Age-dependent decline in beta-cell proliferation restricts the capacity of beta-cell regeneration in mice.

ObjectiveThe aim of this study was to elucidate whether age plays a role in the expansion or regeneration of beta-cell mass.Research design and methodsWe analyzed the capacity of beta-cell expansion in 1.5- and 8-month-old mice in response to a high-fat diet, after short-term treatment with the glucagon-like peptide 1 (GLP-1) analog exendin-4, or after streptozotocin (STZ) administration.ResultsYoung mice responded to high-fat diet by increasing beta-cell mass and beta-cell proliferation and maintaining normoglycemia. Old mice, by contrast, did not display any increases in beta-cell mass or beta-cell proliferation in response to high-fat diet and became diabetic. To further assess the plasticity of beta-cell mass with respect to age, young and old mice were injected with a single dose of STZ, and beta-cell proliferation was analyzed to assess the regeneration of beta-cells. We observed a fourfold increase in beta-cell proliferation in young mice after STZ administration, whereas no changes in beta-cell proliferation were observed in older mice. The capacity to expand beta-cell mass in response to short-term treatment with the GLP-1 analog exendin-4 also declined with age. The ability of beta-cell mass to expand was correlated with higher levels of Bmi1, a polycomb group protein that is known to regulate the Ink4a locus, and decreased levels of p16(Ink4a)expression in the beta-cells. Young Bmi1(-/-) mice that prematurely upregulate p16(Ink4a)failed to expand beta-cell mass in response to exendin-4, indicating that p16(Ink4a)levels are a critical determinant of beta-cell mass expansion.Conclusionsbeta-Cell proliferation and the capacity of beta-cells to regenerate declines with age and is regulated by the Bmi1/p16(Ink4a)pathway

Two Regulatory Aspects of INO1 Transcription in Yeast

This study focuses on understanding the mechanisms of expression control of a phospholipid biosynthetic gene, INO1. This study also includes investigation into transcriptional regulation of SNA3, a gene in tandem upstream of INO1. INO1 expression is a prevailing model for transcription studies. INO1 is repressed under growth conditions with inositol and derepressed by two transcription activators, Ino2 and Ino4, when inositol is absent. Coordination of the centromeric binding factor, Cbf1, with Ino2 and Ino4 is required for efficient derepression of INO1. Transcription of the INO1 adjacent SNA3 gene is also influenced by inositol. INO1 and SNA3 are co-regulated by Cbf1, Ino2 and Ino4. However, the mechanism of this co-regulation is not fully understood. A separate aspect of INO1 expression is its growth phase regulation. Under inositol depleted conditions, the expression of INO1 increases during log phase and decreases during stationary phase. Most genes in yeast are believed to be expressed at a constant level through all growth phases. It is unclear how INO1 growth phase regulation takes place. The first part of my work focused on exploring the mechanism through which Cbf1, Ino2 and Ino4 control the inositol-mediated regulation of INO1 and SNA3. This included determining the necessity of the Cbf1 binding site for Ino2 and Ino4 binding, as well as for the inositol mediated regulation of INO1 and SNA3. The second part of my work focused on understanding the growth phase regulation of INO1. This includes examining the expression of INO1 in individual cells in a growing population

Synthesis of novel polyimides for the testing of structure-processing and property relations when used to form high temperature polymer matrices

High-performance polymers have found an extreme range of applications in the aerospace industry. Composites which have polymers incorporated in them can usually meet the needs of the design, and are the ideal materials for aerospace applications due to their light weight, high strength, and radar transparency. Phenyl-ethynyl terminated oligomers, for example, have found many uses in the aerospace industry. Phenyl-ethynyl terminated oligomers (AFR-PEPA-N) exhibit glass-transition temperatures of up to 450ðC. Unfortunately crystals form due to interactions of the oligomers. These crystals do not melt until 360ðC after 15 minutes when the resin is already 50% cured. Investigation was performed to find any possible alteration to the end-caps and monomer chain elements of the current AFR-PEPA-N. Several siloxane related amines were added to the AFR-PEPA-N chain to form protective coatings when in service at high temperatures. The new poly(siloxane imide) showed an increase in processability while mantaining AFR-PEPA-N properties. In addition, phenyl-ethnyl end-caps were substituted with an ethynyl end-caps which showed no improvement in processability

Cyclin D2 is sufficient to drive β cell self-renewal and regeneration

Diabetes results from an inadequate mass of functional β cells, due to either β cell loss caused by autoimmune destruction (type I diabetes) or β cell failure in response to insulin resistance (type II diabetes). Elucidating the mechanisms that regulate β cell mass may be key to developing new techniques that foster β cell regeneration as a cellular therapy to treat diabetes. While previous studies concluded that cyclin D2 is required for postnatal β cell self-renewal in mice, it is not clear if cyclin D2 is sufficient to drive β cell self-renewal. Using transgenic mice that overexpress cyclin D2 specifically in β cells, we show that cyclin D2 overexpression increases β cell self-renewal post-weaning and results in increased β cell mass. β cells that overexpress cyclin D2 are responsive to glucose stimulation, suggesting they are functionally mature. β cells that overexpress cyclin D2 demonstrate an enhanced regenerative capacity after injury induced by streptozotocin toxicity. To understand if cyclin D2 overexpression is sufficient to drive β cell self-renewal, we generated a novel mouse model where cyclin D2 is only expressed in β cells of cyclin D2−/− mice. Transgenic overexpression of cyclin D2 in cyclin D2−/− β cells was sufficient to restore β cell mass, maintain normoglycaemia, and improve regenerative capacity when compared with cyclin D2−/− littermates. Taken together, our results indicate that cyclin D2 is sufficient to regulate β cell self-renewal and that manipulation of its expression could be used to enhance β cell regeneration

OARE and SAMS on STS-94/MSL-1

Four microgravity acceleration measurement instruments were included on MSL-1 to measure the accelerations and vibrations to which science experiments were exposed during their operation on the mission. The data were processed and presented to the principal investigators in a variety of formats to aid their assessment of the microgravity environment during their experiment operations. Two accelerometer systems managed by the NASA Lewis Research Center (LeRC) supported the MSL-1 mission: the Orbital Acceleration Research Experiment (OARE), and the Space Acceleration Measurement System (SAMS). In addition, the Microgravity Measurement Assembly (MMA) and the Quasi- Steady Acceleration Measurement (QSAM) system, both sponsored by the Microgravity Research Division, collected acceleration data as a part of the MSL-1 mission. The NIMA was funded and designed by the European Space Agency in the Netherlands (ESA/ESTEC), and the QSAM system was funded and designed by the German Space Agency (DLR). The Principal Investigator Microgravity Services (PIMS) project at the NASA Lewis Research Center (LeRC) supports Principal Investigators (PIs) of the Microgravity science community as they evaluate the effects of acceleration on their experiments. PIMS primary responsibility is to support NASA-sponsored investigators in the area of acceleration data analysis and interpretation. A mission summary report was prepared and published by PIMS in order to furnish interested experiment investigators with a guide for evaluating the acceleration environment during the MSL-1 mission

Neonatal Erythema Multiforme: A Case Report

Erythema multiforme (EM) is an extremely rare condition in infancy. To the best of our knowledge, there have been only three cases of neonatal EM described in the literature, and no such cases have been reported in Korea. A preterm neonate born at 35 weeks and six days of gestation presented with multiple annular erythematous patches with a targetoid shape over his entire body at 36 days of age (corrected age of 7 days). He had no systemic symptoms except for transient mild fever. No triggering factor except for hepatitis B and BCG vaccination was found. Neutropenia was noted upon laboratory analysis. Skin biopsy specimens showed findings suggestive of erythema multiforme. The skin lesions improved rapidly upon administration of intravenous methylprednisolone; however, neutropenia continued for a much longer period. The significance of neutropenia with respect to the development of EM was not clarified. There has been no recurrence of skin lesions over a one-year follow-up period

The Production of Antibody by Invading B Cells Is Required for the Clearance of Rabies Virus from the Central Nervous System

Every year over 50,000 people die from rabies worldwide, primarily due to the poor availability of rabies vaccine in developing countries. However, even when vaccines are available, human deaths from rabies occur if exposure to the causative virus is not recognized and vaccination is not sought in time. This is because rabies virus immunity induced by the natural infection or current vaccines is generally not effective at removing disease-causing rabies virus from brain tissues. Our studies provide insight into why this is the case and how vaccination can be changed so that the immune response can clear the virus from brain tissues. We show that the type of immune response induced by a live-attenuated rabies virus vaccine may be the key. In animal models, live-attenuated rabies virus vaccines are effective at delivering the immune cells capable of clearing the virus into CNS tissues and promote recovery from a rabies virus infection that has spread to the brain while conventional vaccines based on killed rabies virus do not. The production of rabies-specific antibody by B cells that invade the CNS tissues is important for complete elimination of the virus. We hypothesize that similar mechanisms may promote rabies virus clearance from individuals who are diagnosed after the virus has reached, but not extensively spread, through the CNS

Age-Dependent Decline in β-Cell Proliferation Restricts the Capacity of β-Cell Regeneration in Mice

ObjectiveThe aim of this study was to elucidate whether age plays a role in the expansion or regeneration of beta-cell mass.Research design and methodsWe analyzed the capacity of beta-cell expansion in 1.5- and 8-month-old mice in response to a high-fat diet, after short-term treatment with the glucagon-like peptide 1 (GLP-1) analog exendin-4, or after streptozotocin (STZ) administration.ResultsYoung mice responded to high-fat diet by increasing beta-cell mass and beta-cell proliferation and maintaining normoglycemia. Old mice, by contrast, did not display any increases in beta-cell mass or beta-cell proliferation in response to high-fat diet and became diabetic. To further assess the plasticity of beta-cell mass with respect to age, young and old mice were injected with a single dose of STZ, and beta-cell proliferation was analyzed to assess the regeneration of beta-cells. We observed a fourfold increase in beta-cell proliferation in young mice after STZ administration, whereas no changes in beta-cell proliferation were observed in older mice. The capacity to expand beta-cell mass in response to short-term treatment with the GLP-1 analog exendin-4 also declined with age. The ability of beta-cell mass to expand was correlated with higher levels of Bmi1, a polycomb group protein that is known to regulate the Ink4a locus, and decreased levels of p16(Ink4a)expression in the beta-cells. Young Bmi1(-/-) mice that prematurely upregulate p16(Ink4a)failed to expand beta-cell mass in response to exendin-4, indicating that p16(Ink4a)levels are a critical determinant of beta-cell mass expansion.Conclusionsbeta-Cell proliferation and the capacity of beta-cells to regenerate declines with age and is regulated by the Bmi1/p16(Ink4a)pathway

The chemokine receptor CXCR2 and coronavirus-induced neurologic disease.

Inoculation with the neurotropic JHM strain of mouse hepatitis virus (MHV) into the central nervous system (CNS) of susceptible strains of mice results in an acute encephalomyelitis in which virus preferentially replicates within glial cells while excluding neurons. Control of viral replication during acute disease is mediated by infiltrating virus-specific T cells via cytokine secretion and cytolytic activity, however sterile immunity is not achieved and virus persists resulting in chronic neuroinflammation associated with demyelination. CXCR2 is a chemokine receptor that upon binding to specific ligands promotes host defense through recruitment of myeloid cells to the CNS as well as protecting oligodendroglia from cytokine-mediated death in response to MHV infection. These findings highlight growing evidence of the diverse and important role of CXCR2 in regulating neuroinflammatory diseases