Investigation of candidate imprinted tumour suppressor genes

Imprinting is an epigenetic phenomenon that silences one allele of a gene, so that expression in one or more cell types is exclusively monoallelic, and dependent on parental origin. Approaches used to identify novel imprinted genes rely on characteristic features such as the clustering of imprinted genes, or their association with differentially methylated CpG islands.An imprinted tumour suppressor gene involved in pathogenesis of neuroblastoma is believed to lie within chromosome 1p36. In this region, a search was initiated for imprinted genes in the vicinity of the imprinted gene TP73. The DFFB gene, encoding the apoptotic nuclease DNA fragmentation factor, was identified, and its intron -exon structure was elucidated. A pseudogene was also identified on chromosome 9. The tumour suppressor candidacy of DFFB was assessed through a comprehensive mutation screen of 42 neuroblastoma DNAs. No tumour -specific mutations were identified. Imprinting was then assessed by RT -PCR, which revealed biallelic expression of DFFB. It is unlikely that DFFB acts as a tumour suppressor in neuroblastoma.During a systematic screen, a differentially methylated CpG island, NV 149, had been identified. In the present study, this locus was mapped to 6q24. The nearest gene was found to be the cell -cycle control gene, ZAC. Monoallelic expression of ZAC from the paternal allele only was demonstrated in a range of fetal tissues. ZAC may possess a dual role in disease, such that upregulation by paternal duplication or paternal uniparental disomy of chromosome 6 results in transient neonatal diabetes mellitus (TNDM), whereas loss or down regulation of ZAC results in loss of cell cycle control, and hence tumorigenesis. Through analysis of a panel of B cell lymphomas, evidence was found for hypermethylation of the NV 149 CpG island, which may be one mechanism through which expression of ZAC is lost in tumours

A Common Place, Volume 3, Spring 2024

Fiction Widowmaker by Char Lavigne Waning Eve by Lee Kassay Smoker’s Diner by John Travis Bridgham The Rusty Scabbard by Hannah Rice Nonfiction Portraito of My Father by Jordan Mcpherson Poetry Angel Girl by Grace (Asher) Beverly Sons Of Actaeon by Grace (Asher) Beverly Good Soil by Pearl Siff Celestial by Nat Velez-Camp The Hill by Mallory Isabella Davis Hierba Mala Nunca Muere by Mallory Isabella Davis Visual Art Lips by Judson Atkins Discarded Cigarettes by Nyla Mceachin Open Space and Safety by Bradley Pugh Conte Crayon Self-Portrait by Shaylise Jones Untitled 2363 by Judson Atkinshttps://digitalcommons.longwood.edu/special_studentpubs/1218/thumbnail.jp

A global disorder of imprinting in the human female germ line

Imprinted genes are expressed differently depending on whether they are carried by a chromosome of maternal or paternal origin. Correct imprinting is established by germline-specific modifications; failure of this process underlies several inherited human syndromes. All these imprinting control defects are cis-acting, disrupting establishment or maintenance of allele-specific epigenetic modifications across one contiguous segment of the genome. In contrast, we report here an inherited global imprinting defect. This recessive maternal-effect mutation disrupts the specification of imprints at multiple, non-contiguous loci, with the result that genes normally carrying a maternal methylation imprint assume a paternal epigenetic pattern on the maternal allele. The resulting conception is phenotypically indistinguishable from an androgenetic complete hydatidiform mole, in which abnormal extra-embryonic tissue proliferates while development of the embryo is absent or nearly so. This disorder offers a genetic route to the identification of trans-acting oocyte factors that mediate maternal imprint establishment

A Phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points

SU5416 (Z-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone; semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor receptor (VEGFR)2. A Phase I dose escalation study was performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic assessment tool. In all, 27 patients were recruited. SU5416 was administered twice weekly by fixed rate intravenous infusion. Patients were treated in sequential cohorts of three patients at 48, 65, 85 110 and 145 mg m−2. A further dose level of 190 mg m−2 after a 2-week lead in period at a lower dose was completed; thereafter, the cohort at 145 mg m−2 was expanded. SU5416 showed linear pharmacokinetics to 145 mg m−2 with a large volume of distribution and rapid clearance. A significant degree of interpatient variability was seen. SU5416 was well tolerated, by definition a maximum-tolerated dose was not defined. No reproducible changes were seen in DCE-MRI end points. Serial assessments of VEGF in a cohort of patients treated at 145 mg m−2 did not show a statistically significant treatment-related change. Parallel assessments of the impact of SU5416 on coagulation profiles in six patients showed a transient effect within the fibrinolytic pathway. Clinical experience showed that patients who had breaks of therapy longer than a week could not have treatment reinitiated at a dose of 190 mg m−2 without unacceptable toxicity. The 145 mg m−2 dose level is thus the recommended dose for future study

The Iso2k database: a global compilation of paleo-δ18O and δ2H records to aid understanding of common era climate

Reconstructions of global hydroclimate during the Common Era (CE; the past ~2,000 years) are important for providing context for current and future global environmental change. Stable isotope ratios in water are quantitative indicators of hydroclimate on regional to global scales, and these signals are encoded in a wide range of natural geologic archives. Here we present the Iso2k database, a global compilation of previously published datasets from a variety of natural archives that record the stable oxygen (δ18O) or hydrogen (δ²H) isotopic composition of environmental waters, which reflect hydroclimate changes over the CE. The Iso2k database contains 756 isotope records from the terrestrial and marine realms, including: glacier and ground ice (205); speleothems (68); corals, sclerosponges, and mollusks (145); wood (81); lake sediments and other terrestrial sediments (e.g., loess) (158); and marine sediments (99). Individual datasets have temporal resolutions ranging from sub-annual to centennial, and include chronological data where available. A fundamental feature of the database is its comprehensive metadata, which will assist both experts and non-experts in the interpretation of each record and in data synthesis. Key metadata fields have standardized vocabularies to facilitate comparisons across diverse archives and with climate model simulated fields. This is the first global-scale collection of water isotope proxy records from multiple types of geological and biological archives. It is suitable for evaluating hydroclimate processes through time and space using large-scale synthesis, model-data intercomparison and (paleo)data assimilation. The Iso2k database is available for download at: https://doi.org/10.25921/57j8-vs18 (Konecky and McKay, 2020) and is also accessible via through the NOAA/WDS Paleo Data landing page: https://www.ncdc.noaa.gov/paleo/study/29593

From Craft to Nature: The Emergence of Natural Teleology

A teleological explanation is an explanation in terms of an end or a purpose. So saying that ‘X came about for the sake of Y’ is a teleological account of X. It is a striking feature of ancient Greek philosophy that many thinkers accepted that the world should be explained in this way. However, before Aristotle, teleological explanations of the cosmos were generally based on the idea that it had been created by a divine intelligence. If an intelligent power made the world, then it makes sense that it did so with a purpose in mind, so grasping this purpose will help us understand the world. This is the pattern of teleological explanation that we find in the Presocratics and in Plato. However, with Aristotle teleology underwent a change: instead of thinking that the ends were explanatory because a mind had sought to bring them about, Aristotle took the ends to operate in natural beings independently of the efforts of any creative intelligence. Indeed, he thought that his predecessors had failed to understand what was distinctive of nature, namely, that its ends work from the inside of natural beings themselves

Aristotle on the Matter for Birth, Life, and the Elements

This essay considers three case studies of Aristotle’s use of matter, drawn from three different scientific contexts: menstrual fluid as the matter of animal generation in the Generation of Animals, the living body as matter of an organism in Aristotle’s On the Soul (De Anima), and the matter of elemental transformation in Generation and Corruption. I argue that Aristotle conceives of matter differently in these treatises (1) because of the different sorts of changes under consideration, and (2) because sometimes he is considering the matter for one specific change, and sometimes the matter for all of a thing’s natural changes. My account allows me to explain some of the strange features that Aristotle ascribes to the matter for elemental transformation in Generation and Corruption II. These features were interpreted by later commentators as general features of all matter. I argue that they are a result of the specific way that Aristotle thinks about the transmutation of the elements

Socializing One Health: an innovative strategy to investigate social and behavioral risks of emerging viral threats

In an effort to strengthen global capacity to prevent, detect, and control infectious diseases in animals and people, the United States Agency for International Development’s (USAID) Emerging Pandemic Threats (EPT) PREDICT project funded development of regional, national, and local One Health capacities for early disease detection, rapid response, disease control, and risk reduction. From the outset, the EPT approach was inclusive of social science research methods designed to understand the contexts and behaviors of communities living and working at human-animal-environment interfaces considered high-risk for virus emergence. Using qualitative and quantitative approaches, PREDICT behavioral research aimed to identify and assess a range of socio-cultural behaviors that could be influential in zoonotic disease emergence, amplification, and transmission. This broad approach to behavioral risk characterization enabled us to identify and characterize human activities that could be linked to the transmission dynamics of new and emerging viruses. This paper provides a discussion of implementation of a social science approach within a zoonotic surveillance framework. We conducted in-depth ethnographic interviews and focus groups to better understand the individual- and community-level knowledge, attitudes, and practices that potentially put participants at risk for zoonotic disease transmission from the animals they live and work with, across 6 interface domains. When we asked highly-exposed individuals (ie. bushmeat hunters, wildlife or guano farmers) about the risk they perceived in their occupational activities, most did not perceive it to be risky, whether because it was normalized by years (or generations) of doing such an activity, or due to lack of information about potential risks. Integrating the social sciences allows investigations of the specific human activities that are hypothesized to drive disease emergence, amplification, and transmission, in order to better substantiate behavioral disease drivers, along with the social dimensions of infection and transmission dynamics. Understanding these dynamics is critical to achieving health security--the protection from threats to health-- which requires investments in both collective and individual health security. Involving behavioral sciences into zoonotic disease surveillance allowed us to push toward fuller community integration and engagement and toward dialogue and implementation of recommendations for disease prevention and improved health security

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Team Astrology Prediction

Using longitudinal data on personal identifiers in Twitter bios, can we predict which twitter users will add a signifier relating to their astrological symbol