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2016

Medicine and Health Sciences

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Articles 1 - 30 of 35

Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Peptidylarginine Deiminase 1-Catalyzed Histone Citrullination Is Essential For Early Embryo Development, Xiaoqian Zhang, Xiaoqiu Liu, Mei Zhang, Tingting Li, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Xuesen Zhang Dec 2016

Peptidylarginine Deiminase 1-Catalyzed Histone Citrullination Is Essential For Early Embryo Development, Xiaoqian Zhang, Xiaoqiu Liu, Mei Zhang, Tingting Li, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Xuesen Zhang

Thompson Lab Publications

Peptidylarginine deiminase (PADI) enzymes are increasingly being associated with the regulation of chromatin structure and gene activity via histone citrullination. As one of the PADI family members, PADI1 has been mainly reported to be expressed in the epidermis and uterus, where the protein in keratinocytes is thought to promote differentiation by citrullinating filament proteins. However, the roles of PADI1 in preimplantation development have not been addressed. Using a PADI1-specific inhibitor and Padi1-morpholino knockdown, we found that citrullination of histone tails at H4R3 and H3R2/8/17 were markedly reduced in the 2- and 4-cell embryos. Consistent with this observation, early ...


Design, Synthesis, And Evaluation Of Dasatinib-Amino Acid And Dasatinib-Fatty Acid Conjugates As Protein Tyrosine Kinase Inhibitors, Rakesh Tiwari, Alex Brown, Neda Sadeghiani, Amir Nasrolahi Shirazi, Jared Bolton, Amanda Tse, Gennady M. Verkhivker, Keykavous Parang, Gongqin Sun Nov 2016

Design, Synthesis, And Evaluation Of Dasatinib-Amino Acid And Dasatinib-Fatty Acid Conjugates As Protein Tyrosine Kinase Inhibitors, Rakesh Tiwari, Alex Brown, Neda Sadeghiani, Amir Nasrolahi Shirazi, Jared Bolton, Amanda Tse, Gennady M. Verkhivker, Keykavous Parang, Gongqin Sun

Pharmacy Faculty Articles and Research

Derivatives of dasatinib were synthesized via esterification with 25 carboxylic acids including amino acids and fatty acids by extending the inhibitor to interact with more diverse sites and to improve specificity. Dasatinib-L-arginine derivative (Das-R, 7) was the most potent of the inhibitors tested with IC50 values of 4.4 nM, <0.25 nM, and <0.45 nM against Csk, Src, and Abl kinases, respectively. The highest selectivity ratio obtained in our study, 91.4 Csk/Src belonged to compound 18 (Das-C10) with an IC50 of 3.2 μM for Csk compared to 35 nM for Src. Furthermore, many compounds displayed increased selectivity toward Src, as compared with Abl. Compounds 15 (Das-E) and 13 (Das-C) demonstrated the largest gains (10.2 and 10.3 Abl/Src IC50 ratios). Das-R (IC50 = 2.06 μM) was significantly more potent than Das (IC50 = 26.3 μM) against Panc-1 cells while they both showed an IC50 < 51.2 pM against BV-173 and K562 cells. Molecular modeling and binding free energy simulations revealed a good agreement with the experimental results and rationalized differences in selectivity of the studied compounds. Integration of experimental and computational approaches in the design and biochemical screening of dasatinib derivatives facilitated rational engineering and diversification of dasatinib scaffold, providing useful insights into mechanisms of kinase selectivity.


Polymeric Prodrug Combination To Exploit The Therapeutic Potential Of Antimicrobial Peptides Against Cancer Cells., Graeme J. Kelly, A Foltyn-Arfa Kia, F Hassan, S O'Grady, Maria P. Morgan, B S. Creaven, S Mcclean, Judith H. Harmey, Marc Devocelle Oct 2016

Polymeric Prodrug Combination To Exploit The Therapeutic Potential Of Antimicrobial Peptides Against Cancer Cells., Graeme J. Kelly, A Foltyn-Arfa Kia, F Hassan, S O'Grady, Maria P. Morgan, B S. Creaven, S Mcclean, Judith H. Harmey, Marc Devocelle

Chemistry Articles

Antimicrobial Peptides (AMPs) have unique anticancer properties, but their clinical application is currently limited by an inadequate margin of safety. A prodrug strategy associated with a combination therapy approach could address this limitation by increasing their therapeutic index and their efficacy. Accordingly, the first targeted anticancer polymeric prodrug candidates of AMPs, intended for combination therapy with another polymeric prodrug of an approved antineoplastic agent (doxorubicin), were synthesized as either a PEG-based dual-release prodrug or two individual pegylated prodrugs. The latter are based on a cathepsin B-labile peptide linker and an acid-sensitive acyl hydrazone bond for the AMP and doxorubicin prodrugs ...


Synthesis, Self-Assembly, And Immunological Activity Of Α-Galactose-Functionalized Dendron–Lipid Amphiphiles, John Trant, Namrata Jain, D. M. Mazzuca, J Trevor Mcintosh, Bo Fan, S M Mansour Haeryfar, Sebastien Lecommandoux, Elizabeth Gillies Sep 2016

Synthesis, Self-Assembly, And Immunological Activity Of Α-Galactose-Functionalized Dendron–Lipid Amphiphiles, John Trant, Namrata Jain, D. M. Mazzuca, J Trevor Mcintosh, Bo Fan, S M Mansour Haeryfar, Sebastien Lecommandoux, Elizabeth Gillies

Chemistry Publications

Nanoassemblies presenting multivalent displays of biologically active carbohydrates are of significant interest for a wide array of biomedical applications ranging from drug delivery to immunotherapy. In this study, glycodendronlipid hybrids were developed as a new and tunable class of dendritic amphiphiles. A modular synthesis was used to prepare dendronlipid hybrids comprising distearylglycerol and 0 through 4th generation polyester dendrons with peripheral protected amines. Following deprotection of the amines, an isothiocyanate derivative of C-linked α-galactose (α-Gal) was conjugated to the dendron peripheries, affording amphiphiles with 1 to 16 α-Gal moieties. Self-assembly in water through a ...


Strained Alkyne Substituted Near Infrared Bf2 Azadipyrromethene Fluorochrome, Dan Wu, Shane Cheung, Corry James O'Sullivan, Yinghua Gao, Zhi-Long Chen, Donal F. O'Shea Sep 2016

Strained Alkyne Substituted Near Infrared Bf2 Azadipyrromethene Fluorochrome, Dan Wu, Shane Cheung, Corry James O'Sullivan, Yinghua Gao, Zhi-Long Chen, Donal F. O'Shea

Chemistry Articles

The contribution of imaging with near infrared (NIR) fluorophores to the elucidation of complex biological processes continues to rapidly expand. New tools for mild selective bioconjugation are strongly desirable for the construction of NIR labelled biomolecules. This work presents the synthesis and evaluation of a strained alkyne substituted NIR BF2-azadipyrromethene (NIR-AZA) which can conjugate in water with azido-homoalanine and cRGD peptide within 30 min at rt. Imaging analysis of the NIR-AZA–cRGD conjugate in vitro and in vivo showed efficient cellular uptake and good in vivo tumor targeting properties, illustrating the potential for translation to clinical imaging.


Synthesis Of Polymeric Bismuth Chlorido Hydroxamato Complexes; X-Ray Crystal Structure And Antibacterial Activity Of A Novel Bi(Lll) Salicylhydroxamato Complex, Donal M. Keoghan, Lauren E. Fagan, Thayse Marques Passos, Helge Müller-Bunz, Bríd Quilty, Darren M. Griffith Sep 2016

Synthesis Of Polymeric Bismuth Chlorido Hydroxamato Complexes; X-Ray Crystal Structure And Antibacterial Activity Of A Novel Bi(Lll) Salicylhydroxamato Complex, Donal M. Keoghan, Lauren E. Fagan, Thayse Marques Passos, Helge Müller-Bunz, Bríd Quilty, Darren M. Griffith

Chemistry Articles

Reaction of salicylhydroxamic acid (Sha) and 2-aminophenyl hydroxamic acid (2-NH2-pha) with BiCl3 affords the corresponding novel polymeric bismuth chlorido hydroxamato complexes; [BiCl2(-Sha-1H)]∞ and [BiCl3(--Pha-1H)]∞ respectively. The X-ray crystal structure of the THF-solvated polymeric bismuth chlorido salicylhydroxamato complex, [BiCl2(-Sha-1H)(THF)]∞ was solved, confirming the polymeric structure of this class of compounds and the (O,μ-O’)-bidentate bridging coordination mode of the hydroxamato ligand. The antibacterial activity of the THF-free polymeric bismuth chlorido salicylhydroxamato complex, [BiCl2(-Sha-1H)]∞, was investigated against a broad panel of bacteria, further highlighting the antibacterial properties of Bi-based compounds against Gram-positive and Gram-negative pathogenic and ...


Peroxiredoxin Catalysis At Atomic Resolution, Arden Perkins, Derek Parsonage, Kimberly J. Nelson, O. Maduka Ogba, Paul Ha-Yeon Cheong, Leslie B. Poole, P. Andrew Karplus Sep 2016

Peroxiredoxin Catalysis At Atomic Resolution, Arden Perkins, Derek Parsonage, Kimberly J. Nelson, O. Maduka Ogba, Paul Ha-Yeon Cheong, Leslie B. Poole, P. Andrew Karplus

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Peroxiredoxins (Prxs) are ubiquitous cysteine-based peroxidases that guard cells against oxidative damage, are virulence factors for pathogens, and are involved in eukaryotic redox regulatory pathways. We have analyzed catalytically active crystals to capture atomic resolution snapshots of a PrxQ-subfamily enzyme (from Xanthomonas campestris) proceeding through thiolate, sulfenate, and sulfinate species. These analyses provide structures of unprecedented accuracy for seeding theoretical studies, and show novel conformational intermediates giving insight into the reaction pathway. Based on a highly non-standard geometry seen for the sulfenate intermediate, we infer that the sulfenate formation itself can strongly promote local unfolding of the active site to ...


Analysis Of The Intricacies Of Substrate Recognition Of High Mobility Group Proteins And Aminoacyl-Trna Synthetases Using Non-Cognate Substrates, Douglas Van Iverson Ii Aug 2016

Analysis Of The Intricacies Of Substrate Recognition Of High Mobility Group Proteins And Aminoacyl-Trna Synthetases Using Non-Cognate Substrates, Douglas Van Iverson Ii

Dissertations

The studies presented in section 1 (Chapters I-IV) focus on the design and development of nucleic acid four-way junctions (4WJs) to target a member of the high mobility group (HMG) proteins, the proinflammatory cytokine high mobility group box 1 protein (HMGB1). In the present study, hybrid PNA-DNA 4WJs based on a model DNA 4WJ were constructed to improve the thermal stability of 4WJs while maintaining strong binding affinity toward HMGB1. An electrophoretic mobility shift assay (EMSA) was used to examine the binding affinity of an isolated DNA binding domain of HMGB1, the HMGB1 b-box (HMGB1b), toward a set of PNA-DNA ...


Azadipyrromethenes: From Traditional Dye Chemistry To Leading Edge Applications., Yuan Ge, Donal F. O'Shea Jul 2016

Azadipyrromethenes: From Traditional Dye Chemistry To Leading Edge Applications., Yuan Ge, Donal F. O'Shea

Chemistry Articles

Azadipyrromethenes were first described over 70 years ago as blue pigments, but now are rapidly emerging as a compound class with highly desirable near infrared photophysical properties. Since the turn of the century several routes to azadipyrromethenes have been developed and numerous post-synthesis derivatizations have allowed for their exploitation in both biological and material sciences. The relative ease of access to specifically designed derivatives is now allowing their use in multiple technological formats from real-time fluorescence imaging, to solar energy materials, to optoelectronic devices and many more. In this review we have highlighted the synthetic component of this story as ...


Novel Improved Synthesis Of Hsp70 Inhibitor, Pifithrin-Μ. In Vitro Synergy Quantification Of Pifithrin-Μ Combined With Pt Drugs In Prostate And Colorectal Cancer Cells., Aoife M. Mckeon, Alan Egan, Jay Chandanshive, Helena Mcmahon, Darren M. Griffith Jul 2016

Novel Improved Synthesis Of Hsp70 Inhibitor, Pifithrin-Μ. In Vitro Synergy Quantification Of Pifithrin-Μ Combined With Pt Drugs In Prostate And Colorectal Cancer Cells., Aoife M. Mckeon, Alan Egan, Jay Chandanshive, Helena Mcmahon, Darren M. Griffith

Chemistry Articles

We describe a novel improved approach to the synthesis of the important and well-known heat shock protein 70 inhibitor (HSP70), pifithrin-μ, with corresponding and previously unreported characterisation. The first example of a combination study comprising HSP70 inhibitor pifithrin-μ and cisplatin or oxaliplatin is reported. We have determined, using the Chou-Talalay method, (i) moderate synergistic and synergistic effects in co-treating PC-3 prostate cancer cells with pifithrin-μ and cisplatin and (ii) significant synergistic effects including strong synergism in cotreating HT29 colorectal cancer cells with oxaliplatin and pifithrin-μ.


Novel Class Of Bi(Iii) Hydroxamato Complexes: Synthesis, Urease Inhibitory Activity And Activity Against H. Pylori., Donal M. Keogan, Brendan Twamley, Deirdre Fitzgerald-Hughes, Darren M. Griffith Jul 2016

Novel Class Of Bi(Iii) Hydroxamato Complexes: Synthesis, Urease Inhibitory Activity And Activity Against H. Pylori., Donal M. Keogan, Brendan Twamley, Deirdre Fitzgerald-Hughes, Darren M. Griffith

Chemistry Articles

Reaction of Bi(NO3)3 with benzohydroxamic acid (Bha) and salicylhydroxamic acid (Sha) gives the novel Bi(iii) complexes [Bi2(Bha-1H)2(μ-Bha-1H)2(η(2)-NO3)2] () and [Bi6(CH3OH)2(η(1)-NO3)2(η(2)-NO3)(OH2)2(Sha-1H)12](NO3)2 (). X-ray crystal structure of reveals two hydroxamato coordination modes; bidentate bridging (O, O') and bidentate non-bridging (O, O') and of reveals one coordination mode; bidentate bridging (O, O'). , specifically designed to and demonstrated to inhibit the activity of urease, exhibits excellent antibacterial activity against three strains of Helicobacter pylori with MIC ≥ 16 μg mL(-1).


Conformational Dynamics And Stability Associated With Magnesium Or Calcium Binding To Dream In The Regulation Of Interactions Between Dream And Dna Or Presenilins, Khoa Ngoc Pham Jun 2016

Conformational Dynamics And Stability Associated With Magnesium Or Calcium Binding To Dream In The Regulation Of Interactions Between Dream And Dna Or Presenilins, Khoa Ngoc Pham

FIU Electronic Theses and Dissertations

Downstream regulatory element antagonist modulator (DREAM) is involved in various interactions with targets both inside and outside of the nucleus. In the cytoplasm, DREAM interacts with the C-terminal fragments of presenilins to facilitate the production of β-amyloid plaques in Alzheimer’s disease. In the nucleus, Ca2+ free DREAM directly binds to specific downstream regulatory elements of prodynorphin/c-fos gene to repress the gene transcription in pain modulation. These interactions are regulated by Ca2+ and/or Mg2+ association at the EF-hands in DREAM. Therefore, understanding the conformational dynamics and stability associated with Ca2+ and/or Mg ...


Multi-Functional Copper(Ii) Drug Candidates As Potential Anti-Cancer Agents, Tadhg James Patrick Mc Givern Jun 2016

Multi-Functional Copper(Ii) Drug Candidates As Potential Anti-Cancer Agents, Tadhg James Patrick Mc Givern

PhD theses

The development of metal complexes as therapeutic agents remains a focal point of modern medicinal inorganic chemistry. While platinum drugs are well established therapeutic agents, recent progress has shown that some copper complexes possess enhanced cytotoxic activity and in vivo cytotoxic tolerance owing to their DNA binding and DNA scission capabilities. In parallel, the design, synthesis and evaluation of enzyme inhibitors rationally chosen for their potential in suppressing tumour cell proliferation as well as possessing selective toxicity towards tumour over normal cells is another area receiving considerable attention of late.

To date, we have successfully synthesized a library of novel ...


Screening The Low Molecular Weight Fraction Of Human Serum Using Atr-Ir Spectroscopy, Franck Bonnier, Matthew J. Baker, Hugh J. Byrne Jun 2016

Screening The Low Molecular Weight Fraction Of Human Serum Using Atr-Ir Spectroscopy, Franck Bonnier, Matthew J. Baker, Hugh J. Byrne

Articles

Vibrational spectroscopic techniques can detect small variations in molecular content, linked with disease, showing promise for screening and early diagnosis. Biological fluids, particularly blood serum, are potentially valuable for diagnosis purposes. The so-called Low Molecular Weight Fraction (LMWF) contains the associated peptidome and metabolome and has been identified as potentially the most relevant molecular population for disease-associated biomarker research. Although vibrational spectroscopy can deliver a specific chemical fingerprint of the samples, the High Molecular Weight Fraction (HMWF), composed of the most abundant serum proteins, strongly dominates the response and ultimately makes the detection of minor spectral variations a challenging task ...


Abrogation Of Collagen-Induced Arthritis By A Peptidyl Arginine Deiminase Inhibitor Is Associated With Modulation Of T Cell-Mediated Immune Responses, Joanna Kawalkowska, Anne-Marie Quirke, Fatemeh Ghari, Simon Davis, Venkataraman Subramanian, Paul R. Thompson, Richard O. Williams, Roman Fischer, Nicholas B. La Thangue, Patrick J. Venables May 2016

Abrogation Of Collagen-Induced Arthritis By A Peptidyl Arginine Deiminase Inhibitor Is Associated With Modulation Of T Cell-Mediated Immune Responses, Joanna Kawalkowska, Anne-Marie Quirke, Fatemeh Ghari, Simon Davis, Venkataraman Subramanian, Paul R. Thompson, Richard O. Williams, Roman Fischer, Nicholas B. La Thangue, Patrick J. Venables

Open Access Articles

Proteins containing citrulline, a post-translational modification of arginine, are generated by peptidyl arginine deiminases (PAD). Citrullinated proteins have pro-inflammatory effects in both innate and adaptive immune responses. Here, we examine the therapeutic effects in collagen-induced arthritis of the second generation PAD inhibitor, BB-Cl-amidine. Treatment after disease onset resulted in the reversal of clinical and histological changes of arthritis, associated with a marked reduction in citrullinated proteins in lymph nodes. There was little overall change in antibodies to collagen or antibodies to citrullinated peptides, but a shift from pro-inflammatory Th1 and Th17-type responses to pro-resolution Th2-type responses was demonstrated by serum ...


Theoretical And Experimental Analysis Of The Antioxidant And Anti-Amyloid Features Of Synthetic Resveratrol Mimics, William Horton, Anne Kokel, Fanni Török, Chris Tran, Marianna Török, Bela Török May 2016

Theoretical And Experimental Analysis Of The Antioxidant And Anti-Amyloid Features Of Synthetic Resveratrol Mimics, William Horton, Anne Kokel, Fanni Török, Chris Tran, Marianna Török, Bela Török

UMass Center for Clinical and Translational Science Research Retreat

Diaryl hydrazones, possessing similar structure to the popular red wine antioxidant resveratrol, have been previously identified as multitarget compounds interfering with several processes associated with the pathogenesis of Alzheimer’s disease (AD). These compounds exhibited particularly strong inhibition of the amyloid beta (A) peptide self-assembly, including blocking the formation of fibrils and oligomers, species that are widely accepted to be neurotoxic. The molecules were also powerful free radical scavengers and thus have a potential to defend against oxidative stress.

In order to learn more about the mode of action of the compounds, theoretical and experimental studies have been carried out ...


Crystal Protein Cry5b As A Novel And Powerful Anthelmintic, David Koch, Zeynep Mirza, Yan Hu, Thanh-Thanh Nguyen, Gary R. Ostroff, Raffi V. Aroian May 2016

Crystal Protein Cry5b As A Novel And Powerful Anthelmintic, David Koch, Zeynep Mirza, Yan Hu, Thanh-Thanh Nguyen, Gary R. Ostroff, Raffi V. Aroian

UMass Center for Clinical and Translational Science Research Retreat

Soil-transmitted helminths (STHs), most notably, hookworms, whipworms, and Ascaris, are nematodes that infect more than 1.5 billion of the poorest people and are amongst the leading causes of morbidity worldwide. Only two classes of de-worming drugs (anthelmintics) are available for treatment, and only one is commonly used in mass drug administrations. New anthelmintics are urgently needed to overcome emerging resistance and to produce higher cure rates. Crystal (Cry) proteins, in particular Cry5B, made by Bacillus thuringiensis (Bt) are promising new candidates. Cry5B has excellent anthelmintic properties against many free-living and parasitic nematodes, including in vivo efficacy against multiple STH ...


Terpenes As ‘Resistance-Busting” Anthelmintic Drug, Zeynep Mirza, David Koch, Thanh-Thanh Nguyen, Yan Hu, Raffi V. Aroian, Gary R. Ostroff May 2016

Terpenes As ‘Resistance-Busting” Anthelmintic Drug, Zeynep Mirza, David Koch, Thanh-Thanh Nguyen, Yan Hu, Raffi V. Aroian, Gary R. Ostroff

UMass Center for Clinical and Translational Science Research Retreat

There is an urgent need for new therapies for parasitic helminthic diseases affecting 1.5-2 billion people worldwide due to the threat of wide-spread resistance development to existing treatments and due to problems of incomplete efficacies.

Terpenes are plant secondary metabolites and major essential oil constituents. Historically, the terpene thymol was successfully used to cure hookworm infections in the 1900’s. Although effective, large doses were needed and thymol treatment had significant side effects. Because free terpenes are absorbed in the stomach, less than 10% of oral terpenes entered the site where the parasites live. To overcome these problems we ...


Zn(Ii), Cu(Ii), Sn(Ii), And Ni(Ii) And Other Metal Cations Do Not Prevent The Aggregation Of Hiapp, Charles Hoying May 2016

Zn(Ii), Cu(Ii), Sn(Ii), And Ni(Ii) And Other Metal Cations Do Not Prevent The Aggregation Of Hiapp, Charles Hoying

Honors Thesis

The Zn(II) metal ion has been shown to interact with Islet Amyloid Polypeptide (IAPP), a protein implicated in the progression of Type II Diabetes Mellitus, in such a way as to prevent the protein from aggregating into toxic fibers. We set out to find whether other metal ions might similarly prevent IAPP aggregation. Using Thioflavin T (ThT) spectroscopic assays, which measure fluorescence of ThT upon binding to aggregated IAPP, we observed a decrease in aggregation when incubated with Zn(II), Cu(II), Ni(II), and Sn(II). Atomic Force Microscopy (AFM), which can visualize fibril formation, revealed that the ...


Agonist-Mediated Activation Of Sting Induces Apoptosis In Malignant B Cells, Chih-Hang Anthony Tang, Joseph A. Zundell, Sujeewa Ranatunga, Cindy Lin, Yulia Nefedova, Juan R. Del Valle, Chih-Chi Andrew Hu Apr 2016

Agonist-Mediated Activation Of Sting Induces Apoptosis In Malignant B Cells, Chih-Hang Anthony Tang, Joseph A. Zundell, Sujeewa Ranatunga, Cindy Lin, Yulia Nefedova, Juan R. Del Valle, Chih-Chi Andrew Hu

Chemistry Faculty Publications

Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream of STING and that STING agonists selectively trigger mitochondria-mediated apoptosis in normal and malignant B cells. Upon stimulation, STING was degraded less efficiently in B cells, implying that prolonged activation of STING can lead to apoptosis. Transient activation of the IRE-1/XBP-1 pathway partially protected agonist-stimulated malignant B cells from undergoing apoptosis. In Eμ-TCL1 mice with chronic lymphocytic ...


Analysis Of New Hiv-1 Inhibitors As Potential Antiviral Agents For Hiv-2, Rowan Brothers Apr 2016

Analysis Of New Hiv-1 Inhibitors As Potential Antiviral Agents For Hiv-2, Rowan Brothers

Georgia State Undergraduate Research Conference

No abstract provided.


One Year Later: The Politics And Stories Of Post-Earthquake Nepal, Boyer Andrew Apr 2016

One Year Later: The Politics And Stories Of Post-Earthquake Nepal, Boyer Andrew

Independent Study Project (ISP) Collection

A 7.8 magnitude earthquake struck Nepal on April 25th, 2015. This was followed by a second major earthquake of magnitude 7.3 on May 12th , 2015. These disasters took the lives of thousands of Nepali people, destroyed hundreds of thousands of structures, and displaced an estimated two million people. Immediately following the disaster, there was an outpouring of humanitarian aid from around the world. This lead to a conference where $4.1 billion USD of reconstruction funds were pledged to Nepal by international donors. Five months later, a new constitution passed into law and an informal blockade ...


Fabrication Of A Gma-Co-Edma Monolith In A 2.0 Mm I.D. Polypropylene Housing., Marcello Iacono, Damian Connolly, Andreas Heise Mar 2016

Fabrication Of A Gma-Co-Edma Monolith In A 2.0 Mm I.D. Polypropylene Housing., Marcello Iacono, Damian Connolly, Andreas Heise

Chemistry Articles

Polymers are interesting housing materials for the fabrication of inexpensive monolithic chromatography and solid phase extraction (SPE) devices. Challenges arise when polymeric monoliths are formed in non-conical, cylindrical tubes of larger diameter due to potential monolith detachment from the housing wall resulting in loss of separation performance and mechanical stability. Here, a two-step protocol is applied to ensure formation of robust homogeneous methacrylate monolith in polypropylene (PP) tubing with a diameter of 2.0 mm. Detailed Fourier-transform infrared (FTIR) spectroscopic analysis and Scanning Electron Microscopy (SEM) imaging confirm the successful pre-modification of the tubing wall with an anchoring layer of ...


A Sodium Salt Of The Dimer Of Boronoterephthalic Acid Anhydride, Scott Simmons, Albert Fratini, Vladimir Benin Mar 2016

A Sodium Salt Of The Dimer Of Boronoterephthalic Acid Anhydride, Scott Simmons, Albert Fratini, Vladimir Benin

Albert Fratini

The title compound, sodium bis­(6-carb­oxy-1-hy­droxy-3-oxo-1,3-dihydro-2,1-benzoxaborol-1-yl)oxidanium, Na+·C16H15B2O13-, was prepared in two steps from 2-bromo-p-xylene. Its crystal structure was determined at 140 K and has triclinic (P) symmetry. The compound presents a unique structural motif, including two units of the cyclic anhydride of boronoterephthalic acid, joined by a protonated, and thereby trivalent, oxonium center. Association in the crystal is realized by complementary hydrogen bonding of the carboxyl groups, as well as by coordination of the sodium cations to the oxygen centers on the five-membered rings.


Protein Arginine Methylation And Citrullination In Epigenetic Regulation, Jakob Fuhrmann, Paul R. Thompson Mar 2016

Protein Arginine Methylation And Citrullination In Epigenetic Regulation, Jakob Fuhrmann, Paul R. Thompson

Thompson Lab Publications

The post-translational modification of arginine residues represents a key mechanism for the epigenetic control of gene expression. Aberrant levels of histone arginine modifications have been linked to the development of several diseases including cancer. In recent years, great progress has been made in understanding the physiological role of individual arginine modifications and their effects on chromatin function. The present review aims to summarize the structural and functional aspects of histone arginine modifying enzymes and their impact on gene transcription. We will discuss the potential for targeting these proteins with small molecules in a variety of disease states.


“Zipped Synthesis” By Cross-Metathesis Provides A Cystathionine Β‑Synthase Inhibitor That Attenuates Cellular H2S Levels And Reduces Neuronal Infarction In A Rat Ischemic Stroke Model, Christopher D. Mccune, Su Jing Chan, Matthew L. Beio, Weijun Shen, Woo Jin Chung, Laura M. Szczesniak, Chou Chai, Shu Qing Koh, Peter T.-H. Wong, David B. Berkowitz Mar 2016

“Zipped Synthesis” By Cross-Metathesis Provides A Cystathionine Β‑Synthase Inhibitor That Attenuates Cellular H2S Levels And Reduces Neuronal Infarction In A Rat Ischemic Stroke Model, Christopher D. Mccune, Su Jing Chan, Matthew L. Beio, Weijun Shen, Woo Jin Chung, Laura M. Szczesniak, Chou Chai, Shu Qing Koh, Peter T.-H. Wong, David B. Berkowitz

David Berkowitz Publications

The gaseous neuromodulator H2S is associated with neuronal cell death pursuant to cerebral ischemia. As cystathionine β-synthase (CBS) is the primary mediator of H2S biogenesis in the brain, it has emerged as a potential target for the treatment of stroke. Herein, a “zipped” approach by alkene cross-metathesis into CBS inhibitor candidate synthesis is demonstrated. The inhibitors are modeled after the pseudo-C2-symmetric CBS product (L,L)-cystathionine. The “zipped” concept means only half of the inhibitor needs be constructed; the two halves are then fused by olefin cross-metathesis. Inhibitor design is also mechanism-based, exploiting the favorable kinetics ...


Lysosome Triggered Near-Infrared Fluorescence Imaging Of Cellular Trafficking Processes In Real Time., Marco Grossi, Marina Morgunova, Shane Cheung, Dimitri Scholz, Emer Conroy, Marta Terrile, Angela Panarella, Jeremy C. Simpson, William M. Gallagher, Donal F. O'Shea Mar 2016

Lysosome Triggered Near-Infrared Fluorescence Imaging Of Cellular Trafficking Processes In Real Time., Marco Grossi, Marina Morgunova, Shane Cheung, Dimitri Scholz, Emer Conroy, Marta Terrile, Angela Panarella, Jeremy C. Simpson, William M. Gallagher, Donal F. O'Shea

Chemistry Articles

Bioresponsive NIR-fluorophores offer the possibility for continual visualization of dynamic cellular processes with added potential for direct translation to in vivo imaging. Here we show the design, synthesis and lysosome-responsive emission properties of a new NIR fluorophore. The NIR fluorescent probe design differs from typical amine functionalized lysosomotropic stains with off/on fluorescence switching controlled by a reversible phenol/phenolate interconversion. Emission from the probe is shown to be highly selective for the lysosomes in co-imaging experiments using a HeLa cell line expressing the lysosomal-associated membrane protein 1 fused to green fluorescent protein. The responsive probe is capable of real-time ...


Development And Validation Of A Sensitive Uplc-Ms/Ms Method For The Quantitation Of [13c]Sucrose In Rat Plasma, Blood, And Brain: Its Application To The Measurement Of Blood-Brain Barrier Permeability, Mohammad K. Miah, Ulrich Bickel, Reza Mehvar Feb 2016

Development And Validation Of A Sensitive Uplc-Ms/Ms Method For The Quantitation Of [13c]Sucrose In Rat Plasma, Blood, And Brain: Its Application To The Measurement Of Blood-Brain Barrier Permeability, Mohammad K. Miah, Ulrich Bickel, Reza Mehvar

Pharmacy Faculty Articles and Research

Accurate and reproducible measurement of blood-brain barrier (BBB) integrity is critical in the assessment of the pathophysiology of the central nervous system disorders and in monitoring therapeutic effects. The widely-used low molecular weight marker [14C]sucrose is non-specific in the absence of chromatographic separation. The purpose of this study was to develop and validate a sensitive and reproducible LC-MS/MS method for the analysis of stable isotopemodified [13C12]sucrose in brain, plasma, and blood to determine BBB permeability to sucrose. After addition of internal standard (IS, [13C6]sucrose), the marker and IS were recovered from diluted rat blood, plasma, and ...


Citrullination-Acetylation Interplay Guides E2f-1 Activity During The Inflammatory Response, Fatemeh Ghari, Anne-Marie Quirke, Shonagh Munro, Joanna Kawalkowska, Sarah Picaud, Joanna Mcgouran, Venkataraman Subramanian, Aaron Muth, Richard Williams, Benedikt Kessler, Paul R. Thompson, Panagis Fillipakopoulos, Stefan Knapp, Patrick J. Venables, Nicholas B. La Thangue Feb 2016

Citrullination-Acetylation Interplay Guides E2f-1 Activity During The Inflammatory Response, Fatemeh Ghari, Anne-Marie Quirke, Shonagh Munro, Joanna Kawalkowska, Sarah Picaud, Joanna Mcgouran, Venkataraman Subramanian, Aaron Muth, Richard Williams, Benedikt Kessler, Paul R. Thompson, Panagis Fillipakopoulos, Stefan Knapp, Patrick J. Venables, Nicholas B. La Thangue

Thompson Lab Publications

Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains unclear. E2F transcription factors are a family of master regulators that coordinate gene expression during cellular proliferation and diverse cell fates. We show that E2F-1 is citrullinated by PAD4 in inflammatory cells. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells. Mechanistically, citrullination augments binding of the BET (bromodomain and extra-terminal domain) family bromodomain reader BRD4 (bromodomain-containing protein 4) to ...


Structural Basis For Mutation-Induced Destabilization Of Profilin 1 In Als, Sivakumar Boopathy, Tania Silvas, Maeve Tischbein, Silvia Jansen, Shivender Shandilya, Jill Zitzewitz, John Landers, Bruce Goode, Celia Schiffer, Daryl Bosco Jan 2016

Structural Basis For Mutation-Induced Destabilization Of Profilin 1 In Als, Sivakumar Boopathy, Tania Silvas, Maeve Tischbein, Silvia Jansen, Shivender Shandilya, Jill Zitzewitz, John Landers, Bruce Goode, Celia Schiffer, Daryl Bosco

Celia A. Schiffer

Mutations in profilin 1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS); however, the pathological mechanism of PFN1 in this fatal disease is unknown. We demonstrate that ALS-linked mutations severely destabilize the native conformation of PFN1 in vitro and cause accelerated turnover of the PFN1 protein in cells. This mutation-induced destabilization can account for the high propensity of ALS-linked variants to aggregate and also provides rationale for their reported loss-of-function phenotypes in cell-based assays. The source of this destabilization is illuminated by the X-ray crystal structures of several PFN1 proteins, revealing an expanded cavity near the protein core of the ...