RESUMO
Persistent SARS-CoV-2 infections may act as viral reservoirs that could seed future outbreaks1-5, give rise to highly divergent lineages6-8 and contribute to cases with post-acute COVID-19 sequelae (long COVID)9,10. However, the population prevalence of persistent infections, their viral load kinetics and evolutionary dynamics over the course of infections remain largely unknown. Here, using viral sequence data collected as part of a national infection survey, we identified 381 individuals with SARS-CoV-2 RNA at high titre persisting for at least 30 days, of which 54 had viral RNA persisting at least 60 days. We refer to these as 'persistent infections' as available evidence suggests that they represent ongoing viral replication, although the persistence of non-replicating RNA cannot be ruled out in all. Individuals with persistent infection had more than 50% higher odds of self-reporting long COVID than individuals with non-persistent infection. We estimate that 0.1-0.5% of infections may become persistent with typically rebounding high viral loads and last for at least 60 days. In some individuals, we identified many viral amino acid substitutions, indicating periods of strong positive selection, whereas others had no consensus change in the sequences for prolonged periods, consistent with weak selection. Substitutions included mutations that are lineage defining for SARS-CoV-2 variants, at target sites for monoclonal antibodies and/or are commonly found in immunocompromised people11-14. This work has profound implications for understanding and characterizing SARS-CoV-2 infection, epidemiology and evolution.
Assuntos
COVID-19 , Inquéritos Epidemiológicos , Infecção Persistente , SARS-CoV-2 , Humanos , Substituição de Aminoácidos , Anticorpos Monoclonais/imunologia , COVID-19/epidemiologia , COVID-19/virologia , Evolução Molecular , Hospedeiro Imunocomprometido/imunologia , Mutação , Infecção Persistente/epidemiologia , Infecção Persistente/virologia , Síndrome de COVID-19 Pós-Aguda/epidemiologia , Síndrome de COVID-19 Pós-Aguda/virologia , Prevalência , RNA Viral/análise , RNA Viral/genética , SARS-CoV-2/química , SARS-CoV-2/classificação , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , Seleção Genética , Autorrelato , Fatores de Tempo , Carga Viral , Replicação ViralRESUMO
AIMS/HYPOTHESIS: The rapid remission of type 2 diabetes by a diet very low in energy correlates with a marked improvement in glucose-stimulated insulin secretion (GSIS), emphasising the role of beta cell dysfunction in the early stages of the disease. In search of novel mechanisms of beta cell dysfunction after long-term exposure to mild to severe glucotoxic conditions, we extensively characterised the alterations in insulin secretion and upstream coupling events in human islets cultured for 1-3 weeks at ~5, 8, 10 or 20 mmol/l glucose and subsequently stimulated by an acute stepwise increase in glucose concentration. METHODS: Human islets from 49 non-diabetic donors (ND-islets) and six type 2 diabetic donors (T2D-islets) were obtained from five isolation centres. After shipment, the islets were precultured for 3-7 days in RPMI medium containing ~5 mmol/l glucose and 10% (vol/vol) heat-inactivated FBS with selective islet picking at each medium renewal. Islets were then cultured for 1-3 weeks in RPMI containing ~5, 8, 10 or 20 mmol/l glucose before measurement of insulin secretion during culture, islet insulin and DNA content, beta cell apoptosis and cytosolic and mitochondrial glutathione redox state, and assessment of dynamic insulin secretion and upstream coupling events during acute stepwise stimulation with glucose [NAD(P)H autofluorescence, ATP/(ATP+ADP) ratio, electrical activity, cytosolic Ca2+ concentration ([Ca2+]c)]. RESULTS: Culture of ND-islets for 1-3 weeks at 8, 10 or 20 vs 5 mmol/l glucose did not significantly increase beta cell apoptosis or oxidative stress but decreased insulin content in a concentration-dependent manner and increased beta cell sensitivity to subsequent acute stimulation with glucose. Islet glucose responsiveness was higher after culture at 8 or 10 vs 5 mmol/l glucose and markedly reduced after culture at 20 vs 5 mmol/l glucose. In addition, the [Ca2+]c and insulin secretion responses to acute stepwise stimulation with glucose were no longer sigmoid but bell-shaped, with maximal stimulation at 5 or 10 mmol/l glucose and rapid sustained inhibition above that concentration. Such paradoxical inhibition was, however, no longer observed when islets were acutely depolarised by 30 mmol/l extracellular K+. The glucotoxic alterations of beta cell function were fully reversible after culture at 5 mmol/l glucose and were mimicked by pharmacological activation of glucokinase during culture at 5 mmol/l glucose. Similar results to those seen in ND-islets were obtained in T2D-islets, except that their rate of insulin secretion during culture at 8 and 20 mmol/l glucose was lower, their cytosolic glutathione oxidation increased after culture at 8 and 20 mmol/l glucose, and the alterations in GSIS and upstream coupling events were greater after culture at 8 mmol/l glucose. CONCLUSIONS/INTERPRETATION: Prolonged culture of human islets under moderate to severe glucotoxic conditions markedly increased their glucose sensitivity and revealed a bell-shaped acute glucose response curve for changes in [Ca2+]c and insulin secretion, with maximal stimulation at 5 or 10 mmol/l glucose and rapid inhibition above that concentration. This novel glucotoxic alteration may contribute to beta cell dysfunction in type 2 diabetes independently from a detectable increase in beta cell apoptosis.
Assuntos
Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Humanos , Glucose/metabolismo , Secreção de Insulina , Cálcio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ilhotas Pancreáticas/metabolismo , Insulina/metabolismo , Glutationa/metabolismo , Trifosfato de Adenosina/metabolismo , Células CultivadasRESUMO
Understanding how the human virome, and which of its constituents, contributes to health or disease states is reliant on obtaining comprehensive virome profiles. By combining DNA viromes from isolated virus-like particles (VLPs) and whole metagenomes from the same faecal sample of a small cohort of healthy individuals and patients with severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we have obtained a more inclusive profile of the human intestinal DNA virome. Key features are the identification of a core virome comprising tailed phages of the class Caudoviricetes, and a greater diversity of DNA viruses including extracellular phages and integrated prophages. Using an in silico approach, we predicted interactions between members of the Anaerotruncus genus and unique viruses present in ME/CFS microbiomes. This study therefore provides a framework and rationale for studies of larger cohorts of patients to further investigate disease-associated interactions between the intestinal virome and the bacteriome.
Assuntos
Síndrome de Fadiga Crônica , Humanos , Viroma , Interações entre Hospedeiro e Microrganismos , DNARESUMO
The interaction of indomethacin with human serum albumin (HSA) has been studied here considering the primary and secondary binding sites. The Stern-Volmer plots were linear in the lower concentration range of indomethacin while a downward curvature was observed in the higher concentration range, suggesting the presence of more than one binding site for indomethacin inside HSA due to which the microenvironment of the fluorophore changed slightly and some of its fraction was not accessible to the quencher. The Stern-Volmer quenching constants (KSV) for the primary and secondary sites were calculated from the two linear portions of the Stern-Volmer plots. There was around a two-fold decrease in the quenching constants for the low-affinity site as compared to the primary binding site. The interaction takes place via a static quenching mechanism and the KSV decreases at both primary and secondary sites upon increasing the temperature. The binding constants were also evaluated, which show strong binding at the primary site and fair binding at the secondary site. The binding was thermodynamically favorable with the liberation of heat and the ordering of the system. In principle, hydrogen bonding and Van der Waals forces were involved in the binding at the primary site while the low-affinity site interacted through hydrophobic forces only. The competitive binding was also evaluated using warfarin, ibuprofen, hemin, and a warfarin + hemin combination as site markers. The binding profile remained unchanged in the presence of ibuprofen, whereas it decreased in the presence of both warfarin and hemin with a straight line in the Stern-Volmer plots. The reduction in the binding was at a maximum when both warfarin and hemin were present simultaneously with the downward curvature in the Stern-Volmer plots at higher concentrations of indomethacin. The secondary structure of HSA also changes slightly in the presence of higher concentrations of indomethacin. Molecular dynamics simulations were performed at the primary and secondary binding sites of HSA which are drug site 1 (located in the subdomain IIA of the protein) and the hemin binding site (located in subdomain IB), respectively. From the results obtained from molecular docking and MD simulation, the indomethacin molecule showed more binding affinity towards drug site 1 followed by the other two sites.
Assuntos
Indometacina , Albumina Sérica Humana , Humanos , Albumina Sérica Humana/química , Simulação de Acoplamento Molecular , Ligação Proteica , Ibuprofeno , Varfarina , Hemina/metabolismo , Sítios de Ligação , Termodinâmica , Espectrometria de Fluorescência , Dicroísmo CircularRESUMO
An experimental work was conducted to evaluate the effects of Saccharomyces cerevisiae live cells and its culture on dry matter intake (DMI), milk yield, milk composition, body condition score, selected blood metabolites, feed conversion efficiency (FCE), nutrient digestibility, body weight gain, and economics of milk production in lactating multiparous Nili-Ravi buffaloes. In total, 20 buffaloes of age 5 years ± 6 months and weighing 550 ± 20 kg were selected and assigned to four dietary treatments (n=5 buffalo/treatment) under completely randomized design. The dietary treatments include treatment 1 (T1) control, treatment 2 (T2) 5g/head live yeast, treatment 3 (T3) 5g/head yeast culture, and treatment 4 (T4) 10 g/head yeast culture per day for 60 days excluding 14 days as an adjustment period. The results indicated that T4 showed significant (p<0.05) improvement in DMI, milk yield and components, blood glucose level, digestibility of nutrients, and body weight gain while significant decrease in blood urea nitrogen as compared to other treatment groups. Body condition score was not affected among treatments. In conclusion, yeast culture supplementation significantly improved (p <0.05) milk yield, milk composition, DMI, body weight gain, blood glucose level, and digestibility while significantly decreased blood urea level as compare to control. Economic return was also improved. BCS was not improved. Comparatively, yeast culture showed significant improvement in growth and productive performance as compare to live yeast. Meanwhile, 10-g yeast culture showed better results as compare to 5-g yeast culture.
Assuntos
Bison , Búfalos , Animais , Feminino , Ração Animal/análise , Glicemia/metabolismo , Dieta/veterinária , Suplementos Nutricionais , Digestão , Lactação , Leite/metabolismo , Saccharomyces cerevisiae , Aumento de PesoRESUMO
In this manuscript, two thiouronium-based ionic liquids (ILs), namely 2-ethylthiouronium bromide [C2th][Br] and 2-(hydroxyethyl)thiouronium bromide [C2OHth][Br], were tested at different concentrations (1 and 10 wt%) for their ability to affect CO2 (sI) and tetrahydrofuran (THF) (sII) hydrate formation and growth. Two different methods were selected to perform a thermodynamic and kinetic screening of the CO2 hydrates using a rocking cell apparatus: (i) an isochoric pressure search method to map the hydrate phase behavior and (ii) a constant ramping method to obtain the hydrate formation and dissociation onset temperatures. A THF hydrate crystal growth method was also used to determine the effectiveness of the ILs in altering the growth of type sII hydrates at atmospheric pressure. Hydrate-liquid-vapor equilibrium measurements revealed that both ILs act as thermodynamic inhibitors at 10 wt% and suppress the CO2 hydrate equilibria ~1.2 °C. The constant ramping methodology provides interesting results and reveals that [C2OHth][Br] suppresses the nucleation onset temperature and delays the decomposition onset temperatures of CO2 hydrates at 1 wt%, whereas suppression by [C2th][Br] was not statistically significant. Normalized pressure plots indicate that the presence of the ILs slowed down the growth as well as the decomposition rates of CO2 hydrates due to the lower quantity of hydrate formed in the presence of 1 wt% ILs. The ILs were also found to be effective in inhibiting the growth of type sII THF hydrates without affecting their morphology. Therefore, the studied thiouronium ILs can be used as potential dual-function hydrate inhibitors. This work also emphasizes the importance of the methods and conditions used to screen an additive for altering hydrate formation and growth.
Assuntos
Dióxido de Carbono , Líquidos Iônicos , Brometos , Dióxido de Carbono/química , FuranosRESUMO
This study was carried out to find the environmental factors which have a significant effect on the productive and reproductive characteristics of the Balochi sheep. The study used data from 729 ewes and 71 rams for a period of 13 years (2003 to 2016) at the Sheep Research Center, Yet Abad, Balochistan, Pakistan. The productive characteristics considered for current study were weight, birth weight (BW), 90 days weight (3 MW), 180 days weight (6 MW), 270 days weight (9 MW), 365 days (12 MW), and 2 years weight (24 MW). Reproductive characteristics measured were ewe age at first service (AFS), service period (SP) of ewe, age at 1st lambing (AFL) of ewe, lambing interval (LI), and sex ratio. Restricted maximum likelihood (REML) assessments of different characteristics were analyzed for the Balochi sheep on the basis of location, birth year (YOB), season of birth (SOB), type of birth (TOB), and sex of lamb. The average means ± SE for BW, WW, 6 MW, 9 MW, 12 MW, and 24 MW, were 3.28 ± 0.83, 17.20 ± 2.04, 21.94 ± 1.60, 26.20 ± 2.87, 30.21 ± 3.58, and 37.11 ± 2.84 for ram and 2.56 ± 0.53, 15.69 ± 1.45, 19.57 ± 1.77, 24.07 ± 2.70, 27.46 ± 2.09, and 34.61 ± 2.32 for ewes respectively. The results of reproductive performance of the Balochi sheep age of ewe at the time of breeding, age at first service (AFS), service period (SP), age at first lambing (AFL), and lambing interval (LI) were 1078 ± 2.2, 579.61 ± 0.6, 206.25 ± 0.2, 731.67 ± 0.3, and 256.60 ± 0.3 days respectively. The twining and lambing rates were 10.12% and 86.78%, while the sex proportion for ram and ewes was 50.12:49.37. Area, sex, and TOB had a significant (p < 0.05) effect on weight while TOB (twinning rate) was higher in Balochi sheep. These conditions affected the productive and reproductive performance of the Balochi sheep. At Sheep Research Center, Yet Abad, Balochistan, Pakistan, performed fundamentally better in all qualities such as weight gain and reproductive performance. Supplements were given with feed to get maximum profit from the sheep of Yet Abad farm. The birth weight of males was higher than that of females and single conceived Balochi sheep were heavier than that of twins. Thus, it was concluded that the Balochi sheep can be improved with better management practices, feeding, and disease control.
Assuntos
Reprodução , Carneiro Doméstico , Animais , Peso ao Nascer , Feminino , Masculino , Parto , Gravidez , Estações do Ano , OvinosRESUMO
Thalli sheep is a significant breed reared under tropical region of Punjab province of Pakistan. The present study was conducted to predict live body weight (LBW) by means of from some body measurements, i.e., chest girth (CG), belly girth (BG), rump height (RH), withers height (WH), neck girth (NG), and body length (BL) taken from 155 Thalli indigenous sheep of Pakistan. Age factor is determined to be a significant source of variation for BL, BG, CG, BG, WH, and NG (p < 0.05). LBW is correlated significantly with BL (0.850), CG (0.825), BG (0.849), RH (0.579), WH (0.547), and NG (0.7760), respectively (p < 0.01). For LBW prediction, CART and MARS data mining algorithms were comparatively used based on ten cross-validation method. Among 185 candidate MARS models with 1-5 degrees of interaction and 2-38 terms, the MARS model with 7 terms and no interaction effect in R software was the best model for LBW prediction on the basis of the smallest cross-validated RMSE value. Also, the optimal CART tree structure was obtained with 9 terminal nodes for the smallest cross-validated RMSE value. MARS algorithm outperformed CART in LBW prediction and explained 90.3 (%) of variability in LBW of Thalli sheep. Results of the optimal CART structure reflected that Thalli sheep with BL > 75 cm, RH > 83 cm, and NG > 55 cm has the heaviest LBW of 72 kg. The optimal MARS model displays that the heaviest LBW can be produced by Thalli sheep with BL > 71.12 cm, BG > 106.68 cm, WH > 76.2 cm, NG > 50.8 cm in 5th age group. In conclusion, it coud be recommended that MARS predictive modeling may enable animal breeders to obtain elite Thalli sheep population and to detect body measurement positively influencing LBW as indirect selection criteria for not only describing breed characterization and developing flock management standards, but also ensuring sustainable meat production and rural development in Pakistan.
Assuntos
Carneiro Doméstico , Clima Tropical , Animais , Tamanho Corporal , Peso Corporal , Paquistão , OvinosRESUMO
The aim of the present work was to predict live body weight by means of some body measurements, i.e., SH, CG, and BG in indigenous Marecha camel breed. For this purpose, multivariate adaptive regression splines (MARS) algorithm was used at proportions of various training and test sets, i.e., 65:35, 70:30, and 80:20 in V-tenfold cross-validation. In prediction of live body weight of the Marecha camels (160 female and 145 male animals) in the MARS predictive models, pairs of sex-SH (model 1), sex-CG (model 2), and sex-BG (model 3) as potential predictors. The best MARS model in LW prediction was obtained using sex and SH independent variables for 80:20 training and test set. Sex was determined to be an important source of variation in SH, CG, and BG as a result of sexual dimorphism in camels (P < 0.01). MARS results indicated that SH could be used as an indirect selection criterion to obtain elite camel herds on LW of Marecha camels. If genetically confirmed, the Marecha camels whose SH is taller than 165.1 cm could be selected for providing genetic progress in LW. In conclusion, use of MARS algorithm may be worthy of consideration for better identification of camel breed standards and selection of superior Marecha camels for meat productivity in Pakistan.
Assuntos
Camelus , Carne , Animais , Peso Corporal , Feminino , Masculino , PaquistãoRESUMO
Mature weight is a significant trait that can be influenced by age, sex, breed, production system, and climate conditions in camels. In camel breeding, it is essential to describe breed standards of the studied camel breeds as part of morphological characterization and to determine morphological traits positively influencing mature weight within the scope of indirect selection criteria. This study was to find the best one among candidate models in prediction of mature weight from several morphological traits measured for eight camel breeds (Bravhi, Kachi, Kharani, Kohi, Lassi, Makrani, Pishin, and Rodbari) raised under Pakistan conditions. The morphological measurements taken from the camels in the study were birth weight (BW), weaning weight (WW), mature weight (MW), age of ridding (ARD), face length (FL), face width (FW), head length (HL), head width (HW), ear length (EL), ear width (EW), neck length (NL), neck width (NW), hump length (HL), hump width (HuW), heart girth (HG), withers height (WH), body length (BL), fore leg length (FLL), and hind leg length (HLL), respectively. In the prediction of mature body weight as a response variable, the optimal MARS predictive model with 15 terms selected by train function of the caret package produced very high predictive performance without encountering overfitting problem. Goodness of fit criteria were estimated to measure predictive quality of the MARS model using ehaGoF package available in R environment. Morphological characterization of the camel breeds was performed with hierarchical cluster analysis (HCA) on the basis of Euclidean distance-Single linkage. At the first step of hierarchical cluster analysis, the similarity level of Bravhi and Kachi camel breeds was the highest with 85.3569 (%). At the second step, Makrani joined to new cluster of Bravhi and Kachi camels found at the first step, and the similarity level of the new cluster comprising Bravhi, Kachi, and Makrani breeds was found as 84.5562 (%). MW was significantly correlated with BW (0.677), WW (0.536), HL (0.524), HuW (0.529), and ARD (0.375) at P < 0.01, and there was the highest correlation of 0.994 between HHL and FLL (P < 0.01). As a result, it could be suggested that results of MARS modeling may help camel breeders to reproduce the elite camel populations and to describe characteristics associated positively with MW within the scope of indirect selection criteria.
Assuntos
Algoritmos , Camelus , Animais , Análise por Conglomerados , Paquistão , FenótipoRESUMO
In the present study, the potential of transdermal nanoemulsion gel of selegiline hydrochloride for the treatment of Parkinson's disease was investigated. Water-in-oil nanoemulsions were developed by comparing low- and high-energy methods and were subjected to thermodynamic stability tests, in vitro permeation, and characterization studies. In vitro studies indicated that components of nanoemulsion acted as permeation enhancers with highest flux of 3.531 ± 1.94 µg/cm2/h from nanoemulsion SB6 containing 0.5 mg selegiline hydrochloride, 3% distilled water, 21% S mix (Span 85, Tween 80, PEG 400), and 76% isopropyl myristate by weight. SB6 with the least droplet size of 183.4 ± 0.35 nm, polydispersity index of 0.42 ± 0.06 with pH of 5.9 ± 0.32 and viscosity of 22.42 ± 0.14 cps was converted to nanoemulsion gel NEGS4 (viscosity = 22,200 ± 400 cps) by addition of Viscup160® for ease of application and evaluated for permeation, safety, and pharmacokinetic profile in Wistar rats. It provided enhancement ratio 3.69 times greater than conventional gel. NEGS4 showed 6.56 and 5.53 times increase in bioavailability in comparison to tablet and conventional gel, respectively, along with sustained effect. Therefore, the developed water-in-oil nanoemulsion gel promises to be an effective vehicle for transdermal delivery of selegiline hydrochloride.
Assuntos
Antiparkinsonianos/administração & dosagem , Selegilina/administração & dosagem , Administração Cutânea , Animais , Antiparkinsonianos/metabolismo , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/uso terapêutico , Emulsões , Géis , Masculino , Nanoestruturas , Óleos/química , Transtornos Parkinsonianos/tratamento farmacológico , Veículos Farmacêuticos , Ratos , Ratos Wistar , Selegilina/metabolismo , Selegilina/farmacocinética , Selegilina/uso terapêutico , Absorção Cutânea , Termodinâmica , Viscosidade , Água/químicaRESUMO
BACKGROUND: Acute kidney injury (AKI) is a serious clinical problem with high rate of mortality and morbidity. Currently used prophylactic and therapeutic strategies to address AKI are limited and warrant further studies. In the present study an attempt was made to investigate the effect of quinacrine, a phospholipase A2 inhibitor against glycerol induced AKI in rats. METHODS: Adult female Wistar rats were divided in to five groups. After 24 h of water deprivation rats in groups 3, 4 and 5 received an intraperitoneal injection of quinacrine (3 mg/kg, 10 mg/kg and 30 mg/kg of body weight respectively). Thirty minutes after the first injection of quinacrine animals in groups 3, 4 and 5 received an intramuscular injection of 25% glycerol (10 ml/kg of body weight). The animals in group 2 received 25% glycerol (10 ml/kg of body weight) only whereas rats in group 1 served as control . The quinacrine administration was continued once daily for three days, on the fourth day animals were sacrificed, blood and kidney were collected for various biochemical and histopathological studies. RESULTS: Glycerol treatment produced significant renal structural abnormalities and functional impairment (increased urea and creatinine). Increase in myeloperoxidase (MPO) and malondialdehyde (MDA) clearly suggested the involvement of oxidative stress and neutrophilic activity following glycerol administration. Quinacrine dose dependently attenuated glycerol induced structural and functional changes in kidney. CONCLUSION: The reversal of glycerol induced AKI by quinacrine points towards a role of phospholipase A2 (PLA2) in the pathogenesis of renal injury. The result of this study suggests that quinacrine may offer an alternative mode of treatment for AKI.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Inibidores Enzimáticos/farmacologia , Glicerol/toxicidade , Rim/efeitos dos fármacos , Inibidores de Fosfolipase A2/farmacologia , Quinacrina/farmacologia , Animais , Creatinina/metabolismo , Feminino , Rim/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/efeitos dos fármacos , Peroxidase/metabolismo , Ratos , Ratos Wistar , Ureia/metabolismoRESUMO
The eukaryotic initiation factor 5A (eIF5A) is an essential protein involved in translation elongation and cell proliferation. eIF5A undergoes several post-translational modifications including hypusination and acetylation. Hypusination is indispensable for the function of eIF5A. On the other hand, the precise function of acetylation remains unknown, but it may render the protein inactive since hypusination blocks acetylation. Here, we report that acetylation of eIF5A increases under hypoxia. During extended hypoxic periods an increase in the level of eIF5A acetylation correlated with a decrease in HIF-1α, suggesting involvement of eIF5A activity in HIF-1α expression under hypoxia. Indeed, suppression of eIF5A by siRNA oligo-mediated knockdown or treatment with GC7, a deoxyhypusine synthase inhibitor, led to significant reduction of HIF-1α activity. Furthermore, knockdown of eIF5A or GC7 treatment reduced tumor spheroid formation with a concomitant decrease in HIF-1α expression. Our results suggest that functional, hypusinated eIF5A is necessary for HIF-1α expression during hypoxia and that eIF5A is an attractive target for cancer therapy.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Oxigênio/metabolismo , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células , Células HeLa , Humanos , Fator de Iniciação de Tradução Eucariótico 5ARESUMO
Choline chloride + levulinic acid deep eutectic solvent is studied as a suitable material for CO2 capturing purposes. The most relevant physicochemical properties of this solvent are reported together with the CO2 solubility as a function of temperature. The corrosivity of this solvent is studied showing better performance than amine-based solvents. A theoretical study using both density functional theory and molecular dynamics approaches is carried out to analyze the properties of this fluid from the nanoscopic viewpoint, and their relationship with the macroscopic behavior of the system and its ability for CO2 capturing. The behavior of the liquid-gas interface is also studied and its role on the CO2 absorption mechanism is analyzed. The reported combined experimental and theoretical approach leads to a complete picture of the behavior of this new sorbent with regard to CO2, which together with its low cost, and the suitable environmental and toxicological properties of this solvent, lead to a promising candidate for CO2 capturing technological applications.
RESUMO
The 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors known as "statins" are widely prescribed for the management of dyslipidemia. In spite of their muscle toxicity, use of statins has alarmingly increased worldwide. A recent report suggests that vitamin D (VD) levels are closely associated with lipid lowering activity and muscular toxicity of statins. However, data are limited and inconclusive. The present study was undertaken to investigate the effect of VD supplementation on the bioavailability and lipid lowering effect of simvastatin (ST). Adult Sprague-Dawley male rats (250 ± 10 g) were divided into four groups including control, ST (100 mg/kg/day), VD (100 µg/kg/day) and ST + VD group, respectively. After the dosing period of 8 days the animals were sacrificed and the blood was collected for the analysis of ST, its active metabolite simvastatin acid (STA), total cholesterol, triglyceride and liver enzymes including aspartate transaminase and alanine transaminase. The result of this study showed a significant decrease in the level of cholesterol and triglyceride in ST alone treated group, whereas VD alone failed to alter the blood lipid levels. Concomitant treatment with VD produced significant decrease in the bioavailability of ST and STA. However, there was no significant difference in the level of cholesterol in ST alone and in ST + VD treated group. Our results on the liver enzyme suggest that ST alone or in combination with VD does not produce any hepatotoxicity. Further studies using VD along with various statins for a longer duration are suggested.
Assuntos
Colecalciferol/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Fígado/efeitos dos fármacos , Sinvastatina/administração & dosagem , Sinvastatina/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Biomarcadores/sangue , Biotransformação , Colesterol/sangue , Regulação para Baixo , Interações Medicamentosas , Fígado/metabolismo , Masculino , Ratos Sprague-Dawley , Medição de Risco , Sinvastatina/análogos & derivados , Sinvastatina/sangue , Triglicerídeos/sangueRESUMO
BACKGROUND: Haemorrhoids have been diagnosed and treated since the dawn of civilization, yet their cause, nature, symptomatology and especially their treatment options, remain hotly debated. The general principle however is that treatment should be directed by symptoms and the degree of haemorrhoids. The objective of the study is to compare early and late complications and wound healing time in open versus closed methods of haemorrhoidectomy. METHODS: This was a Randomized control trial conducted at Department of Surgery CMH Kharian for a period of 3 years. During the period of study, patients presenting in Surgical OPD (Age Range 20-72 Years) with 3rd or 4th degree haemorrhoids requiring haemorrhoidectomy (n = 364) were divided in two groups:--Group-1 was subjected to haemorrhoidectomy by open (Milligan-Morgan) technique and Group-2 underwent closed (Ferguson) haemorrhoidectomy. All patients were followed up for 2 months post-operatively and assessed for duration of wound healing and post-operative complications. RESULTS: In group-1 (Open haemorrhoidectomy) patients' ages ranged from 21-70 years with a mean age of 43 years (SD ± 12.51). Duration of wound healing in this group was on the average 22 days (SD ± 5.76). Incidence of early post-operative complications including haemorrhage, infection and urinary retention was 4.94%, 8.24% and 7.14% respectively. The only late complication observed was anal stenosis in one patient (0.55%). No fissure or faecal incontinence was observed in this group. In group-2 (subjected to closed haemorrhoidectomy), patients' ages ranged from 20-72 years with a mean age of 42 years (SD ± 10.31). Duration of wound healing was on the average 14 days (SD ± 3.25). Incidence of early post- operative complications, i.e., haemorrhage, infection and urinary retention was 2.19%, 7.69% and 2.75% respectively. No late complications (stenosis, fissure or incontinence) were observed in this group. CONCLUSION: There is no statistical significant difference between open and closed haemorrhoidectomy for the treatment of 3rd and 4th degree haemorrhoids in terms of wound healing time and post-operative complications.
Assuntos
Hemorroidectomia/métodos , Hemorroidas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Adulto , Idoso , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Cicatrização , Adulto JovemRESUMO
The highway of Yongweol-ri, Muan-gun, south-western part of the South Korean Peninsula, is underlain by the abandoned of subsurface cavities, which were discovered in 2005. These cavities lie at shallow depths with the range of 5â¼15 meters below the ground surface. Numerous subsidence events have repeatedly occurred in the past few years, damaging infrastructure and highway. As a result of continuing subsidence issues, the Korean Institute of Geosciences and Mineral Resources (KIGAM) was requested by local administration to resolve the issue. The KIGAM used geophysical methods to delineate subsurface cavities and improve more refined understanding of the cavities network in the study area. Cement based grouting has been widely employed in the construction industry to reinforce subsurface ground. In this research work, time-lapse electrical resistivity surveys were accomplished to monitor the grouting injection in the subsurface cavities beneath the highway, which have provided a quasi-real-time monitoring for modifying the subsurface cavities related to ground reinforcement, which would be difficult with direct methods. The results obtained from time-lapse electrical resistivity technique have satisfactory imaged the grouting injection experiment in the subsurface cavities beneath the highway. Furthermore, the borehole camera confirmed the presence of grouting material in the subsurface cavities, and hence this procedure increases the mechanical resistance of subsurface cavities below the highway.
Assuntos
Fenômenos Geológicos , Modelos Teóricos , Impedância Elétrica , República da CoreiaRESUMO
Introduction: In the present study the cytotoxic and genotoxic effects of Bisphenol-A glycidyl methacrylate (BisGMA) was studied on the third instar larvae of transgenic Drosophila melanogaster (hsp70-lacZ)Bg9. Materials and methods: The concentration of BisGMA i.e. 0.005, 0.010, 0.015 and 0.020 M were established in diet and the larvae were allowed to feed on it for 24 h. Results: A dose dependent significant increase in the activity of ß-galactosidase was observed compared to control. A significant dose dependent tissue damage was observed in the larvae exposed to 0.010, 0.015 and 0.020 M of BisGMA compared to control. A dose dependent significant increase in the Oxidative stress markers was observed compared to control. BisGMA also exhibit significant DNA damaged in the third instar larvae of transgenic D. melanogaster (hsp70-lacZ)Bg9 at the doses of 0.010, 0.015 and 0.020 M compared to control. Conclusion: BisGMA at 0.010, 0.015 and 0.020 M was found to be cytotoxic for the third instar larvae of transgenic D. melanogaster (hsp70-lacZ) Bg9.
RESUMO
The advent of viral metagenomics, or viromics, has improved our knowledge and understanding of global viral diversity. High-throughput sequencing technologies enable explorations of the ecological roles, contributions to host metabolism, and the influence of viruses in various environments, including the human intestinal microbiome. However, bacterial metagenomic studies frequently have the advantage. The adoption of advanced technologies like long-read sequencing has the potential to be transformative in refining viromics and metagenomics. Here, we examined the effectiveness of long-read and hybrid sequencing by comparing Illumina short-read and Oxford Nanopore Technology (ONT) long-read sequencing technologies and different assembly strategies on recovering viral genomes from human faecal samples. Our findings showed that if a single sequencing technology is to be chosen for virome analysis, Illumina is preferable due to its superior ability to recover fully resolved viral genomes and minimise erroneous genomes. While ONT assemblies were effective in recovering viral diversity, the challenges related to input requirements and the necessity for amplification made it less ideal as a standalone solution. However, using a combined, hybrid approach enabled a more authentic representation of viral diversity to be obtained within samples.
Assuntos
Fezes , Microbioma Gastrointestinal , Genoma Viral , Sequenciamento de Nucleotídeos em Larga Escala , Metagenômica , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Metagenômica/métodos , Microbioma Gastrointestinal/genética , Fezes/virologia , Fezes/microbiologia , Nanoporos , Sequenciamento por Nanoporos/métodos , Vírus/genética , Vírus/classificação , Vírus/isolamento & purificação , Viroma/genética , Análise de Sequência de DNA/métodosRESUMO
Some of the most active scientific research fronts of the past decade are centered on ionic liquids. These fluids present characteristic surface behavior and distinctive trends of their surface tension versus temperature. One way to explore and understand their unique nature is to study their surface properties. This critical review analyses most of the surface tension data reported between 2001 and 2010 (187 references).