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Full-Text Articles in Medicine and Health Sciences
An Intramolecular Association Between Two Domains Of The Protein Kinase Fused Is Necessary For Hedgehog Signaling, Manuel Ascano Jr., David J. Robbins
An Intramolecular Association Between Two Domains Of The Protein Kinase Fused Is Necessary For Hedgehog Signaling, Manuel Ascano Jr., David J. Robbins
Dartmouth Scholarship
The protein kinase Fused (Fu) is an integral member of the Hedgehog (Hh) signaling pathway. Although genetic studies demonstrate that Fu is required for the regulation of the Hh pathway, the mechanistic role that it plays remains largely unknown. Given our difficulty in developing an in vitro kinase assay for Fu, we reasoned that the catalytic activity of Fu might be highly regulated. Several mechanisms are known to regulate protein kinases, including self-association in either an intra- or an intermolecular fashion. Here, we provide evidence that Hh regulates Fu through intramolecular association between its kinase domain (ΔFu) and its carboxyl-terminal …
A Vibrio Cholerae Classical Tcpa Amino Acid Sequence Induces Protective Antibody That Binds An Area Hypothesized To Be Important For Toxin-Coregulated Pilus Structure, Ronald K. Taylor, Thomas J. Kirn, Michael D. Meeks, Terri K. Wade, William F. Wade
A Vibrio Cholerae Classical Tcpa Amino Acid Sequence Induces Protective Antibody That Binds An Area Hypothesized To Be Important For Toxin-Coregulated Pilus Structure, Ronald K. Taylor, Thomas J. Kirn, Michael D. Meeks, Terri K. Wade, William F. Wade
Dartmouth Scholarship
Vibrio cholerae is a gram-negative bacterium that has been associated with cholera pandemics since the early 1800s. Whole-cell, killed, and live-attenuated oral cholera vaccines are in use. We and others have focused on the development of a subunit cholera vaccine that features standardized epitopes from various V. cholerae macromolecules that are known to induce protective antibody responses. TcpA protein is assembled into toxin-coregulated pilus (TCP), a type IVb pilus required for V. cholerae colonization, and thus is a strong candidate for a cholera subunit vaccine. Polypeptides (24 to 26 amino acids) in TcpA that can induce protective antibody responses have …
Binding Between The Niemann–Pick C1 Protein And A Photoactivatable Cholesterol Analog Requires A Functional Sterol-Sensing Domain, Nobutaka Ohgami, Dennis C. Ko, Matthew Thomas, Matthew P. Scott, Catherine C. Y. Chang, Ta-Yuan Chang
Binding Between The Niemann–Pick C1 Protein And A Photoactivatable Cholesterol Analog Requires A Functional Sterol-Sensing Domain, Nobutaka Ohgami, Dennis C. Ko, Matthew Thomas, Matthew P. Scott, Catherine C. Y. Chang, Ta-Yuan Chang
Dartmouth Scholarship
Niemann-Pick type C (NPC) 1 protein plays important roles in moving cholesterol and other lipids out of late endosomes by means of vesicular trafficking, but it is not known whether NPC1 directly interacts with cholesterol. We performed photoaffinity labeling of intact cells expressing fluorescent protein (FP)-tagged NPC1 by using [(3)H]7,7-azocholestanol ([(3)H]AC). After immunoprecipitation, (3)H-labeled NPC1-GFP appeared as a single band. Including excess unlabeled sterol to the labeling reaction significantly diminished the labeling. Altering the NPC1 sterol-sensing domain (SSD) with loss-of-function mutations (P692S and Y635C) severely reduced the extent of labeling. To further demonstrate the specificity of labeling, we show that …
Sadb Is Required For The Transition From Reversible To Irreversible Attachment During Biofilm Formation By Pseudomonas Aeruginosa Pa14, Nicky C. Caiazza, George A. O'Toole
Sadb Is Required For The Transition From Reversible To Irreversible Attachment During Biofilm Formation By Pseudomonas Aeruginosa Pa14, Nicky C. Caiazza, George A. O'Toole
Dartmouth Scholarship
Current models of biofilm formation by Pseudomonas aeruginosa propose that (i) planktonic cells become surface associated in a monolayer, (ii) surface-associated cells form microcolonies by clonal growth and/or aggregation, (iii) microcolonies transition to a mature biofilm comprised of exopolysaccharide-encased macrocolonies, and (iv) cells exit the mature biofilm and reenter the planktonic state. Here we report a new class of P. aeruginosa biofilm mutant that defines the transition from reversible to irreversible attachment and is thus required for monolayer formation. The transposon insertion carried by the sadB199 mutant was mapped to open reading frame PA5346 of P. aeruginosa PA14 and encodes …
The Tumor Suppressor Lkb1 Kinase Directly Activates Amp-Activated Kinase And Regulates Apoptosis In Response To Energy Stress, Reuben J. Shaw, Monica Kosmatka, Nabeel Bardeesy, Rebecca L. Hurley, Lee A. Witters, Ronald A. Depinho, Lewis C. Cantley
The Tumor Suppressor Lkb1 Kinase Directly Activates Amp-Activated Kinase And Regulates Apoptosis In Response To Energy Stress, Reuben J. Shaw, Monica Kosmatka, Nabeel Bardeesy, Rebecca L. Hurley, Lee A. Witters, Ronald A. Depinho, Lewis C. Cantley
Dartmouth Scholarship
AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status found in all eukaryotic cells. AMPK is activated by stimuli that increase the cellular AMP/ATP ratio. Essential to activation of AMPK is its phosphorylation at Thr-172 by an upstream kinase, AMPKK, whose identity in mammalian cells has remained elusive. Here we present biochemical and genetic evidence indicating that the LKB1 serine/threonine kinase, the gene inactivated in the Peutz-Jeghers familial cancer syndrome, is the dominant regulator of AMPK activation in several mammalian cell types. We show that LKB1 directly phosphorylates Thr-172 of AMPKalpha in vitro and activates its …
The Pharmacokinetics Of Nebulized Nanocrystal Budesonide Suspension In Healthy Volunteers., Walter Kraft, Barry Steiger, Don Beussink, John N. Quiring, Nancy Fitzgerald, Howard E. Greenberg, Scott A. Waldman
The Pharmacokinetics Of Nebulized Nanocrystal Budesonide Suspension In Healthy Volunteers., Walter Kraft, Barry Steiger, Don Beussink, John N. Quiring, Nancy Fitzgerald, Howard E. Greenberg, Scott A. Waldman
Department of Medicine Faculty Papers
Nanocrystal budesonide (nanobudesonide) is a suspension for nebulization in patients with steroid-responsive pulmonary diseases such as asthma. The pharmacokinetics and safety of the product were compared to those of Pulmicort Respules. Sixteen healthy volunteers were administered nanobudesonide 0.5 and 1.0 mg, Pulmicort Respules 0.5 mg, and placebo in a four-way, randomized crossover design. All nebulized formulations were well tolerated, with no evidence of bronchospasm. Nebulization times were significantly shorter for nanobudesonide compared to Pulmicort Respules. Because of a low oral bioavailability, plasma concentration of budesonide is a good marker of lung-delivered dose. The pharmacokinetics of nanobudesonide 0.5 and 1.0 mg …