High Temperature Alloys Synthesis by Electro-Discharge Compaction

A method is provided for synthesizing high temperature alloys from elemental powders. The method includes the steps of placing the elemental powders to be processed in a die. A relatively high pressure is then applied to the powders. Substantially simultaneously, an electrical discharge is applied to the powders. The discharge is of relatively high voltage and current density to provide alloying. A product fabricated by the present method is also described and claimed

Interleukin-10 containing normal human serum inhibits granzyme B release but not perforin release from alloreactive and EBV-specific T cell clones

Interleukin-10 (IL-10), also known as cytokine synthesis inhibitory factor, has pleiotropic effects in immunoregulation and inflammation. It is capable of inhibiting synthesis of pro-inflammatory cytokines like interferon γ (IFNγ), IL-2, IL-3, tumor necrosis factor α(TNFα) and granulocyte macrophage colony stimulating factor (GM-CSF) made by cells such as macrophages and T helper Type 1 cells. We observed that normal human serum, derived from a healthy individual but containing large amounts of IL-10 (arbitrarily designated as "IL-10 serum"), inhibited cytotoxic activity and interfered with granzyme B release from alloreactive cytotoxic T cell (CTL) clones _in vitro_, but did not affect perforin release. The addition of normal human serum containing high levels of anti-IL-10 IgG (arbitrarily designated as "anti-IL-10 IgG serum") neutralized the inhibitory effects of IL-10 serum. Moreover, we have identified that cytotoxic activity and granzyme B release from an Epstein-Barr virus (EBV)-specific CTL clone was similarly inhibited in the presence of IL-10 serum, while perforin release was unaffected. Anti-IL-10 IgG serum also appeared to neutralize the inhibitory effect of IL-10 serum on an EBV-specific CTL clone

Preparation of Titanium Tetrachloride : Some Experiments for the Determination of its Mechanism

As one of the fundamental experiments on the preparation of titanium tetrachloride, several chlorinations such as that with and without carbon by chlorine gas, that by the mixed gas of chlorine and carbon monoxide, and that by carbon tetrachloride vapour are examined using titanium dioxide and its lower oxides as the material. By the results, it is known that the ignition temperature generally becomes lower as the titanium content in the oxides increases, but it is exceptional in case of the chlorination by the mixed gas of chlorine and carbon monoxide

Glucocorticoids strengthen PD-1 effects

The inhibitory co-receptor programmed cell death 1 (PD-1, Pdcd1) plays critical roles in the regulation of autoimmunity, anti-cancer immunity, and immunity against infections. Immunotherapies targeting PD-1 have revolutionized cancer management and instigated various trials of improved cancer immunotherapies. Moreover, extensive trials are underway to potentiate PD-1 function in order to suppress harmful immune responses. Here, we found that both natural and synthetic glucocorticoids (GCs) up-regulate PD-1 on T cells without altering the expression levels of other co-receptors and cell-surface molecules. The GC-induced up-regulation of PD-1 depended on the transactivation of PD-1 transcription mediated through the glucocorticoid receptor (GR). We further found that a GC response element (GRE) 2525 bp upstream from the transcription start site of Pdcd1 is responsible for GC-mediated transactivation. We also observed that in vivo administration of GCs significantly up-regulates PD-1 expression on tumor-infiltrating T cells. By analyzing T cells differing in PD-1 expression, we directly demonstrated that the amount of PD-1 on the cell surface correlates with its inhibitory effect. Accordingly, GCs potentiated the capacity of PD-1 to inhibit T cell activation, suggesting that this PD-1-mediated inhibition contributes, at least in part, to the anti-inflammatory and immunosuppressive effects of GCs. In light of the critical roles of PD-1 in the regulation of autoimmunity regulation, we expect that the potentiation of PD-1 activity may offer a promising therapeutic strategy for managing inflammatory and autoimmune diseases. Our current findings provide a rationale for strategies seeking to enhance the inhibitory effect of PD-1 by increasing its expression level

PD-1 Primarily Inhibits TCR Signal

Cancer-immunotherapy targeting programmed cell death 1 (PD-1) activates tumor-specific T cells and provides clinical benefits in various cancers. However, the molecular basis of PD-1 function is still enigmatic. Especially, it is unclear which signaling pathway PD-1 primarily targets. Besides, the capacity of PD-1 to inhibit the T cell receptor (TCR)-dependent activation of T cells in the presence of co-stimulation is also controversial. Here we used co-culture systems of T cells and antigen-presenting cells with targeted deletion and overexpression of co-receptors and ligands and examined the inhibitory potency of PD-1 against T cell activation upon TCR stimulation with CD28 and ICOS co-stimulation. As an unambiguous criterion of T cell activation, we used the acquisition of cytokine production capacity, which represents one of the most important functions of T cells. PD-1 inhibited functional T cell activation upon TCR stimulation in the absence as well as in the presence of CD28 co-stimulation, indicating that PD-1 can directly inhibit TCR signal. Notably, CD28 co-stimulation rather attenuated the efficiency of PD-1 in inhibiting TCR-dependent functional T cell activation. In addition, PD-1 inhibited TCR-dependent functional T cell activation with ICOS co-stimulation as efficiently as that with CD28 co-stimulation. Furthermore, we found that the maintenance of antigen-induced follicular helper T (TFH) cells that required ICOS co-stimulation was persistently restrained by PD-1 in vivo. These findings indicate that PD-1 primarily targets TCR signal in the inhibition of functional T cell activation. Thus, PD-1 functions as the rheostat of T cell activation rather than an inhibitor of a specific stimulatory co-receptor

PD-1は自己反応性CD８陽性T細胞の活性化経路を遮断して細胞傷害機能の獲得を阻止する

Anti-PD-1 therapy can induce eradication of tumors and immune-related adverse events (irAEs) in humans and model animals. However, how anti-PD-1 therapy modifies cellular phenotypes of CD8+ T cells to destroy tumors and damage self-tissues remains to be clarified. Here we performed single-cell mRNA expression profiling of autoreactive CD8+ T cells under or beyond PD-1 suppression in target tissues and reconstructed their activation trajectory. Autoreactive CD8+ T cells went through four activation phases and PD-1 strongly attenuated the transition from the second- to the third-phase, where effector functions were acquired. Shifts in cluster composition of autoreactive CD8+ T cells markedly reflected the severity of autoimmunity. In addition, genes up-regulated along the activation-trajectory in autoimmunity were highly expressed in responders of melanoma patients in anti-PD-1 therapy, suggesting that tumor-specific T cells need to be activated in a similar trajectory to destroy tumors in human patients upon PD-1 blockade. These findings reveal that PD-1 blockade facilitates the activation trajectory of CD8+ T cells to boost their effector functions. Targeted manipulation of the trajectory could lead to new therapeutic opportunities

Method of Processing Superconducting Materials and Its Products

A method for fabricating relatively dense monoliths of superconducting material and relatively dense composite monoliths of superconducting material and binder material. The method includes the steps of placing the material to be processed in a die. A relatively high pressure is then applied to the material. Substantially simultaneously, an electrical discharge is applied to the material. The discharge is of a relatively high voltage and current density to provide sharp bonding while maintaining the superconducting properties of the material in the monolith product. A product fabricated by the present method is also described

Tibial Tunnel Positioning Using the Posterolateral (PL) Divergence Guide in Anterior Cruciate Ligament Reconstruction

The aim of this study was to evaluate tunnel coalition and inter-tunnel distance by comparing the tibial tunnel position in double-bundle anterior cruciate ligament (ACL) reconstruction performed with a conventional guide versus a posterolateral (PL) divergence (PLD) guide. Subjects were 43 patients (ACL tip aimer: 20 knees; PLD guide: 23 knees) who underwent double-bundle ACL reconstruction between September 2014 and December 2017. In all cases, the tibial tunnel position, tunnel edge distance and tunnel angles were evaluated based on CT images. Clinical outcome was evaluated using the Lachman test, pivot-shift test, and Lysholm score. Tibial tunnel positions were similar between the conventional and PLD guide groups, while tibial tunnel edge distance was significantly less in the conventional group. Tunnel coalition was observed in 5 knees in the conventional and no knees in the PLD guide group. Distance between two tibial tunnel centers was 9.1 mm for the tip aimer, and 10.5 mm for the PLD guide. Creation of the PL tunnel tended to involve insertion from a more medial aspect for the PLD guide group than the conventional guide group. No differences in clinical outcomes were noted. The PLD guide can be used to create anatomically-positioned PL tunnels, and reduce the probability of occurrence of tunnel coalition