Medicine and Health Sciences Commons^™

Neuronal Growth Cone Retraction Relies Upon Proneurotrophin Receptor Signaling Through Rac, Richard E. Mains, Betty A. Eipper

UCHC Articles - Research

Growth of axons and dendrites is a dynamic process that involves guidance molecules, adhesion proteins, and neurotrophic factors. Although neurite extension during development has been extensively studied, the intracellular mechanisms that mediate neurite retraction are poorly understood. Here, we show that the proneurotrophin, proNGF, induces acute collapse of growth cones of cultured hippocampal neurons. This retraction is initiated by an interaction between p75^NTR and the sortilin family member, SorCS2 (sortilin-related VPS10 domain containing receptor 2). Binding of proNGF to the p75^NTR-SorCS2 complex induced growth cone retraction by initiating the dissociation of the guanine-nucleotide exchange factor Trio from …

In Translation V.2:No.2 (2011:Fall/Winter), Matthew J. Cook

UCHC Articles - Research

The latest issue of In Translation, the CICATS newsletter is now available on the CICATS home page. In this issue, we spotlight the upcoming Community Engagement Seminar on health disparities, recap the events from the CICATS retreat, and introduce Boundary Spanner Dr. Alicia Dugan. Obtain your copy of volume 2 issue 2 at http://cicats.uconn.edu/pdf/newsletter/InTranslation_Fall-Win2011.pdf. Enjoy.

Phosphatidylinositol 4,5-Bisphosphate (Pip2) Controls Magnesium Gatekeeper Trpm6 Activity, Jia Xie, Baonan Sun, Jianyang Du, Wenzhong Yang, Lixia Yue

UCHC Articles - Research

TRPM6 is crucial for human Mg²⁺ homeostasis as patients carrying TRPM6 mutations develop hypomagnesemia and secondary hypocalcemia (HSH). However, the activation mechanism of TRPM6 has remained unknown. Here we demonstrate that phosphatidylinositol-4,5-bisphophate (PIP₂) controls TRPM6 activation and Mg²⁺ influx. Stimulation of PLC-coupled M1-receptors to deplete PIP₂ potently inactivates TRPM6. Translocation of over-expressed 5-phosphatase to cell membrane to specifically hydrolyze PIP₂ also completely inhibits TRPM6. Moreover, depolarization-induced-activation of the voltage-sensitive-phosphatase (Ci-VSP) simultaneously depletes PIP₂ and inhibits TRPM6. PLC-activation induced PIP₂-depletion not only inhibits TRPM6, but also abolishes TRPM6-mediated Mg²⁺ influx. Furthermore, …

Phosphorylation Of Crk On Tyrosine 251 In The Rt Loop Of The Sh3c Domain Promotes Abl Kinase Transactivation, Bruce J. Mayer, Kazuya Machida

UCHC Articles - Research

Here, we report the identification and characterization of a novel tyrosine phosphorylation site in the carboxy-terminal Src Homology 3 (SH3) (SH3C) domain of the Crk adaptor protein. Y251 is located in the highly conserved RT loop structure of the SH3C, a region of Crk involved in the allosteric regulation of the Abl kinase. Exploiting kinase assays to show that Y251 is phosphorylated by Abl in vitro, we generated affinity-purified antisera against phosphorylated Y251 in Crk and showed that Abl induces phosphorylation at Y251 in vivo, and that the kinetics of phosphorylation at Y251 and the negative regulatory Y221 site in …

Associations Of Ionizing Radiation And Breast Cancer-Related Serum Hormone And Growth Factor Levels In Cancer-Free Female A-Bomb Survivors, Richard G. Stevens

UCHC Articles - Research

Levels of exposure to ionizing radiation are increasing for women worldwide due to the widespread use of CT and other radiologic diagnostic modalities. Exposure to ionizing radiation as well as increased levels of estradiol and other sex hormones are acknowledged breast cancer risk factors, but the effects of whole-body radiation on serum hormone levels in cancer-free women are unknown. This study examined whether ionizing radiation exposure is associated with levels of serum hormones and other markers that may mediate radiation-associated breast cancer risk. Serum samples were measured from cancer-free women who attended biennial health examinations with a wide range of …

Keratocan Is Expressed By Osteoblasts And Can Modulate Osteogenic Differentiation, John C. Igwe, Qi Gao, Tomislav Kizivat, Ivo Kalajzic

UCHC Articles - Research

Keratocan is an extracellular matrix protein that belongs to the small leucine-rich proteoglycan family which also includes the lumican, biglycan, decorin, mimecan and fibromodulin. Members of this family are known to play a role in regulating cellular processes such as proliferation and modulation of osteoprogenitor lineage differentiation. The aims of this study were to evaluate the expression pattern of the keratocan within the osteoprogenitor lineage and assess its role in regulating osteoblast maturation and function. Results from gene expression analyses of cells at different maturation stages within the osteoblast lineage indicate that keratocan is differentially expressed by osteoblasts and shows …

Affiliation Goals And Health Behaviors, Jerry Cullum, Megan O’Grady, Howard A. Tennen

UCHC Articles - Research

People are inherently driven by the need to form and maintain relationships, and these affiliation goals can influence health behaviors in two ways: (a) indirectly, by increasing a person’s attention to others and subsequently leaving them more likely to emulate the health behaviors of others (social contagion); (b) directly, by leading people to be more likely to engage in health behaviors they perceive as helping them to form and maintain relationships with others (self-initiated behavioral engagement). In this review, we discuss the evidence for the catalyzing role of affiliation goals in these two processes for a variety of positive (e.g., …

Prevalence And Prognostic Role Of Triple-Negative Breast Cancer By Race: A Surveillance Study, Helen Swede, David I. Gregorio, Susan H. Tannenbaum, Jessica A. Brockmeyer, Lori L. Wilson, Mellisa A. Pensa, Richard G. Stevens, Carolyn D. Runowicz

UCHC Articles - Research

A possible explanation for the relatively poor survival from breast cancer among blacks is the much higher rate of the adverse Triple-Negative sub-type. In a study of 1372 patients, blacks had twice the risk of death compared to whites among those with advanced cancer whether or not tumors were Triple-Negative. More research is still warranted to determine why blacks with advanced, but not local, breast cancer have a consistently higher rate of death.

Introduction

Emerging research suggests a substantially greater prevalence of the adverse triple-negative (TN) subtype (human epidermal growth factor receptor [HER]2⁻, estrogen receptor [ER]⁻, …

Early Postoperative Serum Cystatin C Predicts Severe Acute Kidney Injury Following Pediatric Cardiac Surgery, Zhu Wang

UCHC Articles - Research

n this multicenter, prospective study of 288 children (half under 2 years of age) undergoing cardiac surgery, we evaluated whether the measurement of pre- and postoperative serum cystatin C (CysC) improves the prediction of acute kidney injury (AKI) over that obtained by serum creatinine (SCr). Higher preoperative SCr-based estimated glomerular filtration rates predicted higher risk of the postoperative primary outcomes of stage 1 and 2 AKI (adjusted odds ratios (ORs) 1.5 and 1.9, respectively). Preoperative CysC was not associated with AKI. The highest quintile of postoperative (within 6 h) CysC predicted stage 1 and 2 AKI (adjusted ORs of 6 …

The Branched Actin Nucleator Arp2/3 Promotes Nuclear Migrations And Cell Polarity In The C. Elegans Zygote, William A. Mohler

UCHC Articles - Research

Regulated movements of the nucleus are essential during zygote formation, cell migrations, and differentiation of neurons. The nucleus moves along microtubules (MTs) and is repositioned on F-actin at the cellular cortex. Two families of nuclear envelope proteins, SUN and KASH, link the nucleus to the actin and MT cytoskeletons during nuclear movements. However, the role of actin nucleators in nuclear migration and positioning is poorly understood. We show that the branched actin nucleator, Arp2/3, affects nuclear movements throughout embryonic and larval development in C. elegans, including nuclear migrations in epidermal cells and neuronal precursors. In one-cell embryos the migration …

Division Of Labor Between Subsets Of Lymph Node Dendritic Cells Determines The Specificity Of The Cd8 Recall Response To Influenza Infection, Jenny E. Suárez-Ramírez, Tao Wu, Young-Tae Lee, Carolina C. Aguila, Keith R. Bouchard, Linda Linda Cauley

UCHC Articles - Research

Cytotoxic T lymphocytes are important targets for vaccines against a wide variety of infections that enter the body via mucosal tissues. To induce effective immunity these vaccines must include the most protective epitopes and elicit rapid recall responses at the site of infection. Although live attenuated viruses are sometimes used to induce cellular immunity against recurrent influenza infections, the mechanisms that determine the magnitude of the response to individual viral components are very poorly defined. Heterosubtypic infections in B6 mice illustrate an additional level of complexity, when the antigen-specificity of the response shifts dramatically between primary and secondary challenge. This …

In Translation V.2:No.1 (2011:Summer), Matthew J. Cook

UCHC Articles - Research

We are pleased to present the Summer 2011 issue (volume 2, issue 1) of In Translation, the CICATS newsletter. In this issue, you can learn about Community Health Center, Inc., CICATS' newest partner institution which provides primary care services throughout the state. Dr. Laurencin shares his congratulations to seven faculty members who began sharing $250,000 in pilot grant funding in July. Dr. Martin Cherniack writes about two Occupational and Environmental Medicine centers and their clinical and translational research activities. Other stories report on several exciting summer events which took place at CICATS partner institutions and the launch of CICATS …

T Cells Expanded In Presence Of Il-15 Exhibit Increased Antioxidant Capacity And Innate Effector Molecules, Nitya G. Chakraborty, Bijay Mukherji

UCHC Articles - Research

Persistence of effector cytotoxic T lymphocytes (CTLs) during an immunological response is critical for successfully controlling a viral infection or tumor growth. Various cytokines are known to play an important part in regulating the immune response. The IL-2 family of cytokines that includes IL-2 and IL-15 are known to function as growth and survival factors for antigen-experienced T cells. IL-2 and IL-15 possess similar properties, including the ability to induce T cell proliferation. Whereas long term IL-2 exposure has been shown to promote apoptosis and limit CD8⁺ memory T cell survival and proliferation, it is widely believed that IL-15 …

The Impaired Bone Anabolic Effect Of Pth In The Absence Of Endogenous Fgf2 Is Partially Due To Reduced Atf4 Expression, Yurong Fei, Liping Xiao, Marja M. Hurley

UCHC Articles - Research

Parathyroid hormone (PTH) is currently the only approved anabolic agent for osteoporosis pharmacotherapy in the USA. However, the molecular and cellular mechanisms underlying which intermittent PTH stimulates bone formation are not fully established.

Activating transcription factor 4 (ATF4) was recently identified to be a downstream target of PTH signaling in osteoblasts and FGF2 is able to rapidly increase ATF4 mRNA and protein expression in osteoblasts. Furthermore, ATF4 expression is markedly reduced in Fgf2−/− osteoblasts. In addition, FGF2 is required for the anabolic action of PTH on bone formation. Therefore, we hypothesize that the impaired anabolic effect of PTH in Fgf2−/− …

Sex Differences In Chondrocyte Maturation In The Mandibular Condyle From A Decreased Occlusal Loading Model, J. Chen, Takanori Sobue, Achint Utreja, Zana Kalajzic, Sunil Wadhwa, M. Xu

UCHC Articles - Research

Temporomandibular joint disorders (TMDs) predominantly afflict women of childbearing age. Defects in mechanical loading-induced temporomandibular joint (TMJ) remodeling are believed to be a major etiological factor in the development of TMD. The goal of this study was to determine if there are sex differences in CD-1 and C57BL/6 mice exposed to a decreased occlusal loading TMJ remodeling model. Male and female CD-1 and C57BL/6 mice, 21 days old, were each divided into two groups. They were fed either a normal pellet diet (normal loading) or a soft diet and had their incisors trimmed out of occlusion (decreased occlusal loading) for …

Loss Of Dna Mismatch Repair Imparts A Selective Advantage In Planarian Adult Stem Cells, Jessica P. Hollenbach, Alissa M. Resch, Dasaradhi Palakodeti, Brenton R. Graveley, Christopher D. Heinen

UCHC Articles - Research

Lynch syndrome (LS) leads to an increased risk of early-onset colorectal and other types of cancer and is caused by germline mutations in DNA mismatch repair (MMR) genes. Loss of MMR function results in a mutator phenotype that likely underlies its role in tumorigenesis. However, loss of MMR also results in the elimination of a DNA damage-induced checkpoint/apoptosis activation barrier that may allow damaged cells to grow unchecked. A fundamental question is whether loss of MMR provides pre-cancerous stem cells an immediate selective advantage in addition to establishing a mutator phenotype. To test this hypothesis in an in vivo system, …

Up-Regulated Dicer Expression In Patients With Cutaneous Melanoma, Soheil S. Dadras, Elizabeth Fleming, Helen Swede

UCHC Articles - Research

Background

MicroRNAs (miRNAs) are small non-coding RNAs (18–24 nucleotides) that have recently been shown to regulate gene expression during cancer progression. Dicer, a central enzyme in the multi-component miRNA biogenesis pathway, is involved in cutting precursor miRNAs to functionally mature forms. Emerging evidence shows that Dicer expression is deregulated in some human malignancies and it correlates with tumor progression, yet this role has not yet been investigated in skin cancers.

Methods and Findings

Using an anti-human monoclonal antibody against Dicer and immunohistochemistry, we compared the expression of Dicer protein among 404 clinically annotated controls and skin tumors consisting of melanocytic …

Occupational Disease In Connecticut 2011, Tim Morse, Paula Schenck

UCHC Articles - Research

This report focuses on occupational disease reports from 2009 and 2008, and recent trends in reported cases. It does not address traumatic occupational injuries, which are addressed in the annual report on occupational injuries and illnesses by the Connecticut Department of Labor (http://www.ctdol.state.ct.us/osha/shstats.htm). Occupational diseases are typically harder to detect than injuries, since they often occur over longer periods of time, and can have multiple (including non-occupational) risks. Therefore, this report uses data from three primary sources as a way of establishing a more complete picture of occupational disease: Workers’ Compensation First Report of Injury cases (WCC), physicians’ reports under …

Modulation Of Fibroblast Inflammatory Response By Surface Modification Of A Perfluorinated Ionomer, Thelma Iris Valdes

UCHC Articles - Research

An ideal surface for implantable glucose sensors would be able to evade the events leading to chronic inflammation and fibrosis, thereby extending its utility in an in vivo environment. Nafion™, a perfluorinated ionomer, is the membrane material preferred for in situ glucose sensors. Unfortunately, the surface properties of Nafion™ promote random protein adsorption and eventual foreign body encapsulation, thus leading to loss of glucose signal over time. Details of the techniques to render Nafion™ nonprotein fouling are given in a previous article [T. I. Valdes et al., Biomaterials 29, 1356 (2008)]. Once random protein adsorption is prevented, a …

Mekk3 Regulates Ifn-Γ Production In T Cells Through The Rac1/2-Dependent Mapk Cascades, Xiaofang Wang

UCHC Articles - Research

MEKK3 is a conserved Ser/Thr protein kinase belonging to the MAPK kinase kinase (MAP3K) family. MEKK3 is constitutively expressed in T cells, but its function in T cell immunity has not been fully elucidated. Using Mekk3 T cell conditional knockout (T-cKO) mice, we show that MEKK3 is required for T cell immunity in vivo. Mekk3 T-cKO mice had reduced T cell response to bacterial infection and were defective in clearing bacterial infections. The Ag-induced cytokine production, especially IFN-γ production, was impaired in Mekk3-deficient CD4 T cells. The TCR-induced ERK1/2, JNK, and p38 MAPKs activation was also defective in Mekk3 …

Identification Of Three Prominin Homologs And Characterization Of Their Messenger Rna Expression In Xenopus Laevis Tissues, Zhou Han, David S. Papermaster

UCHC Articles - Research

Purpose Prominin is a family of pentaspan transmembrane glycoproteins. They are expressed in various types of cells, including many stem/progenitor cells. Prominin-1 plays an important role in generating and maintaining the structure of the photoreceptors. In this study, we identified three prominin homologs in Xenopus laevis, a model animal widely used in vision research, and characterized their messenger RNA (mRNA) expression in selected tissues of this frog. Methods Reverse-transcription PCR (RT–PCR) and rapid amplification of cDNA ends (RACE) were used to isolate cDNAs of prominin homologs. Semiquantitative RT–PCR was used to measure the relative expression levels of mRNAs of …

A Methodology For Building Culture And Gender Norms Into Intervention: An Example From Mumbai, India, Kristin M. Kostick,, Stephen L. Schensul, Pertti Pelto

UCHC Articles - Research

This paper responds to the call for culturally relevant intervention research by introducing a methodology for identifying community norms and resources in order to more effectively implement sustainable interventions strategies. Results of an analysis of community norms, specifically attitudes toward gender equity, are presented from an HIV/STI research and intervention project in a low income community in Mumbai, India (2008–2012). Community gender norms were explored because of their relevance to sexual risk in settings characterized by high levels of gender inequity. This paper recommends approaches that interventionists and social scientists can take to incorporate cultural insights into formative assessments and …

Generation And Characterization Of Col10a1 -Mcherry Reporter Mice, Peter Maye, Yu Fu, Yaling Liu, Mary Louise Stover, Xi Jiang, David W. Rowe

UCHC Articles - Research

We report here on the generation of a new fluorescent protein reporter transgenic mouse line, Col10a1 -mCherry, which can be used as a tool to study chondrocyte biology and pathology. Collagen, Type X, alpha 1(Col10a1) is highly expressed in hypertrophic chondrocytes and commonly used as a gene marker for this cell population. TheCol10a1-mCherry reporter line was generated using a bacterial recombination strategy with the mouse BAC clone RP23-192A7. To aid in the characterization of this animal model, we intercrossed Col10a1-mCherry mice with Collagen, Type II, alpha 1 (Col2a1) enhanced cyan fluorescent protein (ECFP) reporter mice and characterized the expression of …

Tumor Recognition And Self-Recognition Induce Distinct Transcriptional Profiles In Antigen-Specific Cd4 T Cells, Adam J. Adler

UCHC Articles - Research

Tumors express a wide variety of both mutated and nonmutated Ags. Whether these tumor Ags are broadly recognized as self or foreign by the immune system is currently unclear. Using an autochthonous prostate cancer model in which hemagglutinin (HA) is specifically expressed in the tumor (ProHA × TRAMP mice), as well as an analogous model wherein HA is expressed in normal tissues as a model self-Ag (C3HA^high), we examined the transcriptional profile of CD4 T cells undergoing Ag-specific division. Consistent with our previous data, transfer of Ag-specific CD4 T cells into C3HA^high resulted in a functionally inactivated …

Mold And Alternaria Skin Test Reactivity And Asthma In Children In Connecticut, Todd W. Lyons, Dorothy B. Wakefield, Michelle M. Cloutier

UCHC Articles - Research

Background

Sensitivity to mold has been associated with asthma incidence, persistence, and severity.

Objective

To examine the relationship between skin test reactivity (STR) to molds and specifically to Alternaria and asthma severity in a group of ethnically diverse children in Connecticut.

Methods

Demographics and STR to 14 local allergens, including Alternaria, Penicillium, and mold mix, were obtained for 914 Puerto Rican, African American, and non-Hispanic white children.

Results

A total of 126 children (14%) had a positive skin test result to mold, and 58 (6%) demonstrated STR to Alternaria. Compared with non-Hispanic white children, there was no difference in the …

Inhibitory Activities Of Omega-3 Fatty Acids And Traditional African Remedies On Keloid Fibroblasts, I-Ping Chen, Richard S. Feinn, Ernst J. Reichenberger

UCHC Articles - Research

Keloids develop when scar tissue responds to skin trauma with proliferative fibrous growths that extend beyond the boundaries of the original wound and progress for several months or years. Keloids most frequently occur in individuals of indigenous sub-Saharan African origin. The etiology for keloids is still unknown and treatment can be problematic as patients respond differently to various treatment modalities. Keloids have a high rate of recurrence following surgical excision. Some West African patients claim to have had successful outcomes with traditional African remedies—boa constrictor oil (BCO) and shea butter—leading the authors to investigate their effects on cultured fibroblasts. The …

Calcium Intake In The United States From Dietary And Supplemental Sources Across Adult Age Groups: New Estimates From The National Health And Nutrition Examination Survey 2003–2006, Kelsey M. Mangano, Stephen J. Walsh, Anne M. Kenny, Jane E. Kerstetter

UCHC Articles - Research

Background

Adequate lifelong calcium intake is essential in optimizing bone health. Recent National Health and Nutrition Examination Survey data were used to quantify variation in calcium intake across adult age groups and to relate age-associated changes in calcium intake with energy intake. Additional goals were to assess differences in dietary calcium intake between supplemental calcium users and nonusers and to evaluate associations between age and calcium density in the diet.

Design

This cross-sectional analysis determined calcium and energy intake for National Health and Nutrition Examination Survey respondents during 2003–2006. Diet was assessed with 24-hour recall and supplement use via questionnaire. …

In Translation V.1:No.3 (2011:Spring), Matthew J. Cook

UCHC Articles - Research

The Winter-Spring issue features an article on Dr. James Grady, the new director of the Biostatistics Center, and describes the biostatistics services being offered to CICATS investigators. You can also read about a TRIPP Center pilot and planning grant awarded to Dr. Rick Fortinsky and colleagues which helped to support a $400K grant from the National Institute for Nursing Research. Additional stories describe the activities of the Biomedical Informatics Division and the Correctional Health Services Research Core Interest Group (CIG)

Beliefs About Racism And Health Among African American Women With Diabetes: A Qualitative Study, Julie A. Wagner, Lisa M. Budris, Sophia Belay, Howard A. Tennen

UCHC Articles - Research

Exposure to racism has been linked to poor health outcomes. Little is known about the impact of racism on diabetes outcomes. This study explored African American (AA) women’s beliefs about how racism interacts with their diabetes self-management and control. Four focus groups were conducted with a convenience sample of 28 adult AA women with type 2 diabetes who were recruited from a larger quantitative study on racism and diabetes. The focus group discussions were transcribed verbatim and analyzed by the authors. Women reported that exposure to racism was a common phenomenon, and their beliefs did in fact link racism to …

Phagosomal Signaling By Borrelia Burgdorferi In Human Monocytes Involves Toll-Like Receptor (Tlr) 2 And Tlr8 Cooperativity And Tlr8-Mediated Induction Of Ifn-Β, Jorge L. Cervantes, Star M. Dunham-Ems, Carson J. La Vake, Mary M. Petzke, Justin D. Radolf, Juan C. Salazar

UCHC Articles - Research

Phagocytosed Borrelia burgdorferi (Bb) induces inflammatory signals that differ both quantitatively and qualitatively from those generated by spirochetal lipoproteins interacting with Toll-like receptor (TLR) 1/2 on the surface of human monocytes. Of particular significance, and in contrast to lipoproteins, internalized spirochetes induce transcription of IFN-β. Using inhibitory immunoregulatory DNA sequences (IRSs) specific to TLR7, TLR8, and TLR9, we show that the TLR8 inhibitor IRS957 significantly diminishes production of TNF-α, IL-6, and IL-10 and completely abrogates transcription of IFN-β in Bb-stimulated monocytes. We demonstrate that live Bb induces transcription of TLR2 and TLR8, whereas IRS957 interferes with their transcriptional regulation. Using …