Effects of Heavy Metals and Psychostimulants on Dopamine Transporter Function

Heavy metals may alter the abuse liability of drugs due to actions on the dopamine transporter (DAT). This study examined the effects of extended, low-level heavy metal and psychostimulant co-exposure on DAT function. SK-N-SH cells, incubated in the presence of multiple concentrations of lead (Pb), mercury (Hg), cocaine (COC) and methamphetamine (MA), were used to measure LDH activity to determine optimum time/concentration for sublethal exposure assays. Parallel studies were conducted on non-neuronal vs. neuronal cell lines, COS-7(hDAT) and N2A(hDAT) respectively. [3H]GBR12935 binding assays were performed to determine DAT expression at the plasma membrane. [3H]Dopamine uptake assays were conducted to establish effects on DAT functioning. LDH activity significantly increased in both a concentration- and time-dependent manner. Sublethal concentrations of drugs/metals were chosen for further studies (10 ?M for HgCl2 and PbCl2; 100 nM for COC and MA), using a 72 h exposure. COS-7(hDAT) cells revealed expression of DAT, but no DA uptake. N2A(hDAT) cells showed higher expression of functioning DAT. Statistical analysis of the treatment effect on DAT density or DA uptake through the DAT revealed no significance in either cell line. Overall, a trend was observed where DAT density was increased, but caused functional decreases in DA clearance were observed. Individuals exposed to low-levels of Hg, may be at risk for increased DA neurotransmission/ turnover following psychostimulant use, resulting in an elevated addictive, or toxic, potential of these already addictive drugs.Department of Biochemistry and Molecular Biolog

Sox21b underlies the rapid diversification of a novel male genital structure between Drosophila species

The emergence and diversification of morphological novelties is a major feature of animal evolution. However, relatively little is known about the genetic basis of the evolution of novel structures and the mechanisms underlying their diversification. The epandrial posterior lobes of male genitalia are a novelty of particular Drosophila species. The lobes grasp the female ovipositor and insert between her abdominal tergitesand, therefore, are important for copulation and species recognition. The posterior lobes likely evolved from co-option of a Hox-regulated gene network from the posterior spiracles and have sincediversified in morphology in the D.simulans clade, in particular, over the last 240,000 years, drivenby sexual selection. The genetic basis of this diversification is polygenic but, to the best ofour knowledge, none of the causative genes have been identified. Identifying the genes underlyingthe diversification of these secondary sexual structures is essential to understanding theevolutionary impact on copulation and species recognition. Here, we show that Sox21b negatively regulates posterior lobe size. This is consistent with expanded Sox21b expression in D.mauritiana, which develops smaller posterior lobes than D.simulans. We tested this by generating reciprocal hemizygotes and confirmed that changes in Sox21b underlie posterior lobe evolution between these species. Furthermore, we found that posterior lobe size differences caused by the species-specific allele of Sox21b significantly affect copulation duration. Taken together, our study reveals the genetic basis for the sexual-selection-driven diversification of a novel morphological structure and its functional impact on copulatory behavior. [Abstract copyright: Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

The Habitable Exoplanet Observatory (HabEx) Mission Concept Study Final Report

The Habitable Exoplanet Observatory, or HabEx, has been designed to be the Great Observatory of the 2030s. For the first time in human history, technologies have matured sufficiently to enable an affordable space-based telescope mission capable of discovering and characterizing Earthlike planets orbiting nearby bright sunlike stars in order to search for signs of habitability and biosignatures. Such a mission can also be equipped with instrumentation that will enable broad and exciting general astrophysics and planetary science not possible from current or planned facilities. HabEx is a space telescope with unique imaging and multi-object spectroscopic capabilities at wavelengths ranging from ultraviolet (UV) to near-IR. These capabilities allow for a broad suite of compelling science that cuts across the entire NASA astrophysics portfolio. HabEx has three primary science goals: (1) Seek out nearby worlds and explore their habitability; (2) Map out nearby planetary systems and understand the diversity of the worlds they contain; (3) Enable new explorations of astrophysical systems from our own solar system to external galaxies by extending our reach in the UV through near-IR. This Great Observatory science will be selected through a competed GO program, and will account for about 50% of the HabEx primary mission. The preferred HabEx architecture is a 4m, monolithic, off-axis telescope that is diffraction-limited at 0.4 microns and is in an L2 orbit. HabEx employs two starlight suppression systems: a coronagraph and a starshade, each with their own dedicated instrument

The Habitable Exoplanet Observatory (HabEx) Mission Concept Study Final Report

The Habitable Exoplanet Observatory, or HabEx, has been designed to be the Great Observatory of the 2030s. For the first time in human history, technologies have matured sufficiently to enable an affordable space-based telescope mission capable of discovering and characterizing Earthlike planets orbiting nearby bright sunlike stars in order to search for signs of habitability and biosignatures. Such a mission can also be equipped with instrumentation that will enable broad and exciting general astrophysics and planetary science not possible from current or planned facilities. HabEx is a space telescope with unique imaging and multi-object spectroscopic capabilities at wavelengths ranging from ultraviolet (UV) to near-IR. These capabilities allow for a broad suite of compelling science that cuts across the entire NASA astrophysics portfolio. HabEx has three primary science goals: (1) Seek out nearby worlds and explore their habitability; (2) Map out nearby planetary systems and understand the diversity of the worlds they contain; (3) Enable new explorations of astrophysical systems from our own solar system to external galaxies by extending our reach in the UV through near-IR. This Great Observatory science will be selected through a competed GO program, and will account for about 50% of the HabEx primary mission. The preferred HabEx architecture is a 4m, monolithic, off-axis telescope that is diffraction-limited at 0.4 microns and is in an L2 orbit. HabEx employs two starlight suppression systems: a coronagraph and a starshade, each with their own dedicated instrument.Comment: Full report: 498 pages. Executive Summary: 14 pages. More information about HabEx can be found here: https://www.jpl.nasa.gov/habex

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Species-specific regulation of angiogenesis by glucocorticoids reveals contrasting effects on inflammatory and angiogenic pathways

<div><p>Glucocorticoids are potent inhibitors of angiogenesis in the rodent <i>in vivo</i> and <i>in vitro</i> but the mechanism by which this occurs has not been determined. Administration of glucocorticoids is used to treat a number of conditions in horses but the angiogenic response of equine vessels to glucocorticoids and, therefore, the potential role of glucocorticoids in pathogenesis and treatment of equine disease, is unknown. This study addressed the hypothesis that glucocorticoids would be angiostatic both in equine and murine blood vessels.The mouse aortic ring model of angiogenesis was adapted to assess the effects of cortisol in equine vessels. Vessel rings were cultured under basal conditions or exposed to: foetal bovine serum (FBS; 3%); cortisol (600 nM), cortisol (600nM) plus FBS (3%), cortisol (600nM) plus either the glucocorticoid receptor antagonist RU486 or the mineralocorticoid receptor antagonist spironolactone. In murine aortae cortisol inhibited and FBS stimulated new vessel growth. In contrast, in equine blood vessels FBS alone had no effect but cortisol alone, or in combination with FBS, dramatically increased new vessel growth compared with controls. This effect was blocked by glucocorticoid receptor antagonism but not by mineralocorticoid antagonism. The transcriptomes of murine and equine angiogenesis demonstrated cortisol-induced down-regulation of inflammatory pathways in both species but up-regulation of pro-angiogenic pathways selectively in the horse. Genes up-regulated in the horse and down-regulated in mice were associated with the extracellular matrix. These data call into question our understanding of glucocorticoids as angiostatic in every species and may be of clinical relevance in the horse.</p></div

Towards interdisciplinarity in Egyptology

This paper serves as an introductory remark to the proceeding Special Issue of Interdisciplinary Egyptology. It sets out the ideas and concepts behind interdisciplinarity in Egyptology, and defines what the journal’s Editorial Board considers interdisciplinary to mean with regard to 21st century Egyptology. While setting out a definition of “interdisciplinary” in Egyptology, we simultaneously define the terms intra-, multi-, cross- and transdisciplinary to avoid miscommunication

Using DosiVox to Reconstruct Radiation Transport through Complex Archaeological Environments

The DosiVox programme is used to reconstruct radiation transport in complex depositional environments. Using two archaeological case studies from ancient Egypt, the burial environments for a selection of ceramic vessels are reconstructed using the DosiVox programme, allowing the simulation of the emission and transport of radiation throughout these burial environments. From this simulation we can extract the external dose rate of the archaeological samples, a measurement necessary for determine a luminescence age. We describe in detail how DosiVox can be used to best advantage at sites with complex depositional histories and highlight that DosiVox is a valuable tool in luminescence dating. This work illustrates that DosiVox is, at present, unparalleled in reconstructing a more accurate and detailed external gamma dose rate which can significantly improve upon simplistic scaled geometric models

iii TABLE OF CONTENTS

I would like to sincerely thank Dr. David Wallace, my thesis advisor, for his guidance and support (and sushi lunches!) during my research and preparation of this thesis. He is a talented teacher and passionate scientist. I also thank Dr. Wallace for appreciating my research strengths and patiently encouraging me to improve in my weaker areas. Graduate school can be a difficult, draining experience. I am proud to say my experience in the Wallace lab was intellectually exciting and fun, and has energized me to continue in academic research. I wish to thank my committee members, Dr. Robert Allen and Dr. Tom Glass for their ideas and suggestions during the course of my research work. I am grateful to Dr. Greg Sawyer and Crystal Shults for providing technical assistance on molecular DNA studies. I thank Dr. Karley Little for generously providing the N2A(hDAT) cells. I would like to thank all my friends in the Forensics Program for providing a fun environment at school. I am especially grateful to my husband and best friend, Wesley, for hi