Multiple tissue-specific requirements for the BMP antagonist Noggin in development of the mammalian craniofacial skeleton

AbstractProper morphogenesis is essential for both form and function of the mammalian craniofacial skeleton, which consists of more than twenty small cartilages and bones. Skeletal elements that support the oral cavity are derived from cranial neural crest cells (NCCs) that develop in the maxillary and mandibular buds of pharyngeal arch 1 (PA1). Bone Morphogenetic Protein (BMP) signaling has been implicated in most aspects of craniofacial skeletogenesis, including PA1 development. However, the roles of the BMP antagonist Noggin in formation of the craniofacial skeleton remain unclear, in part because of its multiple domains of expression during formative stages. Here we used a tissue-specific gene ablation approach to assess roles of Noggin (Nog) in two different tissue domains potentially relevant to mandibular and maxillary development. We found that the axial midline domain of Nog expression is critical to promote PA1 development in early stages, necessary for adequate outgrowth of the mandibular bud. Subsequently, Nog expression in NCCs regulates craniofacial cartilage and bone formation. Mice lacking Nog in NCCs have an enlarged mandible that results from increased cell proliferation in and around Meckel׳s cartilage. These mutants also show complete secondary cleft palate, most likely due to inhibition of posterior palatal shelf elevation by disrupted morphology of the developing skull base. Our findings demonstrate multiple roles of Noggin in different domains for craniofacial skeletogenesis, and suggest an indirect mechanism for secondary cleft palate in Nog mutants that may be relevant to human cleft palate as well

Novel results in STM, ARPES, HREELS, Nernst, neutron, Raman, and isotope substitution experiments and their relation to bosonic modes and charge inhomogeneity, from perspective of negative-Ueff boson-fermion modelling of HTSC

This paper seeks to synthesize much recent work on the HTSC materials around the latest STM results from Davis and coworkers. The conductance diffuse scattering results in particular are used as point of entry to discuss bosonic modes, both of condensed and uncondensed form. The bosonic mode picture is essential to understanding an ever growing range of observations within the HTSC field. The work is expounded within the context of the negative-U, boson-fermion modelling long advocated by the author. This general approach is presently seeing much theoretical development, into which I have looked to couple many of the experimental advances. While the formal theory is not yet sufficiently detailed to cover adequately all the experimental complexities presented by the real cuprate systems, it is clear that it affords very appreciable support to the line taken. An attempt is made throughout to say why and how it is that these events are tied so very closely to this particular set of materials.Comment: 36 pages pdf with 3 figures and 1 table included, Submitted to J. Phys. Cond. Mat

Correction: Gustafson et al., Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree. Genes 2017, 8, 210.

Following publication of our article [1], we identified discrepancies between the pedigree shown in Figure 1 and the rest of the text.[...]

Improving Underrepresented Minority Student Persistence in STEM.

Members of the Joint Working Group on Improving Underrepresented Minorities (URMs) Persistence in Science, Technology, Engineering, and Mathematics (STEM)-convened by the National Institute of General Medical Sciences and the Howard Hughes Medical Institute-review current data and propose deliberation about why the academic "pathways" leak more for URM than white or Asian STEM students. They suggest expanding to include a stronger focus on the institutional barriers that need to be removed and the types of interventions that "lift" students' interests, commitment, and ability to persist in STEM fields. Using Kurt Lewin's planned approach to change, the committee describes five recommendations to increase URM persistence in STEM at the undergraduate level. These recommendations capitalize on known successes, recognize the need for accountability, and are framed to facilitate greater progress in the future. The impact of these recommendations rests upon enacting the first recommendation: to track successes and failures at the institutional level and collect data that help explain the existing trends

Separate GABA Afferents to Dopamine Neurons Mediate Acute Action of Opioids, Development of Tolerance, and Expression of Withdrawal

SummaryGABA release from interneurons in VTA, projections from the nucleus accumbens (NAc), and rostromedial tegmental nucleus (RMTg) was selectively activated in rat brain slices. The inhibition induced by μ-opioid agonists was pathway dependent. Morphine induced a 46% inhibition of IPSCs evoked from the RMTg, 18% from NAc, and IPSCs evoked from VTA interneurons were almost insensitive (11% inhibition). In vivo morphine treatment resulted in tolerance to the inhibition of RMTg, but not local interneurons or NAc, inputs. One common sign of opioid withdrawal is an increase in adenosine-dependent inhibition. IPSCs evoked from the NAc were potently inhibited by activation of presynaptic adenosine receptors, whereas IPSCs evoked from RMTg were not changed. Blockade of adenosine receptors selectively increased IPSCs evoked from the NAc during morphine withdrawal. Thus, the acute action of opioids, the development of tolerance, and the expression of withdrawal are mediated by separate GABA afferents to dopamine neurons

Tiam1 interaction with the PAR complex promotes talin-mediated Rac1 activation during polarized cell migration.

Migrating cells acquire front-rear polarity with a leading edge and a trailing tail for directional movement. The Rac exchange factor Tiam1 participates in polarized cell migration with the PAR complex of PAR3, PAR6, and atypical protein kinase C. However, it remains largely unknown how Tiam1 is regulated and contributes to the establishment of polarity in migrating cells. We show here that Tiam1 interacts directly with talin, which binds and activates integrins to mediate their signaling. Tiam1 accumulated at adhesions in a manner dependent on talin and the PAR complex. The interactions of talin with Tiam1 and the PAR complex were required for adhesion-induced Rac1 activation, cell spreading, and migration toward integrin substrates. Furthermore, Tiam1 acted with talin to regulate adhesion turnover. Thus, we propose that Tiam1, with the PAR complex, binds to integrins through talin and, together with the PAR complex, thereby regulates Rac1 activity and adhesion turnover for polarized migration

Removal of steroid estrogens in carbonaceous and nitrifying activated sludge processes

This is the post-print version of the final paper published in Chemosphere. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2010 Elsevier B.V.A carbonaceous (heterotrophic) activated sludge process (ASP), nitrifying ASP and a nitrifying/denitrifying ASP have been studied to examine the role of process type in steroid estrogen removal. Biodegradation efficiencies for total steroid estrogens (ΣEST) of 80 and 91% were recorded for the nitrifying/denitrifying ASP and nitrifying ASP respectively. Total estrogen biodegradation (ΣEST) was only 51% at the carbonaceous ASP, however, the extent of biodegradation in the absence of nitrification clearly indicates the important role of heterotrophs in steroid estrogen removal. The low removal efficiency did not correlate with biomass activity for which the ASPcarbonaceous recorded 80 μg kg−1 biomass d−1 compared to 61 and 15 μg kg−1 biomass d−1 at the ASPnitrifying and ASPnitrifying/denitrifying respectively. This finding was explained by a moderate correlation (r2 = 0.55) between total estrogen loading (ΣEST mg m−3 d−1) and biomass activity (μg ΣEST degraded kg−1 d−1) and has established the impact of loading on steroid estrogen removal at full-scale. At higher solids retention time (SRT), steroid estrogen biodegradation of >80% was observed, as has previously been reported. It is postulated that hydraulic retention time (HRT) is as important as SRT as this governs both reaction time and loading. This observation is based on the high specific estrogen activity determined at the ASPcarbonaceous plant, the significance of estrogen loading and the positive linear correlation between SRT and HRT.Public Utilities Board of Singapore, Anglian Water Ltd., Severn Trent Water Ltd., Thames Water Utilities Ltd., United Utilities Plc., and Yorkshire Water Services Ltd

Effects of ethanol on photoreceptors and visual function in developing zebrafish

PURPOSE. Children born to mothers who have consumed alcohol during pregnancy have an array of retinal abnormalities and visual dysfunctions. In the past, rodent systems have been used to study the teratogenic effects of ethanol on vertebrate embryonic development. The exact developmental windows in which ethanol causes specific developmental defects have been difficult to determine because rodents and other mammals develop in utero. In this study, we characterized how ethanol affects the function and development of the visual system in an ex utero embryonic system, the zebrafish. METHODS. Zebrafish embryos were raised in fish water containing various concentrations of ethanol from 2 to 5 days after fertilization. The effects of ethanol on retinal morphology were assessed by histologic and immunohistochemical analyses and those on retinal function were analyzed by optokinetic response (OKR) and electroretinography (ERG). RESULTS. Zebrafish embryos exposed to moderate and high levels of ethanol during early embryonic development had morphological abnormalities of the eye characterized by hypoplasia of the optic nerve and inhibition of photoreceptor outer segment growth. Ethanol treatment also caused an increased visual threshold as measured by the OKR. Analysis with the ERG indicated that there was a severe reduction of both the a-and b-waves, suggesting that ethanol affects the function of the photoreceptors. Indeed, low levels of ethanol that did not cause obvious morphologic changes in either the body or retina did affect both the OKR visual threshold and the a-and b-wave amplitudes. CONCLUSIONS. Ethanol affects photoreceptor function at low concentrations that do not disturb retinal morphology. Higher levels of ethanol inhibit photoreceptor development and cause hypoplasia of the optic nerve. (Invest Ophthalmol Vis Sci. 2006;47:4589 -4597) DOI:10.1167/iovs.05-0971 S ome children born to mothers who have consumed alcohol during pregnancy have a number of morphologic, sensory, and cognitive abnormalities, including vision deficits, collectively known as fetal alcohol syndrome (FAS). It was originally thought that FAS was the result of alcohol abuse; however, smaller doses or shorter durations of prenatal alcohol consumption also produce harmful, though more subtle, effects referred to as alcohol-related birth defects (ARBDs) or alcoholrelated neurodevelopment disorder (ARND). 1 Even though FAS was described several decades ago, 2 little is known about the mechanistic underpinnings of ethanol teratogenicity. 3 The retina is one of the organs affected by ethanol during embryogenesis. As many as 90% of children in whom FAS is diagnosed have some type of ocular problem, ranging from microphthalmia and retinal dysmorphologies to reduced visual function. One of the challenges of analyzing ethanol's teratogenicity in vertebrates using rodents as model systems is that mammals develop in utero. Therefore, ethanol concentrations and exposure times that result in a specific phenotype are difficult to determine because the metabolic function of the mother must be considered. Other vertebrates, such as zebrafish and Xenopus laevis, develop ex utero, so specific concentrations of ethanol over specific developmental periods are easily achieved. Treating zebrafish and Xenopus embryos with ethanol results in phenotypes comparable to those described for children with FAS, suggesting that the same molecular mechanisms are disturbed by ethanol treatment in vertebrates. 9 -11 Moreover, unlike mouse, zebrafish contain abundant cone photoreceptors that differentiate relatively early, making it a better system for the study of color vision in vertebrates. MATERIALS AND METHODS Breeding Fish and Treating Zebrafish Embryos with Ethanol Ekkwill and AB strain zebrafish were maintained as an inbred stock at the Harvard zebrafish facility and were bred as previously described