Novel type of prion involved in glucose signaling and environmental sensing in S. cerevisiae

This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2008.Includes bibliographical references.Several well-characterized fungal proteins act as prions, proteins capable of multiple conformations, each with different activities, at least one of which is selfpropagating. We report a protein-based heritable element that confers resistance to glucosamine, [GAR⁺]. Genetically it resembles other yeast prions: it appears spontaneously at a rate higher than mutations and is transmissible by non-Mendelian, cytoplasmic inheritance. However, [GAR⁺] is in other ways profoundly different from known prions. [GAR⁺] propagation involves Pmal, the plasma membrane protein pump, and [GAR⁺] formation is induced by Stdl, a member of the Snf3/Rgt2 glucose signaling pathway. Also, [GAR⁺] does not appear to involve the formation of an amyloid template and the prion state represents only a fraction of the Pmal protein in the cell,· consistent with the prion form constituting a complex between Pmal and Stdl, a much lower abundance protein. [GAR⁺] propagation is subject to a strong species barrier, as substitution of PMAl from other Saccharomyces species blocks propagation to s.. cerevisiae PMAl. Direct competition between [gar-] and [GAR⁺] cells indicate that cells carrying [GAR⁺] have an advantage under certain environmental conditions. [GAR⁺] appears spontaneously in a yeast isolated from a variety of sources and can be induced by co-culturing yeast and a number of Staphylococcus species. Overall, [GAR⁺] expands the conceptual framework for self-propagating protein-based elements of inheritance to include non-amyloid, potentially multicomponent systems such as transmembrane proteins and signal transducers.by Jessica C. S. Brown.Ph.D

Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment

Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB’s role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors

Sometimes you have to take the person and show them how : adapting behavioral activation for peer recovery specialist-delivery to improve methadone treatment retention

BACKGROUND: Despite efficacy of medication for opioid use disorder, low-income, ethno-racial minoritized populations often experience poor opioid use disorder treatment outcomes. Peer recovery specialists, individuals with lived experience of substance use and recovery, are well-positioned to engage hard-to-reach patients in treatment for opioid use disorder. Traditionally, peer recovery specialists have focused on bridging to care rather than delivering interventions. This study builds on research in other low-resource contexts that has explored peer delivery of evidence-based interventions, such as behavioral activation, to expand access to care. METHODS: We sought feedback on the feasibility and acceptability of a peer recovery specialist-delivered behavioral activation intervention supporting retention in methadone treatment by increasing positive reinforcement. We recruited patients and staff at a community-based methadone treatment center and peer recovery specialist working across Baltimore City, Maryland, USA. Semi-structured interviews and focus groups inquired about the feasibility and acceptability of behavioral activation, recommendations for adaptation, and acceptability of working with a peer alongside methadone treatment. RESULTS: Participants (N = 32) shared that peer recovery specialist-delivered behavioral activation could be feasible and acceptable with adaptations. They described common challenges associated with unstructured time, for which behavioral activation could be particularly relevant. Participants provided examples of how a peer-delivered intervention could fit well in the context of methadone treatment, emphasizing the importance of flexibility and specific peer qualities. CONCLUSIONS: Improving medication for opioid use disorder outcomes is a national priority that must be met with cost-effective, sustainable strategies to support individuals in treatment. Findings will guide adaptation of a peer recovery specialist-delivered behavioral activation intervention to improve methadone treatment retention for underserved, ethno-racial minoritized individuals living with opioid use disorder

One of the closest exoplanet pairs to the 3:2 Mean Motion Resonance: K2-19b \& c

The K2 mission has recently begun to discover new and diverse planetary systems. In December 2014 Campaign 1 data from the mission was released, providing high-precision photometry for ~22000 objects over an 80 day timespan. We searched these data with the aim of detecting further important new objects. Our search through two separate pipelines led to the independent discovery of K2-19b \& c, a two-planet system of Neptune sized objects (4.2 and 7.2 $R_\oplus$), orbiting a K dwarf extremely close to the 3:2 mean motion resonance. The two planets each show transits, sometimes simultaneously due to their proximity to resonance and alignment of conjunctions. We obtain further ground based photometry of the larger planet with the NITES telescope, demonstrating the presence of large transit timing variations (TTVs), and use the observed TTVs to place mass constraints on the transiting objects under the hypothesis that the objects are near but not in resonance. We then statistically validate the planets through the \texttt{PASTIS} tool, independently of the TTV analysis.Comment: 18 pages, 10 figures, accepted to A&A, updated to match published versio

Interleukin-1β Maturation Triggers Its Relocation to the Plasma Membrane for Gasdermin-D-Dependent and -Independent Secretion

IL-1β requires processing by caspase-1 to generate the active, pro-inflammatory cytokine. Acute IL-1β secretion from inflammasome-activated macrophages requires caspase-1-dependent GSDMD cleavage, which also induces pyroptosis. Mechanisms of IL-1β secretion by pyroptotic and non-pyroptotic cells, and the precise functions of caspase-1 and GSDMD therein, are unresolved. Here, we show that, while efficient early secretion of endogenous IL-1β from primary non-pyroptotic myeloid cells in vitro requires GSDMD, later IL-1β release in vitro and in vivo proceeds independently of GSDMD. IL-1β maturation is sufficient for slow, caspase-1/GSDMD-independent secretion of ectopic IL-1β from resting, non-pyroptotic macrophages, but the speed of IL-1β release is boosted by inflammasome activation, via caspase-1 and GSDMD. IL-1β cleavage induces IL-1β enrichment at PIP2-enriched plasma membrane ruffles, and this is a prerequisite for IL-1β secretion and is mediated by a polybasic motif within the cytokine. We thus reveal a mechanism in which maturation-induced IL-1β trafficking facilitates its unconventional secretion

Beers and blurred boundaries: The spatial and gendered organisation of pre-match venues for English football fans

Academic research into sports fans has grown in recent years with studies examining a variety of aspects associated with fandom. However, recent changes in the professionalisation and commercialisation of sport have resulted in the creation of new spaces for fan experiences. In this article, we examine one of these created spaces, the fan zone. Through a case study on matchgoing fans from Everton Football Club we explore how this new space sits alongside traditional pre-match gathering places such as the ?pub? and examine the gendered organisation of these spaces. Drawing on Bale?s concept of boundaries within sports fan communities we show that traditional venues for pre-match activities enhance, maintain and legitimise masculine boundaries within sports fandom. We argue that fan zones provide an alternative match day atmosphere and experience that is centred on a family-friendly or at least family-inclusive culture

Global Conformational Dynamics of a Y-Family DNA Polymerase during Catalysis

High-resolution analysis of protein, and DNA conformational changes during DNA polymerization, established relationships between the enzymatic function and conformational dynamics of individual domains for a DNA polymerase

A meta-analytic review of stand-alone interventions to improve body image

Objective Numerous stand-alone interventions to improve body image have been developed. The present review used meta-analysis to estimate the effectiveness of such interventions, and to identify the specific change techniques that lead to improvement in body image. Methods The inclusion criteria were that (a) the intervention was stand-alone (i.e., solely focused on improving body image), (b) a control group was used, (c) participants were randomly assigned to conditions, and (d) at least one pretest and one posttest measure of body image was taken. Effect sizes were meta-analysed and moderator analyses were conducted. A taxonomy of 48 change techniques used in interventions targeted at body image was developed; all interventions were coded using this taxonomy. Results The literature search identified 62 tests of interventions (N = 3,846). Interventions produced a small-to-medium improvement in body image (d+ = 0.38), a small-to-medium reduction in beauty ideal internalisation (d+ = -0.37), and a large reduction in social comparison tendencies (d+ = -0.72). However, the effect size for body image was inflated by bias both within and across studies, and was reliable but of small magnitude once corrections for bias were applied. Effect sizes for the other outcomes were no longer reliable once corrections for bias were applied. Several features of the sample, intervention, and methodology moderated intervention effects. Twelve change techniques were associated with improvements in body image, and three techniques were contra-indicated. Conclusions The findings show that interventions engender only small improvements in body image, and underline the need for large-scale, high-quality trials in this area. The review identifies effective techniques that could be deployed in future interventions

The Drosophila Mitochondrial Translation Elongation Factor G1 Contains a Nuclear Localization Signal and Inhibits Growth and DPP Signaling

Mutations in the human mitochondrial elongation factor G1 (EF-G1) are recessive lethal and cause death shortly after birth. We have isolated mutations in iconoclast (ico), which encodes the highly conserved Drosophila orthologue of EF-G1. We find that EF-G1 is essential during fly development, but its function is not required in every tissue. In contrast to null mutations, missense mutations exhibit stronger, possibly neomorphic phenotypes that lead to premature death during embryogenesis. Our experiments show that EF-G1 contains a secondary C-terminal nuclear localization signal. Expression of missense mutant forms of EF-G1 can accumulate in the nucleus and cause growth and patterning defects and animal lethality. We find that transgenes that encode mutant human EF-G1 proteins can rescue ico mutants, indicating that the underlying problem of the human disease is not just the loss of enzymatic activity. Our results are consistent with a model where EF-G1 acts as a retrograde signal from mitochondria to the nucleus to slow down cell proliferation if mitochondrial energy output is low