Pax5 maintains cellular identity by repressing gene expression throughout B cell differentiation.

The transcription factor Pax5 is required for many aspects of B-lymphopoiesis including lineage commitment, immunoglobulin rearrangement, pre-BCR signalling and mature B cell survival. Pax5 regulates B cell lineage commitment by concurrently activating B cell specific gene expression as well as suppressing the expression of genes associated with non-B cell fates. The identity of the molecular targets of Pax5-mediated gene repression is the subject of much current interest. Recent studies have documented the essential nature of the Pax5 repression of the stem cell transcriptional program, as well as the silencing of lineage inappropriate gene expression, for B cell development. Surprisingly the repression of genes by Pax5 continues throughout lymphopoiesis, with the loss of Pax5 in mature B cell resulting in the reactivation of the same Pax5 targets during plasma cell differentiation. These recent insights into the mechanism of action of Pax5 in controlling B cell identity will be discussed

Social control of brain morphology in a eusocial mammal

Social status impacts reproductive behavior in diverse vertebrate species, but little is known about how it affects brain morphology. We explore this in the naked mole-rat, a species with the most rigidly organized reproductive hierarchy among mammals. Naked mole-rats live in large, subterranean colonies where breeding is restricted to a single female and small number of males. All other members of the colony, known as subordinates, are reproductively suppressed. Subordinates can become breeders if removed from the colony and placed with an opposite sex partner, but in nature most individuals never attain reproductive status. We examined the brains of breeding and subordinate naked mole-rats of both sexes, including several regions linked to reproduction and shown to be sexually dimorphic in other mammals. Stereological analyses revealed that neural morphology depends on status, such that breeders, regardless of sex, had more cells than subordinates in the ventromedial nucleus of the hypothalamus and a larger volume of the bed nucleus of the stria terminalis, paraventricular nucleus, and medial amygdala. Several other brain regions examined were unaffected. Surprisingly, males and females did not differ on any measure. These findings provide evidence that a change in social status triggers considerable neural remodeling and indicate that status, rather than sex, has a predominant role in determining neural structure in this remarkably social mammal

Present and future nitrogen deposition to national parks in the United States: critical load exceedances

National parks in the United States are protected areas wherein the natural habitat is to be conserved for future generations. Deposition of anthropogenic nitrogen (N) transported from areas of human activity (fuel combustion, agriculture) may affect these natural habitats if it exceeds an ecosystem-dependent critical load (CL). We quantify and interpret the deposition to Class I US national parks for present-day and future (2050) conditions using the GEOS-Chem global chemical transport model with 1/2° × 2/3° horizontal resolution over North America. We estimate CL values in the range 2.5–5 kg N ha−1 yr−1 for the different parks to protect the most sensitive ecosystem receptors. For present-day conditions, we find 24 out of 45 parks to be in CL exceedance and 14 more to be marginally so. Many of these are in remote areas of the West. Most (40–85%) of the deposition originates from NOx emissions (fuel combustion). We project future changes in N deposition using representative concentration pathway (RCP) anthropogenic emission scenarios for 2050. These feature 52–73% declines in US NOx emissions relative to present but 19–50% increases in US ammonia (NH3) emissions. Nitrogen deposition at US national parks then becomes dominated by domestic NH3 emissions. While deposition decreases in the East relative to present, there is little progress in the West and increases in some regions. We find that 17–25 US national parks will have CL exceedances in 2050 based on the RCP8.5 and RCP2.6 scenarios. Even in total absence of anthropogenic NOx emissions, 14–18 parks would still have a CL exceedance. Returning all parks to N deposition below CL by 2050 would require at least a 50% decrease in US anthropogenic NH3 emissions relative to RCP-projected 2050 levels.Engineering and Applied Science

Management of Fracture Risk in Patients with Chronic Obstructive Pulmonary Disease (COPD): Building a UK Consensus Through Healthcare Professional and Patient Engagement

Introduction: Osteoporosis and bone fractures are common in chronic obstructive pulmonary disease (COPD) and contribute significantly to morbidity and mortality. Current national guidance on COPD management recommends addressing bone health in patients, however, does not detail how. This consensus outlines key elements of a structured approach to managing bone health and fracture risk in patients with COPD.Methods: A systematic approach incorporating multifaceted methodologies included detailed patient and healthcare professional (HCP) surveys followed by a roundtable meeting to reach a consensus on what a pathway would look like.Results: The surveys revealed that fracture risk was not always assessed despite being recognised as an important aspect of COPD management by HCPs. The majority of the patients also stated they would be receptive to discussing treatment options if found to be at risk of osteoporotic fractures. Limited time and resource allocation were identified as barriers to addressing bone health during consultations. The consensus from the roundtable meeting was that a proactive systematic approach to assessing bone health should be adopted. This should involve using fracture risk assessment tools to identify individuals at risk, investigating secondary causes of osteoporosis if a diagnosis is made and reinforcing non-pharmacological and preventative measures such as smoking cessation, keeping active and pharmacological management of osteoporosis and medicines management of corticosteroid use. Practically, prioritising patients with important additional risk factors, such as previous fragility fractures, older age and long-term oral corticosteroid use for an assessment, was felt required.Conclusion: There is a need for integrating fracture risk assessment into the COPD pathway. Developing a systematic and holistic approach to addressing bone health is key to achieving this. In tandem, opportunities to disseminate the information and educational resources are also required

Is authorship sufficient for today’s collaborative research? A call for contributor roles

Assigning authorship and recognizing contributions to scholarly works is challenging on many levels. Here we discuss ethical, social, and technical challenges to the concept of authorship that may impede the recognition of contributions to a scholarly work. Recent work in the field of authorship shows that shifting to a more inclusive contributorship approach may address these challenges. Recent efforts to enable better recognition of contributions to scholarship include the development of the Contributor Role Ontology (CRO), which extends the CRediT taxonomy and can be used in information systems for structuring contributions. We also introduce the Contributor Attribution Model (CAM), which provides a simple data model that relates the contributor to research objects via the role that they played, as well as the provenance of the information. Finally, requirements for the adoption of a contributorship-based approach are discussed

The Inducible lac Operator-Repressor System Is Functional in Zebrafish Cells

BackgroundZebrafish are a foundational model organism for studying the spatio-temporal activity of genes and their regulatory sequences. A variety of approaches are currently available for editing genes and modifying gene expression in zebrafish, including RNAi, Cre/lox, and CRISPR-Cas9. However, the lac operator-repressor system, an E. coli lac operon component which has been adapted for use in many other species and is a valuable, flexible tool for inducible modulation of gene expression studies, has not been previously tested in zebrafish.ResultsHere we demonstrate that the lac operator-repressor system robustly decreases expression of firefly luciferase in cultured zebrafish fibroblast cells. Our work establishes the lac operator-repressor system as a promising tool for the manipulation of gene expression in whole zebrafish.ConclusionOur results lay the groundwork for the development of lac-based reporter assays in zebrafish, and adds to the tools available for investigating dynamic gene expression in embryogenesis. We believe this work will catalyze the development of new reporter assay systems to investigate uncharacterized regulatory elements and their cell-type specific activities

Leadership As We Know It

Leadership as We Know it is a collection of insights into modern leadership compiled by graduate students in Winona State University’s Leadership Education program during the Spring 2019 semester in a course aptly titled, Change Leadership. Each chapter was penned by one of 20 unique class members who offer their vision of leadership based upon their eclectic personal backgrounds and professional experiences, whose fields include athletics, business, education, and more. These diverse narratives offer something for everyone; whether it be a veteran or blossoming leader eager to continue their growth and evolution. Leadership as We Know it provides accounts from seasoned professionals who oversee their own organizational departments as well as emerging leaders just beginning their careers. Throughout these unique stories, clear patterns will emerge for the reader in what it takes to inspire change and provide authentic leadership for followers.https://openriver.winona.edu/leadershipeducationbooks/1003/thumbnail.jp

Characterization of the severe phenotype of pyruvate kinase deficiency

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162766/2/ajh25926.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162766/1/ajh25926_am.pd

Teratology Primer-2nd Edition (7/9/2010)

Foreword: What is Teratology? “What a piece of work is an embryo!” as Hamlet might have said. “In form and moving how express and admirable! In complexity how infinite!” It starts as a single cell, which by repeated divisions gives rise to many genetically identical cells. These cells receive signals from their surroundings and from one another as to where they are in this ball of cells —front or back, right or left, headwards or tailwards, and what they are destined to become. Each cell commits itself to being one of many types; the cells migrate, combine into tissues, or get out of the way by dying at predetermined times and places. The tissues signal one another to take their own pathways; they bend, twist, and form organs. An organism emerges. This wondrous transformation from single celled simplicity to myriad-celled complexity is programmed by genes that, in the greatest mystery of all, are turned on and off at specified times and places to coordinate the process. It is a wonder that this marvelously emergent operation, where there are so many opportunities for mistakes, ever produces a well-formed and functional organism. And sometimes it doesn’t. Mistakes occur. Defective genes may disturb development in ways that lead to death or to malformations. Extrinsic factors may do the same. “Teratogenic” refers to factors that cause malformations, whether they be genes or environmental agents. The word comes from the Greek “teras,” for “monster,” a term applied in ancient times to babies with severe malformations, which were considered portents or, in the Latin, “monstra.” Malformations can happen in many ways. For example, when the neural plate rolls up to form the neural tube, it may not close completely, resulting in a neural tube defect—anencephaly if the opening is in the head region, or spina bifida if it is lower down. The embryonic processes that form the face may fail to fuse, resulting in a cleft lip. Later, the shelves that will form the palate may fail to move from the vertical to the horizontal, where they should meet in the midline and fuse, resulting in a cleft palate. Or they may meet, but fail to fuse, with the same result. The forebrain may fail to induce the overlying tissue to form the eye, so there is no eye (anophthalmia). The tissues between the toes may fail to break down as they should, and the toes remain webbed. Experimental teratology flourished in the 19th century, and embryologists knew well that the development of bird and frog embryos could be deranged by environmental “insults,” such as lack of oxygen (hypoxia). But the mammalian uterus was thought to be an impregnable barrier that would protect the embryo from such threats. By exclusion, mammalian malformations must be genetic, it was thought. In the early 1940s, several events changed this view. In Australia an astute ophthalmologist, Norman Gregg, established a connection between maternal rubella (German measles) and the triad of cataracts, heart malformations, and deafness. In Cincinnati Josef Warkany, an Austrian pediatrician showed that depriving female rats of vitamin B (riboflavin) could cause malformations in their offspring— one of the early experimental demonstrations of a teratogen. Warkany was trying to produce congenital cretinism by putting the rats on an iodine deficient diet. The diet did indeed cause malformations, but not because of the iodine deficiency; depleting the diet of iodine had also depleted it of riboflavin! Several other teratogens were found in experimental animals, including nitrogen mustard (an anti cancer drug), trypan blue (a dye), and hypoxia (lack of oxygen). The pendulum was swinging back; it seemed that malformations were not genetically, but environmentally caused. In Montreal, in the early 1950s, Clarke Fraser’s group wanted to bring genetics back into the picture. They had found that treating pregnant mice with cortisone caused cleft palate in the offspring, and showed that the frequency was high in some strains and low in others. The only difference was in the genes. So began “teratogenetics,” the study of how genes influence the embryo’s susceptibility to teratogens. The McGill group went on to develop the idea that an embryo’s genetically determined, normal, pattern of development could influence its susceptibility to a teratogen— the multifactorial threshold concept. For instance, an embryo must move its palate shelves from vertical to horizontal before a certain critical point or they will not meet and fuse. A teratogen that causes cleft palate by delaying shelf movement beyond this point is more likely to do so in an embryo whose genes normally move its shelves late. As studies of the basis for abnormal development progressed, patterns began to appear, and the principles of teratology were developed. These stated, in summary, that the probability of a malformation being produced by a teratogen depends on the dose of the agent, the stage at which the embryo is exposed, and the genotype of the embryo and mother. The number of mammalian teratogens grew, and those who worked with them began to meet from time to time, to talk about what they were finding, leading, in 1960, to the formation of the Teratology Society. There were, of course, concerns about whether these experimental teratogens would be a threat to human embryos, but it was thought, by me at least, that they were all “sledgehammer blows,” that would be teratogenic in people only at doses far above those to which human embryos would be exposed. So not to worry, or so we thought. Then came thalidomide, a totally unexpected catastrophe. The discovery that ordinary doses of this supposedly “harmless” sleeping pill and anti-nauseant could cause severe malformations in human babies galvanized this new field of teratology. Scientists who had been quietly working in their laboratories suddenly found themselves spending much of their time in conferences and workshops, sitting on advisory committees, acting as consultants for pharmaceutical companies, regulatory agencies, and lawyers, as well as redesigning their research plans. The field of teratology and developmental toxicology expanded rapidly. The following pages will show how far we have come, and how many important questions still remain to be answered. A lot of effort has gone into developing ways to predict how much of a hazard a particular experimental teratogen would be to the human embryo (chapters 9–19). It was recognized that animal studies might not prove a drug was “safe” for the human embryo (in spite of great pressure from legislators and the public to do so), since species can vary in their responses to teratogenic exposures. A number of human teratogens have been identified, and some, suspected of teratogenicity, have been exonerated—at least of a detectable risk (chapters 21–32). Regulations for testing drugs before market release have greatly improved (chapter 14). Other chapters deal with how much such things as population studies (chapter 11), post-marketing surveillance (chapter 13), and systems biology (chapter 16) add to our understanding. And, in a major advance, the maternal role of folate in preventing neural tube defects and other birth defects is being exploited (chapter 32). Encouraging women to take folic acid supplements and adding folate to flour have produced dramatic falls in the frequency of neural tube defects in many parts of the world. Progress has been made not only in the use of animal studies to predict human risks, but also to illumine how, and under what circumstances, teratogens act to produce malformations (chapters 2–8). These studies have contributed greatly to our knowledge of abnormal and also normal development. Now we are beginning to see exactly when and where the genes turn on and off in the embryo, to appreciate how they guide development and to gain exciting new insights into how genes and teratogens interact. The prospects for progress in the war on birth defects were never brighter. F. Clarke Fraser McGill University (Emeritus) Montreal, Quebec, Canad