Fgf signaling is required for zebrafish tooth development

We have investigated fibroblast growth factor (FGF) signaling during the development of the zebrafish pharyngeal dentition with the goal of uncovering novel roles for FGFs in tooth development as well as phylogenetic and topographic diversity in the tooth developmental pathway. We found that the tooth-related expression of several zebrafish genes is similar to that of their mouse orthologs, including both epithelial and mesenchymal markers. Additionally, significant differences in gene expression between zebrafish and mouse teeth are indicated by the apparent lack of fgf8 and pax9 expression in zebrafish tooth germs. FGF receptor inhibition with SU5402 at 32 h blocked dental epithelial morphogenesis and tooth mineralization. While the pharyngeal epithelium remained intact as judged by normal pitx2 expression, not only was the mesenchymal expression of lhx6 and lhx7 eliminated as expected from mouse studies, but the epithelial expression of dlx2a, dlx2b, fgf3, and fgf4 was as well. This latter result provides novel evidence that the dental epithelium is a target of FGF signaling. However, the failure of SU5402 to block localized expression of pitx2 suggests that the earliest steps of tooth initiation are FGF-independent. Investigations of specific FGF ligands with morpholino antisense oligonucleotides revealed only a mild tooth shape phenotype following fgf4 knockdown, while fgf8 inhibition revealed only a subtle down-regulation of dental dlx2b expression with no apparent effect on tooth morphology. Our results suggest redundant FGF signals target the dental epithelium and together are required for dental morphogenesis. Further work will be required to elucidate the nature of these signals, particularly with respect to their origins and whether they act through the mesenchyme. © 2004 Elsevier Inc. All rights reserved

Developmental genetic mechanisms of evolutionary tooth loss in cypriniform fishes

The fossil record indicates that cypriniform fishes, a group including the zebrafish, lost oral teeth over 50 million years ago. Despite subsequent diversification of feeding modes, no cypriniform has regained oral teeth, suggesting the zebrafish as a model for studying the developmental genetic basis of evolutionary constraint. To investigate the mechanism of cypriniform tooth loss, we compared the oral expression of seven genes whose mammalian orthologs are involved in tooth initiation in the zebrafish and the Mexican tetra, Astyanax mexicanus, a related species retaining oral teeth. The most significant difference we found was an absence in zebrafish oral epithelium of expression of dlx2a and dlx2b, transcription factors that are expressed in early Astyanax odontogenic epithelium. Analysis of orthologous genes in the Japanese medaka (Oryzias latipes) and a catfish (Synodontis multipunctatus) suggests that expression was lost in cypriniforms, rather than gained in Astyanax. Treatment of Astyanaxwith an inhibitor of Fibroblast growth factor (Fgf) signaling produced a partial phenocopy of the zebrafish oral region, in that oral teeth, and expression of d1x2a and d1x2b, were lost, whereas shh and pitx2, genes whose expression is present in zebrafish oral epithelium, were unaffected. We hypothesize that a loss of Fgf signaling to oral epithelium was associated with cypriniform tooth loss

Hedgehog signaling is required at multiple stages of zebrafish tooth development

Background. The accessibility of the developing zebrafish pharyngeal dentition makes it an advantageous system in which to study many aspects of tooth development from early initiation to late morphogenesis. In mammals, hedgehog signaling is known to be essential for multiple stages of odontogenesis; however, potential roles for the pathway during initiation of tooth development or in later morphogenesis are incompletely understood. Results. We have identified mRNA expression of the hedgehog ligands shha and the receptors ptc1 and ptc2 during zebrafish pharyngeal tooth development. We looked for, but did not detect, tooth germ expression of the other known zebrafish hedgehog ligands shhb, dhh, ihha, or ihhb, suggesting that as in mammals, only Shh participates in zebrafish tooth development. Supporting this idea, we found that morphological and gene expression evidence of tooth initiation is eliminated in shha mutant embryos, and that morpholino antisense oligonucleotide knockdown of shha, but not shhb, function prevents mature tooth formation. Hedgehog pathway inhibition with the antagonist compound cyclopamine affected tooth formation at each stage in which we applied it: arresting development at early stages and disrupting mature tooth morphology when applied later. These results suggest that hedgehog signaling is required continuously during odontogenesis. In contrast, over-expression of shha had no effect on the developing dentition, possibly because shha is normally extensively expressed in the zebrafish pharyngeal region. Conclusion. We have identified previously unknown requirements for hedgehog signaling for early tooth initiation and later morphogenesis. The similarity of our results with data from mouse and other vertebrates suggests that despite gene duplication and changes in the location of where teeth form, the roles of hedgehog signaling in tooth development have been largely conserved during evolution. © 2010 Jackman et al; licensee BioMed Central Ltd

University vs. Research Institute? The Dual Pillars of German Science Production, 1950–2010

The world’s third largest producer of scientific research, Germany, is the origin of the research university and the independent, extra-university research institute. Its dual-pillar research policy differentiates these organizational forms functionally: universities specialize in advanced research-based teaching; institutes specialize intensely on research. Over the past decades this policy affected each sector differently: while universities suffered a lingering “legitimation crisis,” institutes enjoyed deepening “favored sponsorship”—financial and reputational advantages. Universities led the nation’s reestablishment of scientific prominence among the highly competitive European and global science systems after WWII. But sectoral analysis of contributions to science, technology, engineering, mathematics, and medical and health journal publications (1950–2010) finds that Germany’s small to medium-sized independent research institutes have made significant, growing contributions, particularly in publishing in higher impact journals proportionally more than their size. Simultaneously—despite dual-pillar policy implications—the university sector continues to be absolutely and relatively successful; not eclipsed by the institutes. Universities have consistently produced two-thirds of the nation’s publications in the highest quality journals since at least 1980 and have increased publications at a logarithmic rate; higher than the international mean. Indeed, they led Germany into the global mega-science style of production. Contrary to assumed benefits of functional differentiation, our results indicate that relative to their size, each sector has produced approximately similar publication records. While institutes have succeeded, the larger university sector, despite much less funding growth, has remained fundamental to German science production. Considering these findings, we discuss the future utility of the dual-pillar policy

Factors contributing to disparities in mortality among patients with non-small-cell lung cancer

Historically, non-small-cell lung cancer (NSCLC) patients who are non-white, have low incomes, low educational attainment, and non-private insurance have worse survival. We assessed whether differences in survival were attributable to sociodemographic factors, clinical characteristics at diagnosis, or treatments received. We surveyed a multiregional cohort of patients diagnosed with NSCLC from 2003 to 2005 and followed through 2012. We used Cox proportional hazard analyses to estimate the risk of death associated with race/ethnicity, annual income, educational attainment, and insurance status, unadjusted and sequentially adjusting for sociodemographic factors, clinical characteristics, and receipt of surgery, chemotherapy, and radiotherapy. Of 3250 patients, 64% were white, 16% black, 7% Hispanic, and 7% Asian; 36% of patients had income

Factors contributing to disparities in mortality among patients with non–small‐cell lung cancer

Historically, non–small‐cell lung cancer (NSCLC) patients who are non‐white, have low incomes, low educational attainment, and non‐private insurance have worse survival. We assessed whether differences in survival were attributable to sociodemographic factors, clinical characteristics at diagnosis, or treatments received. We surveyed a multiregional cohort of patients diagnosed with NSCLC from 2003 to 2005 and followed through 2012. We used Cox proportional hazard analyses to estimate the risk of death associated with race/ethnicity, annual income, educational attainment, and insurance status, unadjusted and sequentially adjusting for sociodemographic factors, clinical characteristics, and receipt of surgery, chemotherapy, and radiotherapy. Of 3250 patients, 64% were white, 16% black, 7% Hispanic, and 7% Asian; 36% of patients had incomes <$20 000/y; 23$60 000/y, not attending college, and not having private insurance were all associated with an increased risk of mortality. Black‐white differences were not statistically significant after adjustment for sociodemographic factors, although patients with patients without a high school diploma and patients with incomes <$40 000/y continued to have an increased risk of mortality. Differences by educational attainment were not statistically significant after adjustment for clinical characteristics. Differences by income were not statistically significant after adjustment for clinical characteristics and treatments. Clinical characteristics and treatments received primarily contributed to mortality disparities by race/ethnicity and socioeconomic status in patients with NSCLC. Additional efforts are needed to assure timely diagnosis and use of effective treatment to lessen these disparities.Using data from the Cancer Care Outcomes Research and Surveillance (CanCORS) consortium, a large, multi‐regional observational study of newly diagnosed cancer patients, we documented higher unadjusted mortality for NSCLC among patients who were black, have lower income, less well‐educated, and with non‐private insurance. We used a series of Cox proportional hazards model to estimate the increased risk of death associated with sociodemographic factors, clinical characteristics, and treatments received to determine what accounted for the disparities. We found that patients’ clinical characteristics and treatments received primarily contributed to the mortality disparities that we observed in patients with NSCLC.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146607/1/cam41796.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146607/2/cam41796_am.pd

Manipulation of Fgf and Bmp signaling in teleost fishes suggests potential pathways for the evolutionary origin of multicuspid teeth

Teeth with two or more cusps have arisen independently from an ancestral unicuspid condition in a variety of vertebrate lineages, including sharks, teleost fishes, amphibians, lizards, and mammals. One potential explanation for the repeated origins of multicuspid teeth is the existence of multiple adaptive pathways leading to them, as suggested by their different uses in these lineages. Another is that the addition of cusps required only minor changes in genetic pathways regulating tooth development. Here we provide support for the latter hypothesis by demonstrating that manipulation of the levels of Fibroblast growth factor (Fgf) or Bone morphogenetic protein (Bmp) signaling produces bicuspid teeth in the zebrafish (Danio rerio), a species lacking multicuspid teeth in its ancestry. The generality of these results for teleosts is suggested by the conversion of unicuspid pharyngeal teeth into bicuspid teeth by similar manipulations of the Mexican Tetra (Astyanax mexicanus). That these manipulations also produced supernumerary teeth in both species supports previous suggestions of similarities in the molecular control of tooth and cusp number. We conclude that despite their apparent complexity, the evolutionary origin of multicuspid teeth is positively constrained, likely requiring only slight modifications of a pre-existing mechanism for patterning the number and spacing of individual teeth. © 2013 Wiley Periodicals, Inc

A Novel Bacterium Associated with Lymphadenitis in a Patient with Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is a rare inherited disease of the phagocyte NADPH oxidase system causing defective production of toxic oxygen metabolites, impaired bacterial and fungal killing, and recurrent life-threatening infections. We identified a novel gram-negative rod in excised lymph nodes from a patient with CGD. Gram-negative rods grew on charcoal-yeast extract, but conventional tests could not identify it. The best 50 matches of the 16S rRNA (using BLAST) were all members of the family Acetobacteraceae, with the closest match being Gluconobacter sacchari. Patient serum showed specific band recognition in whole lysate immunoblot. We used mouse models of CGD to determine whether this organism was a genuine CGD pathogen. Intraperitoneal injection of gp91(phox) (−/−) (X-linked) and p47 (phox −/−) (autosomal recessive) mice with this bacterium led to larger burdens of organism recovered from knockout compared with wild-type mice. Knockout mouse lymph nodes had histopathology that was similar to that seen in our patient. We recovered organisms with 16S rRNA sequence identical to the patient's original isolate from the infected mice. We identified a novel gram-negative rod from a patient with CGD. To confirm its pathogenicity, we demonstrated specific immune reaction by high titer antibody, showed that it was able to cause similar disease when introduced into CGD, but not wild-type mice, and we recovered the same organism from pathologic lesions in these mice. Therefore, we have fulfilled Koch's postulates for a new pathogen. This is the first reported case of invasive human disease caused by any of the Acetobacteraceae. Polyphasic taxonomic analysis shows this organism to be a new genus and species for which we propose the name Granulobacter bethesdensis

Broken rotational symmetry in the pseudogap phase of a high-Tc superconductor

The nature of the pseudogap phase is a central problem in the quest to understand high-Tc cuprate superconductors. A fundamental question is what symmetries are broken when that phase sets in below a temperature T*. There is evidence from both polarized neutron diffraction and polar Kerr effect measurements that time- reversal symmetry is broken, but at temperatures that differ significantly. Broken rotational symmetry was detected by both resistivity and inelastic neutron scattering at low doping and by scanning tunnelling spectroscopy at low temperature, but with no clear connection to T*. Here we report the observation of a large in-plane anisotropy of the Nernst effect in YBa2Cu3Oy that sets in precisely at T*, throughout the doping phase diagram. We show that the CuO chains of the orthorhombic lattice are not responsible for this anisotropy, which is therefore an intrinsic property of the CuO2 planes. We conclude that the pseudogap phase is an electronic state which strongly breaks four-fold rotational symmetry. This narrows the range of possible states considerably, pointing to stripe or nematic orders.Comment: Published version. Journal reference and DOI adde

Cumulant Expansions and the Spin-Boson Problem

The dynamics of the dissipative two-level system at zero temperature is studied using three different cumulant expansion techniques. The relative merits and drawbacks of each technique are discussed. It is found that a new technique, the non-crossing cumulant expansion, appears to embody the virtues of the more standard cumulant methods.Comment: 26 pages, LaTe