An Evolving Understanding of a Spectrum “Disorder”

The 2013 publication of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) affected millions of people. Individuals who had previously received a diagnosis of Asperger’s syndrome (AS), or any other pervasive developmental disorder (PDD) with the exception of Rett syndrome (RTT)1, suddenly found themselves placed on the autism spectrum. While some individuals with PDDs viewed this diagnostic change as beneficial, others felt that they had been stripped of a part of their identity. By merging several disorders, the DSM created the “umbrella diagnosis” of autism spectrum disorder (ASD), which features an incredibly varied etiology and diverse clinical outcomes. In this thesis, I argue that (a) many people with ASD do not feel impeded in their daily activities and thus do not meet the definition of “disordered,” (b) these same individuals display signs of neurodiversity, or natural variations in the human genome, and (c) a diagnosis is a snapshot of someone’s life and does not dictate their future experiences. Having received a diagnosis of AS myself, I hope to illustrate a comprehensive portrait of ASD by blending my personal experiences with information on autism research, associated behaviors, assistive measures, and cultural changes

Transcriptional initiation under conditions of anoxia-induced quiescence in mitochondria from Artemia franciscana embryos

In response to anoxia, embryos of the brine shrimp Artemia franciscana are able coordinately to downregulate metabolism to levels low enough to permit survival for several years at room temperature. In addition to dramatic decreases in free ATP levels and heat production, intracellular pH drops from 7.8 to 6.3 overnight. Use of isolated mitochondria to study transcriptional responses to anoxia offers several advantages: (1) the localized nature of transcript initiation, processing and degradation, all of which may be followed in organello; (2) the relatively simple cis- and trans-machinery involved and (3) the ability to provide relevant physiological treatments in vitro. In response to anoxic incubation of embryos in vivo for 4h followed by anoxic mitochondrial isolation and anoxic transcription assay at pH 6.4, a significant decrease in overall UTP incorporation (77%) was seen after 30min relative to normoxic, pH 7.9 controls. A less severe inhibition of transcription under anoxia (52%) was observed compared with controls when pH was raised to 7.9. Similarly, under normoxia, the incubation at low pH (6.4) reduced transcription by 59%. Ribonuclease protection assays showed that the contribution of in vitro initiation during the assay fell from 78% at pH 7.9 to approximately 32% at pH 6.4 under either normoxic or anoxic conditions. DNA footprinting of putative transcriptional promoters revealed proteins at regular intervals upstream of the 12S rRNA in the control region, which previously had been indirectly inferred to contain promoters for H-strand transcription. The area between 12030 and 12065 contains a sequence in the tRNAleu gene believed to bind the transcription termination factor mTERF or TERM, and we provide the first evidence that this sequence is protein-bound in A. franciscana. However, our hypothesis that initiation is reduced at low pH because of a change in DNA binding by mitochondrial transcription factors was not confirmed. We propose that regulation of initiation may be mediated by covalent modification or by protein-protein interactions not detected by footprinting

Mitochondrial mRNA stability and polyadenylation during anoxia-induced quiescence in the brine shrimp Artemia franciscana

Polyadenylation of messenger RNA is known to be an important mechanism for regulating mRNA stability in a variety of systems, including bacteria, chloroplasts and plant mitochondria. By comparison, little is known about the role played by polyadenylation in animal mitochondrial gene expression. We have used embryos of the brine shrimp Artemia franciscana to test hypotheses regarding message stability and polyadenylation under conditions simulating anoxia-induced quiescence. In response to anoxia, these embryos undergo a profound and acute metabolic downregulation, characterized by a steep drop in intracellular pH (pHi) and ATP levels. Using dot blots of total mitochondrial RNA, we show that during in organello incubations both O 2 deprivation and acidic pH (pH 6.4) elicit increases in half-lives of selected mitochondrial transcripts on the order of five- to tenfold or more, relative to normoxic controls at pH 7.8. Polyadenylation of these transcripts was measured under the same incubation conditions using a reverse transcriptase-polymerase chain reaction (RT-PCR)-based assay. The results demonstrate that low pH and anoxia promote significant deadenylation of the stabilized transcripts in several cases, measured either as change over time in the amount of polyadenylation within a given size class of poly(A)+ tail, or as the total amount of polyadenylation at the endpoint of the incubation. This study is the first direct demonstration that for a metazoan mitochondrion, polyadenylation is associated with destabilized mRNA. This pattern has also been demonstrated in bacteria, chloroplasts and plant mitochondria and may indicate a conserved mechanism for regulating message half-life that differs from the paradigm for eukaryotic cytoplasm, where increased mRNA stability is associated with polyadenylation

Kennedy Space Center's NASA/Contractor Team-Centered Total Quality Management Seminar: Results, methods, and lessons learned

It is apparent to everyone associated with the Nation's aeronautics and space programs that the challenge of continuous improvement can be reasonably addressed only if NASA and its contractors act together in a fully integrated and cooperative manner that transcends the traditional boundaries of proprietary interest. It is, however, one thing to assent to the need for such integration and cooperation; it is quite another thing to undertake the hard tasks of turning such a need into action. Whatever else total quality management is, it is fundamentally a team-centered and team-driven process of continuous improvement. The introduction of total quality management at KSC, therefore, has given the Center a special opportunity to translate the need for closer integration and cooperation among all its organizations into specific initiatives. One such initiative that NASA and its contractors have undertaken at KSC is a NASA/Contractor team-centered Total Quality Management Seminar. It is this seminar which is the subject of this paper. The specific purposes of this paper are to describe the following: Background, development, and evolution of Kennedy Space Center's Total Quality Management Seminar; Special characteristics of the seminar; Content of the seminar; Meaning and utility of a team-centered design for TQM training; Results of the seminar; Use that one KSC contractor, EG&G Florida, Inc. has made of the seminar in its Total Quality Management initiative; and Lessons learned

Loss assessment of tall buildings from a vulnerability perspective

As the number of tall buildings in seismic areas around the world continues to grow, the ability to perform loss assessments becomes increasingly important. Due to their size, tall buildings house many businesses and/or residents, and any damage to these buildings has the potential to affect a large number of people. Furthermore, these buildings are expensive to build and repair. The financial resources needed to recover from the damage induced by earthquakes are generally not trivial amounts, and thus the ability to realistically model losses in tall buildings becomes essential. The loss assessment of tall buildings presents unique challenges, including the tendency for significant damage to be concentrated in a few stories rather than distributed throughout the building. The presence of excessive residual drifts in one or a few stories can result in the building being declared a total loss and demolished, even when the levels of damage in the rest of the building are relatively low. Accessibility issues can increase repair costs in a tall building relative to a shorter building as, for example, it is much easier to replace the window on the 2nd story of a 5-story building versus on the 20th story of a 50-story building. The long first-mode periods of tall buildings as well as the significant contribution of higher modes means that the ground motions used to assess the structural response must be carefully considered as both the low frequency and high frequency components of the ground motion affect the response. The evolution of building design is also an important factor in the loss assessment of tall buildings. The trend in recent years toward performance-based designs and a growing awareness for designs that reduce expected seismic losses play an important role in differentiating the expected losses of newer versus older tall buildings. This is in addition to the effects of advances in building codes and design practice that are typically seen over time, such as improvements in designing for ductility and reducing the risk of connection fractures in steel moment-resisting frames. This study examines the loss assessment of tall buildings from a vulnerability perspective, drawing on the unique characteristics of tall buildings previously noted. It discusses how the vulnerability characteristics of tall buildings affect the relative seismic risk and uses examples of major cities in North America and New Zealand to illustrate the effects

Contrasting effects of sleep fragmentation and angiotensin-II treatment upon pro-inflammatory responses of mice

Disordered sleep promotes inflammation in brain and peripheral tissues, but the mechanisms that regulate these responses are poorly understood. One hypothesis is that activation of the sympathetic nervous system (SNS) from sleep loss elevates blood pressure to promote vascular sheer stress leading to inflammation. As catecholamines produced from SNS activation can directly regulate inflammation, we pharmacologically altered blood pressure using an alternative approach-manipulation of the renin-angiotensin system (RAS). Male C57BL6/J mice were treated with angiotensin or captopril to elevate and reduce blood pressure, respectively and then exposed to 24-h of sleep fragmentation (SF) or allowed to sleep (control). Pro- and anti-inflammatory cytokine gene expression and as endothelial adhesion gene expression as well as serum glucocorticoids (corticosterone) were measured. RAS manipulation elevated cytokines and endothelial adhesion expression in heart and aorta while SF increased cytokine expression in peripheral tissues, but not brain. However, there were interactive effects of angiotensin-II and SF upon cytokine gene expression in hippocampus and hypothalamus, but not prefrontal cortex. SF, but not RAS manipulation, elevated serum corticosterone concentration. These findings highlight the contrasting effects of RAS manipulation and SF, implying that inflammation from SF is acting on different pathways that are largely independent of RAS manipulation

Benefit-Cost Analysis in Environmental, Health, and Safety Regulation: A Statement of Principles

Benefit-cost analysis can play a very important role in legislative and regulatory policy debates on improving the environment, health, and safety. It can help illustrate the tradeoffs that are inherent in public policymaking as well as make those tradeoffs more transparent. It can also help agencies set regulatory priorities. Benefit-cost analysis should be used to help decisionmakers reach a decision. Contrary to the views of some, benefit-cost analysis is neither necessary nor sufficient for designing sensible public policy. If properly done, it can be very helpful to agencies in the decisionmaking process. Decisionmakers should not be precluded from considering the economic benefits and costs of different policies in the development of regulations. Laws that prohibit costs or other factors from being considered in administrative decisionmaking are inimical to good public policy. Currently, several of the most important regulatory statutes have been interpreted to imply such prohibitions. Benefit-cost analysis should be required for all major regulatory decisions, but agency heads should not be bound by a strict benefit-cost test. Instead, they should be required to consider available benefit-cost analyses and to justify the reasons for their decision in the event that the expected costs of a regulation far exceed the expected benefits. Agencies should be encouraged to use economic analysis to help set regulatory priorities. Economic analyses prepared in support of particularly important decisions should be subjected to peer review both inside and outside government. Benefits and costs of proposed major regulations should be quantified wherever possible. Best estimates should be presented along with a description of the uncertainties. Not all benefits or costs can be easily quantified, much less translated into dollar terms. Nevertheless, even qualitative descriptions of the pros and cons associated with a contemplated action can be helpful. Care should be taken to ensure that quantitative factors do not dominate important qualitative factors in decisionmaking. The Office of Management and Budget, or some other coordinating agency, should establish guidelines that agencies should follow in conducting benefit-cost analyses. Those guidelines should specify default values for the discount rate and certain types of benefits and costs, such as the value of a small reduction in mortality risk. In addition, agencies should present their results using a standard format, which summarizes the key results and highlights major uncertainties.

Is There a Role for Benefit-Cost Analysis in Environmental, Health, and Safety Regulation?

Benefit-cost analysis has a potentially important role to play in helping inform regulatory decision-making, although it should not be the sole basis for such decision-making. This paper offers eight principles on the appropriate use of benefit-cost analysis.Environment, Health and Safety, Regulatory Reform

Gene networks in Drosophila melanogaster: integrating experimental data to predict gene function

The first computational interaction network built from Drosophila melanogaster protein-protein and genetic interaction data allows the functional annotation of orphan genes and reveals clusters of functionally-related genes

Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors

<p>Abstract</p> <p>Background</p> <p>Aberrant promoter hypermethylation of cancer-associated genes occurs frequently during carcinogenesis and may serve as a cancer biomarker. In this study we aimed at defining a quantitative gene promoter methylation panel that might identify the most prevalent types of renal cell tumors.</p> <p>Methods</p> <p>A panel of 18 gene promoters was assessed by quantitative methylation-specific PCR (QMSP) in 85 primarily resected renal tumors representing the four major histologic subtypes (52 clear cell (ccRCC), 13 papillary (pRCC), 10 chromophobe (chRCC), and 10 oncocytomas) and 62 paired normal tissue samples. After genomic DNA isolation and sodium bisulfite modification, methylation levels were determined and correlated with standard clinicopathological parameters.</p> <p>Results</p> <p>Significant differences in methylation levels among the four subtypes of renal tumors were found for <it>CDH1 </it>(<it>p </it>= 0.0007), <it>PTGS2 </it>(<it>p </it>= 0.002), and <it>RASSF1A </it>(<it>p </it>= 0.0001). <it>CDH1 </it>hypermethylation levels were significantly higher in ccRCC compared to chRCC and oncocytoma (<it>p </it>= 0.00016 and <it>p </it>= 0.0034, respectively), whereas <it>PTGS2 </it>methylation levels were significantly higher in ccRCC compared to pRCC (<it>p </it>= 0.004). <it>RASSF1A </it>methylation levels were significantly higher in pRCC than in normal tissue (<it>p </it>= 0.035). In pRCC, <it>CDH1 </it>and <it>RASSF1A </it>methylation levels were inversely correlated with tumor stage (<it>p </it>= 0.031) and nuclear grade (<it>p </it>= 0.022), respectively.</p> <p>Conclusion</p> <p>The major subtypes of renal epithelial neoplasms display differential aberrant <it>CDH1</it>, <it>PTGS2</it>, and <it>RASSF1A </it>promoter methylation levels. This gene panel might contribute to a more accurate discrimination among common renal tumors, improving preoperative assessment and therapeutic decision-making in patients harboring suspicious renal masses.</p