First measurements of the in-flight shape of imploding inertial confinement fusion (ICF) capsules at the National Ignition Facility (NIF) were obtained by using two-dimensional x-ray radiography. The ...sequence of area-backlit, time-gated pinhole images is analyzed for implosion velocity, low-mode shape and density asymmetries, and the absolute offset and center-of-mass velocity of the capsule shell. The in-flight shell is often observed to be asymmetric even when the concomitant core self-emission is round. A ∼ 15 μm shell asymmetry amplitude of the Y(40) spherical harmonic mode was observed for standard NIF ICF hohlraums at a shell radius of ∼ 200 μm (capsule at ∼ 5× radial compression). This asymmetry is mitigated by a ∼ 10% increase in the hohlraum length.
An important proposed mechanism in nanothermites reactions - reactive sintering - plays a significant role on the combustion performance of nanothermites by rapidly melting and coalescing aggregated ...metal nanoparticles, which increases the initial size of the reacting composite powders before burning. Here, we demonstrate a high-speed microscopy/thermometry capability that enables ~ µs time and ~ µm spatial resolution as applied to highly exothermic reaction propagation to directly observe reactive sintering and the reaction front at high spatial and temporal resolution. Experiments on the Al+CuO nanocomposite system reveal a reaction front thickness of ~30 μm and temperatures in excess of 3000 K, resulting in a thermal gradient in excess of 10
K m
. The local microscopic reactive sintering velocity is found to be an order of magnitude higher than macroscale flame velocity. In this observed mechanism, propagation is very similar to the general concept of laminar gas reaction theory in which reaction front velocity ~ (thermal diffusivity x reaction rate)
.
Subsets of tumor-produced cell surface and secreted proteins can bind to IgG1 type antibodies and suppress their immune-effector activities. As they affect antibody and complement-mediated immunity, ...we call these proteins humoral immuno-oncology (HIO) factors. Antibody-drug conjugates (ADCs) use antibody targeting to bind cell surface antigens, internalize into the cell, then kill target cells upon liberation of the cytotoxic payload. Binding of the ADC antibody component by a HIO factor may potentially hamper ADC efficacy due to reduced internalization. To determine the potential effects of HIO factor ADC suppression, we evaluated the efficacy of a HIO-refractory, mesothelin-directed ADC (NAV-001) and a HIO-bound, mesothelin-directed ADC (SS1). The HIO factor MUC16/CA125 binding to SS1 ADC was shown to have a negative effect on internalization and tumor cell killing. The MUC16/CA125 refractory NAV-001 ADC was shown to have robust killing of MUC16/CA125 expressing and non-expressing tumor cells in vitro and in vivo at single, sub-mg/kg dosing. Moreover, NAV-001-PNU, which contains the PNU-159682 topoisomerase II inhibitor, demonstrated good stability in vitro and in vivo as well as robust bystander activity of resident cells while maintaining a tolerable safety profile in vivo. Single-dose NAV-001-PNU demonstrated robust tumor regression of a number of patient-derived xenografts from different tumor types regardless of MUC16/CA125 expression. These findings suggest that identification of HIO-refractory antibodies to be used in ADC format may improve therapeutic efficacy as observed by NAV-001 and warrants NAV-001-PNU's advancement to human clinical trials as a monotherapy to treat mesothelin-positive cancers.
Architects and engineers are beginning to consider a new dimension of indoor air: the structure and composition of airborne microbial communities. A first step in this emerging field is to understand ...the forces that shape the diversity of bioaerosols across space and time within the built environment. In an effort to elucidate the relative influences of three likely drivers of indoor bioaerosol diversity – variation in outdoor bioaerosols, ventilation strategy, and occupancy load – we conducted an intensive temporal study of indoor airborne bacterial communities in a high‐traffic university building with a hybrid HVAC (mechanically and naturally ventilated) system. Indoor air communities closely tracked outdoor air communities, but human‐associated bacterial genera were more than twice as abundant in indoor air compared with outdoor air. Ventilation had a demonstrated effect on indoor airborne bacterial community composition; changes in outdoor air communities were detected inside following a time lag associated with differing ventilation strategies relevant to modern building design. Our results indicate that both occupancy patterns and ventilation strategies are important for understanding airborne microbial community dynamics in the built environment.
Mesothelin (MSLN) is a cell surface protein overexpressed in a number of cancer types. Several antibody‐ and cellular‐based MSLN targeting agents have been tested in clinical trials where their ...therapeutic efficacy has been moderate at best. Previous studies using antibody and Chimeric Antigen Receptor–T cells (CAR‐T) strategies have shown the importance of particular MSLN epitopes for optimal therapeutic response, while other studies have found that certain MSLN‐positive tumors can produce proteins that can bind to subsets of IgG1‐type antibodies and suppress their immune effector activities. In an attempt to develop an improved anti‐MSLN targeting agent, we engineered a humanized divalent anti‐MSLN/anti‐CD3ε bispecific antibody that avoids suppressive factors, can target a MSLN epitope proximal to the tumor cell surface, and is capable of effectively binding, activating, and redirecting T cells to the surface of MSLN‐positive tumor cells. NAV‐003 has shown significantly improved tumor cell killing against lines producing immunosuppressive proteins in vitro and in vivo. Moreover, NAV‐003 demonstrated good tolerability in mice and efficacy against patient‐derived mesothelioma xenografts co‐engrafted with human peripheral blood mononuclear cells. Together these data support the potential for NAV‐003 clinical development and human proof‐of‐concept studies in patients with MSLN‐expressing cancers.
NAV‐003 is a full‐length bispecific IgG targeting mesothelin and CD3, allowing tumor killing via CD3‐redirected, T‐cell‐mediated cytotoxicity. NAV‐003 is refractory to tumor‐produced CA125 because it binds to an epitope that is distant from the region where CA125 binds mesothelin, and it is also refractory to humoral immunosuppression by HIO‐3 because its main mechanism is independent of Fc‐receptor‐mediated killing.
Optimizing the number and utility of features to use in a classification analysis has been the subject of many research studies. Most current models use end-classifications as part of the feature ...reduction process, leading to circularity in the methodology. The approach demonstrated in the present research uses item response theory (IRT) to select features independent of the end-classification results without the biased accuracies that this circularity engenders. Dichotomous and polytomous IRT models were used to analyze 30 histological breast cancer features from 569 patients using the Wisconsin Diagnostic Breast Cancer data set. Based on their characteristics, three features were selected for use in a machine learning classifier. For comparison purposes, two machine learning–based feature selection protocols were run—recursive feature elimination (RFE) and ridge regression—and the three features selected from these analyses were also used in the subsequent learning classifier. Classification results demonstrated that all three selection processes performed comparably. The non-biased nature of the IRT protocol and information provided about the specific characteristics of the features as to why they are of use in classification help to shed light on understanding which attributes of features make them suitable for use in a machine learning context.
Graphical abstract
The use of organic materials presents a tremendous opportunity to significantly impact the functionality and pervasiveness of large-area electronics. Commercialization of this technology requires ...reduction in manufacturing costs by exploiting inexpensive low-temperature deposition and patterning techniques, which typically lead to lower device performance. We report a low-cost approach to control the microstructure of solution-cast acene-based organic thin films through modification of interfacial chemistry. Chemically and selectively tailoring the source/drain contact interface is a novel route to initiating the crystallization of soluble organic semiconductors, leading to the growth on opposing contacts of crystalline films that extend into the transistor channel. This selective crystallization enables us to fabricate high-performance organic thin-film transistors and circuits, and to deterministically study the influence of the microstructure on the device characteristics. By connecting device fabrication to molecular design, we demonstrate that rapid film processing under ambient room conditions and high performance are not mutually exclusive.
Energy-transport effects can alter the structure that develops as a supernova evolves into a supernova remnant. The Rayleigh-Taylor instability is thought to produce structure at the interface ...between the stellar ejecta and the circumstellar matter, based on simple models and hydrodynamic simulations. Here we report experimental results from the National Ignition Facility to explore how large energy fluxes, which are present in supernovae, affect this structure. We observed a reduction in Rayleigh-Taylor growth. In analyzing the comparison with supernova SN1993J, a Type II supernova, we found that the energy fluxes produced by heat conduction appear to be larger than the radiative energy fluxes, and large enough to have dramatic consequences. No reported astrophysical simulations have included radiation and heat conduction self-consistently in modeling supernova remnants and these dynamics should be noted in the understanding of young supernova remnants.
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