Gegenstand der vorliegenden Arbeit ist die Präfigierung der Verben im Deutschen und Litauischen. Das Hauptgewicht dieser Arbeit liegt auf dem deutschen Präfix er- und seinen semantischen und syntaktischen Funktionen, die es zusammen mit einem Basisverb ausdrücken kann. Dann werden die Entsprechungen des Präfixes er- in der litauischen Sprache festgestellt und die Funktionen des Präfixes er- mit den Funktionen der entsprechenden litauischen Präfixen verglichen. / Priešdėlinių er- veiksmažodžių semantinės ir sintaksinės funkcijos vokiečių kalboje ir jų atitikmenys lietuvių kalboje. / Semantical and syntactical functions of the verbs with the prefix "er" in German and Lithuanian languages.

Type 2 diabetes (T2D) is a growing health-care and economic burden. Obesity is a risk factor for developing T2D, but the underlying molecular mechanisms are not well understood. However, mechanisms such as lipotoxicity, endoplasmic reticulum stress and inflammation are becoming increasingly well-recognised in obesity, and may underlie the development and progression of T2D. A central player in these mechanisms is Protein Kinase R (PKR), proposed to have a role within nutrient- and pathogen-sensing pathways, and is activated by ER stress and lipotoxicity. A small molecule inhibitor Compound-16, adenoviral vectors and RNAi techniques in BRIN-BD11 rodent pancreatic β-cells, were used to demonstrate that PKR knockdown affords significant protection against palmitate-induced cell death. Furthermore, PKR knockdown potentiates palmitoleate cytoprotection during lipotoxicity, suggesting the cytotoxic and cytoprotective actions of long-chain fatty acid species may function via the PKR signalling pathway. The use of a novel 1.1B4 human pancreatic β-cell line has shown that important differences exist between human and rodent cell responses to fatty acids in vitro. In 1.1B4 cells, long-chain saturated and monounsaturated fatty acids do not provide increasing protection as their chain-length increases, in contrast to rodent cell models. Furthermore, methyl-saturated fatty acid species are well tolerated, and methyl-monounsaturated fatty acids are cytoprotective to 1.1B4 β-cells. TXNIP overexpression in an INS-TXNIP β-cell model has a proapoptotic role in conditions of glucotoxicity, but not glucolipotoxicity. Furthermore, in this cell model, succinate is cytoprotective against glucotoxicity, but not glucolipotoxicity. By contrast in 1.1B4 β-cells, succinate significantly protects against apoptosis induced by both glucotoxic and glucolipotoxic conditions. Chronic inflammation has been implicated in the development and progression of T2D. At the centre of this response is the pro-inflammatory cytokine IL-1β. The cellular origin of IL-1β is unclear, but IL-1β secretion has been linked to activation of the NLRP3 inflammasome, recently implicated in pancreatic β-cell death in T2D. Results suggest that IL-1β is secreted by INS-TXNIP and 1.1B4 pancreatic β-cells under lipotoxic conditions, thus offering a potential role for targeted IL-1β therapy in T2D.

No description available.

No description available.

Abstract Alternative splicing provides a versatile mechanism by which cells can generate proteins with different or even antagonistic properties. Herein we describe a novel splice variant of the hypoxia-inducible death gene Bnip3. Sequence analysis of the new Bnip3 protein revealed an N-terminus that was identical to Bnip3 but contained an Endoplasmic reticulum (ER) retention motif within the C-terminus, therefore we designated the new Bnip3 isoform NIPLET for (Nip-Like ER Target). While Bnip3 was predominately localized to mitochondria and promoted mitochondrial perturbations and cell death, NIPLET was preferentially localized to the ER and opposed the cytotoxic actions of Bnip3. Interestingly, NIPLET suppressed mitochondrial injury from Bnip3 activation and mitochondrial permeability transition pore opening by a mechanism dependent upon the dynamin motor protein Mitofusin-2 (MFN2). Notably, mutations of NIPLET within the critical ER retention motif rendered NIPLET defective for interacting with MFN2 and suppressed necrosis induced by Bnip3 or hypoxia. Hence, our findings reveal a novel signaling pathway that functionally couples ER and mitochondria for cell survival to a mechanism that is mutually dependent and obligatorily linked to a novel BNIP3 protein in cardiac myocytes. / May 2016

Thesis advisor: Robert C. Bartlett / A translation and close study of the “myths” of the afterlife that conclude Plato’s Republic and Gorgias. This thesis attempts to understand the essential political teachings of the dialogues in question—about the definition of justice, its rightness, and its consequences—through the lens of their final stories. Glaucon and Callicles represent two responses to the apparent problem that the unjust fare better than the just. To Callicles, Socrates offers his “political art in truth” in the place of Gorgias’ “art” of rhetoric. To Glaucon, Socrates presents an orderly universe and an orderly city that seem to mirror justice in the soul. Both men require different, salutary accounts of justice from Socrates. These are not false or unphilosophic fables, but true images of τὰ ἔσχατα, of the ultimate and most extreme things—not as guides to any underworld but to the best way of life possible among living human beings. / Thesis (BA) — Boston College, 2013. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: College Honors Program. / Discipline: Political Science Honors Program. / Discipline: Political Science.

MCDS is an autosomal dominant skeletal dysplasia disorder caused by mutations in collagen X. In most cases, mutations in collagen X result in a misfolded protein which is retained within the ER of hypertrophic chondrocytes, causing increased ER stress. It has previously been demonstrated that increased ER stress causes hypertrophic chondrocytes to de-differentiate in an attempt to avoid the stress. The altered differentiation results in reduced cell hypertrophy and impaired vascular invasion accounting for reduced bone growth. The presence of increased ER stress in hypertrophic chondrocytes is sufficient to cause the MCDS pathology; therefore reducing ER stress may be beneficial in terms of improving the associated pathology. The autophagy enhancing drug carbamazepine (CBZ) has been shown to be capable of reducing ER stress in cells expressing the MCDS-causing p.N617K collagen X mutation. I show in this thesis that CBZ treatment reduced ER stress in HeLa cells transiently expressing a further 3 MCDS-causing collagen X mutations. I have also demonstrated that CBZ treatment induced the degradation of mutant collagen X proteins either through autophagy or proteasomal degradation depending on the nature of the mutation. The drug was tested in vivo using the p.N617K collagen X mouse model of MCDS. In MCDS mice, CBZ reduced the severity of the disease pathology based on histological analyses, restored hypertrophic chondrocyte differentiation toward normal, increased long bone growth rates and decreased the severity of the hip dysplasia. Gene expression analyses on RNA isolated from microdissected hypertrophic chondrocytes revealed that CBZ shifted the pattern of hypertrophic differentiation markers in MCDS mice toward the wild-type pattern, most likely through its stimulation of gene expression associated with intracellular proteolytic pathways. The results presented in this thesis have contributed to the identification of a potential treatment strategy for MCDS- the stimulation of intracellular proteolysis of mutant collagen X. CBZ is FDA approved for the use of epilepsy and bipolar disorder and has a strong safety record in humans. Therefore CBZ could be a potential treatment strategy for MCDS.

Perturbations that derail the proper folding and assembly of proteins in the endoplasmic retriculum (ER) cause misfolded protein accrual in the ER – a toxic condition known as ER stress. The Unfolded Protein Response (UPR) is a signaling system evolved to detect and rectify ER stress. The work I present herein pertains to the most ancient member of the ER stress transducers, IRE1. ER stress stimulates IRE1 to activate a UPR-dedicated transcription factor called XBP1 in metazoans (or HAC1 in yeast) to bolster the productive capacity of the ER and purge misfolded proteins from the ER. To activate XBP1/HAC1, IRE1 cleaves XBP1/HAC1 mRNA twice to eliminate an inhibitory intron using a dormant nuclease function in its cytoplasmic effector region (IRE1cyto). My focus was to understand the mechanism of XBP1/HAC1 activation by IRE1, the regulation of IRE1 function and the manipulation of IRE1 signaling output using chemical tools. To better understand IRE1 mechanism, I determined the crystal structure of IRE1cyto bound to ADP. Structural and mutational analyses uncovered a probable novel IRE1 nuclease active site, allowing a catalytic mechanism of RNA cleavage to be inferred. Further genetic and biophysical experiments revealed that the ordered sequence of events: autophosphorylation, nucleotide binding and dimerization; orchestrates the assembly of the IRE1 nuclease active site to potentiate nuclease function. The flavanol quercetin was identified in a chemical screen as a potent stimulator of IRE1 nuclease output. To understand the mechanism of action of quercetin, I determined the crystal structure of IRE1cyto in complex with quercetin and ADP. Quercetin docked to a novel ligand binding site, termed the Q-site, at the interface of IRE1 dimers. Biophysical and genetic analyses revealed that quercetin engagement of the Q-site promotes IRE1 dimerization, thereby enhancing IRE1 nuclease activity. To gain insight on how IRE1 recognizes RNA, I performed bioinformatic analysis to identify a conserved sequence element in XBP1/HAC1 mRNA (termed XBP1mini) that may compose a higher-order structure recognized by IRE1. I developed an RNA production scheme to generate XBP1mini RNA for structural and biophysical studies. Preliminary X-ray diffraction studies indicate that XBP1mini may indeed adopt an ordered crystallizable tertiary structure.

Musiklärarexamen. Examensarbete 15 hp.

Persistent organic pollutants (POPs), which include polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs), are widely distributed in the environment. Some investigations have demonstrated that these pollutants will cause potential impacts such as carcinogenic and mutagenic for human health. In this study, we analyzed the concentrations and distributions of PAHs and PCBs in sediments of the Er-ren River, as well as the relations with total organic carbon (TOC) and particle sizes. Several molecular ratios were utilized to distinguish the major sources in this study. Results showed that PAH and PCB concentrations in Er-ren River ranged from 12.1 to 1460 and 0.45-591 (ng/g dw), respectively. The maximum concentrations of PAHs and PCBs were mostly found in sediments from Sanyegong River. In comparison with other studies all over the world, the concentrations of PAHs in this study were between low and mid-low levels. PCB concentrations in sediments of the Er-ren River were lower than those reported from previous studies. PAH and PCB concentrations showed no significant correlation between TOC and particle size. Petrogenic and petroleum combustion origin were the main sources of PAHs in sediments of Er-ren River In addition, perylene was the most dominant compound in Er-ren River, suggesting that it could be a useful indicator to differentiate various PAH sources in sediments. The results of hierarchical cluster analysis (HCA) and principal components analysis (PCA) indicated that PAH groups were clustered based on the loading of perylene, while PCB groups were clustered by the compositional homologues of PCBs. Comparing with sediments quality guidelines (SQGs), the PAH concentrations in all the sampling sites were below ERL value, suggesting that few adverse ecological effects would arise from the PAHs. However, the PCB concentrations in 14 sampling sites ranged between TEL and PEL values, indicating that adverse effects could arise for benthic organisms. The £UESBTUFCV of PAHs and the toxic equivalents (TEQ) of PCBs were both lower than quality values reported, suggesting that adverse ecological effects might be not expected.