Different Poses for Ligand and Chaperone in Inhibitor Bound Hsp90 and GRP94: Implications for Paralog-specific Drug Design

Hsp90 chaperones contain an N-terminal ATP binding site that has been effectively targeted by competitive inhibitors. Despite the myriad of inhibitors, none to date have been designed to bind specifically to just one of the four mammalian hsp90 paralogs, which are cytoplasmic Hsp90α and β, ER GRP94, and mitochondrial Trap-1. Given that each of the hsp90 paralogs is responsible for chaperoning a distinct set of client proteins, specific targeting of one hsp90 paralog may result in higher efficacy and therapeutic control. Specific inhibitors may also help elucidate the biochemical roles of each hsp90 paralog. Here we present side by side comparisons of the structures of yeast Hsp90 and mammalian GRP94, bound to the pan-hsp90 inhibitors Geldanamycin and Radamide. These structures reveal paralog specific differences in the Hsp90 and GRP94 conformations in response to Geldanamycin binding. We also report significant variation in the pose and disparate binding affinities for the Geldanamycin-Radicicol chimera Radamide when bound to the two paralogs, which may be exploited in the design of paralog-specific inhibitors

The Fading Optical Counterpart of GRB~970228, Six Months and One Year Later

We report on observations of the fading optical counterpart of the gamma-ray burst GRB 970228, made with the Hubble Space Telescope STIS CCD approximately six months after outburst and with the HST/NICMOS and Keck/NIRC approximately one year after outburst. The unresolved counterpart is detected by STIS at V=28.0 +/- 0.25, consistent with a continued power-law decline with exponent -1.14 +/- 0.05. The counterpart is located within, but near the edge of, a faint extended source with diameter ~0."8 and integrated magnitude V=25.8 +/- 0.25. A reanalysis of HST and NTT observations performed shortly after the burst shows no evidence of proper motion of the point source or fading of the extended emission. Only the extended source is visible in the NICMOS images with a magnitude of H=23.3 +/- 0.1. The Keck observations find K = 22.8 +/- 0.3. Several distinct and independent means of deriving the foreground extinction in the direction of GRB 970228 all agree with A_V = 0.75 +/- 0.2. After adjusting for Galactic extinction, we find that the size of the observed extended emission is consistent with that of galaxies of comparable magnitude found in the Hubble Deep Field (HDF) and other deep HST images. Only 2% of the sky is covered by galaxies of similar or greater surface brightness; therefore the extended source is almost certainly the host galaxy. Additionally, we find that the extinction-corrected V - H and V - K colors of the host are as blue as any galaxy of comparable or brighter magnitude in the HDF. Taken in concert with recent observations of GRB 970508, GRB 971214, and GRB 980703 our work suggests that all four GRBs with spectroscopic identification or deep multicolor broad-band imaging of the host lie in rapidly star-forming galaxies.Comment: 24 pages, Latex, 4 PostScript figures, to appear in the May 10 issue of The Astrophysical Journal (Note: displayed abstract is abridged

Electrostatic potential profiles of molecular conductors

The electrostatic potential across a short ballistic molecular conductor depends sensitively on the geometry of its environment, and can affect its conduction significantly by influencing its energy levels and wave functions. We illustrate some of the issues involved by evaluating the potential profiles for a conducting gold wire and an aromatic phenyl dithiol molecule in various geometries. The potential profile is obtained by solving Poisson's equation with boundary conditions set by the contact electrochemical potentials and coupling the result self-consistently with a nonequilibrium Green's function (NEGF) formulation of transport. The overall shape of the potential profile (ramp vs. flat) depends on the feasibility of transverse screening of electric fields. Accordingly, the screening is better for a thick wire, a multiwalled nanotube or a close-packed self-assembled monolayer (SAM), in comparison to a thin wire, a single-walled nanotube or an isolated molecular conductor. The electrostatic potential further governs the alignment or misalignment of intramolecular levels, which can strongly influence the molecular I-V characteristic. An external gate voltage can modify the overall potential profile, changing the current-voltage (I-V) characteristic from a resonant conducting to a saturating one. The degree of saturation and gate modulation depends on the metal-induced-gap states (MIGS) and on the electrostatic gate control parameter set by the ratio of the gate oxide thickness to the channel length.Comment: to be published in Phys. Rev. B 69, No.3, 0353XX (2004

Molecular Analysis Confirming the Introduction of Nile Crocodiles, Crocodylus niloticus Laurenti 1768 (Crocodylidae), in Southern Florida, with an Assessment of Potential for Establishment, Spread, and Impacts.

The state of Florida, USA, has more introduced herpetofauna than any other governmental region on Earth. Four species of nonnative crocodilians have been introduced to Florida (all since 1960), one of which is established. Between 2000–2014 we field-collected three nonnative crocodilians in Miami-Dade County, Florida, and one in Hendry County, Florida. We used DNA barcoding and molecular phylogenetics to determine species identification and native range origin. Also, we described diet, movement, and growth for one crocodile. Our molecular analyses illustrated that two of the crocodiles we collected are most closely related to Nile Crocodiles (Crocodylus niloticus) from South Africa, suggesting this region as a source population. We, thus, documented the first known introduction of C. niloticus in Florida. Two, and possibly three of the introduced crocodiles shared the same haplotype, suggesting they are likely from the same introduction pathway or source. One animal was captured, measured, marked, and released, then recaptured 2 y later allowing us to calculate growth rate (40.5 cm/y) and movement. The most likely route of travel by waterway (i.e., canal) illustrates that this animal traveled at least 29 km from its original capture site. One crocodile escaped from a facility in Hendry County, Florida, and survived in 1,012 ha of semi-wild habitat for three to four years, confirming that this species can survive in southern Florida

ACR Appropriateness Criteria® Hodgkin Lymphoma-Favorable Prognosis Stage I and II

This topic addresses the treatment of newly diagnosed patients with favorable prognosis stage I and II Hodgkin lymphoma. In most cases, combined modality therapy (chemotherapy followed by involved site radiation therapy) constitutes the current standard of care. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the appropriate use of combined modality therapy for favorable prognosis stage I and II Hodgkin lymphoma. Increasing information about the late effects of treatment has led to attempts to decrease toxicity by using less chemotherapy (decreased duration and/or intensity or different agents) and less radiation therapy (reduced volume and/or dose) while maintaining excellent efficacy

看護学部教官業績目録 ; 2003年1月～12月

Acinetobacter baumannii ATCC 19606 tolerates loss of lipopolysaccharide (LPS) caused by inactivation of early LPS pathway genes. However, mutations in pathway genes encoding steps downstream of LpxD have not been reported, implying that later biosynthetic steps may be essential for viability. Here, we determined if LpxH, the UDP-2,3-diacylglucosamine hydrolase that generates UMP-2,3-diacylglucosamine 1-phosphate (lipid X), was essential in A. baumannii ATCC 19606. Multiple attempts to disrupt lpxH on the genome were unsuccessful. When expression of LpxH was placed under control of an isopropyl β-D-1-thiogalactopyranoside (IPTG) inducible promoter, the cells failed to grow under standard laboratory conditions without IPTG induction. Growth under LpxH depletion conditions (-IPTG) was rescued by chemical inhibition of LpxC, upstream of LpxH, indicating that toxic accumulation of LPS pathway intermediates underlies LpxH essentiality. Consistent with this, the levels of LpxH substrate (product of LpxD) and a C14:0(3-OH) acyl variant of the LpxD substrate had accumulated in cells that were depleted of LpxH causing a growth defect. Intriguingly, under these partial depletion conditions, there was also a smaller but reproducible accumulation of the downstream pathway intermediates disaccharide 1-monophosphate and lipid IVA suggesting a complex downstream response to LpxH depletion

Detection, Estimation, and Modulation Theory

Contains research objectives and summary of research on four research projects.Joint Services Electronics Program (Contract DAAB07-75-C-1346)Woods Hole Oceanographic Institution Purchase Order 455

ACR Appropriateness Criteria® Recurrent Hodgkin Lymphoma

This topic addresses the management of recurrent Hodgkin lymphoma. While autologous stem cell transplantation may be appropriate for select cases of recurrent disease following comprehensive combined-modality therapy, other options exist for patients treated with lower-dose therapy for early-stage disease. Additionally, innovative targeted therapies provide newer salvage options to consider. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the complex decisionmaking associated with the management of recurrent Hodgkin lymphoma

In Vivo Fate Analysis Reveals the Multipotent and Self-Renewal Features of Embryonic AspM Expressing Cells

Radial Glia (RG) cells constitute the major population of neural progenitors of the mouse developing brain. These cells are located in the ventricular zone (VZ) of the cerebral cortex and during neurogenesis they support the generation of cortical neurons. Later on, during brain maturation, RG cells give raise to glial cells and supply the adult mouse brain of Neural Stem Cells (NSC). Here we used a novel transgenic mouse line expressing the CreERT2 under the control of AspM promoter to monitor the progeny of an early cohort of RG cells during neurogenesis and in the post natal brain. Long term fate mapping experiments demonstrated that AspM-expressing RG cells are multi-potent, as they can generate neurons, astrocytes and oligodendrocytes of the adult mouse brain. Furthermore, AspM descendants give also rise to proliferating progenitors in germinal niches of both developing and post natal brains. In the latter –i.e. the Sub Ventricular Zone- AspM descendants acquired several feature of neural stem cells, including the capability to generate neurospheres in vitro. We also performed the selective killing of these early progenitors by using a Nestin-GFPflox-TK allele. The forebrain specific loss of early AspM expressing cells caused the elimination of most of the proliferating cells of brain, a severe derangement of the ventricular zone architecture, and the impairment of the cortical lamination. We further demonstrated that AspM is expressed by proliferating cells of the adult mouse SVZ that can generate neuroblasts fated to become olfactory bulb neurons

Evidence for Extended Hydrogen-Poor CSM in the Three-Peaked Light Curve of Stripped Envelope Ib Supernova

We present multi-band ATLAS photometry for SN 2019tsf, a stripped-envelope Type Ib supernova (SESN). The SN shows a triple-peaked light curve and a late (re-)brightening, making it unique among stripped-envelope systems. The re-brightening observations represent the latest photometric measurements of a multi-peaked Type Ib SN to date. As late-time photometry and spectroscopy suggest no hydrogen, the potential circumstellar material (CSM) must be H-poor. Moreover, late (>150 days) spectra show no signs of narrow emission lines, further disfavouring CSM interaction. On the contrary, an extended CSM structure is seen through a follow-up radio campaign with Karl G. Jansky Very Large Array (VLA), indicating a source of bright optically thick radio emission at late times, which is highly unusual among H-poor SESNe. We attribute this phenomenology to an interaction of the supernova ejecta with spherically-asymmetric CSM, potentially disk-like, and we present several models that can potentially explain the origin of this rare Type Ib supernova. The warped disc model paints a novel picture, where the tertiary companion perturbs the progenitors CSM, that can explain the multi-peaked light curves of SNe, and here we apply it to SN 2019tsf. This SN 2019tsf is likely a member of a new sub-class of Type Ib SNe and among the recently discovered class of SNe that undergo mass transfer at the moment of explosionComment: 23 pages, Comments are welcome, Submitted to Ap