Comparison of methods for estimating the effect of salvage therapy in prostate cancer when treatment is given by indication

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102122/1/sim5890.pd

Direct Determination of Multiple Ligand Interactions with the Extracellular Domain of the Calcium Sensing Receptor

Numerous in vivo functional studies have indicated that the dimeric extracellular domain (ECD) of the CaSR plays a crucial role in regulating Ca2+ homeostasis by sensing Ca2+ and L-Phe. However, direct interaction of Ca2+ and Phe with the receptor’s ECD and the resultant impact on its structure and associated conformational changes have been hampered by the large size of the ECD, its high degree of glycosylation, and the lack of biophysical methods to monitor weak interactions in solution. In the present study, we purified the glycosylated extracellular domain of CaSR (ECD) (residues 20~612), containing either complex or high mannose N-glycan structures depending on the host cell line employed for recombinant expression. Both glycosylated forms of the CaSR ECD were purified as dimers and exhibit similar secondary structures with ~50% -helix, ~20% -sheet content and a well buried Trp environment. Using various spectroscopic methods, we have shown that both protein variants bind Ca2+ with a Kd of 3.0~5.0 mM. The local conformational changes of the proteins induced by their interactions with Ca2+ were visualized by NMR with specific 15N Phe-labeled forms of the ECD. Saturation transfer difference (STD) NMR approaches demonstrated for the first time a direct interaction between the CaSR ECD and L-Phe. We further demonstrated that L-Phe increases the binding affinity of the CaSR ECD for Ca2+. Our findings provide new insights into the mechanisms by which Ca2+ and amino acids regulate the CaSR and may pave the way for exploration of the structural properties of CaSR and other members of family C of the GPCR superfamily

The electronic properties of bilayer graphene

We review the electronic properties of bilayer graphene, beginning with a description of the tight-binding model of bilayer graphene and the derivation of the effective Hamiltonian describing massive chiral quasiparticles in two parabolic bands at low energy. We take into account five tight-binding parameters of the Slonczewski-Weiss-McClure model of bulk graphite plus intra- and interlayer asymmetry between atomic sites which induce band gaps in the low-energy spectrum. The Hartree model of screening and band-gap opening due to interlayer asymmetry in the presence of external gates is presented. The tight-binding model is used to describe optical and transport properties including the integer quantum Hall effect, and we also discuss orbital magnetism, phonons and the influence of strain on electronic properties. We conclude with an overview of electronic interaction effects.Comment: review, 31 pages, 15 figure

Galaxy and Mass Assembly (GAMA): A WISE study of the activity of emission-line systems in G23

We present a detailed study of emission-line systems in the Galaxy And Mass Assembly (GAMA) G23 region, making use of Wide-field Infrared Survey Explorer (WISE) photometry that includes carefully measured resolved sources. After applying several cuts to the initial catalog of. 41,000 galaxies, we extract a sample of 9809 galaxies. We then compare the spectral diagnostic Baldwin, Philips & Terlevich (BPT) classification of 1154 emission-line galaxies (38% resolved in W1) to their location in the WISE color-color diagram, leading to the creation of a new zone for mid-infrared warm galaxies located 2μm above the star-forming sequence, below the standard WISE active galactic nucleus (AGN) region. We find that the BPT and WISE diagrams agree on the classification for 85% and 8% of the galaxies as non-AGN (star-forming = SF) and AGN, respectively, and disagree on. 7% of the entire classified sample. Thirty-nine percent of the AGNs (all types) are broad-line systems for which the [N II] and [Hα] fluxes can barely be disentangled, giving in most cases spurious [N II]/[Hα] flux ratios. However, several optical AGNs appear to be completely consistent with SF in WISE. We argue that these could be low-power AGNs, or systems whose hosts dominate the IR emission. Alternatively, given the sometimes high [O III] luminosity in these galaxies, the emission lines may be generated by shocks coming from super-winds associated with SF rather than AGN activity. Based on our findings, we have created a new diagnostic: [W1 - W2] versus [N II]/[Hα], which has the virtue of separating SF from AGNs and high-excitation sources. It classifies 3 to ∼5 times more galaxies than the classic BPT

Microgeometry capture using an elastomeric sensor

We describe a system for capturing microscopic surface geometry. The system extends the retrographic sensor [Johnson and Adelson 2009] to the microscopic domain, demonstrating spatial resolution as small as 2 microns. In contrast to existing microgeometry capture techniques, the system is not affected by the optical characteristics of the surface being measured---it captures the same geometry whether the object is matte, glossy, or transparent. In addition, the hardware design allows for a variety of form factors, including a hand-held device that can be used to capture high-resolution surface geometry in the field. We achieve these results with a combination of improved sensor materials, illumination design, and reconstruction algorithm, as compared to the original sensor of Johnson and Adelson [2009].National Science Foundation (U.S.) (Grant 0739255)National Institutes of Health (U.S.) (Contract 1-R01-EY019292-01

Histone/Protein Deacetylase 11 Targeting Promotes Foxp3+ Treg Function.

Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models. Global HDAC11 deletion had no effect on health or development, and compared to WT controls, Foxp3+ Tregs lacking HDAC11 showed increased suppressive function, and increased expression of Foxp3 and TGF-β. Likewise, compared to WT recipients, conditional deletion of HDAC11 within Tregs led to long-term survival of fully MHC-mismatched cardiac allografts, and prevented development of transplant arteriosclerosis in an MHC class II-mismatched allograft model. The translational significance of HDAC11 targeting was shown by the ability of an HDAC11i to promote long-term allograft allografts in fully MHC-disparate strains. These data are powerful stimuli for the further development and testing of HDAC11-selective pharmacologic inhibitors, and may ultimately provide new therapies for transplantation and autoimmune diseases

Galaxy and Mass Assembly (GAMA): A WISE Study of the Activity of Emission-line Systems in G23

We present a detailed study of emission-line systems in the GAMA G23 region, making use of WISE photometry that includes carefully measured resolved sources. After applying several cuts to the initial catalogue of ∼41,000 galaxies, we extract a sample of 9,809 galaxies. We then compare the spectral diagnostic (BPT) classification of 1154 emission-line galaxies (38% resolved in W1) to their location in the WISE colour-colour diagram, leading to the creation of a new zone for mid-infrared “warm” galaxies located 2σ above the star-forming sequence, below the standard WISE AGN region. We find that the BPT and WISE diagrams agree on the classification for 85% and 8% of the galaxies as non-AGN (star forming = SF) and AGN, respectively, and disagree on ∼7% of the entire classified sample. 39% of the AGN (all types) are broad-line systems for which the [N ii] and [Hα] fluxes can barely be disentangled, giving in most cases spurious [N ii]/[Hα] flux ratios. However, several optical AGN appear to be completely consistent with SF in WISE. We argue that these could be low power AGN, or systems whose hosts dominate the IR emission. Alternatively, given the sometimes high [O iii] luminosity in these galaxies, the emission lines may be generated by shocks coming from super-winds associated with SF rather than the AGN activity. Based on our findings, we have created a new diagnostic: [W1-W2] vs [N ii]/[Hα], which has the virtue of separating SF from AGN and high-excitation sources. It classifies 3∼5 times more galaxies than the classic BPT

Design, Synthesis, and Evaluation of Hydroxamic Acid-Based Molecular Probes for In Vivo Imaging of Histone Deacetylase (HDAC) in Brain

Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention. To explore the rodent and non-human primate (NHP) brain permeability of hydroxamic acid-based HDAC inhibitors using positron emission tomography (PET), we modified the structures of belinostat (PXD101) and panobinostat (LBH-589) to incorporate carbon-11. We also labeled PCI 34051 through carbon isotope substitution. After characterizing the in vitro affinity and efficacy of these compounds across nine recombinant HDAC isoforms spanning Class I and Class II family members, we determined the brain uptake of each inhibitor. Each labeled compound has low uptake in brain tissue when administered intravenously to rodents and NHPs. In rodent studies, we observed that brain accumulation of the radiotracers were unaffected by the pre-administration of unlabeled inhibitors. Knowing that CNS-penetration may be desirable for both imaging applications and therapy, we explored whether a liquid chromatography, tandem mass spectrometry (LC-MS-MS) method to predict brain penetrance would be an appropriate method to pre-screen compounds (hydroxamic acid-based HDACi) prior to PET radiolabeling. LC-MS-MS data were indeed useful in identifying additional lead molecules to explore as PET imaging agents to visualize HDAC enzymes in vivo. However, HDACi brain penetrance predicted by LC-MS-MS did not strongly correlate with PET imaging results. This underscores the importance of in vivo PET imaging tools in characterizing putative CNS drug lead compounds and the continued need to discover effect PET tracers for neuroepigenetic imaging.Chemistry and Chemical Biolog

Analysis of Neptune's 2017 Bright Equatorial Storm

We report the discovery of a large ($\sim$8500 km diameter) infrared-bright storm at Neptune's equator in June 2017. We tracked the storm over a period of 7 months with high-cadence infrared snapshot imaging, carried out on 14 nights at the 10 meter Keck II telescope and 17 nights at the Shane 120 inch reflector at Lick Observatory. The cloud feature was larger and more persistent than any equatorial clouds seen before on Neptune, remaining intermittently active from at least 10 June to 31 December 2017. Our Keck and Lick observations were augmented by very high-cadence images from the amateur community, which permitted the determination of accurate drift rates for the cloud feature. Its zonal drift speed was variable from 10 June to at least 25 July, but remained a constant $237.4 \pm 0.2$ m s$^{-1}$ from 30 September until at least 15 November. The pressure of the cloud top was determined from radiative transfer calculations to be 0.3-0.6 bar; this value remained constant over the course of the observations. Multiple cloud break-up events, in which a bright cloud band wrapped around Neptune's equator, were observed over the course of our observations. No "dark spot" vortices were seen near the equator in HST imaging on 6 and 7 October. The size and pressure of the storm are consistent with moist convection or a planetary-scale wave as the energy source of convective upwelling, but more modeling is required to determine the driver of this equatorial disturbance as well as the triggers for and dynamics of the observed cloud break-up events.Comment: 42 pages, 14 figures, 6 tables; Accepted to Icaru