Virtual screening consists of using computational tools to predict potentially bioactive compounds from files containing large libraries of small molecules. Virtual screening is becoming increasingly ...popular in the field of drug discovery as in silico techniques are continuously being developed, improved, and made available. As most of these techniques are easy to use, both private and public organizations apply virtual screening methodologies to save resources in the laboratory. However, it is often the case that the techniques implemented in virtual screening workflows are restricted to those that the research team knows. Moreover, although the software is often easy to use, each methodology has a series of drawbacks that should be avoided so that false results or artifacts are not produced. Here, we review the most common methodologies used in virtual screening workflows in order to both introduce the inexperienced researcher to new methodologies and advise the experienced researcher on how to prevent common mistakes and the improper usage of virtual screening methodologies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This work evaluated the reprocessing of PLA with a high melt flow index (MFI). PLA samples were prepared by extrusion using a chain extender (Joncryl ADR‐4368) and subjected to two additional ...extrusion cycles with or without exposure to accelerated weathering. The results showed drastic affectations of PLA properties by weathering. The MFI increased from 65 to 137 g/10 min by reprocessing, while reprocessed and weathered samples reached a MFI of 417 g/10 min after three extrusion cycles. The addition of Joncryl prevented PLA degradation (MFI of 170 g/10 min after three extrusion cycles, even when weathering was performed). Additionally, the tensile strengths of weathered samples were substantially decreased (67%) compared to only reprocessed samples (14%). In this sense, PLA mechanical recycling is a good alternative if it is not exposed to harsh weathering conditions, in which case a chain extender is needed to get reasonable properties. Otherwise, reprocessing accelerated the composting of PLA, and the chain extender addition did not limit it.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract The dopamine (DA) transporter (DAT), a membrane glycoprotein expressed in dopaminergic neurons, clears DA from extracellular space and is regulated by diverse presynaptic proteins like ...protein kinases, α-synuclein, D2 and D3 autoreceptors. DAT dysfunction is implicated in Parkinson's disease and depression, which are therapeutically treated by dopaminergic D2 /D3 receptor (D2 /D3 R) agonists. It is, then, important to improve our understanding of interactions between D3 R and DAT. We show that prolonged administration of pramipexole (0.1 mg/kg/day, 6 to 21 days), a preferential D3 R agonist, leads to a decrease in DA uptake in mouse striatum that reflects a reduction in DAT affinity for DA in the absence of any change in DAT density or subcellular distribution. The effect of pramipexole was absent in mice with genetically-deleted D3 R (D3 R−/− ), yet unaffected in mice genetically deprived of D2 R (D2 R−/− ). Pramipexole treatment induced a physical interaction between D3 R and DAT, as assessed by co-immunoprecipitation and in situ proximity ligation assay. Furthermore, it promoted the formation of DAT dimers and DAT association with both D2 R and α-synuclein, effects that were abolished in D3 R−/− mice, yet unaffected in D2 R−/− mice, indicating dependence upon D3 R. Collectively, these data suggest that prolonged treatment with dopaminergic D3 agonists provokes a reduction in DA reuptake by dopaminergic neurons related to a hitherto-unsuspected modification of the DAT interactome. These observations provide novel insights into the long-term antiparkinson, antidepressant and additional clinical actions of pramipexole and other D3 R agonists.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
High-energy pilon fractures are challenging injuries. Multiple options are described for the definitive surgical management of these fractures, but there is no level I evidence for optimal ...management. The current management and recommendations for treatment will be reviewed in this article.Anatomical reduction of the fracture, restoration of joint congruence and reconstruction of the posterior column with a correct limb axis minimising the soft-tissue insult are the key points to a good outcome when treating pilon fractures.Even when these goals are achieved, there is no guarantee that results will be acceptable in the mid-term due to the frequent progression to post-traumatic arthritis.In high-energy fractures with soft-tissue compromise, a staged treatment is generally accepted as the best way to take care of these devastating fractures and is considered a local 'damage control' strategy.The axial cuts from the CT scan images are essential in order to define the location of the main fracture line, the fracture pattern (sagittal or coronal) and the number of fragments. All of this information is crucial for pre-operative planning, incision placement and articular surface reduction.No single method of fixation is ideal for all pilon fractures, or suitable for all patients. Definitive decision making is mostly dependent on the fracture pattern, condition of the soft-tissues, the patient's profile and surgical expertise. Cite this article: Tomás-Hernández J. High-energy pilon fractures management: state of the art.
2016;1:354-361. DOI: 10.1302/2058-5241.1.000016.
Huntington’s disease (HD) is an autosomal dominant, incurable neurodegenerative disease caused by mutation in the huntingtin gene (HTT). HTT mutation leads to protein misfolding and aggregation, ...which affect cells’ functions and structural features. Because these changes might modify the scattering strength of affected cells, we propose that random lasing (RL) is an appropriate technique for detecting cells that express mutated HTT. To explore this hypothesis, we used a cell model of HD based on the expression of two different forms—pathogenic and non-pathogenic—of HTT. The RL signals from both cell profiles were compared. A multivariate statistical analysis of the RL signals based on the principal component analysis (PCA) and linear discriminant analysis (LDA) techniques revealed substantial differences between cells that expressed the pathogenic and the non-pathogenic forms of HTT.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Cortical onlay strut allografts, as the primary method of fixation or as a supplementary fixation when a plate is used, have been a common option to treat B1 and C type PFF in the past ...decades since the technique was described by Penenberg et al. in 1989 5 . Strut grafts were described as a useful treatment option because they provide structural support to the internal fixation while increasing the host bone stock without the harvesting complications. However, the use of struts have some concerns such as if the soft tissue stripping required for its application may lead into a delayed bone healing or increase the infection rate. Other concerns are the role as disease carrier, immune reactions, incorporation to the host bone in the long term and, in some centres, the availability and costs 27. This article reviews the literature regarding the use of struts in PFF and provides an overview on the use of strut grafts with actual recommendations based on the authors experience and the data from literature.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The significant environmental issue of water pollution caused by emerging contaminants underscores the imperative for developing novel cleanup methods that are efficient, economically viable, and ...that are intended to operate at high capacity and under continuous flows at the industrial scale. This study shows the results of the operational design to build a prototype for the retention at lab scale of pollutant residues in water by using as adsorbent material, insoluble polymers prepared by β-cyclodextrin and epichlorohydrin as a cross-linking agent. Laboratory in-batch tests were run to find out the adsorbent performances against furosemide and hydrochlorothiazide as pollutant models. The initial evaluation concerning the dosage of adsorbent, pH levels, agitation, and concentration of pharmaceutical pollutants enabled us to identify the optimal conditions for conducting the subsequent experiments. The adsorption kinetic and the mechanisms involved were evaluated revealing that the experimental data perfectly fit the pseudo second-order model, with the adsorption process being mainly governed by chemisorption. With K
constant values of 0.044 (L/g) and 0.029 (L/g) for furosemide and hydrochlorothiazide, respectively, and the determination coefficient (R
) being higher than 0.9 for both compounds, Freundlich yielded the most favorable outcomes, suggesting that the adsorption process occurs on heterogeneous surfaces involving both chemisorption and physisorption processes. The maximum monolayer adsorption capacity (q
) obtained by the Langmuir isotherm revealed a saturation of the β-CDs-EPI polymer surface 1.45 times higher for furosemide (q
= 1.282 mg/g) than hydrochlorothiazide (q
= 0.844 mg/g). Based on these results, the sizing design and building of a lab-scale model were carried out, which in turn will be used later to evaluate its performance working in continuous flow in a real scenario.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Introducción y objetivo: La cicatrización y los planos tisulares alterados se suman a la ya compleja anatomía del cuello y dificultan la localización de recidivas o metástasis no palpables en las ...reintervenciones cervicales del cáncer de tiroides. Síntesis: Describimos el uso de diversos técnicos de señalización empleadas para optimizar la cirugía y los resultados terapéuticos de pacientes con carcinoma papilar de tiroides con enfermedad cervical persistente o metastásica. Especialmente nos centramos en la técnica de localización utilizando semillas radiactivas (RSL) en la que se ha descrito, al igual que en la mama, excelentes resultados. Conclusiones: La RSL es una técnica segura, asociada a una mayor satisfacción del cirujano, con excelente tolerancia por el paciente, que, además, reduce el tiempo de la intervención quirúrgica proporciona mejores resultados cosméticos reduciendo el riesgo de morbilidad en comparación con el uso de colorantes, arpones y tatuajes. Además, permite el desacoplamiento completo de los programas de radiología y cirugía optimizando los tiempos y la programación de los quirófanos.
Purpose
Low prolactin (PRL) serum levels are associated with glucose intolerance and type 2 diabetes in adults, and with metabolic syndrome and obesity in children. In obese rodents, PRL treatment ...promotes insulin sensitivity by maintaining adipose tissue fitness, and lack of PRL signaling exacerbates obesity-derived metabolic alterations. Since adipose tissue dysfunction is a key factor triggering metabolic alterations, we evaluated whether PRL serum levels are associated with adipocyte hypertrophy (a marker of adipose tissue dysfunction), insulin resistance, and metabolic syndrome in lean, overweight, and obese adult men and women.
Methods
Samples of serum and adipose tissue from 40 subjects were obtained to evaluate insulin resistance index (homeostasis model assessment of insulin resistance (HOMA-IR)), signs of metabolic syndrome (glucose levels, high-density lipoproteins, triglycerides, blood pressure, and waist circumference), as well as adipocyte size and gene expression in fat.
Results
Lower PRL serum levels are associated with adipocyte hypertrophy, in visceral but not in subcutaneous fat, and with a higher HOMA-IR. Furthermore, low systemic PRL levels together with high waist circumference predict an elevated HOMA-IR whereas low serum PRL values in combination with high blood glucose predicts visceral adipocyte hypertrophy. In agreement, visceral fat from insulin resistant subjects shows reduced expression of prolactin receptor. However, there is no association between PRL levels and obesity or signs of metabolic syndrome.
Conclusions
Our results support that low levels of PRL are markers of visceral fat dysfunction and insulin resistance, and suggest the potential therapeutic value of medications elevating PRL levels to help maintain metabolic homeostasis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract The dopamine (DA) transporter (DAT) is a plasma membrane glycoprotein expressed in dopaminergic (DA-) cells that takes back DA into presynaptic neurons after its release. DAT dysfunction has ...been involved in different neuro-psychiatric disorders including Parkinson's disease (PD). On the other hand, numerous studies support that the glial cell line-derived neurotrophic factor (GDNF) has a protective effect on DA-cells. However, studies in rodents show that prolonged GDNF over-expression may cause a tyrosine hydroxylase (TH, the limiting enzyme in DA synthesis) decline. The evidence of TH down-regulation suggests that another player in DA handling, DAT, may also be regulated by prolonged GDNF over-expression, and the possibility that this effect is induced at GDNF expression levels lower than those inducing TH down-regulation. This issue was investigated here using intrastriatal injections of a tetracycline-inducible adeno-associated viral vector expressing human GDNF cDNA (AAV-tetON-GDNF) in rats, and doxycycline (DOX; 0.01, 0.03, 0.5 and 3 mg/ml) in the drinking water during 5 weeks. We found that 3 mg/ml DOX promotes an increase in striatal GDNF expression of 12 × basal GDNF levels and both DA uptake decrease and TH down-regulation in its native and Ser40 phosphorylated forms. However, 0.5 mg/ml DOX promotes a GDNF expression increase of 3 × basal GDNF levels with DA uptake decrease but not TH down-regulation. The use of western-blot under non-reducing conditions, co-immunoprecipitation and in situ proximity ligation assay revealed that the DA uptake decrease is associated with the formation of DAT dimers and an increase in DAT–α-synuclein interactions, without changes in total DAT levels or its compartmental distribution. In conclusion, at appropriate GDNF transduction levels, DA uptake is regulated through DAT protein–protein interactions without interfering with DA synthesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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