Quantifying the limits of CAR T-cell delivery in mice and men

CAR (Chimeric Antigen Receptor) T cells have demonstrated clinical success for the treatment of multiple lymphomas and leukaemias, but not for various solid tumours, despite promising data from murine models. Lower effective CAR T-cell delivery rates to human solid tumours compared to haematological malignancies in humans and solid tumours in mice might partially explain these divergent outcomes. We used anatomical and physiological data for human and rodent circulatory systems to calculate the typical perfusion of healthy and tumour tissues, and estimated the upper limits of immune cell delivery rates across different organs, tumour types and species. Estimated maximum delivery rates were up to 10 000-fold greater in mice than humans yet reported CAR T-cell doses are typically only 10–100-fold lower in mice, suggesting that the effective delivery rates of CAR T cells into tumours in clinical trials are far lower than in corresponding mouse models. Estimated delivery rates were found to be consistent with published positron emission tomography data. Results suggest that higher effective human doses may be needed to drive efficacy comparable to mouse solid tumour models, and that lower doses should be tested in mice. We posit that quantitation of species and organ-specific delivery and homing of engineered T cells will be key to unlocking their potential for solid tumours.     

Word length and lexical activation: Longer is better.

Many models of spoken word recognition posit the existence of lexical and sublexical representations, with excitatory and inhibitory mechanisms used to affect the activation levels of such representations. Bottom-up evidence provides excitatory input, and inhibition from phonetically similar representations leads to lexical competition. In such a system, long words should produce stronger lexical activation than short words, for 2 reasons: Long words provide more bottom-up evidence than short words, and short words are subject to greater inhibition due to the existence of more similar words. Four experiments provide evidence for this view. In addition, reaction-time-based partitioning of the data shows that long words generate greater activation that is available both earlier and for a longer time than is the case for short words. As a result, lexical influences on phoneme identification are extremely robust for long words but are quite fragile and condition-dependent for short words. Models of word recognition must consider words of all lengths to capture the true dynamics of lexical activation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Capture of Organic Vapors Using Adsorption and Electrothermal Regeneration

Activated-carbon-fiber cloth (ACFC) is an alternative adsorbent to granular activated carbon (GAC) for removing and recovering organic vapors from gas streams. Electrothermal desorption (ED) of ACFC provides rapid regeneration while requiring less energy compared to traditional regeneration techniques used with GAC. This paper provides proof-of-concept results from a bench-scale ACFC adsorption system. The automated system captured 1,000 ppmv of hazardous air pollutants/volatile organic compounds (HAPs/VOCs) from air streams and demonstrated the use of ED, using ac voltage, to recover the HAP/VOC as a pure liquid. The desorbed HAP/VOC condensed onto the inner walls of the adsorber and was collected at the bottom of the vessel, without the use of ancillary cooling. Seventy percent of the HAP/VOC was collected per cycle as condensate, with the balance being retained in the regenerated adsorber or recycled to the second adsorber. ED with in-vessel condensation results in minimal N2 consumption and short regeneration cycle times allowing the process to be cost competitive with conventional GAC-based adsorption processes. This technology extends the application of carbon adsorption systems to situations that were previously economically and physically impractical.     

Simulated recruitment of riparian trees and shrubs under natural and regulated flow regimes on the Wisconsin River,USA

Models that link ecological responses to hydrologic changes are important for assessing the effects of flow regulation on aquatic and riparian ecosystems. Based on the Recruitment Box Model, a graphical model used to prescribe environmental flows for cottonwood (Populus spp.) recruitment, we designed a simulation model to represent the influence of river flow dynamics on seedling recruitment of riparian pioneer woody plants. The model simulates the influence of temporal patterns of river stage on dispersal, germination, initial recruitment and over‐winter survival of first‐year seedlings of riparian pioneer shrubs and trees. We used the model to simulate seedling recruitment patterns for five species (Acer saccharinum, Betula nigra, Populus deltoides, Salix nigra and Salix exigua) on the Wisconsin River (Wisconsin, USA) under three flow scenarios: historic (1935–2002), simulated natural (1915–1975) and simulated regulated flows (1915–1975). Simulation results agreed well with field‐observed relative differences among years (1997–2000) in seedling densities for the five focal species. Simulated successful recruitment years were highly synchronous among species, but species differed in their sensitivity to flows at different times during the growing season, consistent with among‐species differences in seed dispersal timing. Comparison of simulated natural and regulated flows for 1915–1975 showed that flow regulation decreased monthly flow variability, increased late summer to winter baseflow and reduced the magnitude of spring peaks. Simulated recruitment and over‐winter survival of tree seedlings of all species was enhanced under the regulated flow scenario, likely due to increased summer baseflow and reductions in peak flood magnitude. Our analyses show the utility of extending the Recruitment Box Model to include multiple species of riparian shrubs and trees, and the effects of post‐colonization flows on their recruitment success. However, some key functional relationships between flow patterns and woody seedling demography (e.g. shear stress thresholds for seedling mortality) have not been adequately quantified and merit further study. Copyright © 2006 John Wiley & Sons, Ltd.     

Techniques for microstructural characterization of powder-processed nickel-based superalloys

Methods are described for sample preparation of polycrystalline Ni-based superalloys in order to perform a detailed microstructural characterization. Specific techniques for the precise definition of the various phases present are outlined and these are shown to be useful for the measurement of size, volume fractions and distribution. A number of optical, scanning and transmission microscopy techniques are used to provide the necessary information.     

如何用硅振荡器替代晶体和陶瓷谐振器

对于绝大多数微控制器时钟电路而言，硅振荡器是一种简单且有效的解决方案。与晶体和陶瓷谐振器不同，基于硅材料的定时器具有抗振动、抗撞击和抗电磁干扰的优点。同时，硅振荡器不需要严格匹配的定时元件和线路板走线。     

A General Role for Early Onset Cues and Intra-Event Learning; Comment on McDonald and Siegel (2004).

Research on classical conditioning with drug unconditional stimuli has had a profound effect on the understanding of general conditioning processes. The experiment reported by R. V. McDonald and S. Siegel (see record 2004-10475-001) demonstrates that cues coincident with the onset of an event can become associated with the rest of the event. This sort of learning is probably ubiquitous and has been proposed as a mechanism behind the development of panic disorder, in which interoceptive cues coincident with the start of a panic attack can be associated with the rest of the attack and can eventually come to elicit full-blown panic on their own. Evidence that extinction exposure to early onset cues can reduce their power is especially important. Drug conditioning research continues to provide a powerful testing ground for important general principles of learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Robust crossfeed design for hovering rotorcraft

Control law design for rotorcraft fly-by-wire systems normally attempts to decouple the angular responses using fixed-gain crossfeeds. This approach can lead to poor decoupling over the frequency range of pilot inputs and increase the load on the feedback loops. In order to improve the decoupling performance, dynamic crossfeeds should be adopted. Moreover, because of the large changes that occur in the aircraft dynamics due to small changes about the nominal design condition, especially for near-hovering flight, the crossfeed design must be ‘robust’. A new low-order matching method is presented here to design robust crossfeed compensators for multi-input, multi-output (MIMO) systems. The technique minimizes cross-coupling given an anticipated set of parameter variations for the range of flight conditions of concern. Results are presented in this paper of an analysis of the pitch/roll coupling of the UH-60 Black Hawk helicopter in near-hovering flight. A robust crossfeed is designed that shows significant improvement in decoupling perfomance and robustness over the fixed-gain or single point dynamic compensators. The design method and results are presented in an easily used graphical format that lends significant physical insight to the design procedure. This plant precompensation technique is an appropriate preliminary step to the design of robust feedback control laws for rotorcraft.