Coordination Between Autophagy and the Heat Shock Response: Evidence From Exercise in Animals and Humans

Proteins play a critical role in nearly every biological activity. In consequence, organismal health and homeostasis often hinges on the ability of intracellular regulatory systems to sustain the quality and function of these diverse, structurally complex macromolecules. Correct protein function depends on correct form, and during periods of destabilizing cellular stress, protein quality is managed in part by the heat shock response, which acts to support, isolate, and reform new or damaged proteins, and in part by the autophagic recycling of abnormal proteins, cytotoxic protein aggregates, and terminally damaged organelles. We conducted a pooled analysis of available research in humans and rodents regarding heat shock and autophagic activity through the unique proteostatic challenges presented by acute exercise and the post-exercise progression from catabolism to anabolism. This analysis reinforces a model of regulatory coordination between these protein management pathways, offering interspecies support for an Hsp70-moderated transition away from the presiding catabolic influence of autophagy in the immediate post-exercise window, toward an anabolic phase of restoration and remodeling. This relationship has been demonstrated with direct human cellular research, and may help shed light on the molecular underpinning of epidemiological associations between health and physical activity. Differential responses were also observed in these two primary proteostatic systems according to exercise intensity and tissue of origin, which may have important implications for research design, and perhaps eventually for exercise prescription

Autophagy and Aging: Maintaining the Proteome through Exercise and Caloric Restriction

Accumulation of dysfunctional and damaged cellular proteins and organelles occursduring aging, resulting in a disruption of cellular homeostasis and progressive degen-eration and increases the risk of cell death. Moderating the accrual of these defunctcomponents is likely a key in the promotion of longevity. While exercise is knownto promote healthy aging and mitigate age‐related pathologies, the molecular under-pinnings of this phenomenon remain largely unclear. However, recent evidencessuggest that exercise modulates the proteome. Similarly, caloric restriction (CR), aknown promoter of lifespan, is understood to augment intracellular protein quality.Autophagy is an evolutionary conserved recycling pathway responsible for thedegradation, then turnover of cellular proteins and organelles. This housekeepingsystem has been reliably linked to the aging process. Moreover, autophagic activitydeclines during aging. The target of rapamycin complex 1 (TORC1), a central kinaseinvolved in protein translation, is a negative regulator of autophagy, and inhibitionof TORC1 enhances lifespan. Inhibition of TORC1 may reduce the production ofcellular proteins which may otherwise contribute to the deleterious accumulationobserved in aging. TORC1 may also exert its effects in an autophagy‐dependentmanner. Exercise and CR result in a concomitant downregulation of TORC1 activityand upregulation of autophagy in a number of tissues. Moreover, exercise‐inducedTORC1 and autophagy signaling share common pathways with that of CR. There-fore, the longevity effects of exercise and CR may stem from the maintenance ofthe proteome by balancing the synthesis and recycling of intracellular proteins andthus may represent practical means to promote longevity

Design of a Vehicle Based Intervention System to Prevent Ozone Loss

This project was designed to be completed over a period of three years. Overall project goals were: (1) To understand the processes that contribute to stratospheric ozone loss; (2) To determine the best prevention scheme for loss; (3) To design a delivery vehicle to accomplish the prevention scheme. The 1994-1995 design objectives included: (1) To review the results of the 1993-1994 design team, including a reevaluation of the major assumptions and criteria selected to choose a vehicle; (2) To evaluate preliminary vehicle concepts and perform quantitative trade studies to select the optimal vehicle concept

Measurements of electron-proton elastic cross sections for 0.4<Q2<5.5(GeV/c)20.4 < Q^2 < 5.5 (GeV/c)^2

We report on precision measurements of the elastic cross section for electron-proton scattering performed in Hall C at Jefferson Lab. The measurements were made at 28 unique kinematic settings covering a range in momentum transfer of 0.4 $<$ $Q^2$ $<$ 5.5 $(\rm GeV/c)^2$. These measurements represent a significant contribution to the world's cross section data set in the $Q^2$ range where a large discrepancy currently exists between the ratio of electric to magnetic proton form factors extracted from previous cross section measurements and that recently measured via polarization transfer in Hall A at Jefferson Lab.Comment: 17 pages, 18 figures; text added, some figures replace

Microbial ligand costimulation drives neutrophilic steroid-refractory asthma

Funding: The authors thank the Wellcome Trust (102705) and the Universities of Aberdeen and Cape Town for funding. This research was also supported, in part, by National Institutes of Health GM53522 and GM083016 to DLW. KF and BNL are funded by the Fonds Wetenschappelijk Onderzoek, BNL is the recipient of an European Research Commission consolidator grant and participates in the European Union FP7 programs EUBIOPRED and MedALL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Nuclear transparency from quasielastic A(e,e'p) reactions uo to Q^2=8.1 (GeV/c)^2

The quasielastic (e,e$^\prime$p) reaction was studied on targets of deuterium, carbon, and iron up to a value of momentum transfer $Q^2$ of 8.1 (GeV/c)$^2$. A nuclear transparency was determined by comparing the data to calculations in the Plane-Wave Impulse Approximation. The dependence of the nuclear transparency on $Q^2$ and the mass number $A$ was investigated in a search for the onset of the Color Transparency phenomenon. We find no evidence for the onset of Color Transparency within our range of $Q^2$. A fit to the world's nuclear transparency data reflects the energy dependence of the free proton-nucleon cross section.Comment: 11 pages, 6 figure

An Integrated-Photonics Optical-Frequency Synthesizer

Integrated-photonics microchips now enable a range of advanced functionalities for high-coherence applications such as data transmission, highly optimized physical sensors, and harnessing quantum states, but with cost, efficiency, and portability much beyond tabletop experiments. Through high-volume semiconductor processing built around advanced materials there exists an opportunity for integrated devices to impact applications cutting across disciplines of basic science and technology. Here we show how to synthesize the absolute frequency of a lightwave signal, using integrated photonics to implement lasers, system interconnects, and nonlinear frequency comb generation. The laser frequency output of our synthesizer is programmed by a microwave clock across 4 THz near 1550 nm with 1 Hz resolution and traceability to the SI second. This is accomplished with a heterogeneously integrated III/V-Si tunable laser, which is guided by dual dissipative-Kerr-soliton frequency combs fabricated on silicon chips. Through out-of-loop measurements of the phase-coherent, microwave-to-optical link, we verify that the fractional-frequency instability of the integrated photonics synthesizer matches the $7.0*10^{-13}$ reference-clock instability for a 1 second acquisition, and constrain any synthesis error to $7.7*10^{-15}$ while stepping the synthesizer across the telecommunication C band. Any application of an optical frequency source would be enabled by the precision optical synthesis presented here. Building on the ubiquitous capability in the microwave domain, our results demonstrate a first path to synthesis with integrated photonics, leveraging low-cost, low-power, and compact features that will be critical for its widespread use.Comment: 10 pages, 6 figure

Probing host pathogen cross-talk by transcriptional profiling of both Mycobacterium tuberculosis and infected human dendritic cells and macrophages

This study provides the proof of principle that probing the host and the microbe transcriptomes simultaneously is a valuable means to accessing unique information on host pathogen interactions. Our results also underline the extraordinary plasticity of host cell and pathogen responses to infection, and provide a solid framework to further understand the complex mechanisms involved in immunity to M. tuberculosis and in mycobacterial adaptation to different intracellular environments