Open Access. Powered by Scholars. Published by Universities.®
Articles 1 - 12 of 12
Full-Text Articles in Medicine and Health Sciences
The Sequence Dependent Nanoscale Structure Of Cenp-A Nucleosomes, Tommy Stormberg, Yuri L. Lyubchenko
The Sequence Dependent Nanoscale Structure Of Cenp-A Nucleosomes, Tommy Stormberg, Yuri L. Lyubchenko
Journal Articles: Pharmaceutical Sciences
CENP-A is a histone variant found in high abundance at the centromere in humans. At the centromere, this histone variant replaces the histone H3 found throughout the bulk chromatin. Additionally, the centromere comprises tandem repeats of α-satellite DNA, which CENP-A nucleosomes assemble upon. However, the effect of the DNA sequence on the nucleosome assembly and centromere formation remains poorly understood. Here, we investigated the structure of nucleosomes assembled with the CENP-A variant using Atomic Force Microscopy. We assembled both CENP-A nucleosomes and H3 nucleosomes on a DNA substrate containing an α-satellite motif and characterized their positioning and wrapping efficiency. We …
Patient-Derived Induced Pluripotent Stem Cell Models For Phenotypic Screening In The Neuronal Ceroid Lipofuscinoses, Ahmed Morsy, Angelica V. Carmona, Paul C. Trippier
Patient-Derived Induced Pluripotent Stem Cell Models For Phenotypic Screening In The Neuronal Ceroid Lipofuscinoses, Ahmed Morsy, Angelica V. Carmona, Paul C. Trippier
Journal Articles: Pharmaceutical Sciences
Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal, inherited neurodegenerative lysosomal storage disorders. Numerous genes (CLN1-CLN8, CLN10-CLN14) were identified in which mutations can lead to NCL; however, the underlying pathophysiology remains elusive. Despite this, the NCLs share some of the same features and symptoms but vary in respect to severity and onset of symptoms by age. Some common symptoms include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and in the rare adult-onset, dementia. Currently, all forms of NCL are fatal, and no curative treatments are available. Induced pluripotent stem …
Aldo-Keto Reductases And Cancer Drug Resistance, Trevor M. Penning, Sravan Jonnalagadda, Paul C. Trippier, Tea Lanišnik Rižner
Aldo-Keto Reductases And Cancer Drug Resistance, Trevor M. Penning, Sravan Jonnalagadda, Paul C. Trippier, Tea Lanišnik Rižner
Journal Articles: Pharmaceutical Sciences
Human aldo-keto reductases (AKRs) catalyze the NADPH-dependent reduction of carbonyl groups to alcohols for conjugation reactions to proceed. They are implicated in resistance to cancer chemotherapeutic agents either because they are directly involved in their metabolism or help eradicate the cellular stress created by these agents (e.g., reactive oxygen species and lipid peroxides). Furthermore, this cellular stress activates the Nuclear factor-erythroid 2 p45-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 pathway. As many human AKR genes are upregulated by the NRF2 transcription factor, this leads to a feed-forward mechanism to enhance drug resistance. Resistance to major classes of chemotherapeutic agents (anthracyclines, …
Direct Oral Anticoagulants For The Prevention Of Stroke In Patients With Nonvalvular Atrial Fibrillation: Understanding Differences And Similarities., Paul P. Dobesh, John Fanikos
Direct Oral Anticoagulants For The Prevention Of Stroke In Patients With Nonvalvular Atrial Fibrillation: Understanding Differences And Similarities., Paul P. Dobesh, John Fanikos
Journal Articles: Pharmacy Practice
The presence of atrial fibrillation (AF), the most common sustained cardiac arrhythmia, significantly increases the risk for stroke. Current guidelines recommend that the vitamin K antagonist warfarin or direct oral anticoagulants (DOACs), such as the approved direct thrombin inhibitor dabigatran and the approved direct factor Xa inhibitors apixaban, rivaroxaban, and edoxaban, should be used for thromboprophylaxis in patients with nonvalvular AF at risk for stroke or systemic embolic events (SEE). Warfarin, the mainstay of stroke prevention in AF, increases the risk of major bleeding. Furthermore, warfarin therapy comes with several limitations including frequent monitoring and the need for dose adjustments, …
Samhd1 Is A Single-Stranded Nucleic Acid Binding Protein With No Active Site-Associated Nuclease Activity., Kyle J. Seamon, Zhiqiang Sun, Luda S. Shlyakhtenko, Yuri L. Lyubchenko, James T. Stivers
Samhd1 Is A Single-Stranded Nucleic Acid Binding Protein With No Active Site-Associated Nuclease Activity., Kyle J. Seamon, Zhiqiang Sun, Luda S. Shlyakhtenko, Yuri L. Lyubchenko, James T. Stivers
Journal Articles: Pharmaceutical Sciences
The HIV-1 restriction factor SAMHD1 is a tetrameric enzyme activated by guanine nucleotides with dNTP triphosphate hydrolase activity (dNTPase). In addition to this established activity, there have been a series of conflicting reports as to whether the enzyme also possesses single-stranded DNA and/or RNA 3'-5' exonuclease activity. SAMHD1 was purified using three chromatography steps, over which the DNase activity was largely separated from the dNTPase activity, but the RNase activity persisted. Surprisingly, we found that catalytic and nucleotide activator site mutants of SAMHD1 with no dNTPase activity retained the exonuclease activities. Thus, the exonuclease activity cannot be associated with any …
New Oral Anticoagulants For The Treatment Of Venous Thromboembolism: Understanding Differences And Similarities., Paul P. Dobesh, John Fanikos
New Oral Anticoagulants For The Treatment Of Venous Thromboembolism: Understanding Differences And Similarities., Paul P. Dobesh, John Fanikos
Journal Articles: Pharmacy Practice
Venous thromboembolism (VTE) is a major cause of morbidity, mortality, and healthcare expenditure. In the United States, approximately 0.1 % of the population experiences an initial VTE event each year. Anticoagulation therapy is the cornerstone of acute VTE treatment and for prevention of recurrent VTE events. Conventional anticoagulants, including heparin, low-molecular-weight heparins, fondaparinux, and vitamin K antagonists are widely used but have limitations. Newer oral anticoagulant agents, including direct thrombin inhibitors (e.g., dabigatran etexilate) and direct factor Xa inhibitors (e.g., rivaroxaban, apixaban, and edoxaban) have been developed to attempt to overcome some of the limitations of conventional anticoagulant therapy. These …
Ticagrelor: Pharmacokinetics, Pharmacodynamics, Clinical Efficacy, And Safety., Paul P. Dobesh, Julie H. Oestreich
Ticagrelor: Pharmacokinetics, Pharmacodynamics, Clinical Efficacy, And Safety., Paul P. Dobesh, Julie H. Oestreich
Journal Articles: Pharmacy Practice
Dual antiplatelet therapy, composed of aspirin plus a P2Y12 -receptor antagonist, is the cornerstone of treatment for patients with acute coronary syndrome (ACS). A number of U.S. Food and Drug Administration-approved P2Y12 -receptor antagonists are available for treating patients with ACS, including the thienopyridine compounds clopidogrel and prasugrel. Ticagrelor, the first of a new class of antiplatelet agents, is a noncompetitive, direct-acting P2Y12 -receptor antagonist. Unlike the thienopyridine compounds, ticagrelor does not require metabolism for activity. Also, whereas clopidogrel and prasugrel are irreversible inhibitors of the P2Y12 receptor, ticagrelor binds reversibly to inhibit receptor signaling and subsequent platelet activation. In …
Clinical Use Of Rivaroxaban: Pharmacokinetic And Pharmacodynamic Rationale For Dosing Regimens In Different Indications., Toby Trujillo, Paul P. Dobesh
Clinical Use Of Rivaroxaban: Pharmacokinetic And Pharmacodynamic Rationale For Dosing Regimens In Different Indications., Toby Trujillo, Paul P. Dobesh
Journal Articles: Pharmacy Practice
Target-specific oral anticoagulants have become increasingly available as alternatives to traditional agents for the management of a number of thromboembolic disorders. To date, the direct Factor Xa inhibitor rivaroxaban is the most widely approved of the new agents. The dosing of rivaroxaban varies and adheres to specific schedules in each of the clinical settings in which it has been investigated. These regimens were devised based on the results of phase II dose-finding studies and/or pharmacokinetic modeling, and were demonstrated to be successful in randomized, phase III studies. In most cases, the pharmacodynamic profile of rivaroxaban permits once-daily dosing. A once-daily …
Mechanism Of Amyloid Β-Protein Dimerization Determined Using Single-Molecule Afm Force Spectroscopy., Zhengjian Lv, Robin Roychaudhuri, Margaret M Condron, David B. Teplow, Yuri L. Lyubchenko
Mechanism Of Amyloid Β-Protein Dimerization Determined Using Single-Molecule Afm Force Spectroscopy., Zhengjian Lv, Robin Roychaudhuri, Margaret M Condron, David B. Teplow, Yuri L. Lyubchenko
Journal Articles: Pharmaceutical Sciences
Aβ42 and Aβ40 are the two primary alloforms of human amyloid β-protein (Aβ). The two additional C-terminal residues of Aβ42 result in elevated neurotoxicity compared with Aβ40, but the molecular mechanism underlying this effect remains unclear. Here, we used single-molecule force microscopy to characterize interpeptide interactions for Aβ42 and Aβ40 and corresponding mutants. We discovered a dramatic difference in the interaction patterns of Aβ42 and Aβ40 monomers within dimers. Although the sequence difference between the two peptides is at the C-termini, the N-terminal segment plays a key role in the peptide interaction in the dimers. This is an unexpected finding …
Mechanism Of Amyloid Β-Protein Dimerization Determined Using Single-Molecule Afm Force Spectroscopy., Zhengjian Lv, Robin Roychaudhuri, Margaret M. Condron, David B. Teplow, Yuri L. Lyubchenko
Mechanism Of Amyloid Β-Protein Dimerization Determined Using Single-Molecule Afm Force Spectroscopy., Zhengjian Lv, Robin Roychaudhuri, Margaret M. Condron, David B. Teplow, Yuri L. Lyubchenko
Journal Articles: Pharmaceutical Sciences
Aβ42 and Aβ40 are the two primary alloforms of human amyloid β-protein (Aβ). The two additional C-terminal residues of Aβ42 result in elevated neurotoxicity compared with Aβ40, but the molecular mechanism underlying this effect remains unclear. Here, we used single-molecule force microscopy to characterize interpeptide interactions for Aβ42 and Aβ40 and corresponding mutants. We discovered a dramatic difference in the interaction patterns of Aβ42 and Aβ40 monomers within dimers. Although the sequence difference between the two peptides is at the C-termini, the N-terminal segment plays a key role in the peptide interaction in the dimers. This is an unexpected finding …
Effect Of Spermidine On Misfolding And Interactions Of Alpha-Synuclein., Alexey V. Krasnoslobodtsev, Jie Peng, Josephat M. Asiago, Jagadish Hindupur, Jean-Christophe Rochet, Yuri L. Lyubchenko
Effect Of Spermidine On Misfolding And Interactions Of Alpha-Synuclein., Alexey V. Krasnoslobodtsev, Jie Peng, Josephat M. Asiago, Jagadish Hindupur, Jean-Christophe Rochet, Yuri L. Lyubchenko
Journal Articles: Pharmaceutical Sciences
Alpha-synuclein (α-Syn) is a 140 aa presynaptic protein which belongs to a group of natively unfolded proteins that are unstructured in aqueous solutions. The aggregation rate of α-Syn is accelerated in the presence of physiological levels of cellular polyamines. Here we applied single molecule AFM force spectroscopy to characterize the effect of spermidine on the very first stages of α-Syn aggregation--misfolding and assembly into dimers. Two α-Syn variants, the wild-type (WT) protein and A30P, were studied. The two protein molecules were covalently immobilized at the C-terminus, one at the AFM tip and the other on the substrate, and intermolecular interactions …
Triplet Repeat Dna Structures And Human Genetic Disease: Dynamic Mutations From Dynamic Dna., Richard R. Sinden, Vladimir N. Potaman, Elena A. Oussatcheva, Christopher E. Pearson, Yuri L. Lyubchenko, Luda S. Shlyakhtenko
Triplet Repeat Dna Structures And Human Genetic Disease: Dynamic Mutations From Dynamic Dna., Richard R. Sinden, Vladimir N. Potaman, Elena A. Oussatcheva, Christopher E. Pearson, Yuri L. Lyubchenko, Luda S. Shlyakhtenko
Journal Articles: Pharmaceutical Sciences
Fourteen genetic neurodegenerative diseases and three fragile sites have been associated with the expansion of (CTG)n (CAG)n, (CGG)n (CCG)n, or (GAA)n (TTC)n repeat tracts. Different models have been proposed for the expansion of triplet repeats, most of which presume the formation of alternative DNA structures in repeat tracts. One of the most likely structures, slipped strand DNA, may stably and reproducibly form within triplet repeat sequences. The propensity to form slipped strand DNA is proportional to the length and homogeneity of the repeat tract. The remarkable stability of slipped strand DNA may, in part, be due to loop-loop interactions facilitated …