Pereira G.,German Cancer Research Center |
Yamashita Y.M.,Michigan Science Center
Trends in Cell Biology | Year: 2011
Cell division is generally thought to be a process that produces an exact copy of the mother cell by precisely replicating its genomic DNA, doubling organelles, and segregating them into two cells. Many cell types from bacteria to human cells divide asymmetrically, however, to generate daughter cells with distinct characteristics. Such asymmetric divisions are fundamental to the lifespan of a cell, to embryonic development, and to stem cell homeostasis. Asymmetric division requires coordination of cellular asymmetry and the cell division machinery. Accumulating evidence suggests that the basic molecular mechanisms that govern this process are conserved from yeast to humans. In this review we highlight similarities in the mechanisms of asymmetric cell division in yeast and Drosophila male germline stem cells (GSCs) in the hope of extracting common themes underlying several systems. © 2011 Elsevier Ltd.
Yamashita Y.M.,Michigan Science Center
Seminars in Cell and Developmental Biology | Year: 2013
The immortal strand hypothesis, which emerged four decades ago, proposes that certain cells retain a template copy of chromosomal DNA to protect against replication-induced mutations. As the interest in stem cells rose in recent years, researchers speculated that stem cells, which must maintain proliferative capacity throughout the life of the organism, may be the population that most needs the strong protection afforded by immortal strand segregation. Alternative hypotheses have also been proposed to explain observed non-random sister chromatid segregation. We recently found that Drosophila male germline stem cells segregate sister chromatids non-randomly, but such bias was limited to the sex chromosomes. Interestingly, the biased segregation does not lead to immortal strand segregation. We will discuss the implications of this observation and molecular mechanisms, which might be applicable to non-random sister chromatid segregation in other systems as well. © 2013 Elsevier Ltd.
Ma D.,Michigan Science Center |
Panda S.,Salk Institute for Biological Studies |
Lin J.D.,Michigan Science Center
EMBO Journal | Year: 2011
Temporal organization of tissue metabolism is important for maintaining nutrient and energy homeostasis in mammals. Autophagy is a conserved cellular pathway that is activated in response to nutrient limitation, resulting in the degradation of cytoplasmic components and the release of amino acids and other nutrients. Here, we show that autophagy exhibits robust circadian rhythm in mouse liver, which is accompanied by cyclic induction of genes involved in various steps of autophagy. Functional analyses of transcription factors and cofactors identified C/EBPβ as a potent activator of autophagy. C/EBPβ is rhythmically expressed in the liver and is regulated by both circadian and nutritional signals. In cultured primary hepatocytes, C/EBPβ stimulates the program of autophagy gene expression and is sufficient to activate autophagic protein degradation. Adenoviral-mediated RNAi knockdown of C/EBPβ in vivo abolishes diurnal autophagy rhythm in the liver. Further, circadian regulation of C/EBPβ and autophagy is disrupted in mice lacking a functional liver clock. We have thus identified C/EBPβ as a key factor that links autophagy to biological clock and maintains nutrient homeostasis throughout light/dark cycles. © 2011 European Molecular Biology Organization | All Rights Reserved.
Valley T.S.,Michigan Science Center
Critical Care Medicine | Year: 2016
OBJECTIVE:: Despite increasing use, evidence is mixed as to the appropriate use of noninvasive ventilation in patients with pneumonia. We aimed to determine the relationship between receipt of noninvasive ventilation and outcomes for patients with pneumonia in a real-world setting. DESIGN, SETTING, PATIENTS:: We performed a retrospective cohort study of Medicare beneficiaries (aged > 64 yr) admitted to 2,757 acute-care hospitals in the United States with pneumonia, who received mechanical ventilation from 2010 to 2011. EXPOSURES:: Noninvasive ventilation versus invasive mechanical ventilation. MEASUREMENT AND MAIN RESULTS:: The primary outcome was 30-day mortality with Medicare reimbursement as a secondary outcome. To account for unmeasured confounding associated with noninvasive ventilation use, an instrumental variable was used—the differential distance to a high noninvasive ventilation use hospital. All models were adjusted for patient and hospital characteristics to account for measured differences between groups. Among 65,747 Medicare beneficiaries with pneumonia who required mechanical ventilation, 12,480 (19%) received noninvasive ventilation. Patients receiving noninvasive ventilation were more likely to be older, male, white, rural-dwelling, have fewer comorbidities, and were less likely to be acutely ill as measured by organ failures. Results of the instrumental variable analysis suggested that, among marginal patients, receipt of noninvasive ventilation was not significantly associated with differences in 30-day mortality when compared with invasive mechanical ventilation (54% vs 55%; p = 0.92; 95% CI of absolute difference, –13.8 to 12.4) but was associated with significantly lower Medicare spending ($18,433 vs $27,051; p = 0.02). CONCLUSIONS:: Among Medicare beneficiaries hospitalized with pneumonia who received mechanical ventilation, noninvasive ventilation use was not associated with a real-world mortality benefit. Given the wide CIs, however, substantial harm associated with noninvasive ventilation could not be excluded. The use of noninvasive ventilation for patients with pneumonia should be cautioned, but targeted enrollment of marginal patients with pneumonia could enrich future randomized trials. Copyright © by 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Yang D.,Michigan Science Center
Journal of visualized experiments : JoVE | Year: 2013
Apolipoprotein (Apo) C-III (ApoCIII) resides on the surface of plasma chylomicron (CM), very low density lipoprotein (VLDL) and high density lipoproteins (HDL). It has been recognized that high levels of plasma ApoCIII constitutea risk factor for cardiovascular diseases (CVD). Elevated plasma ApoCIII level often correlates with insulin resistance, obesity, and hypertriglyceridemia. Invaluable knowledge on the roles of ApoCIIIin lipid metabolisms and CVD has been obtained from transgenic mouse models including ApoCIII knockout (KO) mice; however, it is noted that the metabolism of lipoprotein in mice is different from that of humans in many aspects. It is not known until now whether elevated plasma ApoCIII is directly atherogenic. We worked to develop ApoCIII KO rabbits in the present study based on the hypothesis that rabbits can serve as a reasonablemodelfor studying human lipid metabolism and atherosclerosis. Zinc finger nuclease (ZFN) sets targeting rabbit ApoCIIIgene were subjected to in vitro validation prior to embryo microinjection. The mRNA was injected to the cytoplasm of 35 rabbit pronuclear stage embryos, and evaluated the mutation rates at the blastocyst state. Of sixteen blastocysts that were assayed, a satisfactory 50% mutation rate (8/16) at the targeting site was achieved, supporting the use of Set 1 for in vivo experiments. Next, we microinjected 145 embryos with Set 1 mRNA, and transferred these embryos to 7 recipient rabbits. After 30 days gestation, 21 kits were born, out of which five were confirmed as ApoCIII KO rabbits after PCR sequencing assays. The KO animal rate (#KO kits/total born) was 23.8%. The overall production efficiency is 3.4% (5 kits/145 embryos transferred). The present work demonstrated that ZFN is a highly efficient method to produce KO rabbits. These ApoCIII KO rabbits are novel resources to study the roles of ApoCIII in lipid metabolisms.
Berlin C.M.,Penn State Childrens Hospital |
van den Anker J.N.,Michigan Science Center
Seminars in Fetal and Neonatal Medicine | Year: 2013
The two ultimate goals of using maternal medications during breastfeeding are (i) to provide definitive therapy for maternal conditions for which the drugs have been prescribed, and (ii) to assure protection of the nursing infant from any adverse event related to his/her mother's treatment. Fortunately there are only a few drugs that have been identified as potentially causing harm to the infant. Analytic techniques exist to measure compounds in concentrations as small as nanograms per liter of milk. For nearly all compounds these very small amounts would not be able to exert pharmacological activity, even if absorbed by the infant via the oral route. For environmental chemicals, this ability to measure very small amounts exceeds our knowledge of any biological activity. Concern over any possible adverse event to the nursing infant should take into account the drug, its dose, the age of the infant, recognition of the interindividual variation in drug response and the role of pharmacogenetics. The latter two variables are closely linked. © 2012.
Buchstaller J.,Michigan Science Center |
McKeever P.E.,University of Michigan |
Morrison S.J.,Michigan Science Center |
Morrison S.J.,Howard Hughes Medical Institute
Cancer Cell | Year: 2012
Tumor-initiating cells have been suggested to be rare in many cancers. We tested this in mouse malignant peripheral nerve sheath tumors (MPNSTs) and found that 18% of primary and 49% of passaged MPNST cells from Nf1 +/-; Ink4a/Arf -/- mice formed tumors upon transplantation, whereas only 1.8% to 2.6% of MPNST cells from Nf1 +/-; p53 +/- mice did. MPNST cells of both genotypes require laminin binding to β1-integrin for clonogenic growth. Most MPNST cells from Nf1 +/-; Ink4a/Arf -/- mice expressed laminin, whereas most MPNST cells from Nf1 +/-; p53 +/- mice did not. Exogenous laminin increased the percentage of MPNST cells from Nf1 +/-; p53 +/- but not Nf1 +/-; Ink4a/Arf -/- mice that formed tumorigenic colonies. Tumor-forming potential is common among MPNST cells, but the assay conditions required to detect it vary with tumor genotype. © 2012 Elsevier Inc.
Yamashita Y.M.,Michigan Science Center
Current Opinion in Cell Biology | Year: 2010
Adult stem cells inevitably communicate with their cellular neighbors within the tissues they sustain. Indeed, such communication, particularly with components of the stem cell niche, is essential for many aspects of stem cell behavior, including the maintenance of stem cell identity and asymmetric cell division. Cell adhesion mediates this communication by placing stem cells in proximity to the signaling source and by providing a polarity cue that orients stem cells. Here, I review the recent discovery that cell adhesion molecules govern the behavior of stem cells. © 2010 Elsevier Ltd.
Zhao X.-Y.,Michigan Science Center |
Li S.,Michigan Science Center |
Wang G.-X.,Michigan Science Center |
Yu Q.,Michigan Science Center |
Lin J.D.,Michigan Science Center
Molecular Cell | Year: 2014
Brown and beige/brite fats generate heat via uncoupled respiration to defend against cold. The total mass and activity of thermogenic adipose tissues are also tightly linked to systemic energy and nutrient homeostasis. Despite originating from distinct progenitors, brown and beige adipocytes acquire remarkably similar molecular and metabolic characteristics during differentiation through the action of a network of transcription factors and cofactors. How this regulatory network interfaces with long noncoding RNAs (lncRNAs), an emerging class of developmental regulators, remains largely unexplored. Here, we globally profiled lncRNA gene expression during thermogenic adipocyte formation and identified Brown fat lncRNA 1 (Blnc1) as a nuclear lncRNA that promotes brown and beige adipocyte differentiation and function. Blnc1 forms a ribonucleoprotein complex with transcription factor EBF2 to stimulate the thermogenic gene program. Further, Blnc1 itself is a target of EBF2, thereby forming a feedforward regulatory loop to drive adipogenesis toward thermogenic phenotype. © 2014 Elsevier Inc.
News Article | July 14, 2015