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This supplementary file contains Supplemental Figures 1-6. Supplemental Figure 1 shows that 7-day ex vivo culture of NK cells with IL-15 and 5 μM CHIR99021 leads to an increase in the frequencies of NK cells with heterogeneous adaptive NK cell phenotypes (defined by expression of CD57, PLZF, SYK and FcεR1γ) relative to DMSO controls. Supplemental Figure 2 contains a detailed phenotypic characterization of receptor expression and cytotoxic granule component levels in sorted CD3-CD56dimCD57- and CD3-CD56dimCD57+ NK cells cultured for 7 days with IL-15 and either DMSO or 5 μM CHIR99021. Supplementary Figure 3 shows an analysis of NK cell phenotype, viability and proliferation after 7-day culture with IL-15 and either DMSO or CHIR99021 at several concentrations (1 μM, 3 μM and 5 μM). Supplemental Figure 4 shows an analysis of NK cell function (CD107a and IFN-γ) against K562 cells. NK cells were cultured for 7 days in IL-15 and either DMSO or 5 μM CHIR99021. Function was determined for individual CD3-CD56+ NK cell subsets gated on CD57 and NKG2C. Supplemental Figure 5 shows an analysis of NK cell function (CD107a and IFN-γ) against K562 cells. NK cells were cultured for 7 days in IL-15 and either DMSO or 5 μM CHIR99021. Function was determined for individual CD3-CD56+ NK cell subsets gated on CD57 and KIR. Supplemental Figure 6 shows the frequency of ex vivo expanded NK cells expressing CD57 and/or NKG2C 14 days after adoptive transfer into NSG mice.

Maturation of human natural killer (NK) cells as defined by accumulation of cell-surface expression of CD57 is associated with increased cytotoxic character and TNF and IFNγ production upon target-cell recognition. Notably, multiple studies point to a unique role for CD57+ NK cells in cancer immunosurveillance, yet there is scant information about how they mature. In this study, we show that pharmacologic inhibition of GSK3 kinase in peripheral blood NK cells expanded ex vivo with IL15 greatly enhances CD57 upregulation and late-stage maturation. GSK3 inhibition elevated the expression of several transcription factors associated with late-stage NK-cell maturation including T-BET, ZEB2, and BLIMP-1 without affecting viability or proliferation. When exposed to human cancer cells, NK cell expanded ex vivo in the presence of a GSK3 inhibitor exhibited significantly higher production of TNF and IFNγ, elevated natural cytotoxicity, and increased antibody-dependent cellular cytotoxicity. In an established mouse xenograft model of ovarian cancer, adoptive transfer of NK cells conditioned in the same way also displayed more robust and durable tumor control. Our findings show how GSK3 kinase inhibition can greatly enhance the mature character of NK cells most desired for effective cancer immunotherapy. Cancer Res; 77(20); 5664–75. ©2017 AACR.

β-phase gallium oxide (Ga2O3) is an emerging ultrawide bandgap (UWBG) semiconductor (EG ∼ 4.8 eV), which promises generational improvements in the performance and manufacturing cost over today's commercial wide bandgap power electronics based on GaN and SiC. However, overheating has been identified as a major bottleneck to the performance and commercialization of Ga2O3 device technologies. In this work, a novel Ga2O3/4H-SiC composite wafer with high heat transfer performance and an epi-ready surface finish has been developed using a fusion-bonding method. By taking advantage of low-temperature metalorganic vapor phase epitaxy, a Ga2O3 epitaxial layer was successfully grown on the composite wafer while maintaining the structural integrity of the composite wafer without causing interface damage. An atomically smooth homoepitaxial film with a room-temperature Hall mobility of ∼94 cm2/Vs and a volume charge of ∼3 × 1017 cm-3 was achieved at a growth temperature of 600 °C. Phonon transport across the Ga2O3/4H-SiC interface has been studied using frequency-domain thermoreflectance and a differential steady-state thermoreflectance approach. Scanning transmission electron microscopy analysis suggests that phonon transport across the Ga2O3/4H-SiC interface is dominated by the thickness of the SiNx bonding layer and an unintentionally formed SiOx interlayer. Extrinsic effects that impact the thermal conductivity of the 6.5 μm thick Ga2O3 layer were studied via time-domain thermoreflectance. Thermal simulation was performed to estimate the improvement of the thermal performance of a hypothetical single-finger Ga2O3 metal-semiconductor field-effect transistor fabricated on the composite substrate. This novel power transistor topology resulted in a ∼4.3× reduction in the junction-to-package device thermal resistance. Furthermore, an even more pronounced cooling effect is demonstrated when the composite wafer is implemented into the device design of practical multifinger devices. These innovations in device-level thermal management give promise to the full exploitation of the promising benefits of the UWBG material, which will lead to significant improvements in the power density and efficiency of power electronics over current state-of-the-art commercial devices.

GaN radio frequency (RF) power amplifiers offer many benefits including high power density, reduced device footprint, high operating voltage, and excellent gain and power-added efficiency. Accordingly, these parts are enabling next-generation technologies such as fifth-generation (5G) base transceiver stations and defense/aerospace applications such as high-performance radar and communication systems. However, these benefits can be overshadowed by device overheating that compromises the performance and reliability. In response to this, researchers have focused on GaN-on-diamond integration during the past decade. However, manufacturability, scalability, and long-term reliability remain as critical challenges toward the commercialization of the novel device platform. In this work, a diamond-incorporated flip-chip integration scheme is proposed that takes advantage of existing semiconductor device processing and growth techniques. Using an experimentally validated GaN-on-SiC multifinger device model, the theoretical limit of the cooling effectiveness of the device-level thermal management solution has been evaluated. Simulation results show that by employing a $\sim 2-\mu \text{m}$ diamond passivation overlayer, gold thermal bumps, and a commercial polycrystalline carrier wafer, the power amplifier’s dissipated heat can be effectively routed toward the package, which leads to a junction-to-package thermal resistance lower than GaN-on-diamond high electron mobility transistors (HEMTs). Furthermore, simulation results show that this approach is even more promising for lowering the device thermal resistance of emerging ultra-wide bandgap devices based on $\beta $ -Ga2O3 and AlGaN, below that for today’s state-of-the-art GaN-on-diamond HEMTs.

The demand for high power and high-frequency radio frequency (RF) power amplifiers makes AlGaN/GaN high electron mobility transistors (HEMTs) an attractive option due to their large critical field, high saturation velocity, and reduced device footprint as compared to Si-based counterparts. However, due to the high operating power densities, intense device self-heating occurs, which degrades the electrical performance and compromises the device’s reliability. The self-heating behavior of AlGaN/GaN HEMTs is known to be not solely a function of the dissipated power but is highly bias-dependent. As the operation of RF power amplifiers involves alteration of the device operation from fully-open to pinched-off channel conditions, it is critical to experimentally map the full channel temperature profile as a function of bias conditions. However, such measurement is difficult using optical thermography techniques due to the lack of optical access underneath the gate electrode, where the peak temperature is expected to occur. To address this challenge, an AlGaN/GaN HEMT employing a transparent gate made of indium tin oxide (ITO) was fabricated, which enables full channel temperature mapping using Raman spectroscopy. It was found that the maximum channel temperature rise under a partially pinched-off condition is more than ∼93% higher than that for an open channel condition, although both conditions would lead to an identical power dissipation level. The channel peak temperature probed in an ITO-gated device (underneath the gate) is ∼33% higher than the highest channel temperature that can be measured for a standard metal-gated AlGaN/GaN HEMT (i.e., next to the metal gate structure) operating under an identical bias condition. This indicates that one may significantly underestimate the device’s thermal resistance when solely relying on performing thermal characterization on the optically accessible region of a standard AlGaN/GaN HEMT. The outcomes of this study are important in terms of conducting a more accurate lifetime prediction of the device lifetime and designing thermal management solutions.

Aluminum gallium nitride (AlGaN) high electron mobility transistors (HEMTs) are candidates for next-generation power conversion and radio frequency (RF) applications. AlxGa1-xN channel HEMT devices (x = 0.3, x = 0.7) were investigated using multiple in-situ thermal characterization methods and electro-thermal simulation. The thermal conductivity, contact resistivity, and channel mobility were characterized as a function of temperature to understand and compare the heat generation profile and electro-thermal transport within these devices. In contrast to GaN-based HEMTs, the electrical output characteristics of Al0.70Ga0.30 N channel HEMTs exhibit remarkably lower sensitivity to the ambient temperature rise. Also, during 10kHz pulsed operation, the difference in peak temperature between the AlGaN channel HEMTs and GaN HEMTs reduced significantly.

The compound Ni4V3O10 forms a new structure type in the tetragonal space group P4/n. The material can be produced using solid-state synthesis in a narrow temperature range, and the structure was confirmed using X-ray and neutron powder diffraction data. The phase contains occupationally disordered Ni/V in tetrahedral, square pyramidal, and octahedral sites. Bond valence and neutron/X-ray co-refinements give evidence for three vanadium oxidation states (V^3+, V^4+, V^5+), making it distinct in the Ni-V-O system and placing it in a class of only nine other oxides with transition metals exhibiting three oxidation states. With a Néel temperature of 38 K and a Curie-Weiss parameter θ = -234 K, it displays frustrated antiferromagnetism, evidenced by a broad hump in the heat capacity below T_N. The structure has a percolating distorted rock-salt-like network, leading to strong superexchange, but square pyramidal linkages frustrate magnetic ordering. The magnetic structure is assumed to be incommensurate, as simple propagation vectors can be ruled out by powder neutron diffraction.

Single crystals of rhombohedral KBiS2 were synthesized for the first time, and the structure, growth habit and properties of this layered semiconductor are presented. The single crystals form from a reactive K2S5 salt flux and are still embedded in the residual flux, without removal from the reaction vessel throughout the whole study. Laboratory diffraction contrast tomography (LabDCT) is used to identify the crystalline phase, orientation, and microstructure of crystals. Meanwhile, powder and single crystal X-ray diffraction were performed to determine detailed crystallographic information. Morphology of the crystalline assemblies observed by absorption contrast tomography reveals screw-dislocation-driven growth to be the dominant mechanism. First-principles electronic structure simulations predict rhombohedral KBiS2 to be a semiconductor with an indirect band gap, which was confirmed by experiment. This study demonstrates how non-destructive tomography imaging and 3D crystallography methods can lead to advances in discovering new materials and studying crystal growth mechanisms.

Type 1 diabetes (T1D) is characterized by the loss of immune self-tolerance, resulting in an aberrant immune responses against self-tissue. A few therapeutics have been partially successful in reverting or slowing down T1D progression in patients, and the infusion of autologous hematopoietic stem cells (HSCs) is emerging as an option to be explored. In this study, we proposed to pharmacologically enhance by ex vivo modulation with small molecules the immunoregulatory and trafficking properties of HSCs to provide a safer and more efficacious treatment option for patients with T1D and other autoimmune disorders. A high-throughput targeted RNA sequencing screening strategy was used to identify a combination of small molecules (16,16-dimethyl PGE2 and dexamethasone), which significantly upregulate key genes involved in trafficking (e.g., CXCR4) and immunoregulation (e.g., programmed death ligand 1). The pharmacologically enhanced, ex vivo–modulated HSCs (regulatory HSCs [HSC.Regs]) have strong trafficking properties to sites of inflammation in a mouse model of T1D, reverted autoimmune diabetes in NOD mice, and delayed experimental multiple sclerosis and rheumatoid arthritis in preclinical models. Mechanistically, HSC.Regs reduced lymphocytic infiltration of pancreatic β cells and inhibited the activity of autoreactive T cells. Moreover, when tested in clinically relevant in vitro autoimmune assays, HSC.Regs abrogated the autoimmune response. Ex vivo pharmacological modulation enhances the immunoregulatory and trafficking properties of HSCs, thus generating HSC.Regs, which mitigated autoimmune diabetes and other autoimmune disorders.

β-phase gallium oxide (Ga

Beta-phase gallium oxide (β-Ga2O3) has garnered considerable attention for power devices due to (i) its large critical electric field strength and (ii) the availability of low cost/high quality melt-grown substrates, both of which are advantages over silicon carbide (SiC) and gallium nitride (GaN). However, because of the low thermal conductivity of β-Ga2O3, thermal management strategies at the device-level are required to achieve high-power operation. In this work, electrically identical MOSFETs (fixed current channel length) with varying spacings between the gate electrode and drain metal contact (thus, thermally different) have been fabricated, to study the effectiveness of heat extraction by the drain metal electrode. Results show that the topside features of lateral β-Ga2O3 MOSFETs are important in both electrical and thermal design perspectives.

Background Although CAR T cells have been shown to be effective and potent in treating several hematologic malignancies, engineered T-cell therapies have had limited success in addressing solid tumors. Unlike liquid tumors where uniformly expressed antigens are accessible and can be effectively targeted, tumor access and antigen heterogeneity are a significant barrier to the successful development of CAR-T cells in solid tumors. Methods Here we demonstrate that the combination of a bi-specific T-cell engager (BiTE) targeting EpCAM with a CAR T cell targeting HER2 enhances the in vitro and in vivo anti-tumor activity against heterogenous solid tumors. Results We observed a dose-dependent enhancement of cytolytic activity when EpCAM-specific BiTEs were titrated alongside 4D5-based HER2-specific CAR T cells against HER2low tumors, enhancing maximal cytolysis by two-fold compared to CAR T cells alone (figure 1). Moreover, the escape of HER2low tumor cells in mixed heterogenous culture systems was circumvented by the combination of HER2-specific CAR T cells and EpCAM-specific BiTEs. The enhancement of efficacy was further demonstrated in an established HER2low MDA-MB-231 xenografts. HER2-specific CAR T cells were unable to contain Her2low tumors, whereas tumor growth was effectively controlled in mice receiving both EpCAM-specific BiTEs and HER2-specific CAR T cells. Conclusions Collectively, these data demonstrate that multi-antigen targeting mediated by BiTEs and CARs extends overall anti-tumor efficacy in preclinical models of heterogenous solid tumors. Fate Therapeutics is currently using its proprietary induced pluripotent stem cell (iPSC) product platform to generate iPSC-derived CAR T cells and iPSC-derived CAR NK cells that secrete BiTEs for the treatment of solid tumors. Ethics Approval These studies were approved by Fate Therapeutics Institutional Animal Care and Use Committee and were carried out in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals.

With the advent of gallium nitride (GaN) as an enabling material system for the solid-state lighting industry, high-power and high-brightness light-emitting diodes (LEDs) with wavelengths ranging from near ultraviolet to blue are being manufactured as part of a tremendously large and ever-increasing market. However, device self-heating and the environment temperature significantly deteriorate the LED's optical performance. Hence, it is important to accurately quantify the LED's temperature and correlate its impact on optical performance. In this work, three different characterization methods and thermal simulation were used to measure and calculate the temperature rise of an InGaN/GaN LED, as a result of self-heating. Nanoparticle-assisted Raman thermometry was used to measure the LED mesa surface temperature. A transient Raman thermometry technique was utilized to investigate the transient thermal response of the LED. It was found that under a 300 mW input power condition, self-heating is negligible for an input current pulse width of 1 ms or less. The temperature measured using nanoparticle-assisted Raman thermometry was compared with data obtained by using the forward voltage method (FVM) and infrared (IR) thermal microscopy. The IR and Raman measurement results were in close agreement whereas the data obtained from the widely accepted FVM underestimated the LED temperature by 5–10%. It was also observed that an increase in environment temperature from 25 °C to 100 °C would degrade the LED optical power output by 12%.