Current alternatives to traditional radial approach for coronary interventions: A randomized prospective study of the ulnar and distal radial approaches.

BACKGROUND: The radial artery is the standard access for coronary intervention; however, it is essential to have alternative accesses as it may be used as a conduit during coronary artery bypass grafting or for dialysis fistula. Ulnar and distal radial artery accesses have emerged as alternative accesses for traditional radial artery. AIM: To compare distal radial artery access and ulnar artery access as alternatives to traditional radial artery access regarding safety, efficacy, and success rate. METHODS: Two-hundred patients were included (100 traditional radial [TRA], 50 distal radial [DRA] and 50 ulnar). Access artery follow up ultrasound was performed up to 28 days. RESULTS: Procedural success rate was 97%, 74%, and 92% in the TRA, DRA and ulnar groups, respectively (p < 0.001). Crossover occurred in 3 patients (3%) in TRA, 13 patients (26%) in DRA and 4 cases (8%) in ulnar group (p < 0.001). The most common cause of crossover was failure of artery cannulation. Regarding cannulation time, the mean access time in seconds was 80.19 ± 25.98, 148.4 ± 29.60, 90.5 ± 21.84 in TRA, DRA and ulnar groups, respectively (p < 0.001). CONCLUSIONS: Our study concluded that these new approaches proved to be potential alternatives to traditional radial approach; however, ulnar artery access proved to be superior to distal radial artery access as regards success rate and cannulation time.

The Atrial FibriLlatiOn (FLOW-AF) Registry in the Middle East and North Africa: Patient Characteristics, Treatment Patterns and Outcomes.

INTRODUCTION: Limited data on atrial fibrillation (AF) are available from the Middle East and North Africa region (MENA). The aim of the FLOW-AF registry was to evaluate the characteristics, treatment patterns, and clinical and economic outcomes of patients with newly diagnosed non-valvular atrial fibrillation (NVAF) in MENA. METHODS: This multi-center, prospective, observational study (the FLOW-AF registry) enrolled patients newly diagnosed with NVAF across Egypt, Lebanon, Kingdom of Saudi Arabia, and United Arab Emirates. The data collection occurred at enrollment (baseline) and after 6- and 12-months (follow-up). Baseline data included demographics, AF characteristics, medical history, and anti-thrombotic treatment patterns. Clinical events, healthcare resource utilization, and direct costs were collected at follow-up. RESULTS: The study enrolled a total of 1418 patients (52.7% males and 47.3% females). The mean age of the patients was 64.5 years and 90.6% were white. The mean (standard deviation) CHA2DS2-VASc and HAS-BLED risk scores were 2.7 (1.6) and 1.6 (1.2), respectively. Non-vitamin K antagonist oral anticoagulants, antiplatelet therapy, and vitamin K antagonists were prescribed to 65.8%, 16.4%, and 12.9% patients, respectively. During follow-up, the following rates of clinical outcomes were observed: bleeding events (1.7%), transient ischemic attack (1.7%), all-cause mortality (1.7%), stroke (0.6%), myocardial infarction (0.2%), and systemic embolism (0.08%). CONCLUSIONS: This MENA patient population was younger and had lower mean baseline CHA2DS2-VASc and HAS-BLED scores. The rates of clinical outcomes over 1-year in this study were low. Longer follow-up is required to comprehensively assess clinical outcomes in this patient population.

The use of urodynamic to assess the mechanism of incontinence in patients with Yang-Monti based catheterizable cutaneous stomas.

OBJECTIVE: To analyze the static and dynamic urodynamic parameters of reservoirs and continent conduits in continent cutaneous urinary diversion with catheterizable stoma. MATERIALS AND METHODS: 76 patients had augmented ileocystoplasty or continent urinary diversion with catheterizable urinary stoma based on Mitrofanoff principle and Yang-Monti procedure using subserous tunnel as continence mechanism. They were followed up for at least 6 months post-operatively for continence through stoma and divided into two groups (continents vs non-continent) according to stomal continence. Both groups had urodynamic assessment performed via the stoma to assess reservoir capacity, pressure and contractions, efferent limb functional length, reservoir overactivity, static and dynamic maximal closure pressures and leak point pressure. RESULTS: Continence rate was 87%. Continent group included 66 patients and incontinent group included 10 patients. In both groups at rest, the reservoir pressure after filling did not exceed 25 cm H2O. During peristaltic contraction, the pressure did not exceed 30 cm H2O and the duct remained continent. After Valsalva maneuver, the reservoir pressure increased up to 34 (+ 7.4) cm H2O and leakage occur in 10 patients (13%). Reservoir (wall) overactivity was recorded in 54 patients, with insignificant rise in intraluminal pressure during the contractions. In both groups, the efferent tract closing pressure was always higher than the reservoir pressure. The mean of maximal closing pressure at Valsalva was 82.5 (+ 4.18) cm H2O in the continent group and 61.66 (+ 8.16) cm H2O in the incontinent group. The mean functional length of the conduit was 4.95 + 1.62 in the continent group and 2.80 + 1.50 cm in the incontinent group. CONCLUSIONS: Urodynamic evaluation of continent catheterizable cutaneous stoma after Yang-Monti procedure has a practical significance. Functional length of the conduit seems to be the most influential factor for continence reflecting static & dynamic maximal closure pressure. Higher conduit closing pressure is associated with better continence. Contractions of the pouch and peristaltic contraction of the conduit has no effect on continence mechanism.

2-Methoxyestradiol ameliorates doxorubicin-induced cardiotoxicity by regulating the expression of GLUT4 and CPT-1B in female rats.

The clinical usage of doxorubicin (DOX) is hampered due to cardiomyopathy. Studies reveal that estrogen (E2) modulates DOX-induced cardiotoxicity. Yet, the exact mechanism is unclear. The objective of the current study is to evaluate the influence of E2 and more specifically its metabolite 2-methoxyestradiol (2ME) on cardiac remodeling and the reprogramming of cardiac metabolism in rats subjected to DOX cardiotoxicity. Seventy-two female rats were divided into groups. Cardiotoxicity was induced by administering DOX (2.5 mg/kg three times weekly for 2 weeks). In some groups, the effect of endogenous E2 was abolished by ovariectomy (OVX) or by using the estrogen receptor (ER) blocker Fulvestrant (FULV). The effect of administering exogenous E2 or 2ME in the OVX group was studied. Furthermore, the influence of entacapone (COMT inhibitor) on induced cardiotoxicity was investigated. The evaluated cardiac parameters included ECG, histopathology, cardiac-related enzymes (creatine kinase isoenzyme-MB (CK-MB) and lactate dehydrogenase (LDH)), and lipid profile markers (total cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL)). The expression levels of key metabolic enzymes (glucose transporter-4 (GLUT4) and carnitine palmitoyltransferase-1B (CPT-1B)) were assessed. Our results displayed that co-treatment of E2 and/or 2ME with DOX significantly reduced DOX-induced cardiomyopathy and enhanced the metabolism of the heart through the maintenance of GLUT4 and CPT-1B enzymes. On the other hand, co-treatment of DOX with OVX, entacapone, or FULV increased the toxic effect of DOX by further reducing these important metabolic enzymes. E2 and 2ME abrogate DOX-induced cardiomyopathy partly through modulation of GLUT 4 and CPT-1B enzymes.

Quinazolines and thiazolidine-2,4-dions as SARS-CoV-2 inhibitors: repurposing, in silico molecular docking and dynamics simulation.

This paper presents an extensive analysis of COVID-19 with a specific focus on VEGFR-2 inhibitors as potential treatments. The investigation includes an overview of computational methodologies employed in drug repurposing and highlights in silico research aimed at developing treatments for SARS-CoV-2. The study explores the possible effects of twenty-eight established VEGFR-2 inhibitors, which include amide and urea linkers, against SARS-CoV-2. Among these, nine inhibitors exhibit highly promising in silico outcomes (designated as 3-6, 11, 24, 26, 27, and sorafenib) and are subjected to extensive molecular dynamics (MD) simulations to evaluate the binding modes and affinities of these inhibitors to the SARS-CoV-2 Mpro across a 100 ns timeframe. Additionally, MD simulations are conducted to ascertain the binding free energy of the most compelling ligand-pocket complexes identified through docking studies. The findings provide valuable understanding regarding the dynamic and thermodynamic properties of the interactions between ligands and pockets, reinforcing the outcomes of the docking studies and presenting promising prospects for the creation of therapeutic treatments targeting COVID-19.

Marine Predator Algorithm-Based Optimal PI Controllers for LVRT Capability Enhancement of Grid-Connected PV Systems.

Photovoltaic (PV) systems are becoming essential to our energy landscape as renewable energy sources become more widely integrated into power networks. Preserving grid stability, especially during voltage sags, is one of the significant difficulties confronting the implementation of these technologies. This attribute is referred to as low-voltage ride-through (LVRT). To overcome this issue, adopting a Proportional-Integral (PI) controller, a control system standard, is proving to be an efficient solution. This paper provides a unique algorithm-based approach of the Marine Predator Algorithm (MPA) for optimized tuning of the used PI controller, mainly focusing on inverter control, to improve the LVRT of the grid, leading to improvements in the overshoot, undershoot, settling time, and steady-state response of the system. The fitness function is optimized using the MPA to determine the settings of the PI controller. This process helps to optimally design the controllers optimally, thus improving the inverter control and performance and enhancing the system's LVRT capability. The methodology is tested in case of a 3L-G fault. To test its validity, the proposed approach is compared with rival standard optimization-based PI controllers, namely Grey Wolf Optimization and Particle Swarm Optimization. The comparison shows that the used algorithm provides better results with a higher convergence rate with overshoot ranging from 14% to 40% less in the case of DC-Link Voltage and active power and also settling times in the case of MPA being less than PSO and GWO by 0.76 to 0.95 s.

Clinical features, socioeconomic status, management, short and long-term outcomes of patients with acute myocardial infarction: Phase I results of PEACE MENA registry.

BACKGROUND: The Program for the Evaluation and Management of Cardiac Events in the Middle East and North Africa (PEACE MENA) is a prospective registry program in Arabian countries that involves in patients with acute myocardial infarction (AMI) or acute heart failure (AHF). METHODS: This prospective, multi-center, multi-country study is the first report of the baseline characteristics and outcomes of inpatients with AMI who were enrolled during the first 14-month recruitment phase. We report the clinical characteristics, socioeconomic, educational levels, and management, in-hospital, one month and one-year outcomes. RESULTS: Between April 2019 and June 2020, 1377 patients with AMI were enrolled (79.1% males) from 16 Arabian countries. The mean age (± SD) was 58 ± 12 years. Almost half of the population had a net income < $500/month, and 40% had limited education. Nearly half of the cohort had a history of diabetes mellitus, hypertension, or hypercholesterolemia; 53% had STEMI, and almost half (49.7%) underwent a primary percutaneous intervention (PCI) (lowest 4.5% and highest 100%). Thrombolytics were used by 36.2%. (Lowest 6.45% and highest (90.9%). No reperfusion occurred in 13.8% of patients (lowest was 0% and highest 72.7%).Primary PCI was performed less frequently in the lower income group vs. high income group (26.3% vs. 54.7%; P<0.001). Recurrent ischemia occurred more frequently in the low-income group (10.9% vs. 7%; P = 0.018). Re-admission occurred in 9% at 1 month and 30% at 1 year, whereas 1-month mortality was 0.7% and 1-year mortality 4.7%. CONCLUSION: In the MENA region, patients with AMI present at a young age and have a high burden of cardiac risk factors. Most of the patients in the registry have a low income and low educational status. There is heterogeneity among key performance indicators of AMI management among various Arabian countries.

Structure determination by cryoEM at 100 keV.

Electron cryomicroscopy can, in principle, determine the structures of most biological molecules but is currently limited by access, specimen preparation difficulties, and cost. We describe a purpose-built instrument operating at 100 keV-including advances in electron optics, detection, and processing-that makes structure determination fast and simple at a fraction of current costs. The instrument attains its theoretical performance limits, allowing atomic resolution imaging of gold test specimens and biological molecular structure determination in hours. We demonstrate its capabilities by determining the structures of eleven different specimens, ranging in size from 140 kDa to 2 MDa, using a fraction of the data normally required. CryoEM with a microscope designed specifically for high-efficiency, on-the-spot imaging of biological molecules will expand structural biology to a wide range of previously intractable problems.

Development of Multiplex Real-Time RT-qPCR Assays for the Detection of SARS-CoV-2, Influenza A/B, and MERS-CoV.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19) is a serious threat to the general public's health. During influenza seasons, the spread of SARS-CoV-2 and other respiratory viruses may cause a population-wide burden of respiratory disease that is difficult to manage. For that, the respiratory viruses SARS-CoV-2, Influenza A, Influenza B, and Middle East respiratory syndrome (MERS-CoV) will need to be carefully watched over in the upcoming fall and winter seasons, particularly in the case of SARS-CoV-2, Influenza A, and Influenza B, which share similar epidemiological factors like susceptible populations, mode of transmission, and clinical syndromes. Without target-specific assays, it can be challenging to differentiate among cases of these viruses owing to their similarities. Accordingly, a sensitive and targeted multiplex assay that can easily differentiate between these viral targets will be useful for healthcare practitioners. In this study, we developed a real-time reverse transcriptase-PCR-based assay utilizing an in-house developed R3T one-step RT-qPCR kit for simultaneous detection of SARS-CoV-2, Influenza A, Influenza B, and SARS-CoV-2, MERS-CoV. With as few as 10 copies of their synthetic RNAs, we can successfully identify SARS-CoV-2, Influenza A, Influenza B, and MERS-CoV targets simultaneously with 100% specificity. This assay is found to be accurate, reliable, simple, sensitive, and specific. The developed method can be used as an optimized SARS-CoV-2, Influenza A, Influenza B, and SARS-CoV-2, MERS-CoV diagnostic assay in hospitals, medical centers, and diagnostic laboratories as well as for research purposes.

miRNAs orchestration of gallbladder cancer - Particular emphasis on diagnosis, progression and drug resistance.

Gallbladder cancer (GBC) is characterized by a highly invasive nature and a poor prognosis, with adenocarcinoma being the main histological subtype. According to statistical data, patients diagnosed with advanced GBC have a survival rate of less than 5% for 5 years. Despite the novel therapeutic techniques, the unsatisfactory results could be related to the underlying biology of tumor cells and resistance to chemotherapy. Early diagnosis is more important than clinical therapy as it assists in determining the pathological stage of cancer and facilitates the selection of appropriate medication. Hence, it is very important to understand the precise pathogenesis of GBC and to discover potential novel biomarkers for early diagnosis of GBC. Non-coding RNAs, such as microRNAs, long non-coding RNAs, and circular RNAs, have been found to influence the transcriptional regulation of target genes associated with cancer, either directly or indirectly. microRNAs are a group of small, non-coding, single-stranded RNAs that are expressed endogenously. miRNAs play significant roles in various fundamental cellular processes. Therefore, miRNAs have the potential to serve as valuable biomarkers and therapeutic targets for GBC.

Clinical Features, Socioeconomic Status, Management, and Outcomes of Acute Heart Failure: PEACE MENA Registry Phase I Results.

INTRODUCTION: PEACE MENA (Program for the Evaluation and Management of Cardiac Events in the Middle East and North Africa) is a prospective registry in Arab countries for in-patients with acute myocardial infarction (AMI) or acute heart failure (AHF). Here, we report the baseline characteristics and outcomes of in-patients with AHF who were enrolled during the first 14 months of the recruitment phase. METHODS: A prospective, multi-centre, multi-country study including patients hospitalized with AHF was conducted. Clinical characteristics, echocardiogram, BNP (B-type natriuretic peptide), socioeconomic status, management, 1-month, and 1-year outcomes are reported. RESULTS: Between April 2019 and June 2020, a total of 1258 adults with AHF from 16 Arab countries were recruited. Their mean age was 63.3 (±15) years, 56.8% were men, 65% had monthly income ≤US$ 500, and 56% had limited education. Furthermore, 55% had diabetes mellitus, 67% had hypertension; 55% had HFrEF (heart failure with reduced ejection fraction), and 19% had HFpEF (heart failure with preserved ejection fraction). At 1 year, 3.6% had a heart failure-related device (0-22%) and 7.3% used an angiotensin receptor neprilysin inhibitor (0-43%). Mortality was 4.4% per 1 month and 11.77% per 1-year post-discharge. Compared with higher-income patients, lower-income patients had a higher 1-year total heart failure hospitalization rate (45.6 vs 29.9%, p=0.001), and the 1-year mortality difference was not statistically significant (13.2 vs 8.8%, p=0.059). CONCLUSION: Most of the patients with AHF in Arab countries had a high burden of cardiac risk factors, low income, and low education status with great heterogeneity in key performance indicators of AHF management among Arab countries.

Strain Rate Changes during Stress Echocardiography Are the Most Accurate Predictors of Significant Coronary Artery Disease in Patients with Previously Treated Acute Coronary Syndrome.

BACKGROUND AND AIMS: Dobutamine stress echocardiography (DSE) is a well-established non-invasive investigation for the detection of ischemic myocardial dysfunction. The aim of this study was to evaluate the accuracy of myocardial deformation parameters measured by speckle tracking echocardiography (STE) in predicting culprit coronary artery lesions in patients with prior revascularization and acute coronary syndrome (ACS). METHODS: We prospectively studied 33 patients with ischemic heart disease, a history of at least one episode of ACS and prior revascularization. All patients underwent a complete stress Doppler echocardiographic examination, including the myocardial deformation parameters of peak systolic strain (PSS), peak systolic strain rate (SR) and wall motion score index (WMSI). The regional PSS and SR were analyzed for different culprit lesions. RESULTS: The mean age of patients was 59 ± 11 years and 72.7% were males. At peak dobutamine stress, the change in regional PSS and SR in territories supplied by the LAD showed smaller increases compared to those in patients without culprit LAD lesions (p < 0.05 for all). Likewise, the regional parameters of myocardial deformation were reduced in patients with culprit LCx lesions compared to those with non-culprit LCx lesions and in patients with culprit RCA legions compared to those with non-culprit RCA lesions (p < 0.05 for all). In the multivariate analysis, the △ regional PSS (1.134 (CI = 1.059-3.315, p = 0.02)) and the △ regional SR (1.566 (CI = 1.191-9.013, p = 0.001)) for LAD territories predicted the presence of LAD lesions. Similarly, in a multivariable analysis, the △ regional PSS and the △SR predicted LCx culprit lesions and RCA culprit lesions (p < 0.05 for all). In an ROC analysis, the PSS and SR had higher accuracies compared to the regional WMSI in predicting culprit lesions. A △ regional SR of -0.24 for the LAD territories was 88% sensitive and 76% specific (AUC = 0.75; p < 0.001), a △ regional PSS of -1.20 was 78% sensitive and 71% specific (AUC = 0.76, p < 0.001) and a △ WMSI of -0.35 was 67% sensitive and 68% specific (AUC = 0.68, p = 0.02) in predicting LAD culprit lesions. Similarly, the △ SR for LCx and RCA territories had higher accuracies in predicting LCx and RCA culprit lesions. CONCLUSIONS: The myocardial deformation parameters, particularly the change in regional strain rate, are the most powerful predictors of culprit lesions. These findings strengthen the role of myocardial deformation in increasing the accuracy of DSE analyses in patients with prior cardiac events and revascularization.

Prognostic value of right ventricular diastolic dysfunction in patients with inferior ST-elevated myocardial infarction.

BACKGROUND: Right ventricle infarction (RVI) is predominantly a complication of inferior wall myocardial infarction; it occurs in approximately one third of these patients. Right ventricular dysfunction in patients with inferior STEMI and RV infarction was under assessed. Nevertheless, studies which targeted RV assessment by echocardiography, did not routinely evaluate RV diastolic dysfunction. In this study, we aimed to evaluate RV diastolic dysfunction and its prognostic value in patients with inferior STEMI and RVI. RESULTS: Sixty patients with inferior STEMI and RV infarction, who underwent primary PCI were enrolled in the study. Patients with pre-existing clinical conditions that might affect RV function, were excluded. Echocardiography was performed within twenty-four hours following the PCI, to assess the RV systolic and diastolic functions with special focus on tricuspid inflow velocities (E velocity, A velocity and E/A ratio) by pulsed wave (PW) doppler and tricuspid annular velocities by tissue doppler index (TDI) (E', A' and E/E' ratio). Clinical features and MACE, including cardiogenic shock, arrhythmia, stroke, reinfarction and death were analyzed in all our patients within 3 months follow up period. The average age of the study population was 51.58 ± 10.11 years, 10% were females. Five patients developed MACE (death, cardiogenic shock and pulmonary edema, anterior STEMI and cardiogenic shock, recurrent inferior STEMI, and arrhythmia and stroke), of whom four occurred in hospital within the first 48 h. Patients who developed MACE had high filling pressures, as all of them had E/E' > 6. E' velocity ≤ 6 cm/sec was associated with increased MACE as 25% of patients with E' velocity ≤ 6 had MACE compared with 2.3% of patients with E' velocity > 6 with a p value of 0.015. CONCLUSIONS: Tricuspid annular velocities by TDI are essential when evaluating RV diastolic dysfunction. E/E' and E' velocity have a prognostic value in patients with inferior STEMI and RV infarction; E/E' > 6 and E' velocity ≤ 6 cm/sec were associated more MACE in patients with inferior STEMI and RVI.

Detection and Diagnosis of Cardiac Amyloidosis in Egypt.

Cardiac amyloidosis is a life-threatening disease that occurs when amyloid proteins, most commonly immunoglobulin light chain or transthyretin, mutate or become unstable, misfold, deposit as amyloid fibrils, and accumulate in the myocardium. Early diagnosis of cardiac amyloidosis is hindered by insufficient awareness, specifically regarding clinical red flags and diagnostic pathways. Cardiac amyloidosis diagnosis comprises two important phases, clinical suspicion (phase one) followed by definitive diagnosis (phase two). Each phase is associated with specific clinical techniques. For example, clinical features, electrocardiography, echocardiography, and cardiac magnetic resonance imaging serve to raise suspicion of cardiac amyloidosis and facilitate early diagnosis, whereas laboratory tests (i.e., blood or urine electrophoresis with immunofixation), biopsy, scintigraphy-based nuclear imaging, and genetic testing provide a definitive diagnosis of cardiac amyloidosis. In Egypt, both the lack of cardiac amyloidosis awareness amongst healthcare providers and the unavailability of clinical expertise for the use of diagnostic techniques must be overcome to improve the prognosis of cardiac amyloidosis in the region. Previously published diagnostic algorithms for cardiac amyloidosis have amalgamated techniques that can raise clinical suspicions of cardiac amyloidosis with those that definitively diagnose cardiac amyloidosis. Though such algorithms have been successful in developed countries, diagnostic tools like echocardiography, scintigraphy, and cardiac magnetic resonance imaging are not ubiquitously available across Egyptian facilities. This review presents the current state of knowledge regarding cardiac amyloidosis in Egypt and outlines a new diagnostic algorithm which leverages regional nuclear imaging expertise. Importantly, the proposed diagnostic algorithm guides accurate amyloid-typing to mitigate misdiagnosis and erroneous treatment selection and improve the cardiac amyloidosis diagnostic accuracy in Egypt.

Diagnostic algorithms are useful tools for guiding clinical diagnosis by summarizing diagnostic approaches and defining the patient pathway. The diagnostic algorithms for cardiac amyloidosis amalgamate techniques that raise suspicion of the disease with those that can definitively diagnose the disease. These algorithms, for the early detection and diagnosis of cardiac amyloidosis, are designed in accordance with developed healthcare systems that have the resources and infrastructure for diagnostic equipment and clinical expertise. There are limited financial resources across healthcare facilities in Egypt for diagnostic equipment like echocardiograms (ECHO), scintigraphy, and cardiac magnetic resonance imaging (cMRI), and the required clinical training for the diagnosis of cardiac amyloidosis. This reduces the possibility of early diagnosis of the disease and subsequent early intervention. Evidently, there is a significant unmet clinical need to develop an algorithm for the diagnosis of cardiac amyloidosis in accordance with the Egyptian healthcare system. This review article details the current awareness regarding the diagnosis of cardiac amyloidosis and the associated challenges in Egypt. Accordingly, a diagnostic algorithm that leverages nuclear imaging expertise to guide accurate amyloid-typing in order to mitigate misdiagnosis and erroneous treatment, and also improve the diagnostic accuracy of cardiac amyloidosis, has been proposed.

New [1,2,4]triazolo[4,3-c]quinazolines as intercalative Topo II inhibitors: Design, synthesis, biological evaluation, and in silico studies.

Fifteen quinazoline derivatives were designed and synthesized as DNA intercalators. The cytotoxicity of the designed members was assessed against HCT-116 and HepG2 cancer cell lines. In addition, the topoisomerase II (Topo II) inhibitory effect was assessed. Compound 16 was the most cytotoxic and Topo II inhibitor with low cytotoxicity against Vero cells. Compounds 16, 17, and 18 showed significant DNA binding affinities. Compound 16 showed Topo II catalytic inhibitory effect at a concentration of 10 µM. Further mechanistic investigations revealed the capability of compound 16 to induce apoptosis in HCT-116 cells and arrest the growth at the S and G2/M phases. Also, compound 16 showed a significant increase in the level of BAX (2.18-fold) and a marked decrease in the level of Bcl-2 (1.9-fold) compared to the control cells. In silico studies revealed the ability of the synthesized members to bind to the DNA-Topo II complex.

A scanning-to-incision switch in TFIIH-XPG induced by DNA damage licenses nucleotide excision repair.

Nucleotide excision repair (NER) is critical for removing bulky DNA base lesions and avoiding diseases. NER couples lesion recognition by XPC to strand separation by XPB and XPD ATPases, followed by lesion excision by XPF and XPG nucleases. Here, we describe key regulatory mechanisms and roles of XPG for and beyond its cleavage activity. Strikingly, by combing single-molecule imaging and bulk cleavage assays, we found that XPG binding to the 7-subunit TFIIH core (coreTFIIH) stimulates coreTFIIH-dependent double-strand (ds)DNA unwinding 10-fold, and XPG-dependent DNA cleavage by up to 700-fold. Simultaneous monitoring of rates for coreTFIIH single-stranded (ss)DNA translocation and dsDNA unwinding showed XPG acts by switching ssDNA translocation to dsDNA unwinding as a likely committed step. Pertinent to the NER pathway regulation, XPG incision activity is suppressed during coreTFIIH translocation on DNA but is licensed when coreTFIIH stalls at the lesion or when ATP hydrolysis is blocked. Moreover, ≥15 nucleotides of 5'-ssDNA is a prerequisite for efficient translocation and incision. Our results unveil a paired coordination mechanism in which key lesion scanning and DNA incision steps are sequentially coordinated, and damaged patch removal is only licensed after generation of ≥15 nucleotides of 5'-ssDNA, ensuring the correct ssDNA bubble size before cleavage.

Nucleotide excision repair (NER) removes bulky DNA lesions and is thereby crucial in maintaining transcription and genomic integrity. Here, the authors show a dual function for the XPG nuclease that is critical for finding and excising the damage. During the separation of the damage-containing strand from the undamaged strand, XPG stimulates TFIIH dependent dsDNA unwinding 10 fold. In return, when TFIIH stalls at the damage it stimulates XPG nuclease activity 700 fold. Remarkably, this mutually exclusive coordination requires a bubble longer than 15 nucleotides. This study addressees why a bubble of a certain size is needed to facilitate NER and why XPG is recruited at the beginning of NER when its endonucleolytic activity is required at the very end.

In silico molecular docking, dynamics simulation and repurposing of some VEGFR-2 inhibitors based on the SARS-CoV-2-main-protease inhibitor N3.

The global and rapid spread of the novel human coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has brought immediate urgency to the discovery of favorable targets for COVID-19 treatment. Here, we consider drug reuse as an attractive methodology for drug discovery by reusing existing drugs to treat diseases other than their initial indications. Here, we review current information concerning the global health issue of COVID-19 including VEGFR-2 inhibitors. Besides, we describe computational approaches to be used in drug repurposing and highlight examples of in silico studies of drug development efforts against SARS-CoV-2. The present study suggests the potential anti-SARS-CoV-2 activities of 35 reported VEGFR-2 inhibitors containing the amide and urea linkers. Nineteen members revealed the best in silico results and hence, were subjected to further molecular dynamics (MD) simulation for their inhibitory activities against SARS-CoV-2 Mpro across 100 ns. Furthermore, MD simulations followed by calculations of the free energy of binding were also carried out for the most promising ligand-pocket complexes from docking studies to clarify some information on their dynamic and thermodynamic properties and approve the docking results. These results we obtained probably provided an excellent lead candidate for the development of therapeutic drugs against COVID-19.Communicated by Ramaswamy H. Sarma.

Associative effects between Chlorella vulgaris microalgae and Moringa oleifera leaf silage used at different levels decreased in vitro ruminal greenhouse gas production and altered ruminal fermentation.

Moringa oleifera leaf silage and Chlorella vulgaris microalgae mixture used at different levels replacing concentrate feed mixture in the diets of ruminant were evaluated using an in vitro gas production technique. C. vulgaris was included in rations at 1, 2, and 3% concentrations. The concentrate feed mixture was replaced by M. oleifera silage up to 100%. Productions of total gas, methane (CH4), and carbon dioxide (CO2) and ruminal fermentation were measured. Interactions between M. oleifera and C. vulgaris levels were observed for the rate of total gas production, lag time of CH4 production, pH, and concentrations of ammonia-N (NH3-N), total volatile fatty acid (VFA), and propionate. The lower level of C. vulgaris increased total gas production and decreased CH4 and CO2 production as well as improved nutrient degradability compared to the other levels of C. vulgaris which showed less improvement in these parameters. The replacement levels of concentrate at 10 to 40% with M. oleifera linearly increased the asymptotic total gas production and degradabilities of dry matter and acid detergent fiber (P<0.05), while the replacement levels of 80 to 100% lowered the asymptotic (P<0.01) for the ration containing 1% C. vulgaris. Rations containing M. oleifera linearly increased the lag time of total gas production (P<0.05), neutral detergent fiber degradability, and ruminal bacteria count and decreased the asymptotic CH4 and CO2 production and ruminal protozoal count (P<0.05). For the rations containing 2 and 3% C. vulgaris, M. oleifera linearly (P<0.01) decreased the asymptotic total gas, CH4 and CO2 production, and ruminal protozoal count. The lag time of CH4 production was not affected at 1% C. vulgaris, but reduced linearly at 2% and 3% C. vulgaris. Ruminal pH was not affected by M. oleifera, but was increased by C. vulgaris at 3% level. Overall, M. oleifera in the ration containing C. vulgaris at all levels increased ruminal NH3-N concentration; however, C. vulgaris at 2% level and M. oleifera at levels up to 40% lowered NH3-N concentration. M. oleifera rations with 1% and 2% C. vulgaris increased the concentrations of total VFA and propionate, whereas these variables were not affected at 3% C. vulgaris level. In conclusion, replacement of concentrate mixture with M. oleifera at 30% level and C. vulgaris at 1% in the diet due to associative effects may improve ruminal fermentation and feed degradability while decreasing CH4 production.

Analysis of the Facial Measurements and Dental Arch Dimensions for the Construction of Dental Prostheses among Adult Yemenis.

AIM: To investigate the dental arch dimension (width, length, and height) and facial measurements including inner-canthal width (ICW), bizygomatic width (BZW), inter-alar width (IAW), and mouth width (MW), and to assess the correlation between these facial measurements and dental arch width (canine width [CW], inter-first premolar width [I1PW], and inter-first molar width [I1MW]), to establish a preliminary reference for artificial teeth selection in Yemeni adult. MATERIALS AND METHODS: The study included 80 individuals (40 males and 40 females) with symmetrical faces and normal class I occlusion ranging in age from 20 to 35. Maxillary and mandibular stone casts were made for each individual. The dimensions of dental casts and facial measurements, including ICW, BZW, IAW, and MW, were assessed using a digital caliper. The collected data were analyzed by using the SPSS software program. The descriptive statistics for each measurement were made. Differences between males and females were tested using an independent-sample t-test with p-values below 0.05 considered significant. Pearson correlation coefficient between facial measurements and dental arch width was also done. RESULTS: Most dental arch dimensions and facial measurements exhibited larger mean values in the male than in the female group, with the greatest significant difference in the maxillary dental arch width and the lowest in mandibular dental arch length. A highly significant correlation is observed between ICW and maxillary canine width (CW) (r = 0.318, p = 0.004). In contrast, no significant correlation between dental arch width and BZW, IAW, and MW is shown. CONCLUSIONS: Within this study's limitations, the ICW can determine the ideal dimension of the artificial teeth in the anterior maxillary arch. While the other facial parameters, including BZW, IAW, and MW, cannot be used for artificial teeth selection in Yemeni populations. CLINICAL SIGNIFICANCE: The findings of this study established a reference database of facial measurements and their correlation to dental arch and teeth width in Yemeni populations. So, it can be implemented in artificial teeth and dental prostheses design and construction.

Acute Heart Failure and Coronary Blood Flow in ST-Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention: An Observational Cohort Study.

Background and objective The Global Registry of Acute Coronary Events (GRACE) study showed poor outcomes in ST-elevation myocardial infarction (STEMI) patients with acute heart failure (AHF) at hospital admission in terms of increased in-hospital and six-month mortality and readmission rates. In this study, we aimed to examine the effects of AHF at the time of admission on the coronary thrombus burden and post-primary percutaneous coronary intervention (PPCI) coronary flow among STEMI patients. Methods We conducted a cohort study involving 210 consecutive STEMI patients who presented to a single PPCI centre between June 2016 and January 2017. We classified them into two groups based on their Killip class at the time of presentation to the emergency department: no heart failure (NHF) and AHF groups. The primary outcome was the incidence of Thrombolysis In Myocardial Infarction (TIMI) flow grade of less than 3 in the stented coronary artery in the absence of mechanical obstruction or dissection (also known as no-reflow). The secondary outcome was the presence of a heavy thrombus burden (TIMI grade 4 or 5) at the time of angiography. Results The AHF group had a significantly higher incidence of no-reflow than the NHF group (25% vs. 8.4%, p=0.019). However, the prevalence of heavy thrombus burden did not differ significantly between the two groups (50% in the AHF group vs. 43.16% in the NHF group, p=0.557). The multivariable logistic regression analysis showed that AHF was an independent predictor of no-reflow in STEMI patients post-PPCI [Odds ratio (OR): 3.59, 95% confidence interval (CI): 1.09-11.83, p=0.035]. Conclusion Based on our findings, AHF is associated with an increased risk of no-reflow in STEMI patients post-PPCI, irrespective of the coronary thrombus load.