Diabetic retinopathy, oxidative stress and sirtuins: an in depth look in enzymatic patterns and new therapeutic horizons

Diabetic retinopathy (DR) is one of the leading causes of blindness in the world. DR represents the most common microvascular complication of diabetes, and its incidence is constantly rising. The complex interactions between inflammation, oxidative stress, and the production of free oxygen radicals caused by prolonged exposure to hyperglycemia determine the development of DR. Sirtuins (SIRTs) are a recently discovered class of 7 histone deacetylases involved in cellular senescence, regulation of cell cycle, metabolic pathways, and DNA repair. SIRTs participate in the progress of several pathologies such as cancer, neurodegenerative and metabolic diseases. In DR, sirtuins 1,3,5 and 6 play an important role as they regulate the activation of the inflammatory response, insulin sensibility, and both glycolysis and gluconeogenesis. A wide spectrum of direct and indirect activators of SIRTs pathways (e.g. antagomiR, resveratrol, or glycyrrhizin) is currently being developed to treat the inflammatory cascade occurring in DR. We focuse on the main metabolic and inflammatory pathways involving SIRTs and DR, as well as recent evidence on SIRTs activators that may be employed as novel therapeutic approaches to DR

Quiescent neuronal progenitors are activated in the juvenile guinea pig lateral striatum and give rise to transient neurons

In the adult brain, active stem cells are a subset of astrocytes residing in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. Whether quiescent neuronal progenitors occur in other brain regions is unclear. Here, we describe a novel neurogenic system in the external capsule and lateral striatum (EC-LS) of the juvenile guinea pig that is quiescent at birth but becomes active around weaning. Activation of neurogenesis in this region was accompanied by the emergence of a neurogenic-like niche in the ventral EC characterized by chains of neuroblasts, intermediate-like progenitors and glial cells expressing markers of immature astrocytes. Like neurogenic astrocytes of the SVZ and DG, these latter cells showed a slow rate of proliferation and retained BrdU labeling for up to 65 days, suggesting that they are the primary progenitors of the EC-LS neurogenic system. Injections of GFPtagged lentiviral vectors into the SVZ and the EC-LS of newborn animals confirmed that new LS neuroblasts originate from the activation of local progenitors and further supported their astroglial nature. Newborn EC-LS neurons existed transiently and did not contribute to neuronal addition or replacement. Nevertheless, they expressed Sp8 and showed strong tropism for white matter tracts, wherein they acquired complex morphologies. For these reasons, we propose that EC-LS neuroblasts represent a novel striatal cell type, possibly related to those populations of transient interneurons that regulate the development of fiber tracts during embryonic life

Dysbiosis triggers ACF development in genetically predisposed subjects

Background: Colorectal cancer (CRC) is the third most common cancer worldwide, characterized by a multifactorial etiology including genetics, lifestyle, and environmental factors including microbiota composition. To address the role of microbial modulation in CRC, we used our recently established mouse model (theWinnie-APCMin/+) combining inflammation and genetics. Methods: Gut microbiota profiling was performed on 8-week-old Winnie-APCMin/++ mice and their littermates by 16S rDNA gene amplicon sequencing. Moreover, to study the impact of dysbiosis induced by the mother’s genetics in ACF development, the large intestines of APCMin/++ mice born from wild type mice were investigated by histological analysis at 8 weeks. Results: ACF development in 8-week-old Winnie-APCMin/++ mice was triggered by dysbiosis. Specifically, the onset of ACF in genetically predisposed mice may result from dysbiotic signatures in the gastrointestinal tract of the breeders. Additionally, fecal transplant from Winnie donors to APCMin/++ hosts leads to an increased rate of ACF development. Conclusions: The characterization of microbiota profiling supporting CRC development in genetically predisposed mice could help to design therapeutic strategies to prevent dysbiosis. The application of these strategies in mothers during pregnancy and lactation could also reduce the CRC risk in the offspring

CD90 is regulated by notch1 and hallmarks a more aggressive intrahepatic cholangiocarcinoma phenotype

Background: Intrahepatic Cholangiocarcinoma (iCCA) is characterized by a strong stromal reaction playing a role in tumor progression. Thymus cell antigen 1 (THY1), also called Cluster of Differentiation 90 (CD90), is a key regulator of cell–cell and cell–matrix interaction. In iCCA, CD90 has been reported to be associated with a poor prognosis. In an iCCA PDX model, we recently found that CD90 was downregulated in mice treated with the Notch γ-secretase inhibitor Crenigacestat. The study aims to investigate the role of CD90 in relation to the NOTCH pathway. Methods: THY1/CD90 gene and protein expression was evaluated in human iCCA tissues and xenograft models by qRT-PCR, immunohistochemistry, and immunofluorescence. Notch1 inhibition was achieved by siRNA. THY1/CD90 functions were investigated in xenograft models built with HuCCT1 and KKU-M213 cell lines, engineered to overexpress or knockdown THY1, respectively. Results: CD90 co-localized with EPCAM, showing its epithelial origin. In vitro, NOTCH1 silencing triggered HES1 and THY1 down-regulation. RBPJ, a critical transcriptional regulator of NOTCH signaling, exhibited putative binding sites on the THY1 promoter and bound to the latter, implying CD90 as a downstream NOTCH pathway effector. In vivo, Crenigacestat suppressed iCCA growth and reduced CD90 expression in the PDX model. In the xenograft model, Crenigacestat inhibited tumor growth of HuCCT1 cells transfected to overexpress CD90 and KKU-M213 cells constitutively expressing high levels of CD90, while not affecting the growth of HuCCT1 control cells and KKU-M213 depleted of CD90. In an iCCA cohort, patients with higher expression levels of NOTCH1/HES1/THY1 displayed a significantly shorter survival. Conclusions: iCCA patients with higher NOTCH1/HES1/THY1 expression have the worst prognosis, but they are more likely to benefit from Notch signaling inhibition. These findings represent the scientific rationale for testing NOTCH1 inhibitors in clinical trials, taking the first step toward precision medicine for iCCA

Computing the lower and upper bounds of Laplace eigenvalue problem: by combining conforming and nonconforming finite element methods

This article is devoted to computing the lower and upper bounds of the Laplace eigenvalue problem. By using the special nonconforming finite elements, i.e., enriched Crouzeix-Raviart element and extension $Q_1^{\rm rot}$, we get the lower bound of the eigenvalue. Additionally, we also use conforming finite elements to do the postprocessing to get the upper bound of the eigenvalue. The postprocessing method need only to solve the corresponding source problems and a small eigenvalue problem if higher order postprocessing method is implemented. Thus, we can obtain the lower and upper bounds of the eigenvalues simultaneously by solving eigenvalue problem only once. Some numerical results are also presented to validate our theoretical analysis.Comment: 19 pages, 4 figure

A real quaternion spherical ensemble of random matrices

One can identify a tripartite classification of random matrix ensembles into geometrical universality classes corresponding to the plane, the sphere and the anti-sphere. The plane is identified with Ginibre-type (iid) matrices and the anti-sphere with truncations of unitary matrices. This paper focusses on an ensemble corresponding to the sphere: matrices of the form \bY= \bA^{-1} \bB, where \bA and \bB are independent $N\times N$ matrices with iid standard Gaussian real quaternion entries. By applying techniques similar to those used for the analogous complex and real spherical ensembles, the eigenvalue jpdf and correlation functions are calculated. This completes the exploration of spherical matrices using the traditional Dyson indices $\beta=1,2,4$. We find that the eigenvalue density (after stereographic projection onto the sphere) has a depletion of eigenvalues along a ring corresponding to the real axis, with reflective symmetry about this ring. However, in the limit of large matrix dimension, this eigenvalue density approaches that of the corresponding complex ensemble, a density which is uniform on the sphere. This result is in keeping with the spherical law (analogous to the circular law for iid matrices), which states that for matrices having the spherical structure \bY= \bA^{-1} \bB, where \bA and \bB are independent, iid matrices the (stereographically projected) eigenvalue density tends to uniformity on the sphere.Comment: 25 pages, 3 figures. Added another citation in version

Simulation of the arterial elasticity influence on the Ambulatory Arterial Stiffness Index AASI

Recientemente se propuso un índice de rigidez arterial denominado AASI (Ambulatory Arterial Stiffness Index) derivado de mediciones ambulatorias de presión arterial durante 24 horas. Su asociación como índice de rigidez y la infl uencia estadística de la dispersión en los valores presivos continúa bajo discusión. Proponemos estudiar estas controversias en el contexto de un modelo estadístico. Se realizó una simulación con valores similares a los de pacientes de arterias normales, rígidas y compliantes, utilizando 3 curvas exponenciales presión-diámetro. Se generaron diámetros pulsátiles aleatorios siguiendo distribuciones normales y se obtuvieron presiones sistólicas y diastólicas en tiempos paramétricos equivalentes a 24 horas. Se calculó el AASI como uno menos la pendiente de la regresión de presión arterial sistólica y diastólica. El AASI del grupo normal resultó 0,42, aumentó a 0,50 en el rígido y disminuyó a 0,34 en el compliante (siempre con r2>0,9). Disminuir la dispersión del rango de presiones provocó una disminución de r2 en la regresión de la nube de puntos de presión sistólica y diastólica, aumentando artifi cialmente el AASI. Por primera vez la elasticidad no-lineal de la pared arterial ayuda a explicar la asociación del AASI como índice de rigidez arterial. La simulación corrobora que la dispersión de los valores presivos condicionan el cálculo del AASI debido a su naturaleza estadística.Recently, an arterial stiffness index called AASI (Ambulatory Arterial Stiffness Index) calculated from ambulatory blood pressure measurements during 24 hours was proposed. The associations with arterial stiffness and the pressure dispersion dependence remain under discussion. We propose to study these controversies in a statistical model framework. A simulation was performed including values similar to the ones in patients with normal, rigid and compliant arteries. Three exponential curves of pressure-diameter were simulated. Based on diameters randomly generated following normal distributions, systolic and diastolic pressures were calculated in a 24h parametric time. AASI was calculated as one minus the slope of the regression of systolic to diastolic pressure. The AASI for the normal group was 0,42, increased to 0,50 in the rigid group and decreased to 0,34 in the compliant case (always r2>0,9). A dispersion decrease in the pressure values was followed by an r2 decrease in the diastolic vs systolic pressure regression, artifi cially increasing AASI. For the fi rst time the non-linearity of the arterial wall helps to explain the association of AASI with a stiffness index. The simulation corroborates that 24 h pressure variability conditions AASI values due to its statistical nature

Goal-recognition-based adaptive brain-computer interface for navigating immersive robotic systems

© 2017 IOP Publishing Ltd. Objective. This work proposes principled strategies for self-adaptations in EEG-based Brain-computer interfaces (BCIs) as a way out of the bandwidth bottleneck resulting from the considerable mismatch between the low-bandwidth interface and the bandwidth-hungry application, and a way to enable fluent and intuitive interaction in embodiment systems. The main focus is laid upon inferring the hidden target goals of users while navigating in a remote environment as a basis for possible adaptations. Approach. To reason about possible user goals, a general user-agnostic Bayesian update rule is devised to be recursively applied upon the arrival of evidences, i.e. user input and user gaze. Experiments were conducted with healthy subjects within robotic embodiment settings to evaluate the proposed method. These experiments varied along three factors: the type of the robot/environment (simulated and physical), the type of the interface (keyboard or BCI), and the way goal recognition (GR) is used to guide a simple shared control (SC) driving scheme. Main results. Our results show that the proposed GR algorithm is able to track and infer the hidden user goals with relatively high precision and recall. Further, the realized SC driving scheme benefits from the output of the GR system and is able to reduce the user effort needed to accomplish the assigned tasks. Despite the fact that the BCI requires higher effort compared to the keyboard conditions, most subjects were able to complete the assigned tasks, and the proposed GR system is additionally shown able to handle the uncertainty in user input during SSVEP-based interaction. The SC application of the belief vector indicates that the benefits of the GR module are more pronounced for BCIs, compared to the keyboard interface. Significance. Being based on intuitive heuristics that model the behavior of the general population during the execution of navigation tasks, the proposed GR method can be used without prior tuning for the individual users. The proposed methods can be easily integrated in devising more advanced SC schemes and/or strategies for automatic BCI self-adaptations

High field level crossing studies on spin dimers in the low dimensional quantum spin system Na2_2T2_2(C2_2O4_4)3_3(H2_2O)2_2 with T=Ni,Co,Fe,Mn

In this paper we demonstrate the application of high magnetic fields to study the magnetic properties of low dimensional spin systems. We present a case study on the series of 2-leg spin-ladder compounds Na$_2$T$_2$(C$_2$O$_4$)$_3$(H$_2$O)$_2$ with T = Ni, Co, Fe and Mn. In all compounds the transition metal is in the $T^{2+}$ high spin configuation. The localized spin varies from S=1 to 3/2, 2 and 5/2 within this series. The magnetic properties were examined experimentally by magnetic susceptibility, pulsed high field magnetization and specific heat measurements. The data are analysed using a spin hamiltonian description. Although the transition metal ions form structurally a 2-leg ladder, an isolated dimer model consistently describes the observations very well. This behaviour can be understood in terms of the different coordination and superexchange angles of the oxalate ligands along the rungs and legs of the 2-leg spin ladder. All compounds exhibit magnetic field driven ground state changes which at very low temperatures lead to a multistep behaviour in the magnetization curves. In the Co and Fe compounds a strong axial anisotropy induced by the orbital magnetism leads to a nearly degenerate ground state and a strongly reduced critical field. We find a monotonous decrease of the intradimer magnetic exchange if the spin quantum number is increased