Comment on "Limits on the Time Variation of the Electromagnetic Fine-Structure Constant in the Low Energy Limit from Absorption Lines in the Spectra of Distant Quasars"

In their Letter [Phys. Rev. Lett. 92, 121302 (2004)] (also [Astron. Astrophys. 417, 853 (2004)]), Srianand et al. analysed optical spectra of heavy-element species in 23 absorption systems along background quasar sight-lines, reporting limits on relative variations in the fine-structure constant: da/a=(-0.06+/-0.06) x 10^{-5}. Here we demonstrate basic flaws in their analysis, using the same data and absorption profile fits, which led to spurious values of da/a and significantly underestimated uncertainties. We conclude that these data and fits offer no stringent test of previous evidence for a varying alpha. In their Reply (arXiv:0711.1742) to this Comment, Srianand et al. state or argue several points regarding their original analysis and our new analysis. We discuss these points here, dismissing all of them because they are demonstrably incorrect or because they rely on a flawed application of simple statistical arguments.Comment: 1+2 pages, 1 EPS figure. Page 1 accepted as PRL Comment on arXiv:astro-ph/0402177 . Further details available in arXiv:astro-ph/0612407 . v2: Added critical discussion of Reply from Srianand et al. (arXiv:0711.1742

Moving forward to address key unanswered questions on targeting PD-1/PD-L1 in cancer: limitations in preclinical models and the need to incorporate human modifying factors.

The tremendous clinical success of immune checkpoint inhibition (ICI), particularly targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1/2 (PD-L1/2) pathway, has resulted in application to multiple cancers, as a monotherapy and as a companion to both conventional and novel agents. Despite this, the precise mechanisms underlying the anti-tumor effects of PD-1/PD-L1 blockade remain unclear. Emphasis has centered on its reversal of tumor-specific CD8+ T-cell exhaustion, although many cell types and processes are likely impacted. Due to the complex and pervasive roles of PD-1/PD-L1 on T-cell biology, including on initial T-cell priming, PD-1 blockade likely affects all aspects of T- cell responses, and these other effects may be even more critical for durable anti-tumor responses. Delineating these complex interactions necessitates in vivo modeling. By far, the healthy, young and inbred laboratory mouse, transplanted with an extensively cultured tumor cell line, has been the predominant preclinical model used to assess potential therapeutic efficacies. However, these mouse models often do not adequately reflect the tumor progression and cellular and genetic heterogeneity found within human cancers. Furthermore, laboratory mice also present with a vastly restricted immune profile compared to humans. This commentary discusses some of the critical questions that need to be addressed to optimize the use of ICI as well as caveats and limitations for consideration when extrapolating preclinical mouse data to the human cancer scenario

Measuring brand image: Shopping centre case studies

'Branding' is well known for consumer products but power has shifted from manufacturers' brands towards retailers'. The term 'image' is more common than 'brand' in the context of shopping centres, but 'branding' may become more important. In this study, the authors first investigated qualitatively, asking shoppers to describe centres in 'personality' terms and eliciting clear descriptive differences between centres. For example, one in-town centre was 'dull, boring and old-fashioned . . . not exciting, just OK'; a larger regional centre was 'trendy, prestigious . . . strong, vibrant, big and colourful'. Second, the authors evaluated six UK shopping centres quantitatively using a questionnaire survey (n = 287). The 'strong and vibrant' centre scored significantly higher than the 'dull and boring' one. Despite 'branding' being little used by shopping centres, those with the better 'brand images' tended to have larger catchment areas, sales and rental incomes. The authors contend that brand management could pay rewards in terms of customer numbers, sales turnover and rental income

Analysis of lunar and solar effects on the motion of close earth satellites

Lunar and solar effects on motion of close earth satellite

Waveguide physical modeling of vocal tract acoustics: flexible formant bandwidth control from increased model dimensionality

Digital waveguide physical modeling is often used as an efficient representation of acoustical resonators such as the human vocal tract. Building on the basic one-dimensional (1-D) Kelly-Lochbaum tract model, various speech synthesis techniques demonstrate improvements to the wave scattering mechanisms in order to better approximate wave propagation in the complex vocal system. Some of these techniques are discussed in this paper, with particular reference to an alternative approach in the form of a two-dimensional waveguide mesh model. Emphasis is placed on its ability to produce vowel spectra similar to that which would be present in natural speech, and how it improves upon the 1-D model. Tract area function is accommodated as model width, rather than translated into acoustic impedance, and as such offers extra control as an additional bounding limit to the model. Results show that the two-dimensional (2-D) model introduces approximately linear control over formant bandwidths leading to attainable realistic values across a range of vowels. Similarly, the 2-D model allows for application of theoretical reflection values within the tract, which when applied to the 1-D model result in small formant bandwidths, and, hence, unnatural sounding synthesized vowels

A constraint on a varying proton--electron mass ratio 1.5 billion years after the Big Bang

A molecular hydrogen absorber at a lookback time of 12.4 billion years, corresponding to 10$\%$ of the age of the universe today, is analyzed to put a constraint on a varying proton--electron mass ratio, $\mu$. A high resolution spectrum of the J1443$+$2724 quasar, which was observed with the Very Large Telescope, is used to create an accurate model of 89 Lyman and Werner band transitions whose relative frequencies are sensitive to $\mu$, yielding a limit on the relative deviation from the current laboratory value of $\Delta\mu/\mu=(-9.5\pm5.4_{\textrm{stat}} \pm 5.3_{\textrm{sys}})\times 10^{-6}$.Comment: Accepted for publication in PRL. Includes supplemental materia

'Unlicensed' natural killer cells dominate the response to cytomegalovirus infection.

Natural killer (NK) cells expressing inhibitory receptors that bind to self major histocompatibility complex (MHC) class I are 'licensed', or rendered functionally more responsive to stimulation, whereas 'unlicensed' NK cells lacking receptors for self MHC class I are hyporesponsive. Here we show that contrary to the licensing hypothesis, unlicensed NK cells were the main mediators of NK cell-mediated control of mouse cytomegalovirus infection in vivo. Depletion of unlicensed NK cells impaired control of viral titers, but depletion of licensed NK cells did not. The transfer of unlicensed NK cells was more protective than was the transfer of licensed NK cells. Signaling by the tyrosine phosphatase SHP-1 limited the proliferation of licensed NK cells but not that of unlicensed NK cells during infection. Thus, unlicensed NK cells are critical for protection against viral infection