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M E Hartman

Publications and source records attributed to M E Hartman.

10 recordsLinked to original sources
PubMed2004

Macrophage hypo-responsiveness to interferon-gamma in aged mice is associated with impaired signaling through Jak-STAT.

Since macrophages (Mphis) are a first line of defense against pathogens, and are involved in both innate and adaptive immunity, understanding the impact of aging on Mphi function is important. In the past studies, we and others have shown that aging decreases Mphi responsiveness to classical activating signals (e.g. IFN-gamma and lipopolysaccharide, LPS). In this study, we examined the impact of aging on Mphi signaling through the IFN-gamma receptor pathway. Mphis from male Balb/c mice aged 2 (young) and 18-24 (old) months were purified and then stimulated with IFN-gamma. Western blotting revealed a significant reduction ( approximately 50%) in IFN-gamma-stimulated tyrosine phosphorylation of signal transducer and activator of transcription-1 (STAT-1) alpha and beta in Mphis from aged, when compared with young mice. This reduction in phospho-STAT-1 was associated with a significant constitutive reduction ( approximately 80%) in total STAT-1alpha protein and a complete inhibition of STAT-1 gene expression in response to IFN-gamma in old compared to young mice. These data may, in part, explain why classical Mphi responses like reactive nitrogen and oxygen species generation, tumor killing and microbicidal activity are lower in Mphis from aged subjects. We conclude that peritoneal Mphis from aged mice have an intrinsic defect in Jak-STAT signaling which prevents them from fully responding to IFN-gamma.

Aging↗
PubMed2001

Frap-dependent serine phosphorylation of IRS-1 inhibits IRS-1 tyrosine phosphorylation.

We have previously shown that interferon-alpha (IFN alpha)-dependent tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) is impaired by serine phosphorylation of IRS-1 due to the reduced ability of serine phosphorylated IRS-1 to serve as a substrate for Janus kinase 1 (JAK1). Here we report that FKBP12-rapamycin-associated protein (FRAP) is a physiologic IRS-1 kinase that blocks IFN alpha signaling by serine phosphorylating IRS-1. We found that both FRAP and insulin-activated p70 S6 kinase (p70(s6k)) serine phosphorylated IRS-1 between residues 511 and 772 (IRS-1(511-772)). Importantly, only FRAP-dependent IRS-1(511-772) serine phosphorylation inhibited by 50% subsequent JAK1-dependent tyrosine phosphorylation of IRS-1. Furthermore, treatment of U266 cells with the FRAP inhibitor rapamycin increased IFN alpha-dependent tyrosine phosphorylation by twofold while reducing constitutive IRS-1 serine phosphorylation within S/T-P motifs by 80%. Taken together, these data indicate that FRAP, but not p70(s6k), is a likely physiologic IRS-1 serine kinase that negatively regulates JAK1-dependent IRS-1 tyrosine phosphorylation and suggests that FRAP may modulate IRS-dependent cytokine signaling.

Amino Acid Sequence↗
PubMed1986

Comparison of performances of transfer students and first-year acceptees.

Graduates of the Medical College of Pennsylvania during 1970-1977 were studied to determine the impact of three types of preclinical training on prelicensure clinical performance. The 586 students who comprised these groups consisted of 471 students admitted to the first year, 53 students admitted with advanced standing from U.S. medical or graduate programs, and 62 students admitted with advanced standing from foreign medical schools. Academic performances among the groups differed as measured by scores on the examinations of the National Board of Medical Examiners. However, perceived clinical performances of both transfer groups, as measured by honors awarded in year four and by first-year residency evaluation, were on a par with that of the original matriculants.

College Admission Test↗
PubMed1981

Mechanism of chemotherapeutic drug action in mouse vaginal epithelium.

The mouse vaginal assay was modified to study mechanisms of drug action in epithelial cells in relation to the cell cycle. An evaluation of the labeling index, mitotic index, and the percent labeled mitoses in the vaginal epithelium was used to determine the site of drug action in the cell cycle. Systemic absorption from the vaginal epithelium was also monitored by these same measurements in rectal mucosa. Thirty drugs was tested; 17 showed cell kinetic perturbations in the vaginal mucosa and four of these had both vaginal (local) and rectal (systemic) effects. Thirteen drugs had no effect, suggesting inadequate concentration, penetration, duration of drugs exposure, or lack of biochemical action. These 30 drugs were tested in concentrations and vehicles also used for topical screening in psoriatic patients. Only 15 of the 30 drugs tested in this model predicted the clinical results.

Animals↗