TGFβ-Treated Placenta-Derived Mesenchymal Stem Cells Selectively Promote Anti-Adipogenesis in Thyroid-Associated Ophthalmopathy

Orbital fibroblasts (OFs) in thyroid-associated ophthalmopathy (TAO) are differentiated from pre-adipocytes and mature adipocytes; increased lipid and fat expansion are the major characteristics of ophthalmic manifestations. Human placental mesenchymal stem cells (hPMSCs) were reported to immunomodulate pathogenesis and suppress adipogenesis in TAO OFs. Here, we prepared transforming growth factor β (TGFβ, 20 ng/mL)-treated hPMSCs (TGFβ-hPMSCs) in order to enhance anti-adipogenic effects in vitro and in TAO mice. TAO OFs were grown in a differentiation medium and then co-cultured with hPMSCs or TGFβ-hPMSCs. TAO OFs were analyzed via quantitative real-time polymerase chain reaction, Oil red O staining, and western blotting. The results showed that TGFβ-hPMSCs reduced the expression of adipogenic, lipogenic, and fibrotic genes better than hPMSCs in TAO OFs. Moreover, the adipose area decreased more in TAO mice injected with TGFβ-hPMSCs compared to those injected with hPMSCs or a steroid. Further, TGFβ-hPMSCs inhibited inflammation as effectively as a steroid. In conclusion, TGFβ-hPMSCs suppressed adipogenesis and lipogenesis in vitro and in TAO mice, and the effects were mediated by the SMAD 2/3 pathways. Furthermore, TGFβ-hPMSCs exhibited anti-inflammatory and anti-fibrotic functions, which suggests that they could be a new and safe method to promote the anti-adipogenic function of hPMSCs to treat TAO patients.     

Clinically Applicable Assessment of Tisagenlecleucel CAR T Cell Treatment by Digital Droplet PCR for Copy Number Variant Assessment

Chimeric antigen receptor (CAR) T cell therapy is an innovative immunotherapy for treating cancers in both children and adults with proven utility in numerous clinical trials. Significantly, some CAR T cell therapies have now been approved by relevant national regulatory bodies across numerous countries for clinical therapeutic use outside of clinical trials. One such recently licensed product is tisagenlecleucel, a CAR T therapy approved for the treatment of B-cell acute lymphoblastic leukemia (B-ALL) using autologous T cells from the patient. The genetically engineered T cells target a protein called CD19, common to B cells, through a CAR incorporating a 4-1BB costimulatory domain to improve response. Since tisagenlecleucel is now a standard of care treatment for B-ALL, it is clinically essential to be able to accurately monitor these CAR T cells in patients. Assessment of the copy number variant (CNV) of the CAR T cell products allows this within a clinically acceptable timeframe for optimal patient benefit. However, no standardized method with high reproducibility and efficiency has been described within a routine clinical laboratory setting. Here, we demonstrated a novel digital droplet PCR (ddPCR)-based methodology for the study of CNV (ddPCR-CNV) in 4-1BB CD19-specific CAR T cells with universal applicability across clinical diagnostic laboratories.     

Hyperinsulinemic Hypoglycemia Associated with a CaV1.2 Variant with Mixed Gain- and Loss-of-Function Effects

The voltage-dependent L-type calcium channel isoform Ca_V1.2 is critically involved in many physiological processes, e.g., in cardiac action potential formation, electromechanical coupling and regulation of insulin secretion by beta cells. Gain-of-function mutations in the calcium voltage-gated channel subunit alpha 1 C (CACNA1C) gene, encoding the Ca_V1.2 α₁-subunit, cause Timothy syndrome (TS), a multisystemic disorder that includes autism spectrum disorders and long QT (LQT) syndrome. Strikingly, TS patients frequently suffer from hypoglycemia of yet unproven origin. Using next-generation sequencing, we identified a novel heterozygous CACNA1C mutation in a patient with congenital hyperinsulinism (CHI) and associated hypoglycemic episodes. We characterized the electrophysiological phenotype of the mutated channel using voltage-clamp recordings and in silico action potential modeling experiments. The identified Ca_V1.2^L566P mutation causes a mixed electrophysiological phenotype of gain- and loss-of-function effects. In silico action potential modeling supports that this mixed electrophysiological phenotype leads to a tissue-specific impact on beta cells compared to cardiomyocytes. Thus, CACNA1C variants may be associated with non-syndromic hyperinsulinemic hypoglycemia without long-QT syndrome, explained by very specific electrophysiological properties of the mutated channel. We discuss different biochemical characteristics and clinical impacts of hypoglycemia in the context of CACNA1C variants and show that these may be associated with significant morbidity for Timothy Syndrome patients. Our findings underline that the potential of hypoglycemia warrants careful attention in patients with CACNA1C variants, and such variants should be included in the differential diagnosis of non-syndromic congenital hyperinsulinism.     

Can computers carry content ‘inexplicitly’?

I examine whether it is possible for content relevant to a computer's behavior to be carried without an explicit internal representation. I consider three approaches. First, an example of a chess playing computer carrying emergent content is offered from Dennett. Next I examine Cummins response to this example. Cummins says Dennett's computer executes a rule which is inexplicitly represented. Cummins describes a process wherein a computer interprets explicit rules in its program, implements them to form a chess-playing device, then this device executes the rules in a way that exhibits them inexplicitly. Though this approach is intriguing, I argue that the chess-playing device cannot exist as imagined. The processes of interpretation and implementation produce explicit representations of the content claimed to be inexplicit. Finally, the Chinese Room argument is examined and shown not to save the notion of inexplicit information. This means the strategy of attributing inexplicit content to a computer which is executing a rule, fails.I wish to thank Fred Dretske, JOhn Perry, and an anonymous reviewer for helpful comments and suggestions. Earlier versions of this paper were read at the American Philosophical Association Pacific Division Meeting in San Francisco in March, 1993, and at the 7th International Conference on Computing and Philosophy in Orlando in August, 1992.     

Audience-induced inhibition of overt practice during learning.

Three experiments with 204 undergraduates examined the hypothesis that an audience can inhibit overt practice and thereby impair learning of unfamiliar words and enhance learning of familiar words. This hypothesis was derived from an analysis of motoric and symbolic mediation during learning. In comparison with learning while alone, the results show that the audience inhibited overt practice of unfamiliar and familiar words and that reduced practice was detrimental to learning unfamiliar words. Inhibition of overt practice with an audience enhanced learning of familiar words in only 1 of the experiments. Instructions to practice overtly reduced the audience-inhibition effect in learning unfamiliar words. The studies are discussed in the context of drive-theory explanations for social facilitation effects in learning. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A Fast Hardware Approach for Approximate, Efficient Logarithm and Antilogarithm Computations

The realization of functions such as log() and antilog() in hardware is of considerable relevance, due to their importance in several computing applications. In this paper, we present an approach to compute log() and antilog() in hardware. Our approach is based on a table lookup, followed by an interpolation step. The interpolation step is implemented in combinational logic, in a field-programmable gate array (FPGA), resulting in an area-efficient, fast design. The novelty of our approach lies in the fact that we perform interpolation efficiently, without the need to perform multiplication or division, and our method performs both the log() and antilog() operation using the same hardware architecture. We compare our work with existing methods, and show that our approach results in significantly lower memory resource utilization, for the same approximation errors. Also our method scales very well with an increase in the required accuracy, compared to existing techniques.     

跳频与扩频：无线机器对机器接口

无线机器对机器接口代表了计算机发展的第三次浪潮.第一次浪潮是企业计算机、昂贵的主机以及只有大企业才有能力购买的超级计算机.这一阶段为上世纪的六十和七十年代.第二次计算机浪潮开始于1981年,当时IBM推出了个人计算机(PC).这一时期为上世纪的八十和九十年代.新世纪带来了第三次计算机浪潮.在此期间成本降低、新技术不断涌现,使计算机中采用嵌入式处理器及无线通信像烤箱一样普及.这些处理器独立工作时可提供特定的功能,但当它们在无人为干预时,自身间相互通信时作用更大.随着小型廉价计算机的发展,无线技术应运而生.无线移动电话技术的出现领导了这些进步技术.这些技术包括用于手机的无线网络和增长迅速的无线热点现象(图1).     

Convective Delivery of Electroactive Species to Annular Nanoband Electrodes Embedded in Nanocapillary‐Array Membranes

Significant technological drivers motivate interest in the use of reaction sites embedded within nanometer‐scale channels, and an important class of these structures is realized by an embedded annular nanoband electrode (EANE) in a cylindrical nanochannel. In this structure, the convective delivery of electroactive species to the nanoelectrode is tightly coupled to the electrochemical overpotential via electroosmotic flow. Simulation results indicate that EANE arrays significantly outperform comparable microband electrode/microchannel structures, producing higher conversion efficiencies at low Peclet number. The results of this in‐depth analysis are useful in assessing possible implementation of the EANE geometry for a wide range of electrochemical targets within microscale total analysis systems.     

Photoelectrochemical Synthesis of Ammonia with Black Phosphorus

Efficient production of ammonia using environmentally friendly techniques under ambient conditions is crucial to renewable energy storage and industrial applications, and catalysts with new reaction pathways are highly desirable. In this work, black phosphorus (BP) is used as a metal‐free 2D catalyst for the photoelectrochemical (PEC) nitrogen reduction reaction (NRR). The electrode is fabricated by layer‐by‐layer assembly of BP nanosheets on an indium tin oxide substrate. The PEC NRR activity in the N₂ saturated aqueous electrolyte without a sacrificial agent is excellent, as exemplified by an ammonia yield rate of 102.4 µg h^?1 mgcat.^?1 and Faradaic efficiency of 23.3% at ?0.4 V, which are the best among nonmetal catalysts for synthesis of ammonia by photocatalysis and electrocatalysis. Furthermore, the BP electrode shows excellent stability after 6 consecutive cycles. The excellent PEC catalytic properties are attributed to the light excitation enhanced electrocatalytic process and that the external bias promoted photocatalytic process improves ammonia production synergistically. The results not only demonstrate the great potential of BP in PEC catalysis, but also identify a promising technique to produce ammonia under ambient conditions using solar energy and electric energy.