Current success in organ transplantation is dependent upon the use of calcineurin‐inhibitor‐based immunosuppressive regimens. Unfortunately, current immunotherapy targets molecules with ubiquitous ...expression resulting in devastating non‐immune side effects. T‐cell costimulation has been identified as a new potential immunosuppressive target. The best characterized pathway includes CD28, its homologue CTLA4 and their ligands CD80 and CD86. While an immunoglobulin fusion protein construct of CTLA4 suppressed rejection in rodents, it lacked efficacy in primate transplant models. In an attempt to increase the biologic potency of the parent molecule a novel, modified version of CTLA4‐Ig, LEA29Y (belatacept), was constructed. Two amino acid substitutions (L104E and A29Y) gave rise to slower dissociation rates for both CD86 and CD80. The increased avidity resulted in a 10‐fold increase in potency in vitro and significant prolongation of renal allograft survival in a pre‐clinical primate model. The use of immunoselective biologics may provide effective maintenance immunosuppression while avoiding the collateral toxicities associated with conventional immunsuppressants.
Stac protein regulates release of neuropeptides Hsu, I-Uen; Linsley, Jeremy W.; Zhang, Xiaoli ...
Proceedings of the National Academy of Sciences - PNAS,
11/2020, Letnik:
117, Številka:
47
Journal Article
Recenzirano
Odprti dostop
Neuropeptides are important for regulating numerous neural functions and behaviors. Release of neuropeptides requires long-lasting, high levels of cytosolic Ca2+. However, the molecular regulation of ...neuropeptide release remains to be clarified. Recently, Stac3 was identified as a key regulator of L-type Ca2+ channels (CaChs) and excitation–contraction coupling in vertebrate skeletal muscles. There is a small family of stac genes in vertebrates with other members expressed by subsets of neurons in the central nervous system. The function of neural Stac proteins, however, is poorly understood. Drosophila melanogaster contain a single stac gene, Dstac, which is expressed by muscles and a subset of neurons, including neuropeptide-expressing motor neurons. Here, genetic manipulations, coupled with immunolabeling, Ca2+ imaging, electrophysiology, and behavioral analysis, revealed that Dstac regulates L-type CaChs (Dmca1D) in Drosophila motor neurons and this, in turn, controls the release of neuropeptides.
The association between acute pancreatitis (AP) and diabetes mellitus (DM) has long been established, with the initial descriptions of AP patients presenting with DM after a bout of AP published in ...the 1940s and 50s. However, the potential mechanisms involved, particularly those components related to the immune system, have not been well defined. The Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM) study is a multicenter clinical study designed to understand the frequency and phenotype of DM developing after AP. This article describes one objective of the DREAM study: to determine the immunologic mechanisms of DM after AP, including the contribution of β-cell autoimmunity. This component of the study will assess the presence of islet autoimmunity, as well as the magnitude and kinetics of the innate and adaptive immune response at enrollment and during longitudinal follow-up after 1 or more episodes of AP. Finally, DREAM will evaluate the relationship between immune features, DM development, and pancreatitis etiology and severity.
In much of the equatorial Pacific, surface nitrate is consistently available due to upwelling of sub-Antarctic Mode Water-derived nitrate from the thermocline. However, in the low-latitude western ...boundary current (WBC) region, surface nitrate is limited due to reduced upwelling and less nitrate-replete thermocline water masses. In order to explore South Pacific WBC paleoceanography via upper ocean nitrate dynamics, we present a new bulk sediment δ15N record from within this WBC region at International Ocean Discovery Program Site U1486 (2°22′S, 144°36′E) in the Bismarck Sea north of New Guinea. This record spans from 1420 ka to recent – surpassing nearby sediment δ15N reconstructions by over a million years and allowing for direct comparison to low-latitude Pacific sediment core δ15N records of similar length. Core-top and down-core bulk sediment δ15N, TOC/TN and δ13Corg values indicate minimal or no terrestrial influence on the organic fraction at Site U1486, which is consistent with previous studies of modern processes in the region. After comparison, differences in orbital variability and secular trends throughout the Middle and Late Pleistocene suggest that nitrate dynamics along the equator and in the WBCs were relatively disparate. We observe that δ15N at Site U1486 is consistent with patterns of eastern Pacific denitrification, while we suggest increasing δ15N after the mid-Pleistocene Transition (MPT; ∼1250–700 ka) at Sites 806 (0°19′N, 110°30′W) and 849 (0°19′N, 160°E) is linked to increasing Southern Ocean nitrate utilization. Enhanced nitrate utilization is a key indicator of the strengthened biological pump that contributed to a reduction in atmospheric pCO2 during the last glacial. Therefore, a post-MPT increase in nitrate utilization may bolster the role of the Southern Ocean biological pump in driving the deeper and longer glacial periods of the 100-kyr world.
•A new 1420-kyr δ15Nbulk record from the northern New Guinea margin extends regional δ15N data by over a million years.•Similarity of this record to a California margin record suggests fidelity and basin-wide significance of δ15Nbulk signals.•δ15Nbulk from the equatorial Pacific may reveal increased nitrate utilization within the sub-Antarctic Zone after the MPT.
Information on the bond strength of milled polymethyl methacrylate interim restorations when relined with chairside reline materials is lacking.
The purpose of this in vitro study was to measure the ...shear bond strength of various combinations of 3 different chairside reline materials bonded to milled polymethyl methacrylate blocks with 3 different types of surface treatments.
Uniform blocks (10×10×22 mm) were milled from tooth-colored polymethyl methacrylate disks (Vivid PMMA; Pearson Dental Supply Co). The surface treatments tested were airborne-particle abrasion with 50-μm particle size aluminosilicate, application of acrylic resin monomer (Jet Liquid; Lang Dental Manufacturing Co) for 180 seconds, and airborne-particle abrasion with monomer application. The control groups were blocks with no surface treatment. The chairside reline materials tested were Jet acrylic resin (Jet Powder; Lang Dental Manufacturing Co), bis-acryl resin (Integrity; Dentsply Sirona), and flowable composite resin (Reveal; Bisco). All materials were applied through a Ø1.5×3-mm bonding ring. Ten specimens for each of the 12 groups were tested in a universal testing machine. Load was applied at a crosshead speed of 1 mm/min. Fracture surfaces were then analyzed for cohesive versus adhesive or mixed failure. Data were analyzed using 2-way ANOVA and Tukey-Kramer post hoc analysis (α=.05).
The mean shear bond strength values ranged from 1.77 ±0.79 MPa to 28.49 ±5.75 MPa. ANOVA revealed that reline material (P<.05), surface treatment (P<.05), and their interactions (P<.05) significantly affected the shear bond strength among the experimental groups. The strongest combination was Jet acrylic resin applied on specimens treated with airborne-particle abrasion and monomer. All 3 failure modalities (adhesive, cohesive, and mixed modes) were observed.
Of the materials tested, the most reliable material to bond to milled polymethyl methacrylate was Jet acrylic resin, and the bond strength values were increased substantially when the milled polymethyl methacrylate surface was airborne-particle abraded and monomer was applied.
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