Transcriptional Governance of Hair Follicle Stem Cell Quiescence and Niche Maintenance in Long-Term Tissue Regeneration

Adult stem cells are endowed with the remarkable ability to maintain, regenerate and repair tissues throughout the lifetime of the organism. Whether parsimonious utilization of adult stem cells is necessary to preserve their long-term potential has not been fully explored. I investigated this issue using the adult murine hair follicle stem cell (HFSC) as my paradigm. HFSCs reside in their niche called the bulge, and mostly remain in a quiescent state, becoming mobilized only transiently to fuel cyclical bouts of hair follicle regeneration. By ablating a key HFSC transcription factor, Forkhead Box C1 (FOXC1), I discovered that hair follicles underwent more rounds of regeneration and yet were unable to result in a thickening of the animal’s hair coat. Mechanistically, unlike WT HFSCs, FOXC1-deficient HFSCs failed to remain in prolonged durations of quiescence. Instead, they were primed to re-enter the cell cycle and launch new rounds of hair regeneration prematurely. After activation, they failed to re-establish quiescence promptly, and remained in a primed state to proliferate. In turn, their expression of cell adhesion proteins remained low. As new hairs grew, wild-type (WT) HFSCs that had returned to quiescence and restored their repertoire of adhesion-associated proteins were able to anchor their bulge niche and the older hairs in place. However, FOXC1- deficient HFSCs were unable to do so, resulting in the gradual loss of their bulge and old hair coats. As the bulge is also a cellular source of HFSC-inhibitory factors, its loss exacerbated the inability of FOXC1-deficient HFSCs to maintain quiescence. Consequently, as these mutant mice aged, their hair coat appeared sparse. Indeed, their HFSC numbers and ability to regenerate new hairs upon stimulation had declined. Therefore, through FOXC1, HFSCs couple their quiescence to an adhesion-mediated niche maintenance to achieve long-term tissue homeostasis

Contemporary design philosophy in American architecture

Call number: LD2668 .R4 1966 L42

Biologically guided implant therapy: A diagnostic and therapeutic strategy of conservation and preservation based on periodontal staging and grading

Biologically guided implant therapy is based on the new periodontitis classification system recently released by the American Academy of Periodontology and the European Federation of Periodontology that uses staging and grading for the diagnosis of periodontitis. This paper proposes that periodontitis staging and grading should be used in dental implant therapy as a means to ensure maximum conservation of teeth and maximum preservation of alveolar bone. These biologic principles should guide the treatment planning process and supersede a mechanically based, restoratively driven rationale that should be secondary to the biologic principles of conservation and preservation but part of the collaborative treatment planning process. And treatment alternatives throughout the patient’s lifetime should be provided for in case of prosthesis loss due to periâ implantitis. The use of grading will help with recognition of systemic aspects that can have a negative impact.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149297/1/jper10267_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149297/2/jper10267.pd

Using periodontal staging and grading system as a prognostic factor for future tooth loss: A long- term retrospective study

BackgroundA new classification of periodontal diseases aimed to identify periodontal disease based on a multidimensional staging and grading system has been recently proposed. However, up to date, its prognostic predictive capability has not been investigated. The aim of this study was to assess if parameters included in the new classification were predictive of tooth loss after a long- term follow- up (>10 years) in patients with periodontitis.MethodsPatients presented with periodontitis at the University of Michigan between January 1966 and January 2004 were screened and categorized according to the new classification of periodontitis. Number/Reasons of teeth loss in patients who underwent at least one session/year of maintenance during the entire follow- up period were extracted and used to analyze the prognostic capabilities of variables (staging, grading, and Extent) included in the new classification.ResultsA total number of 292 patients with a mean follow- up of 289.7 ± 79.6 months were included. 31 (10.6%) patients were classified as Stage 1, 85 (29.1%) as Stage 2, 146 (50%) as Stage 3, and 30 (10.3%) as Stage 4. For grading, 34 (11.7%) were classified as Grade A, 193 (66.1%) as Grade B, and 65 (22.2%) as Grade C. Results of multilevel Cox regression analyses revealed a statistically significant association between stage (HR:3.73 between Stage 4 and Stage 1) and grade (HR: 4.83 between Grade C and Grade A) at baseline and periodontal related tooth loss, whereas no differences were detected for the extent of periodontitis.ConclusionThis study provides the initial evidence regarding the predictive ability of the new classification of periodontitis. Patients in either Stage 4 or Grade C showed a significantly higher periodontal- related tooth loss.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154975/1/jper10442_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154975/2/jper10442.pd

Darwin -— an experimental astronomy mission to search for extrasolar planets

As a response to ESA call for mission concepts for its Cosmic Vision 2015–2025 plan, we propose a mission called Darwin. Its primary goal is the study of terrestrial extrasolar planets and the search for life on them. In this paper, we describe different characteristics of the instrument

Regulation of expression of the rat orthologue of mouse double minute 2 (MDM2) by H2O2-induced oxidative stress in neonatal rat cardiac myocytes.

The Mdm2 ubiquitin ligase is an important regulator of p53 abundance and p53-dependent apoptosis. Mdm2 expression is frequently regulated by a p53 Mdm2 autoregulatory loop whereby p53 stimulates Mdm2 expression and hence its own degradation. Although extensively studied in cell lines, relatively little is known about Mdm2 expression in heart where oxidative stress (exacerbated during ischemia-reperfusion) is an important pro-apoptotic stimulus. We demonstrate that Mdm2 transcript and protein expression are induced by oxidative stress (0.2 mm H(2)O(2)) in neonatal rat cardiac myocytes. In other cells, constitutive Mdm2 expression is regulated by the P1 promoter (5' to exon 1), with inducible expression regulated by the P2 promoter (in intron 1). In myocytes, H(2)O(2) increased Mdm2 expression from the P2 promoter, which contains two p53-response elements (REs), one AP-1 RE, and two Ets REs. H(2)O(2) did not detectably increase expression of p53 mRNA or protein but did increase expression of several AP-1 transcription factors. H(2)O(2) increased binding of AP-1 proteins (c-Jun, JunB, JunD, c-Fos, FosB, and Fra-1) to an Mdm2 AP-1 oligodeoxynucleotide probe, and chromatin immunoprecipitation assays showed it increased binding of c-Jun or JunB to the P2 AP-1 RE. Finally, antisense oligonucleotide-mediated reduction of H(2)O(2)-induced Mdm2 expression increased caspase 3 activation. Thus, increased Mdm2 expression is associated with transactivation at the P2 AP-1 RE (rather than the p53 or Ets REs), and Mdm2 induction potentially represents a cardioprotective response to oxidative stress

Portfolio Vol. IV N 1

Phillips, Alison. Reflection. Poetry. 2. Rood, John. The Accused. Picture. 2. Lay, Mary Virginia. Irony. Poetry. 6. Lay, Mary Virginia. Not Know God? Poetry. 6. Shields, Margaret. Hope. Poetry. 6. Rogers, Tom. Football and Education. Prose. 7. Hammer, John. Red? Prose. 3-4. Brown, Kenneth I. The Christmas Guest. Prose. 5. Price III, Ira. Thomas Carlyle-Political Reactionary. Prose. 8-10. Tinnerman, Betty. Greater Love Hath No Man. Prose. 11. Hall, Jim. Gentlement--To Arms! Prose. 12-13. Benson, Virginia. Drop That Hammer! Prose. 14-15. Wilson, William. Thomas Wolfe--Volcano. Prose. 16. Seagrave, Leslie. Trelawney. Prose. 16. Chester, Bob. Keeping the Records Straight. Prose. 17. Wurdman, Audrey. I, II, XLIX. Poetry. 18. Auslander, Joseph. These Are the Wounds. Poetry. 19. Auslander, Joseph. Christmas Encyclical. Poetry. 19. Auslander, Joseph. Encounter With Keats. Poetry. 19. Koncana, Jean. Backstage at the Opera House. Prose. 20. Timrud, David. Ward Seventy Tonight. Prose. 21-22. Roach, Margaret. Wedding Bells. Prose. 23-26. Close, Dean. Back Country. Picture. 6

γCOP Is Required for Apical Protein Secretion and Epithelial Morphogenesis in Drosophila melanogaster

Background: There is increasing evidence that tissue-specific modifications of basic cellular functions play an important role in development and disease. To identify the functions of COPI coatomer-mediated membrane trafficking in Drosophila development, we were aiming to create loss-of-function mutations in the γCOP gene, which encodes a subunit of the COPI coatomer complex. Principal Findings: We found that γCOP is essential for the viability of the Drosophila embryo. In the absence of zygotic γCOP activity, embryos die late in embryogenesis and display pronounced defects in morphogenesis of the embryonic epidermis and of tracheal tubes. The coordinated cell rearrangements and cell shape changes during tracheal tube morphogenesis critically depend on apical secretion of certain proteins. Investigation of tracheal morphogenesis in γCOP loss-of-function mutants revealed that several key proteins required for tracheal morphogenesis are not properly secreted into the apical lumen. As a consequence, γCOP mutants show defects in cell rearrangements during branch elongation, in tube dilation, as well as in tube fusion. We present genetic evidence that a specific subset of the tracheal defects in γCOP mutants is due to the reduced secretion of the Zona Pellucida protein Piopio. Thus, we identified a critical target protein of COPI-dependent secretion in epithelial tube morphogenesis. Conclusions/Significance: These studies highlight the role of COPI coatomer-mediated vesicle trafficking in both general and tissue-specific secretion in a multicellular organism. Although COPI coatomer is generally required for protein secretion, we show that the phenotypic effect of γCOP mutations is surprisingly specific. Importantly, we attribute a distinct aspect of the γCOP phenotype to the effect on a specific key target protein

The Chromatin Modifier MSK1/2 Suppresses Endocrine Cell Fates during Mouse Pancreatic Development

Type I diabetes is caused by loss of insulin-secreting beta cells. To identify novel, pharmacologically-targetable histone-modifying proteins that enhance beta cell production from pancreatic progenitors, we performed a screen for histone modifications induced by signal transduction pathways at key pancreatic genes. The screen led us to investigate the temporal dynamics of ser-28 phosphorylated histone H3 (H3S28ph) and its upstream kinases, MSK1 and MSK2 (MSK1/2). H3S28ph and MSK1/2 were enriched at the key endocrine and acinar promoters in E12.5 multipotent pancreatic progenitors. Pharmacological inhibition of MSK1/2 in embryonic pancreatic explants promoted the specification of endocrine fates, including the beta-cell lineage, while depleting acinar fates. Germline knockout of both Msk isoforms caused enhancement of alpha cells and a reduction in acinar differentiation, while monoallelic loss of Msk1 promoted beta cell mass. Our screen of chromatin state dynamics can be applied to other developmental contexts to reveal new pathways and approaches to modulate cell fates

Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases