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Blake T Riley, Olga Ilyichova, Mauricio G S Costa, Benjamin T Porebski, Simon J de Veer, Joakim E Swedberg, Itamar Kass, Jonathan M Harris, David E Hoke, Ashley M Buckle
The kallikrein-related peptidase (KLK) family of proteases is involved in many aspects of human health and disease. One member of this family, KLK4, has been implicated in cancer development and metastasis. Understanding mechanisms of inactivation are critical to developing selective KLK4 inhibitors. We have determined the X-ray crystal structures of KLK4 in complex with both sunflower trypsin inhibitor-1 (SFTI-1) and a rationally designed SFTI-1 derivative to atomic (~1 Å) resolution, as well as with bound nickel...
October 21, 2016: Scientific Reports
Jeffrey T Ehmsen, Yong Liu, Yue Wang, Nikhil Paladugu, Anna E Johnson, Jeffrey D Rothstein, Sascha du Lac, Mark P Mattson, Ahmet Höke
SLC7A10 (Asc-1) is a sodium-independent amino acid transporter known to facilitate transport of a number of amino acids including glycine, L-serine, L-alanine, and L-cysteine, as well as their D-enantiomers. It has been described as a neuronal transporter with a primary role related to modulation of excitatory glutamatergic neurotransmission. We find that SLC7A10 is substantially enriched in a subset of astrocytes of the caudal brain and spinal cord in a distribution corresponding with high densities of glycinergic inhibitory synapses...
October 19, 2016: Scientific Reports
Maria C Bewley, Lisa Reinhart, Matthew S Stake, Shorena Nadaraia-Hoke, Leslie J Parent, John M Flanagan
HIV Gag, a multidomain polyprotein that orchestrates the assembly and release of the human immunodeficiency virus (HIV), is an active target of antiretroviral inhibitor development. However, highly pure, stable, recombinant Gag has been difficult to produce in quantities sufficient for biophysical studies due to its susceptibility to proteolysis by cellular proteases during purification. Stability has been improved by using a construct that omits the p6 domain (deltap6Gag). Since in vivo, p6 is crucial to the budding process and interacts with protein complexes in the ESCRT pathway, it has been difficult to study its role the context of Gag using in vitro approaches...
October 6, 2016: Protein Expression and Purification
Stephen J Bonasera, Jyothi Arikkath, Michael D Boska, Tammy R Chaudoin, Nicholas W DeKorver, Evan H Goulding, Traci A Hoke, Vahid Mojtahedzedah, Crystal D Reyelts, Balasrinivasa Sajja, A Katrin Schenk, Laurence H Tecott, Tiffany A Volden
We describe age-related molecular and neuronal changes that disrupt mobility or energy balance based on brain region and genetic background. Compared to young mice, aged C57BL/6 mice exhibit marked locomotor (but not energy balance) impairments. In contrast, aged BALB mice exhibit marked energy balance (but not locomotor) impairments. Age-related changes in cerebellar or hypothalamic gene expression accompany these phenotypes. Aging evokes upregulation of immune pattern recognition receptors and cell adhesion molecules...
September 20, 2016: Aging
T Wesley Templeton, Lauren K Hoke, Jill Yaung, Carol A Aschenbrenner, Danielle M Rose, Leah B Templeton, Yvon F Bryan
STUDY OBJECTIVE: To determine quantitative differences in several routinely measured ventilation parameters using a standardized anesthetic technique and 3 different ventilation modalities in pediatric patients with a ProSeal laryngeal mask airway (PLMA). DESIGN: Randomized prospective study. SETTING: Pediatric hospital of a tertiary care academic medical center. PATIENTS: Thirty-three, American Society of Anesthesiologists classification 1-2, pediatric patients (12 months to 5 years)...
November 2016: Journal of Clinical Anesthesia
T P Hoke, B Vakili, H Goldstein, E K Saks
No abstract text is available yet for this article.
November 2015: Journal of Minimally Invasive Gynecology
Martín O Pereyra, Molly C Womack, J Sebastián Barrionuevo, Boris L Blotto, Diego Baldo, Mariane Targino, Jhon Jairo Ospina-Sarria, Juan M Guayasamin, Luis A Coloma, Kim L Hoke, Taran Grant, Julián Faivovich
Most anurans possess a tympanic middle ear (TME) that transmits sound waves to the inner ear; however, numerous species lack some or all TME components. To understand the evolution of these structures, we undertook a comprehensive assessment of their occurrence across anurans and performed ancestral character state reconstructions. Our analysis indicates that the TME was completely lost at least 38 independent times in Anura. The inferred evolutionary history of the TME is exceptionally complex in true toads (Bufonidae), where it was lost in the most recent common ancestor, preceding a radiation of >150 earless species...
September 28, 2016: Scientific Reports
Benjamin T Porebski, Shani Keleher, Jeffrey J Hollins, Adrian A Nickson, Emilia M Marijanovic, Natalie A Borg, Mauricio G S Costa, Mary A Pearce, Weiwen Dai, Liguang Zhu, James A Irving, David E Hoke, Itamar Kass, James C Whisstock, Stephen P Bottomley, Geoffrey I Webb, Sheena McGowan, Ashley M Buckle
The rugged folding landscapes of functional proteins puts them at risk of misfolding and aggregation. Serine protease inhibitors, or serpins, are paradigms for this delicate balance between function and misfolding. Serpins exist in a metastable state that undergoes a major conformational change in order to inhibit proteases. However, conformational labiality of the native serpin fold renders them susceptible to misfolding, which underlies misfolding diseases such as α1-antitrypsin deficiency. To investigate how serpins balance function and folding, we used consensus design to create conserpin, a synthetic serpin that folds reversibly, is functional, thermostable, and polymerization resistant...
September 26, 2016: Scientific Reports
Saumya Tiwari, Jai Raman, Vijaya Reddy, Andrew Ghetler, Richard P Tella, Yang Han, Christopher R Moon, Charles D Hoke, Rohit Bhargava
Fourier transform infrared (FT-IR) spectroscopic imaging has been widely tested as a tool for stainless digital histology of biomedical specimens, including for the identification of infiltration and fibrosis in endomyocardial biopsy samples to assess transplant rejection. A major barrier in clinical translation has been the slow speed of imaging. To address this need, we tested and report here the viability of using high speed discrete frequency infrared (DFIR) imaging to obtain stain-free biochemical imaging in cardiovascular samples collected from patients...
October 18, 2016: Analytical Chemistry
W Blum, B L Sanford, R Klisovic, D J DeAngelo, G Uy, B L Powell, W Stock, M R Baer, J E Kolitz, E S Wang, E Hoke, K Mrózek, J Kohlschmidt, C D Bloomfield, S Geyer, G Marcucci, R M Stone, R A Larson
In this prospective phase 2 clinical trial conducted by Cancer and Leukemia Group B (CALGB, now the Alliance), we studied decitabine as maintenance therapy for younger adults with acute myeloid leukemia (AML) who remained in first complete remission (CR1) following intensive induction and consolidation. Given that decitabine is clinically active in AML and with hypomethylating activity distinct from cytotoxic chemotherapy, we hypothesized that 1 year of maintenance therapy would improve disease-free survival (DFS) for AML patients <60 years, who did not receive allogeneic stem cell transplantation in CR1...
October 7, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Aafke C van der Heijden, Ulas Höke, Joep Thijssen, C Jan Willem Borleffs, Ron Wolterbeek, Martin J Schalij, Lieselot van Erven
Super-response to cardiac resynchronization therapy (CRT) is associated with significant left ventricular (LV) reverse remodeling and improved clinical outcome. The study aimed to: (1) evaluate whether LV reverse remodeling remains sustained during long-term follow-up in super-responders and (2) analyze the association between the course of LV reverse remodeling and ventricular arrhythmias. Of all, primary prevention super-responders to CRT were selected. Super-response was defined as LV end-systolic volume reduction of ≥30% 6 months after device implantation...
October 15, 2016: American Journal of Cardiology
Benjamin T Porebski, Paul J Conroy, Nyssa Drinkwater, Peter Schofield, Rodrigo Vazquez-Lombardi, Morag R Hunter, David E Hoke, Daniel Christ, Sheena McGowan, Ashley M Buckle
The favorable biophysical attributes of non-antibody scaffolds make them attractive alternatives to monoclonal antibodies. However, due to the well-known stability-function trade-off, these gains tend to be marginal after functional selection. A notable example is the fibronectin Type III (FN3) domain, FNfn10, which has been previously evolved to bind lysozyme with 1 pM affinity (FNfn10-α-lys), but suffers from poor thermodynamic and kinetic stability. To explore this stability-function compromise further, we grafted the lysozyme-binding loops from FNfn10-α-lys onto our previously engineered, ultra-stable FN3 scaffold, FN3con The resulting variant (FN3con-α-lys) bound lysozyme with a markedly reduced affinity, but retained high levels of thermal stability...
August 29, 2016: Protein Engineering, Design & Selection: PEDS
Molly C Womack, Jakob Christensen-Dalsgaard, Kim L Hoke
Most vertebrates have evolved a tympanic middle ear that enables effective hearing of airborne sound on land. Although inner ears develop during the tadpole stages of toads, tympanic middle ear structures are not complete until months after metamorphosis, potentially limiting the sensitivity of post-metamorphic juveniles to sounds in their environment. We tested the hearing of five species of toads to determine how delayed ear development impairs airborne auditory sensitivity. We performed auditory brainstem recordings to test the hearing of the toads and used micro-CT and histology to relate the development of ear structures to hearing ability...
August 12, 2016: Journal of Experimental Biology
Aarti Gautam, Raina Kumar, George Dimitrov, Allison Hoke, Rasha Hammamieh, Marti Jett
miRNAs act as important regulators of gene expression by promoting mRNA degradation or by attenuating protein translation. Since miRNAs are stably expressed in bodily fluids, there is growing interest in profiling these miRNAs, as it is minimally invasive and cost-effective as a diagnostic matrix. A technical hurdle in studying miRNA dynamics is the ability to reliably extract miRNA as small sample volumes and low RNA abundance create challenges for extraction and downstream applications. The purpose of this study was to develop a pipeline for the recovery of miRNA using small volumes of archived serum samples...
October 2016: Molecular Biology Reports
B Kern, J D Budihardjo, S Mermulla, A Quan, C Cadmi, J Lopez, M Khusheim, S Xiang, J Park, G J Furtmüller, K A Sarhane, S Schneeberger, W P A Lee, A Hoke, S Tuffaha, G Brandacher
Improved nerve regeneration and functional outcomes would greatly enhance the utility of vascularized composite allotransplantation (VCA) such as hand and upper extremity transplantation. However, research aimed at achieving this goal has been limited by the lack of a functional VCA animal model. We have developed a novel rat mid-humeral forelimb transplant model that allows for the characterization of upper extremity functional recovery following transplantation. At the final end-point of 12 weeks, we found that animals with forelimb transplantation including median, ulnar, and radial nerve coaptation demonstrated significantly improved grip strength (1...
August 8, 2016: American Journal of Transplantation
J Samuel Zigler, Colin A Hodgkinson, Megan Wright, Andrew Klise, Olof Sundin, Karl W Broman, Fielding Hejtmancik, Hao Huang, Bonnie Patek, Yuri Sergeev, Stacey Hose, Cory Brayton, Jiao Xaiodong, David Vasquez, Nicholas Maragakis, Susumu Mori, David Goldman, Ahmet Hoke, Debasish Sinha
A novel mutation, causing a phenotype we named frogleg because its most obvious characteristic is a severe splaying of the hind limbs, arose spontaneously in a colony of Sprague-Dawley rats. Frogleg is a complex phenotype that includes abnormalities in hind limb function, reduced brain weight with dilated ventricles and infertility. Using micro-satellite markers spanning the entire rat genome, the mutation was mapped to a region of rat chromosome 1 between D1Rat131 and D1Rat287. Analysis of whole genome sequencing data within the linkage interval, identified a missense mutation in the branched-chain alpha-keto dehydrogenase kinase (Bckdk) gene...
2016: PloS One
Nicole Hoke, Christine Bradway
: Postoperative urinary retention (POUR) is the inability to void when the bladder is full after surgery. It is a common complication in postoperative patients, especially in patients undergoing spinal surgery. At our institution, patients who were discharged from the postanesthesia care unit (PACU) to the inpatient surgical unit typically had bladder distention and a bladder volume of more than 450 mL. In an effort to address this situation, an interprofessional group of advanced practice RNs and physicians formed a team, reviewed the existing literature, examined the PACU nursing practice guideline for evaluating and managing POUR, and devised a quality improvement (QI) project to raise the PACU nursing staff's awareness of the potential for POUR among postoperative patients and to develop an updated nursing practice algorithm for the evaluation and management of POUR in spinal surgery patients...
August 2016: American Journal of Nursing
Tae Chung, Jae Sung Park, Sangri Kim, Nataly Montes, Jeremy Walston, Ahmet Höke
INTRODUCTION: Age-associated muscle strength decline is a major contributing factor to increased late life functional decline and co-morbidity, and is strongly associated with early mortality. Although all parts of the neuromuscular system seem to be affected by aging, dying-back of motor axons likely plays a major role. METHODS: We compared the degeneration in ventral roots and NMJ denervation in young and aged mice and correlated the findings with strength and electrophysiological measures...
July 27, 2016: Muscle & Nerve
Jami L Scheib, Ahmet Höke
Although peripheral nerves are capable of regeneration, advanced age decreases the potential for functional recovery after injury. The cellular mechanisms for this are not currently understood. Here, we performed sciatic nerve grafting with young (2 months old) and aged (18 months old) Brown-Norway male rats, in which 1 cm nerve grafts from young or aged rats were sutured into nerves of young or aged rats. Axons were allowed to regenerate until the nerve grafts and distal nerves were harvested at 1, 3, and 7 days and 2 and 6 weeks...
September 2016: Neurobiology of Aging
Jami Scheib, Ahmet Höke
Although many observational studies have shown that peripheral nerve regeneration is impaired with aging, underlying cellular and molecular mechanisms have remained obscure until recently. A series of recent genetic, live imaging and heterochronic parabiosis experiments are providing new insights into the underlying mechanisms of reduced regenerative capacity with aging. These studies show that Schwann cells in the aged animal pose a primary impediment to axon regeneration in older animals as they fail to support regenerating axons, while the contribution from macrophages remains an unresolved issue...
July 20, 2016: Experimental Neurology
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