Synthesis and Molecular Docking Study of Novel Pyrimidine Derivatives against COVID-19.

A novel series of pyrido[2,3-d]pyrimidines; pyrido[3,2-e][1,3,4]triazolo; and tetrazolo[1,5-c]pyrimidines were synthesized via different chemical transformations starting from pyrazolo[3,4-b]pyridin-6-yl)-N,N-dimethylcarbamimidic chloride 3b (prepared from the reaction of o-aminonitrile 1b and phosogen iminiumchloride). The structures of the newly synthesized compounds were elucidated based on spectroscopic data and elemental analyses. Designated compounds are subjected for molecular docking by using Auto Dock Vina software in order to evaluate the antiviral potency for the synthesized compounds against SARS-CoV-2 (2019-nCoV) main protease M pro. The antiviral activity against SARS-CoV-2 showed that tested compounds 7c, 7d, and 7e had the most promising antiviral activity with lower IC50 values compared to Lopinavir, "the commonly used protease inhibitor". Both in silico and in vitro results are in agreement.

Advances on Therapeutic Strategies for Alzheimer's Disease: From Medicinal Plant to Nanotechnology.

Alzheimer's disease (AD) is a chronic dysfunction of neurons in the brain leading to dementia. It is characterized by gradual mental failure, abnormal cognitive functioning, personality changes, diminished verbal fluency, and speech impairment. It is caused by neuronal injury in the cerebral cortex and hippocampal area of the brain. The number of individuals with AD is growing at a quick rate. The pathology behind AD is the progress of intraneuronal fibrillary tangles, accumulation of amyloid plaque, loss of cholinergic neurons, and decrease in choline acetyltransferase. Unfortunately, AD cannot be cured, but its progression can be delayed. Various FDA-approved inhibitors of cholinesterase enzyme such as rivastigmine, galantamine, donepezil, and NDMA receptor inhibitors (memantine), are available to manage the symptoms of AD. An exhaustive literature survey was carried out using SciFinder's reports from Alzheimer's Association, PubMed, and Clinical Trials.org. The literature was explored thoroughly to obtain information on the various available strategies to prevent AD. In the context of the present scenario, several strategies are being tried including the clinical trials for the treatment of AD. We have discussed pathophysiology, various targets, FDA-approved drugs, and various drugs in clinical trials against AD. The goal of this study is to shed light on current developments and treatment options, utilizing phytopharmaceuticals, nanomedicines, nutraceuticals, and gene therapy.

Performance of loop-mediated isothermal amplification (LAMP) for detection of Schistosoma mansoni infection compared with Kato-Katz and real-time PCR.

The performance of loop-mediated isothermal amplification (LAMP) for detection of Schistosoma mansoni DNA from stool and urine samples in comparison with Kato-Katz and real-time polymerase chain reaction (PCR) was studied. After obtaining informed consent, 50 children participated in the present study and agreed to submit stool and urine samples. Stool samples were examined by Kato-Katz. Both real-time PCR and LAMP techniques were applied on stool and urine samples. The overall prevalence of S. mansoni was 46% in stool and urine samples as detected by the employed techniques, and 90% of cases had light infection intensity. The highest percentage of infection was diagnosed by real-time PCR (44%), followed by Kato-Katz (42%) and LAMP in the stool (36%), while the lowest percentages of infection were diagnosed by real-time PCR and LAMP in urine samples (24% and 14%, respectively). Kato-Katz, real-time PCR and LAMP showed 100% specificity where the sensitivity was 91.3%, 95.7% and 78.3%, respectively, in stool samples. Real-time PCR and LAMP showed lower sensitivity in urine samples. The LAMP assay is a promising technique for S. mansoni diagnosis in endemic countries of moderate and high-intensity infection. Yet, it needs further optimization, particularly in urine samples.

Click chemistry based synthesis, cytotoxic activity and molecular docking of novel triazole-thienopyrimidine hybrid glycosides targeting EGFR.

In the current study, new thienopyrimidine conjugates bearing 1,2,3-triazole core and different sugar moieties have been designed and synthesized by Cu(I)-catalysed click dipolar cycloaddition. The cytotoxic activity of the synthesised conjugates 2, 5, 7, and 13-18 was studied against HCT-116 and MCF-7 cell lines by the MTT assay. The triazole glycosides 16 and 18 provided significant cytotoxic activities against HCT-116 cell lines comparable to that of doxorubicin and other studied compounds. The cytotoxic behaviour against MCF-7 exhibited that all the investigated compounds were more potent than doxorubicin. Moreover, all screened targets were evaluated against mutant EGFR kinase type L858R and the results revealed that the acetylated 1,2,3-triazole glycosides 13-18 exhibited excellent EGFR inhibitory activity in comparison with gefitinib. Furthermore, molecular modelling studies were performed to investigate the binding affinity of the most active compounds to EGFR enzyme.

Synthesis and Cytotoxic Activity of New Thiazolopyrimidine Sugar Hydrazones and Their Derived Acyclic Nucleoside Analogues.

New thienyl- or chlorophenyl-substituted thiazolopyrimidine derivatives and their derived sugar hydrazones incorporating acyclic d-galactosyl or d-xylosyl sugar moieties in addition to their per-O-acetylated derivatives were synthesized. Heterocyclization of the formed sugar hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the cyclization process. The cytotoxic activity of the synthesized compounds was studied against human breast cancer MCF7 and MDA-MB-231 cell lines as well as human colorectal cancer HCT 116 and Caco-2 cell lines. High activities were revealed by compounds 1, 8, 10, 11, and 13 against Caco-2 and MCF7 cells in addition to moderate activities exhibited by other compounds against HCT116 or MDA-MB-231 cells.

Pancreatic stellate cells in pancreatic cancer: In focus.

Pancreatic stellate cells are stromal cells that have multiple physiological functions such as the production of extracellular matrix, stimulation of amylase secretion, phagocytosis and immunity. In pancreatic cancer, stellate cells exhibit a different myofibroblastic-like morphology with the expression of alpha-smooth muscle actin, the activated form is engaged in several mechanisms that support tumorigenesis and cancer invasion and progression. In contrast to the aforementioned observations, eliminating the stromal cells that are positive for alpha-smooth muscle actin resulted in immune-evasion of the cancer cells and resulted in worse prognosis in animal models. Understanding the cancer-stromal signaling in pancreatic adenocarcinoma will provide novel strategies for therapy. Here we provide an updated review of studies that handle the topic "pancreatic stellate cells in cancer" and recent experimental approaches that can be the base for future directions in therapy.

Simulation-based optimization framework for reuse of agricultural drainage water in irrigation.

A simulation-based optimization framework for agricultural drainage water (ADW) reuse has been developed through the integration of a water quality model (QUAL2Kw) and a genetic algorithm. This framework was applied to the Gharbia drain in the Nile Delta, Egypt, in summer and winter 2012. First, the water quantity and quality of the drain was simulated using the QUAL2Kw model. Second, uncertainty analysis and sensitivity analysis based on Monte Carlo simulation were performed to assess QUAL2Kw's performance and to identify the most critical variables for determination of water quality, respectively. Finally, a genetic algorithm was applied to maximize the total reuse quantity from seven reuse locations with the condition not to violate the standards for using mixed water in irrigation. The water quality simulations showed that organic matter concentrations are critical management variables in the Gharbia drain. The uncertainty analysis showed the reliability of QUAL2Kw to simulate water quality and quantity along the drain. Furthermore, the sensitivity analysis showed that the 5-day biochemical oxygen demand, chemical oxygen demand, total dissolved solids, total nitrogen and total phosphorous are highly sensitive to point source flow and quality. Additionally, the optimization results revealed that the reuse quantities of ADW can reach 36.3% and 40.4% of the available ADW in the drain during summer and winter, respectively. These quantities meet 30.8% and 29.1% of the drainage basin requirements for fresh irrigation water in the respective seasons.

Hyponatraemia in cancer: association with type of cancer and mortality.

Hyponatraemia is common in patients with cancer. The objectives of this study are to investigate the severity distribution of hyponatraemia and its association with mortality. We retrospectively reviewed medical records for patients admitted to a national centre for cancer care and research in Qatar between 2008 and 2012. A model was built through multivariate analyses to investigate the role of hyponatraemia in mortality. Patients were grouped into those who had moderate-severe hyponatraemia (Na < 130) and those who only had normal-mild hyponatraemia (Na ≥ 130). A total of 2048 patients were included in this study. Prostate (57.1%), pancreatic (50%), liver (49%) and lung (40.2%) cancers showed the highest frequency of moderate-severe hyponatraemia, while breast cancer showed the lowest frequency at 23.5%. In the multivariate analyses, patients with moderate-severe hyponatraemia (Na < 130 mmol/L) were 4.28 times more likely to die than those with normal-mild hyponatraemia (Na ≥ 130) (P < 0.05). The present study shows that hyponatraemia is a common electrolyte disturbance among hospitalised patients with cancer diagnoses. The severity of hyponatraemia was a statistically significant independent factor associated with higher in-hospital mortality. This is in accordance with the reported literature and emphasises the importance of early diagnosis and correction of hyponatraemia.

Immunohistochemical expression of vimentin, E-cadherin, and CD45 in natural cases of canine cutaneous round tumors.

Round cell tumors are common cutaneous lesions in dogs, with increased occurrence percentages among different skin tumors. This study aimed to investigate the frequency as well as gross and pathological characteristics of round cell tumors in natural cases of tumorous dogs in relation to breed, sex, and age. Moreover, it aimed to evaluate the immunohistochemical expression of a panel of immunohistochemical stains, including vimentin, E-cadherin, and cluster of differentiation (CD45) as an adjunct technique for the differential diagnosis of cutaneous round cell neoplasm. Data were collected from 64 dogs of both sexes (36 females and 28 males), various breeds, and different ages (8 months to 7 years). The histopathological nature of neoplastic growth was reported, and neoplasm prevalence was classified using age, sex, breed, and site on the body. We observed 48 cases of transmissible venereal tumors, 12 cutaneous histiocytomas, and 4 histiocytic sarcoma. Immunohistochemical characterization revealed an intense positive immunoreactivity for vimentin in transmissible venereal tumor cells and moderate positive immunoreactivity for E-cadherin and CD45 in cutaneous histiocytoma and histiocytic sarcoma cells. In conclusion, the canine transmissible venereal tumor was the most frequent form of round cell tumor; thus, a definitive cutaneous neoplasm diagnosis should be based on histopathological morphology and immunohistochemical findings.

Portable through-metal ultrasonic power transfer using a dry-coupled detachable transmitter.

Ultrasonic waves can be used to transfer power and data efficiently through metallic enclosures when feedthroughs are not practical due to structural or electromagnetic shielding considerations. Previous implementations of ultrasonic power transfer (UPT) used a piezoelectric transducer permanently bonded to the metal for efficient ultrasonic coupling. For portable operation, it is essential to have a detachable transmitter (charger) that is only attached to the enclosure while transferring power. This requirement presents several design challenges; notably, detachable ultrasonic coupling typically relies on liquid or gel couplant, which may become inconvenient or less robust during repeated attachment and detachment. Thus, this work develops a dry-coupled detachable UPT system to transfer power efficiently through a metallic enclosure without the need for a liquid couplant. Low attenuation soft elastomers are experimentally tested with a magnetic setup to evaluate their dry-coupled efficiency. Samples with different materials and thicknesses are experimentally tested to select the best configuration for dry ultrasonic coupling. The softest elastomer tested yielded the best ultrasonic efficiency (AC-to-AC) of 68% at 1 MHz. A full DC-to-DC portable (battery-operated) UPT system was then developed and experimentally characterized. The system was capable of delivering up to 3 W of DC power to a resistive load with a total efficiency of 50%.

Ultrasonic testing of thick and thin Inconel 625 alloys manufactured by laser powder bed fusion.

Additive manufacturing of alloys enables low-volume production of functional metallic components with complex geometries. Ultrasonic testing can ensure the quality of these components and detect typical defects generated during laser powder bed fusion (LPBF). However, it is difficult to find a single ultrasonic inspection technique that can detect defects in the large variety of geometries generated using LPBF. In this work, phased array ultrasonic testing (PAUT) is suggested to inspect thick LPBF components, while guided waves are explored for thin curved ones. PAUT is used to detect cylindrical lack of fusion defects in thick LPBF rectangular parts. Practical defects are generated by reducing the laser power at prespecified locations in the samples. The defects' shape and density are verified using optical microscopy and X-ray computed tomography. Partially fused defects down to 0.25 mm in diameter are experimentally detected using a 10 MHz PAUT probe with the total focusing method post-processing. The experimental results are compared to defect images predicted by finite element simulations. For thin components with curved geometry, guided waves are used to detect powder-filled cylindrical defects. The waves are generated using piezoelectric transducers, and the spatiotemporal wavefield is measured using a scanning laser Doppler vibrometer. Using root-mean-square imaging of the wavefield, defects down to 1 mm are clearly detected despite the complex internal features in the samples.

Neuroecotoxicology: Effects of environmental heavy metal exposure on the brain of African giant rats and the contribution of vanadium to the neuropathology.

Increased exploitation of minerals has led to pollution of confined environments as documented in Nigeria Niger Delta. Information on the effects on brain of such exposure is limited. Due to its exploratory activities, the African giant rat (Cricetomys gambianus) (AGR) provides a unique model for neuroecotoxicological research to determine levels of animal and human exposure to different pollutants. This study aims to unravel neuropathological features of AGR sampled from three agro-ecological zones of Nigeria. Fifteen AGR were sampled according to previously determined data on heavy metal exposure: high vanadium, high lead, and low metals. Eighteen AGR were collected from low metal zone and divided into two groups. Control group received vehicle while SMV exposed group received 3 mg/kg sodium metavanadate (SMV) intraperitoneally for 14days. Brain immunohistochemical analyses were conducted, and ultrastructural changes were studied in experimentally exposed group. Results showed significant loss of tyrosin hydroxylase, parvalbumin, orexin-A and melanin concentration hormone containing neuronal populations in brains obtained from high vanadium and high lead zones and in experimentally intoxicated SMV groups. Similarly, significant decrease numbers of dendritic arborations; extracellular matrix density, perineuronal nets; astrocytes and microglia activations are documented in same groups. Ultrastructural studies revealed mass denudation, cilia loss, disintegration of ependymal layer and intense destructions of myelin sheaths in SMV exposed group. These are the first "neuroecotoxicological" findings in distinct neuronal cells. The implications of these findings are highly relevant for human population living in these areas, not only in Nigeria but also in similarly polluted areas elsewhere in the world.

Prenatal and perinatal acrylamide disrupts the development of cerebellum in rat: Biochemical and morphological studies.

Acrylamide is known to cause neurotoxicity in the experimental animals and humans. The literature on its neurotoxic effect in the adult animals is huge, but the effect of acrylamide on the embryonic and postnatal development is relatively less understood. The present study examined its effects on the development of external features and cerebellum in albino rats. Acrylamide was orally administered to non-anesthetized pregnant females by gastric intubation 10 mg/kg/day. The animals were divided into three groups as follows. (1) Group A, newborn from control animals; (2) Group B; newborns from mothers treated with acrylamide from day 7 (D7) of gestation till birth (prenatal intoxicated group); (3) Group C; newborns from mothers treated with acrylamide from D7 of gestation till D28 after birth (perinatally intoxicated group). Acrylamide administered either prenatally or perinatally has been shown to induce significant retardation in the newborns' body weights development, increase of thiobarbituric acid-reactive substances (TBARS) and oxidative stress (significant reductions in glutathione reduced [GSH], total thiols, superoxide dismutase [SOD] and peroxidase activities) in the developing cerebellum. Acrylamide treatment delayed the proliferation in the granular layer and delayed both cell migration and differentiation. Purkinje cell loss was also seen in acrylamide-treated animals. Ultrastructural studies of Purkinje cells in the perinatal group showed microvacuolations and cell loss. The results of this study show that prenatal and perinatal acrylamide or its metabolites disrupts the biochemical machinery, cause oxidative stress and induce structural changes in the developing rat cerebellum.

Rehabilitation of patients with peripheral arterial disease.

Vascular rehabilitation is an essential and effective treatment of peripheral arterial obstructive disease (PAOD). It is recommended in the first line by the European and American scientific societies. The rehabilitation to the walk remains the basic treatment of the arteriopathy of the lower limbs. Different walking protocols can be proposed. For similar effectiveness, vascular rehabilitation consists of an outpatient or specialized institution management program based on a comprehensive approach involving all or many of the following techniques: relaxation, active analytical exercises, gait rehabilitation, exercise re-entry, physical activities adapted to the patient's daily life and illness, respiratory physiotherapy, therapeutic education of the patient, smoking cessation aid. Vascular rehabilitation of arteritis requires a variety of skills but still faces a clear lack of suitable structures; it remains poorly prescribed and poorly known by usual prescribers (general practitioner, vascular surgeon).

Synthesis, anticancer activity and molecular docking of new triazolo[4,5-d]pyrimidines based thienopyrimidine system and their derived N-glycosides and thioglycosides.

A series of new substituted triazolo[4,5-d]pyrimidine derivatives linked to thienopyrimidine ring system were prepared as a hybrid heterocyclic systems, as possible nucleobases analogs, starting from the key carboxamide derivative 2 and its azide precursor via heterocyclization reactions and their structures were characterized. Glycosylation of the prepared triazolopyrimidine derivatives was performed and afforded, regioselctively, the corresponding thienopyrimidine-triazolopyrimidine hybrid N1-glycosides and their thioglycoside analogues in good yields. The synthesized glycosyl heterocycles were studied for their cytotoxic activity against HepG-2 and MCF-7 human cancer cells and significant results were obtained. Compounds 7a, 8 b, 9 b, 9a and 7 b demonstrated promising activities comparable to the activity of the doxorubicin for (HepG-2) cell line. Furthermore, a number of the afforded triazolopyrimidine glycosides were found potent against cancer cells (MCF-7). Furthermore, docking simulation the promising thienopyrimidine analogues 7-13 was done against EGFR kinase to provide a binding model that could serve in discovery of further anticancer agents.

Melatonin administration ameliorates cadmium-induced oxidative stress and morphological changes in the liver of rat.

The oxidative status and the morphological changes of liver of rats exposed to cadmium (5 mg Cd/kg body weight subcutaneously) for 22 days and the protective role of melatonin (10mg/kg b.w.) against the toxicity of cadmium was studied. The concentration of malondialdehyde (MDA), as an indicator of lipid peroxidation, activity of the antioxidant enzyme superoxide dismutase (SOD) as well as the concentration of glutathione (GSH) was measured in the liver. The morphological changes were investigated using both light and electron microscopes. The exposure to Cd led to an increase of MDA levels and a decrease of both the activity of SOD and GSH concentration in the liver. In contrast, melatonin administration restored the previous changes to nearly the normal levels. Morphologically, Cd led to different histopathological changes such as loss of normal architecture of the parenchymatous tissue, cytoplasmic vacuolization, cellular degeneration and necrosis, congested blood vessels, destructed cristae mitochondria, fat globules, severe glycogen depletion, lipofuscin pigments, and collagenous fibers formation. Again, melatonin administration counteracts all changes and the tissue appears more or less normal. The rate of recovery was faster when melatonin was administered for treatment after the exposure to cadmium than if the animals left without any treatment. The results suggest that melatonin may be useful as an antioxidant in combating free radical-induced oxidative stress and tissue injury that is a result of cadmium toxicity.

Streptococcus anginosus group infections: Management and outcome at a tertiary care hospital.

BACKGROUND: Data on patients with invasive Streptococcus anginosus group (SAG) infections is limited, as it's been considered commensal bacteria in the human microbiota. We conducted an analysis of SAG infections to assist clinicians in understanding their burden and clinical outcomes. METHODS: A retrospective study of medical records, identifying invasive SAG bacteria of sterile-site isolates that were managed from May 2015 to April 2017, at a tertiary care hospital in Riyadh, Saudi Arabia. Demographic data, clinical presentation, site of infection, antibiotic use, and outcome were recorded and analyzed to identify factors associated with poor outcome and/or polymicrobial growth. RESULTS: We identified 105 cases of SAG infections in adults, with 52% of the patients being male and the mean age of 52.4 years with comorbidities occurring in more than half of the cases such as diabetes (38%) and malignancy (15%). Overall mortality was 6%, and it was statistically associated with age older than 65 years, polymicrobial growth and a history of malignancy. The infection frequencies were skin and soft tissue infections (SSTI; 55%), intra-abdominal infections (24%), bacteremia (14%), genitourinary infections (8.5%), and pleuropulmonary infections (5%). Abscesses accounted for 68% of cases. Polymicrobial infection (46%) with Enterobacteriaceae and Gram-negative anaerobes coincided with SAG infection. Polymicrobial growth was significantly associated with abscess formation, intra-abdominal source of infections, and poor outcome. In addition, death in patients with SAG was statistically associated with patients older than 65 years of age and those with history of cancer or transplant. CONCLUSION: SSTIs and intra-abdominal infections are the most common clinical presentations in our cohort. Bacteremia was uncommon; however, the prognosis is less favorable. Overall susceptibility to penicillin was 91%, therefore ß-lactam antibiotics are the drug of choice and additional coverage for anaerobic and gram-negative bacteria should be considered for intra-abdominal collection and solid or organ abscesses.

Surgical and functional outcomes of two types of transcutaneous bone conduction implants.

OBJECTIVE: This study aimed to evaluate surgical and functional outcomes, in a tertiary referral centre, of two different types of semi-implantable transcutaneous bone conduction devices. METHOD: This study involved prospective data collection and review of patients implanted between November 2014 and December 2016. Glasgow Hearing Aid Inventory (Glasgow Hearing Aid Benefit Profile or Glasgow Hearing Aid Difference Profile) and Client Oriented Scale of Improvement were completed where appropriate. Surgical and audiological outcomes were recorded in the surgical notes. RESULTS: Glasgow Hearing Aid Difference Profile and Glasgow Hearing Aid Benefit Profile showed similar mean score in the active and the passive transcutaneous bone conduction devices. Client Oriented Scale of Improvement showed improvements in listening situations. Post-operative speech reception threshold showed better mean threshold in the active transcutaneous bone conduction devices group when compared with the passive transcutaneous bone conduction devices group. No device failures or surgical complications existed in either group, with the surgical time being less in the passive transcutaneous bone conduction devices group. CONCLUSION: Both devices are reliable semi-implantable transcutaneous bone conduction devices with excellent surgical and functional outcomes and patient satisfaction. Overall surgical time was much less in the passive transcutaneous bone conduction devices group with no necessity for pre-planning. This is much easier to remove with the possibility of conversion to other devices in the manufacturer's portfolio and wide-ranging wireless accessories. Further studies are needed to assess the longer-term results in a bigger population.

Molecular detection of Candidatus Anaplasma camelii in camels (Camelus dromedarius) from Asir Province, Saudi Arabia.

Knowledge of molecular identification of tick-borne pathogens in camels in Saudi Arabia is very limited; few molecular epidemiological studies have been under taken. This study was to detect Anaplasma spp. and Piroplasma spp. in camels from Asir Province, Saudi Arabia. A total of 150 blood samples were collected from camels in Asir Province and investigated by polymerase chain reaction (PCR) that targeted 18S rRNA and 23S rRNA to detect the DNA of Piroplasma spp. and Anaplasma spp., respectively. The positive samples for 23S rRNA were assayed again by PCR targeting the 16S rRNA. All the blood samples were free from Piroplasma spp. infection. Three camels (2%) were found to be positive for Anaplasma infection through use of PCR that targeted the 23S rRNA gene. There were no significant differences between ages or sexes in the camels that tested positive for Anaplasma. All positive Anaplasma infections were recorded in camels that were infested by ticks. Two Anaplasma sequences for the16S rRNA gene were deposited in GenBank with accession numbers MN882724 and MN882725. They recorded 99.16% and 99.34% similarities (respectively) with KF843825.1 (Candidatus Anaplasma camelii reported in Unizah, Saudi Arabia). Phylogenetic analyses revealed that the two sequences recorded in this study were close to each other; both were located in one cluster with Candidatus Anaplasma camelii isolates that were recorded before in the adjacent areas of Unizah in Saudi Arabia and Iran. In conclusion: two new Anaplasma genotypes close to Candidatus Anaplasma camelii were found in camels in Asir Province, Saudi Arabia for the first time. The camels in this province were found to be free of Piroplasma infection.