Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Optical Control of Mammalian Endogenous Transcription and Epigenetic States

The dynamic nature of gene expression enables cellular programming, homeostasis, and environmental adaptation in living systems. Dissection of causal gene functions in cellular and organismal processes therefore necessitates approaches that enable spatially and temporally precise modulation of gene expression. Recently, a variety of microbial and plant-derived light-sensitive proteins have been engineered as optogenetic actuators, enabling high precision spatiotemporal control of many cellular functions1-11. However, versatile and robust technologies that enable optical modulation of transcription in the mammalian endogenous genome remain elusive. Here, we describe the development of Light-Inducible Transcriptional Effectors (LITEs), an optogenetic two-hybrid system integrating the customizable TALE DNA-binding domain12-14 with the light-sensitive cryptochrome 2 protein and its interacting partner CIB1 from Arabidopsis thaliana. LITEs do not require additional exogenous chemical co-factors, are easily customized to target many endogenous genomic loci, and can be activated within minutes with reversibility3,4,6,7,15. LITEs can be packaged into viral vectors and genetically targeted to probe specific cell populations. We have applied this system in primary mouse neurons, as well as in the brain of awake mice in vivo to mediate reversible modulation of mammalian endogenous gene expression as well as targeted epigenetic chromatin modifications. The LITE system establishes a novel mode of optogenetic control of endogenous cellular processes and enables direct testing of the causal roles of genetic and epigenetic regulation in normal biological processes and disease states

Overcoming Multidrug Resistance via Photodestruction of ABCG2-Rich Extracellular Vesicles Sequestering Photosensitive Chemotherapeutics

Multidrug resistance (MDR) remains a dominant impediment to curative cancer chemotherapy. Efflux transporters of the ATP-binding cassette (ABC) superfamily including ABCG2, ABCB1 and ABCC1 mediate MDR to multiple structurally and functionally distinct antitumor agents. Recently we identified a novel mechanism of MDR in which ABCG2-rich extracellular vesicles (EVs) form in between attached neighbor breast cancer cells and highly concentrate various chemotherapeutics in an ABCG2-dependent manner, thereby sequestering them away from their intracellular targets. Hence, development of novel strategies to overcome MDR modalities is a major goal of cancer research. Towards this end, we here developed a novel approach to selectively target and kill MDR cancer cells. We show that illumination of EVs that accumulated photosensitive cytotoxic drugs including imidazoacridinones (IAs) and topotecan resulted in intravesicular formation of reactive oxygen species (ROS) and severe damage to the EVs membrane that is shared by EVs-forming cells, thereby leading to tumor cell lysis and the overcoming of MDR. Furthermore, consistent with the weak base nature of IAs, MDR cells that are devoid of EVs but contained an increased number of lysosomes, highly accumulated IAs in lysosomes and upon photosensitization were efficiently killed via ROS-dependent lysosomal rupture. Combining targeted lysis of IAs-loaded EVs and lysosomes elicited a synergistic cytotoxic effect resulting in MDR reversal. In contrast, topotecan, a bona fide transport substrate of ABCG2, accumulated exclusively in EVs of MDR cells but was neither detected in lysosomes of normal breast epithelial cells nor in non-MDR breast cancer cells. This exclusive accumulation in EVs enhanced the selectivity of the cytotoxic effect exerted by photodynamic therapy to MDR cells without harming normal cells. Moreover, lysosomal alkalinization with bafilomycin A1 abrogated lysosomal accumulation of IAs, consequently preventing lysosomal photodestruction of normal breast epithelial cells. Thus, MDR modalities including ABCG2-dependent drug sequestration within EVs can be rationally converted to a pharmacologically lethal Trojan horse to selectively eradicate MDR cancer cells

At-risk elementary school children with one year of classroom music instruction are better at keeping a beat

Temporal processing underlies both music and language skills. There is increasing evidence that rhythm abilities track with reading performance and that language disorders such as dyslexia are associated with poor rhythm abilities. However, little is known about how basic time-keeping skills can be shaped by musical training, particularly during critical literacy development years. This study was carried out in collaboration with Harmony Project, a non-profit organization providing free music education to children in the gang reduction zones of Los Angeles. Our findings reveal that elementary school children with just one year of classroom music instruction perform more accurately in a basic finger-tapping task than their untrained peers, providing important evidence that fundamental time-keeping skills may be strengthened by short-term music training. This sets the stage for further examination of how music programs may be used to support the development of basic skills underlying learning and literacy, particularly in at-risk populations which may benefit the most

Synchronized Multimedia Integration Language (SMIL) 1.0

This document specifies version 1 of the Synchronized Multimedia Integration Language (SMIL 1.0, pronounced "smile"). SMIL allows integrating a set of independent multimedia objects into a synchronized multimedia presentation. Using SMIL, an author can 1. describe the temporal behavior of the presentation 2. describe the layout of the presentation on a screen 3. associate hyperlinks with media objects This specification is structured as follows: Section 1 presents the specification approach. Section 2 defines the "smil" element. Section 3 defines the elements that can be contained in the head part of a SMIL document. Section 4 defines the elements that can be contained in the body part of a SMIL document. In particular, this Section defines the time model used in SMIL. Section 5 describes the SMIL DTD

Investigation of protective clothing materials being in contact with hot bodies

W artykule przedstawiono wyniki badań zestawów komponentów ubrań specjalnych na innowacyjnym stanowisku do badania materiałów ochron osobistych będących w kontakcie z ciałami o podwyższonej temperaturze, powstałym w trakcie realizacji projektu innoos. Autorzy przebadali 120 próbek materiałów ubrań strażackich pod kątem skuteczności ochrony przed oparzeniem ii stopnia. Wykorzystano kryterium oparte o całkę Henriquesa oraz zaproponowane przez wykonawców kryterium chti. Uzyskane wyniki podkreślają wagę kwestii doprecyzowania norm wykorzystywanych do oceny jakości specjalnych ubrań strażackich w Polsce.The paper presents the results of investigation of sets of protective clothing components sets, performed on innovative stand for testing personal protective materials being in contact with bodies at elevated temperature, that was built during the innoos project. The authors examined 120 samples of firefighting clothing materials, regarding their effectiveness in protection against second degree burn injuries. A criterion based on the Henriques integral and chti criterion proposed by authors was used. The results emphasize the importance of clarification of the standards for the evaluation of the quality of protective clothing for firefighters in Poland