Evaluation of the potency of FDA-approved drugs on wild type and mutant SARS-CoV-2 helicase (Nsp13)

SARS-CoV-2 has caused COVID-19 outbreak with nearly 2 M infected people and over 100K death worldwide, until middle of April 2020. There is no confirmed drug for the treatment of COVID-19 yet. As the disease spread fast and threaten human life, repositioning of FDA approved drugs may provide fast options for treatment. In this aspect, structure-based drug design could be applied as a powerful approach in distinguishing the viral drug target regions from the host. Evaluation of variations in SARS-CoV-2 genome may ease finding specific drug targets in the viral genome. In this study, 3458 SARS-CoV-2 genome sequences isolated from all around the world were analyzed. Incidence of C17747T and A17858G mutations were observed to be much higher than others and they were on Nsp13, a vital enzyme of SARS-CoV-2. Effect of these mutations was evaluated on protein-drug interactions using in silico methods. The most potent drugs were found to interact with the key and neighbor residues of the active site responsible from ATP hydrolysis. As result, cangrelor, fludarabine, folic acid and polydatin were determined to be the most potent drugs which have potency to inhibit both the wild type and mutant SARS-CoV-2 helicase. Clinical data supporting these findings would be important towards overcoming COVID-19

Targeting SARS-CoV-2 Nsp12/Nsp8 interactioninterface with approved and investigational drugs:an in silico structure-based approach

In this study, the Nsp12–Nsp8 complex of SARS-CoV-2 was targeted with structure-based and com-puter-aided drug design approach because of its vital role in viral replication. Sequence analysis ofRNA-dependent RNA polymerase (Nsp12) sequences from 30,366 different isolates were analysed forpossible mutations. FDA-approved and investigational drugs were screened for interaction with bothmutant and wild-type Nsp12–Nsp8 interfaces. Sequence analysis revealed that 70.42% of Nsp12sequences showed conserved P323L mutation, located in the Nsp8 binding cleft. Compounds werescreened for interface interaction, any with XP GScores lower than 7.0kcal/mol were considered aspossible interface inhibitors. RX-3117 (fluorocyclopentenyl cytosine) and Nebivolol had the highestbinding affinities in both mutant and wild-type enzymes, therefore they were selected and resultantprotein–ligand complexes were simulated for analysis of stability over 100ns. Although the selectedligands had partial mobility in the binding cavity, they were not removed from the binding pocketafter 100ns. The ligand RX-3117 remained in the same position in the binding pocket of the mutantand wild-type enzyme after 100ns MD simulation. However, the ligand Nebivolol folded andembedded in the binding pocket of mutant Nsp12 protein. Overall, FDA-approved and investigationaldrugs are able to bind to the Nsp12–Nsp8 interaction interface and prevent the formation of theNsp12–Nsp8 complex. Interruption of viral replication by drugs proposed in this study should be fur-ther tested to pave the way forin vivostudies towards the treatment of COVID-19

Targeting SARS-CoV-2 Nsp12/Nsp8 interaction interface with approved and investigational drugs: anin silicostructure-based approach

In this study, the Nsp12-Nsp8 complex of SARS-CoV-2 was targeted with structure-based and computer-aided drug design approach because of its vital role in viral replication. Sequence analysis of RNA-dependent RNA polymerase (Nsp12) sequences from 30,366 different isolates were analysed for possible mutations. FDA-approved and investigational drugs were screened for interaction with both mutant and wild-type Nsp12-Nsp8 interfaces. Sequence analysis revealed that 70.42% of Nsp12 sequences showed conserved P323L mutation, located in the Nsp8 binding cleft. Compounds were screened for interface interaction, any with XP GScores lower than -7.0 kcal/mol were considered as possible interface inhibitors. RX-3117 (fluorocyclopentenyl cytosine) and Nebivolol had the highest binding affinities in both mutant and wild-type enzymes, therefore they were selected and resultant protein-ligand complexes were simulated for analysis of stability over 100 ns. Although the selected ligands had partial mobility in the binding cavity, they were not removed from the binding pocket after 100 ns. The ligand RX-3117 remained in the same position in the binding pocket of the mutant and wild-type enzyme after 100 ns MD simulation. However, the ligand Nebivolol folded and embedded in the binding pocket of mutant Nsp12 protein. Overall, FDA-approved and investigational drugs are able to bind to the Nsp12-Nsp8 interaction interface and prevent the formation of the Nsp12-Nsp8 complex. Interruption of viral replication by drugs proposed in this study should be further tested to pave the way forin vivostudies towards the treatment of COVID-19

Histopatološke i apoptotske promjene u bubrezima uzrokovane subakutnom izloženosti arokloru 1254 u štakora s nedostatnim i nadomjesnim unosom selenija

Aroclor 1254 (A1254), a mixture of polychlorinated biphenyls, exerts hepatic, renal, and reproductive toxicity in rodents. This study aimed to determine a protective role of selenium on histopathological changes, oxidative stress, and apoptosis caused by A1254 in rat kidney. It included a control group, which received regular diet containing 0.15 mg/kg Se (C), a Se-supplemented group (SeS) receiving 1 mg/kg Se, a Se-deficient group (SeD) receiving Se-deficient diet of ≤0.05 mg/ kg Se, an A1254-treated group (A) receiving 10 mg/kg of Aroclor 1254 and regular diet, an A1254-treated group receiving Se-supplementation (ASeS), and an A1254-treated group receiving Se-deficient diet (ASeD). Treatments lasted 15 days. After 24 h of the last dose of A1254, the animals were decapitated under anaesthesia and their renal antioxidant enzyme activities, lipid peroxidation (LP), glutathione, protein oxidation, and total antioxidant capacity levels measured. Histopathological changes were evaluated by light and electron microscopy. Apoptosis was detected with the TUNEL assay. Kidney weights, CAT activities, and GSH levels decreased significantly in all A1254-treated groups. Renal atrophic changes and higher apoptotic cell counts were observed in the A and ASeD groups. Both groups also showed a significant drop in GPx1 activities (A – 34.92 % and ASeD – 86.46 %) and rise in LP (A – 30.45 % and ASeD – 20.44 %) vs control. In contrast, LP levels and apoptotic cell counts were significantly lower in the ASeS group vs the A group. Histopathological changes and renal apoptosis were particularly visible in the ASeD group. Our findings suggest that selenium supplementation provides partial protection against renal toxicity of Aroclor 1254.Mješavina polikloriranih bifenila poznata pod nazivom aroklor 1254 (A1254) dokazano je toksična za jetru, bubrege i reprodukcijski sustav u glodavaca. Cilj ovoga istraživanja bio je na temelju histoloških promjena te parametara oksidacijskoga stresa i apoptoze utvrditi u kojoj mjeri selenij (Se) štiti bubrege od njegove toksičnosti. Istraživanje je obuhvatilo kontrolnu skupinu na normalnoj prehrani, koja je sadržavala 0,15 mg/kg Se, zatim skupinu čija je prehrana bila obogaćena selenijem (SeS) u dozi od 1 mg/kg, skupinu čija je prehrana bila osiromašena selenijem (SeD) (≤0.05 mg/ kg), skupinu koja je uz uobičajenu prehranu bila izložena arokloru 1254 (A) u dozi od 10 mg/kg tjelesne težine, skupinu koja je uz prehranu obogaćenu selenijem bila izložena arokloru 1254 (ASeS) i konačno skupinu koja je uz prehranu osiromašenu selenijem bila izložena arokloru 1254 (ASeD). Izloženost arokloru 1254 trajala je 15 dana. Životinje su 24 sata nakon primitka posljednje doze aroklora 1254 bile dekapitirane pod općom anestezijom te su im izmjerene vrijednosti bubrežnih enzimskih aktivnosti, lipidne peroksidacije (LP), glutationa (GSH), proteinske oksidacije i ukupnoga antioksidacijskoga kapaciteta. Histopatološke promjene utvrđene su pomoću svjetlosne i elektronske mikroskopije. Broj apoptotskih stanica utvrđen je TUNEL metodom. U svih skupina izloženih arokloru 1254 uočen je pad težine bubrega te aktivnosti katalaze i glutationa. U skupinama A i ASeD također je uočen povišen broj apoptotskih stanica i atrofija bubrežnoga tkiva, značajan pad aktivnosti GPX1 (u skupini A za 34,92 %, a u skupini ASeD za 86,46 %) te porast lipidnih peroksida (u skupini A za 30,45 %, a u skupini ASeD za 20,44 %) u odnosu na kontrolnu skupinu. Nasuprot skupini A, razine lipidnih peroksida i broj apoptotskih stanica bili su značajno niži u skupini ASeS, koja je primala hranu obogaćenu selenijem. Histopatološke promjene i apoptoza bubrežnih stanica osobito su se isticale u skupini ASeD na hrani osiromašenoj selenijem. Naši rezultati upućuju na to da nadomjesna primjena selenija pruža barem djelomičnu zaštitu od toksičnoga djelovanja aroklora 1254 na bubrege

An X-Band Robust GaN Low-Noise Amplifier MMIC with sub 2 dB Noise Figure

This paper presents a low-noise amplifier (LNA) operating between 8-11 GHz. Measurement results show that the LNA has a gain of more than 20 dB while achieving a noise figure of less than 2 dB. The three stage topology achieves high linearity, providing an OIP3 of 29 dBm at 0.6 W power dissipation. The robustness tests show that the circuit survives to at least 2.5 W (34 dBm) input power. With a size of just 2.8 x 1.3 mm(2) (3.6 mm(2)) the presented LNA is compact when compared to the state of the art. The circuit is realized using the 0.25 mu m Power GaN/SiC HEMT process by WIN Semiconductor

Autologous conditioned serum increases fat graft viability mmore than platelet-rich plasma in a controlled rat model

Platelet-rich plasma has been used to support fat graft retention, but it may include inflammatory mediators such as interleukin-1β. Autologous conditioned serum also contains high levels of various anti-inflammatory cytokines. The authors hypothesized that combining autologous conditioned serum with fat graft would increase fat graft survival more than platelet-rich plasma. Methods: Twenty-seven adult, male, Sprague-Dawley rats were divided into three groups of nine. Ten nonstudy rats were used to prepare platelet-rich plasma, autologous conditioned serum, and fat grafts. Next, 0.7-ml fat graft with a combination of 0.2 ml of autologous conditioned serum, platelet-rich plasma, or phosphate-buffered saline was applied to their dorsa. Fat graft volume was assessed on postoperative day 2 and on the day of euthanization at 1, 3, and 5 months postoperatively. Histopathologic analysis was performed to measure integrity, inflammation, fibrosis, and vascularization. Results: The median volume percentages and interquartile ranges at 1 month postoperatively were 97.3 percent (77.3 to 119.6 percent), 40.4 percent (30.9 to 46.9 percent), and 72.1 percent (53.6 to 84.9 percent) in autologous conditioned serum plus fat graft, phosphate-buffered saline plus fat graft, and platelet-rich plasma plus fat graft, respectively (p < 0.05); at 3 months postoperatively, values were 82.3 percent (70.3 to 88.3 percent), 36.6 percent (29.4 to 43.1 percent), and 48.3 percent (31.4 to 57.9 percent) (p < 0.001); and at 5 months postoperatively, values had increased to 83.9 percent (58.3 to 102.4 percent), 40.3 percent (20.1 to 50.6 percent), and 56.3 percent (37.7 to 74.9 percent), respectively (p < 0.05). Conclusions: Autologous conditioned serum and platelet-rich plasma improved fat graft outcomes compared to saline, whereas autologous conditioned serum was associated with less inflammation, greater fat viability, and more integrity. Clinical Relevance Statement: Combining fat graft with autologous conditioned serum may be a better option to minimize resorption rate and improve graft survival

An econometric analysis of imported timber demand in Turkey

UCAL, Meltem/0000-0003-3707-1948WOS: 000315996100001This paper attempts to understand and explain determinants of Turkish demand for foreign timber imported to Turkey. Explanatory variables in the propounded model include price of imported timber, price of domestically-produced sawlog as an imperfect substitute, income per capita, country population, and capacity utilization rates (CUR's) and industrial production indices (IPI's) of forest industry sectors. For empirical purpose we used a time series data covering the 15-year period between 1995 and 2009. The econometric model set for there appears to be able to explain more than 96% of the variation in demand for imported timber, with all of the parameter estimates, except for population parameter, being statistically significant. Estimation results confirm the existence of the price elasticity and substitute cross-price elasticity of demand for imported timber. Results also imply that the Turkish firms importing timber tend to consider domestic sawlog prices as much as, even more than, the price of foreign timber. The hypothesized effects of production changes in wood products and furniture industries on imported timber demand do not appear to be substantiated by this study, which can partly be attributed to the partial method of measuring CUR's and IPI's. Meanwhile, possible effects of income, population and exchange rate index of the Turkish currency on the imported timber demand of the country are not evidenced by the empirical findings of this research. Finally, our model forecasts, ceteris paribus, that by 2016 the level of Turkish demand for imported timber demand can reasonably be expected to exceed 2 million m(3)/year. This corresponds to the level of timber import observed in the years preceding the global economic crisis in 2009.TUBITAK, The Scientific and Technological Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [107 O 781]Authors express hereby their gratitude for the financial support received from TUBITAK, The Scientific and Technological Research Council of Turkey, through a research project (Project no: 107 O 781)

Renal changes and apoptosis caused by subacute exposure to Aroclor 1254 in selenium-deficient and selenium-supplemented rats.

Aroclor 1254 (A1254), a mixture of polychlorinated biphenyls, exerts hepatic, renal, and reproductive toxicity in rodents. This study aimed to determine a protective role of selenium on histopathological changes, oxidative stress, and apoptosis caused by A1254 in rat kidney. It included a control group, which received regular diet containing 0.15 mg/kg Se (C), a Se-supplemented group (SeS) receiving 1 mg/kg Se, a Se-deficient group (SeD) receiving Se-deficient diet of ≤0.05 mg/kg Se, an A1254-treated group (A) receiving 10 mg/kg of Aroclor 1254 and regular diet, an A1254-treated group receiving Se-supplementation (ASeS), and an A1254-treated group receiving Se-deficient diet (ASeD). Treatments lasted 15 days. After 24 h of the last dose of A1254, the animals were decapitated under anaesthesia and their renal antioxidant enzyme activities, lipid peroxidation (LP), glutathione, protein oxidation, and total antioxidant capacity levels measured. Histopathological changes were evaluated by light and electron microscopy. Apoptosis was detected with the TUNEL assay. Kidney weights, CAT activities, and GSH levels decreased significantly in all A1254-treated groups. Renal atrophic changes and higher apoptotic cell counts were observed in the A and ASeD groups. Both groups also showed a significant drop in GPx1 activities (A - 34.92 % and ASeD - 86.46 %) and rise in LP (A - 30.45 % and ASeD - 20.44 %) vs control. In contrast, LP levels and apoptotic cell counts were significantly lower in the ASeS group vs the A group. Histopathological changes and renal apoptosis were particularly visible in the ASeD group. Our findings suggest that selenium supplementation provides partial protection against renal toxicity of Aroclor 1254