Direct Interrogation of Viral Peptides Presented by the Class I HLA of HIV-Infected T Cells

Identification of CD8+ cytotoxic T lymphocyte (CTL) epitopes has traditionally relied upon testing of overlapping peptide libraries for their reactivity with T cells in vitro. Here, we pursued deep ligand sequencing (DLS) as an alternative method of directly identifying those ligands that are epitopes presented to CTLs by the class I human leukocyte antigens (HLA) of infected cells. Soluble class I HLA-A*11:01 (sHLA) was gathered from HIV-1 NL4-3-infected human CD4+ SUP-T1 cells. HLA-A*11:01 harvested from infected cells was immunoaffinity purified and acid boiled to release heavy and light chains from peptide ligands that were then recovered by size-exclusion filtration. The ligands were first fractionated by high-pH high-pressure liquid chromatography and then subjected to separation by nano-liquid chromatography (nano-LC)–mass spectrometry (MS) at low pH. Approximately 10 million ions were selected for sequencing by tandem mass spectrometry (MS/MS). HLA-A*11:01 ligand sequences were determined with PEAKS software and confirmed by comparison to spectra generated from synthetic peptides. DLS identified 42 viral ligands presented by HLA-A*11:01, and 37 of these were previously undetected. These data demonstrate that (i) HIV-1 Gag and Nef are extensively sampled, (ii) ligand length variants are prevalent, particularly within Gag and Nef hot spots where ligand sequences overlap, (iii) noncanonical ligands are T cell reactive, and (iv) HIV-1 ligands are derived from de novo synthesis rather than endocytic sampling. Next-generation immunotherapies must factor these nascent HIV-1 ligand length variants and the finding that CTL-reactive epitopes may be absent during infection of CD4+ T cells into strategies designed to enhance T cell immunity.

SMRT-mediated co-shuttling enables export of class IIa HDACs independent of their CaM kinase phosphorylation sites

The Class IIa histone deacetylases (HDAC)4 and HDAC5 play a role in neuronal survival and behavioral adaptation in the CNS. Phosphorylation at 2/3 N-terminal sites promote their nuclear export. We investigated whether non-canonical signaling routes to Class IIa HDAC export exist because of their association with the co-repressor Silencing Mediator Of Retinoic And Thyroid Hormone Receptors (SMRT). We found that, while HDAC5 and HDAC4 mutants lacking their N-terminal phosphorylation sites (HDAC4(MUT), HDAC5(MUT)) are constitutively nuclear, co-expression with SMRT renders them exportable by signals that trigger SMRT export, such as synaptic activity, HDAC inhibition, and Brain Derived Neurotrophic Factor (BDNF) signaling. We found that SMRT's repression domain 3 (RD3) is critical for co-shuttling of HDAC5(MUT), consistent with the role for this domain in Class IIa HDAC association. In the context of BDNF signaling, we found that HDAC5(WT), which was more cytoplasmic than HDAC5(MUT), accumulated in the nucleus after BDNF treatment. However, co-expression of SMRT blocked BDNF-induced HDAC5(WT) import in a RD3-dependent manner. In effect, SMRT-mediated HDAC5(WT) export was opposing the BDNF-induced HDAC5 nuclear accumulation observed in SMRT's absence. Thus, SMRT's presence may render Class IIa HDACs exportable by a wider range of signals than those which simply

Semantic domain and grammatical class effects in the picture-word interference paradigm

The role of grammatical class in lexical access and representation is still not well understood. Grammatical effects obtained in picture-word interference experiments have been argued to show the operation of grammatical constraints during lexicalization when syntactic integration is required by the task. Alternative views hold that the ostensibly grammatical effects actually derive from the coincidence of semantic and grammatical differences between lexical candidates. We present three picture-word interference experiments conducted in Spanish. In the first two, the semantic relatedness (related or unrelated) and the grammatical class (nouns or verbs) of the target and the distracter were manipulated in an infinitive form action naming task in order to disentangle their contributions to verb lexical access. In the third experiment, a possible confound between grammatical class and semantic domain (objects or actions) was eliminated by using action-nouns as distracters. A condition in which participants were asked to name the action pictures using an inflected form of the verb was also included to explore whether the need of syntactic integration modulated the appearance of grammatical effects. Whereas action-words (nouns or verbs), but not object-nouns, produced longer reaction times irrespective of their grammatical class in the infinitive condition, only verbs slowed latencies in the inflected form condition. Our results suggest that speech production relies on the exclusion of candidate responses that do not fulfil task-pertinent criteria like membership in the appropriate semantic domain or grammatical class. Taken together, these findings are explained by a response-exclusion account of speech output. This and alternative hypotheses are discussed.

Synthesis of angiotensin-converting enzyme (ACE) inhibitors: an important class of antihypertensive drugs

This report outlines the discovery, the design and development of new compounds, and, structure-activity relationships for this drug category. Updated approaches to planned syntheses of new worthy ACE-inhibitors are also exploited.

Celebrating Creative Consciousness: Insights Into Oscar Wilde’s Aesthetics

Tutkielmani valottaa irlantilaisen kirjailijan Oscar Wilden (1854-1900) vähemmän tunnettua työtä ja ajattelua taidekriitikkona fin de sièclen ja modernismin välisen siirtymävaiheen estetiikassa. Wilden voidaan sanoa olleen edellä aikaansa estetiikkakäsityksensä suhteen: Hän käsittelee taidekritiikissään teemoja, jotka tulivat keskeisiksi modernismin ja postmodernismin myötä – esimerkiksi kielen pettävyyttä, sellaisten käsitteiden kuin ’todellisuus’, ’luonto’ tai ’yhteiskunta’ sattumanvaraisuutta sekä yhteisön ja yksilön identiteettien fragmentoitumista. Wilde myös kyseenalaistaa – paradoksien, kielellisten nokkeluuksien ja ironian avulla – monia länsimaisessa filosofiassa ’normatiivisina’ pidettyjä arvoja, kuten totuuteen pyrkimisen. Lisäksi hän haastaa taiteenkritiikin akateemisen tradition hylkäämällä sellaiset sen hyveinä pitämät piirteet kuin johdonmukaisuus ja ristiriidattomuus. Tarkastelen Wilden estetiikkakäsitystä pääasiassa esseekokoelman Intentions (1891), etenkin esseen Valehtelun rappio, sekä De Profundis –teoksen (1905) kautta. Tekstejä analysoimalla ja vertaamalla osoitan miten 1890-luvun alkupuolen ja vankilatuomiotaan istuvan Wilden estetiikkakäsitys muuttui ja kehittyi. Wilden kohdalla on syytä puhua taidefilosofiasta taiteenteorian sijaan. Hänen kriittiset esseensä eivät tähtää ’harmonisen’ kokonaisuuden luomiseen tai pragmaattis-loogisen mallin rakentamiseen taiteen ymmärtämiseksi vaan tulvivat ironiaa ja ristiriitaisuuksia. Wildella taideteoksen tarkasteluun liittyy aina eettisiä, ontologisia ja metafyysisiä kysymyksiä, jotka syventävät mutta myös monimutkaistavat esteettistä kokemusta. Keskeinen teema Wildelle onkin taiteen ja elämän vastakkainasettelu sekä niiden välisen yhteyden tunnistaminen ja tunnustaminen: taide on sekä autonomista että subjektiivista. Tämä paradoksi kulminoituu esteettisessä kokemuksessa. Wildelle luomistyö ja vastaanottajan elämys ovat tiedostamattomia prosesseja – tietoista luovuutta ei ole. Esteettinen kuitenkin voidaan yhdistää tietoisuuteen, mutta se edellyttää että myös tietoisuuden on oltava luovaa. Siksipä lähestyäkseen taidetta kritiikin on tultava enemmän taiteen kaltaiseksi – epänormatiiviseksi ja epäloogiseksi. Tässä prosessissa paradokseilla on merkittävä tehtävä: ne muistuttavat siitä, että puhuttaessa taiteesta ei ole oikeita vastauksia, on vain hyviä kysymyksiä.

Synthesis, characterization, and biological activity of a new class of dialkylphosphorylhydrazone derivatives of isatin

Sixteen dialkylphosphorylhydrazones were synthesized by condensation of phosphorylhydrazines with substituted isatins. Products were characterized by FTIR, ¹H-NMR, 13C-NMR, and 31P-NMR. Fungicidal activities of these compounds against Rhizoctonia solani and Fusarium oxysporum were also evaluated. Some compounds inhibited the growth of Rhizoctonia solani and Fusarium oxysporum by 43% and 51%, respectively. These compounds exhibited no effects on germination of lettuce seeds (Lactuca sativa L).

Customer consciousness in the production process of a steel factory

The purpose of this thesis is to examine the level of customer consciousness of the production process employees in a steel factory and to investigate the methods of internal marketing in order to propose development practices to enhance the customer consciousness of the case company employees. The significance of the level of customer consciousness is discussed and practices already implemented affecting the level of customer consciousness in the company are examined. The literature review gives an insight to the role of customer consciousness in the CRM philosophy of a manufacturing company and examines the means of internal marketing in enhancing customer consciousness. In the empirical part of the study, the level and significance of customer consciousness is determined by conducting individual and focus group interviews. The interviews are also used to examine the practices that could function in enhancing the customer consciousness of the employees. Development suggestions to improve the level of customer consciousness in the production process are given based on the results. The level of customer consciousness is at a poor level in the production process and influences above all on work motivation and job satisfaction, but possibly on customer satisfaction as well. The enhancement of customer consciousness in the production process should be done e.g. by ensuring the distribution of right knowledge coherently to all of the employees, gathering large customer reference database to exploit in work and in training, using visual illustration in presenting the customer information, training proactively and letting the employees to participate in the customer oriented development activities. Customer satisfaction focused reward system can be considered.

Book review of Consciousness by Christopher Hill

Christopher S. Hill advances a theory of conscious experience that employs the idea of representation to unify and explain a wide range of subjective phenomena, including emotions and pain. The theory shows the relevance of philosophical thought in a multidisciplinary view of the mind.

Clinical evaluation of enalapril maleate and furosemide usage in dogs with degenerative myxomatous mitral valve, CHF functional class Ib

Degenerative myxomatous mitral valve (DMMV) is a heart disease of high incidence in small animal clinical medicine, affecting mainly older dogs and small breeds. Thus, a scientific investigation was performed in order to evaluate the clinical use of the medicines furosemide and enalapril maleate in dogs with this disease in CHF functional class Ib before and after the treatment was established. For this purpose 16 dogs with the given valve disease were used, separated into two groups: the first received furosemide (n=8) and the second received enalapril maleate (n=8) throughout 56 days. The dogs were evaluated in four stages (T0, T14, T28 and T56 day) in relation to clinical signs, hematological, biochemical and serum assessment, which included serum angiotensin converting enzyme (ACE) and aldosterone, as well as radiography, electrocardiography, Doppler-echocardiography and blood pressure. The results regarding the clinical, hematological and serum chemistry evaluations revealed no significant changes in both groups, but significant reductions in the values of ACE and aldosterone in the group receiving enalapril maleate were verified. The radiographic examination revealed reductions of VHS values and variable Pms wave of the electrocardiogram in both groups, but no changes in blood pressure values were identified. The echocardiogram showed a significant decrease of the variables LVDd/s in the studied groups and the FS% in animals that received only enalapril. Therefore, analysis of results showed that monotherapy based on enalapril maleate showed better efficiency of symptoms control in patients with CHF functional class Ib.

Sivistyksestä sivilisaatioon. Kulttuurikäsitys J. V. Snellmanin historiallisessa ajattelussa

From Bildung to Civilisation. Conception of Culture in J. V. Snellman’s Historical Thinking The research explores Johan Vilhelm Snellman’s (1806–1881) conception of culture in the context of his historical thinking. Snellman was a Finnish, Swedish-speaking journalist, teacher and thinker, who held a central position in the Finnish national discourse during the nineteenth century. He has been considered as one of the leading theorists of a Finnish nation, writing widely about the themes such as the advancement of the national education, Finnish language and culture. Snellman is already a widely studied person in Finnish intellectual history, often characterised as a follower of G. W. F. Hegel’s philosophical system. My own research introduces a new kind of approach on Snellman’s texts, emphasising the conceptual level of his thought. With this approach, my aim is to broaden the Finnish research tradition on conceptual history. I consider my study as a cultural history of concepts, belonging also to the field of intellectual history. My focus is on one hand on the close reading of Snellman’s texts and on the other hand on contextualising his texts to the European intellectual tradition of the time. A key concept of Snellman’s theoretical thinking is his concept of bildning, which can be considered as a Swedish counterpart of the German concept of Bildung. The Swedish word incorporated all the main elements of the German concept. It could mean education or the so-called high culture, but most fundamentally it was about the self-formation of the individual. This is also the context in which Snellman’s concept of bildning has often been interpreted. In the study, I use the concept of bildning as a starting point of my research but I broaden my focus on the cognate concepts such as culture (kultur), spirit (anda) and civilisation. The purpose of my study is thus to illustrate how Snellman used and modified these concepts and from these observations to draw a conclusion about the nature of his conception of culture. Snellman was an early Finnish philosopher of history but also interested in the practice of the writing of history. He did not write any historical presentations himself but followed the publications in the field of history and introduced European historical writing to the Finnish, Swedish-speaking reading audience in his newspapers. The primary source material consists of different types of Snellman’s texts, including philosophical writings, lecture material, newspaper articles and private letters. I’m reading Snellman’s texts in the context of other texts produced both by his Finnish predecessors and contemporaries and by Swedish, German and French writers. Snellman’s principal philosophical works, Versuch einer spekulativen Entwicklung der Idee der Persönlichkeit (1841) and Läran om staten (1842), were both written abroad. Both of the works were contributions to contemporary debates on the international level, especially in Germany and Sweden. During the 1840s and 1850s Snellman had two newspapers of his own, Saima and Litteraturblad, which were directed towards the Swedish-speaking educated class. Both of the newspapers were very popular and their circulations were among the largest of their day in Finland. The topics of his articles and reviews covered literature, poetry, philosophy and education as well as issues concerning the economic, industrial and technical development in Finland. In his newspapers Snellman not only brought forth his own ideas but also spread the knowledge of European events and ideas to his readers. He followed very carefully the cultural and political situation in Western Europe. He also followed European magazines and newspapers and was well acquainted with German, French and also English literature – and of course Swedish literature to with which he had the closest ties. In his newspapers Snellman wrote countless number of literary reviews and critics, introducing his readers to European literature. The study consists of three main chapters in which I explore my research question in three different, yet overlapping contexts. In the first of these chapters, I analyse Snellman’n theoretical thinking and his concepts of bildning, kultur, anda and civilisation in the context of earlier cultural discourse in Finland as well as the tradition of German idealistic philosophy and neo-humanism. With the Finnish cultural discourse I refer to the early cultural discussion in Finland, which emerged after the year 1809, when Finland became an autonomous entity of its own as a Grand Duchy of Russia. Scholars of the Academy of Turku opened a discussion on the themes such as the state of national consciousness, the need for national education and the development of the Finnish language as a national language of Finland. Many of these academics were also Snellman’s teachers in the early years of his academic career and Snellman clearly formulated his own ideas in the footsteps of these Finnish predecessors. In his theoretical thinking Snellman was a collectivist; according to him an individual should always be understood in connection with the society, its values and manners, as well as to the traditions of a culture where an individual belongs to. In his philosophy of the human spirit Snellman was in many ways a Hegelian but his notion of education or ‘bildning’ includes also elements that connect him with the wider tradition of German intellectual history, namely the neo-humanist tradition and, at least to some extent, to the terminology of J. G. Herder or J. G. Fichte, for example. In this chapter, I also explore Snellman’s theory of history. In his historical thinking Snellman was an idealist, believing in the historical development of the human spirit (Geist in German language). One can characterise his theory of history by stating that it is a mixture of a Hegelian triumph of the spirit and Herderian emphasis on humanity (Humanität) and the relative nature of ‘Bildung’. For Snellman, the process of ‘bildning’ or ‘Bildung’ is being realised in historical development through the actions of human beings. Snellman believed in the historical development of the human civilization. Still Snellman himself considered that he had abandoned Hegel’s idea about the process of world history. Snellman – rightly or wrongly – criticised Hegel of emphasising the universal end of history (the realisation of the freedom of spirit) at the expense of the historical plurality and the freedom of each historical era. Snellman accused Hegel of neglecting the value and independency of different historical cultures and periods by imposing the abstract norm, the fulfilment of the freedom of spirit, as the ultimate goal of history. The historicist in Snellman believed in the individuality of each historical period; each historical era or culture had values, traditions and modes of thought of its own. This historicist in Snellman could not accept the talk about one measure or the end of history. On the other hand Snellman was also a universalist. He believed that mankind had a common task and that task was the development of ‘Bildung’, freedom or humanity. The second main chapter consists of two parts. In the first part, I explore the Finnish nationalistic discourse from the cultural point of view by analysing the notions such as a nation, national spirit or national language and showing how Snellman formulated his own ideas in a dialogic situation, participating in the Finnish discourse but also reacting to international discussions on the themes of the nation and nationality. For Snellman nationality was to a great extent the collective knowledge and customs or practices of the nation. Snellman stated that nationality is to be considered as a form of ‘bildning’. This could be seen not simply as affection for the fatherland but also for the mental identity of the nation, its ways of thinking, its practices, national language, customs and laws, the history of the nation. The simplest definition of nationality that Snellman gives is that nationality is the social life of the people. In the second part of the chapter I exam Snellman’s historical thinking and his understanding about historical development, interaction between different nations and cultures in the course of history, as well as the question of historical change; how do cultures or civilisations develop and who are the creators of culture? Snellman did not believe in one dominating culture but understood the course of history as a dialogue between different cultures. On the other hand, his views are very Eurocentric – here he follows the ideas of Hegel or for example the French historian François Guizot – for Snellman Europe represented the virtue of pluralism; in Europe one could see the diversity of cultures which, on the other hand, were fundamentally based on a common Christian tradition. In the third main chapter, my focus is on the writing of history, more precisely on Snellman’s ideas on the nature of history as a science and on the proper way of writing historical presentations. Snellman wrote critics on the works of history and introduced his readers to the writing of history especially in France, Sweden and German-speaking area – in some extend also in Britain. Snellman’s collectivistic view becomes evident also in his reviews on historical writing. For Snellman history was not about the actions of the states and their heads, nor about the records of ruling families and battles fought. He repeatedly stressed that history is a discipline that seeks to provide a total view of a phenomenon. A historian should not only collect information on historical events, since this information touches only the surface of a certain epoch or civilisation; he has to understand an epoch as totality. This required an understanding about the major contours in history, connections between civilisations and an awareness of significant turning points in historical development. In addition, it required a holistic understanding about a certain culture or historical era, including also the so-called inner life of a specific nation, a common people and their ways of life. Snellman wrote explicitly about ‘cultural history’ in his texts, referring to this kind of broad understanding of a society. In historical writing Snellman found this kind of broader view from the works of the French historians such as François Guizot and Jules Michelet. In all of these chapters, I elaborate the conceptual dimension of Snellman’s historical thinking. In my study I argue that Snellman not only adopted the German concepts of Bildung or Kultur in his own thinking but also developed the Swedish concepts in a way that include personal and innovative aspects. Snellman’s concept of bildning is not only a translation from ‘Bildung’ but he uses the Swedish concept in a versatile way that includes both the moral aspect of human development and social dimension of a human life. Along with ‘bildning’ Snellman used also the terms ‘kultur’ and ‘civilisation’ when referring to the totality of a certain nation or historical era, including both the so-called high culture (arts, science, religion) and the modes of thought as well as ways of life of the people as a whole. Unlike many of his Finnish contemporaries, Snellman did not use civilisation as a negative concept, lacking the moral essence of German term ‘Bildung’ or ‘Kultur’. Instead, for Snellman civilisation was a neutral term and here he comes close to the French tradition of using the term. In the study I argue that Snellman’s conception of culture in fact includes a synthesis of the German tradition of ‘Bildung’ and the French tradition of ‘civilisation’.

The Effects of Anesthetic Induced Loss of Consciousness on Quantitative Electroen Cephalogram, and Bispectral and Spectral Entropy Indices. Studies on Healthy Male

Changes in the electroencephalography (EEG) signal have been used to study the effects of anesthetic agents on the brain function. Several commercial EEG based anesthesia depth monitors have been developed to measure the level of the hypnotic component of anesthesia. Specific anesthetic related changes can be seen in the EEG, but still it remains difficult to determine whether the subject is consciousness or not during anesthesia. EEG reactivity to external stimuli may be seen in unconsciousness subjects, in anesthesia or even in coma. Changes in regional cerebral blood flow, which can be measured with positron emission tomography (PET), can be used as a surrogate for changes in neuronal activity. The aim of this study was to investigate the effects of dexmedetomidine, propofol, sevoflurane and xenon on the EEG and the behavior of two commercial anesthesia depth monitors, Bispectral Index (BIS) and Entropy. Slowly escalating drug concentrations were used with dexmedetomidine, propofol and sevoflurane. EEG reactivity at clinically determined similar level of consciousness was studied and the performance of BIS and Entropy in differentiating consciousness form unconsciousness was evaluated. Changes in brain activity during emergence from dexmedetomidine and propofol induced unconsciousness were studied using PET imaging. Additionally, the effects of normobaric hyperoxia, induced during denitrogenation prior to xenon anesthesia induction, on the EEG were studied. Dexmedetomidine and propofol caused increases in the low frequency, high amplitude (delta 0.5-4 Hz and theta 4.1-8 Hz) EEG activity during stepwise increased drug concentrations from the awake state to unconsciousness. With sevoflurane, an increase in delta activity was also seen, and an increase in alpha- slow beta (8.1-15 Hz) band power was seen in both propofol and sevoflurane. EEG reactivity to a verbal command in the unconsciousness state was best retained with propofol, and almost disappeared with sevoflurane. The ability of BIS and Entropy to differentiate consciousness from unconsciousness was poor. At the emergence from dexmedetomidine and propofol induced unconsciousness, activation was detected in deep brain structures, but not within the cortex. In xenon anesthesia, EEG band powers increased in delta, theta and alpha (8-12Hz) frequencies. In steady state xenon anesthesia, BIS and Entropy indices were low and these monitors seemed to work well in xenon anesthesia. Normobaric hyperoxia alone did not cause changes in the EEG. All of these results are based on studies in healthy volunteers and their application to clinical practice should be considered carefully.

Local Features in Image and Video Processing - Object Class Matching and Video Shot Detection

The usage of digital content, such as video clips and images, has increased dramatically during the last decade. Local image features have been applied increasingly in various image and video retrieval applications. This thesis evaluates local features and applies them to image and video processing tasks. The results of the study show that 1) the performance of different local feature detector and descriptor methods vary significantly in object class matching, 2) local features can be applied in image alignment with superior results against the state-of-the-art, 3) the local feature based shot boundary detection method produces promising results, and 4) the local feature based hierarchical video summarization method shows promising new new research direction. In conclusion, this thesis presents the local features as a powerful tool in many applications and the imminent future work should concentrate on improving the quality of the local features.

The improvement of enclosure protection class of power electronics device

Tässä diplomityössä tutkittiin vaihtoehtoja tehoelektroniikkalaitteiden kotelointiluokan kehittämiseksi. Haasteena paremman suojauksen suunnittelussa on laitteiden tuottama suuri määrä lämpöä, joka vaatii tehokkaan jäähdytyksen. Työn tuloksena saatu prototyyppi IP33 luokkaa varten täyttää standardissa SFS-EN 60529+A1 asetetut vaatimukset kyseiselle kotelointiluokalle. Rakenteessa ja valmistettavuudessa havaittiin muutama ongelma, jotka ovat korjattavissa pienillä muutoksilla. Korkeampia suojausluokkia varten testattiin IP54-luokiteltujen filtterituulettimien vaikutusta laitteen jäähdytykseen. Testien perusteella jäähdytysteho on riittävä ja filtterituulettimet todettiin toimivaksi ratkaisuksi korkeammille suojausluokille. Työn perusteella voidaan todeta, että nykyiset laitteet voidaan muokata vastaamaan IP33 luokan vaatimuksia kohtuullisen pienillä muutoksilla. Tätä korkeammat suojausluokat vaatisivat niin suuria muutoksia designiin, että todennäköisesti täysin uuden laitteen suunnittelu olis kannattavin vaihtoehto.