8,231 research outputs found
Chapter 04: Strengthening Medical Oncology at MD Anderson with the Aid of NCI Researchers in the Department of Biostatistics
No full textDr. Gehan recollects Dr. R. Lee Clark’s approach to funding, recruitment, and management and the attraction of MD Anderson/Houston to Dr. “Tom” Frei III, his wife Elizabeth “Liz” (nee Smith), as well as himself. Dr. Olson mentions from Kenneth Endicott (NCI Director) to Dr. R. Lee Clark (President, MD Anderson) lamenting the move of Dr’s Frei III and Freireich to MD Anderson. When Dr. Gehan started at MD Anderson in 1967, Dr. Lee D. Cady Jr. was the Head of the Department of Biomathematics. Dr. Gehan talks about the impact of the arrival of Dr’s Frei III and Freireich on MD Anderson Research. Dr. Gehan cites the cooperative group collaboration model of NCI/NIH Clinical Chairman Dr. C. Gordon Zubrod and biostatistician Marvin A. Schneiderman on the first randomized trials in acute leukemia and solid tumors. He recalls the members of the administration and the research team at MD Anderson before the arrival of Dr’s Frei III and Freireich: Dr. H. Grant Taylor, Chairman of the Southwest Oncology Group (Southwest Oncology Group), epidemiologist Eleanor Josephine McDonald (known for creating the National Cancer Registry) statistician Kenneth M. Griffith, Dr. Roy C. Heflebower, Joe E. Boyd and Dr. Stuart O. Zimmerman, Chairman of the Biomathematics Department. He also mentions other MD Anderson administrators and researchers: Terry L. Smith, Dr. Peter F. Thall, Dr. J. Jack Lee, President Dr. Charles A. LeMaistre, Dr. Frederick F. Becker and President Dr. John Mendelsohn. Finally, he talks about the Department of Biostatistics, how it differs from Biomathematics, and the effort to strengthen medical oncology at MD Anderson.https://openworks.mdanderson.org/mchv_interviewchapters/1313/thumbnail.jp
Measurement of the B0–B0 oscillation frequency Δmd with the decays B0→D−π+ and B0→ J/ψK∗0
No full textThe B
0
–B
0
oscillation frequency Δmd is measured by the LHCb experiment using a dataset corresponding
to an integrated luminosity of 1.0 fb−1
of proton–proton collisions at √
s = 7 TeV, and is found to be
Δmd
=0.5156±0.0051 (stat.)±0.0033 (syst.) ps−1
. The measurement is based on results from analyses
of the decays B
0
→ D
−π
+ (D
−
→ K
+π
−π
−) and B
0
→ J/ψK
∗0
(J/ψ →μ
+μ
−,K
∗0
→ K
+π
−) and
their charge conjugated modes
Joel Glaser, MD: A Scholar\u27s Scholar
No full textJoel Glaser, MD is considered one of the great scholars of neuro-ophthalmology. His published contributions touch nearly every aspect of the field. The principal author of the highly respected textbook Neuro-Ophthalmology, he has trained over 50 fellows who occupy important academic positions across the planet.curriculum_fellow; IC-H1-history-of-neuro-ophthalmolog
Clark, Rebecca (Death, 1874-07-16)
No full textAddress: 63 George St.Age at death: 24 yrsPg 119/337/1874/F W M/Md./Dr. D McCarthy/Sullivan/St.Joseph'sOriginal record filed in drawer labeled 'CLARK, N.-COHEN'
Supplemental Data for A Phase II Study of Talazoparib Tosylate in Advanced Cancer Patients with Somatic and Germline (Not Breast or Ovarian Cancer) Alterations of BRCA1/2, Mutations/Deletions/Amplification in Other Homologous Recombination Repair Pathway Genes and PTEN or PTEN loss
No full textThe de-identified participant data and dataset generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Custom code that was used in the generation or analysis of the datasets is available upon reasonable request.
Corresponding Author: Sarina Piha-Paul,Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, TX. Phone: (713)-563-1055, Fax:(713)-792-3535, [email protected]://openworks.mdanderson.org/ict/1000/thumbnail.jp
Structural mechanisms of class B GPCR signaling: the case of the parathyroid hormone receptor
No full textThe parathyroid hormone (PTH) type 1 receptor (PTHR), a class B G protein-coupled receptor (GPCR), is the key regulator of bone turnover and mineral ion homeostasis. A thorough understanding of the structural mechanisms of PTHR function is necessary to develop therapeutics for bone and mineral disorders (e.g., osteoporosis). To further this aim, we used an interdisciplinary approach, which included cryo-EM, NMR spectroscopy, and MD simulations to investigate several steps in the PTHR signaling pathway: ligand binding, receptor activation, coupling to effector proteins, and termination of signaling.
We solved high-resolution cryo-EM structures of PTHR in complex with the stimulatory G protein (Gs) for adenylyl cyclases and a long-acting PTH analog (LA-PTH). These structures provide insights into the mechanism of PTHR activation. We also sought determine how LA-PTH triggers prolonged sustained cAMP signaling in endosomes compared to PTH. In MD simulations, the N-terminal part of LA-PTH makes more contacts with PTHR in comparison to PTH. Therefore, LA-PTH remains bound to active receptor despite endosomal acidification, which destabilizes interactions between PTHR and the C-terminal part of the ligand. Next, we probed the mechanism of PTH binding to PTHR. Our results show that initial binding of the PTH C-terminal part to PTHRECD during the first step reduces the mobility of the PTH N-terminal part, which primes the N-terminal part to interact with the receptor transmembrane domain during the second step.
An allosteric link between PTHR interactions with the PTH N-terminal part and receptor coupling to intracellular effectors was demonstrated through the investigation of two PTH mutations, His9->Ala9 (PTHH9A) Leu7 L->D (PTH7d), which inhibit β-arrestin coupling through distinct mechanisms, leading to transient and sustained cAMP production at the plasma membrane, respectively. PTHH9A promotes an inward conformation of receptor intracellular loop 3 to prevent interactions with β-arrestin’s finger loop. PTH7d enhances a receptor polar network stabilizing an outward kink of the intracellular part of transmembrane helix 6 (TM6), which prevents the inward TM6 movement necessary for β-arrestin coupling. In total, our results likely extend to other class B GPCRs and provide a structural framework for drug design targeting bone and mineral disorders
Intrinsic versus mutation dependent instability/flexibility: A comparative analysis of the structure and dynamics of wild-type transthyretin and its pathogenic variants
No full textTransthyretin (TTR) is one of the about 20 known human proteins associated with amyloidosis which is characterized by the accumulation of amyloid fibrils in tissues or extracellular matrix surrounding vital organs. Unlike Alzheimer\u27s fibrils that comprise a fragment of a large precursor protein, TTR amyloid fibrils are composed of both full-length protein and fragments of the molecule. The native state of TTR is a homotetramer with eight β-strands organized into a β-sandwich in each monomer. To elucidate the structural reorganization mechanisms preceding amyloid formation, it is important to characterize the dynamic features of the wild-type native state as well as to reveal the influence of disease-associated mutations on the structure and dynamics. Molecular dynamics (MD) simulations complement X-ray crystallography and D-H exchange to capture the intrinsically unstable/flexible sites of the wild-type as well as the mutation dependent unstable sites of the pathogenic variants. Our results of MD simulations have shown that the Leu55 → Pro (L55P) mutation occurs in an intrinsically unstable site, leading to substantial local and global structural changes. This observation supports the early speculation that the C-strand-loop-D-strand rearrangement leads to the formation of amyloidogenic intermediates. In addition to the D strand, the α-helical region and the strands at the monomer-monomer interface are also intrinsically unstable. The central channel of L55P-TTR undergoes opening and closing fluctuations, which may provide an explanation for the fact that while the mutation is far from the channel, the mutant shows a substantial low binding affinity of thyroxine. © 2004 Elsevier Inc. All rights reserved
MS002: R. Lee Clark and Three Other Men Viewing a Cobalt-60 Iradiator
No full textR. Lee Clark and three other men viewing M. D. Anderson Hospital\u27s Cobalt-60 Iradiator. See more at Ernst William Bertner, MD Papers and its finding aid.https://digitalcommons.library.tmc.edu/bertner/1012/thumbnail.jp
The disordered negatively charged C-terminus of the large HECT E3 ubiquitin ligase HERC2 provides structural and thermal stability to the HECT C-lobe
No full textHomologous to the C-terminus of E6AP (HECT) and RCC1-like domain (RLD)-containing protein 2 (HERC2) is a large, 528 kDa E3 ubiquitin ligase that is associated with cancer, oculocutaneous albanism type 2, Prader-Willi syndrome, and other neurological diseases. HERC2 has been found to contribute to double-stranded DNA break repairs, tumor suppression, maintaining centrosome architecture, and ubiquitylation. The C-terminal portion of the HECT domain (C-lobe) of HERC2 is responsible for transferring ubiquitin to a substrate but the precise function of the other eight domains in HERC2 are unknown. Interestingly, HERC2 contains a unique and negatively charged C-terminal tail adjoined to the C-lobe that is predicted to act as a linker to promote interactions between HERC2 and its binding partners. This study aims to better understand the function and relevance of HERC2 in disease by investigating the structural aspects of the HERC2 C-lobe and HERC2 C-terminal tail using AlphaFold followed by molecular dynamics (MD) simulations, multidimensional nuclear magnetic resonance (NMR), and circular dichroism (CD). Secondary structure content analysis from MD simulations and the fully resonance assigned 1H-15N HSQC spectra of the HERC2 C-lobe and the isolated C-terminal tail confirm that the C-lobe is well-folded but the C-terminal tail is disordered. CD melting curves indicate that the flexible C-terminal tail provides improved stability to the C-lobe. Additionally, MD simulations have identified that the interaction between residues D4829 and R4728 is prevalent among the non-bonded contacts between the tail and the C-lobe. Overall, our results demonstrate that the negatively charged C-terminal tail is disordered, provides stability to the C-lobe, and may act as a flexible scaffold for protein–protein interactions
The sequence-dependent unfolding pathway plays a critical role in the amyloidogenicity of transthyretin
No full textHuman transthyretin (TTR) is an amyloidogenic protein whose aggregation is associated with several types of amyloid diseases. The following mechanism of TTR amyloid formation has been proposed. TTR tetramer at first dissociates into native monomers, which is the rate-limiting step in fibril formation. The monomeric species then partially unfold to form amyloidogenic intermediates that subsequently undergo a downhill self-assembly process. The amyloid deposit can be facilitated by disease-associated point mutations. However, only subtle structural differences were observed between the crystal structures of the wild type and the disease-associated variants. To investigate how single-point mutations influence the effective energy landscapes of TTR monomers, molecular dynamics (MD) simulations were performed on wild-type TTR and two pathogenic variants. Principal coordinate analysis on MD-generated ensembles has revealed multiple unfolding pathways for each protein. Amyloidogenic intermediates with the dislocated C strand-loop-D strand motif were observed only on the unfolding pathways of V30M and L55P variants and not for wild-type TTR. Our study suggests that the sequence-dependent unfolding pathway plays a crucial role in the amyloidogenicity of TTR. Analyses of side chain concerted motions indicate that pathogenic mutations on edge strands disrupt the delicate side chain correlated motions, which in turn may alter the sequence of unfolding events. © 2006 American Chemical Society
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