The Negative Impact of an Uncertain Residence Status: Analysis of Migration-Related Stressors in Outpatients with Turkish Migration Background and Psychiatric Disorders in Germany Over a 10-Year Period (2005-2014).

Several studies indicate that immigration is associated with a higher risk for mental disorders, particularly in refugees and asylum seekers. We investigated migration-related distress in outpatients with Turkish migration background and a psychiatric disorder. Asylum applicants (ASA) and migrants with a permanent residency status (PRS) from a specialized German psychiatric outpatient service were compared with respect to clinical variables and stressors related to migration and acculturation. Of n = 620 migrant outpatients (main diagnosis: 3.9% ICD-10 F2, 58.2% F3, 36.5% F4, 1.5% F60), n = 78 (12.6%) were ASA with larger proportions of illiteracy and language difficulties. Communication problems, stress related to migration, shame feelings, homesickness and perceived discrimination occurred more often in ASA whereas family conflicts were more frequent in PRS (P < 0.05). According to our results, adaptation to the new environment of asylum applicants implies more difficulties, especially language problems, feelings of shame, and experience of discrimination. Asylum seeking seems to denote an additional severe psychological stressor.

Assessment of Perceived Stress Related to Migration and Acculturation in Patients with Psychiatric Disorders (MIGSTR10)-Development, Reliability, and Dimensionality of a Brief Instrument.

Assessment of stressors related to migration and acculturation in patients with psychiatric disorder and migration background could help improve culturally sensitive concepts of psychiatry and psychotherapy for diagnosis and treatment. The present overview delineates development and psychometric properties of an instrument (MIGSTR10) for assessment of stressors related to migration and acculturation, particularly for application in patients with psychiatric disorders. Ten migration-related stressors were derived from a qualitative content analysis of case histories of patients with psychiatric disorder and migration background and put into a suitable interview and questionnaire format (MIGSTR10; 10 questions, answer format: categorical yes/no, and dimensional 0-10) for self-assessment and observer ratings in several languages. Reliability (interrater agreement, internal consistency) and dimensionality (multi-dimensional scaling, MDS) were investigated in n = 235 patients with migration background and n = 612 indigenous German patients. Interrater agreement (ICC) for MIGSTR10 single items and sum scores (categorical and dimensional) was sufficiently high (≥.58); internal consistency (Cronbach's α) reached medium to high values (.56-.73). MDS revealed a two-dimensional solution with two item clusters (A: communication, migration history, forced marriage, homesickness, discrimination, other stressors; B: family conflicts, loss of status, feelings of shame, guilt feelings). The MIGSTR10 is a rationally developed, straightforward 10-item screening instrument with satisfactory psychometric properties for the assessment of individual and specific stressors related to migration and acculturation.

Tubulin detyrosination promotes monolayer formation and apical trafficking in epithelial cells.

The role of post-translational tubulin modifications in the development and maintenance of a polarized epithelium is not well understood. We studied the balance between detyrosinated (detyr-) and tyrosinated (tyr-) tubulin in the formation of MDCK cell monolayers. Increased quantities of detyrosinated microtubules were detected during assembly into confluent cell sheets. These tubules were composed of alternating stretches of detyr- and tyr-tubulin. Constant induction of tubulin tyrosination, which decreased the levels of detyr-tubulin by overexpression of tubulin tyrosine ligase (TTL), disrupted monolayer establishment. Detyr-tubulin-depleted cells assembled into isolated islands and developed a prematurely polarized architecture. Thus, tubulin detyrosination is required for the morphological differentiation from non-polarized cells into an epithelial monolayer. Moreover, membrane trafficking, in particular to the apical domain, was slowed down in TTL-overexpressing cells. This effect could be reversed by TTL knockdown, which suggests that detyr-tubulin-enriched microtubules serve as cytoskeletal tracks to guide membrane cargo in polarized MDCK cells.

A link between ER tethering and COP-I vesicle uncoating.

The yeast Dsl1p vesicle tethering complex, comprising the three subunits Dsl1p, Dsl3p, and Tip20p, is stably associated with three endoplasmic reticulum-localized Q-SNAREs and is believed to play a central role in the tethering and fusion of Golgi-derived COP-I transport vesicles. Dsl1p also interacts directly with COP-I subunits. We now show that binding of Dsl1p to COP-I subunits involves binding sites identical to those involved in interactions between COP-I subunits that stabilize the COP-I coat. Cells with defects in Dsl/SNARE complex function show massive accumulation of COP-I-coated vesicles in a cluster to which COP-II coat proteins are also recruited. Our results suggest that binding of Dsl/SNARE complex to the COP-I coat complex serves two functions: to mediate vesicle tethering and to assist the uncoating process by blocking domains in COP-I that drive repolymerization and the formation of large COP-I aggregates.

tRNA and protein methylase complexes mediate zymocin toxicity in yeast.

Modification of Saccharomyces cerevisiae tRNA anticodons at the wobble uridine (U34) position is required for tRNA cleavage by the zymocin tRNase killer toxin from Kluyveromyces lactis. Hence, U34 modification defects including lack of the U34 tRNA methyltransferase Trm9 protect against tRNA cleavage and zymocin. Using zymocin as a tool, we have identified toxin-resistant mutations in TRM9 that are likely to affect the U34 methylation reaction. Most strikingly, C-terminal truncations in Trm9 abolish interaction with Trm112, a protein shown to individually purify with Lys9 and two more methylases, Trm11 and Mtq2. Downregulation of a GAL1-TRM112 allele protects against zymocin whereas LYS9, TRM11 and MTQ2 are dosage suppressors of zymocin. Based on immune precipitation studies, the latter scenario correlates with competition for Trm112 and in excess, some of these Trm112 partners interfere with formation of the toxin-relevant Trm9.Trm112 complex. In contrast to trm11Delta or lys9Delta cells, trm112Delta and mtq2Delta null mutants are zymocin resistant. In line with the identified role that methylation of Sup45 by Mtq2 has for translation termination by the release factor dimer Sup45.Sup35, we observe that SUP45 overexpression and sup45 mutants suppress zymocin. Intriguingly, this suppression correlates with upregulated levels of tRNA species targeted by zymocin's tRNase activity.

Dosage suppression of the Kluyveromyces lactis zymocin by Saccharomyces cerevisiae ISR1 and UGP1.

The Kluyveromyces lactis zymocin complex kills Saccharomyces cerevisiae cells in a process that involves tRNA cleavage by its tRNAse gamma-toxin subunit. In contrast to the gamma-toxin mode of action, the early steps of the zymocin response are less well characterized. Here, we present high-dosage suppressors of zymocin that encode a putative Pkc1-related kinase (ISR1) and UDP-glucose pyrophosphorylase (UGPase) (UGP1). Anti-UGPase Western blots and GAL10 - ISR1 overexpression suggest that zymocin suppression correlates with overproduction of UGPase or Isr1. As judged from protection against exo-zymocin and unaltered sensitivity to endogenous gamma-toxin, high-copy ISR1 and UGP1 operate in early, nontarget steps of the zymocin pathway. Consistent with a recent report on in vitro phosphorylation of Isr1 and UGPase by the CDK Pho85, high-copy ISR1 and UGP1 suppression of zymocin is abolished in a pho85 null mutant lacking CDK activity of Pho85. Moreover, suppression requires UGPase enzyme activity, and ISR1 overexpression also protects against CFW, a chitin-interfering poison. Our data agree with roles for UGPase in cell wall biosynthetic processes and for Isr1 in Pkc1-related cell wall integrity. In sum, high-copy ISR1 and UGP1 cells affect early steps of the zymocin response and potentially prevent the lethal K. lactis killer complex from establishing cell surface recognition and/or contact.

tRNAGlu wobble uridine methylation by Trm9 identifies Elongator's key role for zymocin-induced cell death in yeast.

Zymocin-induced cell death in Saccharomyces cerevisiae requires the toxin-target (TOT) effector Elongator, a protein complex with functions in transcription, exocytosis and tRNA modification. In line with the latter, trm9Delta cells lacking a tRNA methylase specific for wobble uridine (U(34)) residues survive zymocin and in excess, the Trm9 substrate tRNA(Glu) copies zymocin protection of Elongator mutants. Phenotypes typical of a tot3/elp3Delta Elongator mutant are absent from trm9Delta cells but copied in a tot3Deltatrm9Delta double mutant suggesting that Elongator acts upstream of Trm9. Consistent with Elongator-dependent tRNA modification being more important to mRNA decoding than Trm9, SUP4 and SOE1TRNA suppressors are highly sensitive to loss of Elongator and tRNA U(34) hypomodification. As Trm9 overexpression counteracts the effect of high-copy tRNA(Glu), zymocin suppression by high-copy tRNA(Glu) may reflect tRNA hypomethylation of trm9Delta cells. Thus, Trm9 methylation may enable recognition of tRNA by zymocin, a notion supported by a dramatic reduction of tRNA(Glu) levels in zymocin-treated cells and by cytotoxic zymocin residues conserved between bacterial nucleases and a tRNA modifying GTPase. In sum, Trm9 is a bona fideTOT pathway component whose methylation may be hijacked by zymocin to target tRNA function and eventually, mRNA translation.

Mannosyl-diinositolphospho-ceramide, the major yeast plasma membrane sphingolipid, governs toxicity of Kluyveromyces lactis zymocin.

Kluyveromyces lactis zymocin, a trimeric (alphabetagamma) protein toxin complex, inhibits proliferation of Saccharomyces cerevisiae cells. Here we present an analysis of kti6 mutants, which resist exogenous zymocin but are sensitive to intracellular expression of its inhibitory gamma-toxin subunit, suggesting that KTI6 encodes a factor needed for toxin entry into the cell. Consistent with altered cell surface properties, kti6 cells resist hygromycin B, syringomycin E, and nystatin, antibiotics that require intact membrane potentials or provoke membrane disruption. KTI6 is allelic to IPT1, coding for mannosyl-diinositolphospho-ceramide [M(IP)(2)C] synthase, which produces M(IP)(2)C, the major plasma membrane sphingolipid. kti6 membranes lack M(IP)(2)C and sphingolipid mutants that have reduced levels of M(IP)(2)C precursors, including the sphingolipid building block ceramide survive zymocin. In addition, kti6/ipt1 cells allow zymocin docking but prevent import of its toxic gamma-subunit. Genetic analysis indicates that Kti6 is likely to act upstream of lipid raft proton pump Kti10/Pma1, a previously identified zymocin sensitivity factor. In sum, M(IP)(2)C operates in a plasma membrane step that follows recognition of cell wall chitin by zymocin but precedes the involvement of elongator, the potential toxin target.