Nutrigenetic reprogramming of oxidative stress

Retinal disorders such as retinitis pigmentosa, age-related retinal degeneration, oxygen-induced retinopathy, and ischemia-reperfusion injury cause debilitating and irreversible vision loss. While the exact mechanisms underlying these conditions remain unclear, there has been a growing body of evidence demonstrating the pathological contributions of oxidative stress across different cell types within the eye. Nuclear factor erythroid-2-related factor (Nrf2), a transcriptional activator of antioxidative genes, and its regulator Kelch-like ECH-associated protein 1 (Keap1) have emerged as promising therapeutic targets. The purpose of this review is to understand the protective role of the Nrf2-Keap1 pathway in different retinal tissues and shed light on the complex mechanisms underlying these processes. In the photoreceptors, we highlight that Nrf2 preserves their survival and function by maintaining oxidation homeostasis. In the retinal pigment epithelium, Nrf2 similarly plays a critical role in oxidative stabilization but also maintains mitochondrial motility and autophagy-related lipid metabolic processes. In endothelial cells, Nrf2 seems to promote proper vascularization and revascularization through concurrent activation of antioxidative and angiogenic factors as well as inhibition of inflammatory cytokines. Finally, Nrf2 protects retinal ganglion cells against apoptotic cell death. Importantly, we show that Nrf2-mediated protection of the various retinal tissues corresponds to a preservation of functional vision. Altogether, this review underscores the potential of the Nrf2-Keap1 pathway as a powerful tool against retinal degeneration. Key insights into this elegant oxidative defense mechanism may ultimately pave the path toward a universal therapy for various inherited and environmental retinal disorders

Damage Patterns/Response of Deep Stiff Clay in Oakland

The 1985 Mexico City earthquake and the 1989 Loma Prieta earthquake provided well-documented evidence of the effect of local ground conditions on site response and damage patterns. Deep soft clay deposits, in particular, were often cited as the culprit of amplified ground motions. However, during the 1989 Loma Prieta earthquake, ground accelerations in the downtown Oakland area were amplified by a factor of two to four and a significant number of structures were heavily damaged, despite the fact that much of the area is underlain by deposits of deep stiff clay. A preliminary review of damage patterns in the Oakland area and preliminary site response analyses were performed to investigate the influence of deep stiff clay deposits on the observed ground motions

Dirac-Electrons-Mediated Magnetic Proximity Effect in Topological Insulator / Magnetic Insulator Heterostructures

The possible realization of dissipationless chiral edge current in a topological insulator / magnetic insulator heterostructure is based on the condition that the magnetic proximity exchange coupling at the interface is dominated by the Dirac surface states of the topological insulator. Here we report a polarized neutron reflectometry observation of Dirac electrons mediated magnetic proximity effect in a bulk-insulating topological insulator (Bi$_{0.2}$Sb$_{0.8}$)$_{2}$Te$_{3}$ / magnetic insulator EuS heterostructure. We are able to maximize the proximity induced magnetism by applying an electrical back gate to tune the Fermi level of topological insulator to be close to the charge neutral point. A phenomenological model based on diamagnetic screening is developed to explain the suppressed proximity induced magnetism at high carrier density. Our work paves the way to utilize the magnetic proximity effect at the topological insulator/magnetic insulator hetero-interface for low-power spintronic applications.Comment: 5 pages main text with 4 figures; 2 pages supplemental materials; suggestions and discussions are welcome

CD94 and a Novel Associated Protein (94AP) Form a NK Cell Receptor Involved in the Recognition of HLA-A, HLA-B, and HLA-C Allotypes

AbstractWhereas the human killer cell inhibitory receptors (KIRs) for HLA class I are immunoglobulin-like monomeric type I glycoproteins, the murine Ly49 receptors for H-2 are type II homodimers of the C-type lectin superfamily. Here, we demonstrate that human NK cells also express C-type lectin receptors that influence recognition of polymorphic HLA-A, HLA-B, and HLA-C molecules. These receptors are heterodimers composed of CD94 chains covalently associated with novel tyrosine-phosphorylated glycoproteins (94AP). Some NK clones recognize a common HLA-C ligand using both KIRs and CD94–94AP receptors. These findings suggest the existence of human inhibitory MHC class I receptors of the immunoglobulin and C-type lectin superfamilies and indicate overlap in ligand specificity

Delays in Leniency Application: Is There Really a Race to the Enforcer's Door?

This paper studies cartels’ strategic behavior in delaying leniency applications, a take-up decision that has been ignored in the previous literature. Using European Commission decisions issued over a 16-year span, we show, contrary to common beliefs and the existing literature, that conspirators often apply for leniency long after a cartel collapses. We estimate hazard and probit models to study the determinants of leniency-application delays. Statistical tests find that delays are symmetrically affected by antitrust policies and macroeconomic fluctuations. Our results shed light on the design of enforcement programs against cartels and other forms of conspiracy

In Vitro-In Vivo Translation of Lipid Nanoparticles for Hepatocellular siRNA Delivery

A significant challenge in the development of clinically viable siRNA delivery systems is a lack of in vitro–in vivo translatability: many delivery vehicles that are initially promising in cell culture do not retain efficacy in animals. Despite its importance, little information exists on the predictive nature of in vitro methodologies, most likely due to the cost and time associated with generating in vitro–in vivo data sets. Recently, high-throughput techniques have been developed that have allowed the examination of hundreds of lipid nanoparticle formulations for transfection efficiency in multiple experimental systems. The large resulting data set has allowed the development of correlations between in vitro and characterization data and in vivo efficacy for hepatocellular delivery vehicles. Consistency of formulation technique and the type of cell used for in vitro experiments was found to significantly affect correlations, with primary hepatocytes and HeLa cells yielding the most predictive data. Interestingly, in vitro data acquired using HeLa cells were more predictive of in vivo performance than mouse hepatoma Hepa1-6 cells. Of the characterization parameters, only siRNA entrapment efficiency was partially predictive of in vivo silencing potential, while zeta-potential and, surprisingly, nanoparticle size (when <300 nm) as measured by dynamic light scattering were not. These data provide guiding principles in the development of clinically viable siRNA delivery materials and have the potential to reduce experimental costs while improving the translation of materials into animals.Alnylam Pharmaceuticals (Firm)National Institutes of Health (U.S.) (Fellowship Award F32EB009623

The increasing trend in preterm birth in public hospitals in northern Argentina

Objective: To identify factors associated with the increasing incidence of preterm birth in northern Argentina. Methods: In an observational study, data were reviewed from a prospective, population-based registry of pregnancy outcomes in six cities in 2009-2012. The primary outcome was preterm birth (at 20-37 weeks). Bivariate tests and generalized estimating equations were used within a conceptual hierarchical framework to estimate the cluster-corrected annual trend in odds of preterm birth. Results: The study reviewed data from 11 433 live births. There were 484 (4.2%) preterm births. The incidence of preterm births increased by 38% between 2009 and 2012, from 37.5 to 51.7 per 1000 live births. Unadjusted risk factors for preterm birth included young or advanced maternal age, normal body mass index, nulliparity, no prenatal care, no vitamins or supplements during pregnancy, multiple gestation, and maternal hypertension or prepartum hemorrhage. The prevalence of many risk factors increased over the study period, but variations in these factors explained less than 1% of the increasing trend in preterm birth. Conclusion: The incidence of preterm births insix small cities in northern Argentina increased greatly between 2009 and 2012. This trend was unexplained by the risk factors measured. Other factors should be assessed in future studies.Fil: Weaver, Emily H.. University of North Carolina School at Chapel Hill; Estados UnidosFil: Gibbons, Luz. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Belizan, Jose. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Althabe, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Efectividad Clínica y Sanitaria; Argentin

Reduction of freezing of gait in Parkinson's disease by repetitive robot-assisted treadmill training: a pilot study

<p>Abstract</p> <p>Background</p> <p>Parkinson's disease is a chronic, neurodegenerative disease characterized by gait abnormalities. Freezing of gait (FOG), an episodic inability to generate effective stepping, is reported as one of the most disabling and distressing parkinsonian symptoms. While there are no specific therapies to treat FOG, some external physical cues may alleviate these types of motor disruptions. The purpose of this study was to examine the potential effect of continuous physical cueing using robot-assisted sensorimotor gait training on reducing FOG episodes and improving gait.</p> <p>Methods</p> <p>Four individuals with Parkinson's disease and FOG symptoms received ten 30-minute sessions of robot-assisted gait training (Lokomat) to facilitate repetitive, rhythmic, and alternating bilateral lower extremity movements. Outcomes included the FOG-Questionnaire, a clinician-rated video FOG score, spatiotemporal measures of gait, and the Parkinson's Disease Questionnaire-39 quality of life measure.</p> <p>Results</p> <p>All participants showed a reduction in FOG both by self-report and clinician-rated scoring upon completion of training. Improvements were also observed in gait velocity, stride length, rhythmicity, and coordination.</p> <p>Conclusions</p> <p>This pilot study suggests that robot-assisted gait training may be a feasible and effective method of reducing FOG and improving gait. Videotaped scoring of FOG has the potential advantage of providing additional data to complement FOG self-report.</p