Genetics of Growth Disorders-Which Patients Require Genetic Testing?

The second 360° European Meeting on Growth Hormone Disorders, held in Barcelona, Spain, in June 2017, included a session entitled Pragmatism vs. Curiosity in Genetic Diagnosis of Growth Disorders, which examined current concepts of genetics and growth in the clinical setting, in terms of both growth failure and overgrowth. For patients with short stature, multiple genes have been identified that result in GH deficiency, which may be isolated or associated with additional pituitary hormone deficiencies, or in growth hormone resistance, primary insulin-like growth factor (IGF) acid-labile subunit deficiency, IGF-I deficiency, IGF-II deficiency, IGF-I resistance, and primary PAPP-A2 deficiency. While genetic causes of short stature were previously thought to primarily be associated with the GH-IGF-I axis, it is now established that multiple genetic anomalies not associated with the GH-IGF-I axis can result in short stature. A number of genetic anomalies have also been shown to be associated with overgrowth, some of which involve the GH-IGF-I axis. In patients with overgrowth in combination with an intellectual disability, two predominant gene families, the epigenetic regulator genes, and PI3K/AKT pathway genes, have now been identified. Specific processes should be followed for decisions on which patients require genetic testing and which genes should be examined for anomalies. The decision to carry out genetic testing should be directed by the clinical process, not merely for research purposes. The intention of genetic testing should be to direct the clinical options for management of the growth disorder

Monoamine oxidase-A modulates apoptotic cell death induced by staurosporine in human neuroblastoma cells

Monoamine oxidases (MAOs) are mitochondrial enzymes which control the levels of neurotransmitters in the brain and dietary amines in peripheral tissues via oxidative deamination. MAO has also been implicated in cell signalling. In this study, we describe the MAO-A isoform as functional in apoptosis induced by staurosporine (STS) in human dopaminergic neuroblastoma cells (SH-SY5Y). Increased levels of MAO-A activity were induced by STS, accompanied by increased MAO-A protein and activation of the initiator of the intrinsic pathway, caspase 9, and the executioner caspase 3. MAO-A mRNA levels were unaffected by STS, suggesting that changes in MAO-A protein are due to post-transcriptional events. Two unrelated MAO-A inhibitors reduced caspase activation. STS treatment resulted in sustained activation of the mitogen-activated protein kinase pathway enzymes extracellular regulated kinase, c-jun terminal kinase and p38, and depletion of the anti-apoptotic protein Bcl-2. These changes were significantly reversed by MAO inhibition. Production of reactive oxygen species was increased following STS exposure, which was blocked by both MAO inhibition and the antioxidant N-acetylcysteine. Therefore our data provide evidence that MAO-A, through its production of reactive oxygen species as a by-product of its catalytic activity on the mitochondrial surface, is recruited by the cell to enhance apoptotic signalling

Domain Model Explains Propagation Dynamics and Stability of Histone H3K27 and H3K36 Methylation Landscapes

Chromatin states must be maintained during cell proliferation to uphold cellular identity and genome integrity. Inheritance of histone modifications is central in this process. However, the histone modification landscape is challenged by incorporation of new unmodified histones during each cell cycle, and the principles governing heritability remain unclear. We take a quantitative computational modeling approach to describe propagation of histone H3K27 and H3K36 methylation states. We measure combinatorial H3K27 and H3K36 methylation patterns by quantitative mass spectrometry on subsequent generations of histones. Using model comparison, we reject active global demethylation and invoke the existence of domains defined by distinct methylation endpoints. We find that H3K27me3 on pre-existing histones stimulates the rate of de novo H3K27me3 establishment, supporting a read-write mechanism in timely chromatin restoration. Finally, we provide a detailed quantitative picture of the mutual antagonism between H3K27 and H3K36 methylation and propose that it stabilizes epigenetic states across cell division

An evolutionary missing link? A modest-mass early-type galaxy hosting an oversized nuclear black hole

SAGE1C J053634.78-722658.5 is a galaxy at redshift z = 0.14, discovered behind the Large Magellanic Cloud in the Spitzer Space Telescope`Surveying the Agents of Galaxy Evolution' Spectroscopy survey. It has very strong silicate emission at 10 μm but negligible far-IR and UV emission. This makes it a candidate for a bare active galactic nuclei (AGN) source in the IR, perhaps seen pole-on, without significant IR emission from the host galaxy. In this paper we present optical spectra taken with the Southern African Large Telescope to investigate the nature of the underlying host galaxy and its AGN. We find broad H α emission characteristic of an AGN, plus absorption lines associated with a mature stellar population (>9 Gyr), and refine its redshift determination to z = 0.1428 ± 0.0001. There is no evidence for any emission lines associated with star formation. This remarkable object exemplifies the need for separating the emission from any AGN from that of the host galaxy when employing IR diagnostic diagrams. We estimate the black hole mass, MBH = 3.5 ± 0.8 × 108 M⊙, host galaxy mass, M_stars=2.5^{2.5}_{1.2}× 10^{10} M⊙, and accretion luminosity, Lbol(AGN) = 5.3 ± 0.4 × 1045 erg s-1 (≈12 per cent of the Eddington luminosity), and find the AGN to be more prominent than expected for a host galaxy of this modest size. The old age is in tension with the downsizing paradigm in which this galaxy would recently have transformed from a star-forming disc galaxy into an early-type, passively evolving galaxy

“Could You, Perhaps, Pretty Please?”: Request Directness in Cross-Cultural Speech Act Realization

I am grateful to Professor Beebe for introducing me to the field of discourse analysis. Since that first introductory class, I have continued to be intrigued by the many facets of discourse studies. I was so affected that in subsequent courses, if the option was available, I chose to focus my assigned research on an area related to discourse, including studies in pragmatics and conversation analysis. In addition, I have internalized much of what I learned from Professor Beebe and have a tendency to apply it to everyday conversations (sometimes to the dismay of my friends and family members). The article below is an excerpt from the first paper that I submitted to Professor Beebe. I remember it fondly and will always be thankful for her assistance and influence

The tension between political commitment and academic neutrality in the W.E.A.

Throughout the history of the W. E. A. there have been arguments, and sometimes bitter conflicts, about the relationship between educational aims and political objectives. This thesis examines the tensions and the dilemmas generally experienced in any education involving social and political values, by taking the clash of principles between the W. E. A. (non-party, unsectarian, with its formal emphasis upon objectivity in teaching) and the N. C. L. C. (with its proclaimed Marxist partisanship) as a fundamental challenge for critical re-assessment in the light of contemporary thinking and research. The study begins with a consideration of six crucial, and even determining, individual experiences and contributions: those of Albert Mansbridge, R. H. Tawney, J. M. Mactavish, J. P. M. Millar, G. D. H. Cole and Raymond Williams. This is followed by detailed surveys of three particular areas of work - Residential Adult Education, Literature as a W. E. A. Subject, and Community Education from 1960 to 1980 - each of which illustrates how a basic tension between political commitment and academic neutrality permeates all aspects of thinking and practice in the adult education movement. The final chapter draws together the threads from the survey of particular lives, histories and thematic studies to address theoretical questions about the concepts of liberal education and academic neutrality; - about Marxist and other attitudes towards objectivity and dogmatism; about the nature of the relationship between the Labour movement and the adult education movement. The tensions are shown to be deep, enduring and seemingly irreconcilable but changes of emphasis and intensity are apparent as the general history and the wider forces and movements in society determine the ideological parameters and the 'paradigm shifts' within which, or against which, the W. E. A. operates. On the strength of eighty four years' experience, if the W. E. A. celebrates its one hundredth birthday in 2003, it will (and should) do so embodying similar fundamental tensions

Linear modeling of possible mechanisms for parkinson tremor generation

The power of Parkinson tremor is expressed in terms of possibly changed frequency response functions between relevant variables in the neuromuscular system. The derivation starts out from a linear loopless equivalent model of mechanisms for general tremor generation. Hypothetical changes in this model from the substrate of the disease are indicated, and possible ones are inferred from literature about experiments on patients. The result indicates that in these patients tremor appears to have been generated in loops, which did not include the brain area which in surgery usually is inactivated. For some patients in the literature, these loops could involve muscle length receptors, the static sensitivity of which may have been enlarged by pathological brain activity