Timing and duration of MHC I positive selection signals are adjusted in the thymus to prevent lineage errors.

Major histocompatibility complex class I (MHC I) positive selection of CD8+ T cells in the thymus requires that T cell antigen receptor (TCR) signaling end in time for cytokines to induce Runx3d, the CD8-lineage transcription factor. We examined the time required for these events and found that the overall duration of positive selection was similar for all CD8+ thymocytes in mice, despite markedly different TCR signaling times. Notably, prolonged TCR signaling times were counter-balanced by accelerated Runx3d induction by cytokines and accelerated differentiation into CD8+ T cells. Consequently, lineage errors did not occur except when MHC I-TCR signaling was so prolonged that the CD4-lineage-specifying transcription factor ThPOK was expressed, preventing Runx3d induction. Thus, our results identify a compensatory signaling mechanism that prevents lineage-fate errors by dynamically modulating Runx3d induction rates during MHC I positive selection.

ECM1 controls T(H)2 cell egress from lymph nodes through re-expression of S1P(1).

Type 2 helper T cells (T(H)2) are critically involved in allergies and asthma. Here we demonstrate that extracellular matrix protein-1 (ECM1) is highly and selectively expressed in T(H)2 cells. ECM1 deficiency caused impaired T(H)2 responses and reduced allergic airway inflammation in vivo. Functional analysis demonstrated that although the T(H)2 polarization of ECM1-deficient cells was unimpaired, these cells had a defect in migration and were retained in peripheral lymphoid organs. This was associated with reduced expression of KLF2 and S1P(1). We also found that ECM1 could directly bind the interleukin-2 (IL-2) receptor to inhibit IL-2 signaling and activate S1P(1) expression. Our data identify a previously unknown function of ECM1 in regulating T(H)2 cell migration through control of KLF2 and S1P(1) expression.

Surface amorphous coating for an economical and high-stability current collector for rechargeable aluminum-ion batteries.

Rechargeable aluminum-ion batteries (AIBs) are regarded as the next-generation energy storage devices due to their low flammability, low cost and high power density as well as abundant aluminum (Al) reserves. However, these popular ionic liquid electrolytes contain highly corrosive acid, which always corrodes the most used positive current collector, thus hindering the commercialization of AIBs. This study proposes an efficient and economical method of coating amorphous Ni3S2compound on a nickel metal current collector (Ni-S/Ni). The conductivity and the onset oxidation potential of amorphous Ni3S2coating can be up to 2.3 × 106S m-1and 2.7 V respectively. A Ni-S/Ni current collector can provide excellent cycling stability with no electrochemical corrosion in the AIBs. The AIBs fabricated using a Ni-S/Ni current collector exhibits a specific capacity of 65 mAh/g at 1 A g-1, high coulombic efficiency of 99% and cyclability of at least 2000 cycles. Moreover, the total cost of the Ni-S/Ni current collector can be limited to less than 3.3 USD/m2. The comprehensive performances of these AIBs are better than most reported results so far, which indicates that this method can advance the commercialization of AIBs.

CS1003, a novel human and mouse cross-reactive PD-1 monoclonal antibody for cancer therapy.

The programmed cell death protein 1 (PD-1) is an immune-checkpoint that negatively regulates the immune system and a key mechanism that tumors utilize to escape from immune surveillance. PD-1 antibodies can block the interaction of PD-1 with its ligands (PD-L1 and PD-L2), restore T cells activation, and elicit antitumor activity. In this paper, we reported a novel PD-1 monoclonal antibody (mAb) CS1003, which is a humanized IgG4 PD-1 mAb generated by conventional hybridoma technology, and currently being developed in multiple clinical trials as monotherapy or in combination with other anticancer agents. We showed that CS1003 bound to recombinant human, cynomolgus monkey, and mouse PD-1 with EC50 values of 0.1757, 0.2459, and 0.3664 nM, respectively. CS1003 blocked PD-1 interaction with its ligands, dose-dependently enhanced T cell proliferation and secretion of cytokines (IL-2 and IFN-γ) to the levels comparable to the reference antibody pembrolizumab. Intraperitoneal administration of CS1003 (0.1, 0.5, 2.5 mg/kg, once every 3 days) dose-dependently suppressed the growth of MC38-hPD-L1 colon cancer in hPD-1 knock-in mice. Pharmacokinetics (PK) study revealed a linear PK profile within the dose range of 2-18 mg/kg following single intravenous administration in cynomolgus monkey. These data provide a comprehensive preclinical characterization of CS1003 that supports its clinical development for cancer immunotherapy.

TRIM30 alpha negatively regulates TLR-mediated NF-kappa B activation by targeting TAB2 and TAB3 for degradation.

Toll-like receptor (TLR) signaling is pivotal to innate and adaptive immune responses and must be tightly controlled. The mechanisms of TLR signaling have been the focus of extensive studies. Here we report that the tripartite-motif protein TRIM30alpha, a RING protein, was induced by TLR agonists and interacted with the TAB2-TAB3-TAK1 adaptor-kinase complex involved in the activation of transcription factor NF-kappaB. TRIM30alpha promoted the degradation of TAB2 and TAB3 and inhibited NF-kappaB activation induced by TLR signaling. In vivo studies showed that transfected or transgenic mice overexpressing TRIM30alpha were more resistant to endotoxic shock. Consistent with that, in vivo 'knockdown' of TRIM30alpha mRNA by small interfering RNA impaired lipopolysaccharide-induced tolerance. Finally, expression of TRIM30alpha depended on NF-kappaB activation. Our results collectively indicate that TRIM30alpha negatively regulates TLR-mediated NF-kappaB activation by targeting degradation of TAB2 and TAB3 by a 'feedback' mechanism.

Effects of electrode thickness and crystal water on pseudocapacitive performance of layered birnessite MnO2.

Manganese dioxide (MnO2) nanomaterials with two-dimensional (2D) layered birnessite structures are promising pseudocapacitive electrode materials. However, the effects of structural factors on their electrochemical performance is not fully understood. We synthesize alkali-free crystal water containing 2D layered birnessite MnO2 electrodes with controllable mass loading from 0.1 to 19.3 mg cm-2 to investigate the effects of electrode thickness and crystal water functions on crystal structure and pseudocapacitive behavior, to promote its industrialization. We find that the crystal water enlarges the interlayer space of birnessite MnO2 with electrolyte ions transported much more easily, resulting in higher specific capacitance of 702 F g-1 (70.2 mF cm-2) and excellent cycling stability of 20 000 charge-discharge cycles even at a mass loading of up to 10.8 mg cm-2. Such gains in specific capacitance are weakened significantly with raised mass loading. Thus, compared to a carbon cloth substrate, a carbon nanotube film with enhanced electron space transport capability presents better performance, indicating an effective strategy for higher mass loading cases. The present work sheds light on an efficient method for achieving high capacitance and mass loading together, for practical applications.

Chromosome choice for initiation of V-(D)-J recombination is not governed by genomic imprinting.

V-(D)-J recombination generates the antigen receptor diversity necessary for immune cell function, while allelic exclusion ensures that each cell expresses a single antigen receptor. V-(D)-J recombination of the Ig, Tcrb, Tcrg and Tcrd antigen receptor genes is ordered and sequential so that only one allele generates a productive rearrangement. The mechanism controlling sequential rearrangement of antigen receptor genes, in particular how only one allele is selected to initiate recombination while at least temporarily leaving the other intact, remains unresolved. Genomic imprinting, a widespread phenomenon wherein maternal or paternal allele inheritance determines allele activity, could represent a regulatory mechanism for controlling sequential V-(D)-J rearrangement. We used strain-specific single-nucleotide polymorphisms within antigen receptor genes to determine if maternal vs paternal inheritance could underlie chromosomal choice for the initiation of recombination. We found no parental chromosomal bias in the initiation of V-(D)-J recombination in T or B cells, eliminating genomic imprinting as a potential regulator for this tightly regulated process.

The Solvent Induced Inter-Dimensional Phase Transformations of Cobalt Zeolitic-Imidazolate Frameworks.

Studying inter-dimensional phase transitions of zeolitic-imidazolate frameworks (ZIFs) is essential for developing strategies in controlling morphology and properties. Herein, the inter-dimensional topotactic phase transformations of 3D ZIF-67 to 2D ZIF-L are investigated in detail by employing a simple and efficient solvent-induced growth method. In addition to ZIF-67 and ZIF-L, a series of novel core-shell composites of ZIF-67@ZIF-L, with unprecedented morphologies, are also obtained and well-defined. The different behaviors of the amine hydrogen of 2-MIM in the solvents play a pivotal role for inter-dimensional phase transformations, and in combination with the concentration of 2-MIM, the 2D to 3D phase transformations are also revealed. The findings are very beneficial for morphological design of the ZIFs, along with exploration of the corresponding properties. Impressively, Co-ZIFs exhibit interesting tunable CO2 adsorption behaviors with the phase evolution, which might bring broader understanding for designing CO2 detection and adsorption devices.

Formation of nickel-doped magnetite hollow nanospheres with high specific surface area and superior removal capability for organic molecules.

A strategy for the formation of magnetic Ni x Fe3-x O4 hollow nanospheres with very high specific surface areas was designed through a facile solvothermal method in mixed solvents of ethylene glycol and water in this work. The Ni/Fe ratios and the crystal phases of the Ni x Fe3-x O4 hollow nanocrystals can be readily tuned by changing the molar ratios of Ni to Fe in the precursors. An inside-out Ostwald ripening mechanism was proposed for the formation of uniform Ni x Fe3-x O4 hollow nanospheres. Moreover, the obtained Ni x Fe3-x O4 hollow nanospheres exhibited excellent adsorption capacity towards organic molecules such as Congo red in water. The maximum adsorption capacities of Ni x Fe3-x O4 hollow nanospheres for Congo red increase dramatically from 263 to 500 mg g-1 with the increase of the Ni contents (x) in Ni x Fe3-x O4 hollow nanospheres from 0.2 to 0.85. The synthesized Ni x Fe3-x O4 nanoparticles can be potentially applied for waste water treatment.

High-efficiency piezoelectric micro harvester for collecting low-frequency mechanical energy.

A single-layer zinc oxide (ZnO) nanorod array-based micro energy harvester was designed and integrated with a piezoelectric metacapacitor. The device presents outstanding low-frequency (1-10 Hz) mechanical energy harvesting capabilities. When compared with conventional pristine ZnO nanostructured piezoelectric harvesters or generators, both open-circuit potential and short-circuit current are significantly enhanced (up to 3.1 V and 124 nA cm-2) for a single mechanical knock (∼34 kPa). Higher electromechanical conversion efficiency (1.3 pC/Pa) is also observed. The results indicate that the integration of the piezoelectric metacapacitor is a crucial factor for improving the low-frequency energy harvesting performance. A double piezoelectric-driven mechanism is proposed to explain current higher output power, in which the metacapacitor plays the multiple roles of charge pumping, storing and transferring. An as-fabricated prototype device for lighting an LED demonstrates high power transference capability, with over 95% transference efficiency to the external load.

[A high content screening method for detection of anaphylactoid reaction of injection formulations].

Anaphylactoid reaction (AR) is the most common adverse reaction of injection formulations, however, there are obvious drawbacks in available methods for AR detection. A novel in vitro detection method for AR was established based on fluorescent labeling and high content screen (HCS) system in present study. With the use of RBL-2H3 cells degranulation model, positive cell count was determined with specific cellular membrane fluorescent dye FM4-64 labeling vesicle recycle, and total cells count was determined with specific nucleus fluorescent dye Hochest 3334, and then the ratio of cells degranulation after drug stimulation was calculated. In order to verify the reliability of this HCS method, positive drug Compound 48/80 was first used to confirm the consistence of HCS method with the traditional ß-hexosaminidase release test and the Evans blue staining ears test in mice. The results showed high consistence between HCS method and traditional testing methods, and the HCS method showed higher sensitivity than the other two tests. Then 30 samples of Danhong injection (DHI) with clinical allergy symptoms further were used to confirm the reliability of this HCS method. The HCS results showed high consistence with the clinical report, and the HCS method had the advantage in reducing the interference by drug color. Therefore, this HCS method is reliable, sensitive, simple and high-throughput method in detection of AR, applicable for the AR evaluation of injection formulations, and can provide guidance for safety of clinical application in clinical practice.

Dosimetric differences between intensity-modulated radiotherapy based on equivalent uniform dose and dose-volume optimization in stage III non-small cell lung cancer.

OBJECTIVE: To determine the dosimetric differences between biological and physical functions of equivalent uniform dose (EUD) and dose volume (DV) therapy in patients with phase III non-small cell lung cancer. METHODS: Four different radiotherapy plans (DV+DV, DV-EUD+DV, EUD+EUD and EUD-DV+EUD) were developed for 15 patients with stage III NSCLC. To study physical function (DV+DV) the target area was optimized by introducing the conditions of biological function optimization, while the organs at risk were optimized by means of physical function (DV-EUD+DV). Biological function optimization (EUD+EUD) was performed for the target area by applying conditions of physical function optimization while biological function optimization (EUD-DV+DV) was conducted for the organs at risk to compare dosimetric parameters among the four groups of treatment plans. RESULTS: PTV: D2%, D98%, D50%, V105% and Dmax of both the DV-EUD+DV group and EDU-DV+EUD group were the minimum (P<0.05). The minimum and average dose of the EUD+EUD group showed an increasing trend and high-dose area became observable. For homogeneity index (HI), DV-EUD+DV group and EUD-DV+EUD results were compared with the other groups (P<0.05), no significant difference was observed statistically between the DV-EUD+DV group and EUD DV+EUD (P=0.659). With regard to conformability index (CI), the results of the four groups showed no significant difference (P>0.05). For the organs at risk, the mean dose of lung tissue (MLD), V5, V10, V20, V30, heart V30, V40, and Dmean also revealed no significant difference (P>0.05). For the spinal cord, the D1 % of the EUD+EUD group and EUD-DV+EUD groups were significantly different (P<0.05) than the other groups. While no significant difference (P=0.32) was found between the EUD+EUD and EUD-DV+EUD groups. When comparing the number of machine unions (MU) no significant difference was revealed (P>0.05) among the results of the 4 groups. CONCLUSION: The methods featuring optimization of physical and biological functions are effective in improving the uniformity of target area to have better outcome of the treatment. Biological function optimization or the combination of biological and physical function optimization is conducive to significantly reduce the required dose for the spinal cord.

Dec2 promotes Th2 cell differentiation by enhancing IL-2R signaling.

Th cell differentiation is precisely regulated by thousands of genes at different stages. In the present study, we demonstrate that Dec2, a transcription factor belonging to the bHLH (basic helix-loop-helix) superfamily, is progressively induced during the course of Th2 differentiation, especially at the late stage. The up-regulated Dec2 can strongly promote Th2 development under Th2-inducing conditions, as evidenced by retrovirus-mediated gene transfer or transgenic manipulation. In addition, an enhancement of Th2 responses is also detectable in Dec2 transgenic mice in vivo. Conversely, RNA interference-mediated suppression of endogenous Dec2 could attenuate Th2 differentiation. Finally, we show that the enhanced Th2 development is at least in part due to substantial up-regulation of CD25 expression elicited by Dec2, thereby resulting in hyperresponsiveness to IL-2 stimulation.

A three-dimensional interconnected hierarchical FeOOH/TiO2/ZnO nanostructural photoanode for enhancing the performance of photoelectrochemical water oxidation.

A novel ZnO/TiO2/FeOOH hierarchical nanostructure has been synthesized by a low temperature chemical bath deposition method. The integrated three-dimensional (3D) nanostructure consists of one-dimensional (1D) ZnO/TiO2 core-shell nanowire arrays and two-dimensional (2D) interconnected FeOOH nanosheets. By applying such a hierarchical nanostructure as a photoanode for photoelectrochemical water reaction, higher photostability and photocurrent density are gained compared with the reported ZnO based nanostructures. It is concluded that the giant enhancement of the properties is because, in the process of photoelectrochemical reaction, electron-hole separation and transfer are enhanced efficiently through the ZnO/TiO2 heterojunction, and in the meanwhile, terminal interconnected FeOOH nanosheets play both the roles of a surface catalyst and a protective layer effectively to accelerate water splitting reaction and enhance photostability. Based on such an environmentally friendly hierarchical nanostructure, photoelectrochemical water splitting and other similar reactions could be performed effectively and economically.

Current understanding of Th2 cell differentiation and function.

Helper T cell (Th) has been identified as a critical immune cell for regulating immune response since 1980s. The type 2 helper Tcell (Th2), characterized by the production of interleukin-4 (IL-4), IL-5 and IL-13, plays a critical role in immune response against helminths invading cutaneous or mucosal sites. It also has a functional role in the pathophysiology of allergic diseases such as asthma and allergic diarrhea. Currently, most studies have shed light on Th2 cell function and behavior in specific diseases, such as asthma and helminthes inflammation, but not on Th2 cell itself and its differentiation. Based on different cytokines and specific behavior in recent research, Th2 cell is also regarded as new subtypes of T cell, such as IL-9 secreting T cell (Th9) and CXCR5(+) T follicular helper cells. Here, we will discuss the latest view of Th2 cell towards their function and the involvement of Th2 cell in diseases.

Negative regulation of virus-triggered IFN-beta signaling pathway by alternative splicing of TBK1.

Induction of Type I IFNs is a central event in antiviral responses and must be tightly controlled. The protein kinase TBK1 is critically involved in virus-triggered type I IFN signaling. In this study, we identify an alternatively spliced isoform of TBK1, termed TBK1s, which lacks exons 3-6. Upon Sendai virus (SeV) infection, TBK1s is induced in both human and mouse cells and binds to RIG-1, disrupting the interaction between RIG-I and VISA. Consistent with that result, overexpression of TBK1s inhibits IRF3 nuclear translocation and leads to a shutdown of SeV-triggered IFN-beta production. Taken together, our data indicate that TBK1s plays an inhibitory role in virus-triggered IFN-beta signaling pathways.

Differential expression of neutrophilic granule proteins between Th1 and Th2 cells.

T helper cell type 1 (Th1) and 2 (Th2) play central roles in immune regulation. To identify the novel genes differentially expressed between Th1 and Th2 cells, CD4+ T cells were isolated from DO11.10 transgenic mice and induced under Th1 or Th2 conditions. Microarray showed differential expression of neutrophilic granule proteins (NGP) between Th1 and Th2 cells. NGP was first identified as a myeloid-specific granule protein with homology to the cystatin superfamily. Here we confirmed greater expression of NGP in Th2 cells by reverse transcription-polymerase chain reaction and real-time polymerase chain reaction analysis. We also showed that the expression of NGP mRNA had a peak expression after 5 d culture under Th2- but not Th1-biasing conditions. Antibody against NGP was prepared, and in concert with the results of mRNA analysis, the level of NGP protein in Th2 cells detected by Western blot analysis was also higher than that in Th1 cells. GFP-NGP fusion proteins overexpressed in HeLa cells were localized to the cytoplasm. These results suggest NGP is a novel marker distinguishing Th2 from Th1 cells and maybe a novel cytokine secreted by Th2 cells.

IL-12p40 is not required for islet allograft rejection.

AIM: To investigate whether IL-12p40 plays a crucial role in regulating islet allograft rejection in a streptozotocin (STZ)-induced diabetes mouse model. METHODS: C57BL/6 and IL-12p40 gene knockout mice were selected as recipient mice, to which the diabetes was induced with a treatment of STZ (150-200 mg/kg) by a single ip injection. BALB/c mice were selected as donor mice and islet cells were isolated from the mice. The 500 islets were transplanted into recipient mice beneath the capsule of the left kidney. Following the islet transplantation the glucose from the mice sera was monitored and the rejection rate of islets was analyzed. RESULTS: STZ could induce diabetes in the recipient mice within 1 week. After transplantation of allograft islets, the increased glucose in wild-type (WT) mice returned to normal level and was maintained for 10 d. Unexpectedly, the rejection rate of islet allograft between IL-12p40-deficient mice and WT mice was similar. CONCLUSION: The results suggested that, although islet allograft rejection is believed to be Th1-cell predominant, the Th1 response inducer, IL-12 and IL-23 are not essential to induce islet allograft rejection.