A Portrait of the GET Pathway as a Surprisingly Complicated Young Man

Many eukaryotic membrane proteins have a single C-terminal transmembrane domain that anchors them to a variety of organelles in secretory and endocytic pathways. These tail-anchored (TA) proteins are post-translationally inserted into the endoplasmic reticulum by molecular mechanisms that have long remained mysterious. This review describes how, in just the past 5 years, intense research by a handful of laboratories has led to identification of all the key components of one such mechanism, the guided entry of TA proteins (GET) pathway, which is conserved from yeast to man. The GET pathway is both surprisingly complicated and yet more experimentally tractable than most other membrane insertion mechanisms, and is rapidly revealing new fundamental concepts in membrane protein biogenesis.Molecular and Cellular Biolog

The poetics of suffering and refuge in newer Serbian literature of Kosovo and Metohija

In the paper, we talk about the newer Serbian literature of Kosovo and Metohija which deals with the problem of persecution and fleeing of people from their home places and hearths. Such poetics has been especially present during the last few decades as a proof of massive affliction. Partially colored by neo-patriotic nuances, this kind of literature has more epic qualities than lyric ones; it is more of an expression of general suffering and sorrow, than sadness over personal fat

ER Targeting and Insertion of Tail-Anchored Membrane Proteins by the GET Pathway

Hundreds of eukaryotic membrane proteins are anchored to membranes by a single transmembrane domain at their C-terminus. Many of these tail-anchored (TA) proteins are post-translationally targeted to the endoplasmic reticulum (ER) membrane for insertion by the Guided-Entry of TA protein insertion (GET) pathway. In recent years most of the components of this conserved pathway have been biochemically and structurally characterized. Get3 is the pathway targeting factor that utilizes nucleotide-linked conformational changes to mediate the delivery of TA proteins between the GET pre-targeting machinery in the cytosol and the transmembrane pathway components in the ER. Here we focus on the mechanism of the yeast GET pathway and make a speculative analogy between its membrane insertion step and the ATPase-driven cycle of ABC transporters.Molecular and Cellular Biolog

Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis

Despite its eponymous association with the heat shock response, yeast heat shock factor 1 (Hsf1) is essential even at low temperatures. Here we show that engineered nuclear export of Hsf1 results in cytotoxicity associated with massive protein aggregation. Genome-wide analysis revealed that Hsf1 nuclear export immediately decreased basal transcription and mRNA expression of 18 genes, which predominately encode chaperones. Strikingly, rescuing basal expression of Hsp70 and Hsp90 chaperones enabled robust cell growth in the complete absence of Hsf1. With the exception of chaperone gene induction, the vast majority of the heat shock response was Hsf1 independent. By comparative analysis of mammalian cell lines, we found that only heat shock-induced but not basal expression of chaperones is dependent on the mammalian Hsf1 homolog (HSF1). Our work reveals that yeast chaperone gene expression is an essential housekeeping mechanism and provides a roadmap for defining the function of HSF1 as a driver of oncogenesis

Cinematic ethics of migration:First-person voices in contemporary documentary

This PhD research joins the growing interdisciplinary scholarship concerned with the relationship between migration and media by focusing on the ethical demands of first-person voices in contemporary documentary. First-person filmmaking, as I argue in this dissertation, comprises an everyday practice that is integral to migrants’ negotiation of various bordering mechanisms in Europe towards more sustaining ways of sharing the world with others. This raises two questions: How can first-person voices negotiate the confining forces of the European border regime to envision and enact alternative configurations of the everyday? And what are the ethically salient aspects of the collaborative labour involved in the production of first-person voices? To answer these questions, I draw from critical border studies, affect theory, and film-ethics to offer an audio-visual and production analysis of a corpus of films that together address diverse experiences of migration in Europe, including the decision to migrate, the migration journey itself, and the experiences of displacement and belonging. With this theoretical and methodological backdrop, I examine how first-person voices interrogate the various impasses created by the European border regime’s confinement of migrants’ knowledge production, mobility, inclusion and belonging. On the basis of this analysis, I argue that first-person voices enact migrants’ epistemic rights by defying the European border regime’s discursive practices; the right to autonomy of migration by grappling with the processes of migrant interpellation by the European border regime; the right to opacity by resisting the racialising, homogenising and reductive forces of the European border regime; and the right to in-betweenness by refusing the European border regime’s conflation of belonging with a singular location. In addition, on the basis of interviews with the directors of the films in corpus, I articulate how the process of expressing a first-person voice involves an extensive negotiation of vulnerability, trust, as well as contractual and creative rights. Overall, this dissertation elaborates how first-person voices in contemporary documentary advance a cinematic ethics of migration that is invested in transgressing the confinement effected by the contemporary coloniality of migration in Europe

Cinematic ethics of migration:First-person voices in contemporary documentary

This PhD research joins the growing interdisciplinary scholarship concerned with the relationship between migration and media by focusing on the ethical demands of first-person voices in contemporary documentary. First-person filmmaking, as I argue in this dissertation, comprises an everyday practice that is integral to migrants’ negotiation of various bordering mechanisms in Europe towards more sustaining ways of sharing the world with others. This raises two questions: How can first-person voices negotiate the confining forces of the European border regime to envision and enact alternative configurations of the everyday? And what are the ethically salient aspects of the collaborative labour involved in the production of first-person voices? To answer these questions, I draw from critical border studies, affect theory, and film-ethics to offer an audio-visual and production analysis of a corpus of films that together address diverse experiences of migration in Europe, including the decision to migrate, the migration journey itself, and the experiences of displacement and belonging. With this theoretical and methodological backdrop, I examine how first-person voices interrogate the various impasses created by the European border regime’s confinement of migrants’ knowledge production, mobility, inclusion and belonging. On the basis of this analysis, I argue that first-person voices enact migrants’ epistemic rights by defying the European border regime’s discursive practices; the right to autonomy of migration by grappling with the processes of migrant interpellation by the European border regime; the right to opacity by resisting the racialising, homogenising and reductive forces of the European border regime; and the right to in-betweenness by refusing the European border regime’s conflation of belonging with a singular location. In addition, on the basis of interviews with the directors of the films in corpus, I articulate how the process of expressing a first-person voice involves an extensive negotiation of vulnerability, trust, as well as contractual and creative rights. Overall, this dissertation elaborates how first-person voices in contemporary documentary advance a cinematic ethics of migration that is invested in transgressing the confinement effected by the contemporary coloniality of migration in Europe

The role of CDC48 in the retro-translocation of non-ubiquitinated toxin substrates in plant cells

When the catalytic A subunits of the castor bean toxins ricin and Ricinus communis agglutinin (denoted as RTA and RCA A, respectively) are delivered into the endoplasmic reticulum (ER) of tobacco protoplasts, they become substrates for ER-associated protein degradation (ERAD). As such, these orphan polypeptides are retro-translocated to the cytosol, where a significant proportion of each protein is degraded by proteasomes. Here we begin to characterise the ERAD pathway in plant cells, showing that retro-translocation of these lysine-deficient glycoproteins requires the ATPase activity of cytosolic CDC48. Lysine polyubiquitination is not obligatory for this step. We also show that while RCA A is found in a mannose-untrimmed form prior to its retro-translocation, a significant proportion of newly synthesised RTA cycles via the Golgi and becomes modified by downstream glycosylation enzymes. Despite these differences, both proteins are similarly retro-translocated

Progressive Structural Defects in Canine Centronuclear Myopathy Indicate a Role for HACD1 in Maintaining Skeletal Muscle Membrane Systems

Mutations in HACD1/PTPLA cause recessive congenital myopathies in humans and dogs. Hydroxyacyl-coA dehydratases are required for elongation of very long chain fatty acids, and HACD1 has a role in early myogenesis, but the functions of this striated muscle-specific enzyme in more differentiated skeletal muscle remain unknown. Canine HACD1 deficiency is histopathologically classified as a centronuclear myopathy (CNM). We investigated the hypothesis that muscle from HACD1-deficient dogs has membrane abnormalities in common with CNMs with different genetic causes. We found progressive changes in tubuloreticular and sarcolemmal membranes and mislocalized triads and mitochondria in skeletal muscle from animals deficient in HACD1. Furthermore, comparable membranous abnormalities in cultured HACD1-deficient myotubes provide additional evidence that these defects are a primary consequence of altered HACD1 expression. Our novel findings, including T-tubule dilatation and disorganization, associated with defects in this additional CNM-associated gene provide a definitive pathophysiologic link with these disorders, confirm that dogs deficient in HACD1 are relevant models, and strengthen the evidence for a unifying pathogenesis in CNMs via defective membrane trafficking and excitation-contraction coupling in muscle. These results build on previous work by determining further functional roles of HACD1 in muscle and provide new insight into the pathology and pathogenetic mechanisms of HACD1 CNM. Consequently, alterations in membrane properties associated with HACD1 mutations should be investigated in humans with related phenotypes

Timing matters: species-specific interactions between spawning time, substrate quality, and recruitment success in three salmonid species

Substratum quality and oxygen supply to the interstitial zone are crucial for the reproductive success of salmonid fishes. At present, degradation of spawning grounds due to fine sediment deposition and colmation are recognized as main factors for reproductive failure. In addition, changes in water temperatures due to climate change, damming, and cooling water inlets are predicted to reduce hatching success. We tested the hypothesis that the biological effects of habitat degradation depend strongly on the species-specific spawning seasons and life-history strategies (e. g., fall-vs. spring-spawners, migratory vs. resident species) and assessed temperature as an important species-specific factor for hatching success within river substratum. We studied the species-specific differences in their responses to such disturbances using egg-to-fry survival of Danube Salmon (Hucho hucho),resident brown trout (Salmo trutta fario), and migratory brown trout (Salmo trutta lacustris) as biological endpoint. The egg incubation and hatching success of the salmonids and their dependence on temperature and stream substratum quality were compared. Hatching rates of Danube salmon were lower than of brown trout, probably due to higher oxygen demands and increased interstitial respiration in spring. Increases in maximum water temperature reduced hatching rates of resident and migratory brown trout (both fall-spawners) but were positively correlated with hatching rates of Danube salmon (a spring-spawner). Significantly longer incubation periods of resident and migratory brown trout coincided with relatively low stream substratum quality at the end of the egg incubation. Danube salmon seem to avoid low oxygen concentrations in the hyporheic zone by faster egg development favored by higher water temperatures. Consequently, the prediction of effects of temperature changes and altered stream substratum properties on gravel-spawning fishes and biological communities should consider the observed species-specific variances in life-history strategies to increase conservation success

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy