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Identification Of Novel Phosphorylation Sites In Sars-Cov-2 Nucleocapsid Protein, Josie Daldegan Rezende

Theses and Dissertations

COVID-19, the 2019 disease outbreak, continues to cause severe mortality worldwide. Fast and reliable tests that identify the SARS-CoV-2 virus, which is responsible for causing the COVID-19 disease, are crucial for controlling the spread of the virus. Antigen tests are ideal for the rapid diagnosis of COVID-19. Current antigen tests for COVID-19 detect the SARS-CoV-2 nucleocapsid (N) protein. The nucleocapsid is the most abundant protein produced by the virus upon infection, which makes it a superior target for detection by an antigen test. Nucleocapsid proteins from several coronaviruses, including SARS, have previously been shown to be modified by posttranslational modification …

Emerging Biomedical Applications Of The Vesicular Stomatitis Virus Glycoprotein, Sheeba Rehman, Suman Bishnoi, Rajarshi Roy, Anshu Kumari, Harikrishnan Jayakumar, Sharad Gupta, Parimal Kar, Asit K. Pattnaik, Bebasis Nayak

School of Veterinary and Biomedical Sciences: Faculty Publications

Nanoparticles (NPs) made of metals, polymers, micelles, and liposomes are increasingly being used in various biomedical applications. However, most of these NPs are hazardous for long- and short-term use and hence have restricted biomedical applications. Therefore, naturally derived, biocompatible, and biodegradable nanoconstructs are being explored for such applications. Inspired by the biology of viruses, researchers are exploring the viral proteins that hold considerable promise in biomedical applications. The viral proteins are highly stable and further amenable to suit specific biological applications. Among various viral proteins, vesicular stomatitis virus glycoprotein (VSV-G) has emerged as one of the most versatile platforms for …

Phip-Seq Reveals Autoantibodies For Ubiquitously Expressed Antigens In Viral Myocarditis, Mahima T. Rasquinha, Ninaad Lasrado, Erika M. Petro-Turnquist, Eric A. Weaver, Thiagarajan Venkataraman, Daniel R. Anderson, H. Benjamin Larman, Jay Reddy

School of Veterinary and Biomedical Sciences: Faculty Publications

Simple Summary: Myocarditis is the inflammation of the heart muscle, and viral infections are a common cause of this disease. Myocarditis in some patients can progress to dilated cardiomyopathy (DCM). The mouse model of coxsackievirus B3 (CVB3) is commonly used to understand this disease progression in DCM patients. In this paper, we have attempted to analyze antibodies for heart antigens that could be produced as a result of heart damage in animals infected with CVB3 using a technique called Phage ImmunoPrecipitation Sequencing (PhIP-Seq). The analyses led us to identify antibodies for several proteins that were not previously reported that may …

Methamphetamine Use: A Narrative Review Of Adverse Effects And Related Toxicities., Amber N. Edinoff, Sarah E. Kaufman, Keionne M. Green, Daniel A. Provenzano, Jesse Lawson, Elyse M. Cornett, Kevin S. Murnane, Adam M. Kaye, Alan David Kaye

School of Pharmacy Faculty Articles

Methamphetamine has been labeled "America's most dangerous drug" and has received significant public health attention. Stimulant addiction and tolerance are heavily documented in the literature; increasingly larger doses maintain euphoria in short time periods to withstand stimulant tolerance. Stimulant deaths are high in the United States and abroad. Between 2013 and 2019, deaths related to methamphetamine use quadrupled from 3,616 to 16,127. Methamphetamine use increased four-fold from 2015 to 2016. Due to this increase in methamphetamine use and its associated medical complications, the mortality rate associated with methamphetamine use has doubled over the past ten years. Cardiopulmonary symptoms include chest …

Arginine Catabolism And Polyamine Biosynthesis Pathway Disparities Within Francisella Tularensis Subpopulations, Yinshi Yue, Bhanwar Lal Puniya, Tomáš Helikar, Benjamin Girardo, Steven H. Hinrichs, Marilyn A. Larson

Department of Biochemistry: Faculty Publications

Francisella tularensis is a highly infectious zoonotic pathogen with as few as 10 organisms causing tularemia, a disease that is fatal if untreated. Although F. tularensis subspecies tularensis (type A) and subspecies holarctica (type B) share over 99.5% average nucleotide identity, notable differences exist in genomic organization and pathogenicity. The type A clade has been further divided into subtypes A.I and A.II, with A.I strains being recognized as some of the most virulent bacterial pathogens known. In this study, we report on major disparities that exist between the F. tularensis subpopulations in arginine catabolism and subsequent polyamine biosynthesis. The genes …

Evaluation Of Oasl And Herc5’S Role In The Non-Lytic Clearance Of Influenza A Virus From Club Cells, Steve Crisafulli

West Chester University Master’s Theses

Influenza A virus (IAV) is a highly infectious pathogen responsible for causing severe respiratory illness and death in humans and animals worldwide. Due to highly effective strategies to negate host antiviral defenses, IAV leads to the death of nearly all infected cells. Furthermore, IAV induces high levels of genome-damaging oxidative stress within infected cells and suppresses the cellular mismatch repair (MMR) mechanism, thereby inhibiting expression of key antiviral genes, which further contributes to cell death. However, recent studies have demonstrated that a subset of respiratory epithelial cells, called club cells, are able to non-lytically clear IAV and continue to survive …

Understanding The Impact Of Human Germline Single-Nucleotide Variants, Samuel Adjei

Electronic Theses and Dissertations

All genetic variations in the human genome are due to mutations, and therefore determining the impact of the different categories of mutations, particularly nonsynonymous single nucleotide variants (SNVs) which are the most abundant in the population is essential for understanding the genetics of human diseases. Generations of mutation studies have focused on a relatively small number, partly due to technological limitations. However, advances in next-generation sequencing have allowed for empirical assessments of genome-wide mutations. genome sequence of any individual contains extensive protein-altering genetic variation (missense mutations) and of which only a few are unambiguously deleterious. Characterizing the phenotypes of these …

Growing Meat On Plants: Using Intermediate Cbd-Rgd Fusion Proteins To Improve Bovine Satellite Cell Attachment On Cellulose-Based Scaffolds, Julian Cohen

Pitzer Senior Theses

Cellular agriculture is an emerging technology aiming to replace existing methods for animal agriculture with tissue engineering and cell culture-based technologies. Cultured meat falls within this purview, using a biomimetic approach to recreate animal muscle tissue through tissue engineering. In the attempt to diminish the necessity of animal-derived materials within this process, plant-based scaffolds can be used as a substrate upon which stem cells are cultured. Due to the unfavorable environment of cellulose for mammalian cell-surface proteins, the approach was taken of coating cellulose nanofiber films with a fusion protein composed of a cellulose binding domain (CBD) protein and the …

Synthesis Of Oligonucleotides Containing Unnatural Backbone And Regulation Of Crispr Activity Using Inverse Electron Demand Diels-Alder Chemistry, Alyssa Hoy

Legacy Theses & Dissertations (2009 - 2024)

This thesis describes the synthesis of an oligonucleotide containing an unnatural neutralbackbone. The backbone was constructed using bio-orthogonal inverse electron demand Diels- Alder chemistry between trans-cyclooctene (TCO) and tetrazine (Tz). A TCO phosphoramidite was synthesized and attached to solid support for strand propagation. Uridine monomers containing either bis-TCO or bis-Tz were also synthesized. The oligonucleotide strand was formed by sequential ligation of the bis-Tz and bis-TCO monomers. The oligonucleotide was analyzed using mass spectrometry. This thesis also describes the synthesis of sgRNAs containing non-canonical nucleobases, m1A, m6A, s2U and s4U using the ‘split-and-click’ methodology. The synthetic sgRNAs were assembled using …

Dissecting The Cellular Landscape And Transcriptome Network In Viral Myocarditis By Single-Cell Rna Sequencing, Ninaad Lasrado, Nicholas Borcherding, Rajkumar Arumugam, Timothy K. Starr, Jay Reddy

School of Veterinary and Biomedical Sciences: Faculty Publications

Coxsackievirus B3 (CVB3)-induced myocarditis is commonly employed to study viral pathogenesis in mice.Chronically affected micemaydevelop dilated cardiomyopathy, which may involve the mediation of immune and nonimmune cells. To dissect this complexity, we performed single-cell RNA sequencing on heart cells from healthy and myocarditic mice, leading us to note significant proportions of myeloid cells, T cells, and fibroblasts. Although the transcriptomes of myeloid cells were mainly of M2 phenotype, the Th17 cells, CTLs, and Treg cells had signatures critical for cytotoxic functions. Fibroblasts were heterogeneous expressing genes important in fibrosis and regulation of inflammation and immune responses. The intercellular communication networks …

Mhc Diversity Analysis Of Spheniscus Demersus For In Situ And Ex Situ Populations, Antonieta Van Den Berg Monsalve

Undergraduate Honors Thesis Projects

The South African Penguin has been listed as endangered by the International Union for Conservation of Nature. Major histocompatibility complex (MHC) alleles provide valuable statistics because of their variation in terms of vertebrate genomes and are pertinent to immune and reproductive health. A greater number of MHC alleles correlates with survivability of a population because the genes control the immune and reproductive systems. Legacy research by Otterbein alumni and Dr. Simon Lawrance studied MHC samples from wild, in situ, and captive, ex situ, penguin populations. By comparing these populations' major histocompatibility complexes through biostatistical analysis, contributions to conservation of the …

Molecular Mechanism Of Damage-Associated Molecular Patterns In Association With Acute Hepatopancreatic Necrosis Disease Resistance Of Heat Stressed-Shrimp Penaeus Vannamei, Supitcha Wanvimonsuk

Chulalongkorn University Theses and Dissertations (Chula ETD)

Non-lethal heat shock (NLHS) is known to enhance resistance to acute hepatopancreatic necrosis disease caused by Vibrio parahaemolyticus (VPAHPND) in the Pacific white shrimp Penaeus vannamei. Generally, cell damage induced by stresses leads to the release of damage-associated molecular patterns (DAMPs), molecules that act as endogenous danger signals to promote immune response. The first part of this research aims to study molecular mechanism of DAMPs that can enhance innate immunity upon NLHS treatment on VPAHPND resistance. We identified and characterized the candidate NLHS-induced DAMP that can activate innate immune responses against VPAHPND. The candidate DAMP genes were retrieved from the …

Development Of Novel Pyridazine Derivatives And Drug Delivery Systems Against Dengue, Janae A. Culmer

College of Graduate Studies: Theses & Dissertations

The lack of approved vaccines, medications and treatment regimens has significantly contributed to the rapid spread of mosquito-borne viruses such as Dengue and Zika virus. The complex immunopathology of these viruses presents limitations for the development and implementation of a definitive, safe and effective approach to combat infections.Previous research has demonstrated that vector control strategies such as the elimination of larval habitats, larviciding with insecticides, the use of biological agents and the application of adulticides have been unsuccessful in the reduction of viral transmission leading to the need for the continued development of antivirals. This research proposes an approach for …

Investigating The Main Protease (Mpro) Of Sars-Cov-2 As A Potential Drug Target, Valerie Giovina Pascetta

Honors Theses and Capstones

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 19 (COVID-19) pandemic has claimed the lives of roughly 6.2 million people worldwide as of May 2022. The virus’s main protease (M^pro ) has been identified as an attractive drug target due to the critical role it plays in the viral life cycle. The roughly 34 kDa M^pro cleaves functional viral polypeptides out of two long polyproteins at conserved cut sites, allowing them to fulfill their role in processes like transcription and replication. Here, we have studied the enzymatic activity …

Simulation Of An Inflammatory Model Using Schwann Cells, Caitlyn E. Henry, Peyton Kimmel, Mackenzie Wilcox, Angela Asirvatham

SURF Posters 2022

Schwann cells are a type of glial cell in the peripheral nervous system that produce the myelin sheath surrounding neuronal axons. This myelin insulates the neurons and promotes the rapid conduction of electrical impulses throughout the body. Schwann cells have also been found to play a critical role in neuron repair following nerve injury. During nerve injury, the myelin sheath is damaged, stimulating Schwann cells to release cytokines, or inflammatory mediators, that recruit immune cells to the site of injury so that the myelin debris can be cleared, and repair can take place.1 Then neuronal growth is facilitated by heregulin …

Evaluation Of Ivermectin Antiviral Activity Against Avian Infectious Bronchitis Virus Using A Chicken Embryo Model, Donald L. Reynolds, E. Barry Simpson

School of Veterinary and Biomedical Sciences: Faculty Publications

Ivermectin is widely used in both animals and humans as an FDA-approved parasiticide. Ivermectin has also been reported to have antiviral activity against several viruses including coronaviruses. There are reports that indicate ivermectin may have some role in diminishing the disease caused by SARS-CoV-2, but the evidence is inconclusive. The objective of this study was to determine if ivermectin was efficacious in inhibiting avian infectious bronchitis virus (IBV, a coronavirus) replication in chicken embryos. Briefly, our approach was to use the Massachusetts vaccine strain of IBV in combination with various doses of ivermectin and then inoculate these preparations into chicken …

Structural Variant-Based Pangenome Construction Has Low Sensitivity To Variability Of Haplotype-Resolved Bovine Assemblies, Alexander S. Leonard, Danang Crysnanto, Zih-Hua Fang, Michael P. Heaton, Brian L. Vander Ley, Carolina Herrera, Heinrich Bollwein, Derek M. Bickhart, Benjamin D. Rosen, Hubert Pausch

School of Veterinary and Biomedical Sciences: Faculty Publications

Advantages of pangenomes over linear reference assemblies for genome research have recently been established. However, potential effects of sequence platform and assembly approach, or of combining assemblies created by different approaches, on pangenome construction have not been investigated. Here we generate haplotype-resolved assemblies from the offspring of three bovine trios representing increasing levels of heterozygosity that each demonstrate a substantial improvement in contiguity, completeness, and accuracy over the current Bos taurus reference genome. Diploid coverage as low as 20x for HiFi or 60x for ONT is sufficient to produce two haplotype-resolved assemblies meeting standards set by the Vertebrate Genomes Project. …

Does Swab Type Matter? Comparing Methods For Mannheimia Haemolytica Recovery And Upper Respiratory Microbiome Characterization In Feedlot Cattle, William B. Crosby, Lee Pinnell, John T. Richeson, Cory Wolfe, Jake Castle, John Dustin Loy, Sheryl P. Gow, Keun Seok Seo, Sarah F. Capik, Amelia R. Woolums, Paul S. Morley

School of Veterinary and Biomedical Sciences: Faculty Publications

Background: Bovine respiratory disease (BRD) is caused by interactions among host, environment, and pathogens. One standard method for antemortem pathogen identification in cattle with BRD is deep-guarded nasopharyngeal swabbing, which is challenging, costly, and waste generating. The objective was to compare the ability to recover Mannheimia haemolytica and compare microbial community structure using 29.5 inch (74.9 cm) deep-guarded nasopharyngeal swabs, 16 inch (40.6 cm) unguarded proctology swabs, or 6 inch (15.2 cm) unguarded nasal swabs when characterized using culture, real time-qPCR, and 16S rRNA gene sequencing. Samples for aerobic culture, qPCR, and 16S rRNA gene sequencing were collected from the …

Rna Nanovaccine Protects Against White Spot Syndrome Virus In Shrimp, Yashdeep Phanse, Supraja Puttamreddy, Duan Loy, Julia Vela Ramirez, Kathleen A. Ross, Ignacio Alvarez-Castro, Mark Mogler, Scott Broderick, Krishna Rajan, Balaji Narasimhan, Lyric C. Bartholomay

School of Veterinary and Biomedical Sciences: Faculty Publications

In the last 15 years, crustacean fisheries have experienced billions of dollars in economic losses, primarily due to viral diseases caused by such pathogens as white spot syndrome virus (WSSV) in the Pacific white shrimp Litopenaeus vannamei and Asian tiger shrimp Penaeus monodon. To date, no effective measures are available to prevent or control disease outbreaks in these animals, despite their economic importance. Recently, double-stranded RNA-based vaccines have been shown to provide specific and robust protection against WSSV infection in cultured shrimp. However, the limited stability of double-stranded RNA is the most significant hurdle for the field application of these …

Structural Basis Of Bacterial Flagellin For Naip5 Binding And Nlrc4 Inflammasome Activation And The Mechanism Of Flagellin Induced Release Of Cytokines In Vivo, Jian Cui

Theses and Dissertations--Chemistry

The bacterial flagellum is a whip-like structure that protrudes from the cell membrane and is one of the most complex and dynamic biological molecular machines that propels bacteria to swim toward beneficial environments and the sites of infection. It is composed of a basal body, a hook, and a long filament. The flagellar filament contains thousands of copies of the protein flagellin (FliC) monomer arranged helically and ending with a filament cap composed of oligomer protein FliD. The overall structure of the filament core is preserved across bacterial species, while the outer domains exhibit high variability, and in some cases …

Mechanism Of Antibiotic Permeability Through The Gram-Negative Bacterial Envelope, Olaniyi Alegun

Theses and Dissertations--Chemistry

The outer membrane of Gram-negative bacteria (GN) makes them distinct among superbugs that are associated with the development of antibiotic resistance. The outer membrane, and inner membrane, separated by the periplasm, form a double-membrane barrier to the entry of antibiotics into the cell. Several studies have been conducted to examine the role of outer membrane modifications such as porins, lipopolysaccharides, and efflux pumps on antibiotic resistance. However, there is a paucity of knowledge on how antibiotics behave in the periplasm, to gain access into their target region. My thesis focuses on understanding the mechanism of antibiotic permeability through the cellular …

Antibiotic Permeation In Gram-Negative Bacteria And Contribution Of Inflammasome Activation And Pyroptosis In Pathogenesis Of Salmonella Systemic Infection, Ankit Pandeya

Theses and Dissertations--Chemistry

Antibiotic resistance is one of the major global issues in the field of public health and medicine. Good antibiotic candidates need to be selectively toxic, inhibit cellular target, and effectively penetrate and accumulate in bacterial cells. The last factor is a formidable barrier in the development of antimicrobials effective in Gram-negative bacteria, due to the presence of two layers of cell envelope. The first half of my thesis focuses on understanding the permeation of small molecules through this formidable cell envelope, distribution inside the cell of Gram-negative bacteria, and design of novel methods to make small molecules effectively cross the …

The Role Of Rad51 In Trichomonas Vaginalis, Dominique Hall

University of the Pacific Theses and Dissertations

Drug resistance to the current treatments on the market is on the rise, therefore there is strong interest in understanding what could be causing the resistance, how resistance could be spreading through the population, and finding some possible new drug targets. One protein of interest is Radiation Sensitive Protein 51 (Rad51). It is a protein that is involved in homologous recombination as well as other processes such as DNA damage repair. While Trichomonas vaginalis traditionally has been known to replicate via binary fission, a modified form of closed mitosis, there is some evidence that meiosis, or at least some form …

Isolation And Characterization Of Bacteriophage Targeting Acute Hepatopancreatic Necrosis Disease-Causing Vibrio Parahaemolyticus, Khrongkhwan Thammatinna

Chulalongkorn University Theses and Dissertations (Chula ETD)

Vibrio parahaemolyticus causing Acute hepatopancreatic necrosis disease (VPAHPND) has been a major cause of serious shrimp aquaculture economic losses. Moreover, many isolates have exhibited the resistance of various antibiotic drugs. Most recently, bacteriophage or phage, the killer of bacteria, has been gaining interest as an alternative tool to prevent and control pathogens. In this study, we discovered two novel vibriophages - vibriophage Seahorse and vibriophage phiKT1024 – that target various strains of VPAHPND. vibriophage Seahorse and vibriophage phiKT1024 were assigned to the family Siphoviridae and Myoviridae, respectively. Based on the cut-off of genome size that is less than 200 kbp …

Adult Memory T Cell Responses To The Respiratory Syncytial Virus Fusion Protein During A Single Rsv Season (2018-2019), Brittani N Blunck, Laura S Angelo, David Henke, Vasanthi Avadhanula, Matthew Cusick, Laura Ferlic-Stark, Lynn Zechiedrich, Brian E Gilbert, Pedro A Piedra

Faculty, Staff and Students Publications

Respiratory Syncytial Virus (RSV) is ubiquitous and re-infection with both subtypes (RSV/A and RSV/B) is common. The fusion (F) protein of RSV is antigenically conserved, induces neutralizing antibodies, and is a primary target of vaccine development. Insight into the breadth and durability of RSV-specific adaptive immune response, particularly to the F protein, may shed light on susceptibility to re-infection. We prospectively enrolled healthy adult subjects (n = 19) and collected serum and peripheral blood mononuclear cells (PBMCs) during the 2018–2019 RSV season. Previously, we described their RSV-specific antibody responses and identified three distinct antibody kinetic profiles associated with infection …

Capsaicinoids From Capsicum Annuum As An Alternative Fabh Inhibitor Of Mycobacterium Tuberculosis: In Silico Study, Gabriella Chandrakirana Krisnamurti, Dewi Ratih Tirto Sari, Yohanes Bare

Makara Journal of Science

The number of tuberculosis (TB) cases worldwide reached 1.5 million in 2018; thus, TB is considered a deadly disease. TB is caused by Mycobacterium tuberculosis and involves lipid synthesis. Considering the importance of lipid metabolism in bacteria, FabH may be an essential protein target for repressing lipid synthesis. Capsaicinoids from Capsicum annuum demonstrate potent antibacterial activity. This study predicted the ability of capsaicinoid compounds to inhibit FabH. In silico analysis was performed by retrieving the structure of FabH from PDB and those of selected capsaicinoid derivatives from PubChem. The compounds were docked using AutoDock Vina in PyRx 0.8 software. The …

Likely Community Transmission Of Covid-19 Infections Between Neighboring, Persistent Hotspots In Ontario, Canada, Ben C. Shirley, Eliseos J. Mucaki, Peter Rogan

Biochemistry Publications

Introduction: This study aimed to produce community-level geo-spatial mapping of confirmed COVID-19 cases in Ontario Canada in near real-time to support decision-making. This was accomplished by area-to-area geostatistical analysis, space-time integration, and spatial interpolation of COVID-19 positive individuals.
Methods: COVID-19 cases and locations were curated for geostatistical analyses from March 2020 through June 2021, corresponding to the first, second, and third waves of infections. Daily cases were aggregated according to designated forward sortation area (FSA), and postal codes (PC) in municipal regions Hamilton, Kitchener/Waterloo, London, Ottawa, Toronto, and Windsor/Essex county. Hotspots were identified with area-to-area tests including Getis-Ord Gi*, Global …

Cryptococcus Neoformans Melanization Incorporates Multiple Catecholamines To Produce Polytypic Melanin, Rosanna P. Baker, Christine Chrissian, Ruth E. Stark, Arturo Casadevall

Publications and Research

Melanin is a major virulence factor in pathogenic fungi that enhances the ability of fungal cells to resist immune clearance. Cryptococcus neoformans is an important human pathogenic fungus that synthesizes melanin from exogenous tissue catecholamine precursors during infection, but the type of melanin made in cryptococcal meningoencephalitis is unknown. We analyzed the efficacy of various catecholamines found in brain tissue in supporting melanization using animal brain tissue and synthetic catecholamine mixtures reflecting brain tissue proportions. Solid-state NMR spectra of the melanin pigment produced from such mixtures yielded more melanin than expected if only the preferred constituent dopamine had been incorporated, …

Arginine-Rich Polypeptides Are Potent Inhibitors Of Human Papillomavirus Infection And Powerful Tools To Investigate Viral Attachment And Entry, Jesse Mckay Young

Biomedical Sciences ETDs

HPV is the most common sexually transmitted infection. It is estimated that 80% of sexually active adults will contract an HPV infection. Thus, there is a significant need for low-cost and easily distributable HPV antivirals that can be used alongside vaccines to combat infection. Herein I have identified protamine sulfate (PS) as a potent microbicide against HPV infection. PS was agnostic to genotype and efficacious pre and post HPV exposure. PS application topically reduced HPV internalization by altering epidermal growth factor receptor (EGFR) signaling and suppressed EGFR-stimulated HPV entry. Our preliminary data also suggest that heparin binding epidermal growth factor …

Intrinsically Disordered Protein Regions In Human Evolution And As Therapeutic Targets, Karen Paco Mendivil

KGI Theses and Dissertations

Intrinsically disordered proteins (IDPs) and IDP regions (IDPRs) fail to form stable structures but have important biological functions via interacting with various molecular partners (proteins, DNA, RNA, glycosaminoglycans). We hypothesized that IDPRs are potential targets for therapeutics development because they are reservoirs of evolutionary innovation, and they play crucial roles in adaptation to pathogens.

We first studied the evolution of IDPRs in the human proteome and compared it with the proteome of non-human primates. We have found that evolutionary young protein-coding genes have included low conserved regions in the N-terminal part of proteins, and such regions are linked to high …