Molecular dynamics of MHC genesis unraveled by sequence analysis of the 1,796,938-bp HLA class I region

The intensely studied MHC has become the paradigm for understanding the architectural evolution of vertebrate multigene families. The 4-Mb human MHC (also known as the HLA complex) encodes genes critically involved in the immune response, graft rejection, and disease susceptibility. Here we report the continuous 1,796,938-bp genomic sequence of the HLA class I region, linking genes between MICB and HLA-F. A total of 127 genes or potentially coding sequences were recognized within the analyzed sequence, establishing a high gene density of one per every 14.1 kb. The identification of 758 microsatellite provides tools for high-resolution mapping of HLA class I-associated disease genes. Most importantly, we establish that the repeated duplication and subsequent diversification of a minimal building block, MIC-HCGIX-3.8–1-P5-HCGIV-HLA class I-HCGII, engendered the present-day MHC. That the currently nonessential HLA-F and MICE genes have acted as progenitors to today’s immune-competent HLA-ABC and MICA/B genes provides experimental evidence for evolution by “birth and death,” which has general relevance to our understanding of the evolutionary forces driving vertebrate multigene families.

Dynamics of Gene Expression Revealed by Comparison of Serial Analysis of Gene Expression Transcript Profiles from Yeast Grown on Two Different Carbon SourcesD⃞

We describe a genome-wide characterization of mRNA transcript levels in yeast grown on the fatty acid oleate, determined using Serial Analysis of Gene Expression (SAGE). Comparison of this SAGE library with that reported for glucose grown cells revealed the dramatic adaptive response of yeast to a change in carbon source. A major fraction (>20%) of the 15,000 mRNA molecules in a yeast cell comprised differentially expressed transcripts, which were derived from only 2% of the total number of ∼6300 yeast genes. Most of the mRNAs that were differentially expressed code for enzymes or for other proteins participating in metabolism (e.g., metabolite transporters). In oleate-grown cells, this was exemplified by the huge increase of mRNAs encoding the peroxisomal β-oxidation enzymes required for degradation of fatty acids. The data provide evidence for the existence of redox shuttles across organellar membranes that involve peroxisomal, cytoplasmic, and mitochondrial enzymes. We also analyzed the mRNA profile of a mutant strain with deletions of the PIP2 and OAF1 genes, encoding transcription factors required for induction of genes encoding peroxisomal proteins. Induction of genes under the immediate control of these factors was abolished; other genes were up-regulated, indicating an adaptive response to the changed metabolism imposed by the genetic impairment. We describe a statistical method for analysis of data obtained by SAGE.

Nonlinear dynamics in discretionary accruals: An analysis of bank loan-loss provisions

Several studies have analyzed discretionary accruals to address earnings-smoothing behaviors in the banking industry. We argue that the characteristic link between accruals and earnings may be nonlinear, since both the incentives to manipulate income and the practical way to do so depend partially on the relative size of earnings. Given a sample of 15,268 US banks over the period 1996–2011, the main results in this paper suggest that, depending on the size of earnings, bank managers tend to engage in earnings-decreasing strategies when earnings are negative (“big-bath”), use earnings-increasing strategies when earnings are positive, and use provisions as a smoothing device when earnings are positive and substantial (“cookie-jar” accounting). This evidence, which cannot be explained by the earnings-smoothing hypothesis, is consistent with the compensation theory. Neglecting nonlinear patterns in the econometric modeling of these accruals may lead to misleading conclusions regarding the characteristic strategies used in earnings management.

Dynamics of the Developing Chick Chorioallantoic Membrane Assessed by Stereology, Allometry, Immunohistochemistry and Molecular Analysis.

The chick chorioallantoic membrane (CAM) is a widely used model for the study of angiogenesis, tumour growth, as well as drug efficacy. In spite of this, little is known about the developmental alteration from its appearance to the time of hatching. In the current study the CAM has been studied by classical stereology and allometry. Expression levels of selected angiogenesis-related molecules were estimated by RT-PCR and cell dynamics assessed by proliferation and apoptosis assays. Absolute CAM volume increased from a low of 0.47 ± 0.11 cm3 at embryonic day 8 (E8) to a high of 2.05 ± 0.27 cm3 at E18, and then decreased to 1.6 ± 0.47 cm3 at E20. On allometric analysis, three growth phases were identifiable. Between E8-13 (phase I), the CAM grew fastest; moderately in phase II (E13-18) but was regressing in phase III (E18-20). The chorion, the mesenchyme and the allantoic layers grew fastest in phase I, but moderately in phase II. The mesenchyme grew slowly in phase III while the chorion and allantois were regressing. Chorionic cell volume increased fastest in phase I and was regressing in phase III. Chorionic capillaries grew steadily in phase I and II but regressed in phase III. Both the chorion and the allantois grew by intrinsic cell proliferation as well as recruitment of cells from the mesenchyme. Cell proliferation was prominent in the allantois and chorion early during development, declined after E17 and apoptosis started mainly in the chorion from E14. VEGFR2 expression peaked at E11 and declined steadily towards E20, VEGF peaked at E13 and E20 while HIF 1α had a peak at E11 and E20. Studies targeting CAM growth and angiogenesis need to take these growth phases into consideration.

Study of automobile market dynamics. Volume II: analysis. Final report.

Transportation Systems Center, Cambridge, Mass.

An analysis of track mechanics to improve the simulation of the ride dynamics of tracklaying vehicles; final report,

"Performed under the technical supervision of the Dynamic Simulations Laboratory, Ordnance Tank-Automotive Command, Detroit Arsenal."

Analysis of articulatory dynamics in dysarthria following brain injury in childhood using electromagnetic articulography and electropalatography

Two physiological assessments, electromagnetic articulography (EMA) and electropalatography (EPG), were used simultaneously to investigate the articulatory dynamics in an 18-year-old male with dysarthria 9 years following traumatic brain injury (TBI). Eight words consisting of /t, s, integral, k/ in word initial and word final positions were produced up to 10 times. A nonneurologically impaired male served as a control subject. Six parameters were analyzed using EMA: velocity, acceleration, deceleration, distance, duration, and motion path of tongue movements. Using EPG, the pattern and amount of tongue-to-palate contact and the duration of the closure/constriction phase of each consonant produced were assessed. Timing disturbances in the TBI speaker's speech were highlighted in perceptual assessments in the form of prolonged phonemes and a reduced speech rate. EMA analysis revealed that the approach and release phase durations of the consonant productions were within normal limits. Kinematic strategies such as decreased velocity and decreased distances traveled by the tongue, however, may have counterbalanced each other to produce these appropriate results. EPG examination revealed significantly longer closure/constriction phase periods, which may have contributed to the prolonged phonemes and reduced speech rate observed. The implications of these findings for the development of treatment programs for dysarthria subsequent to TBI will be highlighted.

FRAP analysis of nucleocytoplasmic dynamics of the vitamin D receptor splice variant VDRB1: preferential targeting to nuclear speckles

Although the key components of the cellular nuclear transport machinery have largely been characterized through extensive efforts in recent years, in vivo measurements of the kinetics of nuclear protein import/export are patently few. The present study applies the approach of FRAP (fluorescence recovery after photobleaching) to examine the nucleocytoplasmic flux of a novel human VDRB1 (vitamin D receptor B I) isoform in living cells. Through an N-terminal extension containing a consensus nuclear targeting sequence, VDRB1 is capable of localizing in nuclear speckles adjacent to SC-35 (35 kDa splicing component)containing speckles as well as in the nucleoplasm, dependent on ligand. Investigation of VDRB1 nucleocytoplasmic transport using FRAP indicates for the first time that the VDRB1 has a serum-modulated, active nuclear-import mechanism. There is no evidence of an efficient, active export mechanism for VDRB1, probably as a result of nuclear retention. VDRB1 nuclear import in the absence of serum occurred more rapidly and to a greater extent to nuclear speckles compared with import to other nuclear sites. This preferential transport from the cytoplasm to and accumulation within nuclear speckles is consistent with the idea that the latter represent dynamic centres of VDRB1 interaction with other nuclear proteins. The results are consistent with the existence of specialized pathways to target proteins to nuclear subdomains.

A mathematical modelling technique for the analysis of the dynamics of a simple continuous EDA

This paper presents some initial attempts to mathematically model the dynamics of a continuous estimation of distribution algorithm (EDA) based on a Gaussian distribution and truncation selection. Case studies are conducted on both unimodal and multimodal problems to highlight the effectiveness of the proposed technique and explore some important properties of the EDA. With some general assumptions, we show that, for ID unimodal problems and with the (mu, lambda) scheme: (1). The behaviour of the EDA is dependent only on the general shape of the test function, rather than its specific form; (2). When initialized far from the global optimum, the EDA has a tendency to converge prematurely; (3). Given a certain selection pressure, there is a unique value for the proposed amplification parameter that could help the EDA achieve desirable performance; for ID multimodal problems: (1). The EDA could get stuck with the (mu, lambda) scheme; (2). The EDA will never get stuck with the (mu, lambda) scheme.

The dynamics of organizational change : an analysis of power, professions and new managerialism in the case of CoastElectric

It is widely accepted that the Thatcher years and their immediate aftermath were associated with substantive social and organizational change. The privatisation programme, 'the rolling back of the State', prosecuted by the successive Conservative Governments from 1979-1997 was a central pillar of Governmental policy. This thesis seeks to engage with privatization through the of CoastElectric, a newly privatised Regional Electricity Company. This thesis contributes to the extant understanding of the dynamics of organizational change in four major ways. Firstly, the study into CoastElectric addresses the senior management decision making within the organization: in particular, it will attempt to make sense of 'why' particular decisions were made. The theoretical backdrop to this concern will draw on the concepts of normalization, cultural capital and corporate fashion. The argument presented in this thesis is that the decision-making broadly corresponded with that which could be considered to be at the vanguard of mangerialist thought. However, a detailed analysis suggested that at different junctures in CoastElectric's history there were differences in the approach to decision making that warranted further analysis. The most notable finding was that the relative levels of new managerialist cultural capital possessed by the decision-making elite had an important bearing upon whether the decision was formulated either endogenously or exogenously, with the assistance of cultural intermediaries such as management consultants. The thesis demonstrates the importance of the broader discourse of new managerialism in terms of shaping what is considered to be a 'commonsensical, rational' strategy. The second concern of this thesis is that of the process of organizational change. The study of CoastElectric attempts to provide a rich account of the dynamics of organizational change. This is realized through, first, examining the pre-existing context of the organization; second, through analyzing the power politics of change interventions. The master concepts utilised in this endeavour are that of: dividing practices, the establishment of violent hierarchies between competing discourses; symbolic violence; critical turning points; recursiveness; creative destruction; legitimation strategies and the reconstitution of subjects in the workplace.