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Though TCRs have been subject to limited engineering in the context of therapeutic design and optimization, they are used largely as found in nature. On the other hand, CARs are artificial, composed of different segments of proteins that function in the immune system. This characteristic raises the possibility of altered response to immune regulatory stimuli. Here we describe a large-scale, systematic comparison of CARs and TCRs across 5 different pMHC targets, with a total of 19 constructs examined in vitro. These functional measurements include CAR- and TCR-mediated activation, proliferation, and cytotoxicity in both acute and chronic settings. Surprisingly, we find no consistent difference between CARs and TCRs as receptor classes with respect to their relative sensitivity to major regulators of T cell activation: PD-L1, CD80/86 and IL-2. Though TCRs often emerge from human blood directly as potent, selective receptors, CARs must be heavily optimized to attain these properties for pMHC targets. Nonetheless, when iteratively improved and compared head to head in functional tests, CARs appear remarkably similar to TCRs with respect to immune modulation.

Supplemental Digital Content is available in the text., Next-generation T-cell therapies will likely continue to utilize T-cell receptors (TCRs) and chimeric antigen receptors (CARs) because each receptor type has advantages. TCRs often possess exceptional properties even when tested unmodified from patients’ T cells. CARs are generally less sensitive, possibly because their ligand-binding domains are grafted from antibodies selected for binding affinity or avidity and not broadly optimized for a functional response. Because of the disconnect between binding and function among these receptor types, the ultimate potential of CARs optimized for sensitivity and selectivity is not clear. Here, we focus on a thoroughly studied immuno-oncology target, the HLA-A*02/HPV-E629–38 complex, and show that CARs can be optimized by a combination of high-throughput binding screens and low-throughput functional assays to have comparable activity to clinical TCRs in acute assays in vitro. These results provide a case study for the challenges and opportunities of optimizing high-performing CARs, especially in the context of targets utilized naturally by TCRs.

Chimeric antigen receptors (CARs) and their parent signaling molecule, the T cell receptor (TCR), are fascinating proteins of increasing relevance to disease therapy. Here we use a collection of 1221 pMHC-directed CAR constructs representing 10 pMHC targets to study aspects of CAR structure-activity relationships (SAR), with particular focus on the extracellular and transmembrane structural components. These experiments that involve pMHC targets whose number/cell can be manipulated by peptide dosing in vitro enable systematic analysis of the SAR of CARs in carefully controlled experimental situations (Harris and Kranz, 2016). We find that CARs tolerate a wide range of structural variation, with the ligand-binding domains (LBDs) dominating the SAR of CAR antigen sensitivity. Notwithstanding the critical role of the LBD, CAR antigen-binding on the cell surface, measured by pMHC tetramer staining, is not an effective predictor of functional sensitivity. These results have important implications for the design and testing of CARs aimed toward the clinic.

Cell therapy is an emerging therapeutic modality with the power to exploit new cancer targets and potentially achieve positive outcomes for patients with few other options. Like all synthetic treatments, cell therapy has the risk of toxicity via unpredicted off-target behavior. We describe an empirical method to model off-tumor, off-target reactivity of receptors used for investigational T cell therapies. This approach utilizes an optimal panel of diverse human cell-lines to capture the large majority of protein-coding gene expression in adult human tissues. We apply this cell-line set to test Jurkat and primary T cells engineered with a dual-signal integrator, called Tmod

Solid-state light-emitting electrochemical cells (LECs) show several advantages over conventional organic light-emitting devices (OLEDs) such as simple device structure compatible with solution processes, low operation voltage and capability of utilizing inert cathode metals. However, device performance of LECs must be improved, e.g. enhancing light extraction, to meet the requirements for practical applications. Among the optical modes trapped in LECs, light trapped in substrate mode is easier to be extracted, e.g. , by simply roughing the output surface. Therefore, increasing the percentage of substrate mode is beneficial in improving light extraction. In this work, the contributions of optical modes in LECs employing substrates with various refractive indices are analyzed. Higher-refractive-index substrates are shown to trap more light in the substrates. Smaller refractive index difference between higher-refractive-index substrate and indium tin oxide (ITO) layer also increases the cutoff spectral range of light waveguided in ITO layer. Furthermore, light intensity in surface plasmon mode significantly reduces as the refractive index of the substrate increases. Reducing the percentage of surface plasmon mode facilitates light extraction since it requires more complicated methods for outcoupling light in this mode. With commercially available unpolished sapphire substrates, light output of LECs is enhanced by 56%. When a scattering layer was inserted between ITO and sapphire substrate, more light in substrate mode can be extracted and 71% enhancement in light output is realized. High external quantum efficiency up to 5.5% is consequently obtained in LECs based on a ruthenium complex. Such device efficiency is among the highest reported values for red-emitting LECs and thus confirms that utilizing higher-refractive-index substrates would offer a simple and feasible approach to improve light output of LECs. In comparison to OLEDs, increased EL trapped in substrates of LECs mainly comes from surface plasmon mode rather than waveguide mode.

Lexicon-based sentiment analysis is a popular and practical approach for sentiment analysis. However, sentiment lexicons, which may be abundant in some language such as English, are scarce in many other languages. The cross-lingual lexicon learning aims to extend lexicons for the language with less resources from those lexicons available in other languages. In this paper, we propose an approach that builds a skip-gram variant to map word spaces across languages so as to construct lexicons for the language with less resources. We show in our preliminary experiment that our approach can generate lexicons that are similar to those crafted by human experts.

Here we address questions of comparative TCR and CAR function: How different are CARs from TCRs with regard to antigen sensitivity, selectivity, co-stimulation dependence, checkpoint control, cytokine sensitivity, and antigen-dependent exhaustion (defined as loss of cytotoxicity and proliferative capacity over time). We used optimized CARs and TCRs matched to the same target pMHCs, allowing direct comparison of these important parameters. We describe a large-scale, systematic comparison of 17 CARs and 5 TCRs directed at 5 different pMHC targets in both acute and chronic settings in vitro. Surprisingly, we find little fundamental difference between CARs and TCRs with respect to their relative sensitivity to known regulators of T cell activation, including co-stimulation, checkpoint, and cytokine control. Though TCRs often emerge from human blood directly as potent, selective receptors, CARs must be heavily optimized to attain these properties for pMHC targets. Nonetheless, when iteratively improved, CARs can achieve levels of sensitivity and selectivity similar to their vaunted counterparts. Thus, other than signaling sensitivity (and perhaps selectivity), there may be little to distinguish CARs from TCRs in the context of engineered-cell therapy. CARs appear similar to TCRs with regard to immune control, undermining the notion that CARs can, of themselves, overcome regulators that limit T cell activity. Nevertheless, CARs tolerate much more sequence variability within their structural components and this, coupled with their capability to bind different antigen classes, smaller size and subunit simplicity, confers advantages that may foster a leading role for CARs in the next generation of cell therapeutics. We believe that the major conclusions reached here should instruct thinking about the boundaries around therapeutic designs for CARs, which appear to be very wide, and those around differentiation from TCRs, which appear to be much narrower. Citation Format: Xueyin Wang, Aaron D. Martin, Kathleen Negri, Michele McElvain, Julyun Oh, Ming-Lun Wu, Wen-Hua Lee, Agnes Hamburger, Han Xu, Alexander Kamb. CARs and TCRs: Myth and reality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1540.

Solid-state white light-emitting electrochemical cells (LECs) are potential candidates in solid-state lighting due to their promising advantages of simple device structure, low-voltage operation and compatibility with inert cathode metals. Adjusting the correlated color temperature (CCT) of background illumination is highly desired for modern smart lighting systems. In this work, a novel technique to tune the CCT of electroluminescence (EL) from white LECs is proposed. Color tuning is based on adjusting the applied voltage pulse period on the host–guest white LECs and the working mechanism is illustrated. A shorter voltage pulse period is insufficient to completely charge the capacitive LEC device and thus the effective voltage applied on the device is lower. Since the host–guest energy level offsets favor carrier trapping, a lower effective applied voltage results in a more pronounced guest emission, rendering redder white EL with a lower CCT. On the other hand, a longer voltage pulse period facilitates more complete charging and the effective voltage applied on the white LEC is higher. A higher bias facilitates direct exciton formation on the host molecule and subsequent partial host–guest energy transfer generates bluer white EL with a higher CCT. By tuning the voltage pulse period from 0.2 to 20 ms, the CCT of EL resulting from white LECs ranges from 2482 to 5723 K. The CCT tuning range is sufficient for general lighting applications. In contrast to color tuning of white LECs under constant-voltage driving, in which >10× brightness enhancement is accompanied by higher-CCT white EL, the discharging half-period in pulse-voltage driving provides relaxation time to turn off the device and reduces the average brightness of the white LECs driven under a longer voltage pulse period. Therefore, similar brightness can be achieved for white EL with different CCTs. No additional optical filtering device is needed for this novel color tuning technique and it has potential for use in solid-state lighting.

In this paper, we present the effect of micron size holes on proliferation and growth of human aortic endothelial cells (HAECs). Square shaped micron size holes (5, 10, 15, 20 and 25 μm) separated by 10 μm wide struts are fabricated on 5 μm thick sputter deposited Nitinol films. HAECs are seeded onto these micropatterned films and analyzed after 30 days with fluorescence microscopy. Captured images are used to quantify the nucleus packing density, size, and aspect ratio. The films with holes ranging from 10 to 20 μm produce the highest cell packing densities with cell nucleus contained within the hole. This produces a geometrically regular grid like cellular distribution pattern. The cell nucleus aspect ratio on the 10–20 μm holes is more circular in shape when compared to aspect ratio on the continuous film or larger size holes. Finally, the 25 μm size holes prevented the formation of a continuous cell monolayer, suggesting the critical length that cells cannot bridge is between 20 to 25 μm.

Gezaixi (Taiwanese opera) is generally considered to be a member of the Chinese regional xiqu (regional Chinese opera) family according to the many xiqu characteristics gezaixi exhibits. Gezaixi, like most regional xiqu in China, is performed in local dialect. Gezaixi absorbed and adapted the performing styles and methods of other xiqu and eventually was viewed as an independent performance style. The Chinese xiqu forms that influenced early gezaixi are Shanghai jingju (Beijing opera from Shanghai), fitzhouxi (Fuzhou opera), luantanxi (Zhangzhou opera), and gaojiaxi (Jinjiang and Quanzhou regional opera), the former two in particular (Lin Ho-Yi 2003: 50). Gezaixi and the Early Ming Hwa Yuan The ancestors of the Taiwanese immigrated to Taiwan from China's Fujian Province across the Taiwan Strait. These immigrants retained much of the culture and lifestyle of southeastern coast of China, including religion, a dialect called Min Nan, and, later, its entertainment (Rubinstein 2007: 4). The earliest full-fledged gezaixi presumably arose in the 1900s during the early Japanese colonial period. At first the genre had only outdoor performances, but no later than 1925 gezaixi started to be staged in theatres. It was in January 1929 that Chen Ming Ji bought a gaojiaxi troupe, Hosheng Ban (United Voices Group), and reorganized it into a gezaixi company. In 1930, Chen Ming-Ji renamed his company Mingsheng (Bright Voices), and then Ming Hwa (Brightness and Splendor). In 1945, Chen added the conclusive word "Yuan" after "Ming Hwa" to express his hope for a prosperous family (Lin Mau-Xian 2006: 130). The group has survived through two major shifts under the leadership of Chen Ming Ji: Japanese assimilation efforts and ROC Mandarinization attempts. JAPANESE KOMINKA POLICY When World War II broke out, the Japanese government launched the kominka (Japan's assimilation policy) movement to prevent the frontier Taiwan from betraying Japan as colonizer and imperialist power. From 1937, every kind of xiqu performance, including gezaixi, was banned within Taiwan. More than three hundred gezaixi companies had to disband, but among them about thirty survived by renaming themselves gailiangju (reformed drama). These companies produced a kind of performance that was a mixture of gezaixi and modern stage plays (which were not forbidden as xinju, "new drama," had become a part of the Japanese moderization idiom): the actors wore Japanese traditional costumes or modern clothing, the plot and settings were contemporary, the gezaixi orchestras were dismissed but the actors still sang gezaixi melodies and the movements were very similar to gezaixi (Lu 1961: 323-333). It was during this period that gezaixi began to borrow ideas directly from the modern stage plays and put them into practice. When the kominka policy was implemented, Ming Hwa Yuan (also called MHY) was one of the gezaixi companies that renamed themselves as gailiangju and played scripts that passed the censors in so-called modern drama. The experiences of gailiangju and the pursuit of spectacle after the war deeply influenced Chen Ming Ji, and these features would be main characteristics that remain in MHY's later style. ROC AND SUPRESSION OF LOCAL FORMS After Japan announced unconditional surrender to the Allies in August 1945, the country returned Taiwan to the Republic of China (ROC). In 1949, the Chinese Communist Party established the People's Republic of China (PRC) and defeated the ROC government, and about two millions refugees retreated to Taiwan. Henceforth the PRC and ROC governments portrayed each other as illegitimate. During the Cultural Revolution in China, the ROC government aimed to transplant Chinese culture to Taiwan so that Taiwan could demonstrate to the world that the ROC was the true protector and heir of orthodox China. To make the transplantation, local Taiwanese culture was suppressed. In the postwar years, the dominant culture was constituted by the Chinese traditional arts, but gezaixi still revived and entered its golden age, from 1945 to the 1960s. …