Endothelial phosphoinositide 3-kinase-β inactivation confers protection from immune-mediated vascular injury.

Heart transplant and recipient survival are limited by immune cell-mediated injury of the graft vasculature. We examined the role of the phosphoinositide 3-kinase-β (PI3Kβ) isoform in endothelial cells (EC) during coronary vascular immune injury and repair in mice. In minor histocompatibility-antigen mismatched allogeneic heart grafts, a robust immune response was mounted to each wild-type, PI3Kβ inhibitor-treated, or endothelial-selective PI3Kβ knockout (ECβKO) graft transplanted to wild-type recipients.

Recellularization of xenograft heart valves reduces the xenoreactive immune response in an in vivo rat model.

Objectives: Our aim was to address the role of autologous mesenchymal stem cell recellularization of xenogenic valves on the activation of the xenoreactive immune response in an in vivo rat model.

Methods: Explanted aortic valve constructs from female Hartley guinea pigs were procured and decellularized, followed by recellularization with autologous Sprague-Dawley rat mesenchymal stem cells. Aortic valve xenografts were then implanted into the infrarenal aorta of recipient rats.

BAD regulates mammary gland morphogenesis by 4E-BP1-mediated control of localized translation in mouse and human models.

Elucidation of non-canonical protein functions can identify novel tissue homeostasis pathways. Herein, we describe a role for the Bcl-2 family member BAD in postnatal mammary gland morphogenesis. In Bad knock-in mice, where BAD cannot undergo phosphorylation at 3 key serine residues, pubertal gland development is delayed due to aberrant tubulogenesis of the ductal epithelium.

Apelin directs endothelial cell differentiation and vascular repair following immune-mediated injury.

Sustained, indolent immune injury of the vasculature of a heart transplant limits long-term graft and recipient survival. This injury is mitigated by a poorly characterized, maladaptive repair response. Vascular endothelial cells respond to proangiogenic cues in the embryo by differentiation to specialized phenotypes, associated with expression of apelin.

Brief electrical stimulation and synkinesis after facial nerve crush injury: a randomized prospective animal study.

Background: Recent studies have examined the effects of brief electrical stimulation (BES) on nerve regeneration, with some suggesting that BES accelerates facial nerve recovery. However, the facial nerve outcome measurement in these studies has not been precise or accurate. Furthermore, no previous studies have been able to demonstrate the effect of BES on synkinesis.

Brief electrical stimulation after facial nerve transection and neurorrhaphy: a randomized prospective animal study.

Background: Recent studies have examined the effects of brief electrical stimulation (BES) on nerve regeneration, with some suggesting that BES accelerates facial nerve recovery. However, the facial nerve outcome measurement in these studies has not been precise or accurate. The objective of this study is to assess the effect of BES on accelerating facial nerve functional recovery from a transection injury in the rat model.

Phosphoinositide 3-kinase β mediates microvascular endothelial repair of thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) commonly involves injury of kidney glomerular endothelial cells (ECs) and fibrin occlusion of the capillaries. The mechanisms underlying repair of the microvasculature and recovery of kidney function are poorly defined. In the developing vasculature, the phosphoinositide 3-kinase (PI3K) α isoform integrates many growth factor cues.

T cells generated in the absence of a thoracic thymus fail to establish homeostasis.

Cervical thymus mimics the thoracic thymus in supporting T-cell development and exists in a subset of mice and humans. Importantly, it remains unknown whether the cervical thymus can generate T cells that are self-tolerant in the complete absence of signals from the thoracic thymus. Using a fetal liver reconstitution model in thoracic thymectomized RAG(-/-) mice, we found that T cells could be generated without contribution from the thoracic thymus.

Experimental glomerular endothelial injury in vivo.

The microvascular endothelium of the kidney glomerulus is injured in Shiga-like toxigenic bacterial infection, genetic or acquired loss of complement regulatory protein function, and allo-immune responses of solid-organ or bone marrow transplantation. Existing models of diseases with glomerular endothelial cell (EC) injury, collectively grouped as thrombotic microangiopathies, are problematic, impeding investigation of the mechanisms of microvascular defense and repair. To develop a model of glomerular endothelial injury in the mouse, we conjugated the M.

Impaired phosphatidylcholine biosynthesis does not attenuate liver regeneration after 70% partial hepatectomy in hepatic CTP:phosphocholine cytidylyltransferase-α deficient mice.

Phosphatidylcholine (PC) is the major component of mammalian membranes, and the induction of PC biosynthesis has been shown to be an essential step in cell proliferation in various cell lines. Cytidine triphosphate (CTP):phosphocholine cytidylyltransferase α (CTα) regulates the primary pathway of PC biosynthesis in the liver. The targeted disruption of CTα in murine liver (LCTα(-/-) mice) decreases hepatic PC mass and the number of cells in the liver, suggesting CTα as an important factor for hepatocyte proliferation.

Hepatitis C virus envelope glycoprotein fitness defines virus population composition following transmission to a new host.

Genetic variability is a hallmark of RNA virus populations. However, transmission to a new host often results in a marked decrease in population diversity. This genetic bottlenecking is observed during hepatitis C virus (HCV) transmission and can arise via a selective sweep or through the founder effect.

Lipoprotein profiles in SCID/uPA mice transplanted with human hepatocytes become human-like and correlate with HCV infection success.

Although multiple determinants for hepatitis C virus (HCV) infection are known, it remains partly unclear what determines the human specificity of HCV infection. Presumably, the presence of appropriate entry receptors is essential, and this may explain why HCV is unable to infect nonhuman hepatocytes. However, using mice with chimeric human livers, we show in this study that the presence of human hepatocytes, and therefore human entry receptors, is not sufficient for HCV infection.

Glutaraldehyde-fixed bioprosthetic heart valve conduits calcify and fail from xenograft rejection.

Background: Glutaraldehyde fixation (G-F) decreases but likely does not eliminate the antigenicity of bioprosthetic heart valves. Rejection (with secondary dystrophic calcification) may be why G-F xenograft valves fail, especially in young patients, who are more immunocompetent than the elderly. Therefore, we sought to determine whether rejection of G-F xenograft occurs and to correlate this with graft calcification.

Costimulation blockade of both inducible costimulator and CD40 ligand induces dominant tolerance to islet allografts and prevents spontaneous autoimmune diabetes in the NOD mouse.

Costimulation blockade is a promising strategy for preventing allograft rejection and inducing tolerance. Using a fully allogeneic mouse model, we tested the effectiveness of the combined blockade of the CD40 ligand and the inducible costimulator (ICOS) on islet allograft survival and in the prevention of autoimmune diabetes in the NOD mouse. Recipients treated with blocking monoclonal antibodies (mAbs) to ICOS and the CD40 ligand had significant prolongation of graft survival, with 26 of 28 functioning for >200 days.