exon-4 mutations using the capillary sequencing method. The most common substitution missense mutation c.395G>A was found in 16 tumors. In the case of adamantinomatous craniopharyngioma, a novel missense mutation in c.472C>T was detected in IDH2 gene. Using next-generation sequencing (NGS), 74 tumors were sequenced for the IDH1 gene, and a total of 8 missense variants were identified in 36 tumors in a population of Saudi Arabia. The missense mutation (c.395G>A) was detected in 29/36 of tumors. A novel intronic mutation in c.414+9T>A was found in 13 cases in the IDH1 gene. In addition, one case exhibited a novel synonymous mutation in c.369A>G. Eleven tumors were found to have compound mutations in the IDH1 gene. In IDH2 gene, out of a total of 16 variants found in 6 out of 45 tumors, nine were missense, five were synonymous and one was intronic. This is the first report from Saudi Arabian laboratories analyzing glioma tumors for EGFRvIII expression, and the first study from Saudi Arabia to analyze IDH mutations in gliomas using the capillary and NGS methods.