The expanding fireball of Nova Delphini 2013.

A classical nova occurs when material accreting onto the surface of a white dwarf in a close binary system ignites in a thermonuclear runaway. Complex structures observed in the ejecta at late stages could result from interactions with the companion during the common-envelope phase. Alternatively, the explosion could be intrinsically bipolar, resulting from a localized ignition on the surface of the white dwarf or as a consequence of rotational distortion. Studying the structure of novae during the earliest phases is challenging because of the high spatial resolution needed to measure their small sizes. Here we report near-infrared interferometric measurements of the angular size of Nova Delphini 2013, starting one day after the explosion and continuing with extensive time coverage during the first 43 days. Changes in the apparent expansion rate can be explained by an explosion model consisting of an optically thick core surrounded by a diffuse envelope. The optical depth of the ejected material changes as it expands. We detect an ellipticity in the light distribution, suggesting a prolate or bipolar structure that develops as early as the second day. Combining the angular expansion rate with radial velocity measurements, we derive a geometric distance to the nova of 4.54 ± 0.59 kiloparsecs from the Sun.

C5 blockade with conventional immunosuppression induces long-term graft survival in presensitized recipients.

We explored whether a functionally blocking anti-C5 monoclonal antibody (mAb) combined with T- and B-cell immunosuppression can successfully prevent antibody-mediated (AMR) and cell-mediated rejection (CMR) in presensitized murine recipients of life-supporting kidney allografts. To mimic the urgent clinical features of AMR experienced by presensitized patients, we designed a murine model in which BALB/c recipients were presensitized with fully MHC-mismatched C3H donor skin grafts one week prior to C3H kidney transplantation. Presensitized recipients demonstrated high levels of circulating and intragraft antidonor antibodies and terminal complement activity, rejecting grafts within 8.5 +/- 1.3 days. Graft rejection was predominantly by AMR, characterized by interstitial hemorrhage, edema and glomerular/tubular necrosis, but also demonstrated moderate cellular infiltration, suggesting CMR involvement. Subtherapeutic treatment with cyclosporine (CsA) and LF15-0195 (LF) did not significantly delay rejection. Significantly, however, the addition of anti-C5 mAb to this CsA/LF regimen prevented terminal complement activity and inhibited both AMR and CMR, enabling indefinite (>100 days) kidney graft survival despite the persistence of antidonor antibodies. Long-term surviving kidney grafts expressed the protective proteins Bcl-x(S/L) and A-20 and demonstrated normal histology, suggestive of graft accommodation or tolerance. Thus, C5 blockade combined with routine immunosuppression offers a promising approach to prevent graft loss in presensitized patients.

A keratin peptide inhibits mannose-binding lectin.

Complement plays a significant role in mediating endothelial injury following oxidative stress. We have previously demonstrated that the lectin complement pathway (LCP), which is initiated by deposition of the mannose-binding lectin (MBL), is largely responsible for activating complement on endothelial cells following periods of oxidative stress. Identifying functional inhibitors that block MBL binding will be useful in characterizing the role of the LCP in disease models. The human cytokeratin peptide SFGSGFGGGY has been identified as a molecular mimic of N-acetyl-D-glucosamine (GlcNAc), a known ligand of MBL. Thus, we hypothesized that this peptide would specifically bind to MBL and functionally inhibit the LCP on endothelial cells following oxidative stress. Using a BIAcore 3000 optical biosensor, competition experiments were performed to demonstrate that the peptide SFGSGFGGGY inhibits binding of purified recombinant human MBL to GlcNAc in a concentration-dependent manner. Solution affinity data generated by BIAcore indicate this peptide binds to MBL with an affinity (K(D)) of 5 x 10(-5) mol/L. Pretreatment of human serum (30%) with the GlcNAc-mimicking peptide (10-50 microg/ml) significantly attenuated MBL and C3 deposition on human endothelial cells subjected to oxidative stress in a dose-dependent manner, as demonstrated by cell surface ELISA and confocal microscopy. Additionally, this decapeptide sequence attenuated complement-dependent VCAM-1 expression following oxidative stress. These data indicate that a short peptide sequence that mimics GlcNAc can specifically bind to MBL and functionally inhibit the proinflammatory action of the LCP on oxidatively stressed endothelial cells.

Cloning and characterization of muscle-specific kinase in chicken.

Muscle-specific kinase (MuSK) is part of the receptor complex that is involved in the agrin-induced formation of the neuromuscular junction. In the rodent, prominent mRNA expression of MuSK is restricted to skeletal muscle while the expression of agrin can also be detected in brain and certain nonneuronal tissues. The recent identification of Xenopus MuSK reveals that MuSK can be detected in tissues other than skeletal muscle, such as the neural tube, eye vesicles, and spleen. In this study, we describe the cloning and characterization of the chicken ortholog of MuSK and demonstrate that the regulation of MuSK expression in muscle is conserved from avian to rodent. Abundant mRNA expression of MuSK can be detected in early embryonic chick muscle and is up-regulated after nerve injury. More importantly, we also demonstrate that, in the chicken, MuSK mRNA is expressed during development in brain and liver, suggesting possible novel functions for MuSK. Furthermore, the regulatory profile of MuSK expression in chick muscle closely parallels that observed for acetylcholine receptor, in terms of both mRNA expression and protein localization. Finally, studies with paralyzed chicken muscle as well as with cultured chick myotubes demonstrate the dependence of MuSK on both electrical activity and trophic factors.

Agrin acts via a MuSK receptor complex.

Formation of th neuromuscular junction depends upon reciprocal inductive interactions between the developing nerve and muscle, resulting in the precise juxtaposition of a differentiated nerve terminal with a highly specialized patch on the muscle membrane, termed the motor endplate. Agrin is a nerve-derived factor that can induced molecular reorganizations at the motor endplate, but the mechanism of action of agrin remains poorly understood. MuSK is a receptor tyrosine kinase localized to the motor endplate, seemingly well positioned to receive a key nerve-derived signal. Mice lacking either agrin or MuSK have recently been generated and exhibit similarly profound defects in their neuromuscular junctions. Here we demonstrate that agrin acts via a receptor complex that includes MuSK as well as a myotube-specific accessory component.

Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury.

While a number of growth factors have been described that are highly specific for particular cell lineages, neither a factor nor a receptor uniquely specific to the skeletal muscle lineage has previously been described. Here we identify a receptor tyrosine kinase (RTK) specific to skeletal muscle, which we term "MuSK" for muscle-specific kinase. MuSK is expressed at low levels in proliferating myoblasts and is induced upon differentiation and fusion. In the embryo, it is specifically expressed in early myotomes and developing muscle. MuSK is then dramatically down-regulated in mature muscle, where it remains prominent only at the neuromuscular junction; MuSK is thus the only known RTK that localizes to the neuromuscular junction. Strikingly, MuSK expression is dramatically induced throughout the adult myofiber after denervation, block of electrical activity, or physical immobilization. In humans, MuSK maps to chromosome 9q31.3-32, which overlaps with the region reported to contain the Fukuyama muscular dystrophy mutation. Identification of MuSK introduces a novel receptor-factor system that seems sure to play an important and selective role in many aspects of skeletal muscle development and function.

The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases.

We report the identification of ligands for Tyro 3 (alternatively called Sky, rse, brt, or tif) and Axl (alternatively, Ark or UFO), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein S, a protease regulator that is a potent anticoagulant, and Gas6, a protein related to protein S but lacking any known function. Our results are reminiscent of recent findings that the procoagulant thrombin, a protease that drives clot formation by cleaving fibrinogen to form fibrin, also binds and activates intracellular signaling via a G protein-coupled cell surface receptor. Proteases and protease regulators that also activate specific cell surface receptors may serve to integrate coagulation with associated cellular responses required for tissue repair and growth, as well as to coordinate protease cascades and associated cellular responses in other systems, such as those involved in growth and remodeling of the nervous system.

Alternative forms of rat TrkC with different functional capabilities.

We have identified transcripts encoding several different forms of rat TrkC, a member of the Trk family of receptor tyrosine kinases that serves as a receptor for neurotrophin-3. Some forms of TrkC lack the intracytoplasmic kinase domain and thus resemble previously defined truncated variants of TrkB. Other forms of TrkC contain variable-sized amino acid insertions within the tyrosine kinase domain. Transcripts encoding all forms of TrkC can be detected throughout the nervous system, displaying substantial overlap as well as mutually exclusive distribution patterns with transcripts for TrkB. Strikingly, only transcripts encoding the truncated forms of TrkB and TrkC are found in astrocytes, peripheral nerve, and nonneural tissues. Finally, forms of TrkC containing insertions within the kinase domain retain their ability to autophosphorylate in response to neurotrophin-3, but cannot mediate proliferation in fibroblasts or neuronal differentiation in PC12 cells.

Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution, and receptor specificity.

Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 (NT-3) are the three members of the neurotrophin family known to exist in mammals. Recently, a fourth neurotrophin (designated neurotrophin-4 or NT-4), which shares all of the features found in the mammalian neurotrophins, has been identified in Xenopus and viper. We used sequences specific to the Xenopus/viper NT-4 to isolate a neurotrophin from both human and rat genomic DNA that appears to represent the mammalian counterpart of Xenopus/viper NT-4. Human NT-4 as well as a human NT-4 pseudogene colocalize to chromosome 19 band q13.3. Mammalian NT-4 has many unusual features compared to the previously identified neurotrophins and is less conserved evolutionarily than the other neurotrophins. However, mammalian NT-4 displays bioactivity and trk receptor specificity similar to that of Xenopus NT-4.