Medical Microbiology Commons^™

Active Dna Demethylation Promotes Cell Fate Specification And The Dna Damage Response, Dongpeng Wang, Wei Wu, Elsa Callen, Raphael Pavani, Nicholas Zolnerowich, Srikanth Kodali, Dali Zong, Nancy Wong, Santiago Noriega, William J Nathan, Gabriel Matos-Rodrigues, Raj Chari, Michael J Kruhlak, Ferenc Livak, Michael Ward, Keith Caldecott, Bruno Di Stefano, André Nussenzweig

Faculty, Staff and Students Publications

Neurons harbor high levels of single-strand DNA breaks (SSBs) that are targeted to neuronal enhancers, but the source of this endogenous damage remains unclear. Using two systems of postmitotic lineage specification-induced pluripotent stem cell-derived neurons and transdifferentiated macrophages-we show that thymidine DNA glycosylase (TDG)-driven excision of methylcytosines oxidized with ten-eleven translocation enzymes (TET) is a source of SSBs. Although macrophage differentiation favors short-patch base excision repair to fill in single-nucleotide gaps, neurons also frequently use the long-patch subpathway. Disrupting this gap-filling process using anti-neoplastic cytosine analogs triggers a DNA damage response and neuronal cell death, which is dependent on TDG. …

Cic Missense Variants Contribute To Susceptibility For Spina Bifida, Xiao Han, Xuanye Cao, Vanessa Aguiar-Pulido, Wei Yang, Menuka Karki, Paula Andrea Pimienta Ramirez, Robert M Cabrera, Ying Linda Lin, Bogdan J Wlodarczyk, Gary M Shaw, M Elizabeth Ross, Cuilian Zhang, Richard H Finnell, Yunping Lei

Faculty, Staff and Students Publications

Neural tube defects (NTDs) are congenital malformations resulting from abnormal embryonic development of the brain, spine, or spinal column. The genetic etiology of human NTDs remains poorly understood despite intensive investigation. CIC, homolog of the Capicua transcription repressor, has been reported to interact with ataxin-1 (ATXN1) and participate in the pathogenesis of spinocerebellar ataxia type 1. Our previous study demonstrated that CIC loss of function (LoF) variants contributed to the cerebral folate deficiency syndrome by downregulating folate receptor 1 (FOLR1) expression. Given the importance of folate transport in neural tube formation, we hypothesized that CIC variants could contribute to increased …

Metabolome And Microbiome Multi-Omics Integration From A Murine Lung Inflammation Model Of Bronchopulmonary Dysplasia, Ahmed El Saie, Chenlian Fu, Sandra L Grimm, Matthew J Robertson, Kristi Hoffman, Vasanta Putluri, Chandra Shekar R Ambati, Nagireddy Putluri, Binoy Shivanna, Cristian Coarfa, Mohan Pammi

Faculty, Staff and Students Publications

BACKGROUND: Respiratory tract microbial dysbiosis can exacerbate inflammation and conversely inflammation may cause dysbiosis. Dysbiotic microbiome metabolites may lead to bronchopulmonary dysplasia (BPD). Hyperoxia and lipopolysaccharide (LPS) interaction alters lung microbiome and metabolome, mediating BPD lung injury sequence.

METHODS: C57BL6/J mice were exposed to 21% (normoxia) or 70% (hyperoxia) oxygen during postnatal days (PND) 1-14. Pups were injected with LPS (6 mg/kg) or equal PBS volume, intraperitoneally on PND 3, 5, and 7. At PND14, the lungs were collected for microbiome and metabolomic analyses (n = 5/group).

RESULTS: Microbiome alpha and beta diversity were similar between groups. Metabolic changes included …

Histopathologic And Transcriptomic Phenotypes Of A Conditional Rankl Transgenic Mouse Thymus, Maria M Szwarc, Lan Hai, Vineet K Maurya, Kimal Rajapakshe, Dimuthu Perera, Michael M Ittmann, Qianxing Mo, Yong Lin, Matthew L Bettini, Cristian Coarfa, John P Lydon

Faculty, Staff and Students Publications

Although conventional knockout and transgenic mouse models have significantly advanced our understanding of Receptor Activator of NF-κB Ligand (RANKL) signaling in intra-thymic crosstalk that establishes self-tolerance and later stages of lymphopoiesis, the unique advantages of conditional mouse transgenesis have yet to be explored. A main advantage of conditional transgenesis is the ability to express a transgene in a spatiotemporal restricted manner, enabling the induction (or de-induction) of transgene expression during predetermined stages of embryogenesis or during defined postnatal developmental or physiological states, such as puberty, adulthood, and pregnancy. Here, we describe the K5: RANKL bigenic mouse, in which transgene derived …

Oleuropein Suppresses Endometriosis Progression And Improves The Fertility Of Mice With Endometriosis, Yuri Park, Yeon Jean Cho, Nuri Sung, Mi Jin Park, Xiaoming Guan, William E Gibbons, Bert W O'Malley, Sang Jun Han

Faculty, Staff and Students Publications

BACKGROUND: Endometriosis is an estrogen-dependent inflammatory reproductive disease. Therefore, systematic estrogen depletion and anti-inflammatory drugs are the current treatment for endometriosis. However, current endometriosis treatments have low efficacy and cause adverse effects in endometriosis patients. Consequently, alternative endometriosis treatments targeting endometriosis-specific factors are in demand. In this context, ERβ was selected as a druggable target for endometriosis due to its critical role in progression. Therefore, selective targeting of ERβ without inhibiting ERα activity would be a new paradigm for endometriosis treatment to overcome the low efficacy and adverse effects of hormonal endometriosis therapy.

METHODS: Cell-based ERβ and ERα activity assay …

Modified Messengers: Flatworm Stem Cells And Regeneration Are Guarded By Rna Methylation, Blair W Benham-Pyle

Faculty, Staff and Students Publications

The contribution of RNA modifications to whole-body regeneration remains unclear. In this issue, Dagan et al (2022) show that m6a mRNA pathway components are critically required for stem cell differentiation, survival, and tissue renewal in the planarian Schmidtea mediterranea.

Triphenyl Phosphate Activates Estrogen Receptor Α/Nf-Κb/ Cyclin D1 Signaling To Stimulate Cell Cycle Progression In Human Ishikawa Endometrial Cancer Cells, Hyun Young Kwon, Seung Bin Park, Myoungseok Han, Jung-Woo Park, Yongmin Lee, Sang Jun Han, Youngmin Kwon, Yeon Jean Cho

Faculty, Staff and Students Publications

OBJECTIVE: Triphenyl phosphate (TPHP) is one of the most commonly used organophosphorus flame retardants that may accumulate in the environment. However, its effects on human reproductive organs have not been well studied. We aimed to investigate the in vitro effects of TPHP in human Ishikawa endometrial cancer cells to elucidate how TPHP exposure disrupts intracellular signaling and cell proliferation in reproductive tissues.

METHODS: Human Ishikawa endometrial cancer cells were exposed to TPHP.

RESULTS: Exposure to TPHP elevated the levels of estrogen receptor (ER) α and progesterone receptor-B and reduced ER β in human Ishikawa endometrial cancer cells. TPHP stimulated phosphoinositide …

Steroid Receptor Coactivator-3 Inhibition Generates Breast Cancer Antitumor Immune Microenvironment, Sang Jun Han, Nuri Sung, Jin Wang, Bert W O'Malley, David M Lonard

Faculty, Staff and Students Publications

BACKGROUND: The tumor immune microenvironment (TIME) generated by cancer-infiltrating immune cells has a crucial role in promoting or suppressing breast cancer progression. However, whether the steroid receptor coactivator-3 (SRC-3) modulates TIME to progress breast cancer is unclear. Therefore, the present study evaluates whether SRC-3 generates a tumor-promoting TIME in breast tumors using a syngeneic immune-intact mouse model of breast cancer.

METHODS: We employed E0771 and 4T1 breast cancer in immune-intact syngeneic female C57BL/6 and BALB/c mice, respectively. SI-2, a specific small-molecule inhibitor of SRC-3, was administered daily (2.5 mg/kg) to E0771 and 4T1 breast tumor-bearing immune-intact mice. In addition, SRC-3 …

Rapid Reconstruction Of Neural Circuits Using Tissue Expansion And Light Sheet Microscopy, Joshua L Lillvis, Hideo Otsuna, Xiaoyu Ding, Igor Pisarev, Takashi Kawase, Jennifer Colonell, Konrad Rokicki, Cristian Goina, Ruixuan Gao, Amy Hu, Kaiyu Wang, John Bogovic, Daniel E Milkie, Linus Meienberg, Brett D Mensh, Edward S Boyden, Stephan Saalfeld, Paul W Tillberg, Barry J Dickson

Faculty, Staff and Student Publications

Brain function is mediated by the physiological coordination of a vast, intricately connected network of molecular and cellular components. The physiological properties of neural network components can be quantified with high throughput. The ability to assess many animals per study has been critical in relating physiological properties to behavior. By contrast, the synaptic structure of neural circuits is presently quantifiable only with low throughput. This low throughput hampers efforts to understand how variations in network structure relate to variations in behavior. For neuroanatomical reconstruction, there is a methodological gulf between electron microscopic (EM) methods, which yield dense connectomes at considerable …

Interferon Signaling In The Endometrium And In Endometriosis, Yuri Park, Sang Jun Han

Faculty, Staff and Students Publications

Endometriosis is an estrogen-dependent inflammatory disease that develops in reproductive-aged women who experience pelvic pain and infertility. Even though endometriosis is not a new disease, its molecular etiology has not been clearly elucidated. Defects in the immune system might be one of the factors that promote endometriosis progression. For example, elevated levels of proinflammatory cytokines are associated with endometriosis. Interferon is one of the cytokines that is elevated in endometriotic tissues compared with normal endometrium. Therefore, high interferon levels play a crucial role in endometriosis progression. In addition to endometriosis, however, interferon has a critical role in endometrial function, particularly …

Sensitive Image-Based Chromatin Binding Assays Using Inducible Erα To Rapidly Characterize Estrogenic Chemicals And Mixtures, Adam T Szafran, Maureen G Mancini, Fabio Stossi, Michael A Mancini

Faculty, Staff and Students Publications

The United States Environmental Protection Agency (EPA) has been pursuing new high throughput in vitro assays to characterize endocrine disrupting chemicals (EDCs) that interact with estrogen receptor signaling. We characterize two new PRL-HeLa cell models expressing either inducible C-terminal (iGFP-ER) or N-terminal (iER-GFP) tagged estrogen receptor-α (ERα) that allows direct visualization of chromatin binding. These models are an order of magnitude more sensitive, detecting 87 - 93% of very weak estrogens tested compared to only 27% by a previous PRL-HeLa variant and compares favorably to the 73% detected by an EPA-developed computational model using in vitro data. Importantly, the chromatin …

Elevated Nras Expression During Dcis Is A Potential Driver For Progression To Basal-Like Properties And Local Invasiveness, Ze-Yi Zheng, Hanan Elsarraj, Jonathan T Lei, Yan Hong, Meenakshi Anurag, Long Feng, Hilda Kennedy, Yichao Shen, Flora Lo, Zifan Zhao, Bing Zhang, Xiang H-F Zhang, Ossama W Tawfik, Fariba Behbod, Eric C Chang

Faculty, Staff and Students Publications

BACKGROUND: Ductal carcinoma in situ (DCIS) is the most common type of in situ premalignant breast cancers. What drives DCIS to invasive breast cancer is unclear. Basal-like invasive breast cancers are aggressive. We have previously shown that NRAS is highly expressed selectively in basal-like subtypes of invasive breast cancers and can promote their growth and progression. In this study, we investigated whether NRAS expression at the DCIS stage can control transition from luminal DCIS to basal-like invasive breast cancers.

METHODS: Wilcoxon rank-sum test was performed to assess expression of NRAS in DCIS compared to invasive breast tumors in patients. NRAS …

Identification Of An Early Survival Prognostic Gene Signature For Localized Osteosarcoma Patients, Harry Mackay, Chathura J Gunasekara, Kit-Yi Yam, Dollada Srisai, Hari Krishna Yalamanchili, Yumei Li, Rui Chen, Cristian Coarfa, Robert A Waterland

Faculty, Staff and Students Publications

Recent genome-wide association studies corroborate classical research on developmental programming indicating that obesity is primarily a neurodevelopmental disease strongly influenced by nutrition during critical ontogenic windows. Epigenetic mechanisms regulate neurodevelopment; however, little is known about their role in establishing and maintaining the brain's energy balance circuitry. We generated neuron and glia methylomes and transcriptomes from male and female mouse hypothalamic arcuate nucleus, a key site for energy balance regulation, at time points spanning the closure of an established critical window for developmental programming of obesity risk. We find that postnatal epigenetic maturation is markedly cell type and sex specific and …

Plasma Protein Biomarkers For Primary Graft Dysfunction After Lung Transplantation: A Single-Center Cohort Analysis, Lourdes Chacon-Alberty, Rupa S Kanchi, Shengbin Ye, Camila Hochman-Mendez, Daoud Daoud, Cristian Coarfa, Meng Li, Sandra L Grimm, Maher Baz, Ivan Rosas, Gabriel Loor

Faculty, Staff and Students Publications

The clinical use of circulating biomarkers for primary graft dysfunction (PGD) after lung transplantation has been limited. In a prospective single-center cohort, we examined the use of plasma protein biomarkers as indicators of PGD severity and duration after lung transplantation. The study comprised 40 consecutive lung transplant patients who consented to blood sample collection immediately pretransplant and at 6, 24, 48, and 72 h after lung transplant. An expert grader determined the severity and duration of PGD and scored PGD at T0 (6 h after reperfusion), T24, T48, and T72 h post-reperfusion using the 2016 ISHLT consensus guidelines. A bead-based …

Ppm1d In Solid And Hematologic Malignancies: Friend And Foe?, Linda Zhang, Joanne I Hsu, Margaret A Goodell

Faculty, Staff and Students Publications

In the face of constant genomic insults, the DNA damage response (DDR) is initiated to preserve genome integrity; its disruption is a classic hallmark of cancer. Protein phosphatase Mg2+/Mn2+-dependent 1D (PPM1D) is a central negative regulator of the DDR that is mutated or amplified in many solid cancers. PPM1D overexpression is associated with increased proliferative and metastatic behavior in multiple solid tumor types and patients with PPM1D-mutated malignancies have poorer prognoses. Recent findings have sparked an interest in the role of PPM1D in hematologic malignancies. Acquired somatic mutations may provide hematopoietic stem cells with a competitive advantage, leading to a …

Mab21l4 Deficiency Drives Squamous Cell Carcinoma Via Activation Of Ret, Ankit Srivastava, Cristina Tommasi, Dane Sessions, Angela Mah, Tomas Bencomo, Jasmine M Garcia, Tiffany Jiang, Michael Lee, Joseph Y Shen, Lek Wei Seow, Audrey Nguyen, Kimal Rajapakshe, Cristian Coarfa, Kenneth Y Tsai, Vanessa Lopez-Pajares, Carolyn S Lee

Faculty, Staff and Students Publications

UNLABELLED: Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome-wide screen for genes of unknown function that possess inverse expression patterns in differentiating keratinocytes compared with cutaneous SCC (cSCC), leading to the identification of MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids increased expression of RET to enable malignant progression. In addition to transcriptional upregulation of RET, deletion of MAB21L4 preempted recruitment of the CacyBP-Siah1 E3 ligase …

Associations Between Maternal Reports Of Periconceptional Fever From Miscellaneous Causes And Structural Birth Defects, Nithya Lakshmi Mohan Dass, Lorenzo D Botto, Sarah C Tinker, Mark A Canfield, Richard H Finnell, Michael Shayne Gallaway, Syed Shahrukh Hashmi, Adrienne T Hoyt, Wendy N Nembhard, Dorothy K Waller, National Birth Defects Prevention Study

Faculty, Staff and Students Publications

BACKGROUND: Associations between birth defects and fevers attributed to colds, influenza, and urinary tract infections (UTIs) have been observed in previous studies. Our aim was to study associations between birth defects and fevers attributed to other causes.

METHODS: We analyzed data from 34,862 participants in the National Birth Defects Prevention Study, a multistate case-control study of major structural birth defects. Using multivariable logistic regression, we assessed the association between maternal report of fever during early pregnancy due to causes other than colds, influenza, or UTI and 36 categories of birth defects.

RESULTS: Maternal reports of fever due to other causes …

Gene Expression Signatures Identify Biologically And Clinically Distinct Tuberculosis Endotypes, Andrew R Dinardo, Tanmay Gandhi, Jan Heyckendorf, Sandra L Grimm, Kimal Rajapakshe, Tomoki Nishiguchi, Maja Reimann, H Lester Kirchner, Jaqueline Kahari, Qiniso Dlamini, Christoph Lange, Torsten Goldmann, Sebastian Marwitz, Dzif-Tb Cohort Study Group, Abhimanyu, Jeffrey D Cirillo, Stefan H E Kaufmann, Mihai G Netea, Reinout Van Crevel, Anna M Mandalakas, Cristian Coarfa

Faculty, Staff and Students Publications

BACKGROUND:In vitro, animal model and clinical evidence suggests that tuberculosis is not a monomorphic disease, and that host response to tuberculosis is protean with multiple distinct molecular pathways and pathologies (endotypes). We applied unbiased clustering to identify separate tuberculosis endotypes with classifiable gene expression patterns and clinical outcomes.

METHODS: A cohort comprised of microarray gene expression data from microbiologically confirmed tuberculosis patients was used to identify putative endotypes. One microarray cohort with longitudinal clinical outcomes was reserved for validation, as were two RNA-sequencing (seq) cohorts. Finally, a separate cohort of tuberculosis patients with functional immune responses was evaluated …

An Auto-Inhibited State Of Protein Kinase G And Implications For Selective Activation, Rajesh Sharma, Jeong Joo Kim, Liying Qin, Philipp Henning, Madoka Akimoto, Bryan Vanschouwen, Gundeep Kaur, Banumathi Sankaran, Kevin R Mackenzie, Giuseppe Melacini, Darren E Casteel, Friedrich W Herberg, Choel Kim

Faculty, Staff and Students Publications

Cyclic GMP-dependent protein kinases (PKGs) are key mediators of the nitric oxide/cyclic guanosine monophosphate (cGMP) signaling pathway that regulates biological functions as diverse as smooth muscle contraction, cardiac function, and axon guidance. Understanding how cGMP differentially triggers mammalian PKG isoforms could lead to new therapeutics that inhibit or activate PKGs, complementing drugs that target nitric oxide synthases and cyclic nucleotide phosphodiesterases in this signaling axis. Alternate splicing of PRKG1 transcripts confers distinct leucine zippers, linkers, and auto-inhibitory (AI) pseudo-substrate sequences to PKG Iα and Iβ that result in isoform-specific activation properties, but the mechanism of enzyme auto-inhibition and its alleviation …

Exome Sequencing Identifies Genetic Variants In Anophthalmia And Microphthalmia, Jingjing Li, Wei Yang, Yuejun Jessie Wang, Chen Ma, Cynthia J Curry, Daniel Mcgoldrick, Deborah A Nickerson, Jessica X Chong, Elizabeth E Blue, James C Mullikin, Jennita Reefhuis, Wendy N Nembhard, Paul A Romitti, Martha M Werler, Marilyn L Browne, Andrew F Olshan, Richard H Finnell, Marcia L Feldkamp, Faith Pangilinan, Lynn M Almli, Mike J Bamshad, Lawrence C Brody, Mary M Jenkins, Gary M Shaw, University Of Washington Center For Mendelian Genomics, Nisc Comparative Sequencing Program, National Birth Defects Prevention Study

Faculty, Staff and Students Publications

Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 …

Early Growth Response 1 Transcription Factor Is Essential For The Pathogenic Properties Of Human Endometriotic Epithelial Cells, Vineet K Maurya, Maria M Szwarc, Rodrigo Fernandez-Valdivia, David M Lonard, Song Yong, Niraj Joshi, Asgerally T Fazleabas, John P Lydon

Faculty, Staff and Students Publications

Although a non-malignant gynecological disorder, endometriosis displays some pathogenic features of malignancy, such as cell proliferation, migration, invasion and adaptation to hypoxia. Current treatments of endometriosis include pharmacotherapy and/or surgery, which are of limited efficacy and often associated with adverse side effects. Therefore, to develop more effective therapies to treat this disease, a broader understanding of the underlying molecular mechanisms that underpin endometriosis needs to be attained. Using immortalized human endometriotic epithelial and stromal cell lines, we demonstrate that the early growth response 1 (EGR1) transcription factor is essential for cell proliferation, migration and invasion, which represent some of the …

Patients With Lung Cancer Of Different Racial Backgrounds Harbor Distinct Immune Cell Profiles, Yitian Xu, Licheng Zhang, Jose Thaiparambil, Sunny Mai, Dimuthu Nuwan Perera, Jilu Zhang, Ping-Ying Pan, Cristian Coarfa, Kenneth Ramos, Shu-Hsia Chen, Randa El-Zein

Faculty, Staff and Students Publications

UNLABELLED: Tumors accumulated with infiltrated immune cells (hot tumors) have a higher response rate to immune checkpoint blockade, when compared with those with minimal T-cell infiltration (cold tumors). We report here that patients with lung cancer with different racial backgrounds harbored distinct immune cell profiles in the tumor microenvironment. Compared with African Americans (AA), Caucasian Americans (CA) exhibited increased immune cell infiltration and vasculature, and increased survival. Changes of survival and immune profile were most pronounced among active smokers and nonsmokers, compared with former smokers and total patients. Neighborhood analysis showed that immune cells accumulated around cancer cells in CAs …

Hippo-Taz Signaling Is The Master Regulator Of The Onset Of Triple-Negative Basal-Like Breast Cancers, Hirotoshi Soyama, Miki Nishio, Junji Otani, Toshiko Sakuma, Shintaro Takao, Shigeo Hara, Takaaki Masuda, Koshi Mimori, Shinya Toyokuni, John P Lydon, Kazuwa Nakao, Hiroshi Nishina, Takumi Fukumoto, Tomohiko Maehama, Akira Suzuki

Faculty, Staff and Students Publications

A universal oncogenic driver of basal-like breast cancer (BLBC) has resisted identification. We show that continuous transcriptional coactivator with PDZ-binding motif (TAZ) activation in precancerous murine luminal cells generates luminal cancers that later become BLBCs. Subsequent TP53 alteration, a feature of invasive human BLBCs, accelerates tumor progression. Because BLBC development is inhibited by TAZ inactivation in vivo, our work provides a sound rationale for targeting Hippo-TAZ signaling as therapy for human BLBC. Our mouse model of BLBC represents a powerful tool for evaluating such drugs.

Internal Standard Triggered-Parallel Reaction Monitoring Mass Spectrometry Enables Multiplexed Quantification Of Candidate Biomarkers In Plasma, Jacob J Kennedy, Jeffrey R Whiteaker, Richard G Ivey, Aura Burian, Shrabanti Chowdhury, Chia-Feng Tsai, Tao Liu, Chenwei Lin, Oscar D Murillo, Rachel A Lundeen, Lisa A Jones, Philip R Gafken, Gary Longton, Karin D Rodland, Steven J Skates, John Landua, Pei Wang, Michael T Lewis, Amanda G Paulovich

Faculty, Staff and Students Publications

Despite advances in proteomic technologies, clinical translation of plasma biomarkers remains low, partly due to a major bottleneck between the discovery of candidate biomarkers and costly clinical validation studies. Due to a dearth of multiplexable assays, generally only a few candidate biomarkers are tested, and the validation success rate is accordingly low. Previously, mass spectrometry-based approaches have been used to fill this gap but feature poor quantitative performance and were generally limited to hundreds of proteins. Here, we demonstrate the capability of an internal standard triggered-parallel reaction monitoring (IS-PRM) assay to greatly expand the numbers of candidates that can be …

Maternal Adipocyte Connexin43 Gap Junctions Affect Breastmilk Lactose Levels And Neonate Growth In Mice, Mingyang Huang, Anying Song, Xi Chen, Sarah Ishtiaq, Chunmei Wang, Darryl L Hadsell, Qiong A Wang, Yi Zhu

Faculty, Staff and Students Publications

Simple Summary

Breastfeeding offers many health benefits for both mothers and infants. However, overnutrition and a steady increase in obesity in the U.S. has made it harder for many mothers to produce and express breastmilk. Moreover, the quality of breastmilk from obese mothers is frequently compromised in that it contains fewer nutrients and more inflammatory components. In this study, we used mice to model this phenomenon. We found that short-term high-fat feeding at the start of breeding reduces litter size and pups’ body weight. It also impairs adipocyte remodeling during lactation. Connexin43 is the primary building block for gap junctions …

Deletion Of The Lmna Gene In Fibroblasts Causes Senescence-Associated Dilated Cardiomyopathy By Activating The Double-Stranded Dna Damage Response And Induction Of Senescence-Associated Secretory Phenotype, Leila Rouhi, Gaelle Auguste, Qiong Zhou, Raffaella Lombardi, Melis Olcum, Kimia Pourebrahim, Sirisha M Cheedipudi, Saman Asghar, Kui Hong, Matthew J Robertson, Cristian Coarfa, Priyatansh Gurha, Ali J Marian

Faculty, Staff and Students Publications

INTRODUCTION: Mutations in the LMNA gene, encoding Lamin A/C (LMNA), are established causes of dilated cardiomyopathy (DCM). The phenotype is typically characterized by progressive cardiac conduction defects, arrhythmias, heart failure, and premature death. DCM is primarily considered a disease of cardiac myocytes. However, LMNA is also expressed in other cardiac cell types, including fibroblasts.

AIM: The purpose of the study was to determine the contribution of the fibroblasts to DCM caused by LMNA deficiency.

METHODS AND RESULTS: The Lmna gene was deleted by crossing the platelet-derived growth factor receptor α-Cre recombinase (Pdgfra-Cre) and floxed Lmna (LmnaF/F) …

Mir-181a Promotes Multiple Protumorigenic Functions By Targeting Tgfβr3, Vida Chitsazzadeh, Tran N Nguyen, Alvaro De Mingo Pulido, Bruna B Bittencourt, Lili Du, Charles H Adelmann, Ivannie Ortiz Rivera, Kimberly A Nguyen, Leah D Guerra, Andrew Davis, Marco Napoli, Wencai Ma, Richard Eric Davis, Kimal Rajapakshe, Cristian Coarfa, Elsa R Flores, Kenneth Y Tsai

Faculty, Staff and Students Publications

Cutaneous squamous cell carcinoma (cSCC) comprises 15‒20% of all skin cancers and has a well-defined progression sequence from precancerous actinic keratosis to invasive cSCC. To identify targets for chemoprevention, we previously reported a cross-species analysis to identify the transcriptional drivers of cSCC development and identified miR-181a as a potential oncomiR. We show that the upregulation of miR-181a promotes multiple protumorigenic properties by targeting an understudied component of TGFβ signaling, TGFβR3. miR-181a and TGFβR3 are upregulated and downregulated, respectively, in cSCC. miR-181a overexpression (OE) and TGFβR3 knockdown (KD) significantly suppresses UV-induced apoptosis in HaCaT cells and in primary normal human epidermal …

The Evolution And Structure/Function Of Bhlh-Pas Transcription Factor Family, Hailey E Edwards, Daniel A Gorelick

Faculty, Staff and Students Publications

Proteins that contain basic helix-loop-helix (bHLH) and Per-Arnt-Sim motifs (PAS) function as transcription factors. bHLH-PAS proteins exhibit essential and diverse functions throughout the body, from cell specification and differentiation in embryonic development to the proper function of organs like the brain and liver in adulthood. bHLH-PAS proteins are divided into two classes, which form heterodimers to regulate transcription. Class I bHLH-PAS proteins are typically activated in response to specific stimuli, while class II proteins are expressed more ubiquitously. Here, we discuss the general structure and functions of bHLH-PAS proteins throughout the animal kingdom, including family members that do not fit …

Mycn-Driven Fatty Acid Uptake Is A Metabolic Vulnerability In Neuroblastoma, Ling Tao, Mahmoud A Mohammad, Giorgio Milazzo, Myrthala Moreno-Smith, Tajhal D Patel, Barry Zorman, Andrew Badachhape, Blanca E Hernandez, Amber B Wolf, Zihua Zeng, Jennifer H Foster, Sara Aloisi, Pavel Sumazin, Youli Zu, John Hicks, Ketan B Ghaghada, Nagireddy Putluri, Giovanni Perini, Cristian Coarfa, Eveline Barbieri

Faculty, Staff and Students Publications

Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and …

Skin Fibrosis And Recovery Is Dependent On Wnt Activation Via Dpp4, Anna R Jussila, Brian Zhang, Elizabeth Caves, Sakin Kirti, Miarasa Steele, Emily Hamburg-Shields, John Lydon, Yan Ying, Robert Lafyatis, Sanjay Rajagopalan, Valerie Horsley, Radhika P Atit

Faculty, Staff and Students Publications

Fibrosis is the life-threatening, excessive accumulation of the extracellular matrix and is sometimes associated with a loss of lipid-filled cells in the skin and other organs. Understanding the mechanisms of fibrosis and associated lipodystrophy and their reversal may reveal new targets for therapeutic intervention. In vivo genetic models are needed to identify key targets that induce recovery from established fibrosis. Wnt signaling is activated in animal and human fibrotic diseases across organs. Here, we developed a genetically inducible and reversible Wnt activation model and showed that it is sufficient to cause fibrotic dermal remodeling, including extracellular matrix expansion and shrinking …