Digital Commons Network^™

The Caenorhabditis Elegans F-Box Protein Sel-10 Promotes Female Development And May Target Fem-1 And Fem-3 For Degradation By The Proteasome, Sibylle Jager, Hillel T. Schwartz, H. Robert Horvitz, Barbara Conradt

Dartmouth Scholarship

The Caenorhabditis elegans F-box protein SEL-10 and its human homolog have been proposed to regulate LIN-12 Notch signaling by targeting for ubiquitin-mediated proteasomal degradation LIN-12 Notch proteins and SEL-12 PS1 presenilins, the latter of which have been implicated in Alzheimer's disease. We found that sel-10 is the same gene as egl-41, which previously had been defined by gain-of-function mutations that semidominantly cause masculinization of the hermaphrodite soma. Our results demonstrate that mutations causing loss-of-function of sel-10 also have masculinizing activity, indicating that sel-10 functions to promote female development. Genetically, sel-10 acts upstream of the genes fem-1, fem-2, and fem-3 and …

Excess Stroke In Mexican Americans Compared With Non-Hispanic Whites: The Brain Attack Surveillance In Corpus Christi Project, Lewis B Morgenstern, Melinda A Smith, Lynda D Lisabeth, Jan M H Risser, Ken Uchino, Nelda Garcia, Paxton J Longwell, David A Mcfarling, Olubumi Akuwumi, Areej Al-Wabil, Fahmi Al-Senani, Devin L Brown, Lemuel A Moyé

Faculty, Staff and Student Publications

Mexican Americans are the largest subgroup of Hispanics, the largest minority population in the United States. Stroke is the leading cause of disability and third leading cause of death. The authors compared stroke incidence among Mexican Americans and non-Hispanic Whites in a population-based study. Stroke cases were ascertained in Nueces County, Texas, utilizing concomitant active and passive surveillance. Cases were validated on the basis of source documentation by board-certified neurologists masked to subjects' ethnicity. From January 2000 to December 2002, 2,350 cerebrovascular events occurred. Of the completed strokes, 53% were in Mexican Americans. The crude cumulative incidence was 168/10,000 in …

From Biomedicine To Natural History Research: Est Resources For Ambystomatid Aalamanders, Srikrishna Putta, Jeramiah J. Smith, John A. Walker, Mathieu Rondet, David W. Weisrock, James Monaghan, Amy K. Samuels, D. Kevin Kump, David C. King, Nicholas J. Maness, Bianca Habermann, Elly Tanaka, Susan V. Bryant, David M. Gardiner, David M. Parichy, S. Randal Voss

Biology Faculty Publications

BACKGROUND: Establishing genomic resources for closely related species will provide comparative insights that are crucial for understanding diversity and variability at multiple levels of biological organization. We developed ESTs for Mexican axolotl (Ambystoma mexicanum) and Eastern tiger salamander (A. tigrinum tigrinum), species with deep and diverse research histories.

RESULTS: Approximately 40,000 quality cDNA sequences were isolated for these species from various tissues, including regenerating limb and tail. These sequences and an existing set of 16,030 cDNA sequences for A. mexicanum were processed to yield 35,413 and 20,599 high quality ESTs for A. mexicanum and A. t. tigrinum, respectively. Because the …

The Kini Kinesin Kif2a Is Required For Bipolar Spindle Assembly Through A Functional Relationship With Mcak, Neil J. Ganem, Duane A. Compton

Dartmouth Scholarship

Although the microtubule-depolymerizing KinI motor Kif2a is abundantly expressed in neuronal cells, we now show it localizes to centrosomes and spindle poles during mitosis in cultured cells. RNAi-induced knockdown of Kif2a expression inhibited cell cycle progression because cells assembled monopolar spindles. Bipolar spindle assembly was restored in cells lacking Kif2a by treatments that altered microtubule assembly (nocodazole), eliminated kinetochore–microtubule attachment (loss of Nuf2), or stabilized microtubule plus ends at kinetochores (loss of MCAK). Thus, two KinI motors, MCAK and Kif2a, play distinct roles in mitosis, and MCAK activity at kinetochores must be balanced by Kif2a activity at poles for spindle …

Academic Performance Of Psychiatrists Compared To Other Specialists Before, During, And After Medical School., Frederick S. Sierles, Michael Vergare, Mohammadreza Hojat, Joseph S. Gonnella

Department of Psychiatry and Human Behavior Faculty Papers

OBJECTIVE: This study was designed to compare psychiatrists with other physicians on measures of academic performance before, during, and after medical school.

METHOD: More than three decades of data for graduates of Jefferson Medical College (N=5,701) were analyzed. Those who pursued psychiatry were compared to physicians in seven other specialties on 18 performance measures. Analysis of covariance was used to control for gender effect.

RESULTS: Compared to other physicians, psychiatrists scored higher on measures of verbal ability and general information before medical school and on evaluations of knowledge and skills in behavioral sciences during medical school, but they scored lower …

Long-Term Evaluation Of The Use Of The Transdermal Contraceptive Patch In Adolescents, Stephanie Logsdon, Jessica Richards, Hatim A. Omar

Pediatrics Faculty Publications

The transdermal contraceptive patch, Ortho Evra™, was approved in December 2001 and released on the market in June 2002. In this study, we reviewed clinical data of young women who started the patch between June 2002 and December 2003 in the adolescent medicine clinic at a university-based outpatient center. A total of 62 patients started the patch in that period and two of them were lost to follow-up. Mean age of patients was 17.9 years and mean length of use was 10 cycles. Only 10 patients (16.7%) discontinued use. Reasons for discontinuation were moderate to severe skin irritation (3 patients, …

Clinical Profiles, Occurrence, And Management Of Adolescent Patients With Hair-An Syndrome, Hatim A. Omar, Stephanie Logsdon, Jessica Richards

Pediatrics Faculty Publications

The syndrome of hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN) is a subphenotype of the polycystic ovary syndrome. It is one of the most common causes of menstrual problems, hyperandrogenic symptoms, and insulin resistance among young women. Review of clinical data in an outpatient adolescent clinic showed that of the 1,002 young women (ages 10-21 years) attending the clinic over a 2-year period, 50 (5%) were diagnosed with HAIR-AN syndrome. Mean age of the patients was 15.5, initial mean weight at diagnosis was 94.5 kg, and the mean BMI was 33.33 kg/m2. Patients were treated with a weight-stabilization and -reduction …

Transcriptional Activation Of The Human Prostatic Acid Phosphatase Gene By Nf-Kappab Via A Novel Hexanucleotide-Binding Site., Stanislav Zelivianski, Richard Glowacki, Ming-Fong Lin

Journal Articles: Biochemistry & Molecular Biology

Human prostatic acid phosphatase (PAcP) is a prostate epithelium-specific differentiation antigen. Cellular PAcP functions as a neutral protein tyrosine phosphatase and is involved in regulating androgen-promoted prostate cancer cell proliferation. Despite the fact that the promoter of the PAcP gene has been cloned, the transcriptional factors that regulate PAcP expression remain unidentified. This article describes our analyses of the promoter of the PAcP gene. Deletion analyses of the promoter sequence up to -4893 (-4893/+87) revealed that a 577 bp fragment (-1356/-779) represents the unique positive cis-active element in human prostate cancer cells but not in HeLa cervix carcinoma cells. Interestingly, …

Efficacy Of Quality Criteria To Identify Potentially Harmful Information: A Cross-Sectional Survey Of Complementary And Alternative Medicine Web Sites, Muhammad Walji, Smitha Sagaram, Deepak Sagaram, Funda Meric-Bernstam, Craig Johnson, Nadeem Q Mirza, Elmer V Bernstam

Faculty, Staff and Student Publications

BACKGROUND: Many users search the Internet for answers to health questions. Complementary and alternative medicine (CAM) is a particularly common search topic. Because many CAM therapies do not require a clinician's prescription, false or misleading CAM information may be more dangerous than information about traditional therapies. Many quality criteria have been suggested to filter out potentially harmful online health information. However, assessing the accuracy of CAM information is uniquely challenging since CAM is generally not supported by conventional literature. OBJECTIVE: The purpose of this study is to determine whether domain-independent technical quality criteria can identify potentially harmful online CAM content. …

Pv1 Is A Key Structural Component For The Formation Of The Stomatal And Fenestral Diaphragms, Radu V. Stan, Eugene Tkachenko, Ingrid R. Niesman

Dartmouth Scholarship

PV1 is an endothelial-specific integral membrane glycoprotein associated with the stomatal diaphragms of caveolae, transendothelial channels, and vesiculo-vacuolar organelles and the diaphragms of endothelial fenestrae. Multiple PV1 homodimers are found within each stomatal and fenestral diaphragm. We investigated the function of PV1 within these diaphragms and their regulation and found that treatment of endothelial cells in culture with phorbol myristate acetate (PMA) led to upregulation of PV1. This correlated with de novo formation of stomatal diaphragms of caveolae and transendothelial channels as well as fenestrae upon PMA treatment. The newly formed diaphragms could be labeled with anti-PV1 antibodies. The upregulation …

Differences In Peripheral Noradrenergic Function Among Actively Drinking And Abstinent Alcohol-Dependent Individuals., Ashwin A. Patkar, Charles A. Marsden, Prakash C. Naik, David A. Kendall, Raman Gopalakrishnan, Michael J. Vergare, Stephen P. Weinstein

Department of Psychiatry and Human Behavior Faculty Papers

We examined whether excessive alcohol consumption was related to changes in plasma levels of noradrenaline (NA) and whether these changes recover following abstinence. We also explored whether there were differences in NA levels between Type I and Type II alcoholics and controls during active drinking and abstinence. Plasma concentrations of NA were determined in (1) 27 Caucasian men with alcohol dependence who were regularly drinking (active drinkers) within 24 hours of hospitalization, (2) 29 Caucasian alcohol-dependent men who were in remission (abstinent for a minimum of three months), and (3) 28 race- and gender-matched healthy controls. NA concentrations were significantly …

Characterization Of Hemoglobin, Water, And Nir Scattering In Breast Tissue: Analysis Of Intersubject Variability And Menstrual Cycle Changes, Brian W. Pogue, Shudong Jiang, Hamid Dehghani, Christine Kogel, Sandra Soho, Subhadra Srinivasan, Xiaomei Song, Tor D. Tosteson, Steven P. Poplack, Keith D. Paulsen

Dartmouth Scholarship

Near-infrared imaging was used to quantify typical values of hemoglobin concentration, oxygen saturation, water fraction, scattering power, and scattering amplitude within the breast tissue of volunteer subjects. A systematic study of the menstrual variations in these parameters was carried out by measuring a group of seven premenopausal normal women (aged 41 to 47 years) in the follicular (days 7 to 14 of the cycle) and secretory phases (days 21 to 28) of the cycle, for two complete menstrual cycles. An average increase in hemoglobin concentration of 2.6 μM or 13% of the background breast values was observed in the …

The Tumor Suppressor Lkb1 Kinase Directly Activates Amp-Activated Kinase And Regulates Apoptosis In Response To Energy Stress, Reuben J. Shaw, Monica Kosmatka, Nabeel Bardeesy, Rebecca L. Hurley, Lee A. Witters, Ronald A. Depinho, Lewis C. Cantley

Dartmouth Scholarship

AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status found in all eukaryotic cells. AMPK is activated by stimuli that increase the cellular AMP/ATP ratio. Essential to activation of AMPK is its phosphorylation at Thr-172 by an upstream kinase, AMPKK, whose identity in mammalian cells has remained elusive. Here we present biochemical and genetic evidence indicating that the LKB1 serine/threonine kinase, the gene inactivated in the Peutz-Jeghers familial cancer syndrome, is the dominant regulator of AMPK activation in several mammalian cell types. We show that LKB1 directly phosphorylates Thr-172 of AMPKalpha in vitro and activates its …

Indinavir And Rifabutin Drug Interactions In Healthy Volunteers., Walter K. Kraft, Jacqueline B. Mccrea, Gregory A. Winchell, Alexandra Carides, Richard C. Lowry, Eric J. Woolf, Sandra E. Kusma, Paul J. Deutsch, Howard E Greenberg, Scott A. Waldman

Department of Medicine Faculty Papers

Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healthy subjects. Rifabutin, which induces the expression of cytochrome P450 (CYP) 3A, and indinavir, which inhibits that enzyme system, are frequently coadministered in patients infected with HIV. The second study was undertaken to determine if altering the dose of rifabutin coadministered with indinavir would minimize the drug interaction observed in the first study. Two studies, each with a three-period crossover design, were performed. In study 1, standard doses of rifabutin and indinavir (300 mg of rifabutin qd and 800 mg indinavir q8h) were administered as monotherapy (with placebo …

All-1/Mll1, A Homologue Of Drosophila Trithorax, Modifies Chromatin And Is Directly Involved In Infant Acute Leukaemia., E Canaani, T Nakamura, T Rozovskaia, S T Smith, T Mori, C M Croce, Alexander Mazo

Kimmel Cancer Center Faculty Papers

Rearrangements of the ALL-1/MLL1 gene underlie the majority of infant acute leukaemias, as well as of therapy-related leukaemias developing in cancer patients treated with inhibitors of topoisomerase II, such as VP16 and doxorubicin. The rearrangements fuse ALL-1 to any of >50 partner genes or to itself. Here, we describe the unique features of ALL-1-associated leukaemias, and recent progress in understanding molecular mechanisms involved in the activity of the ALL-1 protein and of its Drosophila homologue TRITHORAX.

Muc4 Mucin Expression In Human Pancreatic Tumours Is Affected By Organ Environment: The Possible Role Of Tgfbeta2., A. Choudhury, N. Moniaux, A. B. Ulrich, B. M. Schmied, J. Standop, Parviz M. Pour, S. J. Gendler, Michael A. Hollingsworth, J-P Aubert, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

MUC4 is highly expressed in human pancreatic tumours and pancreatic tumour cell lines, but is minimally or not expressed in normal pancreas or chronic pancreatitis. Here, we investigated the aberrant regulation of MUC4 expression in vivo using clonal human pancreatic tumour cells (CD18/HPAF) grown either orthotopically in the pancreas (OT) or ectopically in subcutaneous tissue (SC) in the nude mice. Histological examination of the OT and SC tumours showed moderately differentiated and anaplastic morphology, respectively. The OT tumour cells showed metastases to distant lymph nodes and faster tumour growth (P

Creation Of Non-Human Primate Neurogenetic Disease Models By Gene Targeting And Nuclear Transfer, Robert B. Norgren

Journal Articles: Genetics, Cell Biology & Anatomy

Genetically modified rhesus macaques are necessary because mouse models are not suitable for a number of important neurogenetic disorders; for example, Kallmann's syndrome, Lesch-Nyhan's disease and Ataxia-Telangiectasia. Mouse models may not be suitable because there may be no mouse ortholog of the human gene of interest, as is the case for Kallmann's syndrome, or because mutant mice do not exhibit the same phenotype observed in humans, as is the the case for Lesch-Nyhan's disease and Ataxia-Telangiectasia. Non-human primate models of neurogenetic diseases are expected to more closely resemble human diseases than existing mouse models. Genetically modified rhesus macaques can be …

Modeling Of Hemoglobin In Dengue Fever And Dengue Hemorrhagic Fever Using Bioelectrical Impedance, F. Ibrahim, N.A. Ismail, M.N. Taib, W.A.B. Wan Abas

Research Publications (2000 to 2005)

This paper describes a model for predicting hemoglobin (Hb) by using bioelectrical impedance analysis (BIA) in dengue patients in the Hospital Universiti Kebangsaan Malaysia (HUKM). Bioelectrical impedance measurements were conducted on 83 (47 males and 36 females) serologically confirmed dengue fever (DF) and dengue hemorrhagic fever (DHF) patients during their hospitalization. The predictive equation for Hb was derived using multivariate analysis. We investigated all the parameters in BIA, patients' symptom and demographic data. In this developed model, four predictors (reactance (Xc), sex, weight and vomiting) were found to be the best predictive factors for modeling Hb in dengue patients. However, …

Vascular Endothelial Growth Factor Transcriptional Activation Is Mediated By Hypoxia-Inducible Factor 1Α, Hdm2, And P70s6k1 In Response To Phosphatidylinositol 3-Kinase/Akt Signaling, Heath D. Skinner, Jenny Z. Zheng, Jing Fang, Faton Agani, Bing-Hua Jiang

Faculty & Staff Scholarship

No abstract provided.

Etoposide Differentially Affects Bone Marrow And Dermal Derived Endothelial Cells, S. W. Adams, Lin Wang, J. Fortney, Laura F. Gibson

Faculty & Staff Scholarship

Chemotherapy alteration of the bone marrow microenvironment has the potential to influence hematopoietic recovery following transplantation. To discern the effect of specific drugs on components of the complex marrow microenvironment, in vitro models have significant utility. In the current study we sought to determine whether dermal (HMEC-1) and marrow derived endothelial cells (BMEC-1) respond differently to identical chemotherapy exposure. BMEC-1 cells were consistently more sensitive to etoposide exposure than HMEC-1 cells, measured as reduced viability. BMEC-1 also had reduced focal adhesion kinase (FAK) and VCAM-1 protein expression following chemotherapy, in contrast to dermal derived endothelial cells in which neither protein …

The Moral Authority Of Symbolic Appeals In Biomedical Ethics, Sharon Sytsma

Faculty Articles, Papers, and Other Scholarship

No abstract provided.

Atm-Dependent Chk2 Activation Induced By Anticancer Agent, Irofulven, Jian Wang, Timothy Wiltshire, Yutian Wang, Carmenza Mikell, Julian Burks, Cynthia Cunningham, Emily S. Van Laar, Stephen J. Waters, Eddie Reed, Weixin Wang

Faculty & Staff Scholarship

Irofulven (6-hydroxymethylacylfulvene, HMAF, MGI 114) is one of a new class of anticancer agents that are semisynthetic derivatives of the mushroom toxin illudin S. Preclinical studies and...

Regulation Of Vertebrate Eye Development By Rx Genes, Travis J. Bailey, Heithem El-Hodiri, Li Zhang, Rina Shah, Peter H. Mathers, Milan Jamrich

Faculty & Staff Scholarship

No abstract provided.

Slbp Is Associated With Histone Mrna On Polyribosomes As A Component Of The Histone Mrnp, Michael L. Whitfield, Handan Kaygun, Judith A. Erkmann, W. H. Davin Townley-Tilson, Zbig Dominski, William F. Marzluff

Dartmouth Scholarship

The stem–loop binding protein (SLBP) binds the 3′ end of histone mRNA and is present both in nucleus, and in the cytoplasm on the polyribosomes. SLBP participates in the processing of the histone pre-mRNA and in translation of the mature message. Histone mRNAs are rapidly degraded when cells are treated with inhibitors of DNA replication and are stabilized by inhibitors of translation, resulting in an increase in histone mRNA levels. Here, we show that SLBP is a component of the histone messenger ribonucleoprotein particle (mRNP). Histone mRNA from polyribosomes is immunoprecipitated with anti-SLBP. Most of the SLBP in cycloheximide-treated cells …

Regulation Of Development By Rx Genes, Travis J. Bailey, Heithiem El-Hodiri, Li Zhang, Rina Shah, Peter H. Mathers, Milan Jamrich

Biology

The paired-like homeobox-containing gene Rx has a critical role in the eye development of several vertebrate species including Xenopus, mouse, chicken, medaka, zebrafish and human. Rx is initially expressed in the anterior neural region of developing embryos, and later in the retina and ventral hypothalamus. Abnormal regulation or function of Rx results in severe abnormalities of eye formation. Overexpression of Rx in Xenopus and zebrafish embryos leads to overproliteration of retinal cells. A targeted elimination of Rx in mice results in a lack of eye formation. Mutations in Rx genes are the cause of the mouse mutation eyeless (ey1), the …

Macrophage Tropism Of Hiv-1 Depends On Efficient Cellular Dntp Utilization By Reverse Transcriptase, Tracy L. Diamond, Mikhail Roshal, Varuni K. Jamburuthugoda, Holly M. Reynolds, Aaron R. Merriam, Kwi Y. Lee, Mini Balakrishnan, Robert A. Bambara, Vincente Planelles, Stephen Dewhurst, Baek Kim

Biology

Retroviruses utilize cellular dNTPs to perform proviral DNA synthesis in infected host cells. Unlike oncoretroviruses, which replicate in dividing cells, lentiviruses, such as human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus, are capable of efficiently replicating in non-dividing cells (terminally differentiated macrophages) as well as dividing cells (i.e. activated CD4+ T cells). In general, non-dividing cells are likely to have low cellular dNTP content compared with dividing cells. Here, by employing a novel assay for cellular dNTP content, we determined the dNTP concentrations in two HIV-1 target cells, macrophages and activated CD4+ T cells. We found that human …

Noninvasive Assessment Of Diffusion Hypoxia Following Administration Of Nitrous Oxide-Oxygen, Arthur H. Jeske, Clark W. Whitmire, Chris Freels, Mike Fuentes

Faculty, Staff and Student Publications

The phenomenon of diffusion hypoxia is commonly believed to occur unless nitrous oxide-oxygen inhalation sedation is followed by "washout" with 100% oxygen for 5 minutes upon termination of the flow of nitrous oxide. When systematically studied, however, this phenomenon generally appears to be unfounded. The present study evaluated the effect of breathing room air instead of 100% oxygen in healthy (ASA 1) human volunteers following administration of sedative concentrations of nitrous oxide. The occurrence of hypoxia was determined objectively, using pulse oximetry and a standardized psychomotor skills test (Trieger test). Diffusion hypoxia was not observed using these criteria.

Developing A Pediatric Oral Health Therapist To Help Address Oral Health Disparities Among Children, David A. Nash

Oral Health Science Faculty Publications

Oral Health in America: A Report of the Surgeon General documented the profound and significant disparities that exist in the oral health of children in the United States. Recently, the country has been issued a National Call to Action to Promote Oral Health, under the leadership of the Office of the Surgeon General. Among the significant factors contributing to the disparities problem is the access to oral health care by disadvantaged populations. There are inadequate numbers of dentists able and willing to treat children, particularly poor and minority children. In the early part of the twentieth century, New Zealand …

Ethical Dilemmas In Retrospective Studies On Genital Surgery In The Treatment Of Intersexual Infants, Sharon Sytsma

Faculty Articles, Papers, and Other Scholarship

Intersexual infants and infants with other genital abnormalities often receive genital surgery for sex assignment or for normalizing purposes. The wisdom and beneficence of these practices have been questioned by intersexual individuals, support groups, some doctors, and the media. Because the practices have been developed without long-term studies to evaluate them, pediatric urologists and parents of such children must face decisions with very little guidance from empirical support. In the face of ignorance about what is really the best medical response to intersexuality or genital abnormalities, some have argued for a moratorium on infant genital surgery until empirical studies are …

Transcriptional Inhibition Of Type I Collagen Gene Expression In Scleroderma Fibroblasts By The Antineoplastic Drug Ecteinascidin 743., Natalia Louneva, Biagio Saitta, David J Herrick, Sergio A. Jimenez

Department of Medicine Faculty Papers

We previously showed that COL1A1 expression is up-regulated at the transcriptional level in systemic sclerosis (SSc) fibroblasts and that the CCAAT-binding factor (CBF) is involved in this increased expression. Ecteinascidin 743 (ET-743) is a chemotherapeutic agent that binds with sequence specificity to the minor groove of DNA and inhibits CBF-mediated transcriptional activation of numerous genes. Therefore, we examined the effects of ET-743 on the increased COL1A1 expression in SSc fibroblasts. The drug caused a potent and dose-dependent inhibition of type I collagen biosynthesis, which reached 70-90% at 700 pM without affecting cell viability. The same drug concentration caused 60-80% reduction …