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Detroit, MI, United States

Berlin C.M.,Milton rshey Medical Center | 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.

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.

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.

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.

PROBLEM: Clinical and translational research is increasing in China, attracting faculty-to-faculty collaborations between U.S. and Chinese researchers. However, examples of successful institution-to-institution collaborations to facilitate this research are limited. The authors describe a partnership between Peking University Health Science Center (PUHSC) and the University of Michigan Medical School (UMMS) designed to enable faculty-initiated joint translational and clinical research projects. APPROACH: In 2009, UMMS leadership identified PUHSC as the most appropriate institutional partner, and the Joint Institute for Translational and Clinical Research was established in 2010. Each contributed $7 million for joint research projects in areas of mutual interest. A shared governance structure, four thematic programs (pulmonary, cardiovascular, liver, and renal diseases), three joint research-enabling cores, and processes for awarding funding have been established along with methods for collaborating and mechanisms to share data and biomaterials. OUTCOMES: As of November 2015, 52 joint faculty proposals have been submitted, and 25 have been funded. These projects have involved more than 100,000 patients in the United States and China and have generated 13 peer-reviewed publications. Pilot data have been leveraged to secure $3.3 million of U.S. extramural funding. Faculty and trainee exchanges take place regularly (including an annual symposium), and mechanisms exist to link faculty seeking collaborations. Critical determinants of success include having co-ownership at all levels with coinvestment of resources. NEXT STEPS: Both institutions are committed to continuing their support with a repeat $7 million investment. Next steps include initiating studies in new clinical areas and pursuing large clinical intervention trials. © 2016 by the Association of American Medical Colleges

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