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Electronic-Cigarette Vehicles And Flavoring Affect Lung Function And Immune Responses In A Murine Model, Brittany N. Szafran, Rakeysha Pinkston, Zakia Perveen, Matthew K. Ross, Timothy Morgan, Daniel B. Paulsen, Arthur L. Penn, Barbara L. F. Kaplan, Alexandra Noel 2020 Mississippi State Univ, Coll Vet Med, Dept Basic Sci, Ctr Environm Hlth Sci, Mississippi State, MS

Electronic-Cigarette Vehicles And Flavoring Affect Lung Function And Immune Responses In A Murine Model, Brittany N. Szafran, Rakeysha Pinkston, Zakia Perveen, Matthew K. Ross, Timothy Morgan, Daniel B. Paulsen, Arthur L. Penn, Barbara L. F. Kaplan, Alexandra Noel

Faculty Publications

The use of electronic nicotine delivery systems (ENDS), also known as electronic-cigarettes (e-cigs), has raised serious public health concerns, especially in light of the 2019 outbreak of e-cig or vaping product use-associated acute lung injury (EVALI). While these cases have mostly been linked to ENDS that contain vitamin E acetate, there is limited research that has focused on the chronic pulmonary effects of the delivery vehicles (i.e., without nicotine and flavoring). Thus, we investigated lung function and immune responses in a mouse model following exposure to the nearly ubiquitous e-cig delivery vehicles, vegetable glycerin (VG) and propylene glycol (PG ...


Weak Binding To The A2re Rna Rigidifies Hnrnpa2 Rrms And Reduces Liquid–Liquid Phase Separation And Aggregation, Veronica H. Ryan, Scott Watters, Joshua Amaya, Balabhadra Khatiwada, Vincenzo Venditti, Mandar T. Naik, Nicolas L. Fawzi 2020 Brown University

Weak Binding To The A2re Rna Rigidifies Hnrnpa2 Rrms And Reduces Liquid–Liquid Phase Separation And Aggregation, Veronica H. Ryan, Scott Watters, Joshua Amaya, Balabhadra Khatiwada, Vincenzo Venditti, Mandar T. Naik, Nicolas L. Fawzi

Chemistry Publications

hnRNPA2 is a major component of mRNA transport granules in oligodendrocytes and neurons. However, the structural details of how hnRNPA2 binds the A2 recognition element (A2RE) and if this sequence stimulates granule formation by enhancing phase separation of hnRNPA2 has not yet been studied. Using solution NMR and biophysical studies, we find that each of the two individual RRMs retain the domain structure observed in complex with RNA but are not rigidly confined (i.e. they move independently) in solution in the absence of RNA. hnRNPA2 RRMs bind the minimal rA2RE11 weakly but at least, and most likely, two hnRNPA2 ...


Pressure Driven Desalination Utilizing Nanomaterials, Fangyou Xie 2020 calpoly san luis obispo

Pressure Driven Desalination Utilizing Nanomaterials, Fangyou Xie

Master's Theses

Nanomaterials such as graphene oxide and carbon nanotubes, have demonstrated excellent properties for membrane desalination, including decrease of maintenance, increase of flux rate, simple solution casting, and impressive chemical inertness. Here, two projects are studied to investigate nanocarbon based membrane desalination. The first project is to prepare hybrid membranes with amyloid fibrils intercalated with graphene oxide sheets. The addition of protein amyloid fibrils expands the interlayer spacing between graphene oxide nanosheets and introduces additional functional groups in the diffusion pathways, resulting in increase of flux rate and rejection rate for the organic dyes. Amyloid fibrils also provide structural assistance to ...


Small Molecule Synthetic Carbohydrate Receptors, Marcelo F. Bravo Carranco 2020 The Graduate Center, City University of New York

Small Molecule Synthetic Carbohydrate Receptors, Marcelo F. Bravo Carranco

Dissertations, Theses, and Capstone Projects

Carbohydrate – receptor interactions are often involved in the attachment of viruses to host cells, and this docking is a necessary step in the virus life cycle that precedes infection and, ultimately, replication. Despite the conserved structures of the glycans involved in docking, they are still considered “undruggable”, meaning these glycans are beyond the scope of conventional pharmacological strategies. Recent advances in the development of synthetic carbohydrate receptors (SCRs) – small molecules that bind carbohydrates – could bring carbohydrate-receptor interactions within the purview of druggable targets. Here we discuss the role of carbohydrate-receptor interactions in viral infection, the evolution of SCRs, and recent ...


Ribosome Inhibition By C9orf72-Als/Ftd-Associated Poly-Pr And Poly-Gr Proteins Revealed By Cryo-Em [Preprint], Anna B. Loveland, Egor Svidritskiy, Denis Susorov, Soojin Lee, Alexander Park, Gabriel Demo, Fen-Biao Gao, Andrei A. Korostelev 2020 University of Massachusetts Medical School

Ribosome Inhibition By C9orf72-Als/Ftd-Associated Poly-Pr And Poly-Gr Proteins Revealed By Cryo-Em [Preprint], Anna B. Loveland, Egor Svidritskiy, Denis Susorov, Soojin Lee, Alexander Park, Gabriel Demo, Fen-Biao Gao, Andrei A. Korostelev

University of Massachusetts Medical School Faculty Publications

Toxic dipeptide repeat (DPR) proteins are produced from expanded G4C2 hexanucleotide repeats in the C9ORF72 gene, which cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥ 20 repeats inhibit the ribosome’s peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryo-EM structures reveal that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center. Consistent with these findings, the macrolide erythromycin, which binds in the tunnel ...


Capsaicin Is A Negative Allosteric Modulator Of The 5-Ht3 Receptor, Eslam El Nebrisi, Tatiana Prytkova, Dietrich Ernst Lorke, Luke Howarth, Asma Hassan Alzaabi, Keun-Hang Susan Yang, Frank Christopher Howarth, Murat Oz 2020 UAE University

Capsaicin Is A Negative Allosteric Modulator Of The 5-Ht3 Receptor, Eslam El Nebrisi, Tatiana Prytkova, Dietrich Ernst Lorke, Luke Howarth, Asma Hassan Alzaabi, Keun-Hang Susan Yang, Frank Christopher Howarth, Murat Oz

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

In this study, effects of capsaicin, an active ingredient of the capsicum plant, were investigated on human 5-hydroxytryptamine type 3 (5-HT3) receptors. Capsaicin reversibly inhibited serotonin (5-HT)-induced currents recorded by two-electrode voltage clamp method in Xenopus oocytes. The inhibition was time- and concentration-dependent with an IC50 = 62 μM. The effect of capsaicin was not altered in the presence of capsazepine, and by intracellular BAPTA injections or trans-membrane potential changes. In radio-ligand binding studies, capsaicin did not change the specific binding of the 5-HT3 antagonist [3H]GR65630, indicating that it is a noncompetitive inhibitor of 5-HT ...


Investigating Photosynthetic Stability: Relation Between Thylakoid Lipid Content And The Stability Of The Cytochrome B6f Complex, Marina Mehling 2020 Purdue University

Investigating Photosynthetic Stability: Relation Between Thylakoid Lipid Content And The Stability Of The Cytochrome B6f Complex, Marina Mehling

The Journal of Purdue Undergraduate Research

The cytochrome b6f complex is an enzyme found in plants, cyanobacteria, and green algae that catalyzes the transport of electrons in the rate-limiting step of oxygenic photosynthesis. This dimeric complex has an extensive lipid architecture that is primarily composed of five distinct lipid classes: monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG), phosphatidyl glycerol (PG), monoglucosyl diacylglycerol (GlcDG), and sulfoquinovosyl diacylglycerol (SQDG). While these lipid classes have been identified, their precise role in the function of the cytochrome complex are only beginning to be understood. Mechanisms describing the relation between thylakoid lipid content on the stability of the b6 ...


Calcineurin, Trevor P. Creamer 2020 University of Kentucky

Calcineurin, Trevor P. Creamer

Molecular and Cellular Biochemistry Faculty Publications

The serine/threonine phosphatase calcineurin acts as a crucial connection between calcium signaling the phosphorylation states of numerous important substrates. These substrates include, but are not limited to, transcription factors, receptors and channels, proteins associated with mitochondria, and proteins associated with microtubules. Calcineurin is activated by increases in intracellular calcium concentrations, a process that requires the calcium sensing protein calmodulin binding to an intrinsically disordered regulatory domain in the phosphatase. Despite having been studied for around four decades, the activation of calcineurin is not fully understood. This review largely focuses on what is known about the activation process and highlights ...


The Role Of The Leucine-Rich (Leur) Domain Of Rho Guanine Nucleotide Exchange Factor (Rgnef) In The Regulation Of Amyotrophic Lateral Sclerosis (Als) Associated Protein Tar Dna-Binding Protein Of 43 Kda (Tdp-43), Hind Amzil 2020 The University of Western Ontario

The Role Of The Leucine-Rich (Leur) Domain Of Rho Guanine Nucleotide Exchange Factor (Rgnef) In The Regulation Of Amyotrophic Lateral Sclerosis (Als) Associated Protein Tar Dna-Binding Protein Of 43 Kda (Tdp-43), Hind Amzil

Electronic Thesis and Dissertation Repository

The presence of neuronal cytoplasmic inclusions (NCIs) composed of RNA-binding proteins (RBPs) and neurofilaments is considered to be ALS’s neuropathological hallmark. RGNEF has been previously shown to interact with TDP-43 and to have a regulatory effect on the expression levels of NEFL mRNA and NFL protein in vitro. Here, I examined the mechanism of the RGNEF N-terminus, leucine-rich domain (LeuR) domain’s interaction with TDP-43. I observed that the minimal domain required is 110 amino acids (LeuR110), that the Ankyrin domain adjacent to LeuR110 does not participate, and that LeuR110 forms of a high molecular weight complex with TDP-43 ...


Genome-Wide Mapping Of Human Dna Replication By Optical Replication Mapping Supports A Stochastic Model Of Eukaryotic Replication Timing [Preprint], Weitao Wang, Kyle Klein, Karel Proesmans, Northwestern University, Claire Marchal, Xiaopeng Zhu, Tyler M. Borrman, Alex Hastie, Zhiping Weng, Simon Fraser University, Paris Sciences et Lettres University, Florida State University, Nicholas R. Rhind 2020 Paris Sciences et Lettres University

Genome-Wide Mapping Of Human Dna Replication By Optical Replication Mapping Supports A Stochastic Model Of Eukaryotic Replication Timing [Preprint], Weitao Wang, Kyle Klein, Karel Proesmans, Northwestern University, Claire Marchal, Xiaopeng Zhu, Tyler M. Borrman, Alex Hastie, Zhiping Weng, Simon Fraser University, Paris Sciences Et Lettres University, Florida State University, Nicholas R. Rhind

University of Massachusetts Medical School Faculty Publications

DNA replication is regulated by the location and timing of replication initiation. Therefore, much effort has been invested in identifying and analyzing the sites of human replication initiation. However, the heterogeneous nature of eukaryotic replication kinetics and the low efficiency of individual initiation site utilization in metazoans has made mapping the location and timing of replication initiation in human cells difficult. A potential solution to the problem of human replication mapping is single-molecule analysis. However, current approaches do not provide the throughput required for genome-wide experiments. To address this challenge, we have developed Optical Replication Mapping (ORM), a high-throughput single-molecule ...


Broad Host Range Of Sars-Cov-2 Predicted By Comparative And Structural Analysis Of Ace2 In Vertebrates, Joana Damas, Elinor K. Karlsson, Harris A. Lewin 2020 University of California, Davis

Broad Host Range Of Sars-Cov-2 Predicted By Comparative And Structural Analysis Of Ace2 In Vertebrates, Joana Damas, Elinor K. Karlsson, Harris A. Lewin

COVID-19 Publications by UMMS Authors

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike ...


A Cross-Reactive Human Iga Monoclonal Antibody Blocks Sars-Cov-2 Spike-Ace2 Interaction, Ejemel Monir, Qi Li, Shurong Hou, Zachary Schiller, Aaron Wallace, Alla Amcheslavsky, Nese Kurt Yilmaz, Jacqueline R. Toomey, Ryan Schneider, Anudeep S. Ramchetty, Chandrashekar Ganesa, Lisa Cavacini, Mark S. Klempner, Celia A. Schiffer, Yan Wang 2020 University of Massachusetts Medical School

A Cross-Reactive Human Iga Monoclonal Antibody Blocks Sars-Cov-2 Spike-Ace2 Interaction, Ejemel Monir, Qi Li, Shurong Hou, Zachary Schiller, Aaron Wallace, Alla Amcheslavsky, Nese Kurt Yilmaz, Jacqueline R. Toomey, Ryan Schneider, Anudeep S. Ramchetty, Chandrashekar Ganesa, Lisa Cavacini, Mark S. Klempner, Celia A. Schiffer, Yan Wang

COVID-19 Publications by UMMS Authors

COVID-19 caused by SARS-CoV-2 has become a global pandemic requiring the development of interventions for the prevention or treatment to curtail mortality and morbidity. No vaccine to boost mucosal immunity, or as a therapeutic, has yet been developed to SARS-CoV-2. In this study, we discover and characterize a cross-reactive human IgA monoclonal antibody, MAb362. MAb362 binds to both SARS-CoV and SARS-CoV-2 spike proteins and competitively blocks ACE2 receptor binding, by overlapping the ACE2 structural binding epitope. Furthermore, MAb362 IgA neutralizes both pseudotyped SARS-CoV and SARS-CoV-2 in 293 cells expressing ACE2. When converted to secretory IgA, MAb326 also neutralizes authentic SARS-CoV-2 ...


The Chemical Structure And Phosphorothioate Content Of Hydrophobically Modified Sirnas Impact Extrahepatic Distribution And Efficacy, Annabelle Biscans, Jillian Caiazzi, Sarah M. Davis, Nicholas McHugh, Jacquelyn Sousa, Anastasia Khvorova 2020 University of Massachusetts Medical School

The Chemical Structure And Phosphorothioate Content Of Hydrophobically Modified Sirnas Impact Extrahepatic Distribution And Efficacy, Annabelle Biscans, Jillian Caiazzi, Sarah M. Davis, Nicholas Mchugh, Jacquelyn Sousa, Anastasia Khvorova

Open Access Articles

Small interfering RNAs (siRNAs) have revolutionized the treatment of liver diseases. However, robust siRNA delivery to other tissues represents a major technological need. Conjugating lipids (e.g. docosanoic acid, DCA) to siRNA supports extrahepatic delivery, but tissue accumulation and gene silencing efficacy are lower than that achieved in liver by clinical-stage compounds. The chemical structure of conjugated siRNA may significantly impact invivo efficacy, particularly in tissues with lower compound accumulation. Here, we report the first systematic evaluation of the impact of siRNA scaffold-i.e. structure, phosphorothioate (PS) content, linker composition-on DCA-conjugated siRNA delivery and efficacy in vivo. We found that ...


Sampling Performance Of Multiple Independent Molecular Dynamics Simulations Of An Rna Aptamer, Shuting Yan, Jason M. Peck, Muslum Ilgu, Marit Nilsen-Hamilton, Monica H. Lamm 2020 Iowa State University

Sampling Performance Of Multiple Independent Molecular Dynamics Simulations Of An Rna Aptamer, Shuting Yan, Jason M. Peck, Muslum Ilgu, Marit Nilsen-Hamilton, Monica H. Lamm

Chemical and Biological Engineering Publications

Using multiple independent simulations instead of one long simulation has been shown to improve the sampling performance attained with the molecular dynamics (MD) simulation method. However, it is generally not known how long each independent simulation should be, how many independent simulations should be used, or to what extent either of these factors affects the overall sampling performance achieved for a given system. The goal of the present study was to assess the sampling performance of multiple independent MD simulations, where each independent simulation begins from a different initial molecular conformation. For this purpose, we used an RNA aptamer that ...


Termi-Luc: A Versatile Assay To Monitor Full-Protein Release From Ribosomes, Denis Susorov, Shawn B. Egri, Andrei A. Korostelev 2020 University of Massachusetts Medical School

Termi-Luc: A Versatile Assay To Monitor Full-Protein Release From Ribosomes, Denis Susorov, Shawn B. Egri, Andrei A. Korostelev

Open Access Articles

Termination of protein biosynthesis is an essential step of gene expression, during which a complete functional protein is released from the ribosome. Premature or inefficient termination results in truncated, non-functional or toxic proteins that may cause disease. Indeed, more than 10% of human genetic diseases are caused by nonsense mutations leading to premature termination. Efficient and sensitive approaches are required to study eukaryotic termination mechanisms and to identify potential therapeutics that modulate termination. Canonical radioactivity-based termination assays are complex, report on a short peptide release, and are incompatible with high-throughput screening. Here we describe a robust and simple in vitro ...


Uprmt Scales Mitochondrial Network Expansion With Protein Synthesis Via Mitochondrial Import [Preprint], Tomer Shpilka, Yunguang Du, Qiyuan Yang, Andrew Melber, Nandhitha Uma Naresh, Joshua Lavelle, Pengpeng Liu, Hilla Weidberg, Rui Li, Jun Yu, Lihua Julie Zhu, Lara Strittmatter, Cole M. Haynes 2020 University of Massachusetts Medical School

Uprmt Scales Mitochondrial Network Expansion With Protein Synthesis Via Mitochondrial Import [Preprint], Tomer Shpilka, Yunguang Du, Qiyuan Yang, Andrew Melber, Nandhitha Uma Naresh, Joshua Lavelle, Pengpeng Liu, Hilla Weidberg, Rui Li, Jun Yu, Lihua Julie Zhu, Lara Strittmatter, Cole M. Haynes

University of Massachusetts Medical School Faculty Publications

As organisms develop, individual cells generate mitochondria to fulfill physiologic requirements. However, it remains unknown how mitochondrial network expansion is scaled to cell growth and impacted by environmental cues. The mitochondrial unfolded protein response (UPRmt) is a signaling pathway mediated by the transcription factor ATFS-1 which harbors a mitochondrial targeting sequence (MTS)1. Here, we demonstrate that ATFS-1 mediates an adaptable mitochondrial expansion program that is active throughout normal development. Developmental mitochondrial network expansion required the relatively inefficient MTS2 in ATFS-1, which allowed the transcription factor to be responsive to parameters that impact protein import capacity of the ...


Testing The Combined Module Swapping And Repair By Modification Strategies: A Step Toward Universal Toolbox, Catherine A. Martini 2020 University of Texas at Tyler

Testing The Combined Module Swapping And Repair By Modification Strategies: A Step Toward Universal Toolbox, Catherine A. Martini

Biology Theses

The crux of synthetic biology is the engineering of biological components to modulate the activity of specific DNA-based promoter(s) to drive gene expression; thus, providing a means to modulate pathways between signal detection and cellular response. However, the longstanding frustration of synthetic biologists has been the inability to transfer those engineered components between cellular systems — this lack of “modular universality” or “universal toolbox” impedes research by forcing a metaphorical reinvention of the wheel in new systems. The modular swapping strategy expanded the available “toolbox” with customizable hybrid repressors formed from “swapping” the DNA-recognition modules (DRMs) and environmental-sensing modules (ESMs ...


A Chemical Interpretation Of Protein Electron Density Maps In The Worldwide Protein Data Bank, Sen Yao, Hunter N. B. Moseley 2020 University of Kentucky

A Chemical Interpretation Of Protein Electron Density Maps In The Worldwide Protein Data Bank, Sen Yao, Hunter N. B. Moseley

Molecular and Cellular Biochemistry Faculty Publications

High-quality three-dimensional structural data is of great value for the functional interpretation of biomacromolecules, especially proteins; however, structural quality varies greatly across the entries in the worldwide Protein Data Bank (wwPDB). Since 2008, the wwPDB has required the inclusion of structure factors with the deposition of x-ray crystallographic structures to support the independent evaluation of structures with respect to the underlying experimental data used to derive those structures. However, interpreting the discrepancies between the structural model and its underlying electron density data is difficult, since derived sigma-scaled electron density maps use arbitrary electron density units which are inconsistent between maps ...


Foliage Type Controls Mercury Input, Storage, And Release In The Boreal Forest, Madelaine J R Anderson 2020 The University of Western Ontario

Foliage Type Controls Mercury Input, Storage, And Release In The Boreal Forest, Madelaine J R Anderson

Electronic Thesis and Dissertation Repository

Mercury (Hg) is a naturally occurring element with a complex biogeochemical cycle. Forests act as net sinks for both carbon (C) and Hg as foliage accumulates Hg with time. Litterfall represents a main input of C and Hg into forest soils. My aim was to investigate how foliage type (coniferous, deciduous) governs the input of Hg into forests with a field-based study that measured Hg accumulation over a growing season, and then investigate the storage and release of Hg from foliar tissues into soil with a laboratory-based incubation experiment. Results from the field-based study demonstrate deciduous leaves have more linear ...


The Rna Phosphatase Pir-1 Regulates Endogenous Small Rna Pathways In C. Elegans [Preprint], Daniel A. Chaves, Hui Dai, Lichao Li, James J. Moresco, Myung Eun Oh, Darryl Conte Jr., John R. Yates III, Craig C. Mello, Weifeng Gu 2020 University of Massachusetts Medical School

The Rna Phosphatase Pir-1 Regulates Endogenous Small Rna Pathways In C. Elegans [Preprint], Daniel A. Chaves, Hui Dai, Lichao Li, James J. Moresco, Myung Eun Oh, Darryl Conte Jr., John R. Yates Iii, Craig C. Mello, Weifeng Gu

University of Massachusetts Medical School Faculty Publications

Eukaryotic cells regulate 5' triphosphorylated (ppp-) RNAs to promote cellular functions and prevent recognition by antiviral RNA sensors. For example, RNA capping enzymes possess triphosphatase domains that remove the γ phosphates of ppp-RNAs during RNA capping. Members of the closely related PIR1 family of RNA polyphosphatases remove both the β and γ phosphates from ppp-RNAs. Here we show that C. elegans PIR-1 dephosphorylates ppp-RNAs made by cellular RdRPs and is required for the maturation of 26G-RNAs, Dicer-dependent small RNAs that regulate thousands of genes during spermatogenesis and embryogenesis. PIR-1 also regulates the CSR-1 22G-RNA pathway and has critical functions in ...


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