45 research outputs found
DFT Study on the Binding of Selected Metal Ions with Phenylalanine Dipeptide, 2019
No full textIn this study, M06-2X/6-311+G(2d,2p) level calculations were performed to examine the binding energies and vibrational frequencies of different conformers of phenylalanine dipeptide interacting with metal ions (Na+, K+, Mg2+ and Ca2+). Four conformers were selected from the list of 20 most stable structures. The main goal was to understand the influence of conformers on the binding affinity of metal ions with different conformers of phenylalanine dipeptide. In agreement with experimental results, interactions of metal ions with two aromatic rings along with lone pair electrons of oxygen produced high stability. Binding energy was lowest for the metal ion interacting with only one aromatic ring. This study revealed the binding affinity order of metal ions Mg2+ > Ca2+ > Na+ > K+ with any of the conformers considered for phenylalanine dipeptide. KEYWORDS: Biochemistry, Physical Chemistr
Assessing The Impact of Oil Price Fluctuations on The Saudi Economy, and Monetary Policy Uncertainty Shocks
No full textThis dissertation seeks to provide a theoretical analysis and overview of the Saudi economy from the 1970s to 2021, then investigates the impact of oil price instability on Saudi’s macroeconomic variables in the first chapter, describes the determinants of monetary policy in Saudi Arabia, especially under uncertainty in the second chapter, and finally assesses The Saudi 2030 Vision by examining the link between the government expenditure, fixed capital formation, and non-Oil GDP. The first two studies utilize The Vector Autoregressive Model (VAR) and the Vector Error Correction Model (VECM) while the third study applied The Autoregressive Distributed Lag Model (ARDL) in addition to the VAR model. The first chapter in this dissertation empirically investigates the effect of oil price fluctuations on several key macroeconomic indicators. Results of the first chapter show that oil prices have an insignificant impact on money supply and inflation except that there is a significant positive impact of oil price fluctuations on government expenditure during the short term. Moreover, IRF results indicate that there is a positive effect of oil price shock on inflation, but the magnitude of response is very slight. However, oil price shocks have a notable positive impact on government expenditure. Similarly, the money supply interacts with the shocks in the oil price, but the magnitude of response is smaller compared with the government expenditure. The second chapter in this dissertation explores whether changes in Saudi interest rate are related to political risks or other variables such as oil prices, money supply, GDP, and US interest rates. The results indicate that the GDP has the most significant negative effect on the Saudi interest rate. The results also suggest that there is an inverse relationship between geopolitical risk and the interest rate, and the response of the Saudi interest rate to its shocks is highly significant compared with other variables. When we extended the model by including the US interest rate, we obtained similar results. The third chapter in this dissertation assesses how The Vision 2030 scheme has contributed to boosting the non-oil GDP by supporting non-oil sectors. The results show that in the short term gross fixed capital formation has a positive impact on the non-oil GDP, while the first lag of government growth expenditure has a negative impact on non-oil. However. in the long term, the results reveal that government growth expenditure and gross fixed capital formation do not have statistically significant effects on non-oil GDP.Embargo status: Restricted to TTU community only. To view, login with your eRaider (top right). Others may request the author grant access exception by clicking on the PDF link to the left
Factors that influence a patient’s decision to engage in genetic research
No full textIntroductionThe most challenging step in clinical research studies is patient recruitment. Many research studies do not reach their targets because of participant rejection. The purpose of this study was to assess patient as well as the community knowledge, motivation, and barriers to participate in genetic research.MethodsA cross-section study was conducted between September 2018 and February 2020 using face-to-face interviews with candidate patients from outpatient clinics at King Fahad Medical City (KFMC), Riyadh, Saudi Arabia. Additionally, an online survey was conducted to assess the community’s knowledge, motivation and barriers to participate in genetic research studies.ResultsIn total, 470 patients were interviewed for this study, with 341 being successfully recruited for the face to face interview, and the other patients being refused owing to time constraints. The majority percentage of the respondents were females. The respondents’ mean age was 30, and 52.6% reported having a college degree. The survey results from 388 participants illustrated that around 90% of the participants, participated voluntarily due to a good understanding of genetics studies. The majority held positive attitudes toward being part of genetic research, which exceeded the reported motivation score of >75%. The survey indicated that >90% of individuals were willing to participate to acquire therapeutic benefits or to receive continued aftercare. However, 54.6% of survey participants were worried about the side effects and the risks involved in genetic testing. A higher proportion (71.4%) of respondents reported that lack of knowledge about genetic research was one of the barriers to rejecting participation.ConclusionRespondents reported relatively high motivation and knowledge for participation in genetic research. However, study participants reported “do not know enough about genetic research” and “lack of time during clinic visit” as a barrier for participation in genetic research
SLMAP-3 is downregulated in human dilated ventricles and its overexpression promotes cardiomyocyte response to adrenergic stimuli by increasing intracellular calcium
No full textStructural dilation of cardiomyocytes (CMs) imposes a decline in cardiac performance that precipitates cardiac failure and sudden death. Since membrane proteins are implicated in dilated cardiomyopathy and heart failure, we evaluated the expression of the sarcolemmal membrane-associated protein (SLMAP) in dilated cardiomyopathy and its effect on CM contraction. We found that all three SLMAP isoforms (SLMAP-1, -2, and -3) are expressed in CMs and are downregulated in human dilated ventricles. Knockdown (KD) of SLMAPs in cultured CMs transduced with recombinant adeno-associated viral particles (AAV) releasing SLMAP-shRNA precipitated reduced spontaneous contractile rate that was not fully recovered in SLMAP-depleted CMs challenged with isoproterenol (ISO), thus phenotypically mimicking heart failure performance. Interestingly, the overexpression (OE) of the SLMAP-3 full-length isoform induced a positive chronotropic effect in CMs that was more pronounced in response to ISO insult (vs. ISO-treated naĂŻve CMs). Confocal live imaging showed that H9c2 cardiac myoblasts overexpressing SLMAP-3 exhibit a higher intracellular calcium transient peak when treated with ISO (vs. ISO-treated cells carrying a control AAV). Proteomics revealed that SLMAP-3 interacts with the regulator of CM contraction, striatin. Collectively, our data demonstrate that SLMAP-3 is a novel regulator of CM contraction rate and their response to adrenergic stimuli. Loss of SLMAPs phenotypically mimics cardiac failure and crystallizes SLMAPs as predictive of dilated cardiomyopathy and heart failure.The presentation of the authors' names and (or) special characters in the title of the pdf file of the accepted manuscript may differ slightly from what is displayed on the item page. The information in the pdf file of the accepted manuscript reflects the original submission by the author
Cardiac striatin interacts with caveolin-3 and calmodulin in a calcium sensitive manner and regulates cardiomyocyte spontaneous contraction rate.
No full textImpaired cardiomyocyte contraction rate is detrimental to cardiac function and often lethal. Despite the advancement in the field, there is a paucity of information regarding the coordination of molecules implicated in regulating the heart rate. Striatin (STRN) is a dynamic protein with binding domains to calmodulin (CaM) and caveolin (Cav), both of which are regulators of myocardial function. However, its role in cardiomyocyte contraction is not yet determined. Herein, we show that STRN is expressed in cardiomyocytes and it is more abundant in atrial myocardium than in ventricles. Cardiac expression of STRN (protein and mRNA) was developmentally regulated with the highest expression being at neonatal stage (day-one) and the lowest in adult rats (13 weeks). CaM pull down assay indicated that the interaction of cardiac STRN with CaM and caveolin-3 (Cav-3) was calcium sensitive. Interestingly, the overexpression of STRN induced an increase (~2 folds) in the rate of the spontaneous contraction of cultured cardiomyocytes while the knockdown of STRN reduced their contraction rate (~40%). The expression level of STRN was inversely proportional to the interaction of Cav-3 with the CaM/STRN complex. Collectively, our data delineate a novel role for STRN in regulating cardiomyocyte spontaneous contraction rate and the dynamics of the STRN/Cav-3/CaM complex.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author
Design of biologically active macromolecules based on ferrocene and arene complexes
No full textIn this research, a series of novel organoiron compounds, polymers, and dendrimers based on three different moieties of biologically active molecules were synthesized using various synthetic approaches and their antimicrobial and cytotoxic activities were evaluated in vitro. The structures were confirmed through spectral data and elemental analysis. The antimicrobial activity of the compounds (4-27) was investigated and tested against several human pathogens: Gram-positive, Gram-negative bacteria, fungi, and mycobacterium using agar well diffusion method. Minimum inhibitory concentrations were reported against each pathogen. Cationic organoiron complexes (16-27) showed significantly potent antimicrobial activity against Gram-positive bacterial compared to reference drugs. Moreover, the cytotoxic activity was also evaluated against HEPG-2, (A549), and MCF-7 cell lines.The compounds exhibited good activity against these cell lines compared to the reference drug. The toxicity of these cationic complexes against human foreskin BJ fibroblast cells was evaluated. A variety of novel functionalized polymers with chromene moieties (29-33) were prepared via nucleophilic aromatic substitution reaction. The structures were confirmed by their spectral data, and the molecular weight was determined by viscosity method. The electrochemical properties, scanning electron microscopy, and thermal stability of the synthesized polymers were studied. All polymers displayed good thermal stability in the range (260-330˚C) following the degradation of the cationic iron moieties. The metal-containing polymers displayed redox activity due to the presence of the iron centres. The antimicrobial activity of these polymeric materials was investigated and tested against five human pathogen Gram-positive and Gram-negative bacteria. Some newly prepared polymeric materials exhibited antimicrobial activity against Gram-positive bacteria compared to reference drugs. The toxicity of these functionalized polymers against human foreskin BJ fibroblast cells, HTB-26, HCT-116, and MCF-7 was evaluated. Sixteen different dendrimers (1-16) containing well-known drugs, paracetamol, and ibuprofen were synthesized via nucloephilic aromatic substitution and addition reactions. The electrochemical properties, scanning electron microscopy, and thermal stability of the dendrimers were studied. All synthesized macromolecular complexes displayed good thermal stability in the range of (250-920˚C). The metal-containing complexes displayed redox activity due to the presence of the iron centres. All newly synthesized dendrimers were tested for in vitro antimicrobial and cytotoxicity activities. Most of the new tested compounds exhibited significant potent antimicrobial activities against Gram-positive bacterial strains compared to reference drugs
Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.
No full textHost genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights
SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues
No full textVariability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types. © 2021 The Author(s
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Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.
No full textHost genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights
Whole-genome sequencing reveals host factors underlying critical COVID-19
No full text: Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
