Persistent Antigen and Prolonged AKT-mTORC1 Activation Underlie Memory CD8 T Cell Impairment in the Absence of CD4 T Cells

Recall responses by memory CD8 T cells are impaired in the absence of CD4 T cells. Although several mechanisms have been proposed, the molecular basis is still largely unknown. Using a local influenza virus infection in the respiratory tract and the lung of CD4[superscript −/−] mice, we show that memory CD8 T cell impairment is limited to the lungs and the lung-draining lymph nodes, where viral Ags are unusually persistent and abundant in these mice. Persistent Ag exposure results in prolonged activation of the AKT–mTORC1 pathway in Ag-specific CD8 T cells, favoring their development into effector memory T cells at the expense of central memory T cells, and inhibition of mTORC1 by rapamycin largely corrects the impairment by promoting central memory T cell development. The findings suggest that the prolonged AKT–mTORC1 activation driven by persistent Ag is a critical mechanism underlying the impaired memory CD8 T cell development and responses in the absence of CD4 T cells.National Institutes of Health (U.S.) (Grant AI69208)Singapore. National Research Foundation (Singapore-MIT Alliance for Research and Technology (SMART). Infectious Disease Research Program)Ivan R. Cottrell Professorship and Research FundNational Cancer Institute (U.S.) (David H. Koch Institute for Integrative Cancer Research at MIT. Support (Core) Grant P30-CA14051

Agreement between clinical screening procedures for neuropathy in the feet

Introduction: The correlation between monofilament testing, symptom surveys, and electrodiagnostic studies for the diagnosis of axonal polyneuropathy has not been well studied. This investigation was done to assess the agreement between these procedures in a non‐random sample of volunteers. Methods: The procedures evaluated included electrodiagnostic tests of the sural nerve, monofilament testing of the great toe, a symptom survey, and a body diagram. Kappa coefficients and sensitivity and specificity, using nerve conduction as a “gold standard,” were used to determine the agreement between various combinations of procedures. Results: Poor agreement (kappa values −0.12–0.44) and sensitivity (sensitivity <30%) were found for all combinations of symptoms and monofilament results in comparison with sural peak latency and amplitude. Conclusions: Overall, the results demonstrated a low discriminatory power for the screening procedures for identifying persons with impaired sural nerve function. The results highlight the need for further development and evaluation of screening methods for distal neuropathy in population‐based studies. Muscle Nerve, 2012Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91168/1/23238_ftp.pd

D-branes at Singularities and String Phenomenology

In these notes we give an introduction to some of the concepts involved in constructing SM-like gauge theories in systems of branes at singularities of CY manifolds. These notes are an expanded version of lectures given by Herman Verlinde at the Cargese 2006 Summer School.Comment: 24 pages, 5 figures, based on lectures of H.Verlinde at the Cargese 2006 summer schoo

Laser Truss Sensor for Segmented Telescope Phasing

A paper describes the laser truss sensor (LTS) for detecting piston motion between two adjacent telescope segment edges. LTS is formed by two point-to-point laser metrology gauges in a crossed geometry. A high-resolution (<30 nm) LTS can be implemented with existing laser metrology gauges. The distance change between the reference plane and the target plane is measured as a function of the phase change between the reference and target beams. To ease the bandwidth requirements for phase detection electronics (or phase meter), homodyne or heterodyne detection techniques have been used. The phase of the target beam also changes with the refractive index of air, which changes with the air pressure, temperature, and humidity. This error can be minimized by enclosing the metrology beams in baffles. For longer-term (weeks) tracking at the micron level accuracy, the same gauge can be operated in the absolute metrology mode with an accuracy of microns; to implement absolute metrology, two laser frequencies will be used on the same gauge. Absolute metrology using heterodyne laser gauges is a demonstrated technology. Complexity of laser source fiber distribution can be optimized using the range-gated metrology (RGM) approach

Using Deep Space Climate Observatory Measurements to Study the Earth as An Exoplanet

Even though it was not designed as an exoplanetary research mission, the Deep Space Climate Observatory (DSCOVR) has been opportunistically used for a novel experiment, in which Earth serves as a proxy exoplanet. More than two years of DSCOVR Earth images were employed to produce time series of multi-wavelength, single-point light sources, in order to extract information on planetary rotation, cloud patterns, surface type, and orbit around the Sun. In what follows, we assume that these properties of the Earth are unknown, and instead attempt to derive them from first principles. These conclusions are then compared with known data about our planet. We also used the DSCOVR data to simulate phase angle changes, as well as the minimum data collection rate needed to determine the rotation period of an exoplanet. This innovative method of using the time evolution of a multi-wavelength, reflected single-point light source, can be deployed for retrieving a range of intrinsic properties of an exoplanet around a distant star

Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy.

Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castration-resistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable AR amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, p &lt; 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization

Visible Thermal Emission from Sub-Band-Gap Laser Excited Cerium Dioxide Particles

Cerium dioxide particles excited in air with sub-band-gap radiation emit very broad radiation in the visible spectrum above a threshold intensity that decreases with increasing ambient temperature. Concomitant with this emission is the near disappearance of the Stokes and anti-Stokes Raman scattering peaks. Both phenomena are reversible in air up to just above threshold, and are seen for nanoparticles and several-micron-diameter particles with particle diameter comparable to or smaller than the laser focus. Temperature estimates using the Stokes/anti-Stokes scattering intensity ratio suggest there is laser heating due to small intragap absorption and possible nonlinear processes, given the very slow thermal conduction. The broad emission in this loose powder may well be due to thermal emission, on the basis of spectral fitting of the high-energy part of the spectrum to a blackbody radiator at ϳ1200-1400°C, although luminescence from a new phase is a possibility. The sudden decrease in Raman scattering and increase in emission in air are consistent with a transition to a new, possibly luminescent, phase, as is the continued disappearance of the Raman peaks in forming gas when the laser power is reduced below the upstroke threshold. Oxygen point defects and their complexes may play an important role in many of these processes

The Reproducibility of Lists of Differentially Expressed Genes in Microarray Studies

Reproducibility is a fundamental requirement in scientific experiments and clinical contexts. Recent publications raise concerns about the reliability of microarray technology because of the apparent lack of agreement between lists of differentially expressed genes (DEGs). In this study we demonstrate that (1) such discordance may stem from ranking and selecting DEGs solely by statistical significance (P) derived from widely used simple t-tests; (2) when fold change (FC) is used as the ranking criterion, the lists become much more reproducible, especially when fewer genes are selected; and (3) the instability of short DEG lists based on P cutoffs is an expected mathematical consequence of the high variability of the t-values. We recommend the use of FC ranking plus a non-stringent P cutoff as a baseline practice in order to generate more reproducible DEG lists. The FC criterion enhances reproducibility while the P criterion balances sensitivity and specificity