FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle

FKBP12, the 12-kDa FK506-binding protein, is a ubiquitous abundant protein that acts as a receptor for the immunosuppressant drug FK506, binds tightly to intracellular calcium release channels and to the transforming growth factor β (TGF-β) type I receptor. We now demonstrate that cells from FKBP12-deficient (FKBP12−/−) mice manifest cell cycle arrest in G1 phase and that these cells can be rescued by FKBP12 transfection. This arrest is mediated by marked augmentation of p21(WAF1/CIP1) levels, which cannot be further augmented by TGF-β1. The p21 up-regulation and cell cycle arrest derive from the overactivity of TGF-β receptor signaling, which is normally inhibited by FKBP12. Cell cycle arrest is prevented by transfection with a dominant-negative TGF-β receptor construct. TGF-β receptor signaling to gene expression can be mediated by SMAD, p38, and ERK/MAP kinase (extracellular signal-regulated kinase/mitogen-activated protein kinase) pathways. SMAD signaling is down-regulated in FKBP12−/− cells. Inhibition of ERK/MAP kinase fails to affect p21 up-regulation. By contrast, activated phosphorylated p38 is markedly augmented in FKBP12−/− cells and the p21 up-regulation is prevented by an inhibitor of p38. Thus, FKBP12 is a physiologic regulator of cell cycle acting by normally down-regulating TGF-β receptor signaling.

Genomic evidence for a complete sexual cycle in Candida albicans

Candida albicans is a diploid fungus that has become a medically important opportunistic pathogen in immunocompromised individuals. We have sequenced the C. albicans genome to 10.4-fold coverage and performed a comparative genomic analysis between C. albicans and Saccharomyces cerevisiae with the objective of assessing whether Candida possesses a genetic repertoire that could support a complete sexual cycle. Analyzing over 500 genes important for sexual differentiation in S. cerevisiae, we find many homologues of genes that are implicated in the initiation of meiosis, chromosome recombination, and the formation of synaptonemal complexes. However, others are striking in their absence. C. albicans seems to have homologues of all of the elements of a functional pheromone response pathway involved in mating in S. cerevisiae but lacks many homologues of S. cerevisiae genes for meiosis. Other meiotic gene homologues in organisms ranging from filamentous fungi to Drosophila melanogaster and Caenorhabditis elegans were also found in the C. albicans genome, suggesting potential alternative mechanisms of genetic exchange.

Gene discovery and gene function assignment in filamentous fungi

Filamentous fungi are a large group of diverse and economically important microorganisms. Large-scale gene disruption strategies developed in budding yeast are not applicable to these organisms because of their larger genomes and lower rate of targeted integration (TI) during transformation. We developed transposon-arrayed gene knockouts (TAGKO) to discover genes and simultaneously create gene disruption cassettes for subsequent transformation and mutant analysis. Transposons carrying a bacterial and fungal drug resistance marker are used to mutagenize individual cosmids or entire libraries in vitro. Cosmids are annotated by DNA sequence analysis at the transposon insertion sites, and cosmid inserts are liberated to direct insertional mutagenesis events in the genome. Based on saturation analysis of a cosmid insert and insertions in a fungal cosmid library, we show that TAGKO can be used to rapidly identify and mutate genes. We further show that insertions can create alterations in gene expression, and we have used this approach to investigate an amino acid oxidation pathway in two important fungal phytopathogens.

Immunoglobulin variable region hypermutation in hybrids derived from a pre-B- and a myeloma cell line.

Somatic mutation of the variable (V) regions of immunoglobulin genes occurs in vivo at rates that have been estimated to be between 10(-3) and 10(-4) per bp per generation. To study this process in vitro, the 18.81 pre-B-cell line and hybrids derived by fusing 18.81 to the NSO myeloma fusion partner were transfected with a mu heavy-chain construct containing a nonsense mutation in the V region (Vn) or the constant region (Cn). Mutation was quantitated by reversion analysis using the ELISA spot assay to detect single cells secreting IgM. Fluctuation analysis revealed that V-region mutations spontaneously occurred in 18.81 cells at an average rate of 5.8 x 10(-6) per bp per cell generation and in selected 18.81-NSO hybrids at greatly increased rates of 1.6 x 10(-3) to 5.8 x 10(-4) per bp per generation. The Vn construct also reverted frequently in transgenic mice, indicating that it contained sufficient information to mutate at high rates both in vivo and in vitro. Sequence analysis of reverted genes revealed that reversion was due to point mutations. Since the rates and nature of the mutations that are occurring in these transfected genes are similar to those reported in vivo, it should be possible to use this system to identify the cis-acting sequences and trans-acting factors that are responsible for V-region somatic hypermutation.

U.S. Democracy Promotion from Bush to Obama. EUSpring Working Paper No. 1, April 2015

Throughout the twenty-first century the United States (U.S.) has attempted to balance its traditional national security interests, whilst also seeking to promote the long-term transformation of the Middle East and North Africa (MENA) towards democracy based on liberal values. With the September 11, 2001 terrorist attacks providing a catalyst for policy change, the U.S. has moved away from its twentieth-century policy of pursuing a regional status quo and instinctively balking at political change. Yet, the U.S. has not abandoned its reliance on autocratic regimes that cooperate on more immediate national security interests such as counter-terrorism, counter-proliferation, and the free-flow energy sources into the global market. Rather, U.S. democracy promotion in the MENA has become incremental by design and is characterized by its gradualist and often collaborative nature. U.S. foreign policy in the MENA is, therefore, depicted by a cautious evolutionary stance rather than supporting revolutionary shifts in power.

US Democracy Promotion from Bush to Obama. EUSpring Working Paper No. 1, 15 April 2015

Throughout the twenty-first century the United States (U.S.) has attempted to balance its traditional national security interests, whilst also seeking to promote the long-term transformation of the Middle East and North Africa (MENA) towards democracy based on liberal values. With the September 11, 2001 terrorist attacks providing a catalyst for policy change, the U.S. has moved away from its twentieth-century policy of pursuing a regional status quo and instinctively balking at political change. Yet, the U.S. has not abandoned its reliance on autocratic regimes that cooperate on more immediate national security interests such as counter-terrorism, counter-proliferation, and the free-flow energy sources into the global market. Rather, U.S. democracy promotion in the MENA has become incremental by design and is characterized by its gradualist and often-collaborative nature. U.S. foreign policy in the MENA is, therefore, depicted by a cautious evolutionary stance rather than supporting revolutionary shifts in power.

CaCO3, organic carbon, and nitrogen at DSDP Hole 93-603B

Contents of organic carbon and carbonate carbon were determined on the same set of Cretaceous samples from DSDP Hole 603B in three different laboratories in order to assess the degree of comparability of organic carbon and carbonate values obtained by different labs using the same or different methods. We report the results of analyses for organic carbon using two different CHN analyzers, LECO, and Rock-Eval II and for carbonate carbon by CHN (total C minus C after acidification), the carbonate bomb technique, and CaCO3 calculated on the basis of total calcium obtained from X-ray fluorescence and induction-coupled plasma techniques. In addition, total nitrogen was obtained by two different labs using a CHN analyzer, but different bases for calculation were used. The various techniques for organic carbon analysis yielded comparable results, with the exception of those obtained by one of the CHN analyses of acid-treated samples. The calculation of organic carbon values and comparison on a whole-rock basis is very sensitive to errors in determination of carbonate contents, and this factor explains most, but not all, of the disparities between the data sets. The carbonate bomb technique gives CaCO3 values that correspond well with those calculated from total calcium concentrations (XRF and ICP analyses), whereas the CaCO3 calculated from CHN total carbon minus acid-soluble carbon consistently overestimated CaCO3. Total nitrogen and C/N results from the two different CHN analyses are not comparable and are subject to more error than the factor related to error in estimation of CaCO3.

Astrotheology: Exoplanets, Christian Concerns, and Human Hopes

Are there planets beyond our solar system? What may appear quite plausible now had only been a hypothesis until about twenty years ago. The search for exoplanets is driven by the interest in the “habitable” ones among them. Could such planets one day in the far future provide resources or even shelter for humankind? Will we find one day a habitable planet that is even inhabited? These kinds of imaginative speculations drive public interest in the subject. Imagining alien intelligent life in the universe is not at all new. When Ted Peters called for establishing the field of “astrotheology,” he was certainly thinking less of historical precedents than of something analogous to the emerging field of astrobiology. Will astrotheology result in the decentering of humanity in cosmic dimensions? One could also conclude that we are alone, at least for all practical purposes.

1986 University of Michigan Football Team

University of Michigan Football Team, 1904

Top Row: assistant coach William Cole, Ted Stuart, James De Pree, Paul Magoffin, Walter Graham, Harry Patrick,

Middle Row: Hal Weeks, Harry Hammond, Thomas Jefferson Smull, Charles Briggs, Adolph "Germany" Schulz, Jay Mack Love, John Garrels, William Dennison Clark, Walter Rheinschild, Edward Hammond, Walter Becker

Front Row: trainer Keene Fitzpatrick, Tom Hammond, John Curtis, Henry Schulte, captain Willie Heston, , Frank Longman, Charles Carter, coach Fielding Yost, student mngr. Albert H. Montgomery

Seated in front: Fred Norcross

University of Michigan 150-pound football team, 1948

Top Row: Dick Bodycomb, Gus Eaton, Bud Marshall, Tony Cybulski, Herb Taggart, Bob Kash, Burl Selden (ass't coach), Cliff Keen (coach).

Third Row: Gene Kiddon, Gordon Smith, Vaughn Lowther, Jim Coleman, Larry Shaw, James Johnson, Frank Whitehouse, Gene Freed, Everet Knapp, George Sipp, Stan Emerling.

Second Row: Bill Clark, James Richter, Jack Keller, Dave Bradbury Fred Koehn, Hyman Berman, Bill Parshall, Bill Connoly, M. Richard Fleishman, Frank Murphy, Jim Briskin, Leon Hinz.

Bottom Row: John Wilcox, Prentice Ryan, Ed Morey, Jim Costa, Barry Breakey, Jere Ogle, Jim Armelagos, Don O'Connell, Jerry Burns, John Picard, James Sakai, Ted Karmazin.

1975 University of Michigan Baseball Team

Top Row: Dan Damiani, Bob Wasilewski, Dave Chapman, Craig McGinnis, Mark Weber, Jim Berra, Bill Stennett

Middle Row: Lary Sorensen, Dick Walterhouse, Greg Lane, Mark Grenkoski, Ted Mahan, Bill Haslerig, Mike Parker, Mark Grinnell, Chuck Rogers

Front Row: asst. coach Doug Swiss, Craig Forhan, Jeff James, coach Moby Benedict, Pete Ross, Randy Hackney, Tom Joyce

1977 University of Michigan Baseball Team

Top Row: Tom Owens, Jim Capoferi, Dan Cooperrider, Dave Chapman, Scott Anderson, Chris Martucci, Steve Perry, John McEldowney, trainer Al Green

Middle Row: Mike Bryant, Steve Howe, Rick Leach, Mike Parker, bob Wasilewski, Craig McGinnis, Bill Stennett, George Foussianes

Top Row: Jim Berra, Greg Lane, Ted Mahan, coach Moby Benedict, Mark Grenkoski, Steve Seyferth, asst. coach Pete Ross, mngr. Frank Young

1988 University of Michigan Baseball Team

Top Row: ?, John Ansted, Chris Gagin, Doug Kaiser, Ross Powell, ?, Dan Ruff, Stacy Katlin, Matt Morse, Ass't coach Ted Mahan, trainer Rex Thompson, ?

Middle Row: ?, ass't coach John Young, Kourtney Thompson, Mike Grimes, Greg Haeger, Jeff Tanderys, John Locker?, Tim Lata, Chris Starr, Phil Price, Rich Samplinski, ass't coach Chuck Froning, head coach Bud Middaugh

Front Row: Dave Peralta, Chris Lutz, Mike Gillette, Rick Leonard, Tom Brock, Steve Finken, Mike Ignasiak, Eddie Woolwine, Bill St. Peter, Darrin Campbell, Jim Abbott, Jim Durham