Dizajn, razvoj i vrednovanje novih nanoemulzija za transdermalnu primjenu celekoksiba

The aim of the present study was to investigate the potential of nanoemulsion formulations for transdermal delivery of celecoxib (CXB). The in vitro skin permeation profile of optimized formulations was compared with CXB gel and nanoemulsion gel. Significant increase in the steady state flux (Jss), permeability coefficient (Kp) and enhancement ratio (Er) was observed in nanoemulsion formulations T1 and T2 (p < 0.05). The highest value of these permeability parameters was obtained in formulation T2, which consisted of 2% m/m of CXB, 10% m/m of oil phase (Sefsol 218 and Triacetin), 50% m/m of surfactant mixture (Tween-80 and Transcutol-P) and 40% m/m of water. The anti-inflammatory effects of formulation T2 showed a significant increase (p < 0.05) in inhibition after 24 h compared to CXB gel and nanoemulsion gel on carrageenean-induced paw edema in rats. These results suggested that nanoemulsions are potential vehicles for improved transdermal delivery of CXB.U radu su opisana ispitivanja nanoemulzija za transdermalnu primjenu celekoksiba (CXB). Profil permeacije kroz kožu ispitivan je in vitro i uspoređivan sa CXB gelom i nanoemulzijskim gelom. U formulacijama T1 i T2 postignuto je značajno povećanje ustaljenog fluksa (Jss), koeficijenta permeabilnosti (Kp) i povećanje omjera (Er) (p < 0.05). Najveće vrijednosti parametara permeabilnosti dobivene su u formulaciji T2 koja je sadržala 2% m/m CXB, 10% m/m uljne faze (Sefsol 218 i Triacetin), 50% m/m površinski-aktivnih tvari (Tween-80 i Transcutol-P) i 40% m/m vode. Protuupalno djelovanje formulacije T2 na edem šape štakora uzrokovan karageninom značajno je povećano (p < 0.05) poslije 24 h u usporedbi sa CXB gelom i nanoemulzijskim gelom. Rezultati ukazuju na poboljšanu isporuku celekoksiba putem nanoemulzija

Visualizing Escherichia coli Sub-Cellular Structure Using Sparse Deconvolution Spatial Light Interference Tomography

Studying the 3D sub-cellular structure of living cells is essential to our understanding of biological function. However, tomographic imaging of live cells is challenging mainly because they are transparent, i.e., weakly scattering structures. Therefore, this type of imaging has been implemented largely using fluorescence techniques. While confocal fluorescence imaging is a common approach to achieve sectioning, it requires fluorescence probes that are often harmful to the living specimen. On the other hand, by using the intrinsic contrast of the structures it is possible to study living cells in a non-invasive manner. One method that provides high-resolution quantitative information about nanoscale structures is a broadband interferometric technique known as Spatial Light Interference Microscopy (SLIM). In addition to rendering quantitative phase information, when combined with a high numerical aperture objective, SLIM also provides excellent depth sectioning capabilities. However, like in all linear optical systems, SLIM's resolution is limited by diffraction. Here we present a novel 3D field deconvolution algorithm that exploits the sparsity of phase images and renders images with resolution beyond the diffraction limit. We employ this label-free method, called deconvolution Spatial Light Interference Tomography (dSLIT), to visualize coiled sub-cellular structures in E. coli cells which are most likely the cytoskeletal MreB protein and the division site regulating MinCDE proteins. Previously these structures have only been observed using specialized strains and plasmids and fluorescence techniques. Our results indicate that dSLIT can be employed to study such structures in a practical and non-invasive manner

The natural wood regime in rivers

International audienc

The Effects of Age on Inflammatory and Coagulation-Fibrinolysis Response in Patients Hospitalized for Pneumonia

Objective: To determine whether inflammatory and hemostasis response in patients hospitalized for pneumonia varies by age and whether these differences explain higher mortality in the elderly. Methods: In an observational cohort of subjects with community-acquired pneumonia (CAP) recruited from emergency departments (ED) in 28 hospitals, we divided subjects into 5 age groups (85% subjects, older subjects had modestly increased hemostasis markers and IL-6 levels (p,0.01). Conclusions: Modest age-related increases in coagulation response occur during hospitalization for CAP; however these differences do not explain the large differences in mortality. Despite clinical recovery, immune resolution may be delayed in older adults at discharge. © 2010 Kale et al

Indicators of river system hydromorphological character and dynamics: understanding current conditions and guiding sustainable river management

The work leading to this paper received funding from the EU’s FP7 programme under Grant Agreement No. 282656 (REFORM). The Indicators were developed within the context of REFORM deliverable D2.1, therefore all partners involved in this deliverable contributed to some extent to their discussion and development

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Allosteric pyruvate kinase-based "logic gate" synergistically senses energy and sugar levels in <i>Mycobacterium tuberculosis</i>

Pyruvate kinase (PYK) is an essential glycolytic enzyme that controls glycolytic flux and is critical for ATP production in all organisms, with tight regulation by multiple metabolites. Yet the allosteric mechanisms governing PYK activity in bacterial pathogens are poorly understood. Here we report biochemical, structural and metabolomic evidence that Mycobacterium tuberculosis (Mtb) PYK uses AMP and glucose-6-phosphate (G6P) as synergistic allosteric activators that function as a molecular "OR logic gate" to tightly regulate energy and glucose metabolism. G6P was found to bind to a previously unknown site adjacent to the canonical site for AMP. Kinetic data and structural network analysis further show that AMP and G6P work synergistically as allosteric activators. Importantly, metabolome profiling in the Mtb surrogate, Mycobacterium bovis BCG, reveals significant changes in AMP and G6P levels during nutrient deprivation, which provides insights into how a PYK OR gate would function during the stress of Mtb infection