A Comprehensive 3-D Model on Gas Metal Arc Welding

A unified comprehensive model was developed to simulate the transport phenomena occurring during the gas metal arc welding process. An interactive coupling between arc plasma; melting of a continuously fed electrode; droplet formation, detachment, transfer, and impingement onto the workpiece under the influences of several competing forces including gravity, electromagnetic force, arc pressure, plasma shear stress, and surface tension; and weld pool dynamics all were considered. The transient distributions of current density, arc temperature, arc pressure, melt flow velocity and melt temperature in the droplet and in the weld pool were all calculated. Based on the unified model, the following investigations were conducted: 1) the effect of welding current on droplet generation, especially the use of pulsed current to achieve the one-droplet-per-pulse (ODPP) metal transfer; 2) the determination of dynamically stabled wire feed speeds for given welding conditions; 3) the effects of surface active elements (Marangoni effect) on the weld pool flow and solidified weld profile; 4) the fundamental mechanisms leading to the formation of ripples; 5) the issues associated with the beginning and the end of the welding (limited penetration and the formations of crater); 6) the deflection of arc plasma by an external magnetic field

Biases and improvements of the boreal winter–spring equatorial undercurrent in the Indian Ocean in the CMIP5 and CMIP6 models

We assessed the performance of state-of-the-art coupled models in reproducing the equatorial undercurrent (EUC) in the Indian Ocean based on the outputs of the Coupled Model Intercomparison Project Phase 6 (CMIP6) models and compared with the Phase 5 (CMIP5) models. Our results showed that the CMIP6 models reproduced the boreal winter–spring Indian Ocean EUC more realistically than the CMIP5 models, although both generations of models underestimated the strength of the Indian Ocean EUC compared with the observations. This underestimation of the Indian Ocean EUC can be attributed to the excessively strong and westward-extended cold tongue in the equatorial Pacific. In the CMIP models, a stronger winter-mean cold tongue favors a stronger zonal sea surface temperature gradient, which forces a strong easterly wind bias over the equatorial western Pacific. This, in turn, contributes to an acceleration of the Walker circulation. This enhanced Walker circulation over the Indo-Pacific Ocean directly causes a lower level westerly wind bias over the equatorial Indian Ocean and drives a shallow west–deep east thermocline tilt bias, ultimately leading to an excessively weak EUC in the Indian Ocean via wind-induced thermocline processes. Compared with the CMIP5 models, the overall improvement in the strength of the winter–spring Indian Ocean EUC in the CMIP6 models can be traced back to the improvement in the degree of the strong and westward-extended cold tongue bias. Our results suggest that efforts should be made to reduce the bias in the mean-state equatorial Pacific sea surface temperature to further improve the simulation and projection of the atmospheric and oceanic circulations in the Indian Ocean

Induction of Mast Cell Accumulation by Tryptase via a Protease Activated Receptor-2 and ICAM-1 Dependent Mechanism

Mast cells are primary effector cells of allergy, and recruitment of mast cells in involved tissue is one of the key events in allergic inflammation. Tryptase is the most abundant secretory product of mast cells, but little is known of its influence on mast cell accumulation. Using mouse peritoneal model, cell migration assay, and flow cytometry analysis, we investigated role of tryptase in recruiting mast cells. The results showed that tryptase induced up to 6.7-fold increase in mast cell numbers in mouse peritoneum following injection. Inhibitors of tryptase, an antagonist of PAR-2 FSLLRY-NH2, and pretreatment of mice with anti-ICAM-1, anti-CD11a, and anti-CD18 antibodies dramatically diminished tryptase induced mast cell accumulation. On the other hand, PAR-2 agonist peptides SLIGRL-NH2 and tc-LIGRLO-NH2 provoked mast cell accumulation following injection. These implicate that tryptase induced mast cell accumulation is dependent on its enzymatic activity, activation of PAR-2, and interaction between ICAM-1 and LFA-1. Moreover, induction of trans-endothelium migration of mast cells in vitro indicates that tryptase acts as a chemoattractant. In conclusion, provocation of mast cell accumulation by mast cell tryptase suggests a novel self-amplification mechanism of mast cell accumulation. Mast cell stabilizers as well as PAR-2 antagonist agents may be useful for treatment of allergic reactions

PHE1-based IgG-like antibody platform provides a novel strategy for enhanced T-cell immunotherapy

IntroductionBispecific antibodies (BsAbs) can simultaneously target two epitopes of different antigenic targets, bringing possibilities for diversity in antibody drug design and are promising tools for the treatment of cancers and other diseases. T-cell engaging bsAb is an important application of the bispecific antibody, which could promote T cell-mediated tumor cell killing by targeting tumor-associated antigen (TAA) and CD3 at the same time.MethodsThis study comprised antibodies purification, Elisa assay for antigen binding, cytotoxicity assays, T cell activation by flow cytometry in vitro and xenogenic tumor model in vivo.ResultsWe present a novel bsAb platform named PHE-Ig technique to promote cognate heavy chain (HC)-light chain (LC) pairing by replacing the CH1/CL regions of different monoclonal antibodies (mAbs) with the natural A and B chains of PHE1 fragment of Integrin β2 based on the knob-in-hole (KIH) technology. We had also verified that PHE-Ig technology can be effectively used as a platform to synthesize different desired bsAbs for T-cell immunotherapy. Especially, BCMA×CD3 PHE-Ig bsAbs exhibited robust anti-multiple myeloma (MM) activity in vitro and in vivo.DiscussionMoreover, PHE1 domain was further shortened with D14G and R41S mutations, named PHE-S, and the PHE-S-based BCMA×CD3 bsAbs also showed anti BCMA+ tumor effect in vitro and in vivo, bringing more possibilities for the development and optimization of different bsAbs. To sum up, PHE1-based IgG-like antibody platform for bsAb construction provides a novel strategy for enhanced T-cell immunotherapy

Ferroelastic-switching-driven colossal shear strain and piezoelectricity in a hybrid ferroelectric

Materials that can produce large controllable strains are widely used in shape memory devices, actuators and sensors. Great efforts have been made to improve the strain outputs of various material systems. Among them, ferroelastic transitions underpin giant reversible strains in electrically-driven ferro/piezoelectrics and thermally- or magneticallydriven shape memory alloys. However, large-strain ferroelastic switching in conventional ferroelectrics is very challenging while magnetic and thermal controls are not desirable for applications. Here, we demonstrate an unprecedentedly large shear strain up to 21.5 % in a hybrid ferroelectric, C6H5N(CH3)3CdCl3. The strain response is about two orders of magnitude higher than those of top-performing conventional ferroelectric polymers and oxides. It is achieved via inorganic bond switching and facilitated by the structural confinement of the large organic moieties, which prevents the undesired 180-degree polarization switching. Furthermore, Br substitution can effectively soften the bonds and result in giant shear piezoelectric coefficient (d35 ~ 4800 pm/V) in Br-rich end of the solid solution, C6H5N(CH3)3CdBr3xCl3(1-x). The superior electromechanical properties of the compounds promise their potential in lightweight and high energy density devices, and the strategy described here should inspire the development of next-generation piezoelectrics and electroactive materials based on hybrid ferroelectrics.Comment: 32 pages, 14 figures, 5 table

GPIbα CAAR-T cells function like a Trojan horse to eliminate autoreactive B cells to treat immune thrombocytopenia

Breakthrough treatment for refractory and relapsed immune thrombocytopenia (ITP) patients is urgently needed. Autoantibody-mediated platelet clearance and megakaryocyte dysfunction are important pathogenic mediators of ITP. Glycoprotein (GP) Ibα is a significant autoantigen found in ITP patients and is associated with poor response to standard immunosuppressive treatments. Here, we engineered human T cells to express a chimeric autoantibody receptor (CAAR) with GPIbα constructed into the ligand-binding domain fused to the CD8 transmembrane domain and CD3ζ-4-1BB signaling domains. We performed cytotoxicity assays to assess GPIbα CAAR-T-cell selective cytolysis of cells expressing anti-GPIbα B-cell receptors (BCRs) in vitro. Furthermore, we demonstrated the potential of GPIbα CAAR-T cells to persist and precisely eliminate GPIbα-specific B cells in vivo. In summary, we present a proof of concept for CAAR-T-cell therapy to eradicate autoimmune B cells while sparing healthy B cells with GPIbα CAAR-T cells that function like a Trojan horse. GPIbα CAAR-Tcell therapy is a promising treatment for refractory and relapsed ITP patients