Cell and Developmental Biology Commons^™

Killi-Data News (Winter), Tyrone Genade

Killifish Research Review

This is the fourth edition, and concluding issue of the first volume, of Killi-Data News and I am happy that it has been well received by readers. At 25 pages this issue is a bit thin- ner than the last but this is because we agreed to make the cut-off for submissions the 1 st of December so we could get this edition out by the New Year. This is an exciting edition full of new species descrip- tions and analyses that will keep taxonomists busy for years to come. Costa has given us two molecular phylogenies on Melanorivulus as …

Killi-Data News (Spring), Tyrone Genade

Killifish Research Review

This is the start of Killi-Data News’ second year. In this first issue of the year we have the usual review of research pub- lications as well as input from Martin Reichard on his lab’s Nothobranchius research. Martin is responding to my reviews of his lab’s work in the previous edition. I am serious about making sure the content in this newsletter is reliable but I erred in the previous edition and Martin has written extensively to correct my mistake in the section “Erratum”. This reply is welcomed and owed to readers. I must confess that I don’t know everything …

Tributyltin Stimulates Synthesis Of Interferon Gamma And Tumor Necrosis Factor Alpha In Human Lymphocytes, Shanieek Lawrence, Farah Ismail, Sarah Z. Jamal, Margaret M. Whalen

Chemistry Faculty Research

Tributyltin (TBT) is found in human blood and other tissues and thus is of considerable concern as to its effects on human health. Previous studies have demonstrated that TBT has detrimental effects on immune function. Recently, we found that exposures to TBT caused increased secretion of two important proinflammatory cytokines, tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ). Elevation of either of these cytokines has the potential to cause chronic inflammation, which is an important factor in a number of diseases including cancer. The current study examined the mechanism of TBT-induced elevations of TNFα and IFNγ secretion and found …

Acute Loss Of Iron-Sulfur Clusters Results In Metabolic Reprogramming And Generation Of Lipid Droplets In Mammalian Cells, Daniel R. Crooks, Nunziata Maio, Andrew N. Lane, Michal Jarnik, Richard M. Higashi, Ronald G. Haller, Ye Yang, Teresa Whei-Mei Fan, W. Marston Linehan, Tracey A. Rouault

Center for Environmental and Systems Biochemistry Faculty Publications

Iron–sulfur (Fe-S) clusters are ancient cofactors in cells and participate in diverse biochemical functions, including electron transfer and enzymatic catalysis. Although cell lines derived from individuals carrying mutations in the Fe-S cluster biogenesis pathway or siRNA-mediated knockdown of the Fe-S assembly components provide excellent models for investigating Fe-S cluster formation in mammalian cells, these experimental strategies focus on the consequences of prolonged impairment of Fe-S assembly. Here, we constructed and expressed dominant–negative variants of the primary Fe-S biogenesis scaffold protein iron–sulfur cluster assembly enzyme 2 (ISCU2) in human HEK293 cells. This approach enabled us to study the early metabolic reprogramming …

Automated Registration And Stitching Of Multiple 3d Ultrasound Images For Monitoring Neonatal Intraventricular Hemorrhage, A. Harris, S. De Ribaupierre, Lori Gardi, Aaron Fenster, Jessica Kishimoto

Anatomy and Cell Biology Publications

Dilatation of the cerebral ventricles is a common condition in preterm neonates with intraventricular hemorrhage (IVH). Post Hemorrhagic Ventricular Dilatation (PHVD) can lead to lifelong neurological impairment caused by ischemic injury due to increased intracranial pressure, and without treatment can lead to death. Previously, we have developed and validated a 3D ultrasound (US) system to monitor the progression of ventricle volumes (VV) in IVH patients; however, many patients with severe PHVD have ventricles so large they cannot be imaged within a single 3D US image. This limits the utility of atlas based segmentation algorithms required to measure VV as parts …

Structure Of Full-Length Human Trpm4, Jingjing Duan, Zongli Li, Jian Li, Ana Santa-Cruz, Silvia Sanchez-Martinez, Jin Zhang, David E. Clapham

Molecular and Cellular Biochemistry Faculty Publications

Transient receptor potential melastatin subfamily member 4 (TRPM4) is a widely distributed, calcium-activated, monovalent-selective cation channel. Mutations in human TRPM4 (hTRPM4) result in progressive familial heart block. Here, we report the electron cryomicroscopy structure of hTRPM4 in a closed, Na⁺-bound, apo state at pH 7.5 to an overall resolution of 3.7 Å. Five partially hydrated sodium ions are proposed to occupy the center of the conduction pore and the entrance to the coiled-coil domain. We identify an upper gate in the selectivity filter and a lower gate at the entrance to the cytoplasmic coiled-coil domain. Intramolecular interactions exist …

Human Body Composition And Immunity: Visceral Adipose Tissue Produces Il-15 And Muscle Strength Inversely Correlates With Nk Cell Function In Elderly Humans, Ahmad Al-Attar, Steven R. Presnell, Jody L. Clasey, Douglas E. Long, R. Grace Walton, Morgan Sexton, Marlene E. Starr, Philip A. Kern, Charlotte A. Peterson, Charles T. Lutz

Pathology and Laboratory Medicine Faculty Publications

Natural killer (NK) lymphocyte-mediated cytotoxicity and cytokine secretion control infections and cancers, but these crucial activities decline with age. NK cell development, homeostasis, and function require IL-15 and its chaperone, IL-15 receptor alpha (IL-15Rα). Macrophages and dendritic cells (DC) are major sources of these proteins. We had previously postulated that additional IL-15 and IL-15Rα is made by skeletal muscle and adipose tissue. These sources may be important in aging, when IL-15-producing immune cells decline. NK cells circulate through adipose tissue, where they may be exposed to local IL-15. The objectives of this work were to determine (1) if human muscle, …

Immune Checkpoint Inhibitors In Large Cell Neuroendocrine Carcinoma: Current Status, Aman Chauhan, Susanne Arnold, Jill M. Kolesar, Hala Elnakat Thomas, B. Mark Evers, Lowell B. Anthony

Markey Cancer Center Faculty Publications

Introduction: Large cell neuroendocrine carcinomas (LCNEC) are a group of rare high grade neuroendocrine tumors that often behave clinically like small cell carcinoma (SCLC) and are treated as such. No major advancement in the management of these tumors has occurred in the last 30 years.

Methods: We present a case series of three cases from Markey Cancer center along with a review of 13 published cases in the literature wherein immune-checkpoint inhibitors were utilized in the management of LCNEC.

Results: Immune-checkpoint inhibitors might have clinical activity in LCNEC.

Conclusion: Role of immune-checkpoint inhibitors should be explored in prospective LCNEC clinical …

Mobilization Of Hematopoietic Stem Cells As A Result Of Innate Immunity-Mediated Sterile Inflammation In The Bone Marrow Microenvironment—The Involvement Of Extracellular Nucleotides And Purinergic Signaling, Mariusz Z. Ratajczak, Mateusz Adamiak, Monika Plonka, Ahmed Abdel-Latif, Janina Ratajczak

Internal Medicine Faculty Publications

Hematopoietic stem/progenitor cells (HSPCs) circulate in peripheral blood (PB) under normal conditions and their number increases in response to stress, inflammation, tissue/organ injury, and may increase up to 100-fold after administration of mobilization-inducing drugs. Mounting evidence suggests that mobilizing agent-induced mobilization of HSPCs from bone marrow into PB is a result of innate immunity-mediated sterile inflammation in the bone marrow (BM) microenvironment. A critical initiating role in this process is played by tissue/organ injury-mediated or pharmacologically induced release from bone marrow-residing granulocytes and monocytes of (i) danger-associated molecular patterns (DAMPs), (ii) reactive oxygen species (ROS), and (iii) proteolytic and lipolytic …

Epigenetic Modifiers Promote Mitochondrial Biogenesis And Oxidative Metabolism Leading To Enhanced Differentiation Of Neuroprogenitor Cells., Martine Uittenbogaard, Christine A Brantner, Anne Chiaramello

Anatomy and Regenerative Biology Faculty Publications

During neural development, epigenetic modulation of chromatin acetylation is part of a dynamic, sequential and critical process to steer the fate of multipotent neural progenitors toward a specific lineage. Pan-HDAC inhibitors (HDCis) trigger neuronal differentiation by generating an "acetylation" signature and promoting the expression of neurogenic bHLH transcription factors. Our studies and others have revealed a link between neuronal differentiation and increase of mitochondrial mass. However, the neuronal regulation of mitochondrial biogenesis has remained largely unexplored. Here, we show that the HDACi, sodium butyrate (NaBt), promotes mitochondrial biogenesis via the NRF-1/Tfam axis in embryonic hippocampal progenitor cells and neuroprogenitor-like PC12-NeuroD6 …

The Incidence And Characteristics Of Stroke In Urban-Dwelling Iranian Women, Amin Amiri Md, Moira Kapral Md Msc, Amanda G. Thrift Phd, Luciano A. Sposato, Hamidreza Saber Md, Reza Behrouz Do Phd, Mahdiyeh Erfanian, Mohammad Taghi Farzadfard Md, Naghmeh Mokhber Md, Reza Azarpazhooh Md

Anatomy and Cell Biology Publications

Background: Population-based data regarding stroke among women are scarce in developing countries. This study was designed to determine whether sex differences exist in stroke incidence, mortality, and recurrence.

Methods: The Mashhad Stroke Incidence Study is a population-based cohort study in Iran. For a period of 1 year, all patients with stroke in 3 geographical regions in Mashhad were recruited and then followed up for 5 years. Age- and sex-specific crude incidence rates were standardized to the World Health Organization New World Population. Male-to-female incidence rate ratios were assessed for all age groups and all subtypes of first-ever stroke (FES). …

Circulating Pander Concentration Is Associated With Increased Hba1c And Fasting Blood Glucose In Type 2 Diabetic Subjects, Catherine B. Marelia, Melanie N. Kuehl, Tiffany A. Shemwell, Amy C. Alman, Brant R. Burkhardt

Molecular Biosciences Faculty Publications

Aim: PANcreatic-DERived factor (PANDER, FAM3B) is a novel hormone that regulates glucose levels via interaction with both the endocrine pancreas and liver. Prior studies examining PANDER were primarily conducted in murine models or in vitro but little is known regarding the circulating concentration of PANDER in humans, especially with regard to the association of type 2 diabetes (T2D) or overall glycemic regulation. To address this limitation, we performed a cross-sectional analysis of circulating serum PANDER concentration in association with other hormones that serve as either markers of insulin resistance (insulin and adiponectin) or to metabolic parameters of glycemic control such …

Rescue Of Neocortical Circuit Deficits With Modified Bone Marrow-Derived Mesenchymal Stem Cells, Sb623, In A Rat Model Of Photothrombotic Stroke, Alexander Urry

Yale Day of Data

The following poster characterizes the effects of a novel stem cell line on treating the neural circuit deficits resulting from stroke.

Ferrocenylchalcone-Uracil Conjugates: Synthesis And Cytotoxic Evaluation, Amandeep Singh, Vishu Mehra, Neda Sadeghiani, Saghar Mozaffari, Keykavous Parang, Vipan Kumar

Pharmacy Faculty Articles and Research

Huisgen’s azide-alkyne cycloaddition reaction was employed to synthesize a series of 1H-1,2,3-triazole-tethered uracil-ferrocenyl chalcone conjugates with the aim of evaluating their in vitro anti-proliferative efficacy on human leukemia (CCRF-CEM) and human breast adenocarcinoma (MDA-MB-468) cell lines. Cytotoxic evaluation studies identified a number of synthesized conjugates that inhibited the proliferation of leukemia cancer cells by ~70% after 72 h. The selected synthesized conjugates were found to be significantly less cytotoxic against normal kidney cell line (LLC-PK1) when compared with CCRF-CEM cancer cells.

Long-Term Results Of Protocol Kidney Biopsy Directing Steroid Withdrawal In Simultaneous Pancreas-Kidney Transplant Patients, Nemin Zhu, Neal E. Rowe, Paul R. Martin, Sean S. Luke, Thomas B. Mcgregor, Frank Myslik, Vivian C. Mcalister, Alp Sener, Patrick P. Luke

Anatomy and Cell Biology Publications

Introduction: We sought to determine whether protocol biopsies could be used to guide treatment and improve outcomes in simultaneous pancreas-kidney (SPK) patients.

Methods: Between 2004 and 2013, protocol biopsies were performed on SPK patients at 3–6 months and one year post-transplant. Maintenance immunosuppression consisted of a calcineurin inhibitor, anti-proliferative agent, and corticosteroid. Corticosteroid was withdrawn in negative early biopsies, maintained in subclinical/ borderline biopsies, and increased if Banff IB or greater rejection was identified. Endpoints included presence of interstitial fibrosis and tubular atrophy on biopsy at one year (IF/TA), rejection episodes, and renal and pancreas function at five years’ followup. …

Diverse Exocytic Pathways For Mast Cell Mediators, Hao Xu, Na-Ryum Bin, Shuzo Sugita

Faculty Publications

Mast cells play pivotal roles in innate and adaptive immunities but are also culprits in allergy, autoimmunity and cardiovascular diseases. Mast cells respond environmental changes by initiating regulated exocytosis/secretion of various biologically active compounds called mediators (e.g., proteases, amines and cytokines). Many of these mediators are stored in granules/lysosomes and rely on an intricate degranulation process for release. Mast cell stabilizers (such as sodium cromoglicate) which prevent such degranulation process have therefore been clinically approved to treat asthma and allergic rhinitis. However, it has become increasingly clear that different mast cell diseases often involve multiple mediators, which seem to rely …

Resveratrol And Pterostilbene Exhibit Anticancer Properties Involving The Downregulation Of Hpv Oncoprotein E6 In Cervical Cancer Cells, Kaushiki Chatterjee, Dina Alsharif, Christina Mazza, Palwasha Syar, Mohamed Al Sharif, Jimmie E. Fata

Publications and Research

Cervical cancer is one of the most common cancers in women living in developing countries. Due to a lack of affordable effective therapy, research into alternative anticancer compounds with low toxicity such as dietary polyphenols has continued. Our aim is to determine whether two structurally similar plant polyphenols, resveratrol and pterostilbene, exhibit anticancer and anti-HPV (Human papillomavirus) activity against cervical cancer cells. To determine anticancer activity, extensive in vitro analyses were performed. Anti-HPV activity, through measuring E6 protein levels, subsequent downstream p53 effects, and caspase-3 activation, were studied to understand a possible mechanism of action. Both polyphenols are effective agents …

Downregulation Of Srebp Inhibits Tumor Growth And Initiation By Altering Cellular Metabolism In Colon Cancer, Yang-An Wen, Xiaopeng Xiong, Yekaterina Y. Zaytseva, Dana L. Napier, Emma Vallee, Austin T. Li, Chi Wang, Heidi L. Weiss, B. Mark Evers, Tianyan Gao

Markey Cancer Center Faculty Publications

Sterol regulatory element-binding proteins (SREBPs) belong to a family of transcription factors that regulate the expression of genes required for the synthesis of fatty acids and cholesterol. Three SREBP isoforms, SREBP1a, SREBP1c, and SREBP2, have been identified in mammalian cells. SREBP1a and SREBP1c are derived from a single gene through the use of alternative transcription start sites. Here we investigated the role of SREBP-mediated lipogenesis in regulating tumor growth and initiation in colon cancer. Knockdown of either SREBP1 or SREBP2 decreased levels of fatty acids as a result of decreased expression of SREBP target genes required for lipid biosynthesis in …

Retinal Progenitor Cells Release Extracellular Vesicles Containing Developmental Transcription Factors, Microrna And Membrane Proteins, Jing Zhou, Alberto Benito-Martin, Jason Mighty, Lynne Chang, Shima Ghoroghi, Hao Wu, Madeline Wong, Sara Guariglia, Petr Baranov, Michael Young, Rajendra Ghardbaran, Mark Emerson, Milica Tesic Mark, Henrik Molina, M. Valeria Canto-Solar, Hector Peinado Selgas, Stephen Redenti

Publications and Research

A range of cell types, including embryonic stem cells, neurons and astrocytes have been shown to release extracellular vesicles (EVs) containing molecular cargo. Across cell types, EVs facilitate transfer of mRNA, microRNA and proteins between cells. Here we describe the release kinetics and content of EVs from mouse retinal progenitor cells (mRPCs). Interestingly, mRPC derived EVs contain mRNA, miRNA and proteins associated with multipotency and retinal development. Transcripts enclosed in mRPC EVs, include the transcription factors Pax6, Hes1, and Sox2, a mitotic chromosome stabilizer Ki67, and the neural intermediate filaments Nestin and GFAP. Proteomic analysis of EV content revealed retinogenic …

Wilms Tumor 1b Defines A Wound-Specific Sheath Cell Subpopulation Associated With Notochord Repair, Juan Carlos Lopez-Baez, Daniel J. Simpson, Laura Lleras Forero, Zhiqiang Zeng, Hannah Brunsdon, Angela Salzano, Alessandro Brombin, Cameron Wyatt, Witold Rybski, Leonie F A Huitema, Rodney M. Dale, Koichi Kawakami, Christoph Englert, Tamir Chandra, Stefan Schulte-Merker, Nicholas D. Hastie, E Elizabeth Patton

Biology: Faculty Publications and Other Works

Regenerative therapy for degenerative spine disorders requires the identification of cells that can slow down and possibly reverse degenerative processes. Here, we identify an unanticipated wound-specific notochord sheath cell subpopulation that expresses Wilms Tumor (WT) 1b following injury in zebrafish. We show that localized damage leads to Wt1b expression in sheath cells, and that wt1b⁺cells migrate into the wound to form a stopper-like structure, likely to maintain structural integrity. Wt1b⁺sheath cells are distinct in expressing cartilage and vacuolar genes, and in repressing a Wt1b-p53 transcriptional programme. At the wound, wt1b⁺and entpd5⁺ cells constitute …