Identification and Characterization of Novel Sir3/MeCP2-Chromatin Interactions

The eukaryotic genome is packaged into chromosomes that are made up of a highly organized and heavily regulated structure called chromatin. The proteins involved in the compaction of DNA into this condensed state are mostly understood at the level of the structure of the nucleosome. The higher order arrangement of chromatin and how it effects gene regulation is only partially understood and characterized. The compaction of nucleosomal arrays into 30-nm and higher structures are partially the responsibility of architectural, or structural, chromatin associated proteins. The following dissertation analyzes the individual chromatin contributions of two well studied architectural proteins, the yeast silencing protein Silent Information Regulator 3 (Sir3) and the human transcriptional regulator methyl CpG binding protein 2 (MeCP2). Silencing in yeast is the responsibility of the SIR family of proteins. Classically, the Sir3 protein has been characterized as associating with chromatin through the hypo-acetylated N-termini of the core histones H3 and H4. The Sir3 protein has recently been found to contain a DNA-binding element, my studies characterized Sir3-nucleic acid interactions and showed that Sir3 can bind to chromatin independently of histone N-termini. In contrast, the MeCP2 protein has classically been characterized as a methylated DNA dependent transcriptional repressor, but recent genome-wide analysis reveals MeCP2 distribution can occur on promoters of active genes. Recent in vitro work with MeCP2 and nucleosomal arrays showed a highly ordered, compacted chromatin structure even in the absence of DNA methylation. MeCP2 is of particular biological interest due to the observed link with the neurodevelopmental iii disorder Rett Syndrome (RTT). My studies demonstrated that MeCP2 can bind in vitro to the Ntermini of core histones H2A, H3, and H4. Additionally, the removal of these tails impacted MeCP2-chromatin interactions, and resulted in a reduced level of nucleosomal array condensation. Importantly, the two RTT mutants analyzed here, R133C and R168X, exhibited differential binding to histone N-termini. These results add to the understanding of chromatin organization and arrangement by demonstrating and characterizing additional chromatin contacts for these two chromatin associated proteins

Soliton quantization and internal symmetry

We apply the method of collective coordinate quantization to a model of solitons in two spacetime dimensions with a global $U(1)$ symmetry. In particular we consider the dynamics of the charged states associated with rotational excitations of the soliton in the internal space and their interactions with the quanta of the background field (mesons). By solving a system of coupled saddle-point equations we effectively sum all tree-graphs contributing to the one-point Green's function of the meson field in the background of a rotating soliton. We find that the resulting one-point function evaluated between soliton states of definite $U(1)$ charge exhibits a pole on the meson mass shell and we extract the corresponding S-matrix element for the decay of an excited state via the emission of a single meson using the standard LSZ reduction formula. This S-matrix element has a natural interpretation in terms of an effective Lagrangian for the charged soliton states with an explicit Yukawa coupling to the meson field. We calculate the leading-order semi-classical decay width of the excited soliton states discuss the consequences of these results for the hadronic decay of the $\Delta$ resonance in the Skyrme model.Comment: 23 pages, LA-UR-93-299

Do advanced mathematics skills predict success in biology and chemistry degrees?

The mathematical preparedness of science undergraduates has been a subject of debate for some time. This paper investigates the relationship between school mathematics attainment and degree outcomes in biology and chemistry across England, a much larger scale of analysis than has hitherto been reported in the literature. A unique dataset which links the National Pupil Database for England (NPD) and Higher Education Statistics Agency (HESA) data is used to track the educational trajectories of a national cohort of 16-year-olds through their school and degree programmes. Multilevel regression models indicate that students who completed advanced mathematics qualifications prior to their university study of biology and chemistry were no more likely to attain the best degree outcomes than those without advanced mathematics. The models do, however, suggest that success in advanced chemistry at school predicts outcomes in undergraduate biology and vice versa. There are important social background differences and the impact of the university attended is considerable. We discuss a range of possible explanations of these findings

MOSFIRE, the multi-object spectrometer for infra-red exploration at the Keck Observatory

This paper describes the as-built performance of MOSFIRE, the multi-object spectrometer and imager for the Cassegrain focus of the 10-m Keck 1 telescope. MOSFIRE provides near-infrared (0.97 to 2.41 μm) multi-object spectroscopy over a 6.1' x 6.1' field of view with a resolving power of R~3,500 for a 0.7" (0.508 mm) slit (2.9 pixels in the dispersion direction), or imaging over a field of view of ~6.9' diameter with ~0.18" per pixel sampling. A single diffraction grating can be set at two fixed angles, and order-sorting filters provide spectra that cover the K, H, J or Y bands by selecting 3rd, 4th, 5th or 6th order respectively. A folding flat following the field lens is equipped with piezo transducers to provide tip/tilt control for flexure compensation at the <0.1 pixel level. Instead of fabricated focal plane masks requiring frequent cryo-cycling of the instrument, MOSFIRE is equipped with a cryogenic Configurable Slit Unit (CSU) developed in collaboration with the Swiss Center for Electronics and Microtechnology (CSEM). Under remote control the CSU can form masks containing up to 46 slits with ~0.007-0.014" precision. Reconfiguration time is < 6 minutes. Slits are formed by moving opposable bars from both sides of the focal plane. An individual slit has a length of 7.0" but bar positions can be aligned to make longer slits in increments of 7.5". When masking bars are retracted from the field of view and the grating is changed to a mirror, MOSFIRE becomes a wide-field imager. The detector is a 2K x 2K H2-RG HgCdTe array from Teledyne Imaging Sensors with low dark current and low noise. Results from integration and commissioning are presented

Solvability, Consistency and the Renormalization Group in Large-NcN_c Models of Hadrons

We establish the following fundamentals about Lagrangian models of meson-baryon interactions in the large-$N_{c}$ limit: 1. Calculating the leading-order contribution to $1$-meson/$2$-baryon Green's functions in the $1/N_c$ expansion involves summing an infinite class of divergent Feynman diagrams. So long as the bare Lagrangian properly obeys all large-$N_c$ selection rules, this all-loops resummation is accomplished exactly by solving coupled classical field equations with a short-distance cutoff. 2. The only effect of the resummation is to renormalize the bare Yukawa couplings, baryon masses and hyperfine baryon mass splittings of the model. 3. In the process, the large-$N_{c}$ renormalization group flow of these bare parameters is completely determined. We conjecture that variants of the Skyrme model emerge as UV fixed points of such flows.Comment: (LaTeX file with accompanying figures

A systematic review of strategies to recruit and retain primary care doctors

Background There is a workforce crisis in primary care. Previous research has looked at the reasons underlying recruitment and retention problems, but little research has looked at what works to improve recruitment and retention. The aim of this systematic review is to evaluate interventions and strategies used to recruit and retain primary care doctors internationally. Methods A systematic review was undertaken. MEDLINE, EMBASE, CENTRAL and grey literature were searched from inception to January 2015.Articles assessing interventions aimed at recruiting or retaining doctors in high income countries, applicable to primary care doctors were included. No restrictions on language or year of publication. The first author screened all titles and abstracts and a second author screened 20%. Data extraction was carried out by one author and checked by a second. Meta-analysis was not possible due to heterogeneity. Results 51 studies assessing 42 interventions were retrieved. Interventions were categorised into thirteen groups: financial incentives (n=11), recruiting rural students (n=6), international recruitment (n=4), rural or primary care focused undergraduate placements (n=3), rural or underserved postgraduate training (n=3), well-being or peer support initiatives (n=3), marketing (n=2), mixed interventions (n=5), support for professional development or research (n=5), retainer schemes (n=4), re-entry schemes (n=1), specialised recruiters or case managers (n=2) and delayed partnerships (n=2). Studies were of low methodological quality with no RCTs and only 15 studies with a comparison group. Weak evidence supported the use of postgraduate placements in underserved areas, undergraduate rural placements and recruiting students to medical school from rural areas. There was mixed evidence about financial incentives. A marketing campaign was associated with lower recruitment. Conclusions This is the first systematic review of interventions to improve recruitment and retention of primary care doctors. Although the evidence base for recruiting and care doctors is weak and more high quality research is needed, this review found evidence to support undergraduate and postgraduate placements in underserved areas, and selective recruitment of medical students. Other initiatives covered may have potential to improve recruitment and retention of primary care practitioners, but their effectiveness has not been established

Skyrmion Quantization and the Decay of the Delta

We present the complete solution to the so-called ``Yukawa problem'' of the Skyrme model. This refers to the perceived difficulty of reproducing---purely from soliton physics---the usual pseudovector pion-nucleon coupling, echoed by pion coupling to the higher spin/isospin baryons $(I=J=3/2 , 5/2 , \cdots , N_c/2 )$ in a manner fixed by large-$N_c$ group theory. The solution involves surprisingly elegant interplay between the classical and quantum properties of a new configuration, the ``new improved skyrmion''. This is the near-hedgehog obtained by minimizing the usual skyrmion mass functional augmented by an all-important isorotational kinetic term. The numerics are pleasing: a $\Delta$ decay width within a few MeV of its measured value, and furthermore, the higher-spin baryons $(I=J \ge 5/2 )$ with widths so large ($\Gamma > 800 MeV$) that these undesirable large-$N_c$ artifacts effectively drop out of the spectrum, and pose no phenomenological problem. Beyond these specific results, we ground the Skyrme model in the Feynman Path Integral, and set up a transparent collective coordinate formalism that makes maximal use of the $1/N_c$ expansion. This approach elucidates the connection between skyrmions on the one hand, and Feynman diagrams in an effective field theory on the other.Comment: This TeX file inputs the macropackage harvmac.tex . Choose the ``b'' (big) option or equations will overrun

From Effective Lagrangians, to Chiral Bags, to Skyrmions with the Large-N_c Renormalization Group

We explicitly relate effective meson-baryon Lagrangian models, chiral bags, and Skyrmions in the following way. First, effective Lagrangians are constructed in a manner consistent with an underlying large-N_c QCD. An infinite set of graphs dress the bare Yukawa couplings at *leading* order in 1/N_c, and are summed using semiclassical techniques. What emerges is a picture of the large-N_c baryon reminiscent of the chiral bag: hedgehog pions for r > 1/\Lambda patched onto bare nucleon degrees of freedom for r < 1/\Lambda, where the ``bag radius'' 1/\Lambda is the UV cutoff on the graphs. Next, a novel renormalization group (RG) is derived, in which the bare Yukawa couplings, baryon masses and hyperfine baryon mass splittings run with \Lambda. Finally, this RG flow is shown to act as a *filter* on the renormalized Lagrangian parameters: when they are fine-tuned to obey Skyrme-model relations the continuum limit \Lambda --> \infty exists and is, in fact, a Skyrme model; otherwise there is no continuum limit.Comment: Figures included (separate file). This ``replaced'' version corrects the discussion of backwards-in-time baryon

MOSFIRE, the multi-object spectrometer for infra-red exploration at the Keck Observatory

This paper describes the as-built performance of MOSFIRE, the multi-object spectrometer and imager for the Cassegrain focus of the 10-m Keck 1 telescope. MOSFIRE provides near-infrared (0.97 to 2.41 μm) multi-object spectroscopy over a 6.1' x 6.1' field of view with a resolving power of R~3,500 for a 0.7" (0.508 mm) slit (2.9 pixels in the dispersion direction), or imaging over a field of view of ~6.9' diameter with ~0.18" per pixel sampling. A single diffraction grating can be set at two fixed angles, and order-sorting filters provide spectra that cover the K, H, J or Y bands by selecting 3rd, 4th, 5th or 6th order respectively. A folding flat following the field lens is equipped with piezo transducers to provide tip/tilt control for flexure compensation at the <0.1 pixel level. Instead of fabricated focal plane masks requiring frequent cryo-cycling of the instrument, MOSFIRE is equipped with a cryogenic Configurable Slit Unit (CSU) developed in collaboration with the Swiss Center for Electronics and Microtechnology (CSEM). Under remote control the CSU can form masks containing up to 46 slits with ~0.007-0.014" precision. Reconfiguration time is < 6 minutes. Slits are formed by moving opposable bars from both sides of the focal plane. An individual slit has a length of 7.0" but bar positions can be aligned to make longer slits in increments of 7.5". When masking bars are retracted from the field of view and the grating is changed to a mirror, MOSFIRE becomes a wide-field imager. The detector is a 2K x 2K H2-RG HgCdTe array from Teledyne Imaging Sensors with low dark current and low noise. Results from integration and commissioning are presented