Integration of autography, proteasomal degradation, unfolded protein responce and apoptosis

A single cell has the potential to kill an entire human being. Efforts to cure cancer are limited by survival of individual cancer cells despite immune surveillance and toxic therapies. Understanding the intricate network of pathways that maintain cellular homeostasis and mediate stress response or default into cell death is critical to the development of strategies to eradicate cancer. Autophagy, proteasomal degradation and the unfolded protein response (UPR) are cellular pathways that degrade and recycle excess or damaged proteins to maintain cellular homeostasis and survival. This review will discuss autophagy and how it is integrated with proteasomal degradation and UPR to govern cell fate through restoration of cellular homeostasis or default into the apoptotic cell death pathway. The first response of autophagy is macroautophagy, which sequesters cytoplasm including organelles inside double-membraned autophagosome vesicles that fuse with lysosomes to degrade and recycle the contents. Ubiquitination patterns on proteins targeted for degradation determine whether adapter proteins will bring them to developing autophagosomes or to proteasomes. Macroautophagy is followed by chaperone-mediated autophagy (CMA), in which Hsc70 (Heat shock cognate 70) selectively binds proteins with exposed KFERQ motifs and pushes them inside lysosomes through the LAMP-2A (Lysosome-associated membrane protein type 2A) receptor. These two processes and the lesser understood microautophagy, which involves direct engulfment of proteins into lysosomes, occur at basal and induced levels. Insufficient proteasome function or ER stress induction of UPR can induce autophagy, which can mitigate damage and stress. If this network is incapable of repairing the damage or overcoming continued stress, the default pathway of apoptosis is engaged to destroy the cell. Induction of macroautophagy by cancer therapeutics has led to clinical trials investigating combinations of HCQ (hydroxychloriquine) suppression of autophagy with apoptosis-inducing agents. Further study of the complex integration of autophagy, proteasomal degradation, UPR and apoptosis is likely to provide additional targets for our fight against cancer. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”

Direct composition profiling in III-V nanostructures by cross-sectional STM

Using cross-sectional STM we have studied the local composition in III–V nanostructures such as GaAs/InGaAs quantum wells, InGaNAs/InP quantum wells and quantum dots, and InAs/GaAs self-assembled quantum dots. We are able to determine the local composition by either simply counting the constituent atoms, measuring the local lattice constant or measuring the relaxation of the cleaved surface due to the elastic field of the buried strained nanostructures

Discrimination, labour markets and the Labour Market Prospects of Older Workers: What Can a Legal Case Teach us?

As governments become increasingly concerned about the fiscal implications of the ageing population, labour market policies have sought to encourage mature workers to remain in the labour force. The ‘human capital’ discourses motivating these policies rest on the assumption that older workers armed with motivation and vocational skills will be able to return to fulfilling work. This paper uses the post-redundancy recruitment experiences of former Ansett Airlines flight attendants to develop a critique of these expectations. It suggests that policies to increase older workers’ labour market participation will not succeed while persistent socially constructed age- and gender- typing shape labour demand. The conclusion argues for policies sensitive to the institutional structures that shape employer preferences, the competitive rationality of discriminatory practices, and the irresolvable tension between workers’ human rights and employers’ property rights

A new photon recoil experiment: towards a determination of the fine structure constant

We report on progress towards a measurement of the fine structure constant to an accuracy of $5\times 10^{-10}$ or better by measuring the ratio of the Planck constant to the mass of the cesium atom. Compared to similar experiments, ours is improved in three significant ways: (i) simultaneous conjugate interferometers, (ii) multi-photon Bragg diffraction between same internal states, and (iii) an about 1000 fold reduction of laser phase noise to -138 dBc/Hz. Combining that with a new method to simultaneously stabilize the phases of four frequencies, we achieve 0.2 mrad effective phase noise at the location of the atoms. In addition, we use active stabilization to suppress systematic effects due to beam misalignment.Comment: 12 pages, 9 figure

A Novel Patient-Reported Outcome-Based Evaluation (PROBE) of Quality of Life in Patients with Inflammatory Bowel Disease

OBJECTIVES:There is increased interest in measuring patient-reported outcomes (PROs) such as quality of life (QoL) among patients with inflammatory bowel disease (IBD). We aimed to create and validate a new measure of QoL to assess the psychosocial burden of IBD using publicly available assessment tools.METHODS:Using the Crohn's & Colitis Foundation's IBD Partners cohort, we performed several cross-sectional and longitudinal analyses to create a new PRO-based evaluation (PROBE) of QoL among patients with Crohn's disease (CD) and ulcerative colitis (UC). We used factor analysis and Pearson correlation test to identify candidate questions for inclusion, Wilcoxon rank-sum test to examine responsiveness of the PROBE to changes in disease activity, and test-retest reliability assessments in patients with stable disease activity. We also compared the PROBE to the Short Inflammatory Bowel Disease Questionnaire to assess construct validity.RESULTS:A total of 4,854 patients (64% CD, 36% UC) completed surveys with 6 items included in the final PROBE. Compared with baseline there was a significant decrease in PROBE scores at follow-up among patients who experienced a flare for UC (25.0 vs 22.2, P = 0.001) and CD (23.1 vs 21.0, P < 0.001). Among patients with stable disease activity, Cronbach alpha was 0.87 in CD and 0.82 in UC. The PROBE correlated well with the Short Inflammatory Bowel Disease Questionnaire in CD (r = 0.88) and UC (r = 0.86).DISCUSSION:We created a novel measure to assess QoL in patients with IBD using publicly available survey items. This new PROBE can be used to facilitate clinical care, clinical and epidemiological research, and quality improvement

Effects of MGA on Prepubertal Crossbred Beef Heifers

A study was conducted using 55 prepubertal replacement crossbred beef heifers to determine the effect of feeding MGA to prepubertal heifers on age at puberty. No difference (P= .65) was detected between MGA treated heifers versus control heifers for age at puberty. There was no difference (P= .80) in age at conception to A1 for the two groups

Energy Level Statistics of the U(5) and O(6) Symmetries in the Interacting Boson Model

We study the energy level statistics of the states in U(5) and O(6) dynamical symmetries of the interacting boson model and the high spin states with backbending in U(5) symmetry. In the calculations, the degeneracy resulting from the additional quantum number is eliminated manually. The calculated results indicate that the finite boson number $N$ effect is prominent. When $N$ has a value close to a realistic one, increasing the interaction strength of subgroup O(5) makes the statistics vary from Poisson-type to GOE-type and further recover to Poisson-type. However, in the case of $N \to \infty$, they all tend to be Poisson-type. The fluctuation property of the energy levels with backbending in high spin states in U(5) symmetry involves a signal of shape phase transition between spherical vibration and axial rotation.Comment: 38 pages, 13 figure

On the Nature and Genesis of EUV Waves: A Synthesis of Observations from SOHO, STEREO, SDO, and Hinode

A major, albeit serendipitous, discovery of the SOlar and Heliospheric Observatory mission was the observation by the Extreme Ultraviolet Telescope (EIT) of large-scale Extreme Ultraviolet (EUV) intensity fronts propagating over a significant fraction of the Sun's surface. These so-called EIT or EUV waves are associated with eruptive phenomena and have been studied intensely. However, their wave nature has been challenged by non-wave (or pseudo-wave) interpretations and the subject remains under debate. A string of recent solar missions has provided a wealth of detailed EUV observations of these waves bringing us closer to resolving their nature. With this review, we gather the current state-of-art knowledge in the field and synthesize it into a picture of an EUV wave driven by the lateral expansion of the CME. This picture can account for both wave and pseudo-wave interpretations of the observations, thus resolving the controversy over the nature of EUV waves to a large degree but not completely. We close with a discussion of several remaining open questions in the field of EUV waves research.Comment: Solar Physics, Special Issue "The Sun in 360",2012, accepted for publicatio

Coronal Shock Waves, EUV Waves, and Their Relation to CMEs. III. Shock-Associated CME/EUV Wave in an Event with a Two-Component EUV Transient

On 17 January 2010, STEREO-B observed in extreme ultraviolet (EUV) and white light a large-scale dome-shaped expanding coronal transient with perfectly connected off-limb and on-disk signatures. Veronig et al. (2010, ApJL 716, 57) concluded that the dome was formed by a weak shock wave. We have revealed two EUV components, one of which corresponded to this transient. All of its properties found from EUV, white light, and a metric type II burst match expectations for a freely expanding coronal shock wave including correspondence to the fast-mode speed distribution, while the transient sweeping over the solar surface had a speed typical of EUV waves. The shock wave was presumably excited by an abrupt filament eruption. Both a weak shock approximation and a power-law fit match kinematics of the transient near the Sun. Moreover, the power-law fit matches expansion of the CME leading edge up to 24 solar radii. The second, quasi-stationary EUV component near the dimming was presumably associated with a stretched CME structure; no indications of opening magnetic fields have been detected far from the eruption region.Comment: 18 pages, 10 figures. Solar Physics, published online. The final publication is available at http://www.springerlink.co

The design, construction and performance of the MICE scintillating fibre trackers

This is the Pre-print version of the Article. The official published version can be accessed from the link below - Copyright @ 2011 ElsevierCharged-particle tracking in the international Muon Ionisation Cooling Experiment (MICE) will be performed using two solenoidal spectrometers, each instrumented with a tracking detector based on diameter scintillating fibres. The design and construction of the trackers is described along with the quality-assurance procedures, photon-detection system, readout electronics, reconstruction and simulation software and the data-acquisition system. Finally, the performance of the MICE tracker, determined using cosmic rays, is presented.This work was supported by the Science and Technology Facilities Council under grant numbers PP/E003214/1, PP/E000479/1, PP/E000509/1, PP/E000444/1, and through SLAs with STFC-supported laboratories. This work was also supportedby the Fermi National Accelerator Laboratory, which is operated by the Fermi Research Alliance, under contract No. DE-AC02-76CH03000 with the U.S. Department of Energy, and by the U.S. National Science Foundation under grants PHY-0301737,PHY-0521313, PHY-0758173 and PHY-0630052. The authors also acknowledge the support of the World Premier International Research Center Initiative (WPI Initiative), MEXT, Japan