Cell and Developmental Biology Commons^™

The Effects Of Alcohol On The Developing Drosophila Nervous System, Erica E. Hassoun

The Cardinal Edge

Ethanol is the most common human teratogen, contributing to fetal alcohol syndrome (FAS) when effects are the most severe. Key effects of fetal alcohol syndrome are observed in the nervous system. The high prevalence of prenatal alcohol exposure necessitates novel treatment and prevention methods. However, ethical issues prevent researching humans in utero. For this reason, the fruit fly Drosophila melanogaster has emerged as a model organism for studying FAS. Because Drosophila is a small and non-placental organism, its environment can be easily controlled, allowing for specific doses and time periods of ethanol exposure to be studied. This review discusses findings …

The Effects Of Ppal-1 In Arabidopsis Gamete Development, Amanda J White, Susana Perez-Martinez, Mark P. Running

The Cardinal Edge

Prenylation is a type of post-translational modification in which a 15- or 20-carbon lipid is added to the carboxyl (C) terminus of the protein. Arabidopsis thaliana contains the PROTEIN PRENYLTRANSFERASE ALPHA SUBUNIT-LIKE (PPAL) gene, which encodes a protein with homology to the α-subunits of the three known prenylation enzymes, PFT, PGGT, and Rab-GGT. We previously identified two mutations in PPAL, one of which is ppal-1, which contains a T-DNA insertion in the fourth intron. We have previously observed that self-fertilizing heterozygous ppal-1 plants produce progeny in which homozygous ppal-1 is underrepresented. This project attempts to ascertain …

Gaps In Public Awareness About Brca And Genetic Testing In Prostate Cancer: Social Media Landscape Analysis, Stacy Loeb, Philip Massey, Amy Leader, Sameer Thakker, Emily Falge, Sabina Taneja, Nataliya Byrne, Meredith Rose, Matthew Joy, Dawn Walter, Matthew S Katz, Risa L Wong, Preethi Selvan, Scott W Keith, Veda N. Giri

Department of Medical Oncology Faculty Papers

BACKGROUND: Genetic testing, particularly for BRCA1/2, is increasingly important in prostate cancer (PCa) care, with impact on PCa management and hereditary cancer risk. However, the extent of public awareness and online discourse on social media is unknown, and presents opportunities to identify gaps and enhance population awareness and uptake of advances in PCa precision medicine.

OBJECTIVE: The objective of this study was to characterize activity and engagement across multiple social media platforms (Twitter, Facebook, and YouTube) regarding BRCA and genetic testing for PCa compared with breast cancer, which has a long history of public awareness, advocacy, and prominent social media …

Phenotypic/Genotypic Profile Of Oxa-10-Like-Harboring, Carbapenem-Resistant Pseudomonas Aeruginosa: Using Validated Pharmacokinetic/Pharmacodynamic In Vivo Models To Further Evaluate Enzyme Functionality And Clinical Implications, Fred C. Tenover, Christian M. Gill, Adrian Brink, Chun Yat Chu, Jennifer Coetzee, George Dimopoulos, Clinton Moodley, Christoffel Johannes Opperman, Spyros Pournaras, Isabella A. Tickler, Hafsah Deepa Tootla, Sophia Vourli, David P. Nicolau

Biology Faculty Publications

In vitro MICs and in vivo pharmacodynamics of ceftazidime and cefepime human-simulated regimens (HSR) against modified carbapenem inactivation method (mCIM)-positive Pseudomonas aeruginosa isolates harboring different OXA-10-like subtypes were described. The murine thigh model assessed ceftazidime (2 g every 8 h [q8h] HSR) and cefepime (2 g and 1 g q8h HSR). Phenotypes were similar despite possessing OXA-10-like subtypes with differing spectra. Ceftazidime produced ≥1-log10 killing in all isolates. Cefepime activity was dose dependent and MIC driven. This approach may be useful in assessing the implications of β-lactamase variants.

Proteoglycan-4 Is An Essential Regulator Of Synovial Macrophage Polarization And Inflammatory Macrophage Joint Infiltration, Marwa Qadri, Gregory D. Jay, Ling X. Zhang, Tannin A. Schmidt, Jennifer Totonchy, Khaled A. Elsaid

Pharmacy Faculty Articles and Research

Background

Synovial macrophages perform a multitude of functions that include clearance of cell debris and foreign bodies, tissue immune surveillance, and resolution of inflammation. The functional diversity of macrophages is enabled by distinct subpopulations that express unique surface markers. Proteoglycan-4 (PRG4) is an important regulator of synovial hyperplasia and fibrotic remodeling, and the involvement of macrophages in PRG4’s synovial role is yet to be defined. Our objectives were to study the PRG4’s importance to macrophage homeostatic regulation in the synovium and infiltration of pro-inflammatory macrophages in acute synovitis and investigate whether macrophages mediated synovial fibrosis in Prg4 gene-trap (Prg4 …

Design And Application Of Hybrid Cyclic-Linear Peptide-Doxorubicin Conjugates As A Strategy To Overcome Doxorubicin Resistance And Toxicity, Saghar Mozaffari, David Salehi, Parvin Mahdipoor, Richard Beuttler, Rakesh Tiwari, Hamidreza Montazeri Aliabadi, Keykavous Parang

Pharmacy Faculty Articles and Research

Doxorubicin (Dox) is used for breast cancer, leukemia, and lymphoma treatment as an effective chemotherapeutic agent. However, Dox use is restricted due to inherent and acquired resistance and an 8-fold increase in the risk of potentially fatal cardiotoxicity. Hybrid cyclic-linear peptide [R5K]W7A and linear peptide R5KW7A were conjugated with Dox through a glutarate linker to afford [R5K]W7A-Dox and R5KW7A-Dox conjugates to generate Dox derivatives. Alternatively, [R5K]W7C was conjugated with Dox via a disulfide linker to generate [R5K]W7C–S–S-Dox conjugate, where S–S is a disulfide bond. Comparative antiproliferative assays between conjugates [R5K]W7A-Dox, [R5K]W7C–S–S-Dox, linear R5KW7A-Dox, the corresponding physical mixtures of the peptides, …

Predicting Drug Sensitivity Of Cancer Cells Based On Dna Methylation Levels, Sofia P. Miranda, Fernanda A. Baião, Julia L. Fleck, Stephen R. Piccolo

Faculty Publications

Cancer cell lines, which are cell cultures derived from tumor samples, represent one of the least expensive and most studied preclinical models for drug development. Accurately predicting drug responses for a given cell line based on molecular features may help to optimize drug-development pipelines and explain mechanisms behind treatment responses. In this study, we focus on DNA methylation profiles as one type of molecular feature that is known to drive tumorigenesis and modulate treatment responses. Using genome-wide, DNA methylation profiles from 987 cell lines in the Genomics of Drug Sensitivity in Cancer database, we used machine-learning algorithms to evaluate the …

Developmental Programming Of Dna Methylation And Gene Expression Patterns Is Associated With Extreme Cardiovascular Tolerance To Anoxia In The Common Snapping Turtle, Ilan Ruhr, Jacob Bierstedt, Turk Rhen, Debojyoti Das, Sunil Kumar Singh, Soleille Miller, Dane A. Crossley Ii, Gina L. J. Galli

Biology Faculty Publications

Background

Environmental fluctuation during embryonic and fetal development can permanently alter an organism’s morphology, physiology, and behaviour. This phenomenon, known as developmental plasticity, is particularly relevant to reptiles that develop in subterranean nests with variable oxygen tensions. Previous work has shown hypoxia permanently alters the cardiovascular system of snapping turtles and may improve cardiac anoxia tolerance later in life. The mechanisms driving this process are unknown but may involve epigenetic regulation of gene expression via DNA methylation. To test this hypothesis, we assessed in situ cardiac performance during 2 h of acute anoxia in juvenile turtles previously exposed to normoxia …

Metabolic Control Of Stem Cell Ageing And Longevity Through Caloric Restriction, Valerie Navarrete

The Yale Undergraduate Research Journal

While prior studies have identified recurring genetic patterns, gaps of knowledge still remain in existing aging mechanisms; where they originate, and how they offer insight to environmental disruptions that dictate health over time. Given the inescapability of age-related deterioration and pathology, stitching together current literature may help demystify the biological process common to all living mammals. The physiological disruption of aged tissue reflects a cellular dependence on environmental cues and historical wear. Retaining the capacity to differentiate into any cell type, a stem cell best parallels a call-and-response relationship between organ and cell. As the longest living proliferative cell in …

Mechanisms Of Substrate Recognition By The Cul3-Based E3 Ligase, Katia Graziella De Oliveira Rebola

Dissertations and Theses

Cul3-based E3 ligase is responsible for regulating a variety of cellular pathways, many of which are known to have profound effects on the proper function of multicellular organisms. Although progress over the past years has been truly impressive, our understanding of the mechanisms of E2 recruitment and selection by the BCR complex and all the roles that Cul3 plays on kidneys remains in its infancy. To explore these aspects, this dissertation aims to analyze the Cul3 complex using two different approaches: (1) We used the powerful tool of chimeric analysis to map the essential domain binding characteristics of Cul3 taking …

College Of Natural Sciences Newsletter, September 2021, College Of Natural Sciences

College of Natural Sciences Newsletters and Reports

Volume 2, Issue 9.

Page 1 Dean's Message
Page 2 Awards and Recognition
Page 3 Student Clubs in Natural Science
Page 4 Media Coverage of CNS
Page 5 Hobo Day Festivities
Page 6 Open PRAIRIE Data; Grants Awarded in CNS
Page 7 One Day for State Recap

Aurora Kinase A Inhibition Reverses The Warburg Effect And Elicits Unique Metabolic Vulnerabilities In Glioblastoma, Trang T. T. Nguyen, Enyuan Shang, Chang Shu, Sungsoo Kim, Angeliki Mela, Nelson Humala, Aayushi Mahajan, Hee Won Yang, Hasan Orhan Akman, Catarina M. Quinzii, Guoan Zhang, Mike-Andrew Westhoff, Georg Karpel-Massler, Jeffrey N. Bruce, Peter Canoll, Markus D. Siegelin

Publications and Research

Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was …

Study Of The Gain-Of-Function Mutant P53 And Parp1 In Triple-Negative Breast Cancer, Devon Lundine

Dissertations, Theses, and Capstone Projects

Cancer cells often lose expression of the p53 protein or express mutant forms of p53. Some of these mutant p53 proteins, called gain-of-function mutant p53, have gained oncogenic functions. Previously, our group observed mutant p53 R273H interacts with replicating DNA and upregulates the chromatin localization of several DNA replication factors including PCNA, MCM2-7, and PARP1 (termed the mtp53-PARP-MCM axis). In this thesis, we explore the contribution of mutant p53 and PARP1 in castration-resistant prostate cancer (mutant p53 P223L and V274F) and triple-negative breast cancer (mutant p53 R273H). In the castration-resistant prostate cancer cell line DU145, we examine two mutant p53 …

The Structural And Functional Role Of Photosensing In Rgs-Lov Proteins, Zaynab Jaber

Dissertations, Theses, and Capstone Projects

Light provides organisms with energy and spatiotemporal information. To survive and adapt, organisms have developed the ability to sense light to drive biochemical effects that underlie vision, entrainment of circadian rhythm, stress response, virulence, and many other important molecularly driven responses. Blue-light sensing Light-Oxygen-Voltage (LOV) domains are ubiquitous across multiple kingdoms of life and modulate various physiological events via diverse effector domains. Using a small molecule flavin chromophore, the LOV domain undergoes light-dependent structural changes leading to activation or repression of these catalytic and non-catalytic effectors. In silico analyses of high-throughput genomic sequencing data has led to the marked expansion …

Analysis Of Transplantable Photoreceptor Replacement Cell Chemotactic Mechanisms In Retinal Biomimetic Ligand Gradients, Onyekwere Onwumere

Dissertations, Theses, and Capstone Projects

Disease or trauma induced loss of rod and cone photoreceptors is a major cause of vision loss worldwide. To replace lost photoreceptors and restore vision, laboratories around the world are investigating photoreceptor replacement strategies using subretinal injection of photoreceptor precursor cells (PPCs) and retinal progenitor cells (RPCs). A major obstacle in the field is that transplanted photoreceptor replacement cells exhibit extremely limited migration into host retina following injection into the subretinal space. In this work, we show that PPCs and host retinal interaction bioinformatics modeling can identify key pathways involved in photoreceptor replacement cell migration and invasion behaviors. In addition, …

Synthesis, Characterization And Applications Of Peptide-Coated Nanoparticles, Mina Sadat Poursharifi

Dissertations, Theses, and Capstone Projects

Ovarian Cancer (OC) is the most lethal female malignancy worldwide, mainly due to its high recurrence rate and poor diagnosis. Most patients present with late stage of the disease, and less than 25% of patients survive the five years mark. Nanotherapy provides significant and unique benefits for drug efficacy, as nanoparticles (NPs) can increase the solubility, bioavailability, and permeability of many potent drugs. Poly(lactic-co-glycolic acid) (PLGA) is one of the most successful biodegradable polymers used in NPs formulations, mainly due to its biocompatibility and biodegradability. Polyethylene glycol (PEG) is one of the most commonly used moieties to prolong the NPs …

The Role Of Tbx2 In Germ Layer Suppression And Dorsoventral Patterning During Early Vertebrate Development, Shoshana Reich

Dissertations, Theses, and Capstone Projects

The differentiation of the three primary germ layers is precisely regulated by inductive cues, the intracellular networks through which these signals are transduced, and a broad array of nuclear proteins, such as transcription factors and epigenetic modifiers. Precise regulation of these various factors is crucial to proper development. Members of the T-box family of DNA-binding proteins play a prominent role in the differentiation of the three primary germ layers. VegT, Brachyury, and Eomesodermin function as transcriptional activators, are expressed in the presumptive mesendoderm and, in addition to directly activating the transcription of endoderm- and mesoderm-specific genes, serve variously as regulators …

Investigation Of Notch Signaling In Cone Fate Specification In Vertebrate Retina, Xueqing Chen

Dissertations, Theses, and Capstone Projects

In the vertebrate retina, cone photoreceptors are crucial for high acuity color vision. Several retinal diseases lead to loss of cones and there is a need to identify the normal developmental genesis of these cells to inform the development of stem cell-based therapies. Cone genesis has previously been shown to be repressed by Notch signaling, however, the mechanism by which Notch signaling controls cone fate determination is still unclear. It has been identified that cone photoreceptors are formed from multipotent retinal progenitor cells (RPCs) that first generate genetically-defined, restricted RPCs with limited mitotic and fate potential to preferentially form cones …

The Slit-Binding Ig1 Domain Is Required For Multiple Axon Guidance Activities Of Drosophila Robo2, Lafreda J. Howard, Marie C. Reichert, Timonthy A. Evans

Biological Sciences Faculty Publications and Presentations

Drosophila Robo2 is a member of the evolutionarily conserved Roundabout (Robo) family of axon guidance receptors. Robo receptors signal midline repulsion in response to Slit ligands, which bind to the N-terminal Ig1 domain in most family members. In the Drosophila embryonic ventral nerve cord, Robo1 and Robo2 signal Slit-dependent midline repulsion, while Robo2 also regulates the medial-lateral position of longitudinal axon pathways and acts non-autonomously to promote midline crossing of commissural axons. While Robo2 signals midline repulsion in response to Slit, it is less clear whether Robo2's other activities are also Slit-dependent. To determine which of Robo2's axon guidance roles …

Identification Of Phenotypic Defects In The Zinc Finger Transcription Factor Ztf-29, Trae Dunn

Symposium of Student Scholars

Aging and many aging-associated diseases such as Alzheimer’s disease and cancer are characterized by a progressive decline in physiological functions and a decline in the ability to respond to stress. The underlying causes for many aging-associated diseases are unknown. Identifying genes that control normal aging will advance our understanding of the molecular changes that underlie the aging process and might help treat age-associated diseases. In order to get a better understanding of the molecular mechanisms behind these diseases, we utilize the nematode Caenorhabditis elegans as a model organism to examine defects in physiology and aging.

The human PRDM genes code …

Temperature Changes Seen In Lower Extremities After Cpn Local Anesthetic Block, Lora Asberry

Symposium of Student Scholars

Many older patients often suffer from walking issues such as Drop Foot. Drop Foot is caused by the malfunction of nerves in the foot, resulting in the loss of control of the front foot muscle. Within all of our patients, there has been a common fibular palsy, caused by the entrapment of the peroneal nerve. Due to this, they cannot lift up their foot. Some cases are permanent, while others are temporary. In the temporary cases, we have indicated a Phoenix Sign. The Phoenix Sign indicates that a nerve, presumed to be dead, has the capability to be recessed back …

Complimenting A Chlamydomonas Reinhardtii Mutation Using Cell Penetrating Peptides, Matthew Mckenzie

Symposium of Student Scholars

Complimenting a Chlamydomonas reinhardtii Mutation Using Cell Penetrating Peptides

Matthew McKenzie and Jennifer L. Cooper

Chlamydomonas reinhardtii is a photosynthetic model organism most notable for its easily manipulatable genetics. C. reinhardtii uses flagella to swim and optimize its growth conditions in the light. We plan to use cell penetrating peptides (CPPs) to compliment C. reinhardtii that is affected with the IFT46 mutation. Cell penetrating peptides are short peptides that can move across a cell membrane. The novel CPP that we are using is called TaT-CaM. It consists of the trans-activator of transcription (TaT) and the calmodulin domain (CaM) that binds …

The Role Of Proneural Transcription Factor Ngn-1/Neurogenin During Caenorhabditis Elegans Embryonic Development, Michaela Diane Crego

Symposium of Student Scholars

Accurate control of neuronal cell identification and movement is crucial to embryonic development. Defects in this process can lead to neurodevelopmental disorders, creating an imperative for further study. The transcription factor neurogenin is required for multiple neurodevelopmental processes during vertebrate embryonic development and mutations in this gene underpin multiple human neurological disorders. Despite this, little is known about how this gene controls nervous system development and function. Neurogenin is deeply conserved across phyla. As such, we can investigate neurogenin function in simple systems such as the nematode Caenorhabditis elegans, which has a close ortholog of neurogenin, ngn-1. Previous work in …

Understanding Molecular Mechanisms Controlling Muscle Type Specificity, Geoffrey Andrews

Symposium of Student Scholars

Skeletal muscle is a compound tissue made of individual muscle fibers. To accommodate everyday activities, such as walking, running, jumping, etc., our muscles are composed of several types of fibers, each expressing a unique set of muscle genes. Interestingly, early in development all muscles in the body are made of the same fiber type, but later they acquire different properties. The mechanism of muscle fiber diversity is not clear, although it may be critical in treating muscle-related diseases or enhancing physical performance. The goal of my project is to identify critical genes and possible mechanisms that control the fate of …

Determining Malignancy: Can Mammogram Results Help Predict The Diagnosis Of Breast Tumors?, Taylor Behrens

Symposium of Student Scholars

Even with advancements in treatment and preventative care, breast cancer remains an epidemic claiming more than 40,000 American male and female lives each year. The mammogram dataset that I am analyzing was initially complied in the early 1990s by a team from the University of Wisconsin - Madison. Past research diagnoses breast cancer from fine-needle aspirates. My research focuses on predicting whether we can determine breast cancer diagnoses without the use of invasive procedures and, in particular, whether we can predict breast cancer based on mammogram data. Do measures of gray-scale texture, radius, concavity, perimeter, compactness, area, and smoothness of …

Growth, Maturation, And Weight Status: Insights From A Longitudinal Cohort Of Nebraska Youth, John William Masker

Kinesiology and Sport Sciences Theses, Dissertations, and Student Creative Activity

Pediatric obesity continues to be a major public health concern in the United States, with well-known short-term and long-term consequences. In efforts to combat pediatric obesity and identify children at high-risk for potential health problems, physicians and health professionals widely practice screening and classifying weight status using age-and-sex-specific body mass index (BMI) percentiles. However, some studies suggest the use of BMI for establishing weight status in relation to health risk in youth is problematic, especially during the period of the adolescent growth spurt. More importantly, maturation-related misclassification may result in overestimations of overweight prevalence among early-maturing youth, and underestimations of …

Vitamin D Modulates Rett Syndrome Phenotypes And Underlying Cellular Pathways In An Mecp2-Mutant Mouse Model, Mayara De Cassia Ribeiro

Dissertations - ALL

Rett syndrome (RTT) is a progressive and severe X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MECP2. There is currently no effective treatment for RTT. Female RTT patients develop relatively normally during the first 6-18 months of life, after which they undergo a period of rapid regression, losing the ability to talk, walk and purposefully use their hands, in addition to suffering from deceleration of head growth, and onset of repetitive, autistic behaviors. RTT symptoms can be partially reversed by the re-expression of Mecp2 in adult mice, suggesting the potential for post-symptomatic therapeutic intervention. Among the many dysfunctions …

Association Of Oral Microbiota With Lung Cancer Risk In A Low-Income Population In The Southeastern Usa, Jiajun Shi, Yaohua Yang, Hua Xie, Xiaofei Wang, Jie Wu, Jirong Long, Regina Courtney, Xiao-Ou Shu, Wei Zheng, William J. Blot, Qiuyin Cai

Biology Faculty Research

Purpose

Oral microbiome plays an important role in oral health and systemic diseases, including cancer. We aimed to prospectively investigate the association of oral microbiome with lung cancer risk.

Methods

We analyzed 156 incident lung cancer cases (73 European Americans and 83 African Americans) and 156 individually matched controls nested within the Southern Community Cohort Study. Oral microbiota were assessed using 16S rRNA gene sequencing in pre-diagnostic mouth rinse samples. Paired t test and the permutational multivariate analysis of variance test were used to evaluate lung cancer risk association with alpha diversity or beta diversity, respectively. Conditional logistic regression models …

Tail-Anchored Protein Insertion Under Er Stress Conditions: Calcium Is Key, Matthew Jordan, Malaiyalam Mariappan

The Yale Undergraduate Research Journal

Tail-anchored (TA) membrane proteins are critical for protein translocation, intracellular trafficking, and programmed cell death. TA proteins contain hydrophobic transmembrane domains and traverse through the cytosol to post-translationally insert into cellular membranes. It is unclear how this post-translational insertion is affected by Endoplasmic Reticulum (ER) stress. Here, we find that TA protein insertion is significantly reduced with ER stress inducer thapsigargin (Tg), a calcium pump inhibitor that blocks the import of calcium into the ER causing ER stress, but not when treated with other ER stress inducers. Interestingly, out data suggests that increased calcium in the cytosol may decrease TA …

Investigating Factors That Affect Hiv-1 Capsid Stability, Max Mao, Joshua Temple

The Yale Undergraduate Research Journal

TKH HIV caSVLd, a SURWHLQ VKHOO cRPSRVHd RI PRQRPHULc XQLWV RI CA, IRUPV a IXOOHUHQH cRQH WKaW SURWHcWV HIV¶V YLUaO JHQRPH aQd enzymes during infection. I am interested in elucidating the factors that influence stability of the capsid shell and capturing the structural interactions between HIV capsid, host restriction factors, and small molecules using biochemical and structural biology techniques. HIV capsid shell was broken down and purified into hexamer and pentamer units for in vitro study. Structural assays were performed using X-ray crystallography and biochemical analysis was performed using pelleting assays. By understanding capsid structure with factors that confer stability, …