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

Strong efficiency improvement of SOI-LEDs through carrier confinement

Contemporary silicon light-emitting diodes in silicon-on-insulator (SOI) technology suffer from poor efficiency compared to their bulk-silicon counterparts. In this letter, we present a new device structure where the carrier injection takes place through silicon slabs of only a few nanometer thick. Its external quantum efficiency of 1.4 • 10−4 at room temperature, with a spectrum peaking at 1130 nm, is almost two orders higher than reported thus far on SOI. The structure diminishes the dominant role of nonradiative recombination at the n+ and p+contacts, by confining the injected carriers in an SOI peninsula.\ud With this approach, a compact infrared light source can be fabricated using standard semiconductor processing steps.\u

Experimental analysis and computational modeling of interburst intervals in spontaneous activity of cortical neuronal culture

Rhythmic bursting is the most striking behavior of cultured cortical networks and may start in the second week after plating. In this study, we focus on the intervals between spontaneously occurring bursts, and compare experimentally recorded values with model simulations. In the models, we use standard neurons and synapses, with physiologically plausible parameters taken from literature. All networks had a random recurrent architecture with sparsely connected neurons. The number of neurons varied between 500 and 5,000. We find that network models with homogeneous synaptic strengths produce asynchronous spiking or stable regular bursts. The latter, however, are in a range not seen in recordings. By increasing the synaptic strength in a (randomly chosen) subset of neurons, our simulations show interburst intervals (IBIs) that agree better with in vitro experiments. In this regime, called weakly synchronized, the models produce irregular network bursts, which are initiated by neurons with relatively stronger synapses. In some noise-driven networks, a subthreshold, deterministic, input is applied to neurons with strong synapses, to mimic pacemaker network drive. We show that models with such “intrinsically active neurons” (pacemaker-driven models) tend to generate IBIs that are determined by the frequency of the fastest pacemaker and do not resemble experimental data. Alternatively, noise-driven models yield realistic IBIs. Generally, we found that large-scale noise-driven neuronal network models required synaptic strengths with a bimodal distribution to reproduce the experimentally observed IBI range. Our results imply that the results obtained from small network models cannot simply be extrapolated to models of more realistic size. Synaptic strengths in large-scale neuronal network simulations need readjustment to a bimodal distribution, whereas small networks do not require such change

Efficiency optimization for Atomic Frequency Comb storage

We study the efficiency of the Atomic Frequency Comb storage protocol. We show that for a given optical depth, the preparation procedure can be optimize to significantly improve the retrieval. Our prediction is well supported by the experimental implementation of the protocol in a \TMYAG crystal. We observe a net gain in efficiency from 10% to 17% by applying the optimized preparation procedure. In the perspective of high bandwidth storage, we investigate the protocol under different magnetic fields. We analyze the effect of the Zeeman and superhyperfine interaction

Sticky Wages. Evidence from Quarterly Microeconomic Data.

This paper documents nominal wage stickiness using an original quarterly firm-level dataset. We use the ACEMO survey, which reports the base wage for up to 12 employee categories in French firms over the period 1998 to 2005, and obtain the following main results. First, the quarterly frequency of wage change is around 35 percent. Second, there is some downward rigidity in the base wage. Third, wage changes are mainly synchronized within firms but to a large extent staggered across .firms. Fourth, standard Calvo or Taylor schemes fail to match micro wage adjustment patterns, but fixed duration "Taylor-like" wage contracts are observed for a minority of firms. Based on a two-thresholds sample selection model, we perform an econometric analysis of wage changes. Our results suggest that the timing of wage adjustments is not state-dependent, and are consistent with existence of predetermined of wage changes. They also suggest that both backward- and forward-looking behavior is relevant in wage setting.Wage stickiness ; Wage predetermination.

Thermodynamic dislocation theory of high-temperature deformation in aluminum and steel

The statistical-thermodynamic dislocation theory developed in previous papers is used here in an analysis of high-temperature deformation of aluminum and steel. Using physics-based parameters that we expect theoretically to be independent of strain rate and temperature, we are able to fit experimental stress-strain curves for three different strain rates and three different temperatures for each of these two materials. Our theoretical curves include yielding transitions at zero strain in agreement with experiment. We find that thermal softening effects are important even at the lowest temperatures and smallest strain rates.Comment: 7 pages, 8 figure

Weak local rules for planar octagonal tilings

We provide an effective characterization of the planar octagonal tilings which admit weak local rules. As a corollary, we show that they are all based on quadratic irrationalities, as conjectured by Thang Le in the 90s.Comment: 23 pages, 6 figure