A study in Pauline evangelism

Thesis (M.A.)--Boston Universit

Heegaard Floer homology of certain mapping tori

We calculate the Heegaard Floer homologies$HF^+(M,s) for mapping tori M associated to certain surface diffeomorphisms, where s is any Spin^c structure on M whose first Chern class is non-torsion. Let gamma and delta be a pair of geometrically dual nonseparating curves on a genus g Riemann surface Sigma_g, and let sigma be a curve separating Sigma_g into components of genus 1 and g-1. Write t-gamma, t_delta, and t_sigma for the right-handed Dehn twists about each of these curves. The examples we consider are the mapping tori of the diffeomorphisms t_gamma^m circ t_delta^n for m,n in Z and that of t_sigma^{+-1}.Comment: Published by Algebraic and Geometric Topology at http://www.maths.warwick.ac.uk/agt/AGTVol4/agt-4-31.abs.htm

Cell replacement strategies for lithium ion battery packs

The economic value of high-capacity battery systems, being used in a wide variety of automotive and energy storage applications, is strongly affected by the duration of their service lifetime. Because many battery systems now feature a very large number of individual cells, it is necessary to understand how cell-to-cell interactions can affect durability, and how to best replace poorly performing cells to extend the lifetime of the entire battery pack. This paper first examines the baseline results of aging individual cells, then aging of cells in a representative 3S3P battery pack, and compares them to the results of repaired packs. The baseline results indicate nearly the same rate of capacity fade for single cells and those aged in a pack; however, the capacity variation due to a few degrees changes in room temperature (\u27±3 ◦C) is significant (\u27±1.5% of capacity of new cell) compared to the percent change of capacity over the battery life cycle in primary applications (\u2720–30%). The cell replacement strategies investigation considers two scenarios: early life failure, where one cell in a pack fails prematurely, and building a pack from used cells for less demanding applications. Early life failure replacement found that, despite mismatches in impedance and capacity, a new cell can perform adequately within a pack of moderately aged cells. The second scenario for reuse of lithium ion battery packs examines the problem of assembling a pack for less-demanding applications from a set of aged cells, which exhibit more variation in capacity and impedance than their new counterparts. The cells used in the aging comparison part of the study were deeply discharged, recovered, assembled in a new pack, and cycled. We discuss the criteria for selecting the aged cells for building a secondary pack and compare the performance and coulombic efficiency of the secondary pack to the pack built from new cells and the repaired pack. The pack that employed aged cells performed well, but its efficiency was reduced

Geophysical characteristics and crustal structure of greenstone terranes: Canadian Shield

Geophysical studies in the Canadian Shield have provided some insights into the tectonic setting of greenstone belts. Greenstone belts are not rooted in deep crustal structures. Geophysical techniques consistently indicate that greenstones are restricted to the uppermost 10 km or so of crust and are underlain by geophysically normal crust. Gravity models suggest that granitic elements are similarly restricted, although magnetic modelling suggests possible downward extension to the intermediate discontinuity around approx. 18 km. Seismic evidence demonstrates that steeply-dipping structure, which can be associated with the belts in the upper crust, is not present in the lower crust. Horizontal intermediate discontinuities mapped under adjacent greenstone and granitic components are not noticeably disrupted in the boundary zone. Geophysical evidence points to the presence of discontinuities between greenhouse-granite and adjacent metasedimentary erranes. Measured stratigraphic thicknesses of greenstone belts are often twice or more the vertical thicknesses determined from gravity modelling. Explantations advanced for the discrepancy include stratigraphy repeated by thrust faulting and/or listric normal faulting, mechanisms which are consistent with certain aspects of conceptual models of greenstone development. Where repetition is not a factor the gravity evidence points to removal of the root zones of greenstone belts. For one region, this has been attributed to magmatic stopping during resurgent caldera activity

Co-designing a mental health training curriculum for staff in the vision impairment sector

Depression and anxiety are common in people with congenital and acquired vision impairment but often go unaddressed. Staff from a variety of professions and roles in the sight impairment sector are well placed to identify mental health issues and signpost individuals for support. However, many of these individuals need training to do this competently. The aim of this project was to develop a mental health training curriculum for staff. We used a seven-step method involving staff and service users from national sight loss charities & local authority and university researchers. The result was a curriculum containing five modules covering an introduction to mental wellbeing, the use of a standardised depression and anxiety screening tool, referral and support options and implementation issues to consider. Future work involves developing the curriculum into an online training programme for wide dissemination across the sight loss sector

On the Topology of Black Hole Event Horizons in Higher Dimensions

In four dimensions the topology of the event horizon of an asymptotically flat stationary black hole is uniquely determined to be the two-sphere $S^2$. We consider the topology of event horizons in higher dimensions. First, we reconsider Hawking's theorem and show that the integrated Ricci scalar curvature with respect to the induced metric on the event horizon is positive also in higher dimensions. Using this and Thurston's geometric types classification of three-manifolds, we find that the only possible geometric types of event horizons in five dimensions are $S^3$ and $S^2 \times S^1$. In six dimensions we use the requirement that the horizon is cobordant to a four-sphere (topological censorship), Friedman's classification of topological four-manifolds and Donaldson's results on smooth four-manifolds, and show that simply connected event horizons are homeomorphic to $S^4$ or $S^2\times S^2$. We find allowed non-simply connected event horizons $S^3\times S^1$ and $S^2\times \Sigma_g$, and event horizons with finite non-abelian first homotopy group, whose universal cover is $S^4$. Finally, following Smale's results we discuss the classification in dimensions higher than six.Comment: 12 pages, minor edits 27/09/0

Novel pyrrolobenzodiazepine benzofused hybrid molecules inhibit NF-κB activity and synergise with bortezomib and ibrutinib in hematological cancers

Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are incurable hematological malignancies that are pathologically linked with aberrant NF-κB activation. In this study, we identified a group of novel C8-linked benzofused Pyrrolo[2,1-c][1,4]benzodiazepines (PBD) monomeric hybrids capable of sequence-selective inhibition of NF-κB with low nanomolar LD50 values in CLL (n=46) and MM cell lines (n=5). The lead compound, DC-1-192, significantly inhibited NF-κB DNA binding after just 4h exposure and demonstrating inhibitory effects on both canonical and non-canonical NF-κB subunits. In primary CLL cells, sensitivity to DC-1-192 was inversely correlated with RelA subunit expression (r2=0.2) and samples with BIRC3 or NOTCH1 mutations showed increased sensitivity (P=0.001). RNA-sequencing and gene set enrichment analysis confirmed the over-representation of NF-κB regulated genes in the down-regulated gene list. Furthermore, In vivo efficacy studies in NOD/SCID mice, using a systemic RPMI 8226 human multiple myeloma xenograft model, showed that DC-1-192 significantly prolonged survival (P=0.017). In addition, DC1-192 showed synergy with bortezomib and ibrutinib; synergy with ibrutinib was enhanced when CLL cells were co-cultured on CD40L-expressing fibroblasts in order to mimic the cytoprotective lymph node microenvironment (P = 0.01). Given that NF-κB plays a role in both bortezomib and ibrutinib resistance mechanisms, these data provide a strong rationale for the use of DC-1-192 in the treatment of NF-κB-driven cancers, particularly in the context of relapsed/refractory disease

Purifying a Mutated Carbon Monoxide Binding Protein, CooA C75S

Proteins in certain organisms have the ability to bind the molecule carbon monoxide. One of these proteins is the CooA protein, which exists in similar forms in two organisms: C. hydrogenoformans and R. rubrum. The R. rubrum CooA protein is very selective for carbon monoxide only, possibly due to the presence of a cysteine amino acid at position 75 in the structure of the protein. The CooA from C. hydrogenoformans does not have a cysteine amino acid in this position and binds more promiscuously, binding nitric oxide as well as carbon monoxide, for example. In order to test the hypothesis that the cysteine amino acid at position 75 causes the high selectivity of the R. rubrum CooA towards carbon monoxide, we expressed and purified a mutated CooA protein from R. rubrum in which the cysteine at position 75 was mutated to a serine amino acid. If the purification is successful, the mutant R. rubrum CooA can then be tested to see if it now binds nitric oxide as well as carbon monoxide, like the C. hydrogenoformans CooA protein

Differential mitochondrial roles for α-synuclein in DRP1-dependent fission and PINK1/Parkin-mediated oxidation

Mitochondria are highly dynamic organelles with strict quality control processes that maintain cellular homeostasis. Within axons, coordinated cycles of fission-fusion mediated by dynamin related GTPase protein (DRP1) and mitofusins (MFN), together with regulated motility of healthy mitochondria anterogradely and damaged/oxidized mitochondria retrogradely, control mitochondrial shape, distribution and size. Disruption of this tight regulation has been linked to aberrant oxidative stress and mitochondrial dysfunction causing mitochondrial disease and neurodegeneration. Although pharmacological induction of Parkinson’s disease (PD) in humans/animals with toxins or in mice overexpressing α-synuclein (α-syn) exhibited mitochondrial dysfunction and oxidative stress, mice lacking α-syn showed resistance to mitochondrial toxins; yet, how α-syn influences mitochondrial dynamics and turnover is unclear. Here, we isolate the mechanistic role of α-syn in mitochondrial homeostasis in vivo in a humanized Drosophila model of Parkinson’s disease (PD). We show that excess α-syn causes fragmented mitochondria, which persists with either truncation of the C-terminus (α-syn1–120) or deletion of the NAC region (α-synΔNAC). Using in vivo oxidation reporters Mito-roGFP2-ORP1/GRX1 and MitoTimer, we found that α-syn-mediated fragments were oxidized/damaged, but α-syn1–120-induced fragments were healthy, suggesting that the C-terminus is required for oxidation. α-syn-mediated oxidized fragments showed biased retrograde motility, but α-syn1–120-mediated healthy fragments did not, demonstrating that the C-terminus likely mediates the retrograde motility of oxidized mitochondria. Depletion/inhibition or excess DRP1-rescued α-syn-mediated fragmentation, oxidation, and the biased retrograde motility, indicating that DRP1-mediated fragmentation is likely upstream of oxidation and motility changes. Further, excess PINK/Parkin, two PD-associated proteins that function to coordinate mitochondrial turnover via induction of selective mitophagy, rescued α-syn-mediated membrane depolarization, oxidation and cell death in a C-terminus-dependent manner, suggesting a functional interaction between α-syn and PINK/Parkin. Taken together, our findings identify distinct roles for α-syn in mitochondrial homeostasis, highlighting a previously unknown pathogenic pathway for the initiation of PD.Fil: Krzystek, Thomas J.. State University of New York; Estados UnidosFil: Banerjee, Rupkatha. State University of New York; Estados UnidosFil: Thurston, Layne. State University of New York; Estados UnidosFil: Huang, JianQiao. State University of New York; Estados UnidosFil: Swinter, Kelsey. State University of New York; Estados UnidosFil: Rahman, Saad Navid. State University of New York; Estados UnidosFil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Gunawardena, Shermali. State University of New York; Estados Unido

Effects of systematic shortening of noncovalent C8 side chain on the cytotoxicity and NF-κB inhibitory capacity of pyrrolobenzodiazepines (PBDs)

The systematic shortening of the noncovalent element of a C8-linked pyrrolobenzodiazepine (PBD) conjugate (13) led to the synthesis of a 19-member library of C8-PBD monomers. The critical elements of 13, which were required to render the molecule cytotoxic, were elucidated by an annexin V assay. The effects of shortening the noncovalent element of the molecule on transcription factor inhibitory capacity were also explored through an enzyme-linked immunosorbent assay-based measurement of nuclear NF-κB upon exposure of JJN-3 cells to the synthesized molecules. Although shortening the noncovalent interactive element of 13 had a less than expected effect upon compound cytotoxicity due to reduced DNA interaction, the transcription factor inhibitory capacity of the molecule was notably altered. This study suggests that a relatively short noncovalent side chain at the C8 position of PBD is sufficient to confer cytotoxicity. The shortened PBD monomers provide a new ADC payload scaffold because of their potent cytotoxicity and druglike properties