Drug-resistant HIV-1 protease regains functional dynamics through cleavage site coevolution

Drug resistance is caused by mutations that change the balance of recognition favoring substrate cleavage over inhibitor binding. Here, a structural dynamics perspective of the regained wild-type functioning in mutant HIV-1 proteases with coevolution of the natural substrates is provided. The collective dynamics of mutant structures of the protease bound to p1-p6 and NC-p1 substrates are assessed using the Anisotropic Network Model (ANM). The drug-induced protease mutations perturb the mechanistically crucial hinge axes that involve key sites for substrate binding and dimerization and mainly coordinate the intrinsic dynamics. Yet with substrate coevolution, while the wild-type dynamic behavior is restored in both p1-p6 ((LP) (1\u27F)p1-p6D30N/N88D) and NC-p1 ((AP) (2) (V)NC-p1V82A) bound proteases, the dynamic behavior of the NC-p1 bound protease variants (NC-p1V82A and (AP) (2) (V)NC-p1V82A) rather resemble those of the proteases bound to the other substrates, which is consistent with experimental studies. The orientational variations of residue fluctuations along the hinge axes in mutant structures justify the existence of coevolution in p1-p6 and NC-p1 substrates, that is, the dynamic behavior of hinge residues should contribute to the interdependent nature of substrate recognition. Overall, this study aids in the understanding of the structural dynamics basis of drug resistance and evolutionary optimization in the HIV-1 protease system

Deciphering Drought Response Mechanisms: Transcriptomic Insights from Drought-Tolerant and Drought-Sensitive Wheat (Triticum aestivum L.) Cultivars

Drought stress poses a significant threat to wheat (Triticum aestivum L.) cultivation, necessitating an in-depth understanding of the molecular mechanisms underpinning drought response in both tolerant and sensitive varieties. In this study, 12 diverse bread wheat cultivars were evaluated for their drought stress responses, with particular emphasis on the contrasting performance of cultivars Atay 85 (sensitive), Gerek 79, and Mufitbey (tolerant). Transcriptomic analysis was performed on the root and leaf tissues of the aforementioned cultivars subjected to 4-hour and 8-hour drought stress and compared with controls. Differentially expressed genes (DEGs) were categorized based on their cellular component, molecular function, and biological function. Notably, there was greater gene expression variability in leaf tissues compared to root tissues. A noticeable trend of decreased gene expression was observed for cellular processes such as protein refolding and cellular metabolic processes like photorespiration as drought stress duration increased (8 hours) in the leaf tissues of drought-tolerant and sensitive cultivars. Metabolic processes related to gene expression were predominantly activated in response to 4-hour and 8-hour drought stress. The drought-tolerant cultivars exhibited increased expression levels of genes related to protein binding, metabolic processes, and cellular functions, indicating their ability to adapt better to drought stress compared to the drought-sensitive cultivar Atay 85. We detected more than 25 differentially expressed TFs in leaf tissues under 4-hour and 8-hour drought stress, while only 4 TFs were identified in the root tissues of sensitive cultivar. In contrast, the tolerant cultivar exhibited more than 80 different TF transcripts in both leaves and roots after 4 hours of drought stress, with this number decreasing to 18 after 8 hours of drought stress. Differentially expressed genes with a focus on metal ion binding, carbohydrate degradation, ABA-related genes, and cell wall-related genes were highlighted. Ferritin (TaFer), TaPME42 and Extensin-like protein (TaExLP), Germin-like protein (TaGLP 9-1), Metacaspase-5 (TaMC5), Arogenate Dehydratase 5 (ADT-5), Phosphoglycerate/ bisphosphoglycerate mutase (TaPGM), Serine/threonine protein phosphatase 2A (TaPP2A), GIGANTEA (TaGI), Polyadenylate-binding protein (TaRBP45B) exhibited differential expression by qRT-PCR in root and leaf tissues of tolerant and sensitive bread wheat cultivars. This study provides valuable insights into the complex molecular mechanisms associated with drought response in wheat, highlighting genes and pathways involved in drought tolerance. Understanding these mechanisms is essential for developing drought-tolerant wheat varieties, enhancing agricultural sustainability, and addressing the challenges posed by water scarcity

Analysis of epidemics of vancomycin-resistant Enterococci in Turkey

The first cases with vancomycin-resistant Enterococci (VRE) isolation were reported in 1988 throughout the world, and in 1998 in Turkey. The number of the papers conducted on cases or epidemics in which VRE was isolated is in increase. In this study, it was aimed to evaluate some studies at this topic. In conclusion, it was observed that the VRE strains isolated in the same clinic within a short period had a high probability to be the same clone, that there was need for extra investigation for teicoplanin resistance in VRE strains in terms of vanB expression, that VRE colonisation was more common in patients with long term intensive care unit stay, and that eradication of VRE could be made with more strict precautions in comparison to other epidemic bacteria

Substrate specificity in HIV-1 protease by a biased sequence search method

Drug resistance in HIV-1 protease can also occasionally confer a change in the substrate specificity. Through the use of computational techniques, a relationship can be determined between the substrate sequence and three-dimensional structure of HIV-1 protease, and be utilized to predict substrate specificity. In this study, we introduce a biased sequence search threading (BSST) methodology to analyze the preferences of substrate positions and correlations between them that might also identify which positions within known substrates can likely tolerate sequence variability and which cannot. The potential sequence space was efficiently explored using a low-resolution knowledge-based scoring function. The low-energy substrate sequences generated by the biased search are correlated with the natural substrates. Octameric sequences were predicted using the probabilities of residue positions in the sequences generated by BSST in three ways: considering each position in the substrate independently, considering pairwise interdependency, and considering triple-wise interdependency. The prediction of octameric sequences using the triple-wise conditional probabilities produces the most accurate results, reproducing most of the sequences for five of the nine natural substrates and implying that there is a complex interdependence between the different substrate residue positions. This likely reflects that HIV-1 protease recognizes the overall shape of the substrate more than its specific sequence

Determination of antibiotic resistance and high-performance liquid chromatography profiles for Mycobacterium species

BackgroundIncidence of mycobacterial infections has been increasing. However, diagnosis and treatment of mycobacterial infections can be difficult. The aim of this study was to investigate high-performance liquid chromatography (HPLC) analysis of the mycolic acids for rapid identification and dendrogram cluster analysis of mycobacterium species

Reversible Myocarditis and Pericarditis after Black Widow Spider Bite or Kounis Syndrome?

Clinical manifestation of black widow spider bite is variable and occasionally leads to death in rural areas. Cases of myocarditis and pericarditis after black widow spider bite are rare and the associated prognostic significance is unknown. Kounis syndrome has been defined as an acute coronary syndrome in the setting of allergic or hypersensitivity and anaphylactic or anaphylactoid insults that manifests as vasospastic angina or acute myocardial infarction or stent thrombosis. Allergic myocarditis is caused by myocardial inflammation triggered by infectious pathogens, toxic, ischemic, or mechanical injuries, such as drug-related inflammation and other immune reactions. A 15-year-old child was admitted to the emergency department with pulmonary edema after spider bite. ST segment depression on ECG, elevated cardiac enzymes and global left ventricular hypokinesia (with ejection fraction of 22%), and local pericardial effusion findings confirmed the diagnosis of myopericarditis. After heart failure and pulmonary edema oriented medical therapy, clinical status improved. Patient showed a progressive improvement and LV functions returned to normal on the sixth day. Myopericarditis complicating spider bite is rare and sometimes fatal. The mechanism is not clearly known. Alpha-latrotoxin of the black widow spider is mostly convicted in these cases. But allergy or hypersensitivity may play a role in myocardial damage

Effects of Trandolapril on İnsulin Concentrations and other Metabolic Variables in Hypertensive Patients

Effects of trandolapril on insulin concentrations and other metabolic variables in hypertensive patientsAuthor links open overlay panelAdnanGokcelTürkanOzerMehmetAliustaogluTugrulUnatM.Yasar YildirimShow moreShareCitehttps://doi.org/10.1016/S0011-393X(97)80057-4Get rights and contentAbstractThe effects of the angiotensin-converting enzyme inhibitor trandolapril on blood pressure, insulin sensitivity, and other metabolic variables were assessed in this open study of 45 patients (27 women and 18 men; mean age, 53.1 ± 14.0 years; mean body weight, 83.4 ± 12.4 kg) with hypertension (blood pressure &gt;140/90 mm Hg). Fasting and postprandial serum insulin and plasma glucose concentrations were measured daily before and after trandolapril administration (2 to 4 mg/d) for 12 weeks. Systolic and diastolic blood pressures and low-density lipoprotein cholesterol concentration were reduced significantly. Mean fasting insulin concentrations fell from 56.4 ± 38.0 pmol/L to 42.4 ± 28.0 pmol/L, and during an oral glucose tolerance test (OGTT) from 341.6 ± 305.0 pmol/L to 242.7 ± 229.0 pmol/L at 2 hours. The ratio of mean fasting insulin to glucose fell from 0.7 ± 0.4 to 0.5 ± 0.4, and during OGTT the ratio fell from 3.3 ± 2.0 to 2.6 ± 1.7 between 1 and 2 hours. Total cholesterol decreased and high-density lipoprotein cholesterol increased, although neither change was significant. After trandolapril treatment, insulin and glucose concentrations improved. The lack of negative effects of trandolapril on metabolic variables may offer advantages not seen with other anti-hypertensive agents such as beta-blockers and diuretics.Effects of trandolapril on insulin concentrations and other metabolic variables in hypertensive patientsAuthor links open overlay panelAdnanGokcelTürkanOzerMehmetAliustaogluTugrulUnatM.Yasar YildirimShow moreShare<div class="ExportCitation u-display-inline-block" id="export-citation" style="marg

Hiperlipidemide oral glukoz tolerans testi.

&nbsp;Hiperlipidemide Oral Glukoz Tolerans Testi.&nbsp;</div