BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects

Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations in BCOR, we sequenced the BCOR gene in patients with (1) OFCD syndrome, (2) putative X-linked ('Lenz') microphthalmia syndrome, (3) isolated ocular defects and (4) laterality phenotypes. We present a new cohort of females with OFCD syndrome and null mutations in BCOR, supporting the hypothesis that BCOR is the sole molecular cause of this syndrome. We identify for the first time mosaic BCOR mutations in two females with OFCD syndrome and one apparently asymptomatic female. We present a female diagnosed with isolated ocular defects and identify minor features of OFCD syndrome, suggesting that OFCD syndrome may be mild and underdiagnosed. We have sequenced a cohort of males diagnosed with putative X-linked microphthalmia and found a mutation, p.P85L, in a single case, suggesting that BCOR mutations are not a major cause of X-linked microphthalmia in males. The absence of BCOR mutations in a panel of patients with non-specific laterality defects suggests that mutations in BCOR are not a major cause of isolated heart and laterality defects. Phenotypic analysis of OFCD and Lenz microphthalmia syndromes shows that in addition to the standard diagnostic criteria of congenital cataract, microphthalmia and radiculomegaly, patients should be examined for skeletal defects, particularly radioulnar synostosis, and cardiac/laterality defects.

The price elasticity of demand for common stock

We study the price elasticity of demand for the common stock of an individual corporation. Despite the prevelance of assumptions that demand is perfectly elastic, there is little if any direct evidence in the literature to either support or reject that contention. Consistent with the notion of finite price elasticities, we find that the announcement of primary stock oferings by regulated firms depresses their stock prices and little if any evidence that this decline is the result of adverse information about future cash flows. Attempts to relate offer announcement effects directly to possible determinants of price elasticities, however, are inconclusive.

Clinical, genetic, and functional characterization of adrenocorticotropin receptor mutations using a novel receptor assay.

The ACTH receptor (MC2R) is expressed predominantly in the adrenal cortex, but is one of five G protein-coupled, seven-transmembrane melanocortin receptors (MCRs), all of which bind ACTH to some degree. Testing of MC2R activity is difficult because most cells express endogenous MCRs; hence, ACTH will elicit background activation of assayable reporter systems. Inactivating mutations of MC2R lead to hereditary unresponsiveness to ACTH, also known as familial glucocorticoid deficiency (FGD). These patients are usually seen in early childhood with very low cortisol concentrations, normal mineralocorticoids, hyperpigmentation, and increased bodily growth. Several MC2R mutations have been reported in FGD, but assays of the activities of these mutants are cumbersome. We saw two patients with typical clinical findings of FGD. Genetic analysis showed that patient 1 was homozygous for the mutation R137W, and patient 2 was a compound heterozygote for S74I and Y254C. We tested the activity of these mutations in OS-3 cells, which are unresponsive to ACTH but have intact downstream cAMP signal transduction. OS-3 cells transfected with a cAMP-responsive luciferase reporter plasmid (pCREluc) were unresponsive to ACTH, but cotransfection with a vector expressing human MC2R increased luciferase activity more than 40-fold. Addition of ACTH to cells cotransfected with the pCREluc reporter and wild-type MC2R activated luciferase expression with a 50% effective concentration of 5.5 x 10(-9) M ACTH, which is similar to previously reported values. By contrast, the MC2R mutant R137W had low activity, and the S74I or Y254C mutants elicited no measurable response. This assay provides excellent sensitivity in an easily assayed transient transfection system, providing a more rapid and efficient measurement of ACTH receptor activity.

Prioritizing Residents' Needs: On the Creation of a Residents as Teachers and Leaders Program

Introduction: Residents are responsible for the majority of medical student teaching and directly supervise, instruct, and evaluate students. Many organizations now recommend that residency training programs include venues specifically designed to develop resident teaching skills. [See PDF for abstract].

Evolutionarily conserved role of calcineurin in phosphodegron-dependent degradation of phosphodiesterase 4D.

Calcineurin is a widely expressed and highly conserved Ser/Thr phosphatase. Calcineurin is inhibited by the immunosuppressant drug cyclosporine A (CsA) or tacrolimus (FK506). The critical role of CsA/FK506 as an immunosuppressant following transplantation surgery provides a strong incentive to understand the phosphatase calcineurin. Here we uncover a novel regulatory pathway for cyclic AMP (cAMP) signaling by the phosphatase calcineurin which is also evolutionarily conserved in Caenorhabditis elegans. We found that calcineurin binds directly to and inhibits the proteosomal degradation of cAMP-hydrolyzing phosphodiesterase 4D (PDE4D). We show that ubiquitin conjugation and proteosomal degradation of PDE4D are controlled by a cullin 1-containing E(3) ubiquitin ligase complex upon dual phosphorylation by casein kinase 1 (CK1) and glycogen synthase kinase 3beta (GSK3beta) in a phosphodegron motif. Our findings identify a novel signaling process governing G-protein-coupled cAMP signal transduction-opposing actions of the phosphatase calcineurin and the CK1/GSK3beta protein kinases on the phosphodegron-dependent degradation of PDE4D. This novel signaling system also provides unique functional insights into the complications elicited by CsA in transplant patients.

Passive transfer of IgG anti-GM1 antibodies impairs peripheral nerve repair.

Anti-GM1 antibodies are present in some patients with autoimmune neurological disorders. These antibodies are most frequently associated with acute immune neuropathy called Guillain-Barré syndrome (GBS). Some clinical studies associate the presence of these antibodies with poor recovery in GBS. The patients with incomplete recovery have failure of nerve repair, particularly axon regeneration. Our previous work indicates that monoclonal antibodies can inhibit axon regeneration by engaging cell surface gangliosides (Lehmann et al., 2007). We asked whether passive transfer of human anti-GM1 antibodies from patients with GBS modulate axon regeneration in an animal model. Human anti-GM1 antibodies were compared with other GM1 ligands, cholera toxin B subunit and a monoclonal anti-GM1 antibody. Our results show that patient derived anti-GM1 antibodies and cholera toxin beta subunit impair axon regeneration/repair after PNS injury in mice. Comparative studies indicated that the antibody/ligand-mediated inhibition of axon regeneration is dependent on antibody/ligand characteristics such as affinity-avidity and fine specificity. These data indicate that circulating immune effectors such as human autoantibodies, which are exogenous to the nervous system, can modulate axon regeneration/nerve repair in autoimmune neurological disorders such as GBS.

Governance and the Capacity to Manage Resilience in Regional Social-Ecological Systems

The sustainability of regional development can be usefully explored through several different lenses. In situations in which uncertainties and change are key features of the ecological landscape and social organization, critical factors for sustainability are resilience, the capacity to cope and adapt, and the conservation of sources of innovation and renewal. However, interventions in social-ecological systems with the aim of altering resilience immediately confront issues of governance. Who decides what should be made resilient to what? For whom is resilience to be managed, and for what purpose? In this paper we draw on the insights from a diverse set of case studies from around the world in which members of the Resilience Alliance have observed or engaged with sustainability problems at regional scales. Our central question is: How do certain attributes of governance function in society to enhance the capacity to manage resilience? Three specific propositions were explored: ( 1) participation builds trust, and deliberation leads to the shared understanding needed to mobilize and self-organize; ( 2) polycentric and multilayered institutions improve the fit between knowledge, action, and social-ecological contexts in ways that allow societies to respond more adaptively at appropriate levels; and ( 3) accountable authorities that also pursue just distributions of benefits and involuntary risks enhance the adaptive capacity of vulnerable groups and society as a whole. Some support was found for parts of all three propositions. In exploring the sustainability of regional social-ecological systems, we are usually faced with a set of ecosystem goods and services that interact with a collection of users with different technologies, interests, and levels of power. In this situation in our roles as analysts, facilitators, change agents, or stakeholders, we not only need to ask: The resilience of what, to what? We must also ask: For whom?

Climate refugia: joint inference from fossil records, species distribution models and phylogeography

Climate refugia, locations where taxa survive periods of regionally adverse climate, are thought to be critical for maintaining biodiversity through the glacial–interglacial climate changes of the Quaternary. A critical research need is to better integrate and reconcile the three major lines of evidence used to infer the existence of past refugia – fossil records, species distribution models and phylogeographic surveys – in order to characterize the complex spatiotemporal trajectories of species and populations in and out of refugia. Here we review the complementary strengths, limitations and new advances for these three approaches. We provide case studies to illustrate their combined application, and point the way towards new opportunities for synthesizing these disparate lines of evidence. Case studies with European beech, Qinghai spruce and Douglas-fir illustrate how the combination of these three approaches successfully resolves complex species histories not attainable from any one approach. Promising new statistical techniques can capitalize on the strengths of each method and provide a robust quantitative reconstruction of species history. Studying past refugia can help identify contemporary refugia and clarify their conservation significance, in particular by elucidating the fine-scale processes and the particular geographic locations that buffer species against rapidly changing climate.

Intra- and interlaboratory reliability of a cryopreserved trout hepatocyte assay for the prediction of chemical bioaccumulation potential

Measured rates of intrinsic clearance determined using cryopreserved trout hepatocytes can be extrapolated to the whole animal as a means of improving modeled bioaccumulation predictions for fish. To date, however, the intra- and interlaboratory reliability of this procedure has not been determined. In the present study, three laboratories determined in vitro intrinsic clearance of six reference compounds (benzo[a]pyrene, 4-nonylphenol, di-tert-butyl phenol, fenthion, methoxychlor and o-terphenyl) by conducting substrate depletion experiments with cryopreserved trout hepatocytes from a single source. O-terphenyl was excluded from the final analysis due to nonfirst-order depletion kinetics and significant loss from denatured controls. For the other five compounds, intralaboratory variability (% CV) in measured in vitro intrinsic clearance values ranged from 4.1 to 30%, while interlaboratory variability ranged from 27 to 61%. Predicted bioconcentration factors based on in vitro clearance values exhibited a reduced level of interlaboratory variability (5.3-38% CV). The results of this study demonstrate that cryopreserved trout hepatocytes can be used to reliably obtain in vitro intrinsic clearance of xenobiotics, which provides support for the application of this in vitro method in a weight-of-evidence approach to chemical bioaccumulation assessment.

Determination of Metabolic Stability Using Cryopreserved Hepatocytes from Rainbow Trout (Oncorhynchus mykiss).

Trout provide a relatively easy source of hepatocytes that can be cryopreserved and used for a range of applications including toxicity testing and determination of intrinsic clearance. Standard protocols for isolating, cryopreserving, and thawing rainbow trout hepatocytes are described, along with procedures for using fresh or cryopreserved hepatocytes to assess metabolic stability of xenobiotics in fish by means of a substrate depletion approach. Variations on these methods, troubleshooting tips, and directions for use of extrapolation factors to express results in terms of in vivo intrinsic clearance are included. These protocols have been developed for rainbow trout, but can be adapted to other fish species with appropriate considerations.

Nonlesions, misdiagnoses, missed diagnoses, and other interpretive challenges in fish histopathology studies: a guide for investigators, authors, reviewers, and readers.

Differentiating salient histopathologic changes from normal anatomic features or tissue artifacts can be decidedly challenging, especially for the novice fish pathologist. As a consequence, findings of questionable accuracy may be reported inadvertently, and the potential negative impacts of publishing inaccurate histopathologic interpretations are not always fully appreciated. The objectives of this article are to illustrate a number of specific morphologic findings in commonly examined fish tissues (e.g., gills, liver, kidney, and gonads) that are frequently either misdiagnosed or underdiagnosed, and to address related issues involving the interpretation of histopathologic data. To enhance the utility of this article as a guide, photomicrographs of normal and abnormal specimens are presented. General recommendations for generating and publishing results from histopathology studies are additionally provided. It is hoped that the furnished information will be a useful resource for manuscript generation, by helping authors, reviewers, and readers to critically assess fish histopathologic data.

Na 1 Nachlass Max Horkheimer, 15 - Korrespondenzen u.a. mit Hans Fried (p. I 8, 1-201)

11 Briefe zwischen Hans Fried und Max Horkheimer, 1938-1940; 1 Brief von Max Horkheimer an die Albert Teachers Agency New York, 21.03.1941; 2 Briefe zwischen dem American Committee for International Studies, Princeton, New York und Max Horkheimer, 11.01.1941, 16.01.1941; 1 Brief von Sullivan & Cromwell New York an Max Horkheimer, 18.03.1940; 12 Briefe zwischen der Columbia University in the City of New York und Max Horkheimer, 1938-1940; 2 Briefe von Hans Fried an die Columbia University in the City of New york, 1938-1939; 1 Brief von Max Horkheimer an das Emergency Committee in Aid of Displaced German Scholars New York; 2 Briefe zwischen der Ittleson Foundation New York und Max Horkheimer, 19.11.1938, 28.11.1938; 1 Brief von Max Goldschmidt an Hans Fried, 21.04.1938; 1 Brief von Max Horkheimer an Max Goldschmidt, 25.04.1938; 2 Briefe von Alice Friedlaender an Max Horkheimer, 1932, 1944; 3 Briefe zwischen Charles S. Friedman und Max Horkheimer, 21.03.1942, 1936, 1942; 4 Briefe von C. J. Friedrich an Max Horkheimer, 1941; 4 Briefe von Franz L. Neumann an C. J. Friedrich, 1941; 8 Briefe zwischen den Friends of Europe London und Max Horkheimer, 1934-1938; 3 Briefe von Max Horkheimer an John W. Fries, 1939; 2 Briefe von Gertrud Fries an Max Horkheimer, 1936; 1 Brief von Josef Fröbes an Max Horkheimer, 24.08.1937; 3 Briefe zwischen Fruin und Max Horkheimer, 1936; 14 Briefe zwischen Eduard Fuchs und Max Horkheimer, 1935-1939;

Na 1 Nachlass Max Horkheimer, 600 - Korrespondenzen u.a. mit Friedrich Pollock (p. VI 42, 211-386)

Briefwechsel zwischen Max Horkheimer, Frederick Pollock und Karl August und Olga Wittfogel; 2 Briefe zwischen Edith B. Bernett und Max Horkheimer, April 1940; 2 Briefe zwischen Max Horkheimer und Philip Vaudrin, Juli 1939; 3 Briefe an David H. Stevens von Max Horkheimer, 26.03.1938; 1 Brief von A. Radcliffe an Frederick Pollock, 18.11.1937; 3 Briefe an Max Horkheimer von der Columbia University Faculty of Political Science (New York), November 1937; 2 Briefe von der Columbia University Department of History (New York) an Max Horkheimer, November 1937; 1 Brief an Max Horkheimer von Sharon Beard, 27.11.1937; 1 Brief von Ruth Benedict an Max Horkheimer, 19.11.1937; 1 Brief an Max Horkheimer von Franz Boas, 19.11.1937; 1 Brief von R. E. Chaddock an Max Horkheimer, 21.11.1937; 1 Brief an Max Horkheimer von Ch'ao-ting Chi, 19.11.1937; 1 Brief von J. M. Clark an Max Horkheimer, 22.11.1937; 1 Brief an Dr. Wertheimer von Morris R. Cohen, 29.11.1937; 1 Brief von Alfred E. Cohn an Max Horkheimer, 26.11.1937; 1 Brief an Max Horkheimer von John J. Coss, 22.11.1937; 1 Brief von George S. Counts an Max Horkheimer, 24.11.1937; 1 Brief an Max Horkheimer von A. P. Evans, 22.11.1937; 3 Briefe von Gertrude Stewart an Max Horkheimer, 20. - 24.11.1937; 1 Brief an Max Horkheimer von L. C. Goodrich, 22.11.1937; 1 Brief von John W. Innes an Max Horkheimer, 20.11.1937; 1 Brief an Max Horkheimer von Philip C. Jessup, 24.11.1937; 1 Brief von John A. Krout an Max Horkheimer, 23.11.1937; 1 Brief an Max Horkheimer von Bruno Lasker, 20.11.1937; 1 Brief von Samuel McCune Lindsay an Max Horkheimer, 24.11.1937; 1 Brief an Max Horkheimer von K. N. Llewellyn, 26.11.1937; 1 Brief von R. S. Lynd an Max Horkheimer, [November 1937]; 1 Brief an Max Horkheimer von R. M. MacIver, 19.11.1937; 1 Brief von Julian W. Mack an Max Horkheimer, 24.11.1937; 1 Brief an Max Horkheimer von Arthur Maxmahon, 20.11.1937; 1 Brief von Jerome Michael an Max Horkheimer, 26.11.1937; 1 Brief an Max Horkheimer von Wesley C. Mitchell, 22.11.1937; 1 Brief von der Columbia University School of Business (New York) an Max Horkheimer, 22.11.1937; 2 Briefe zwischen Max Horkheimer und der John Simon Guggenheim Memorial Foundation (New York), November 1937; 2 Briefe von der Columbia University Department of Psychology (New York) an Max Horkheimer, November 1937; 1 Brief an Max Horkheimer von Goodwin Watson, 23.11.1937; 1 Brief von Otto Nathan an Max Horkheimer, 26.11.937; 1 Brief an Max Horkheimer von John K. Norton, 23.11.1937; 1 Brief von der Columbia University Department of Chinese (New York) an Max Horkheimer, 23.11.1937; 1 Brief an Max Horkheimer von Gerold Tanquary Robinson, 19.11.1937; 1 Brief von der Columbia University Department of Public Law and Government (New York) an Max Horkheimer, 22.11.1937; 1 Brief an Max Horkheimer von R. C. Sailer, 20.11.1937; 1 Brief von Herbert W. Schneider an Max Horkheimer, 22.11.1937; 1 Brief an Max Horkheimer von R. L. Schuyler, 20.11.1937; 1 Brief von Pauline Steorns an Max Horkheimer, 22.11.1937; 1 Brief an Max Horkheimer von Frank Tannenbaum, 19.11.1937; 1 Brief von Alfred Vagés an Max Horkheimer, 26.11.1937;