ER Dysfunction and Protein Folding Stress in ALS

Amyotrophic lateral sclerosis (ALS) is the most frequent paralytic disease in adults. Most ALS cases are considered sporadic with no clear genetic component. The disruption of protein homeostasis due to chronic stress responses at the endoplasmic reticulum (ER) and the accumulation of abnormal protein inclusions are extensively described in ALS mouse models and patient-derived tissue. Recent studies using pharmacological and genetic manipulation of the unfolded protein response (UPR), an adaptive reaction against ER stress, have demonstrated a complex involvement of the pathway in experimental models of ALS. In addition, quantitative changes in ER stress-responsive chaperones in body fluids have been proposed as possible biomarkers to monitor the disease progression. Here we review most recent advances attributing a causal role of ER stress in ALS

Functional Contribution of the Transcription Factor ATF4 to the Pathogenesis of Amyotrophic Lateral Sclerosis

Endoplasmic reticulum (ER) stress represents an early pathological event in amyotrophic lateral sclerosis (ALS). ATF4 is a key ER stress transcription factor that plays a role in both adaptation to stress and the activation of apoptosis. Here we investigated the contribution of ATF4 to ALS. ATF4 deficiency reduced the rate of birth of SOD1G86R transgenic mice. The fraction of ATF4−/−-SOD1G85R transgenic mice that were born are more resistant to develop ALS, leading to delayed disease onset and prolonged life span. ATF4 deficiency completely attenuated the induction of pro-apoptotic genes, including BIM and CHOP, and also led to quantitative changes in the ER protein homeostasis network. Unexpectedly, ATF4 deficiency enhanced mutant SOD1 aggregation at the end stage of the disease. Studies in the motoneuron cell line NSC34 demonstrated that knocking down ATF4 enhances mutant SOD1 aggregation possibly due to alteration in the redox status of the cell. Our results support a functional role of ATF4 in ALS, offering a novel target for disease intervention

Optical Camera Communications for IoT–Rolling-Shutter Based MIMO Scheme with Grouped LED Array Transmitter

In optical camera communications (OCC), the provision of both flicker-free illumination and high data rates are challenging issues, which can be addressed by utilizing the rolling-shutter (RS) property of the image sensors as the receiver (Rx). In this paper, we propose an RS-based multiple-input multiple-output OCC scheme for the Internet of things (IoT) application. A simplified design of multi-channel transmitter (Tx) using a 7.2 × 7.2 cm2 small 8 × 8 distributed light emitting diode (LED) array, based on grouping of LEDs, is proposed for flicker-free transmission. We carry out an experimental investigation of the indoor OCC system by employing a Raspberry Pi camera as the Rx, with RS capturing mode. Despite the small area of the display, flicker-free communication links within the range of 20–100 cm are established with data throughput of 960 to 120 bps sufficient for IoT. A method to extend link spans up to 1.8 m and the data throughput to 13.44 kbps using different configurations of multi-channel Tx is provided. The peak signal-to-noise ratio of ~14 and 16 dB and the rate of successfully received bits of 99.4 and 81% are measured for the shutter speeds of 200 and 800 µs for a link span of 1 m, respectively

The First Study of MIMO Scheme Within Rolling-shutter Based Optical Camera Communications

In this paper, we propose the first study of MIMO (multiple-input multiple-output) scheme using a simplified design of MIMO transmitter (Tx) based on grouping of light-emitting diodes (LED) within an array for flicker-free transmission in optical camera based communications (OCC) link. We carried out an initial experimental investigation of indoor static downlink OCC using a Raspberry Pi camera as the receiver with rolling-shutter capturing mode and a 7.2 cm × 7.2 cm small 64-neopixel LED array as the Tx. The initial study suggests that, despite the small area of the display, communication links from 20 up to 60 cm can be established

SIMULADOR TRIDIMENSIONAL DE LA CINEMÁTICA DEL ROTOR DE UN AEROGENERADOR TRIPALA CON BASE EN LA CONVENCIÓN D-H

ResumenLos simuladores permiten al usuario observar e interactuar con representaciones de situaciones reales o hipotéticas a través del uso de modelos computacionales. La gran diversidad de variables y parámetros en sistemas complejos como los aerogeneradores, limita el uso de simuladores ya existentes para el caso de nuevos diseños. Una alternativa explorada para visualizar el comportamiento de estos sistemas es el uso de representaciones tridimensionales. En este artículo se presenta el modelado cinemático del rotor de un aerogenerador mediante el empleo de la convención Denavit-Hartenberg, y su aplicación en el desarrollo de simulador tridimensional del movimiento del rotor. En una medición de recursos computacionales el porcentaje utilizado por el simulador osciló entre el 12% y 13%, mientras para un software de diseño asistido por computadora fue de 14% y 16%.Palabras Claves: Aerogenerador, Denavit-Hartenberg, modelo cinemático, simulación tridimensional. THREE-DIMENSIONAL SIMULATOR OF THE ROTOR CINEMATICS OF A TRIPALA WIND TURBINE BASED ON THE D-H CONVENTIONAbstractSimulators allow a user to observe and to interact with illustrations of real or hypothetical situations through computational models. The wide range of variables and parameters in these complex systems such as wind turbines restricts the use of existing simulators for new designs. The use of three-dimensional simulators is an alternative which has been explored to visualize the behavior of these systems. This article presents a kinematic model of a wind turbine rotor that uses the Denavit-Hartenberg convention and its application in the development of a three-dimensional rotor motion simulator. The measure of computational resource indicates that the simulator used between 12% and 13% of the resource, unlike the computer-aided design software which used between 14% and 16%.Keywords: Denavit-Hartenberg, kinematic model, wind turbines, 3D simulation

Euler-Lagrange modelling for three-bladed rotors in wind turbines as a multibody system

Con el propósito de desarrollar estrategias para el mayor aprovechamiento del recurso eólico, es necesario disponer de modelos confiables para simular la respuesta de los aerogeneradores. Si bien, los fabricantes cuentan con modelos detallados, estos son generalmente de “caja negra”, lo que los hace incluso inutilizable en nuevos diseños. Así, los llamados modelos genéricos han proliferado. Bajo este enfoque, en este artículo se presenta el modelado dinámico del rotor de un aerogenerador tripala usando la formulación Euler-Lagrange. Para su análisis el rotor es descrito como un sistema multicuerpo de cuatro grados de libertad empleando matrices de transformación simplificadas. Se exponen los detalles de la obtención del modelo, y la interpretación de su simulación tridimensional (3D) bajo diversas condiciones, que garantiza una fácil comprobación de la fiabilidad del modelo.In order to develop strategies to maximize the utilization of wind power, it is necessary to have reliable models to simulate wind turbines’ responses. Manufacturers have detailed models, though these are “black box”, which makes them unusable even in new designs. Thus, so-called generic models have proliferated. Under this approach, this article presents dynamic modeling for a three-bladed rotor in a wind turbine using Euler-Lagrange formulation. For this analysis, the rotor is described as a multibody system with four degrees of freedom using simplified transformation matrices. The details of how the model was obtained and the interpretation of its three-dimensional (3D) simulation are presented using diverse conditions, which guarantees that the model’s reliability can be easily verified

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Gramatica Zapoteca

2 pp