The Developmental Control of Osteoblast-Specific Gene Expression: Role of Specific Transcription Factors and the Extracellular Matrix Environment

Bone formation is a carefully controlled developmental process involving morphogen-mediated patterning signals that define areas of initial mesenchyme condensation followed by induction of cell-specific differentiation programs to produce chondrocytes and osteoblasts. Positional information is conveyed via gradients of molecules, such as Sonic Hedgehog that are released from cells within a particular morphogenic field together with region-specific patterns of hox gene expression. These, in turn, regulate the localized production of bone morphogenetic proteins and related molecules which initiate chondrocyte- and osteoblast-specific differentiation programs. Differentiation requires the initial commitment of mesenchymal stem cells to a given lineage, followed by induction of tissue-specific patterns of gene expression. Considerable information about the control of osteoblast-specific gene expression has come from analysis of the promoter regions of genes encoding proteins like osteocalcin that are selectively expressed in bone. Both general and tissue-specific transcription factors control this promoter. Osf2/Cbfal, the first osteoblast-specific transcription factor to be identified, is expressed early in the osteoblast lineage and interacts with specific DNA sequences in the osteocalcin promoter essential for its selective expression in osteoblasts. The OSF2/CBFA1 gene is necessary for the development of mineralized tissues, and its mutation causes the human disease, cleidocranial dysplasia. Committed osteoprogenitor cells already expressing Osf2/Cbfa1 must synthesize a collagenous ECM before they will differentiate. A ceII:ECM interaction mediated by integrin-type cell-surface receptors is essential for the induction of osteocalcin and other osteoblast-related proteins. This interaction stimulates the binding of Osf2/Cbfa 1 to the osteocalcin promoter through an as-yet-undefined mechanism.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68284/2/10.1177_10454411990100010201.pd

Analysis of transcription factor interactions in osteoblasts using competitive chromatin immunoprecipitation

Chromatin immunoprecipitation (ChIP) is a widely used technique for quantifying protein–DNA interactions in living cells. This method commonly uses fixed (crosslinked) chromatin that is fragmented by sonication (X-ChIP). We developed a simple new ChIP procedure for the immunoprecipitation of sonicated chromatin isolated from osteoblasts in the absence of crosslinking (N-ChIP). The use of noncrosslinked chromatin allowed development of a new modification of the ChIP assay: the combination of N-ChIP and competition with double-stranded oligonucleotides containing specific binding sites for individual transcription factors (Competitive N-ChIP). Using this approach, we were able to discriminate between individual binding sites for the Runx2 transcription factor in the osteocalcin and bone sialoprotein genes that cannot be resolved by traditional X-ChIP. N-ChIP assays were also able to detect several other types of chromatin interactions including those with Dlx homeodomain factors and nuclear proteins such as Sin3a that lack an intrinsic DNA-binding motif and, therefore, bind to chromatin via interactions with other proteins

Modeling of Immunosenescence and Risk of Death from Respiratory Infections: Evaluation of the Role of Antigenic Load and Population Heterogeneity

It is well known that efficacy of immune functions declines with age. It results in an increase of severity and duration of respiratory infections and also in dramatic growth of risk of death due to these diseases after age 65. The goal of this work is to describe and investigate the mechanism underlying the age pattern of the mortality rate caused by infectious diseases and to determine the cause-specific hazard rate as a function of immune system characteristics. For these purposes we develop a three-compartment model explaining observed risk-of-death. The model incorporates up-to-date knowledge about cellular mechanisms of aging, disease dynamics, population heterogeneity in resistance to infections, and intrinsic aging rate. The results of modeling show that the age-trajectory of mortality caused by respiratory infections may be explained by the value of antigenic load, frequency of infections and the rate of aging of the stem cell population (i.e. the population of T-lymphocyte progenitor cells). The deceleration of infection-induced mortality at advanced age can be explained by selection of individuals with a slower rate of stem cell aging. Parameter estimates derived from fitting mortality data indicate that infection burden was monotonically decreasing during the twentieth century, and changes in total antigenic load were gender-specific: it experienced periodic fluctuations in males and increased approximately two-fold in females

The Kondo Effect in the Unitary Limit

We observe a strong Kondo effect in a semiconductor quantum dot when a small magnetic field is applied. The Coulomb blockade for electron tunneling is overcome completely by the Kondo effect and the conductance reaches the unitary-limit value. We compare the experimental Kondo temperature with the theoretical predictions for the spin-1/2 Anderson impurity model. Excellent agreement is found throughout the Kondo regime. Phase coherence is preserved when a Kondo quantum dot is included in one of the arms of an Aharonov-Bohm ring structure and the phase behavior differs from previous results on a non-Kondo dot.Comment: 10 page

Le destin des manuscrits catholiques d’Isaac Papin après sa mort : convoitise et mystère autour de la dépouille intellectuelle d’un sympathisant janséniste

Isaac Papin (1657-1709), né calviniste, est passé à la postérité pour sa conversion au catholicisme. Après avoir été le fer de lance des pajonistes au sein du Refuge, il se convertit entre les mains de Bossuet, en 1690. La seconde partie de sa vie est beaucoup moins connue. Deux dossiers de la collection Port-Royal d’Utrecht permettent de lever le voile sur un aspect totalement inédit de son parcours : ses relations avec le milieu janséniste. Si les traces sont peu nombreuses, ses relations avec Pasquier Quesnel sont attestées. Après sa mort, ses manuscrits sont convoités et finalement récupérés par les jansénistes. Les textes qu’ils contiennent sont publiés par les soins de Quesnel, en 1713, sous le titre Les deux voies opposées en matière de religion

Nuclear Signaling Pathways for 1,25-Dihydroxyvitamin D 3 Are Controlled by the Vitamin A Metabolite, 9-cis-Retinoic Acid

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75392/1/j.1753-4887.1993.tb03060.x.pd

TRANSMIT: Training Research and Applications Network to Support the Mitigation of Ionospheric Threats

TRANSMIT is an initiative funded by the European Commission through a Marie Curie Initial Training Network (ITN). Main aim of such networks is to improve the career perspectives of researchers who are in the first five years of their research career in both public and private sectors. In particular TRANSMIT will provide a coordinated program of academic and industrial training, focused on atmospheric phenomena that can significantly impair a wide range of systems and applications that are at the core of several activities embedded in our daily life. TRANSMIT deals with the harmful effects of the ionosphere on these systems, which will become increasingly significant as we approach the next solar maximum, predicted for 2013. Main aim of the project is to develop real time integrated state of the art tools to mitigate ionospheric threats to Global Navigation Satellite Systems (GNSS) and several related applications, such as civil aviation, marine navigation and land transportation. The project will provide Europe with the next generation of researchers in this field, equipping them with skills developed through a comprehensive and coordinated training program. Theirs research projects will develop real time integrated state of the art tools to mitigate these ionospheric threats to GNSS and several applications that rely on these systems. The main threat to the reliable and safe operation of GNSS is the variable propagation conditions encountered by GNSS signals as they pass through the ionosphere. At a COST 296 MIERS (Mitigation of Ionospheric Effects on Radio Systems) workshop held at the University of Nottingham in 2008, the establishment of a sophisticated Ionospheric Perturbation Detection and Monitoring (IPDM) network (http://ipdm.nottingham.ac.uk/) was proposed by European experts and supported by the European Space Agency (ESA) as the way forward to deliver the state of the art to protect the range of essential systems vulnerable to these ionospheric threats. Through a set of carefully designed research work packages TRANSMIT will be the enabler of the IPDM network. The goal of TRANSMIT is therefore to provide a concerted training programme including taught courses, research training projects, secondments at the leading European institutions, and a set of network wide events, with summer schools, workshops and a conference, which will arm the researchers of tomorrow with the necessary skills and knowledge to set up and run the proposed service. TRANSMIT will count on an exceptional set of partners, encompassing both academia and end users, including the aerospace and satellite communications sectors, as well as GNSS system designers and service providers, major user operators and receiver manufacturers. TRANSMIT's objectives are: A. Develop new techniques to detect and monitor ionospheric threats, with the introduction of new prediction and forecasting models, mitigation tools and improved system design; B. Advance the physical modeling of the underlying processes associated with the ionospheric plasma environment and the knowledge of its influences on human activity; C. Establish a prototype of a real time system to monitor the ionosphere, capable of providing useful assistance to users, which exploits all available resources and adds value for European services and products; D. Incorporate solutions to this system that respond to all end user needs and that are applicable in all geographical regions of European interest (polar, high and mid-latitudes, equatorial region). TRANSMIT will pave the way to establish in Europe a system capable of mitigating ionospheric threats on GNSS signals in real tim