Medicine and Health Sciences Commons^™

On The Need To Develop Guidelines For Characterizing And Reporting Intrinsic Disorder In Proteins, Michael Vincent, Vladimir N. Uversky, Santiago Schnell

Molecular Medicine Faculty Publications

Since the early 2000s, numerous computational tools have been created and used to predict intrinsic disorder in proteins. At present, the output from these algorithms is difficult to interpret in the absence of standards or references for comparison. There are many reasons to establish a set of standard-based guidelines to evaluate computational protein disorder predictions. This viewpoint explores a handful of these reasons, including standardizing nomenclature to improve communication, rigor and reproducibility, and making it easier for newcomers to enter the field. An approach for reporting predicted disorder in single proteins with respect to whole proteomes is discussed. The suggestions …

Cyclized Ndga Modifies Dynamic Α-Synuclein Monomers Preventing Aggregation And Toxicity, Malcolm J. Daniels, J. Brucker Nourse, Hanna Kim, Valerio Sainati, Marco Schiavina, Maria Grazia Murrali, Buyan Pan, John J. Ferrie, Conor M. Haney, Rani Moons, Neal S. Gould, Antonino Natalello, Rita Grandori, Frank Sobott, E. James Petersson, Elizabeth Rhoades, Roberta Pierattelli, Isabella Felli, Vladimir N. Uversky, Kim A. Caldwell, Guy A. Caldwell, Edward S. Krol, Harry Ischiropoulos

Molecular Medicine Faculty Publications

Growing evidence implicates α-synuclein aggregation as a key driver of neurodegeneration in Parkinson’s disease (PD) and other neurodegenerative disorders. Herein, the molecular and structural mechanisms of inhibiting α-synuclein aggregation by novel analogs of nordihydroguaiaretic acid (NDGA), a phenolic dibenzenediol lignan, were explored using an array of biochemical and biophysical methodologies. NDGA analogs induced modest, progressive compaction of monomeric α-synuclein, preventing aggregation into amyloid-like fibrils. This conformational remodeling preserved the dynamic adoption of α-helical conformations, which are essential for physiological membrane interactions. Oxidation-dependent NDGA cyclization was required for the interaction with monomeric α-synuclein. NDGA analog-pretreated α-synuclein did not aggregate even without …

Small Heat Shock Proteins, Big Impact On Protein Aggregation In Neurodegenerative Disease, Jack M. Webster, April L. Darling, Vladimir N. Uversky, Laura J. Blair

Molecular Medicine Faculty Publications

Misfolding, aggregation, and aberrant accumulation of proteins are central components in the progression of neurodegenerative disease. Cellular molecular chaperone systems modulate proteostasis, and, therefore, are primed to influence aberrant protein-induced neurotoxicity and disease progression. Molecular chaperones have a wide range of functions from facilitating proper nascent folding and refolding to degradation or sequestration of misfolded substrates. In disease states, molecular chaperones can display protective or aberrant effects, including the promotion and stabilization of toxic protein aggregates. This seems to be dependent on the aggregating protein and discrete chaperone interaction. Small heat shock proteins (sHsps) are a class of molecular chaperones …

Intrinsically Disordered Proteins And Their “Mysterious” (Meta)Physics, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Recognition of the natural abundance and functional importance of intrinsically disordered proteins (IDPs), and protein hybrids that contain both intrinsically disordered protein regions (IDPRs) and ordered regions, is changing protein science. IDPs and IDPRs, i.e., functional proteins and protein regions without unique structures, can often be found in all organisms, and typically play vital roles in various biological processes. Disorder-based functionality complements the functions of ordered proteins and domains. However, by virtue of their existence, IDPs/IDPRs, which are characterized by remarkable conformational flexibility and structural plasticity, break multiple rules established over the years to explain structure, folding, and functionality of …

Rational Discovery Of Antimetastatic Agents Targeting The Intrinsically Disordered Region Of Mbd2, Min Young Kim, Insung Na, Ji Sook Kim, Seung Han Son, Sungwoo Choi, Seol Eui Lee, Ji-Hun Kim, Kiseok Jang, Gil Alterovitz, Yu Chen, Arjant Van Der Vaar, Hyung-Sik Won, Vladimir N. Uversky, Chul Geun Kim

Molecular Medicine Faculty Publications

Although intrinsically disordered protein regions (IDPRs) are commonly engaged in promiscuous protein-protein interactions (PPIs), using them as drug targets is challenging due to their extreme structural flexibility. We report a rational discovery of inhibitors targeting an IDPR of MBD2 that undergoes disorder-to-order transition upon PPI and is critical for the regulation of the Mi-2/NuRD chromatin remodeling complex (CRC). Computational biology was essential for identifying target site, searching for promising leads, and assessing their binding feasibility and off-target probability. Molecular action of selected leads inhibiting the targeted PPI of MBD2 was validated in vitro and in cell, followed by confirming their …

Intrinsic Disorder-Based Emergence In Cellular Biology: Physiological And Pathological Liquid-Liquid Phase Transitions In Cells, April L. Darling, Boris Zaslavsky, Vladimir N. Uversky

Molecular Medicine Faculty Publications

The visible outcome of liquid-liquid phase transitions (LLPTs) in cells is the formation and disintegration of various proteinaceous membrane-less organelles (PMLOs). Although LLPTs and related PMLOs have been observed in living cells for over 200 years, the physiological functions of these transitions (also known as liquid-liquid phase separation, LLPS) are just starting to be understood. While unveiling the functionality of these transitions is important, they have come into light more recently due to the association of abnormal LLPTs with various pathological conditions. In fact, several maladies, such as various cancers, different neurodegenerative diseases, and cardiovascular diseases, are known to be …

Evolutionary Analyses Of Sequence And Structure Space Unravel The Structural Facets Of Sod1, Sourav Chowdury, Dwipanjan Sanyal, Sagnik Sen, Vladimir N. Uversky, Ujjwal Maulik, Krishnananda Chattopadhyay

Molecular Medicine Faculty Publications

Superoxide dismutase (SOD) is the primary enzyme of the cellular antioxidant defense cascade. Misfolding, concomitant oligomerization, and higher order aggregation of human cytosolic SOD are linked to amyotrophic lateral sclerosis (ALS). Although, with two metal ion cofactors SOD1 is extremely robust, the de-metallated apo form is intrinsically disordered. Since the rise of oxygen-based metabolism and antioxidant defense systems are evolutionary coupled, SOD is an interesting protein with a deep evolutionary history. We deployed statistical analysis of sequence space to decode evolutionarily co-varying residues in this protein. These were validated by applying graph theoretical modelling to understand the impact of the …

Life In Phases: Intra- And Inter- Molecular Phase Transitions In Protein Solutions, Vladimir N. Uversky, Alexey V. Finkelstein

Molecular Medicine Faculty Publications

Proteins, these evolutionarily-edited biological polymers, are able to undergo intramolecular and intermolecular phase transitions. Spontaneous intramolecular phase transitions define the folding of globular proteins, whereas binding-induced, intra- and inter- molecular phase transitions play a crucial role in the functionality of many intrinsically-disordered proteins. On the other hand, intermolecular phase transitions are the behind-the-scenes players in a diverse set of macrosystemic phenomena taking place in protein solutions, such as new phase nucleation in bulk, on the interface, and on the impurities, protein crystallization, protein aggregation, the formation of amyloid fibrils, and intermolecular liquid–liquid or liquid–gel phase transitions associated with the biogenesis …

Structural And Dynamical Order Of A Disordered Protein: Molecular Insights Into Conformational Switching Of Page4 At The Systems Level, Xingcheng Lin, Prakash Kulkarni, Federico Bocci, Nicholas P. Schafer, Susmita Roy, Min-Yeh Tsai, Yanan He, Yihong Chen, Krithika Rajagopalan, Steven M. Mooney, Yu Zeng, Keith Weninger, Alex Grishaev, José N. Onuchic, Herbet Levine, Peter G. Wolynes, Ravi Salgia, Govindan Rangarajan, Vladimir N. Uversky, John Orban, Mohit Kumar Jolly

Molecular Medicine Faculty Publications

Folded proteins show a high degree of structural order and undergo (fairly constrained) collective motions related to their functions. On the other hand, intrinsically disordered proteins (IDPs), while lacking a well-defined three-dimensional structure, do exhibit some structural and dynamical ordering, but are less constrained in their motions than folded proteins. The larger structural plasticity of IDPs emphasizes the importance of entropically driven motions. Many IDPs undergo function-related disorder-to-order transitions driven by their interaction with specific binding partners. As experimental techniques become more sensitive and become better integrated with computational simulations, we are beginning to see how the modest structural ordering …

Intrinsic Disorder Of The Baf Complex: Roles In Chromatin Remodeling And Disease Development, Nashwa El Hadidy, Vladimir N. Uversky

Molecular Medicine Faculty Publications

The two-meter-long DNA is compressed into chromatin in the nucleus of every cell, which serves as a significant barrier to transcription. Therefore, for processes such as replication and transcription to occur, the highly compacted chromatin must be relaxed, and the processes required for chromatin reorganization for the aim of replication or transcription are controlled by ATP-dependent nucleosome remodelers. One of the most highly studied remodelers of this kind is the BRG1- or BRM-associated factor complex (BAF complex, also known as SWItch/sucrose non-fermentable (SWI/SNF) complex), which is crucial for the regulation of gene expression and differentiation in eukaryotes. Chromatin remodeling complex …

Experimental Insight Into The Structural And Functional Roles Of The ‘Black’ And ‘Gray’ Clusters In Recoverin, A Calcium Binding Protein With Four Ef-Hand Motifs, Sergei E. Permyakov, Alisa S. Vologzhannikova, Ekaterina L. Nemashkalova, Alexei S. Kazakov, Alexander I. Denesyuk, Konstantin Denessiouk, Viktoriia E. Baksheeva, Andrey A. Zamyatnin Jr., Eugene Yu. Zernii, Vladimir N. Uversky, Eugene A. Permyakov

Molecular Medicine Faculty Publications

Recently, we have found that calcium binding proteins of the EF-hand superfamily (i.e., a large family of proteins containing helix-loop-helix calcium binding motif or EF-hand) contain two types of conserved clusters called cluster I (‘black’ cluster) and cluster II (‘grey’ cluster), which provide a supporting scaffold for the Ca2+ binding loops and contribute to the hydrophobic core of the EF-hand domains. Cluster I is more conservative and mostly incorporates aromatic amino acids, whereas cluster II includes a mix of aromatic, hydrophobic, and polar amino acids of different sizes. Recoverin is EF-hand Ca2+-binding protein containing two ‘black’ clusters comprised of F35, …

Many-To-One Binding By Intrinsically Disordered Protein Regions, Wei-Lun Alterovitz, Eshel Faraggi, Christopher J. Oldfield, Jingwei Meng, Bin Xue, Fei Huang, Pedro Romero, Andrzej Kloczkowski, Vladimir N. Uversky, A. Keith Dunker

Molecular Medicine Faculty Publications

Disordered binding regions (DBRs), which are embedded within intrinsically disordered proteins or regions (IDPs or IDRs), enable IDPs or IDRs to mediate multiple protein-protein interactions. DBR-protein complexes were collected from the Protein Data Bank for which two or more DBRs having different amino acid sequences bind to the same (100% sequence identical) globular protein partner, a type of interaction herein called many-to-one binding. Two distinct binding profiles were identified: independent and overlapping. For the overlapping binding profiles, the distinct DBRs interact by means of almost identical binding sites (herein called “similar”), or the binding sites contain both common and divergent …

Hiv Vaccine Mystery And Viral Shell Disorder, Gerard Kian-Meng Goh, A. Keith Dunker, James A. Foster, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Hundreds of billions of dollars have been spent for over three decades in the search for an effective human immunodeficiency virus (HIV) vaccine with no success. There are also at least two other sexually transmitted viruses, for which no vaccine is available, the herpes simplex virus (HSV) and the hepatitis C virus (HCV). Traditional textbook explanatory paradigm of rapid mutation of retroviruses cannot adequately address the unavailability of vaccine for many sexually transmissible viruses, since HSV and HCV are DNA and non-retroviral RNA viruses, respectively, whereas effective vaccine for the horsefly-transmitted retroviral cousin of HIV, equine infectious anemia virus (EIAV), …

Intrinsically Disordered Proteins In Chronic Diseases, Prakash Kulkarni, Vladimir N. Uversky

Molecular Medicine Faculty Publications

No abstract provided.

Studies On The Potential Regulation Of Usp30 By Omi/Htra2 Protease, Sunmi Jin

Honors Undergraduate Theses

The intent of this thesis is to determine whether the deubiquitinating enzyme ubiquitin specific protease 30 (USP30) is cleaved by Omi/HtrA2 (hereafter referred to as Omi) protease during mitochondrial stress. USP30 is a mitochondrial protein that is anchored in the outer mitochondrial membrane and has components in the intermembrane space (IMS) as well as in the cytoplasm. USP30's IMS component has a six-amino-acid sequence that is very similar to Omi's consensus cleavage sites. Under normal conditions, Omi resides exclusively within the IMS; therefore, if Omi were to cleave USP30, it would target the part of the protein located in the …

Role Of T-Bet In Production Of Immunoglobulin Isotypes In An Influenza Setting, David Sidhom

Honors Undergraduate Theses

Influenza is one of the most common diseases worldwide, yet the vaccines against influenza are only 35% effective at protecting against infection. Creating a more effective vaccine requires an understanding of the foundation and the factors that contribute to a strong and protective adaptive immune response. T-bet [TBX21] is a transcription factor that plays an instrumental role in the orchestration of the type 1 immune response, which is the specialized response used by the immune system for a cell-mediated response against intracellular pathogens, such as influenza. It has yet to be explored in an influenza setting on the role T-bet …

A Meta-Analysis Of Neuromyelitis Optica Epidemiology In Latin American Nations, Brittany M. Zengotita

Honors Undergraduate Theses

Neuromyelitis Optica (NMO) is a rare, autoimmune, neurodegenerative disease selectively affecting the optic nerves and spinal cord. Relapsing NMO is nine times more prevalent in women than in men and approximately one-quarter of NMO patients have symptoms of another autoimmune disorder (National Institute of Health, 2019). NMO has not been linked to any genetic mutations and the cause of the disorder is unknown beyond the general understanding that the body produces anti-aquaporin-4 antibodies (AQP4) which mistakenly attack cells in the nervous system. NMO affects roughly one percent of that of Multiple Sclerosis (4000-8000 patients total) in the United States, but …

Long-Term Outcomes Of Neonatal Herpes Simplex Virus Infection And Treatment, Genesis M. Brador

Honors Undergraduate Theses

The prevalence of herpes simplex virus (HSV) infection globally is high, and although there is no cure for it, the antiviral drug acyclovir is used to alleviate symptoms. There are two types of HSV: HSV-1, which typically infects the oral area, and HSV-2, which is associated with genital infections. A mother who carries the infection may transmit it to a neonate in different ways, most commonly via vaginal delivery in the presence of active lesions. There are three types of HSV disease that affect newborns: skin, eyes or mouth (SEM) disease, central nervous system (CNS) disease, or disseminated disease. The …

Healthcare Robotics: Key Factors That Impact Robot Adoption In Healthcare, Sujatha Alla, Pilar Pazos

Engineering Management & Systems Engineering Faculty Publications

In the current dynamic business environment, healthcare organizations are focused on improving patient satisfaction, performance, and efficiency. The healthcare industry is considered a complex system that is highly reliant of new technologies to support clinical as well as business processes. Robotics is one of such technologies that is considered to have the potential to increase efficiency in a wide range of clinical services. Although the use of robotics in healthcare is at the early stages of adoption, some studies have shown the capacity of this technology to improve precision, accessibility through less invasive procedures, and reduction of human error during …

Stresi Dhe Niveli I Burn-Out (Shterrimit) Tek Profesionistet E Shëndetit Mendor Në Prizren, Herolind Fanaj

Theses and Dissertations

Stresi në punë si dhe djegia janë gjetur në profesione të ndryshme në nivele të ndryshme. Me qëllim të hulumtimit të nivelit të stresit dhe të djegies (burn-outit) tek punëtorët profesional të shëndetit mendor në Prizren si dhe të njejtën kohë edhe shkaktarët e mundshëm të tyre janë përdorur pyetësorët Maslach Burnout Inventory dhe Forma vetë-raportuese e kënaqësisë në punë dhe shkaktarëve të mundshëm të stresit dhe të djegies (burn-out). Pjesëmarrës në hulumtim ishin (N=24, Mmes=41.19, DS=8.03), respodent të dy gjinive, ka dominuar gjinia femrore me 16 respodent apo 66.7%. Ka rezultuar nivel i lartë i stresit tek 66.7 % …

Characteristics, Services, And Outcomes Of Vocational Rehabilitation Consumers Who Are Deaf-Blind, Jennifer L. Cmar, Michele C. Mcdonnall

JADARA

Limited research has been conducted regarding the characteristics, services, and outcomes of consumers served by Vocational Rehabilitation (VR) agencies in the United States who are deaf-blind. This article provides descriptive information about this population based on Rehabilitation Services Administration Case Service Report (RSA-911) data from fiscal years 2013, 2014, and 2015. The article also includes a discussion of inconsistencies in use of disability category codes to classify VR consumers who are deaf-blind, emphasizing the need for agencies to utilize a consistent classification system that reflects the diverse characteristics of this population.

Prophylactic Treatment Of Hyperbaric Oxygen Treatment Mitigates Inflammatory Response Via Mitochondria Transfer, Trenton Lippert, Cesar V. Borlongan

Neurosurgery and Brain Repair Faculty Publications

No abstract provided.

Concise Review: Stem Cell Therapy For Stroke Patients: Are We There Yet?, Cesar V. Borlongan

Neurosurgery and Brain Repair Faculty Publications

Four decades of preclinical research demonstrating survival, functional integration, and behavioral effects of transplanted stem cells in experimental stroke models have provided ample scientific basis for initiating limited clinical trials of stem cell therapy in stroke patients. Although safety of the grafted cells has been overwhelmingly documented, efficacy has not been forthcoming. Two recently concluded stroke clinical trials on mesenchymal stem cells (MSCs) highlight the importance of strict adherence to the basic science findings of optimal transplant regimen of cell dose, timing, and route of delivery in enhancing the functional outcomes of cell therapy. Echoing the Stem Cell Therapeutics as …

Microrna-133a And Myocardial Infarction, Yi Xiao, Jiling Zhao, Julian P. Tuazon, Cesar V. Borlongan, Guolong Yu

Neurosurgery and Brain Repair Faculty Publications

Myocardial infarction (MI) is the leading cause of morbidity and mortality in the world. The infarcted heart displays typical cell death cascades characterized by a loss of cells and fibrotic scarring in the myocardium. Cardiac hypertrophy and fibrosis largely contribute to ventricular wall thickening and stiffening, altogether defining an adverse cardiac remodeling that ultimately leads to impaired cardiac function and subsequent heart failure. Finding a strategy to promote therapeutic, instead of detrimental, cardiac remodeling may pose as a potent MI treatment. Accumulating evidence shows that microRNAs (miRNAs) may play an essential role in cardiovascular diseases. In particular, microRNA-133a (miR-133a) is …

A Hallmark Clinical Study Of Cord Blood Therapy In Adults With Ischemic Stroke, Paul R. Sanberg, Jared Ehrhart

Neurosurgery and Brain Repair Faculty Publications

The therapeutic application of human umbilical cord blood cells has been an area of great interest for at least the last 25 years. Currently, cord blood cells are approved for reconstitution of the bone marrow following myeloablation in both young and old patients with myeloid malignancies and other blood cancers. Translational studies investigating alternative uses of cord blood have also shown that these cells not only stimulate neurogenesis in the aged brain but are also potentially therapeutic in the treatment of adult neurodegenerative disorders including amyotrophic lateral sclerosis, Alzheimer’s disease, ischemic stroke, traumatic brain injury, and Parkinson’s disease. Recent advances …

Immunomodulation With Human Umbilical Cord Blood Stem Cells Ameliorates Ischemic Brain Injury – A Brain Transcriptome Profiling Analysis, Maple L. Shiao, Ce Yuan, Andrew T. Crane, Joseph P. Voth, Mario Juliano, Laura L. Hocum Stone, Zhenghong Nan, Ying Zhang, Nicole Kuzmin-Nichols, Paul R. Sanberg, Andrew W. Grande, Walter C. Low

Neurosurgery and Brain Repair Faculty Publications

Our group previously demonstrated that administration of a CD34-negative fraction of human non- hematopoietic umbilical cord blood stem cells (UCBSC) 48 h after ischemic injury could reduce infarct volume by 50% as well as significantly ameliorate neurological deficits. In the present study, we explored possible mechanisms of action using next generation RNA sequencing to analyze the brain transcriptome profiles in rats with ischemic brain injury following UCBSC therapy. Two days after ischemic injury, rats were treated with UCBSC. Five days after administration, total brain mRNA was then extracted for RNAseq analysis using Illumina Hiseq 2000. We found 275 genes that …

Awareness Matters: Improving Healthcare Workers’ Self-Efficacy, Knowledge, Skills And Attitudes Related To Mental Illness And Suicide Prevention, Carlana J. Coogle

Doctor of Nursing Practice Projects

Problem Description

Healthcare workers’ (HCWs) negative stigmas, poor attitudes, and lack of knowledge impact the care delivered to patients with a mental illness or who may be suffering with suicidal thoughts.

Rationale

Raising HCWs’ awareness, knowledge and skills have been linked to improving the negative stigmas, biases, and attitudes that impede the care required to achieve optimal health outcomes.

Intervention

Participants attended a 90-minute Question, Persuade, Refer (QPR) gatekeeper training, each participant received six bi-weekly emails about mental health issues, suicide prevention, and community resources. A pre/post survey design using the Mental Illness Clinicians’ Attitude Scale (MICA-4) and the Mental …

Examining Patients’ Satisfaction In Jordanian Emergency Departments Through Business Process Improvement Implementation, Mohammed Shaker Ibrahim

Master's Theses and Doctoral Dissertations

There have been recent advancements in healthcare services provision to enhance patients’ satisfaction. Previous research has concluded that Jordanian ratings of service quality and quality of care provided in public hospitals are lower compared to other nations in the region and abroad. These studies, however, failed to utilize any standardized customer satisfaction tools. At the same little empirical research has attempted to investigate the link of business process improvement in Jordanian hospitals to the enhancement of patients’ satisfaction. This research bridges the gap in the literature by first testing and validating SERVQUAL, a customer satisfaction tool, in Jordanian hospital environments …

Impact Of Physicians’ Medical Jargon Use On Patient Behavior, Rutu Dabhi

Master's Theses and Doctoral Dissertations

An open and easy communication is the key to building doctor-patient relationships. It has become increasingly important for doctors to use the right language with their patients. Since doctor-patient communication may include complex technical language and/or medical terminology, it is often difficult for patients to understand their own diagnoses or treatment plans. The purpose of this research was to understand the relationship between physician use of medical terminology and patient satisfaction. An online research survey was sent to 250 random patients at selected clinics/hospitals during February 2019; responses were received from 39 patients. Questions were asked about the participants' use …

Are First Generation Immigrants More Inclined To Participate In Clinical Research?, Aisha Farha

Master's Theses and Doctoral Dissertations

The number of immigrants entering the United States has increased dramatically in the past 30 years, but minorities and ethnic groups are underrepresented in research studies. This study examined first- and second-generation Arab American immigrants in Dearborn, Michigan, using a survey from 65 participants to determine the impact of generation on clinical research participation. Fifty-one (78%) of the respondents were first-generation immigrants, and 14 (22%) were second generation. There was no statistical difference between first- and second-generation immigrants in their willingness to participate in clinical research. Further research with a larger and more diverse population is needed to evaluate willingness …