Mechanisms of transmembrane cation transport studied by nuclear magnetic resonance spectroscopy

Several molecules like ionophores, vitamins, ion-binding cyclic peptides, acidic phospholipids, surfactants are known to expose the inner side of vesicles, to the externally added cations. Whereas ionophores and certain other systems bring about these changes by a selective transport (influx) of the cation by specialized mechanisms known as the carrier and channel mechanism, other systems cause lysis and vesicle fusion. These systems have been successfully studied using1H,31 P and13C nuclear magnetic resonance spectroscopy after the demonstration, fifteen years ago, of the ability of paramagnetic lanthanide ions to distinguish the inside of the vesicle from the outside. The results of these ’nuclear magnetic resonance kinetics’ experiments are reviewed.

Lost in Translation : Translation Mechanisms in Production of Cocksfoot Mottle Virus Proteins

The present study focuses on the translational strategies of Cocksfoot mottle virus (CfMV, genus Sobemovirus), which infects monocotyledonous plants. CfMV RNA lacks the 5'cap and the 3'poly(A) tail that ensure efficient translation of cellular messenger RNAs (mRNAs). Instead, CfMV RNA is covalently linked to a viral protein VPg (viral protein, genome-linked). This indicates that the viral untranslated regions (UTRs) must functionally compensate for the lack of the cap and poly(A) tail. We examined the efficacy of translation initiation in CfMV by comparing it to well-studied viral translational enhancers. Although insertion of the CfMV 5'UTR (CfMVe) into plant expression vectors improved gene expression in barley more than the other translational enhancers examined, studies at the RNA level showed that CfMVe alone or in combination with the CfMV 3'UTR did not provide the RNAs translational advantage. Mutation analysis revealed that translation initiation from CfMVe involved scanning. Interestingly, CfMVe also promoted translation initiation from an intercistronic position of dicistronic mRNAs in vitro. Furthermore, internal initiation occurred with similar efficacy in translation lysates that had reduced concentrations of eukaryotic initiation factor (eIF) 4E, suggesting that initiation was independent of the eIF4E. In contrast, reduced translation in the eIF4G-depleted lysates indicated that translation from internally positioned CfMVe was eIF4G-dependent. After successful translation initiation, leaky scanning brings the ribosomes to the second open reading frame (ORF). The CfMV polyprotein is produced from this and the following overlapping ORF via programmed -1 ribosomal frameshift (-1 PRF). Two signals in the mRNA at the beginning of the overlap program approximately every fifth ribosome to slip one nucleotide backwards and continue translation in the new -1 frame. This leads to the production of C-terminally extended polyprotein, which encodes the viral RNA-dependent RNA polymerase (RdRp). The -1 PRF event in CfMV was very efficient, even though it was programmed by a simple stem-loop structure instead of a pseudoknot, which is usually required for high -1 PRF frequencies. Interestingly, regions surrounding the -1 PRF signals improved the -1 PRF frequencies. Viral protein P27 inhibited the -1 PRF event in vivo, putatively by binding to the -1 PRF site. This suggested that P27 could regulate the occurrence of -1 PRF. Initiation of viral replication requires that viral proteins are released from the polyprotein. This is catalyzed by viral serine protease, which is also encoded from the polyprotein. N-terminal amino acid sequencing of CfMV VPg revealed that the junction of the protease and VPg was cleaved between glutamate (E) and asparagine (N) residues. This suggested that the processing sites used in CfMV differ from the glutamate and serine (S) or threonine (T) sites utilized in other sobemoviruses. However, further analysis revealed that the E/S and E/T sites may be used to cleave out some of the CfMV proteins.

Food and Indoor Air Isolated Bacillus Non-Protein Toxins: : Structures, Physico-Chemical Properties and Mechanisms of Effects on Eukaryotic Cells

We report here the structures and properties of heat-stable, non-protein, and mammalian cell-toxic compounds produced by spore-forming bacilli isolated from indoor air of buildings and from food. Little information is available on the effects and occurrence of heat-stable non-protein toxins produced by bacilli in moisture-damaged buildings. Bacilli emit spores that move in the air and can serve as the carriers of toxins, in a manner similar to that of the spores of toxic fungi found in contaminated indoor air. Bacillus spores in food cause problems because they tolerate the temperatures applied in food manufacture and the spores later initiate growth when food storage conditions are more favorable. Detection of the toxic compounds in Bacillus is based on using the change in mobility of boar spermatozoa as an indicator of toxic exposure. GC, LC, MS, and nuclear magnetic resonance NMR spectroscopy were used for purification, detection, quantitation, and analysis of the properties and structures of the compounds. Toxicity and the mechanisms of toxicity of the compounds were studied using boar spermatozoa, feline lung cells, human neural cells, and mitochondria isolated from rat liver. The ionophoric properties were studied using the BLM (black-lipid membrane) method. One novel toxin, forming ion channels permeant to K+ > Na+ > Ca2+, was found and named amylosin. It is produced by B. amyloliquefaciens isolated from indoor air of moisture-damaged buildings. Amylosin was purified with an RP-HPLC and a monoisotopic mass of 1197 Da was determined with ESI-IT-MS. Furthermore, acid hydrolysis of amylosin followed by analysis of the amino acids with the GS-MS showed that it was a peptide. The presence of a chromophoric polyene group was found using a NMR spectroscopy. The quantification method developed for amylosin based on RP-HPLC-UV, using the macrolactone polyene, amphotericin B (MW 924), as a reference compound. The B. licheniformis strains isolated from a food poisoning case produced a lipopeptide, lichenysin A, that ruptured mammalian cell membranes and was purified with a LC. Lichenysin A was identified by its protonated molecules and sodium- and potassium- cationized molecules with MALDI-TOF-MS. Its protonated forms were observed at m/z 1007, 1021 and 1035. The amino acids of lichenysin A were analyzed with ESI-TQ-MS/MS and, after acid hydrolysis, the stereoisomeric forms of the amino acids with RP-HPLC. The indoor air isolates of the strain of B. amyloliquefaciens produced not only amylosin but also lipopeptides: the cell membrane-damaging surfactin and the fungicidal fengycin. They were identified with ESI-IT-MS observing their protonated molecules, the sodium- and potassium-cationized molecules and analysing the MS/MS spectra. The protonated molecules of surfactin and fengycin showed m/z values of 1009, 1023, and 1037 and 1450, 1463, 1493, and 1506, respectively. Cereulide (MW 1152) was purified with RP-HPLC from a food poisoning strain of B. cereus. Cereulide was identified with ESI-TQ-MS according to the protonated molecule observed at m/z 1154 and the ammonium-, sodium- and potassium-cationized molecules observed at m/z 1171, 1176, and 1192, respectively. The fragment ions of the MS/MS spectrum obtained from the protonated molecule of cereulide at m/z 1154 were also interpreted. We developed a quantification method for cereulide, using RP-HPLC-UV and valinomycin (MW 1110, which structurally resembles cereulide) as the reference compound. Furthermore, we showed empirically, using the BLM method, that the emetic toxin cereulide is a specific and effective potassium ionophore of whose toxicity target is especially the mitochondria.

Contributions to organic synthesis and reaction mechanisms

Development of new methods, leading to the first stereo-specific total synthesis of a steroid,viz equilenin, and of estrone and their derivatives and of several important synthones, useful for the preparation of physiologically active steroids, and the first conversion of an equilenane to estrane have been described. An account of the achievement of original syntheses of testosterone and its isomers and derivatives and degradation products, urinary steroids, terpenes and their important degradation products has been given. Mechanisms of Dieckmann cyclization, a novel dehydrogenation-addition reaction involving abietic acid and tetrachloro-o-benzoquinone, a rearrangement involving a substitution of cyclopentanone-2-carboxylic ester have been elucidated. An abnormaluv absorption exhibited by saturated 1,2-dicyano esters has been rationalized. Divergences in theord data of testosterone and 19-nortesto-sterone from their isomers have been explained by x-ray crystallographic studies of 8-isotestosterone, 8-iso-10-isotestosterone and 8-iso-10-iso-19-nortestosterone. A tentative explanation for the difference in their physiological activities has been suggested.

Debunking Weak Sustainable Consumption : Towards Strong Sustainable Consumption Governance

Achieving sustainable consumption patterns is a crucial step on the way towards sustainability. The scientific knowledge used to decide which priorities to set and how to enforce them has to converge with societal, political, and economic initiatives on various levels: from individual household decision-making to agreements and commitments in global policy processes. The aim of this thesis is to draw a comprehensive and systematic picture of sustainable consumption and to do this it develops the concept of Strong Sustainable Consumption Governance. In this concept, consumption is understood as resource consumption. This includes consumption by industries, public consumption, and household consumption. Next to the availability of resources (including the available sink capacity of the ecosystem) and their use and distribution among the Earth’s population, the thesis also considers their contribution to human well-being. This implies giving specific attention to the levels and patterns of consumption. Methods: The thesis introduces the terminology and various concepts of Sustainable Consumption and of Governance. It briefly elaborates on the methodology of Critical Realism and its potential for analysing Sustainable Consumption. It describes the various methods on which the research is based and sets out the political implications a governance approach towards Strong Sustainable Consumption may have. Two models are developed: one for the assessment of the environmental relevance of consumption activities, another to identify the influences of globalisation on the determinants of consumption opportunities. Results: One of the major challenges for Strong Sustainable Consumption is that it is not in line with the current political mainstream: that is, the belief that economic growth can cure all our problems. So, the proponents have to battle against a strong headwind. Their motivation however is the conviction that there is no alternative. Efforts have to be taken on multiple levels by multiple actors. And all of them are needed as they constitute the individual strings that together make up the rope. However, everyone must ensure that they are pulling in the same direction. It might be useful to apply a carrot and stick strategy to stimulate public debate. The stick in this case is to create a sense of urgency. The carrot would be to articulate better the message to the public that a shrinking of the economy is not as much of a disaster as mainstream economics tends to suggest. In parallel to this it is necessary to demand that governments take responsibility for governance. The dominant strategy is still information provision. But there is ample evidence that hard policies like regulatory instruments and economic instruments are most effective. As for Civil Society Organizations it is recommended that they overcome the habit of promoting Sustainable (in fact green) Consumption by using marketing strategies and instead foster public debate in values and well-being. This includes appreciating the potential of social innovation. A countless number of such initiatives are on the way but their potential is still insufficiently explored. Beyond the question of how to multiply such approaches, it is also necessary to establish political macro structures to foster them.

Mechanisms of the impact of a weed (grader grass, Themeda quadrivalvis) on reptile assemblage structure in a tropical savannah

Invasive grasses are among the worst threats to native biodiversity, but the mechanisms causing negative effects are poorly understood. To investigate the impact of an invasive grass on reptiles, we compared the reptile assemblages that used native kangaroo grass (Themeda triandra), and black spear grass (Heteropogon contortus), to those using habitats invaded by grader grass (Themeda quadrivalvis). There were significantly more reptile species, in greater abundances, in native kangaroo and black spear grass than in invasive grader grass. To understand the sources of negative responses of reptile assemblages to the weed, we compared habitat characteristics, temperatures within grass clumps, food availability and predator abundance among these three grass habitats. Environmental temperatures in grass, invertebrate food availability, and avian predator abundances did not differ among the habitats, and there were fewer reptiles that fed on other reptiles in the invaded than in the native grass sites. Thus, native grass sites did not provide better available thermal environments within the grass, food, or opportunities for predator avoidance. We suggest that habitat structure was the critical factor driving weed avoidance by reptiles in this system, and recommend that the maintenance of heterogeneous habitat structure, including clumping native grasses, with interspersed bare ground, and leaf litter are critical to reptile biodiversity.

Mechanisms of the impact of a weed (grader grass, Themeda quadrivalvis) on reptile assemblage structure in a tropical savannah

Invasive grasses are among the worst threats to native biodiversity, but the mechanisms causing negative effects are poorly understood. To investigate the impact of an invasive grass on reptiles, we compared the reptile assemblages that used native kangaroo grass (Themeda triandra), and black spear grass (Heteropogon contortus), to those using habitats invaded by grader grass (Themeda quadrivalvis). There were significantly more reptile species, in greater abundances, in native kangaroo and black spear grass than in invasive grader grass. To understand the sources of negative responses of reptile assemblages to the weed, we compared habitat characteristics, temperatures within grass clumps, food availability and predator abundance among these three grass habitats. Environmental temperatures in grass, invertebrate food availability, and avian predator abundances did not differ among the habitats, and there were fewer reptiles that fed on other reptiles in the invaded than in the native grass sites. Thus, native grass sites did not provide better available thermal environments within the grass, food, or opportunities for predator avoidance. We suggest that habitat structure was the critical factor driving weed avoidance by reptiles in this system, and recommend that the maintenance of heterogeneous habitat structure, including clumping native grasses, with interspersed bare ground, and leaf litter are critical to reptile biodiversity.

Enterprise technology governance: New information and technology core competencies for boards of directors

Boards of directors have legal and ethical responsibilities to be competent. Yet, in a world where business models and whole sectors are being disrupted by rapid information and technology change, a majority of directors lack IT governance knowledge and skills. Individual IT competency and collective board Enterprise Technology Governance capability is a global problem. Without capability, boards are potentially flying blind, and risk is increased and opportunities to lead and govern digital transformation lost. To address this capability gap, this research provides the first multi-industry validated Enterprise Technology Governance competency set for use in board evaluation, recruitment and professional development.

On reconsideration of IT governance structures to govern cloud computing services

There is an increase in the uptake of cloud computing services (CCS). CCS is adopted in the form of a utility, and it incorporates business risks of the service providers and intermediaries. Thus, the adoption of CCS will change the risk profile of an organization. In this situation, organisations need to develop competencies by reconsidering their IT governance structures to achieve a desired level of IT-business alignment and maintain their risk appetite to source business value from CCS. We use the resource-based theories to suggest that collaborative board oversight of CCS, competencies relating to CCS information and financial management, and a CCS-related continuous audit program can contribute to business process performance improvements and overall firm performance. Using survey data, we find evidence of a positive association between these IT governance considerations and business process performance. We also find evidence of positive association between business process performance improvements and overall firm performance. The results suggest that the suggested considerations on IT governance structures can contribute to CCS-related IT-business alignment and lead to anticipated business value from CCS. This study provides guidance to organizations on competencies required to secure business value from CCS.

Governing cloud computing services: Reconsideration of IT governance structures

There is an increase in the uptake of cloud computing services (CCS). CCS is adopted in the form of a utility, and it incorporates business risks of the service providers and intermediaries. Thus, the adoption of CCS will change the risk profile of an organization. In this situation, organizations need to develop competencies by reconsidering their IT governance structures to achieve a desired level of IT-business alignment and maintain their risk appetite to source business value from CCS. We use the resource-based theories to suggest that collaborative board oversight of CCS, competencies relating to CCS information and financial management, and a CCS-related continuous audit program can contribute to business process performance improvements and overall firm performance. Using survey data, we find evidence of a positive association between these IT governance considerations and business process performance. We also find evidence of positive association between business process performance improvements and overall firm performance. The results suggest that the suggested considerations on IT governance structures can contribute to CCS-related IT-business alignment and lead to anticipated business value from CCS. This study provides guidance to organizations on competencies required to secure business value from CCS.

EU Multi-level Governance in the Making - The Community Initiative LEADER+ in Finland and Germany

In order to fully understand the process of European integration it is of paramount importance to consider developments at the sub-national and local level. EU integration scholars shifted their attention to the local level only at the beginning of the 1990s with the concept of multi-level governance (MLG). While MLG is the first concept to scrutinise the position of local levels of public administration and other actors within the EU polity, I perceive it as too optimistic in the degree of influence it ascribes to local levels. Thus, learning from and combining MLG with other concepts, such as structural constructivism, helps to reveal some of the hidden aspects of EU integration and paint a more realistic picture of multi-level interaction. This thesis also answers the call for more case studies in order to conceptualise MLG further. After a critical study of theories and concepts of European integration, above all, MLG, I will analyse sub-national and local government in Finland and Germany. I show how the sub-national level and local governments are embedded in the EU s multi-level structure of governance and how, through EU integration, those levels have been empowered but also how their scope of action has partially decreased. After theoretical and institutional contextualisation, I present the results of my empirical study of the EU s Community Initiative LEADER+. LEADER stands for Liaison Entre Actions de Développement de l'Économie Rurale , and aims at improving the economic conditions in Europe s rural areas. I was interested in how different actors construct and shape EU financed rural development, especially in how local actors organised in so-called local action groups (LAGs) cooperate with other administrative units within the LEADER+ administrative chain. I also examined intra-institutional relations within those groups, in order to find out who are the most influential and powerful actors within them. Empirical data on the Finnish and German LAGs was first gathered through a survey, which was then supplemented and completed by interviewing LAG members, LAG-managers, several civil servants from Finnish and German decision-making and managing authorities and a civil servant from the EU Commission. My main argument is that in both Germany and Finland, the Community Initiative LEADER+ offered a space for multi-level interaction and local-level involvement, a space that on the one hand consists of highly motivated people actively contributing to the improvement of the quality of life and economy in Europe s countryside but which is dependent and also restricted by national administrative practices, implementation approaches and cultures on the other. In Finland, the principle of tri-partition (kolmikantaperiaatte) in organising the executive committees of LAGs is very noticeable. In comparison to Germany, for instance, the representation of public administration in those committees is much more limited due to this principle. Furthermore, the mobilisation of local residents and the bringing together of actors from the local area with different social and institutional backgrounds to become an active part of LEADER+ was more successful in Finland than in Germany. Tri-partition as applied in Finland should serve as a model for similar policies in other EU member states. EU integration changed the formal and informal inter-institutional relations linking the different levels of government. The third sector including non-governmental institutions and interest groups gained access to policy-making processes and increasingly interact with government institutions at all levels of public administration. These developments do not necessarily result in the empowering of the local level.

An Optimal Mechanism for Sponsored Search Auctions on the Web and Comparison With Other Mechanisms

In this paper, we first describe a framework to model the sponsored search auction on the web as a mechanism design problem. Using this framework, we describe two well-known mechanisms for sponsored search auction-Generalized Second Price (GSP) and Vickrey-Clarke-Groves (VCG). We then derive a new mechanism for sponsored search auction which we call optimal (OPT) mechanism. The OPT mechanism maximizes the search engine's expected revenue, while achieving Bayesian incentive compatibility and individual rationality of the advertisers. We then undertake a detailed comparative study of the mechanisms GSP, VCG, and OPT. We compute and compare the expected revenue earned by the search engine under the three mechanisms when the advertisers are symmetric and some special conditions are satisfied. We also compare the three mechanisms in terms of incentive compatibility, individual rationality, and computational complexity. Note to Practitioners-The advertiser-supported web site is one of the successful business models in the emerging web landscape. When an Internet user enters a keyword (i.e., a search phrase) into a search engine, the user gets back a page with results, containing the links most relevant to the query and also sponsored links, (also called paid advertisement links). When a sponsored link is clicked, the user is directed to the corresponding advertiser's web page. The advertiser pays the search engine in some appropriate manner for sending the user to its web page. Against every search performed by any user on any keyword, the search engine faces the problem of matching a set of advertisers to the sponsored slots. In addition, the search engine also needs to decide on a price to be charged to each advertiser. Due to increasing demands for Internet advertising space, most search engines currently use auction mechanisms for this purpose. These are called sponsored search auctions. A significant percentage of the revenue of Internet giants such as Google, Yahoo!, MSN, etc., comes from sponsored search auctions. In this paper, we study two auction mechanisms, GSP and VCG, which are quite popular in the sponsored auction context, and pursue the objective of designing a mechanism that is superior to these two mechanisms. In particular, we propose a new mechanism which we call the OPT mechanism. This mechanism maximizes the search engine's expected revenue subject to achieving Bayesian incentive compatibility and individual rationality. Bayesian incentive compatibility guarantees that it is optimal for each advertiser to bid his/her true value provided that all other agents also bid their respective true values. Individual rationality ensures that the agents participate voluntarily in the auction since they are assured of gaining a non-negative payoff by doing so.

Reinventing Nordic Openness : Transparency and State Information in Finland

The study explores new ideational changes in the information strategy of the Finnish state between 1998 and 2007, after a juncture in Finnish governing in the early 1990s. The study scrutinizes the economic reframing of institutional openness in Finland that comes with significant and often unintended institutional consequences of transparency. Most notably, the constitutional principle of publicity (julkisuusperiaate), a Nordic institutional peculiarity allowing public access to state information, is now becoming an instrument of economic performance and accountability through results. Finland has a long institutional history in the publicity of government information, acknowledged by law since 1951. Nevertheless, access to government information became a policy concern in the mid-1990s, involving a historical narrative of openness as a Nordic tradition of Finnish governing Nordic openness (pohjoismainen avoimuus). International interest in transparency of governance has also marked an opening for institutional re-descriptions in Nordic context. The essential added value, or contradictory term, that transparency has on the Finnish conceptualisation of governing is the innovation that public acts of governing can be economically efficient. This is most apparent in the new attempts at providing standardised information on government and expressing it in numbers. In Finland, the publicity of government information has been a concept of democratic connotations, but new internationally diffusing ideas of performance and national economic competitiveness are discussed under the notion of transparency and its peer concepts openness and public (sector) information, which are also newcomers to Finnish vocabulary of governing. The above concepts often conflict with one another, paving the way to unintended consequences for the reforms conducted in their name. Moreover, the study argues that the policy concerns over openness and public sector information are linked to the new drive for transparency. Drawing on theories of new institutionalism, political economy, and conceptual history, the study argues for a reinvention of Nordic openness in two senses. First, in referring to institutional history, the policy discourse of Nordic openness discovers an administrative tradition in response to new dilemmas of public governance. Moreover, this normatively appealing discourse also legitimizes the new ideational changes. Second, a former mechanism of democratic accountability is being reframed with market and performance ideas, mostly originating from the sphere of transnational governance and governance indices. Mobilizing different research techniques and data (public documents of the Finnish government and international organizations, some 30 interviews of Finnish civil servants, and statistical time series), the study asks how the above ideational changes have been possible, pointing to the importance of nationalistically appealing historical narratives and normative concepts of governing. Concerning institutional developments, the study analyses the ideational changes in central steering mechanisms (political, normative and financial steering) and the introduction of budget transparency and performance management in two cases: census data (Population Register Centre) and foreign political information (Ministry for Foreign Affairs). The new policy domain of governance indices is also explored as a type of transparency. The study further asks what institutional transformations are to be observed in the above cases and in the accountability system. The study concludes that while the information rights of citizens have been reinforced and recalibrated during the period under scrutiny, there has also been a conversion of institutional practices towards economic performance. As the discourse of Nordic openness has been rather unquestioned, the new internationally circulating ideas of transparency and the knowledge economy have entered this discourse without public notice. Since the mid 1990s, state registry data has been perceived as an exploitable economic resource in Finland and in the EU public sector information. This is a parallel development to the new drive for budget transparency in organisations as vital to the state as the Population Register Centre, which has led to marketization of census data in Finland, an international exceptionality. In the Finnish Ministry for Foreign Affairs, the post-Cold War rhetorical shift from secrecy to performance-driven openness marked a conversion in institutional practices that now see information services with high regards. But this has not necessarily led to the increased publicity of foreign political information. In this context, openness is also defined as sharing information with select actors, as a trust based non-public activity, deemed necessary amid the global economic competition. Regarding accountability system, deliberation and performance now overlap, making it increasingly difficult to identify to whom and for what the public administration is accountable. These evolving institutional practices are characterised by unintended consequences and paradoxes. History is a paradoxical component in the above institutional change, as long-term institutional developments now justify short-term reforms.

Endoplasmic reticulum stress and cell death mechanisms in the cell model of Huntington’s disease

This thesis clarifies important molecular pathways that are activated during the cell death observed in Huntington’s disease. Huntington’s disease is one of the most common inherited neurodegenerative diseases, which is primarily inherited in an autosomal dominant manner. HD is caused by an expansion of CAG repeats in the first exon of the IT15 gene. IT15 encodes the production of a Huntington’s disease protein huntingtin. Mutation of the IT15 gene results in a long stretch of polyQ residues close to the amino-terminal region of huntingtin. Huntington’s disease is a fatal autosomal neurodegenerative disorder. Despite the current knowledge of HD, the precise mechanism behind the selective neuronal death, and how the disease propagates, still remains an enigma. The studies mainly focused on the control of endoplasmic reticulum (ER) stress triggered by the mutant huntingtin proteins. The ER is a delicate organelle having essential roles in protein folding and calcium regulation. Even the slightest perturbations on ER homeostasis are effective enough to trigger ER stress and its adaptation pathways, called unfolded protein response (UPR). UPR is essential for cellular homeostasis and it adapts ER to the changing environment and decreases ER stress. If adaptation processes fail and stress is excessive and prolonged; irreversible cell death pathways are engaged. The results showed that inhibition of ER stress with chemical agents are able to decrease cell death and formation of toxic cell aggregates caused by mutant huntingtin proteins. The study concentrated also to the NF-κB (nuclear factor-kappaB) pathway, which is activated during ER stress. NF-κB pathway is capable to regulate the levels of important cellular antioxidants. Cellular antioxidants provide a first line of defence against excess reactive oxygen species. Excess accumulation of reactive oxygen species and subsequent activation of oxidative stress damages motley of vital cellular processes and induce cell degeneration. Data showed that mutant huntingtin proteins downregulate the expression levels of NF-κB and vital antioxidants, which was followed by increased oxidative stress and cell death. Treatment with antioxidants and inhibition of oxidative stress were able to counteract these adverse effects. In addition, thesis connects ER stress caused by mutant huntingtin to the cytoprotective autophagy. Autophagy sustains cellular balance by degrading potentially toxic cell proteins and components observed in Huntington’s disease. The results revealed that cytoprotective autophagy is active at the early points (24h) of ER stress after expression of mutant huntingtin proteins. GADD34 (growth arrest and DNA damage-inducible gene 34), which is previously connected to the regulation of translation during cell stress, was shown to control the stimulation of autophagy. However, GADD34 and autophagy were downregulated at later time points (48h) during mutant huntingtin proteins induced ER stress, and subsequently cell survival decreased. Overexpression GADD34 enhanced autophagy and decreased cell death, indicating that GADD34 plays a critical role in cell protection. The thesis reveales new interesting data about the neuronal cell death pathways seen in Huntington’s disease, and how cell degeneration is partly counteracted by various therapeutic agents. Expression of mutant huntingtin proteins is shown to alter signaling events that control ER stress, oxidative stress and autophagy. Despite that Huntington’s disease is mainly an untreatable disorder; these findings offer potential targets and neuroprotective strategies in designing novel therapies for Huntington’s disease.