Trkb-Enhancer Facilitates Functional Recovery After Traumatic Brain Injury,
2017
Brown University
Trkb-Enhancer Facilitates Functional Recovery After Traumatic Brain Injury, John Marshall, Joanna Szmydynger-Chodobska, Mengia S. Rioult-Pedotti, Kara Lau, Andrea T. Chin, Siva K. Reddy Kotla, Rakesh Tiwari, Keykavous Parang, Steven W. Threlkeld, Adam Chodobski
Pharmacy Faculty Articles and Research
Brain-derived neurotrophic factor (BDNF), a key player in regulating synaptic strength and learning, is dysregulated following traumatic brain injury (TBI), suggesting that stimulation of BDNF signaling pathways may facilitate functional recovery. This study investigates whether CN2097, a peptidomimetic ligand which targets the synaptic scaffold protein, postsynaptic density protein 95, to enhance downstream signaling of tropomyosin-related kinase B, a receptor for BDNF, can improve neurological function after TBI. Moderate to severe TBI elicits neuroinflammation and c-Jun-N-terminal kinase (JNK) activation, which is associated with memory deficits. Here we demonstrate that CN2097 significantly reduces the post-traumatic synthesis of proinflammatory mediators and inhibits the …
Improving The Thermal Stability Of Cellobiohydrolase Cel7a From Hypocrea Jecorina By Directed Evolution,
2017
DuPont Industrial Biosciences, The Netherlands
Improving The Thermal Stability Of Cellobiohydrolase Cel7a From Hypocrea Jecorina By Directed Evolution, Frits Goedegebuur, Lydia Dankmeyer, Peter Gualfetti, Saeid Karkehabadi, Henrik Hansson, Suvamay Jana, Vicky Huynh, Bradley R. Kelemen, Paulien Kruithof, Edmund A. Larenas, Pauline J. M. Teunissen, Jerry Ståhlberg, Christina M. Payne, Colin Mitchinson, Mats Sandgren
Chemical and Materials Engineering Faculty Publications
Secreted mixtures of Hypocrea jecorina cellulases are able to efficiently degrade cellulosic biomass to fermentable sugars at large, commercially relevant scales. H. jecorina Cel7A, cellobiohydrolase I, from glycoside hydrolase family 7, is the workhorse enzyme of the process. However, the thermal stability of Cel7A limits its use to processes where temperatures are no higher than 50 °C. Enhanced thermal stability is desirable to enable the use of higher processing temperatures and to improve the economic feasibility of industrial biomass conversion. Here, we enhanced the thermal stability of Cel7A through directed evolution. Sites with increased thermal stability properties were combined, and …
Translational Fidelity, Mistranslation, And The Cellular Responses To Stress,
2017
The Ohio State University
Translational Fidelity, Mistranslation, And The Cellular Responses To Stress, Kyle Mohler, Michael Ibba
Biology, Chemistry, and Environmental Sciences Faculty Articles and Research
Faithful translation of mRNA into the corresponding polypeptide is a complex multistep process, requiring accurate amino acid selection, transfer RNA (tRNA) charging and mRNA decoding on the ribosome. Key players in this process are aminoacyl-tRNA synthetases (aaRSs), which not only catalyse the attachment of cognate amino acids to their respective tRNAs, but also selectively hydrolyse incorrectly activated non-cognate amino acids and/or misaminoacylated tRNAs. This aaRS proofreading provides quality control checkpoints that exclude non-cognate amino acids during translation, and in so doing helps to prevent the formation of an aberrant proteome. However, despite the intrinsic need for high accuracy during translation, …
Carbonyl Reduction By Ymfi Completes The Modification Of Ef-P In Bacillus Subtilis To Prevent Accumulation Of An Inhibitory Modification State,
2017
Indiana University - Bloomington
Carbonyl Reduction By Ymfi Completes The Modification Of Ef-P In Bacillus Subtilis To Prevent Accumulation Of An Inhibitory Modification State, Katherine R. Hummels, Anne Witzky, Andrei Rajkovic, Rodney Tollerson Ii, Lisa A. Jones, Michael Ibba, Daniel B. Kearns
Biology, Chemistry, and Environmental Sciences Faculty Articles and Research
Translation elongation factor P (EF‐P) in Bacillus subtilis is required for a form of surface migration called swarming motility. Furthermore, B. subtilis EF‐P is post‐translationally modified with a 5‐aminopentanol group but the pathway necessary for the synthesis and ligation of the modification is unknown. Here we determine that the protein YmfI catalyzes the reduction of EF‐P‐5 aminopentanone to EF‐P‐5 aminopentanol. In the absence of YmfI, accumulation of 5‐aminopentanonated EF‐P is inhibitory to swarming motility. Suppressor mutations that enhanced swarming in the absence of YmfI were found at two positions on EF‐P, including one that changed the conserved modification site (Lys …
Development Of Self-Assembling Nanoparticles For Drug Delivery Applications,
2017
Purdue University
Development Of Self-Assembling Nanoparticles For Drug Delivery Applications, Young Chan Kim, Craig Sweet, Helen Margaret Flynn, David H. Thompson
The Summer Undergraduate Research Fellowship (SURF) Symposium
Bladder cancer is the ninth most common cancer in the world, and occurs in nearly four percent of all men. Although many cases are diagnosed as early stage cancer and the tumor can be removed by surgery, reoccurrence rates are high making treatment difficult and thus one of the most expensive cancers. To address this problem, drugs are injected intravesically after tumor removal to kill any residual cancer that may cause reoccurrence. While this was a significant improvement over surgery alone, high toxicity along with short residence times in the bladder limited its effectiveness. To combat these shortcomings, we will …
Fret Biosensors: Engineering Fluorescent Proteins As Biological Tools For Studying Parkinson’S Disease,
2017
Purdue University
Fret Biosensors: Engineering Fluorescent Proteins As Biological Tools For Studying Parkinson’S Disease, Nathan J. Leroy, Jacob R. Norley, Saranya Radhakrishnan, Mathew Tantama
The Summer Undergraduate Research Fellowship (SURF) Symposium
Parkinson’s Disease (PD) is a common neurodegenerative disease with over 200,000 new cases each year. In general, the cause of the disease is unknown, but oxidative stress inside of neurons has been associated with the disease’s pathology for some time. Currently, techniques to study the onset of PD inside of neurons are limited. This makes treatments and causes difficult to discover. One solution to this has been fluorescent protein biosensors. In short, these proteins can be engineered to glow when a certain state is achieved inside a cell. The present research discusses the engineering of a genetically-encoded fluorescent protein (FP) …
Blocking An N-Terminal Acetylation-Dependent Protein Interaction Inhibits An E3 Ligase,
2017
St. Jude Children's Research Hospital
Blocking An N-Terminal Acetylation-Dependent Protein Interaction Inhibits An E3 Ligase, Daniel C. Scott, Jared T. Hammill, Jaeki Min, David Y. Rhee, Michele Connelly, Vladislav O. Sviderskiy, Deepak Bhasin, Yizhe Chen, Su-Sien Ong, Sergio C. Chai, Asli N. Goktug, Guochang Huang, Julie K. Monda, Jonathan Low, Ho Shin Kim, Joao A. Paulo, Joe R. Cannon, Anang A. Shelat, Taosheng Chen, Ian R. Kelsall, Arno F. Alpi, Vishwajeeth Pagala, Xusheng Wang, Junmin Peng, Bhuvanesh Singh, J. Wade Harper, Brenda A. Schulman, R. Kiplin Guy
Pharmaceutical Sciences Faculty Publications
N-terminal acetylation is an abundant modification influencing protein functions. Because ∼80% of mammalian cytosolic proteins are N-terminally acetylated, this modification is potentially an untapped target for chemical control of their functions. Structural studies have revealed that, like lysine acetylation, N-terminal acetylation converts a positively charged amine into a hydrophobic handle that mediates protein interactions; hence, this modification may be a druggable target. We report the development of chemical probes targeting the N-terminal acetylation–dependent interaction between an E2 conjugating enzyme (UBE2M or UBC12) and DCN1 (DCUN1D1), a subunit of a multiprotein E3 ligase for the ubiquitin-like protein NEDD8. The inhibitors are …
Application Of Open-Access Databases To Determine Functional Connectivity Between Resveratrol-Binding Protein Qr2 And Colorectal Carcinoma,
2017
New York Medical College
Application Of Open-Access Databases To Determine Functional Connectivity Between Resveratrol-Binding Protein Qr2 And Colorectal Carcinoma, Barbara B. Doonan, Evelien Schaafsma, John T. Pinto, Joseph M. Wu, Tze-Chen Hsieh
NYMC Faculty Publications
Colorectal cancer (CRC) is a major cause of cancer-associated deaths worldwide. Recently, oral administration of resveratrol (trans-3,5,4'-trihydroxystilbene) has been reported to significantly reduce tumor proliferation in colorectal cancer patients, however, with little specific information on functional connections. The pathogenesis and development of colorectal cancer is a multistep process that can be categorized using three phenotypic pathways, respectively, chromosome instability (CIN), microsatellite instability (MSI), and CpG island methylator (CIMP). Targets of resveratrol, including a high-affinity binding protein, quinone reductase 2 (QR2), have been identified with little information on disease association. We hypothesize that the relationship between resveratrol and different CRC etiologies …
Elongation Factor P Interactions With The Ribosome Are Independent Of Pausing,
2017
The Ohio State University
Elongation Factor P Interactions With The Ribosome Are Independent Of Pausing, Rodney Tollerson Ii, Anne Witzky, Michael Ibba
Biology, Chemistry, and Environmental Sciences Faculty Articles and Research
Bacterial elongation factor P (EF-P) plays a pivotal role in the translation of polyproline motifs. To stimulate peptide bond formation, EF-P must enter the ribosome via an empty E-site. Using fluorescence-based single-molecule tracking, Mohapatra et al. (S. Mohapatra, H. Choi, X. Ge, S. Sanyal, and J. C. Weisshaar, mBio 8:e00300-17, 2017, https://doi.org/10.1128/mBio.00300-17 ) monitored the cellular distribution of EF-P and quantified the frequency of association between EF-P and the ribosome under various conditions. Findings from the study showed that EF-P has a localization pattern that is strikingly similar to that of ribosomes. Intriguingly, EF-P was seen to bind ribosomes more …
Syk Inhibitors In Clinical Development For Hematological Malignancies,
2017
New York Medical College
Syk Inhibitors In Clinical Development For Hematological Malignancies, Delong Liu, Aleksandra Mamorska-Dyga
NYMC Faculty Publications
Spleen tyrosine kinase (Syk) is a cytosolic non-receptor protein tyrosine kinase (PTK) and is mainly expressed in hematopoietic cells. Syk was recognized as a critical element in the B-cell receptor signaling pathway. Syk is also a key component in signal transduction from other immune receptors like Fc receptors and adhesion receptors. Several oral Syk inhibitors including fostamatinib (R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659 are being assessed in clinical trials. The second generation compound, entospletinib, showed promising results in clinical trials against B-cell malignancies, mainly chronic lymphoid leukemia. Syk inhibitors are being evaluated in combination regimens in multiple malignancies.
Tumor-Targeted Delivery Of Sirna Using Fatty Acyl-Cgkrk Peptide Conjugates,
2017
Chapman University
Tumor-Targeted Delivery Of Sirna Using Fatty Acyl-Cgkrk Peptide Conjugates, Meenakshi Sharma, Naglaa Salem El-Sayed, Hung Do, Keykavous Parang, Rakesh Tiwari, Hamidreza Montazeri Aliabadi
Pharmacy Faculty Articles and Research
Tumor-targeted carriers provide efficient delivery of chemotherapeutic agents to tumor tissue. CGKRK is one of the well-known tumor targeting peptides with significant specificity for angiogenic blood vessels and tumor cells. Here, we designed fatty acyl conjugated CGKRK peptides, based on the hypothesis that hydrophobically-modified CGKRK peptide could enhance cellular permeation and delivery of siRNA targeted to tumor cells for effective silencing of selected proteins. We synthesized six fatty acyl-peptide conjugates, using a diverse chain of saturated and unsaturated fatty acids to study the efficiency of this approach. At peptide:siRNA weight/weight ratio of 10:1 (N/P ≈ 13.6), almost all the peptides …
Data For High-Throughput Estimation Of Specific Activities Of Enzyme/Mutants In Cell Lysates Through Immunoturbidimetric Assay Of Proteins,
2017
Chongqing Medical University, China
Data For High-Throughput Estimation Of Specific Activities Of Enzyme/Mutants In Cell Lysates Through Immunoturbidimetric Assay Of Proteins, Yiran Feng, Xiaolan Yang, Huimin Chong, Deqiang Wang, Xiaolei Hu, Chang-Guo Zhan, Fei Liao
Molecular Modeling and Biopharmaceutical Center Faculty Publications
Data in this article are associated with the research article “Highthroughput estimation of specific activities of enzyme/mutants in cell lysates through immunoturbidimetric assay of proteins” (Yang et al., 2017) [1]. This article provided data on how to develop an immunoturbidimetric assay (ITA) of enzyme/mutants as proteins in cell lysates in high-throughput (HTP) mode together with HTP assay of their activities to derive their specific activities in cell lysates for comparison, with Pseudomonas aeruginosa arylsulfatase (PAAS) and Bacillus fastidious uricase (BFU) plus their mutants as models. Data were made publicly available for further analyses.
Chloroformate Derivatization For Tracing The Fate Of Amino Acids In Cells And Tissues By Multiple Stable Isotope Resolved Metabolomics (Msirm),
2017
University of Kentucky
Chloroformate Derivatization For Tracing The Fate Of Amino Acids In Cells And Tissues By Multiple Stable Isotope Resolved Metabolomics (Msirm), Ye Yang, Teresa W. -M. Fan, Andrew N. Lane, Richard M. Higashi
Center for Environmental and Systems Biochemistry Faculty Publications
Amino acids have crucial roles in central metabolism, both anabolic and catabolic. To elucidate these roles, steady-state concentrations of amino acids alone are insufficient, as each amino acid participates in multiple pathways and functions in a complex network, which can also be compartmentalized. Stable Isotope-Resolved Metabolomics (SIRM) is an approach that uses atom-resolved tracking of metabolites through biochemical transformations in cells, tissues, or whole organisms. Using different elemental stable isotopes to label multiple metabolite precursors makes it possible to resolve simultaneously the utilization of these precursors in a single experiment. Conversely, a single precursor labeled with two (or more) different …
Quaternary Interactions And Supercoiling Modulate The Cooperative Dna Binding Of Agt,
2017
University of Kentucky
Quaternary Interactions And Supercoiling Modulate The Cooperative Dna Binding Of Agt, Manana Melikishvili, Michael G. Fried
Center for Structural Biology Faculty Publications
Human O6-alkylguanine-DNA alkyltransferase (AGT) repairs mutagenic O6-alkylguanine and O4-alkylthymine adducts in single-stranded and duplex DNAs. The search for these lesions, through a vast excess of competing, unmodified genomic DNA, is a mechanistic challenge that may limit the repair rate in vivo. Here, we examine influences of DNA secondary structure and twist on protein–protein interactions in cooperative AGT complexes formed on lesion-free DNAs that model the unmodified parts of the genome. We used a new approach to resolve nearest neighbor (nn) and long-range (lr) components from the ensemble-average cooperativity, ωave. We found …
Abnormal Dendritic Maturation Of Developing Cortical Neurons Exposed To Corticotropin Releasing Hormone (Crh): Insights Into Effects Of Prenatal Adversity?,
2017
University of California, Irvine
Abnormal Dendritic Maturation Of Developing Cortical Neurons Exposed To Corticotropin Releasing Hormone (Crh): Insights Into Effects Of Prenatal Adversity?, Megan M. Curran, Curt A. Sandman, Elyssia Poggi Davis, Laura M. Glynn, Tallie Z. Baram
Psychology Faculty Articles and Research
Corticotropin releasing hormone (CRH) produced by the hypothalamus initiates the hypothalamic- pituitary-adrenal (HPA) axis, which regulates the body's stress response. CRH levels typically are undetectable in human plasma, but during pregnancy the primate placenta synthesizes and releases large amounts of CRH into both maternal and fetal circulations. Notably, placental CRH synthesis increases in response to maternal stress signals. There is evidence that human fetal exposure to high concentrations of placental CRH is associated with behavioral consequences during infancy and into childhood, however the direct effects on of the peptide on the human brain are unknown. In this study, we used …
Mechanical Stability Of Talin Rod Controls Cell Migration And Substrate Sensing,
2017
University of Tampere, Finland
Mechanical Stability Of Talin Rod Controls Cell Migration And Substrate Sensing, Rolle Rahikainen, Magdaléna Von Essen, Markus Schaefer, Lei Qi, Latifeh Azizi, Conor Kelly, Teemu O. Ihalainen, Bernhard Wehrle-Haller, Martin Bastmeyer, Cai Huang, Vesa P. Hytönen
Markey Cancer Center Faculty Publications
Cells adhere to the surrounding tissue and probe its mechanical properties by forming cell-matrix adhesions. Talin is a critical adhesion protein and participates in the transmission of mechanical signals between extracellular matrix and cell cytoskeleton. Force induced unfolding of talin rod subdomains has been proposed to act as a cellular mechanosensor, but so far evidence linking their mechanical stability and cellular response has been lacking. Here, by utilizing computationally designed mutations, we demonstrate that stepwise destabilization of the talin rod R3 subdomain decreases cellular traction force generation, which affects talin and vinculin dynamics in cell-matrix adhesions and results in the …
Synthesis And Evaluation Of Antimicrobial Activity Of [R4w4k]-Levofloxacin And [R4w4k]-Levofloxacin-Q Conjugates,
2017
Chapman University
Synthesis And Evaluation Of Antimicrobial Activity Of [R4w4k]-Levofloxacin And [R4w4k]-Levofloxacin-Q Conjugates, Neda Riahifard, Kathy Tavakoli, Jason Yamaki, Keykavous Parang, Rakesh Tiwari
Pharmacy Faculty Articles and Research
The development of a new class of antibiotics to fight bacterial resistance is a time-consuming effort associated with high-cost and commercial risks. Thus, modification, conjugation or combination of existing antibiotics to enhance their efficacy is a suitable strategy. We have previously reported that the amphiphilic cyclic peptide [R4W4] had antibacterial activity with a minimum inhibitory concentration (MIC) of 2.97 g/mL against Methicillin-resistant Staphylococcus aureus (MRSA). Herein, we hypothesized that conjugation or combination of the amphiphilic cyclic peptide [R4W4] with levofloxacin or levofloxacin-Q could improve the antibacterial activity of levofloxacin and levofloxacin-Q. Fmoc/tBu solid-phase chemistry was employed to synthesize conjugates of …
B7h6: A Cancer Biomarker For The Development Of Novel Immunotherapy Approaches,
2017
Seton Hall University
B7h6: A Cancer Biomarker For The Development Of Novel Immunotherapy Approaches, Mariana Phillips
Seton Hall University Dissertations and Theses (ETDs)
Cancer-based immunotherapy has led the evolution of biologics that can stimulate immune responses towards tumor eradication. The synthesis of small to intermediate size molecules with the targeting and effector functions of mAb may represent a novel class of immunotherapeutics that may overcome the limitations of their biological counterparts.Towards this objective, B7H6 has been identified as a protein ligand localized on the cell surface of transformed tumor cells. B7H6 binds specifically to the activating receptor NKp30, constitutively expressed on all resting and active NK cells. Upon ligand:receptor binding, B7H6 triggers NK cell activation and release of chemokines and pro-inflammatory cytokines such …
Diversity Oriented Synthesis, Characterization And Anti-Cancer Activity Of Killer Peptide Nucleolipid Bioconjugates,
2017
Seton Hall University
Diversity Oriented Synthesis, Characterization And Anti-Cancer Activity Of Killer Peptide Nucleolipid Bioconjugates, Niki K. Rana
Seton Hall University Dissertations and Theses (ETDs)
The killer peptide sequence D-(KLAKLAK)2 has been originally designed and developed as an antibacterial agent. Despite having excellent cytotoxicity towards bacteria, this sequence maintains low cell cytotoxity in malignant mammalian cell types such as cancer. The chemical basis for its selectivity has been attributed to its poly(cationic) amphiphilic nature, which facilitates cell permeability across the negatively charged bacterial membrane, but with limited permeability across the zwitterionic membrane of mammalian cells. The positively charged D-(KLAKLAK)2 sequence has been found to accumulate on the surface of the mitochondria causing dissipation of the negatively charged mitochondrial membrane potential. This charge disruption …
Novel Effects Of Prefoldin Pathway On Intestinal Homeostasis Via Dietary Restriction In Drosophila Melanogaster,
2017
Dominican University of California
Novel Effects Of Prefoldin Pathway On Intestinal Homeostasis Via Dietary Restriction In Drosophila Melanogaster, Jesse Simons
Dissertations, Masters Theses, Capstones, and Culminating Projects
The field of medicine research is embroiled in a battle against aging. Particular focus is on the extension of lifespan and health-span. Lifespan duration is affected by many factors, one of which is the maintenance of the intestines of the organism. Homeostasis of the intestines is controlled by the regulation of intestine cell apoptosis and intestine cell proliferation. My research explores the role of two protein subunits found in a complex which may have possible functions in the regulation of these processes. The overall complex is formed from six subunit proteins, some of which are known to assist in other …
