β2-microglobulin modified with advanced glycation end products modulates collagen synthesis by human fibroblasts

β2-microglobulin modified with advanced glycation end products modulates collagen synthesis by human fibroblasts. β2-microglobulin amyloidosis (Aβ2m) is a serious complication for patients undergoing long-term dialysis. β2-microglobulin modified with advanced glycation end products (β2m-AGE) is a major component of the amyloid in Aβ2m. It is not completely understood whether β2m-AGE plays an active role in the pathogenesis of Aβ2m, or if its presence is a secondary event of the disease. β2-microglobulin amyloid is mainly located in tendon and osteo-articular structures that are rich in collagen, and local fibroblasts constitute the principal cell population in the synthesis and metabolism of collagen. Recent identification of AGE binding proteins on human fibroblasts lead to the hypothesis that the fibroblast may be a target for the biological action of β2m-AGE. The present study demonstrated that two human fibroblast cell lines exhibited a decrease in procollagen type I mRNA and type I collagen synthesis after exposure to β2m-AGE for 72 hours. Similar results were observed using AGE-modified albumin. Antibody against the RAGE, the receptor for AGE, attenuated this decrease in synthesis, indicating that the response was partially mediated by RAGE. In addition, antibody against epidermal growth factor (EGF) attenuated the decrease in type I procollagen mRNA and type I collagen induced by β2m-AGE, suggesting that EGF acts as an intermediate factor. These findings support the hypothesis that β2m-AGE actively participates in connective tissue and bone remodeling via a pathway involving fibroblast RAGE, and at least one interposed mediator, the growth factor EGF

Addendum Guidelines for the Prevention of Peanut Allergy in the United States: Report of the National Institute of Allergy and Infectious Diseasesâ Sponsored Expert Panel

BackgroundFood allergy is an important public health problem because it affects children and adults, can be severe and even lifeâ threatening, and may be increasing in prevalence. Beginning in 2008, the National Institute of Allergy and Infectious Diseases, working with other organizations and advocacy groups, led the development of the first clinical guidelines for the diagnosis and management of food allergy. A recent landmark clinical trial and other emerging data suggest that peanut allergy can be prevented through introduction of peanutâ containing foods beginning in infancy.ObjectivesPrompted by these findings, along with 25 professional organizations, federal agencies, and patient advocacy groups, the National Institute of Allergy and Infectious Diseases facilitated development of addendum guidelines to specifically address the prevention of peanut allergy.ResultsThe addendum provides three separate guidelines for infants at various risk levels for the development of peanut allergy and is intended for use by a wide variety of health care providers. Topics addressed include the definition of risk categories, appropriate use of testing (specific IgE measurement, skin prick tests, and oral food challenges), and the timing and approaches for introduction of peanutâ containing foods in the health care provider’s office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation.ConclusionsGuidelines have been developed for early introduction of peanutâ containing foods into the diets of infants at various risk levels for peanut allergy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135514/1/pde13093_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135514/2/pde13093.pd

Addendum guidelines for the prevention of peanut allergy in the United States

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135363/1/pde13092.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135363/2/pde13092_am.pd

ERK1 Regulates the Hematopoietic Stem Cell Niches

The mitogen-activated protein kinases (MAPK) ERK1 and ERK2 are among the major signal transduction molecules but little is known about their specific functions in vivo. ERK activity is provided by two isoforms, ERK1 and ERK2, which are ubiquitously expressed and share activators and substrates. However, there are not in vivo studies which have reported a role for ERK1 or ERK2 in HSCs and the bone marrow microenvironment. The present study shows that the ERK1-deficient mice present a mild osteopetrosis phenotype. The lodging and the homing abilities of the ERK1−/− HSC are impaired, suggesting that the ERK1−/−-defective environment may affect the engrafment of HSCs. Serial transplantations demonstrate that ERK1 is involved in the maintenance of an appropriate medullar microenvironment, but that the intrinsic properties of HSCs are not altered by the ERK1−/− defective microenvironment. Deletion of ERK1 impaired in vitro and in vivo osteoclastogenesis while osteoblasts were unaffected. As osteoclasts derive from precursors of the monocyte/macrophage lineage, investigation of the monocytic compartment was performed. In vivo analysis of the myeloid lineage progenitors revealed that the frequency of CMPs increased by approximately 1.3-fold, while the frequency of GMPs significantly decreased by almost 2-fold, compared with the respective WT compartments. The overall mononuclear-phagocyte lineage development was compromised in these mice due to a reduced expression of the M-CSF receptor on myeloid progenitors. These results show that the cellular targets of ERK1 are M-CSFR-responsive cells, upstream to osteoclasts. While ERK1 is well known to be activated by M-CSF, the present results are the first to point out an ERK1-dependent M-CSFR regulation on hematopoietic progenitors. This study reinforces the hypothesis of an active cross-talk between HSCs, their progeny and bone cells in the maintenance of the homeostasis of these compartments

Speech Communication

Contains table of contents for Part V, table of contents for Section 1, reports on six research projects and a list of publications.C.J. Lebel FellowshipDennis Klatt Memorial FundNational Institutes of Health Grant R01-DC00075National Institutes of Health Grant R01-DC01291National Institutes of Health Grant R01-DC01925National Institutes of Health Grant R01-DC02125National Institutes of Health Grant R01-DC02978National Institutes of Health Grant R01-DC03007National Institutes of Health Grant R29-DC02525National Institutes of Health Grant F32-DC00194National Institutes of Health Grant F32-DC00205National Institutes of Health Grant T32-DC00038National Science Foundation Grant IRI 89-05249National Science Foundation Grant IRI 93-14967National Science Foundation Grant INT 94-2114

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

State Support Critical for Programs that Grow Mississippi\u27s Economy

Several UM programs assist business growth and foster entrepreneurshi

β2-Microglobulin modified with advanced glycation end products delays monocyte apoptosis

β2-Microglobulin modified with advanced glycation end products delays monocyte apoptosis.BackgroundA local inflammatory reaction to β2-microglobulin (β2m) amyloid deposits by monocytes/macrophages is a characteristic histologic feature of dialysis-related amyloidosis (DRA). Since β2m modified with advanced glycation end products (AGE-β2m) is a major constituent of amyloid in DRA, we tested the hypothesis that AGE-β2m affects apoptosis and phenotype of human monocytes.MethodsHuman peripheral blood monocytes were incubated with or without in vitro-derived AGE-β2m, and their viability, extent of apoptosis, morphology, and function examined over the subsequent four days.ResultsAGE-modified but not unmodified β2m significantly delayed spontaneous apoptosis of human peripheral blood monocytes in adherent and nonadherent cultures. The effect of AGE-β2m on monocytes apoptosis was time- and dose-dependent and was attenuated by a blocking antibody directed against the human AGE receptor (RAGE). There was no difference in effect between AGE-β2m and that of AGE-modified human serum albumin. Culture of monocytes with AGE-β2m did not alter membrane expression of Fas or Fas ligand. Monocytes cultured with AGE-β2m underwent substantial changes in morphology similar to those observed when monocytes differentiate into macrophages. The cultured cells increased in size and vacuolization, and their content of β-glucuronidase and acid phosphatase increased by 5- to 10-fold at day 4. Expression of the monocyte–macrophage membrane antigens HLA-DR, CD11b, and CD11c also increased at day 4. Although exhibiting phenotypic characteristics of macrophages, monocytes cultured with AGE-β2m functioned differently than macrophages cultured with serum. Superoxide production in response to phorbol myristic acetate was maintained in monocytes cultured with AGE-β2m, but declined with time in cells cultured with serum. Constitutive synthesis of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and prostaglandin E2 (PGE2) increased in monocytes cultured for four to six days with AGE-β2m.ConclusionsThese findings support a novel role for AGE-modified proteins such as AGE-β2m that may contribute to the development of a local inflammatory response, with predominant accumulation of monocytes/macrophages, in DRA