Targeting Adenoviral Gene Therapy Vectors to Head and Neck Squamous Cell Carcinoma and Heart

Gene therapy aims to treat diseases by introducing genetic material to the diseased tissue. For cancer treatment it is important to destroy cancerous cells; this can be achieved by introducing a gene, which induces cell death or by allowing viral vectors to replicate, which also results in destruction of cancerous cells. For cardiac diseases the approach is more like the former, except the gene produces beneficial effects, like angiogenesis. Adenoviruses have many beneficial qualities, which make the virus an interesting gene therapy vector; it can be produced relatively easily, its manipulation is quite easy and it has naturally broad tropism. By removing or replacing certain genes in the adenoviral genome, it can be made non-replicative. In this study, adenoviral receptor expression patterns were characterized in both head and neck squamous cell carcinoma and the human heart. Adenovirus serotype 5 receptor expression in head and neck cancer cell lines was found to be highly variable between cell lines and overall at lower levels, while Ad35 receptor expression was more uniform and at higher levels in all analyzed cell lines. It was also shown that a hybrid virus Ad5/35 is able to infect cells refractory to Ad5, which correlates with receptor expression in these cells. Furthermore, this difference in infection properties extends to cell killing efficiency in case of conditionally replicative viruses. Expression levels of adenoviral receptors CAR, CD46, CD86 and αv-integrins were found to be high both in normal and dilated cardiomyopathy heart tissue. The receptor levels also correlate with transduction efficiency after intracardiac injection. Ad5 showed superior transduction ability compared with Ad5/35, but evoked also a more profound immune reaction when administered this way. Adenoviral gene therapy vectors are the most used delivery vehicles in clinical trials to date. These vectors have proven to be well tolerated and positive results have been obtained when combined with traditional treatments, although poor transduction efficiency has often been reported due to low-level expression of viral receptors on target cells. In spite of this, the results are encouraging and merit for further research.

Pencil grip : a descriptive model and four empirical studies

Previous studies on pencil grip have typically dealt with the developmental aspects in young children while handwriting research is mainly concerned with speed and legibility. Studies linking these areas are few. Evaluation of the existing pencil grip studies is hampered by methodological inconsistencies. The operational definitions of pencil grip arerational but tend to be oversimplified while detailed descriptors tend to be impractical due to their multiplicity. The present study introduces a descriptive two-dimensional model for the categorisation of pencil grip suitable for research applications in a classroom setting. The model is used in four empirical studies of children during the first six years of writing instruction. Study 1 describes the pencil grips observed in a large group of pupils in Finland (n = 504). The results indicate that in Finland the majority of grips resemble the traditional dynamic tripod grip. Significant genderrelated differences in pencil grip were observed. Study 2 is a longitudinal exploration of grip stability vs. change (n = 117). Both expected and unexpected changes were observed in about 25 per cent of the children's grips over four years. A new finding emerged using the present model for categorisation: whereas pencil grips would change, either in terms of ease of grip manipulation or grip configuration, no instances were found where a grip would have changed concurrently on both dimensions. Study 3 is a cross-cultural comparison of grips observed in Finland and the USA (n = 793). The distribution of the pencil grips observed in the American pupils was significantly different from those found in Finland. The cross-cultural disparity is most likely related to the differences in the onset of writing instruction. The differences between the boys' and girls' grips in the American group were non-significant.An implication of Studies 2 and 3 is that the initial pencil grip is of foremost importance since pencil grips are largely stable over time. Study 4 connects the pencil grips to assessment of the mechanics of writing (n = 61). It seems that certain previously not recommended pencil grips might nevertheless be includedamong those accepted since they did not appear to hamper either fluency or legibility.

Verbal learning in mild cognitive impairment and alzheimer's disease : behavioural and neural approaches

The main focus of the present thesis was at verbal episodic memory processes that are particularly vulnerable to preclinical and clinical Alzheimer’s disease (AD). Here these processes were studied by a word learning paradigm, cutting across the domains of memory and language learning studies. Moreover, the differentiation between normal aging, mild cognitive impairment (MCI) and AD was studied by the cognitive screening test CERAD. In study I, the aim was to examine how patients with amnestic MCI differ from healthy controls in the different CERAD subtests. Also, the sensitivity and specificity of the CERAD screening test to MCI and AD was examined, as previous studies on the sensitivity and specificity of the CERAD have not included MCI patients. The results indicated that MCI is characterized by an encoding deficit, as shown by the overall worse performance on the CERAD Wordlist learning test compared with controls. As a screening test, CERAD was not very sensitive to MCI. In study II, verbal learning and forgetting in amnestic MCI, AD and healthy elderly controls was investigated with an experimental word learning paradigm, where names of 40 unfamiliar objects (mainly archaic tools) were trained with or without semantic support. The object names were trained during a 4-day long period and a follow-up was conducted one week, 4 weeks and 8 weeks after the training period. Manipulation of semantic support was included in the paradigm because it was hypothesized that semantic support might have some beneficial effects in the present learning task especially for the MCI group, as semantic memory is quite well preserved in MCI in contrast to episodic memory. We found that word learning was significantly impaired in MCI and AD patients, whereas forgetting patterns were similar across groups. Semantic support showed a beneficial effect on object name retrieval in the MCI group 8 weeks after training, indicating that the MCI patients’ preserved semantic memory abilities compensated for their impaired episodic memory. The MCI group performed equally well as the controls in the tasks tapping incidental learning and recognition memory, whereas the AD group showed impairment. Both the MCI and the AD group benefited less from phonological cueing than the controls. Our findings indicate that acquisition is compromised in both MCI and AD, whereas long13 term retention is not affected to the same extent. Incidental learning and recognition memory seem to be well preserved in MCI. In studies III and IV, the neural correlates of naming newly learned objects were examined in healthy elderly subjects and in amnestic MCI patients by means of positron emission tomography (PET) right after the training period. The naming of newly learned objects by healthy elderly subjects recruited a left-lateralized network, including frontotemporal regions and the cerebellum, which was more extensive than the one related to the naming of familiar objects (study III). Semantic support showed no effects on the PET results for the healthy subjects. The observed activation increases may reflect lexicalsemantic and lexical-phonological retrieval, as well as more general associative memory mechanisms. In study IV, compared to the controls, the MCI patients showed increased anterior cingulate activation when naming newly learned objects that had been learned without semantic support. This suggests a recruitment of additional executive and attentional resources in the MCI group.

Esiopetuskirjojen harjoitukset kielellisen tietoisuuden kehittäjinä

Tutkimus oli kasvatustieteellinen varhaiskasvatuksen alan tutkimus, jossa hyödynnettiin kielitieteellistä käsitteistöä. Tutkimuksen kohteena olivat esiopetuskirjojen kielellisen tietoisuuden harjoitukset. Aineistona oli 12 esiopetuksen harjoituskirjaa ja opettajan opasta. Kirjoissa oli yhteensä yli 2000 sivua ja yli 1300 harjoitusta. Tarkemmassa analyysissä olleiden harjoitusten määrä oli noin 460. Analyysimenetelmänä käytettiin sisällönanalyysiä, jonka avulla tutkittiin, millaisia kielellisen tietoisuuden harjoituksia esiopetuskirjoissa oli ja miten harjoitukset etenivät. Kielellisen tietoisuuden harjoitukset luokiteltiin fonologisen, morfologisen ja syntaktisen tietoisuuden harjoituksiin. Fonologinen tietoisuus käsitettiin lapsen kyvyksi havaita ja käsitellä kielen äännerakennetta. Morfologisella tietoisuudella tarkoitettiin kykyä havaita ja käsitellä kielen morfeemeja eli pienimpiä merkityksellisiä osia. Syntaktisella tietoisuudella tarkoitettiin lapsen tietoisuutta siitä, miten lauseet rakentuvat. Olennaisiksi piirteiksi fonologisen tietoisuuden harjoituksissa identifioituivat harjoitusten edellyttämä tai harjoittama tietoisuuden taso, harjoitusten kohteena olevien lingvististen yksiköiden taso ja harjoitustyyppi sekä morfologisen ja syntaktisen tietoisuuden harjoituksissa tietoisuuden taso ja harjoitustyyppi. Tutkimuksessa luotiin aikaisempien tutkimusten pohjalta mallit siitä, miten eri harjoitukset etenisivät optimaalisesti lapsen kielellisen tietoisuuden kehittymisen kannalta. Eri harjoituskirjojen harjoitusten etenemistä verrattiin näihin malleihin. Fonologisen tietoisuuden harjoituksista voitiin tunnistaa viisi päätyyppiä, joista useat jakautuivat vielä alatyypeiksi. Harjoitusten alatyypit ilmaisivat yleensä harjoituksissa käytettävän kognitiivisen operaation – käytettiinkö harjoituksessa tunnistamista, yhdistämistä vai osiin jakamista. Tämä samoin kuin harjoituksessa käytetty lingvistinen yksikkö (sana, loppusointu, tavu tai äänne) ja tietoisuuden taso olivat yhteydessä harjoituksen vaikeuteen. Tutkimuksissa ja interventioissa esiopetusikäisilläkin käytettyjä muunteluharjoituksia, joissa sanasta tai tavusta poistetaan osa, siihen lisätään osa tai osaa siirretään, harjoituskirjoissa ei ollut. Morfologisen tietoisuuden harjoitukset kohdistuivat yhdyssanoihin, taivutuspäätteisiin tai johdoksiin. Syntaktisen tietoisuuden harjoituksista identifioitui yhdentoista harjoituslajin alatyypin kautta kuusi päätyyppiä. Tutkimusta voidaan hyödyntää esiopetuskirjojen arvioinnissa ja laatimisessa sekä varhaiskasvatus- ja esiopetuspedagogiikassa.

The Influence of Diet and Microbes on Colonic Immune Regulation and their Implications on Type 1 Diabetes

Dietary and microbial factors are thought to contribute to the rapidly increasing prevalence of T1D in many countries worldwide. The impact of these factors on immune regulation and diabetes development in non-obese diabetic (NOD) mice are investigated in this thesis. Diabetes can be prevented in NOD mice through dietary manipulation. Diet affects the composition of intestinal microbiota, which may subsequently influence intestinal immune homeostasis. However, the specific effects of anti-diabetogenic diets on gut immunity and the explicit associations between intestinal immune disruption and type 1 diabetes onset remain unclear. The research presented herein demonstrates that newly weaned NOD mice suffer from a mild level of colitis, which shifts the colonic immune cell balance towards a proinflammatory status. Several aberrations can also be observed in the peritoneal B cells of NOD mice; an increase in activation marker expression, increased trafficking to the pancreatic lymph nodes and significantly higher antigen presenting cell (APC) efficiency towards insulin-specific T cells. A shift towards inflammation is likewise observed in the colon of germ-free NOD mice, but signs of peritoneal B cell activation are lacking in these mice. Remarkably, most of the abnormalities in the colon, peritoneal macrophages and the peritoneal B cell APC activity of NOD mice are abrogated when NOD mice are maintained on a diabetes-preventive, soy-based diet (ProSobee) from the time of weaning. Dietary and microbial factors hence have a significant impact on colonic immune regulation and peritoneal B cell activation and it is suggested that these factors influence diabetes development in NOD mice.

Learning Robot Environment through Simulation

Traditionally simulators have been used extensively in robotics to develop robotic systems without the need to build expensive hardware. However, simulators can be also be used as a “memory”for a robot. This allows the robot to try out actions in simulation before executing them for real. The key obstacle to this approach is an uncertainty of knowledge about the environment. The goal of the Master’s Thesis work was to develop a method, which allows updating the simulation model based on actual measurements to achieve a success of the planned task. OpenRAVE was chosen as an experimental simulation environment on planning,trial and update stages. Steepest Descent algorithm in conjunction with Golden Section search procedure form the principle part of optimization process. During experiments, the properties of the proposed method, such as sensitivity to different parameters, including gradient and error function, were examined. The limitations of the approach were established, based on analyzing the regions of convergence.

Mechanical damage during harvest and loading affect orange postharvest quality

Brazil is the world’s largest orange producer; however, part of this production is lost during postharvest. This loss can be minimized by controlling incidence of physical damage throughout the harvest and loading operations. Impacts can negatively modify quantitative and qualitative fruits aspects. The main goal of this study was to measure the impact magnitude in two types of harvest (manual and detachment) and during all steps from picking into bags until loading for transport to the processing industry and additionally evaluating, in laboratory, the physico-chemical quality of the fruit subjected to various impacts, similar to those found in the field. In order to evaluate the impact magnitude, an instrumented sphere was used (760 mm, Techmark, Inc, USA). The following physico-chemical parameters were evaluated during 6-days of storage: weight loss, soluble solids contents, titratable acidity, ascorbic acid content, pH, firmness and peel color. The greatest impacts were observed during harvest, during the detachment practice, and when loading and unloading from bulk storage, with average acceleration values between 249.5 and 531.52G. The impact incidence in oranges were responsible for reducing the soluble solids, titratable acidity, ascorbic acid and weight by to 5.5%; 8.7%; 4.6% and 0.5%, respectively, compared to the control. Impacts during harvest and the various pre-industry manipulation steps must be controlled as they interfere in postharvest quality and physiology of ‘Valência’ oranges.

Hitsauksen mekanisoinnin ja automatisoinnin oppimisympäristön kehittäminen

Hitsaavan teollisuuden kilpailukyvyn tehostamiseksi yksi keino on hitsauksen mekanisoinnin ja automatisoinnin osuuden lisääminen hitsaustuotannossa. Työn on tehty Etelä-Karjalan aikuisopiston toimeksiannosta hitsauksen mekanisoinnin ja automatisoinnin oppimisympäristön kehittämiseksi paikallisten hitsaavien yritysten koulutustarpeiden mukaisesti. Työ toteutettiin sekä kirjallisuustutkimuksena että haastattelututkimuksena Etelä-Karjalan alueen hitsaavan teollisuuden yrityksissä. Kirjallisuusosiossa on läpikäyty hitsauksen mekanisointia, kappaleenkäsittelyä, orbitaalihitsausta sekä robottihitsausta. Kirjallisen käsittelyn pohjana oli kansainvälisen mekanisoidun-, orbitaali- ja robottihitsauksen henkilöstön operaattorikoulutusohjelma. Operaattorikoulutusohjelmassa koulutuslinjat jaetaan mekanisoituun hitsaukseen, orbitaalihitsaukseen ja robottihitsaukseen. Käytännön osiossa on analysoitu kohdeyrityksille tehdyt haastattelut, määritelty kohdeyritysten hitsauksen automaatiotasot sekä hitsaustyössä käytössä oleva laitekanta. Tutkimuksen tuloksia tullaan käyttämään hyödyksi kehitettäessä Etelä-Karjalan aikuisopiston (AKTIVA) oppimisympäristöä etelä-karjalaisten hitsaavien yritysten tarpeiden mukaisesti.

Tactile-Proprioceptive Robotic Grasping

Robotic grasping has been studied increasingly for a few decades. While progress has been made in this field, robotic hands are still nowhere near the capability of human hands. However, in the past few years, the increase in computational power and the availability of commercial tactile sensors have made it easier to develop techniques that exploit the feedback from the hand itself, the sense of touch. The focus of this thesis lies in the use of this sense. The work described in this thesis focuses on robotic grasping from two different viewpoints: robotic systems and data-driven grasping. The robotic systems viewpoint describes a complete architecture for the act of grasping and, to a lesser extent, more general manipulation. Two central claims that the architecture was designed for are hardware independence and the use of sensors during grasping. These properties enables the use of multiple different robotic platforms within the architecture. Secondly, new data-driven methods are proposed that can be incorporated into the grasping process. The first of these methods is a novel way of learning grasp stability from the tactile and haptic feedback of the hand instead of analytically solving the stability from a set of known contacts between the hand and the object. By learning from the data directly, there is no need to know the properties of the hand, such as kinematics, enabling the method to be utilized with complex hands. The second novel method, probabilistic grasping, combines the fields of tactile exploration and grasp planning. By employing well-known statistical methods and pre-existing knowledge of an object, object properties, such as pose, can be inferred with related uncertainty. This uncertainty is utilized by a grasp planning process which plans for stable grasps under the inferred uncertainty.

Winning time in land warfare : a reading of the classical strategists prior to the age of mechanization

We live in an age where rationalization and demands of efficiency taint every aspect of our lives both as individuals and as a society. Even warfare cannot escape the increased speed of human interaction. Time is a resource to be managed. It has to be optimized, saved and won in military affairs as well. The purpose of this research paper is to analyze the dogmatic texts of military thought to search for answers what the classics of strategy saw in the interrelations of temporality and warfare and if their thoughts remain meaningful in the contemporary conjunction. Since the way a society functions is reflected in the way it conducts its wars, there naturally are differences between an agrarian, industrial and information society. Theorists of different eras emphasize things specific to their times, but warfare, like any human interaction, is always bounded by temporality. Not only is the pace of warfare dependent on the progress of the society, but time permeates warfare in all its aspects. This research paper focuses on two specific topics that arose from the texts themselves; how should time be managed and manipulated in warfare and how to economize and “win” it from the enemy. A method where lengthy quotations are used to illustrate the main point of the strategists has been chosen for this research paper. While Clausewitz is the most prominent source of quotations, thoughts from ancient India and China are represented as well to prove that the combination of right force in the right place at the right time is still the way of the victorious. Tactics change in the course of time but the principles of strategy remain unaltered and are only adapted to suit new situations. While ancient and pre-modern societies had their focus on finding auspicious moments for battle in the flow of kronos-time based on divinities, portents and auguries, we can trace elements of manipulation of time in warfare from the earliest surviving texts. While time as a fourth dimension of the battlespace emerged only in the modern era, all through the history of military thought it has had a profound meaning. In the past time could be squandered, today it always has to be won. This paper asks the question “why”.

Spin-Dynamics in Cold Gases of 87Rb and Atomic Hydrogen. The spins they are a-changin’

In this thesis the dynamics of cold gaseous atoms is studied. Two different atomic species and two different experimental techniques have been used. In the first part of the thesis experiments with Bose-Einstein condensates of Rb-87 are presented. In these experiments the methods of laser cooling and magnetic trapping of atoms were utilized. An atom chip was used as the experimental technique for implementation of magnetic trapping. The atom chip is a small integrated instrument allowing accurate and detailed manipulation of the atoms. The experiments with Rb-87 probed the behaviour of a falling beam of atoms outcoupled from the Bose-Einstein condensate by electromagnetic field induced spin flips. In the experiments a correspondence between the phases of the outcoupling radio frequency field and the falling beam of atoms was found. In the second part of the thesis experiments of spin dynamics in cold atomic hydrogen gas are discussed. The experiments with atomic hydrogen are conducted in a cryostat using a dilution refrigerator as the cooling method. These experiments concentrated on explaining and quantifying modulations in the electron spin resonance spectra of doubly polarized atomic hydrogen. The modifications to the previous experimental setup are described and the observation of electron spin waves is presented. The observed spin wave modes were caused by the identical spin rotation effect. These modes have a strong dependence on the spatial profile of the polarizing magnetic field. We also demonstrated confinement of these modes in regions of strong magnetic field and manipulated their spatial distribution by changing the position of the field maximum.

Effect of the celexoxib in microscopic changes of the esophageal mucosal of rats induced by esofagojejunostomy

OBJECTIVE: To evaluate the protective effect of celecoxib in the esophageal mucosa in rats undergoing esofagojejunostomy.METHODS: Sixty male Wistar rats from the vivarium of the University of Health Sciences of Alagoas were used for the experiment. The animals were divided into four groups: Group I, 15 rats undergoing esofagojejunostomy with the use of celecoxib postoperatively; Group II, 15 rats undergoing esofagojejunostomy without the use of celecoxib; Group III, 15 rats undergoing celiotomy with bowel manipulation; and Group IV, 15 rats without surgery and using celecoxib. The observation period was 90 days. After the death of the animals, the distal segment of the esophagus was resected and sent for microscopic analysis.RESULTS: esofagojejunostomy caused macroscopic and microscopic esophagitis. Esophagitis was equal in both groups I and II. In groups III and IV esophageal lesions were not developed.CONCLUSIONS: celecoxib had neither protective nor inducing effect on esophagitis, but had a protective effect on dysplasia of the animals of group I.

Field evaluation of safety during gestation and horizontal spread of a recombinant differential bovine herpesvirus 1 (BoHV-1) vaccine

Bovine herpesvirus type 1 (BoHV-1) is recognized as a major cause of respiratory, reproductive disease and abortion in cattle. Vaccination is widely applied to minimize losses induced by BoHV-1 infections; however, vaccination of dams during pregnancy with modified live virus (MLV) vaccines has been occasionally associated to abortions. We have previously reported the development of a BoHV-1 recombinant virus, constructed with basis on a Brazilian BoHV-1 (Franco et al. 2002a) from which the gene coding for glycoprotein E (gE) was deleted (gE-) by genetic manipulation. Such recombinant has been previously evaluated in its potential as a differential vaccine (gE- vaccine) that allows differentiation between vaccinated and infected animals. Here, in the first part of the present study, the safety of the gE- vaccine during pregnancy was evaluated by the intramuscular inoculation of 10(7.4) tissue culture 50 % infective doses (TCID50) of the virus into 22 pregnant dams (14 BoHV-1 seronegative; 8 seropositive), at different stages of gestation. Other 15 pregnant dams were kept as non-vaccinated controls. No abortions, stillbirths or fetal abnormalities were seen after vaccination. Seroconversion was observed in both groups of previously seronegative vaccinated animals. In the second part of the study, the potential of the gE- vaccine virus to spread among beef cattle under field conditions was examined. Four heifers were inoculated intranasally with a larger amount (10(7,6) TCID50) of the gE- vaccine (to increase chances of transmission) and mixed with other sixteen animals at the same age and body condition, in the same grazing area, at a population density equal to the average cattle farming density within the region (one cattle head per 10,000 m²), for 180 days. All animals were monitored daily for clinical signs. Serum samples were collected on days 0, 30, 60 and 180 post-vaccination. Seroconversion was observed only in vaccinated heifers. These results indicate that, under the conditions of the present study, the gE- vaccine virus did not cause any noticeable harmful effect on pregnant dams and on its offspring and did not spread horizontally among cattle.

Hitsaustuotannon tehostaminen mekanisoinnin keinoin

Mekanisoinnin ja automaation osuuden lisääminen hitsaustuotannossa on eräs keino hitsaavan teollisuuden kilpailukyvyn tehostamiseksi. Tässä työssä tutkittiin hitsaustyön tehostamista mekanisoinnin keinoin. Työ tehtiin Rämö Oy:n konepajalla Imatralla, todellisia tuotantokappaleita vastaavilla koekappaleilla. Teoriaosuudessa on läpikäyty hitsauksen mekanisointia, kappaleenkäsittelyä ja erilaisia hitsausprosesseja. Osuudessa on käsitelty myös mekanisoidun hitsauksen laatua ja laadunvarmistusta. Kohdeyrityksen tuotannon nykytilanteen kartoitus on esitetty tässä osuudessa. Käytännön osuudessa on käsitelty hitsauskokeiden suoritus, kokeiden tulokset sekä niiden analysointi. Tuloksista voidaan todeta kevytmekanisoinnin olevan kustannustehokas keino hitsaustyön tehokkuuden sekä laadun parantamiseksi. Työn tuloksia tullaan käyttämään hyödyksi kehitettäessä hitsaavaa tuotantoa Rämö Oy:ssä.

Frequency of Leptospira spp. in sheep from Brazilian slaughterhouses and its association with epidemiological variables

Leptospirosis is a worldwide anthropozoonosis that infects livestock, including sheep as the carriers to other animals and humans. The present study aimed to determine the prevalence of Leptospira spp. in sheep from two slaughterhouses in the state of São Paulo, Brazil and its association with epidemiological variables. Serum samples from 182 sheep were evaluated for Leptospira spp. antibodies by microscopic agglutination test (MAT). Results indicated 34/182 (18.68%; CI95% 13.70-24.98%) positive serum samples, mainly to the serovar Copenhageni (17/34; 50%; CI95% 33.99-66.01%). Bacterial growth in the Fletcher medium was detected for 13/34 (38.24%; CI95% 23.87-55.08%) animals, and confirmed by Polymerase Chain Reaction (PCR) and sequencing for only two kidney samples from two animals. Thus, treatment and vaccination of sheep, besides rodent control, can be useful to prevent the infection in the studied region since sheep are important Leptospira spp. carriers, and its transmission to slaughterhouse workers is mainly through the manipulation of visceral tissues.