Genetics and Genomics Commons^™

Steroidogenesis In The Green Anole Lizard Brain And Gonad, Christine Peek

All Graduate Theses, Dissertations, and Other Capstone Projects

Seasonally breeding animals reproduce during certain times of the year and, subsequently, behaviors, steroid hormone levels, and brain morphology change. The green anole lizard (Anolis carolinensis) is an excellent model to study the regulation of steroid hormone production because they have distinct hormonal and behavioral differences between sexes and seasons. As in other vertebrates, steroidogenesis in anoles is under the control of the hypothalamus-pituitary-gonadal (HPG) axis. We tested the hypothesis that natural variations in steroid hormone levels between sexes and seasons are mediated within the brain and gonad by examining four genes involved in steroidogenesis: StAR, Cyp17α1, HSD17β3, and Cyp19α1. …

Development And Characterization Of Histidine-Tagged Hpv16 L2 And Ms2-Arginine-Tagged Recombinant Proteins For Downstream Processes, Tahiyat Alothaim

Dissertations, Master's Theses and Master's Reports

Human papillomaviruses (HPVs) are the most common sexually transmitted infections. Persistent infection with HPV can lead to anogenital cancers including head and neck cancers. Three prophylactic vaccines have been approved to prevent against some types of HPV infection. However, the vaccines are HPV-type specific and protect mostly against the HPV types included in the vaccines. To offer broader protection against more HPV types, studies in the field are developing candidate vaccines targeting a conserved minor capsid protein, L2. Nevertheless, reagents for developing and assessing L2 vaccines are limited. For example, antibodies to assess the antigenicity of some L2 epitopes are …

Paths To Tier 1 Genomics Implementation: A Survey Of Chronic Disease Directors, Amy Ponte

Walden Dissertations and Doctoral Studies

Although evidence is currently available for population-based genetic screening and testing of individuals and their family members for certain hereditary chronic disease conditions (Tier 1), few states have integrated these genomic applications into chronic disease prevention programs. State and territorial chronic disease directors (CDDs) could provide the leadership needed to deliver these applications in more states. The purpose of this study was to determine whether an association exists between current chronic disease genomics funding or specific state genomic activities and the level of knowledge and interests in genomics by these directors. Rogers's diffusion of innovations (DIT) theory was used to …

Characterization Of Staphylococcal Nuclease And Tudor Domain Containing Protein 1 (Snd1) As A Molecular Target In Hepatocellular Carcinoma And Non-Alcoholic Steatohepatitis, Nidhi H. Jariwala

Theses and Dissertations

CHARACTERIZATION OF STAPHYLOCOCCAL NUCLEASE AND TUDOR DOMAIN CONTAINING PROTEIN 1 (SND1) AS A MOLECULAR TARGET IN HEPATOCELLULAR CARCINOMA AND NON-ALCOHOLIC STEATOHEPATITIS

Nidhi Jariwala, PhD

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Integrative Life Sciences

Virginia Commonwealth University, 2017

Devanand Sarkar, M.B.B.S., PhD.

Associate Professor, Department of Human and Molecular Genetics

Virginia Commonwealth University

Richmond, Virginia

SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). Oncoprotein SND1 regulates gene expression at a post-transcriptional level in multiple cancers including hepatocellular carcinoma (HCC). …

Living With Fragile X Syndrome: Occupations As An Outcome Measure In A Clinical Trial, Kaylee E. Gothelf, Ty Duong, Ana Baldinger, Theresa Chase

Student Research Posters

The purpose of this study was to evaluate the use of semi-structured interviews as an outcome measure in a clinical trial for children with fragile X syndrome (FXS) ages 2-6. This qualitative approach was used to analyze twenty-five interviews of parents with children in a double-blind medication trial - sertraline or placebo. The aim was to assess occupational improvements in their child that may not have been detected with the use quantitative outcome measures alone. Results showed greater improvements in the sertraline group in areas of behavior, social participation, sensory-related behaviors, receptive language, education, family impact and therapeutic strategies. Our …

Reactivation Of Hiv-1 Proviruses In Immune-Compromised Mice Engrafted With Human Voa-Negative Cd4+ T Cells, Zhe Yuan, Guobin Kang, Wuxun Lu, Qingsheng Li

Nebraska Center for Virology: Faculty Publications

Background: HIV-1 infection remains incurable on antiretroviral therapy (ART) due to virus latency. To date, enhanced co-culture assays, including viral outgrowth assays (VOA), are commonly used to measure HIV-1 latent reservoirs and evaluate latency-reversing agents (LRAs). However, VOA can only reactivate a small fraction of intact proviruses.

Methods: To explore the utility of NOD scid gamma (NSG) mice as an in vivo model to reactivate HIV-1 proviruses from VOA-negative CD4+ T cells, resting CD4+ T cells from an HIV-1 latently infected individual were isolated and the human CD4+ T cells corresponding to VOA-positive and VOA-negative CD4+ T cells were engrafted …

Analysis Of The Secondary Neurodegenerative Consequences Of Primary Oligodendrocyte Stress Through The Use Of The Novel Obiden Mouse Model, Daniel Zdzislaw Radecki

Wayne State University Dissertations

The work of this project was to develop, test and characterize a potential novel mouse model of the neurodegenerative disease Multiple Sclerosis (MS). Historically, MS has been identified as a primary autoimmune disease of the central nervous system (CNS). However, treatments based on this view have met with limited success, and in most cases, fail to prevent progression of MS from mild to moderate and severe forms. Original observations regarding axonal and neuronal pathology in the white and gray matter of the CNS were rediscovered in the 1990s. These observations indicated that even in the absence of the immune system, …

Investigation On Genetic Modifiers Of Age At Onset Of Major Depressive Disorder, Huseyin Gedik

Theses and Dissertations

Major Depressive Disorder (MDD) is a complex multifactorial disorder, which would lead to disability. Environmental and genetic factors are involved in MDD etiology. The aim of this project was to identify loci modifying age at onset (AAO) of MDD using survival models after adjusting for Childhood Sexual Abuse (CSA). To achieve this aim, a dataset was made available by the China Oxford and VCU Experimental Research on Genetic Epidemiology (CONVERGE) consortium. The study population had 5,220 controls and 5,282 cases with MDD. We performed two univariate association analyses using Cox Proportional Hazard (Cox PH) models. These two are Full Sample …

Epigenetic Editing To Validate Findings From Methylome-Wide Association Studies Of Neuropsychiatric Disorders, Robin F. Chan

Theses and Dissertations

DNA methylation is necessary for learning, memory consolidation and has been implicated in a number of neuropsychiatric disorders. Obtaining high quality and comprehensive data for the three common forms of methylation in brain is challenging for methylome-wide association studies (MWAS). To address this we optimized a panel of enrichment methods for screening the brain methylome. Results show that these enrichment techniques approach the coverage and fidelity of the current gold standard bisulfite based techniques. Our MBD-based method can also be used with low amounts of genomic material from limited human biomaterials. Psychiatric disorders have high prevalence and are often chronic …

Deep Sequencing Transcriptome Analysis Of Murine Wound Healing: Effects Of A Multicomponent, Multitarget Natural Product Therapy-Tr14, Georges St. Laurent Iii, Bernd Seilheimer, Michael Tackett, Jianhua Zhou, Dmitry Shtokalo, Ian Toma, +Several Additional Authors

Clinical Research and Leadership Faculty Publications

Wound healing involves an orchestrated response that engages multiple processes, such as hemostasis, cellular migration, extracellular matrix synthesis, and in particular, inflammation. Using a murine model of cutaneous wound repair, the transcriptome was mapped from 12 h to 8 days post-injury, and in response to a multicomponent, multi-target natural product, Tr14. Using single-molecule RNA sequencing (RNA-seq), there were clear temporal changes in known transcripts related to wound healing pathways, and additional novel transcripts of both coding and non-coding genes. Tr14 treatment modulated >100 transcripts related to key wound repair pathways, such as response to wounding, wound contraction, and cytokine response. …

Drinking Motives Underlying Internalizing And Externalizing Pathways To Alcohol Misuse In College Students, Jeanne Savage

Theses and Dissertations

Alcohol misuse, including heavy episodic use and negative consequences, is a major public health concern and a particular problem among college students. The etiology of alcohol misuse is not well resolved, with multiple and often contradictory factors implicated in its development. Genetic factors influence alcohol misuse but few specific genes have been identified. A potential reason for these challenges is that alcohol misuse is phenotypically and genetically heterogeneous; that is, there are multiple causal pathways underlying its development. Previous typologies have suggested that distinct internalizing and externalizing pathways are involved, with corresponding differences in profiles of personality, temperament, and comorbid …

The Influence Of Genetic And Environmental Factors On Quit Attempt In Adolescent And Young Adult Twins, Gladys Langi

Theses and Dissertations

The purpose of this study was to examine the genetic and environmental influences on lifetime quit attempt in three US adolescent and young adult twin samples (N total = 6,322). The study utilized a common-contingent-causal (CCC) model to estimate these factors for lifetime quit attempts, after accounting for the factors for lifetime cigarette use and cigarettes per day. The study also examined age and sex differences, as well as the degree of relationship between these smoking phenotypes. The results demonstrated significant genetic influences for lifetime quit attempts in adolescents and young adults. No sex differences were observed for the contributions …

The U.S. Culture Collection Network Responding To The Requirements Of The Nagoya Protocol On Access And Benefit Sharing, Kevin Mccluskey, Katharine B. Barker, Hazel A. Barton, Kyria Boundy-Mills, Daniel R. Brown, Jonathan A. Coddington, Kevin Cook, Philippe Desmeth, David Geiser, Jessie A. Glaeser, Stephanie Greene, Seogchan Kang, Michael W. Lomas, Ulrich Melcher, Scott E. Miller, David R. Nobles Jr., Kristina J. Owens, Jerome H. Reichman, Manuela Da Silva, John Wertz, Cale Whitworth, David Smith

Faculty Scholarship

The U.S. Culture Collection Network held a meeting to share information about how culture collections are responding to the requirements of the recently enacted Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilization to the Convention on Biological Diversity (CBD). The meeting included representatives of many culture collections and other biological collections, the U.S. Department of State, U.S. Department of Agriculture, Secretariat of the CBD, interested scientific societies, and collection groups, including Scientific Collections International and the Global Genome Biodiversity Network. The participants learned about the policies of the United …

A Rare Case Of Erythema Elevatum Diutinum Presenting As Diffuse Neuropathy, G H. Nguyen, E L. Guo, D Norris

Faculty, Staff and Students Publications

No abstract provided.

Integrative Genomic And Transcriptomic Analysis For Pinpointing Recurrent Alterations Of Plant Homeodomain Genes And Their Clinical Significance In Breast Cancer, Huimei Yu, Yuanyuan Jiang, Lanxin Liu, Wenqi Shan, Xiaofang Chu, Zhe Yang, Zeng-Quan Yang

Oncology Faculty Publications

A wide range of the epigenetic effectors that regulate chromatin modification, gene expression, genomic stability, and DNA repair contain structurally conserved domains called plant homeodomain (PHD) fingers. Alternations of several PHD finger-containing proteins (PHFs) due to genomic amplification, mutations, deletions, and translocations have been linked directly to various types of cancer. However, little is known about the genomic landscape and the clinical significance of PHFs in breast cancer. Hence, we performed a large-scale genomic and transcriptomic analysis of 98 PHF genes in breast cancer using TCGA and METABRIC datasets and correlated the recurrent alterations with clinicopathological features and survival of …

Comparative Genomic Analysis Of Two Serotype 1/2b Listeria Monocytogenes Isolates From Analogous Environmental Niches Demonstrates The Influence Of Hypervariable Hotspots In Defining Pathogenesis, Aidan Casey, Kieran Jordan, Aidan Coffey, Edward M. Fox, Olivia Mcauliffe

Department of Biological Sciences Publications

The vast majority of clinical human listeriosis cases are caused by serotype 1/2a, 1/2b, 1/2c, and 4b isolates of Listeria monocytogenes. The ability of L. monocytogenes to establish a systemic listeriosis infection within a host organism relies on a combination of genes that are involved in cell recognition, internalization, evasion of host defenses, and in vitro survival and growth. Recently, whole genome sequencing and comparative genomic analysis have proven to be powerful tools for the identification of these virulence-associated genes in L. monocytogenes. In this study, two serotype 1/2b strains of L. monocytogenes with analogous isolation sources, but …

Improved Genome-Scale Multitarget Virtual Screening Via A Novel Collaborative Filtering Approach To Cold-Start Problem, Hansaim Lim, Paul Gray, Lei Xie, Aleksandar Poleksic

Publications and Research

Conventional one-drug-one-gene approach has been of limited success in modern drug discovery. Polypharmacology, which focuses on searching for multi-targeted drugs to perturb disease-causing networks instead of designing selective ligands to target individual proteins, has emerged as a new drug discovery paradigm. Although many methods for single-target virtual screening have been developed to improve the efficiency of drug discovery, few of these algorithms are designed for polypharmacology. Here, we present a novel theoretical framework and a corresponding algorithm for genome-scale multitarget virtual screening based on the one-class collaborative filtering technique. Our method overcomes the sparseness of the protein-chemical interaction data by …

Dna Methylation Signatures Of Chronic Low-Grade Inflammation Are Associated With Complex Diseases, Symen Ligthart, Carola Marzi, Stella Aslibekyan, Michael M. Mendelson, Karen N. Conneely, Toshiko Tanaka, Elena Colicino, Lindsay L. Waite, Roby Joehanes, Weihua Guan, Jennifer A. Brody, Cathy Elks, Riccardo Marioni, Min A. Jhun, Golareh Agha, Jan Bressler, Cavin K. Ward-Caviness, Brian H. Chen, Tianxiao Huan, Kelly Bakulski, Elias L. Salfati, Whi-Empc Investigators, Giovanni Fiorito, Charge Epigenetics Of Coronary Heart Disease, Simone Wahl, Katharina Schramm, Jin Sha, Dena G. Hernandez, Allan C. Just, Jennifer A. Smith, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.

Results: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10^–7) in the discovery panel …

Allelic Variation In Cxcl16 Determines Cd3+ T Lymphocyte Susceptibility To Equine Arteritis Virus Infection And Establishment Of Long-Term Carrier State In The Stallion, Sanjay Sarkar, Ernest Bailey, Yun Young Go, R. Frank Cook, Ted Kalbfleisch, John E. Eberth, R. Lakshman Chelvarajan, Kathleen M. Shuck, Sergey Artiushin, Peter J. Timoney, Udeni B. R. Balasuriya

Maxwell H. Gluck Equine Research Center Faculty Publications

Equine arteritis virus (EAV) is the causative agent of equine viral arteritis (EVA), a respiratory, systemic, and reproductive disease of horses and other equid species. Following natural infection, 10–70% of the infected stallions can become persistently infected and continue to shed EAV in their semen for periods ranging from several months to life. Recently, we reported that some stallions possess a subpopulation(s) of CD3⁺ T lymphocytes that are susceptible to in vitro EAV infection and that this phenotypic trait is associated with long-term carrier status following exposure to the virus. In contrast, stallions not possessing the CD3⁺ T …

Hnrnpa2 Is A Novel Histone Acetyltransferase That Mediates Mitochondrial Stress-Induced Nuclear Gene Expression, Manti Guha, Satish Srinivasan, Kip Guja, Edison Mejia, Miguel Garcia-Diaz, F. Brad Johnson, Gordon Ruthel, Brett A. Kaufman, Eric F. Rappaport, M. Rebecca Glineburg, Ji-Kang Fang, Andres J. Klein-Szanto, Hiroshi Nakagawa, Jeelan Basha, Tapas Kundu, Narayan G. Avadhani

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Reduced mitochondrial DNA copy number, mitochondrial DNA mutations or disruption of electron transfer chain complexes induce mitochondria-to-nucleus retrograde signaling, which induces global change in nuclear gene expression ultimately contributing to various human pathologies including cancer. Recent studies suggest that these mitochondrial changes cause transcriptional reprogramming of nuclear genes although the mechanism of this cross talk remains unclear. Here, we provide evidence that mitochondria-to-nucleus retrograde signaling regulates chromatin acetylation and alters nuclear gene expression through the heterogeneous ribonucleoprotein A2 (hnRNAP2). These processes are reversed when mitochondrial DNA content is restored to near normal cell levels. We show that the mitochondrial stress-induced …

A Microbiomic Approach To The Characterization Of The Impacts And Influences Of Viral, Bacterial, And Harmful Algal Bloom Toxins On The Bottlenose Dolphin, Corey David Russo

Dissertations

As apex predators that display high site fidelity Tursiops truncatus (bottlenose dolphin) are indicators of marine ecosystem health. Bottlenose dolphins, additionally, display pathogenesis and immune response similar to that of humans. Humans and coastal bottlenose dolphins, in particular, are constantly exposed to the same industrial, agricultural and domestic toxins and pathogens, contaminants and pollutants. Thus, studies on the bottlenose dolphin are also valuable in bridging the gap between ocean and human health. Bottlenose dolphins are susceptible to viral bacterial and toxin infection. Infection in the bottlenose dolphin manifests itself in the form of mass stranding events, unusual mortality events, chronic …

Strategies For Enriching Variant Coverage In Candidate Disease Loci On A Multiethnic Genotyping Array, Stephanie Bien, Genevieve L. Wojcik, Niha Zubair, Christopher Gignoux, Alicia R. Martin, Lisa W. Martin, Page Study Investigators

Medicine Faculty Publications

Investigating genetic architecture of complex traits in ancestrally diverse populations is imperative to understand the etiology of disease. However, the current paucity of genetic research in people of African and Latin American ancestry, Hispanic and indigenous peoples in the United States is likely to exacerbate existing health disparities for many common diseases. The Population Architecture using Genomics and Epidemiology, Phase II (PAGE II), Study was initiated in 2013 by the National Human Genome Research Institute to expand our understanding of complex trait loci in ethnically diverse and well characterized study populations. To meet this goal, the Multi-Ethnic Genotyping Array (MEGA) …

A Novel Codon-Optimized Siv Gag-Pol Immunogen For Gene-Based Vaccination, Catherine M. Crosby, Eric A. Weaver, Reeti Khare, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

Simian immunodeficiency virus (SIV) is a robust pathogen used in non-human primates to model HIV vaccines. SIV encodes a number of potential vaccine targets. By far the largest and most conserved protein target in SIV is its gag-pol protein that bears many epitopes to drive multivalent immune T cell responses. While gag-pol is an attractive antigen, it is only translated after a frame shift between gag and pol with the effect that gag and pol are expressed at an approximate 10/1 ratio. The codon bias of native lentiviral genes are also mismatched with the abundance of tRNAs in mammalian cells …

Reexamining Chronic Toxoplasma Gondii Infection: Surprising Activity For A "Dormant" Parasite, Anthony P. Sinai, Elizabeth A. Watts, Animesh Dhara, Robert D. Murphy, Matthew S. Gentry, Abhijit R. Patwardhan

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Purpose of Review

Despite over a third of the world’s population being chronically infected with Toxoplasma gondii, little is known about this largely asymptomatic phase of infection. This stage is mediated in vivo by bradyzoites within tissue cysts. The absence of overt symptoms has been attributed to the dormancy of bradyzoites. In this review, we reexamine the conventional view of chronic toxoplasmosis in light of emerging evidence challenging both the nature of dormancy and the consequences of infection in the CNS.

Recent Findings

New and emerging data reveal a previously unrecognized level of physiological and replicative capacity of bradyzoites …

Using Mouse Models To Define How The P53 R72p Polymorphism Impacts The Adverse Effects Of Doxorubicin And Ionizing Radiation, Emily Dominguez

Dissertations and Theses (Open Access)

The single nucleotide polymorphism (SNP) at codon 72 of the tumor suppressor gene p53 codes for either an arginine (R) or proline (P) (p53 R72P). This SNP may impact how cells respond to genotoxic insult. Studies in cell culture and in tissues from mouse models of the SNP indicate that, in response to gentoxic treatment, the two variants may differentially induce apoptosis and expression of p53 target genes. In epidemiological studies, the P variant is associated with decreased cancer survival and increased risk of side-effects from genotoxic cancer treatment. Genotoxic therapy is still the mainstay of cancer treatment, and doxorubicin …

Concomitant Targeting Of The Mtor/Mapk Pathways: Novel Therapeutic Strategy In Subsets Of Non-Small Cell Lung Cancer, Dennis Ruder

Dissertations and Theses (Open Access)

Over the last decade, a paradigm-shift in lung cancer therapy has evolved into targeted-driven medicinal approaches. However, patients frequently relapse and develop resistance to available therapies. Herein, we utilized genomic mutation data from advanced chemorefractory non-small cell lung cancer (NSCLC) patients enrolled in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-2) clinical trial to characterize novel actionable genomic alterations potentially of clinical relevance. We identified RICTOR alterations (mutations, amplifications) in 17% of lung adenocarcinomas and found RICTOR expression correlates to worse overall survival. There was enrichment of MAPK pathway genetic aberrations in key oncogenes (e.g. KRAS, BRAF, …

Characterization Of Vesicular Monoamine Transporter 2 And Its Role In Parkinson's Disease Pathogenesis Using Drosophila, Antonio Joel Tito Jr., Sheng Zhang

Dissertations and Theses (Open Access)

Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by the selective loss of the dopaminergic neurons in the Substantia nigra pars compacta region of the brain. PD is also the most common neurodegenerative disorder and the second most common movement disorder. PD patients exhibit the cardinal symptoms, including tremor of the extremities, rigidity, slowness of movement, and postural instability, after 70-80% of DA neurons degenerate. It is, therefore, imperative to elucidate the underlying mechanisms involved in the selective degeneration of DA neurons. Although increasing numbers of PD genes have been identified, why these largely widely expressed genes induce …

Consensus Paper: Cerebellar Development, K Leto, M Arancillo, Ebe Becker, A Chiang, Et Al.

Faculty, Staff and Students Publications

The development of the mammalian cerebellum is orchestrated by both cell-autonomous programs and inductive environmental influences. Here, we describe the main processes of cerebellar ontogenesis, highlighting the neurogenic strategies used by developing progenitors, the genetic programs involved in cell fate specification, the progressive changes of structural organization, and some of the better-known abnormalities associated with developmental disorders of the cerebellum.

A Principal Component Meta-Analysis On Multiple Anthropometric Traits Identifies Novel Loci For Body Shape, Janina S. Ried, Janina Jeff M., Audrey Y. Chu, Jennifer L. Bragg-Gresham, Jennifer E. Huffman, Tarunveer S. Ahluwalia, Gemma Cadby, Niina Eklund, John Blangero

School of Medicine Publications

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. …

Exploring Molecular Mechanisms Of Paradoxical Activation In The Braf Kinase Dimers: Atomistic Simulations Of Conformational Dynamics And Modeling Of Allosteric Communication Networks And Signaling Pathways, Amanda Tse, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

The recent studies have revealed that most BRAF inhibitors can paradoxically induce kinase activation by promoting dimerization and enzyme transactivation. Despite rapidly growing number of structural and functional studies about the BRAF dimer complexes, the molecular basis of paradoxical activation phenomenon is poorly understood and remains largely hypothetical. In this work, we have explored the relationships between inhibitor binding, protein dynamics and allosteric signaling in the BRAF dimers using a network-centric approach. Using this theoretical framework, we have combined molecular dynamics simulations with coevolutionary analysis and modeling of the residue interaction networks to determine molecular determinants of paradoxical activation. We …