Medical Cell Biology Commons^™

Interpreting Ppv And Npv Of Diagnostic Tests With Uncertain Prevalence, Yakov Ben-Haim, Clifford C Dacso

Faculty, Staff and Students Publications

OBJECTIVE: Medical decision-making is often uncertain. The positive predictive value (PPV) and negative predictive value (NPV) are conditional probabilities characterizing diagnostic tests and assessing diagnostic interventions in clinical medicine and epidemiology. The PPV is the probability that a patient has a specified disease, given a positive test result for that disease. The NPV is the probability that a patient does not have the disease, given a negative test result for that disease. Both values depend on disease incidence or prevalence, which may be highly uncertain for unfamiliar diseases, epidemics, etc. Probability distributions for this uncertainty are usually unavailable. We develop …

The Interaction Of Endorepellin And Neurexin Triggers Neuroepithelial Autophagy And Maintains Neural Tube Development, Lei Lu, Meizhu Bai, Yufang Zheng, Xiukun Wang, Zhongzhong Chen, Rui Peng, Richard H Finnell, Tongjin Zhao, Chengtao Li, Bo Wu, Yunping Lei, Jinsong Li, Hongyan Wang

Faculty, Staff and Students Publications

Heparan sulfate proteoglycan 2 (HSPG2) gene encodes the matrix protein Perlecan, and genetic inactivation of this gene creates mice that are embryonic lethal with severe neural tube defects (NTDs). We discovered rare genetic variants of HSPG2 in 10% cases compared to only 4% in controls among a cohort of 369 NTDs. Endorepellin, a peptide cleaved from the domain V of Perlecan, is known to promote angiogenesis and autophagy in endothelial cells. The roles of enderepellin in neurodevelopment remain unclear so far. Our study revealed that endorepellin can migrate to the neuroepithelial cells and then be recognized and bind with the …

N-Myc And Stat Interactor Is An Endometriosis Suppressor, Yuri Park, Xiaoming Guan, Sang Jun Han

Faculty, Staff and Students Publications

In patients with endometriosis, refluxed endometrial fragments evade host immunosurveillance, developing into endometriotic lesions. However, the mechanisms underlying this evasion have not been fully elucidated. N-Myc and STAT Interactor (NMI) have been identified as key players in host immunosurveillance, including interferon (IFN)-induced cell death signaling pathways. NMI levels are markedly reduced in the stromal cells of human endometriotic lesions due to modulation by the Estrogen Receptor beta/Histone Deacetylase 8 axis. Knocking down NMI in immortalized human endometrial stromal cells (IHESCs) led to elevated RNA levels of genes involved in cell-to-cell adhesion and extracellular matrix signaling following IFNA treatment. Furthermore, NMI …

Adult Zymosan Re-Exposure Exacerbates The Molecular Alterations In The Brainstem Rostral Ventromedial Medulla Of Rats With Early Life Zymosan-Induced Cystitis, Bhavana Talluri, Sankar Addya, Maia Terashvili, Bidyut K. Medda, Anjishnu Banerjee, Reza Shaker, Jyoti N. Sengupta, Banani Banerjee

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

Recent evidence suggests that the descending modulatory pathways from the brainstem rostral ventromedial medulla (RVM) are important for bladder inflammatory pain. This study aimed to identify the long-term molecular changes in RVM neurons due to early life cystitis during neuronal development and the effect of reexposure later in adulthood. RVM tissues from two treatment protocols were used: (1) neonatal zymosan exposures with acute adult rechallenge (RC) and (2) only neonatal zymosan exposures (NRC). RNAseq analysis showed upregulation of several genes associated with synaptic plasticity (Grin1, Grip2, Notch1, Arc, and Scn2b) in the cystitis groups compared to controls in both protocols. …

Hyaluronan Mediates Cold-Induced Adipose Tissue Beiging, Xi Chen, Yifan Wang, Huiqiao Li, Yanru Deng, Charlise Giang, Anying Song, Yu'e Liu, Qiong A Wang, Yi Zhu

Faculty, Staff and Students Publications

Adipose tissue beiging refers to the process by which beige adipocytes emerge in classical white adipose tissue depots. Beige adipocytes dissipate chemical energy and secrete adipokines, such as classical brown adipocytes, to improve systemic metabolism, which is beneficial for people with obesity and metabolic diseases. Cold exposure and β3-adrenergic receptor (AR) agonist treatment are two commonly used stimuli for increasing beige adipocytes in mice; however, their underlying biological processes are different. Transcriptional analysis of inguinal white adipose tissue (iWAT) has revealed that changes in extracellular matrix (ECM) pathway genes are specific to cold exposure. Hyaluronic acid (HA), a non-sulfated linear …

Genetics Of Mdh In Humans, Adam Haberman, Celeste N. Peterson

Biology: Faculty Scholarship

Malate dehydrogenase (MDH) performs key roles in metabolism, but little is known about its function specifically in human health and disease. In this minireview, we describe the incomplete state of our knowledge of human MDH genetics. Humans have three MDH genes with a total of four validated isoforms. MDH1 and MDH2 are widely expressed, while MDH1B is only expressed in a small subset of tissues. Many mutations in MDH1 and MDH2 have been identified in patients, but only a few have been studied to determine what symptoms they cause. MDH1 has been associated with cancer and a neurodevelopmental disorder. MDH2 …

Refining The Optimal Caf Cluster Marker For Predicting Tme-Dependent Survival Expectancy And Treatment Benefits In Nsclc Patients, Kai Li, Rui Wang, Guo-Wei Liu, Zi-Yang Peng, Ji-Chang Wang, Guo-Dong Xiao, Shou-Ching Tang, Ning Du, Jia Zhang, Jing Zhang, Hong Ren, Xin Sun, Yi-Ping Yang, Da-Peng Liu

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The tumor microenvironment (TME) plays a pivotal role in the onset, progression, and treatment response of cancer. Among the various components of the TME, cancer-associated fibroblasts (CAFs) are key regulators of both immune and non-immune cellular functions. Leveraging single-cell RNA sequencing (scRNA) data, we have uncovered previously hidden and promising roles within this specific CAF subgroup, paving the way for its clinical application. However, several critical questions persist, primarily stemming from the heterogeneous nature of CAFs and the use of different fibroblast markers in various sample analyses, causing confusion and hindrance in their clinical implementation. In this groundbreaking study, we …

Membrane Vectorial Lipidomic Features Of Coral Host Cells’ Plasma Membrane And Lipid Profiles Of Their Endosymbionts Cladocopium, Tatyana V Sikorskaya, Ekaterina V Ermolenko, Taliya T Ginanova, Andrey V Boroda, Kseniya V Efimova, Mikhail Bogdanov

Faculty, Staff and Student Publications

The symbiotic relationships between coral animal host and autotrophic dinoflagellates are based on the mutual exchange and tight control of nutritional inputs supporting successful growth. The corals Sinularia heterospiculata and Acropora aspera were cultivated using a flow-through circulation system supplying seawater during cold and warm seasons of the year, then sorted into host cells and symbionts and subjected to phylogenetic, morphological, and advanced lipid analyses. Here we show, that the lipidomes of the dinoflagellates Cladocopium C1/C3 and acroporide-specific Cladocopium hosted by the corals, are determined by lipidomic features of different thermosensitivity and unique betaine- and phospholipid molecular species. Phosphatidylserines and …

Long G4-Rich Enhancers Physically Interacts With Promoters Via A G4:G4 Dna-Based Mechanism, Jeffrey David Demeis

Graduate Theses and Dissertations (2019 - present)

Enhancers are genomic sequences that function as regulatory elements capable of increasing the transcription of a given gene often located at a considerable distance. The broadly accepted model of enhancer activation involves bringing an enhancer-bound activator protein complex into close spatial proximity to its target promoter through chromatin looping. Equally relevant to the work described herein, roles for guanine (G) rich sequences in transcriptional regulation are now widely accepted. Non-coding G-rich sequences are commonly found in gene promoters and enhancers, and various studies have described specific instances where G-rich sequences regulate gene expression via their capacity to form G-quadruplex (G4) …

Transcriptomic Analysis Reveals The Anti-Cancer Effect Of Gestational Mesenchymal Stem Cell Secretome, Salvatore Vaiasicca, Gianmarco Melone, David W James, Marcos Quintela, Jing Xiao, Seydou Yao, Richard H Finnell, Robert S Conlan, Lewis W Francis, Bruna Corradetti

Faculty, Staff and Students Publications

The environment created during embryogenesis contributes to reducing aberrations that drive structural malformations and tumorigenesis. In this study, we investigate the anti-cancer effect of mesenchymal stem cells (MSCs) derived from 2 different gestational tissues, the amniotic fluid (AF) and the chorionic villi (CV), with emphasis on their secretome. Transcriptomic analysis was performed on patient-derived AF- and CV-MSCs collected during prenatal diagnosis and identified both mRNAs and lncRNAs, involved in tissue homeostasis and inhibiting biological processes associated with the etiology of aggressive cancers while regulating immune pathways shown to be important in chronic disorders. Secretome enrichment analysis also identified soluble moieties …

Systemic Interindividual Dna Methylation Variants In Cattle Share Major Hallmarks With Those In Humans, Wen-Jou Chang, Maria S Baker, Eleonora Laritsky, Chathura J Gunasekara, Uditha Maduranga, Justine C Galliou, Joseph W Mcfadden, Jessica R Waltemyer, Bruce Berggren-Thomas, Brianna N Tate, Hanxue Zhang, Benjamin D Rosen, Curtis P Van Tassell, George E Liu, Cristian Coarfa, Yi Athena Ren, Robert A Waterland

Faculty, Staff and Students Publications

BACKGROUND: We recently identified ~ 10,000 correlated regions of systemic interindividual epigenetic variation (CoRSIVs) in the human genome. These methylation variants are amenable to population studies, as DNA methylation measurements in blood provide information on epigenetic regulation throughout the body. Moreover, establishment of DNA methylation at human CoRSIVs is labile to periconceptional influences such as nutrition. Here, we analyze publicly available whole-genome bisulfite sequencing data on multiple tissues of each of two Holstein cows to determine whether CoRSIVs exist in cattle.

RESULTS: Focusing on genomic blocks with ≥ 5 CpGs and a systemic interindividual variation index of at least 20, …

Full-Length Αiibβ3 Cryo-Em Structure Reveals Intact Integrin Initiate-Activation Intrinsic Architecture, Tong Huo, Hongjiang Wu, Zeinab Moussa, Mehmet Sen, Valerie Dalton, Zhao Wang

Faculty, Staff and Students Publications

Integrin αIIbβ3 is the key receptor regulating platelet retraction and accumulation and a proven drug-target for antithrombotic therapies. Here we resolve the cryoEM structures of the full-length αIIbβ3, which covers three distinct states along the activation pathway. Firstly, we obtain the αIIbβ3 structure at 3Å resolution in the inactive state, revealing the overall topology of the heterodimer with the transmembrane (TM) helices and the ligand-binding domain tucked in a specific angle proximity to the TM region. After the addition of a Mn2+ agonist, we resolve two coexisting structures representing two new states between inactive and active state. Our structures show …

Msl2 Variants Lead To A Neurodevelopmental Syndrome With Lack Of Coordination, Epilepsy, Specific Dysmorphisms, And A Distinct Episignature, Remzi Karayol, Maria Carla Borroto, Sadegheh Haghshenas, Anoja Namasivayam, Jack Reilly, Michael A Levy, Raissa Relator, Jennifer Kerkhof, Haley Mcconkey, Maria Shvedunova, Andrea K Petersen, Kari Magnussen, Christiane Zweier, Georgia Vasileiou, André Reis, Juliann M Savatt, Meghan R Mulligan, Louise S Bicknell, Gemma Poke, Aya Abu-El-Haija, Jessica Duis, Vickie Hannig, Siddharth Srivastava, Elizabeth Barkoudah, Natalie S Hauser, Myrthe Van Den Born, Uri Hamiel, Noa Henig, Hagit Baris Feldman, Shane Mckee, Ingrid P C Krapels, Yunping Lei, Albena Todorova, Ralitsa Yordanova, Slavena Atemin, Mihael Rogac, Vivienne Mcconnell, Anna Chassevent, Kristin W Barañano, Vandana Shashi, Jennifer A Sullivan, Angela Peron, Maria Iascone, Maria P Canevini, Jennifer Friedman, Iris A Reyes, Janell Kierstein, Joseph J Shen, Faria N Ahmed, Xiao Mao, Berta Almoguera, Fiona Blanco-Kelly, Konrad Platzer, Ariana-Berenike Treu, Juliette Quilichini, Alexia Bourgois, Nicolas Chatron, Louis Januel, Christelle Rougeot, Deanna Alexis Carere, Kristin G Monaghan, Justine Rousseau, Kenneth A Myers, Bekim Sadikovic, Asifa Akhtar, Philippe M Campeau

Faculty, Staff and Students Publications

Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding …

Intrinsically Disordered Membrane Anchors Of Rheb, Rhoa, And Diras3 Small Gtpases: Molecular Dynamics, Membrane Organization, And Interactions, Chase M Hutchins, Alemayehu A Gorfe

Faculty, Staff and Student Publications

Protein structure has been well established to play a key role in determining function; however, intrinsically disordered proteins and regions (IDPs and IDRs) defy this paradigm. IDPs and IDRs exist as an ensemble of structures rather than a stable 3D structure yet play essential roles in many cell-signaling processes. Nearly all Ras superfamily GTPases are tethered to membranes by a lipid tail at the end of a flexible IDR. The sequence of the IDR is a key determinant of membrane localization, and interaction between the IDR and the membrane has been shown to affect signaling in RAS proteins through the …

Emergent Emm4 Group A Streptococcus Evidences A Survival Strategy During Interaction With Immune Effector Cells, Chioma M Odo, Luis A Vega, Piyali Mukherjee, Sruti Debroy, Anthony R Flores, Samuel A Shelburne

Faculty, Staff and Student Publications

The major gram-positive pathogen group A Streptococcus (GAS) is a model organism for studying microbial epidemics as it causes waves of infections. Since 1980, several GAS epidemics have been ascribed to the emergence of clones producing increased amounts of key virulence factors such as streptolysin O (SLO). Herein, we sought to identify mechanisms underlying our recently identified temporal clonal emergence among emm4 GAS, given that emergent strains did not produce augmented levels of virulence factors relative to historic isolates. By creating and analyzing isoallelic strains, we determined that a conserved mutation in a previously undescribed gene encoding a putative carbonic …

Persistent Interruption In Parvalbuminpositive Inhibitory Interneurons: Biophysical And Mathematical Mechanisms, Carol M. Upchurch, Christopher J. Knowlton, Simon Chamberland, Carmen C. Canavier

School of Graduate Studies Faculty Publications

Persistent activity in excitatory pyramidal cells (PYRs) is a putative mechanism for maintaining memory traces during working memory. We have recently demonstrated persistent interruption of firing in fastspiking parvalbumin-expressing interneurons (PV-INs), a phenomenon that could serve as a substrate for persistent activity in PYRs through disinhibition lasting hundreds of milliseconds. Here, we find that hippocampal CA1 PV-INs exhibit type 2 excitability, like striatal and neocortical PV-INs. Modeling and mathematical analysis showed that the slowly inactivating potassium current KV1 contributes to type 2 excitability, enables the multiple firing regimes observed experimentally in PV-INs, and provides a mechanism for robust persistent interruption …

Context-Dependent T-Box Transcription Factor Family: From Biology To Targeted Therapy, Siwen Li, Xiangyuan Luo, Mengyu Sun, Yijun Wang, Zerui Zhang, Junqing Jiang, Dian Hu, Jiaqian Zhang, Zhangfan Wu, Yufei Wang, Wenjie Huang, Limin Xia

Faculty, Staff and Student Publications

T-BOX factors belong to an evolutionarily conserved family of transcription factors. T-BOX factors not only play key roles in growth and development but are also involved in immunity, cancer initiation, and progression. Moreover, the same T-BOX molecule exhibits different or even opposite effects in various developmental processes and tumor microenvironments. Understanding the multiple roles of context-dependent T-BOX factors in malignancies is vital for uncovering the potential of T-BOX-targeted cancer therapy. We summarize the physiological roles of T-BOX factors in different developmental processes and their pathological roles observed when their expression is dysregulated. We also discuss their regulatory roles in tumor …

Baseline Data Collections Of Lipopolysaccharide Content In 414 Herbal Extracts And Its Role In Innate Immune Activation, Vindy Tjendana Tjhin, Masataka Oda, Masashi Yamashita, Tomoko Iwaki, Yasuko Fujita, Koji Wakame, Hiroyuki Inagawa, Gen-Ichiro Soma

Faculty, Staff and Student Publications

Some herbal extracts contain relatively high amounts of lipopolysaccharide (LPS). Because orally administered LPS activates innate immunity without inducing inflammation, it plays a role as an active ingredient in herbal extracts. However, the LPS content in herbal extracts remains extensively unevaluated. This study aimed to create a database of LPS content in herbal extracts; therefore, the LPS content of 414 herbal extracts was measured and the macrophage activation potential was evaluated. The LPS content of these hot water extracts was determined using the kinetic-turbidimetric method. The LPS concentration ranged from a few ng/g to hundreds of μg/g (Standard Escherichia coli …

A Pan-Cancer Patient-Derived Xenograft Histology Image Repository With Genomic And Pathologic Annotations Enables Deep Learning Analysis, Brian S White, Xing Yi Woo, Soner Koc, Todd Sheridan, Steven B Neuhauser, Shidan Wang, Yvonne A Evrard, Li Chen, Ali Foroughi Pour, John D Landua, R Jay Mashl, Sherri R Davies, Bingliang Fang, Maria Gabriela Raso, Kurt W Evans, Matthew H Bailey, Yeqing Chen, Min Xiao, Jill C Rubinstein, Brian J Sanderson, Michael W Lloyd, Sergii Domanskyi, Lacey E Dobrolecki, Maihi Fujita, Junya Fujimoto, Guanghua Xiao, Ryan C Fields, Jacqueline L Mudd, Xiaowei Xu, Melinda G Hollingshead, Shahanawaz Jiwani, Saul Acevedo, Pdxnet Consortium, Brandi N Davis-Dusenbery, Peter N Robinson, Jeffrey A Moscow, James H Doroshow, Nicholas Mitsiades, Salma Kaochar, Chong-Xian Pan, Luis G Carvajal-Carmona, Alana L Welm, Bryan E Welm, Ramaswamy Govindan, Shunqiang Li, Michael A Davies, Jack A Roth, Funda Meric-Bernstam, Yang Xie, Meenhard Herlyn, Li Ding, Michael T Lewis, Carol J Bult, Dennis A Dean, Jeffrey H Chuang

Faculty, Staff and Students Publications

Patient-derived xenografts (PDX) model human intra- and intertumoral heterogeneity in the context of the intact tissue of immunocompromised mice. Histologic imaging via hematoxylin and eosin (H&E) staining is routinely performed on PDX samples, which could be harnessed for computational analysis. Prior studies of large clinical H&E image repositories have shown that deep learning analysis can identify intercellular and morphologic signals correlated with disease phenotype and therapeutic response. In this study, we developed an extensive, pan-cancer repository of >1,000 PDX and paired parental tumor H&E images. These images, curated from the PDX Development and Trial Centers Research Network Consortium, had a …

Machine Learning Identifies Prognostic Subtypes Of The Tumor Microenvironment Of Nsclc, Duo Yu, Michael J Kane, Eugene J Koay, Ignacio I Wistuba, Brian P Hobbs

Faculty, Staff and Student Publications

The tumor microenvironment (TME) plays a fundamental role in tumorigenesis, tumor progression, and anti-cancer immunity potential of emerging cancer therapeutics. Understanding inter-patient TME heterogeneity, however, remains a challenge to efficient drug development. This article applies recent advances in machine learning (ML) for survival analysis to a retrospective study of NSCLC patients who received definitive surgical resection and immune pathology following surgery. ML methods are compared for their effectiveness in identifying prognostic subtypes. Six survival models, including Cox regression and five survival machine learning methods, were calibrated and applied to predict survival for NSCLC patients based on PD-L1 expression, CD3 expression, …