Mechanisms Mediating the Biologic Activity of Synthetic Proline, Glycine, and Hydroxyproline Polypeptides in Human Neutrophils

The accumulation of neutrophils at sites of tissue injury or infection is mediated by chemotactic factors released as part of the inflammatory process. Some of these factors are generated as a direct consequence of tissue injury or infection, including degradation fragments of connective tissue collagen and bacterial- or viral-derived peptides containing collagen-related structural motifs. In these studies, we examined biochemical mechanisms mediating the biologic activity of synthetic polypeptides consisting of repeated units of proline (Pro), glycine (Gly), and hydroxyproline (Hyp), major amino acids found within mammalian and bacterial collagens. We found that the peptides were chemoattractants for neutrophils. Moreover, their chemotactic potency was directly related to their size and composition. Thus, the pentameric peptides (Pro-Pro-Gly)(5) and (Pro-Hyp-Gly)(5) were more active in inducing chemotaxis than the corresponding decameric peptides (Pro-Pro-Gly)(10) and (Pro-Hyp-Gly)(10). In addition, the presence of Hyp in peptides reduced chemotactic activity. The synthetic peptides were also found to reduce neutrophil apoptosis. In contrast to chemotaxis, this activity was independent of peptide size or composition. The effects of the peptides on both chemotaxis and apoptosis were blocked by inhibitors of phosphatidylinositol 3-kinase (PI3-K) and p38 mitogen-activated protein (MAP) kinase. However, only (Pro-Pro-Gly)(5) and (Pro-Pro-Gly)(10) induced expression of PI3-K and phosphorylation of p38 MAP kinase, suggesting a potential mechanism underlying reduced chemotactic activity of Hyp-containing peptides. Although none of the synthetic peptides tested had any effect on intracellular calcium mobilization, each induced nuclear binding activity of the transcription factor NF-κB. These findings indicate that polymeric polypeptides containing Gly-X-Y collagen-related structural motifs promote inflammation by inducing chemotaxis and blocking apoptosis. However, distinct calcium-independent signaling pathways appear to be involved in these activities

The FUV spectrum of TW Hya. I. Observations of H2_2 Fluorescence

We observed the classical T Tauri star TW Hya with \textit{HST}/STIS using the E140M grating, from 1150--1700 \AA, with the E230M grating, from 2200--2900 \AA, and with \FUSE from 900--1180 \AA. Emission in 143 Lyman-band H$_2$ lines representing 19 progressions dominates the spectral region from 1250--1650 \AA. The total H$_2$ emission line flux is $1.94 \times 10^{-12}$ erg cm$^{-2}$ s$^{-1}$, which corresponds to $1.90\times10^{-4}$ $L_\odot$ at TW Hya's distance of 56 pc. A broad stellar \Lya line photoexcites the H$_2$ from excited rovibrational levels of the ground electronic state to excited electronic states. The \ion{C}{2} 1335 \AA doublet, \ion{C}{3} 1175 \AA\ multiplet, and \ion{C}{4} 1550 \AA doublet also electronically excite H$_2$. The velocity shift of the H$_2$ lines is consistent with the photospheric radial velocity of TW Hya, and the emission is not spatially extended beyond the 0\farcs05 resolution of \textit{HST}. The H$_2$ lines have an intrinsic FWHM of $11.91\pm0.16$ \kms. One H$_2$ line is significantly weaker than predicted by this model because of \ion{C}{2} wind absorption. We also do not observe any H$_2$ absorption against the stellar \Lya profile. From these results, we conclude that the H$_2$ emission is more consistent with an origin in a disk rather than in an outflow or circumstellar shell. We also analyze the hot accretion-region lines (e.g., \ion{C}{4}, \ion{Si}{4}, \ion{O}{6}) of TW Hya, which are formed at the accretion shock, and discuss some reasons why Si lines appear significantly weaker than other TR region lines.Comment: accepted by ApJ, 42 pages -- 20 text, 11 figure

MagAO Imaging of Long-period Objects (MILO). I. A Benchmark M Dwarf Companion Exciting a Massive Planet around the Sun-like Star HD 7449

We present high-contrast Magellan adaptive optics (MagAO) images of HD 7449, a Sun-like star with one planet and a long-term radial velocity (RV) trend. We unambiguously detect the source of the long-term trend from 0.6-2.15 \microns ~at a separation of \about 0\fasec 54. We use the object's colors and spectral energy distribution to show that it is most likely an M4-M5 dwarf (mass \about 0.1-0.2 \msun) at the same distance as the primary and is therefore likely bound. We also present new RVs measured with the Magellan/MIKE and PFS spectrometers and compile these with archival data from CORALIE and HARPS. We use a new Markov chain Monte Carlo procedure to constrain both the mass ($> 0.17$ \msun ~at 99$\%$ confidence) and semimajor axis (\about 18 AU) of the M dwarf companion (HD 7449B). We also refine the parameters of the known massive planet (HD 7449Ab), finding that its minimum mass is $1.09^{+0.52}_{-0.19}$ \mj, its semimajor axis is $2.33^{+0.01}_{-0.02}$ AU, and its eccentricity is $0.8^{+0.08}_{-0.06}$. We use N-body simulations to constrain the eccentricity of HD 7449B to $\lesssim$ 0.5. The M dwarf may be inducing Kozai oscillations on the planet, explaining its high eccentricity. If this is the case and its orbit was initially circular, the mass of the planet would need to be $\lesssim$ 1.5 \mj. This demonstrates that strong constraints on known planets can be made using direct observations of otherwise undetectable long-period companions.Comment: Corrected planet mass error (7.8 Mj --> 1.09 Mj, in agreement with previous studies

Characterizing the role of brain derived neurotrophic factor genetic variation in Alzheimer’s Disease neurodegeneration

There is accumulating evidence that neurotrophins, like brain-derived neurotrophic factor (BDNF), may impact aging and Alzheimer's Disease. However, traditional genetic association studies have not found a clear relationship between BDNF and AD. Our goal was to test whether BDNF single nucleotide polymorphisms (SNPs) impact Alzheimer's Disease-related brain imaging and cognitive markers of disease. We completed an imaging genetics study on 645 Alzheimer's Disease Neuroimaging Initiative participants (ND=175, MCI=316, AD=154) who had cognitive, brain imaging, and genetics data at baseline and a subset of those with brain imaging data at two years. Samples were genotyped using the Illumina Human610-Quad BeadChip. 13 SNPs in BDNF were identified in the dataset following quality control measures (rs6265(Val66Met), rs12273363, rs11030094, rs925946, rs1050187, rs2203877, rs11030104, rs11030108, rs10835211, rs7934165, rs908867, rs1491850, rs1157459). We analyzed a subgroup of 8 SNPs that were in low linkage disequilibrium with each other. Automated brain morphometric measures were available through ADNI investigators, and we analyzed baseline cognitive scores, hippocampal and whole brain volumes, and rates of hippocampal and whole brain atrophy and rates of change in the ADAS-Cog over one and two years. Three out of eight BDNF SNPs analyzed were significantly associated with measures of cognitive decline (rs1157659, rs11030094, rs11030108). No SNPs were significantly associated with baseline brain volume measures, however six SNPs were significantly associated with hippocampal and/or whole brain atrophy over two years (rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850). We also found an interaction between the BDNF Val66Met SNP and age with whole brain volume. Our imaging-genetics analysis in a large dataset suggests that while BDNF genetic variation is not specifically associated with a diagnosis of AD, it appears to play a role in AD-related brain neurodegeneration

Footprints- In the Footprints of Squier and Davis: Archeological Fieldwork in Ross County, Ohio

TABLE OF CONTENTS Acknowledgements....................................................................iList of Tables...................................................................vii List of Figures...................................................................ix Contributors .........................................................................xiii Chapter 1 In the Footprints of Squier and Davis : Archeological Fieldwork in Ross County, Ohio Mark J. Lynott................................................................................1 Previous Studies in Ohio ...................................................1 Hopewell Studies Today ................................................................4 Recent Field Research ..........................................................................6 Goal of this Volume ................................................................................12 Chapter 2 In Non-mound Space at the Hopewell Mound Group Jennifer Pederson Weinberger .........................................13 Geophysical Survey .......................................................15Western Village Area.....................................................................16 Near the East Village .....................................................................18 Central Area ............................................................................19 Discussion .......................................................................................19 Chapter 3 Field Studies of the Octagon and Great Circle, High Bank Earthworks Ross County, Ohio N’omi B. Greber and Orrin C. Shane III ..............................................23 Excavations at the Octagon ............................................................25 Geophysics at the Great Circle ............................................................30 Excavations at the Great Circle ..........................................................33 Radiocarbon Assays ...........................................................................41 Comments ....................................................................................44 Addendum ..........................................................................................46 Chapter 4 Spruce Hill Earthworks: The 1995-1996 National Park Service Investigations Bret J. Ruby .............................................................................................49 Background .......................................................................................49 The Spruce Hill Earthworks .......................................................................49 Spruce Hill Revisited ......................................................................53 The 1995-1996 National Park Service Investigations ............................53 Discussion and Conclusions ..............................................................61 Chapter 5 Falling Through a Crack in the Core: The Surprise and Demise of Anderson Earthwork William H. Pickard and Jeffrey W. Weinberger ........................................ 67 History and Setting ..................................................................................68 1993 Excavations ..................................................................................70 Discussion ..............................................................................................72 Conclusion ............................................................................................74 Chapter 6 Middle Woodland and Other Settlement Remains in the Overly Tract Near The Hopeton Earthwork, Ross County, Ohio William S. Dancey .....................................................................................................77 Research Design.............................................................................77 Artifact Categories and their Distributions..............................................80 Discussion............................................................................................92 Chapter 7 Hopewell Occupation at the Hopeton Earthworks: Large Scale Surface Survey Using GPS Technology Jarrod Burks and Dawn Walter Gagliano................................................97 The Survey Area ................................................................................98 Survey Methodology .............................................................................99 Survey Results ...................................................................................99 The Surface Data: A Siteless Approach .................................................103 Discussion and Conclusion .........................................................................106 Notes ...................................................................................................107 Chapter 8 Hopewellian Centers in Context: Investigations In and Around the Hopeton Earthworks Bret J. Ruby And Mark J. Lynott .................................................................109 Surface Survey ......................................................................................110 Redwing Site ...........................................................................................111 Comparisons .........................................................................................118 Conclusions ......................................................................................122 Chapter 9 Searching for Hopewell Settlements: The Triangle Site at the Hopeton Earthworks Mark Lynott ...................................................................................... 125 Field Investigations ............................................................................127 Geophysical Survey ............................................................................128 1998 Season ....................................................................................128 Features, Artifacts and Radiocarbon Dating ........................................130 Animal Remains ...............................................................................137 Plant Remains ................................................................................138 Interpretations ..............................................................................139 Chapter 10 Geophysical Investigations at the Hopeton Earthworks John Weymouth, Bruce Bevan, and Rinita Dalan ...............................145 The Cesium Gradiometer Survey ...........................................................146 Cesium Gradiometer Results ...................................................................146 Geoscan Instrument Surveys ..............................................................148 Comparison of Cesium Magnetic and Resistance Data ........................148 Small Circles...........................................................................................149 Trench Excavations ...................................................................................149 Discussion ................................................................................................152 Conclusions ......................................................................................157 Chapter 11 Archeological and Geoarcheological Study of the Rectangular Enclosure at the Hopeton Works Mark J. Lynott and Rolfe D. Mandel ......................................................159 The Study of the Rectangular Earthwork ................................................161 Geophysical Survey ..............................................................................163 Trench Excavations .............................................................................164 Chronology ........................................................................................170 Geoarcheological Analysis of Trench 1 .................................................172 Interpretations ................................................................................174 Chapter 12 Ohio Hopewell Ritual Craft Production Katherine A. Spielmann ............................................................ 179Raw Material Procurement ....................................................................180 Hopewell Crafting ................................................................................181 Deposition ...........................................................................................186 Conclusions ....................................................................................188 References Cited .....................................................................................................18

Predictors of timing of adjuvant chemotherapy in older women with hormone receptor–negative, stages II–III breast cancer

Adherence to consensus guidelines for cancer care may vary widely across health care settings and contribute to differences in cancer outcomes. For some women with breast cancer, omission of adjuvant chemotherapy or delays in its initiation may contribute to differences in cancer recurrence and mortality. We studied adjuvant chemotherapy use among women with stage II or stage III, hormone receptor–negative breast cancer to understand health system and socio-demographic correlates of under-use and delayed adjuvant chemotherapy. We used Surveillance Epidemiology and End Results (SEER)-Medicare linked data to examine the patterns of care for 6,678 women aged 65 and older diagnosed with stage II or stage III hormone receptor–negative breast cancer in 1994–2002, with claims data through 2007. Age-stratified logistic regression was employed to examine the potential role of socio-demographic and structural/organizational health services characteristics in explaining differences in adjuvant chemotherapy initiation. Overall utilization of guideline-recommended adjuvant chemotherapy peaked at 43% in this population. Increasing age, higher co-morbidity burden, and low-income status were associated with lower odds of chemotherapy initiation within 4 months, whereas having positive lymph nodes, more advanced disease, and being married were associated with higher odds (P < 0.05). Health system–related structural/organizational characteristics and race/ethnicity offered little explanatory insight. Timely initiation of guideline-recommended adjuvant chemotherapy was low, with significant variation by age, income, and co-morbidity status. Based on these findings, future studies should seek to explore the more nuanced reasons why older women do not receive chemotherapy and why delays in care occur

Structural/organizational characteristics of health services partly explain racial variation in timeliness of radiation therapy among elderly breast cancer patients

Observed racial/ethnic disparities in the process and outcomes of breast cancer care may be explained, in part, by structural/organizational characteristics of health care systems. We examined the role of surgical facility characteristics and distance to care in explaining racial/ethnic variation in timing of initiation of guideline-recommended radiation therapy (RT) after breast conserving surgery (BCS). We used Surveillance Epidemiology and End Results-Medicare data to identify women ages 65 and older diagnosed with stages I–III breast cancer and treated with BCS in 1994–2002. We used stepwise multivariate logistic regression to examine the interactive effects of race/ethnicity and facility profit status, teaching status, size, and institutional affiliations, and distance to nearest RT on timing of RT initiation, controlling for known covariates. Among 38,574 eligible women who received BCS, 39% received RT within 2 months, 52% received RT within 6 months, and 57% received RT within 12 months post-diagnosis, with significant variation by race/ethnicity. In multivariate models, women attending smaller surgical facilities and those with on-site radiation had higher odds of RT at each time interval, and women attending governmental facilities had lower odds of RT at each time interval (P < 0.05). Increasing distance between patients’ residence and nearest RT provider was associated with lower overall odds of RT, particularly among Hispanic women (P < 0.05). In fully adjusted models including race-by-distance interaction terms, racial/ethnic disparities disappeared in RT initiation within 6 and 12 months. Racial/ethnic disparities in timing of RT for breast cancer can be partially explained by structural/organizational health system characteristics. Identifying modifiable system-level factors associated with quality cancer care may help us target policy interventions that can reduce disparities in outcomes

Qualitative theory of the FitzHugh-Nagumo equations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22693/1/0000247.pd