O metabolismo do triptofano (Trp) se dá pela via das quinureninas (QUIN), pela via serotoninérgica (SER) e pela via das aminas traço. A primeira gera QUIN e uma variedade de outros metabólitos secundários. Quando conduzida pela enzima indolamina 2,3 dioxigenase (IDO) contribui para os fenômenos de tolerância e imune escape de células tumorais; e quando conduzida pela triptofano 2,3 dioxigenase (TDO) no fígado, participa na síntese da niacina e NAD. A via SER leva à formação do neurotransmissor serotonina (SER), que pode gerar o hormônio melatonina (MEL), respectivamente e outros metabólitos biologicamente ativos. Outra via menos estudada, a via das aminas traço, produz produtos neuroativos. Dada a abrangência e importância das rotas metabólicas do Trp, nós desenvolvemos e validamos uma metodologia bioanalítica robusta, seletiva e sensível por cromatografia líquida de alta eficiência (HPLC), acoplado espectrometria de massas (MS) para a determinação simultânea do Trp e seus 15 metabólitos. Para tanto, escolhemos para a avaliação das três vias, linhagens de glioma humano. A escolha por este tipo celular deveu-se ao grande interesse de estudos de metabolismo de Trp em células tumorais, no qual células de glioma tem sido modelo. Nos ensaios com as células de glioma acompanhamos os efeitos de um indutor e inibidores da primeira etapa de metabolização do Trp pela via das quinureninas, ou seja, IFN-γ (indutor da IDO), 1-metiltriptofano (1-MT; inibidor competitivo da IDO) e 680C91 (inibidor seletivo da TDO). Pudemos observar o impacto que a indução ou a inibição do primeiro passo teve sobre os metabólitos subsequentes e as diferenças no metabolismo das duas linhagens estudadas, A172 e T98G. A linhagem T98G só tem atividade de IDO, enquanto que a A172 tem tanto atividade IDO quanto TDO. A indução por IFN-γ mostrou que essa citocina não só atua na formação da via QUIN, mas possui um impacto modesto nas demais rotas. Observamos também que a inibição do 1-MT mostrou seu impacto nos metabólitos invdividualmente, do que a simples relação Trp-QUIN. Contudo, nosso resultados nos permitiu mostrar pela primeira vez a descrição completa dessas vias, em especial nessas linhagens celulares, podendo supor estratégias terapêuticas nessas rotas que estão relacionadas a progressão ou não tumoral. / The tryptophan metabolism (Trp) takes place by means of kynurenine (QUIN), by the serotonin pathway (SER) and by the pathway of trace amines synthesis. The first generates QUIN and a variety of other secondary metabolites. When driven by the enzyme indoleamine 2,3 dioxygenase (IDO) contributes to the phenomena of tolerance and immune escape of tumor cells; and when conducted by tryptophan 2,3 -dioxygenase (TDO) in the liver, participates in the niacin synthesis NAD. The SER pathway leads to the serotonin neurotransmitter (SER) formation, which can generate the hormone melatonin (MEL), respectively and other biologically active metabolites. Another less studied amines trace synthesis pathway produces neuroactive products. Given the scope and importance of Trp metabolic pathways,we developed and validated a robust, sensitive and selective bioanalytical method by high performance liquid chromatography (HPLC) coupled mass spectrometry (MS) for simultaneous determination of TRP and its 16 metabolites. Therefore, we chose to evaluate the three routes, glioma cell lines. The initial choice of this type of cell was due to the great interest in Trp metabolism studies in tumor cells, which glioma cells has been a model. In assays with glioma cells, we followed the effects of an inductor and inhibitors of the first stage of Trp metabolism, via the kynurenine pathway, or IFN -γ (IDO inducer) 1- methyltryptophane (1- MT; competitive IDO inhibitor) and 680C91 (selective TDO inhibitor). We could observe the first step induction or inhibition impact had over the further metabolites and the metabolism differences between the two studied strains, A172 and T98G. The T98G glioma cell has only IDO activity, while the A172 has both IDO and TDO activity as well. The IFN-γ indution showed that this cytokine not only acts in the formation of QUIN route, but has a modest impact on the others routes. Inhibition of IDO showed that the competitive inhibitor has activity in itself than a simple Trp-QUIN relationship. However, our results allow us to show the first time the complete description of these pathways, in particular, in these cell lines that can assume therapeutic strategies in these routes that are related or not with tumor progression.

O metabolismo do triptofano (Trp) se dá pela via das quinureninas (QUIN), pela via serotoninérgica (SER) e pela via das aminas traço. A primeira gera QUIN e uma variedade de outros metabólitos secundários. Quando conduzida pela enzima indolamina 2,3 dioxigenase (IDO) contribui para os fenômenos de tolerância e imune escape de células tumorais; e quando conduzida pela triptofano 2,3 dioxigenase (TDO) no fígado, participa na síntese da niacina e NAD. A via SER leva à formação do neurotransmissor serotonina (SER), que pode gerar o hormônio melatonina (MEL), respectivamente e outros metabólitos biologicamente ativos. Outra via menos estudada, a via das aminas traço, produz produtos neuroativos. Dada a abrangência e importância das rotas metabólicas do Trp, nós desenvolvemos e validamos uma metodologia bioanalítica robusta, seletiva e sensível por cromatografia líquida de alta eficiência (HPLC), acoplado espectrometria de massas (MS) para a determinação simultânea do Trp e seus 15 metabólitos. Para tanto, escolhemos para a avaliação das três vias, linhagens de glioma humano. A escolha por este tipo celular deveu-se ao grande interesse de estudos de metabolismo de Trp em células tumorais, no qual células de glioma tem sido modelo. Nos ensaios com as células de glioma acompanhamos os efeitos de um indutor e inibidores da primeira etapa de metabolização do Trp pela via das quinureninas, ou seja, IFN-γ (indutor da IDO), 1-metiltriptofano (1-MT; inibidor competitivo da IDO) e 680C91 (inibidor seletivo da TDO). Pudemos observar o impacto que a indução ou a inibição do primeiro passo teve sobre os metabólitos subsequentes e as diferenças no metabolismo das duas linhagens estudadas, A172 e T98G. A linhagem T98G só tem atividade de IDO, enquanto que a A172 tem tanto atividade IDO quanto TDO. A indução por IFN-γ mostrou que essa citocina não só atua na formação da via QUIN, mas possui um impacto modesto nas demais rotas. Observamos também que a inibição do 1-MT mostrou seu impacto nos metabólitos invdividualmente, do que a simples relação Trp-QUIN. Contudo, nosso resultados nos permitiu mostrar pela primeira vez a descrição completa dessas vias, em especial nessas linhagens celulares, podendo supor estratégias terapêuticas nessas rotas que estão relacionadas a progressão ou não tumoral. / The tryptophan metabolism (Trp) takes place by means of kynurenine (QUIN), by the serotonin pathway (SER) and by the pathway of trace amines synthesis. The first generates QUIN and a variety of other secondary metabolites. When driven by the enzyme indoleamine 2,3 dioxygenase (IDO) contributes to the phenomena of tolerance and immune escape of tumor cells; and when conducted by tryptophan 2,3 -dioxygenase (TDO) in the liver, participates in the niacin synthesis NAD. The SER pathway leads to the serotonin neurotransmitter (SER) formation, which can generate the hormone melatonin (MEL), respectively and other biologically active metabolites. Another less studied amines trace synthesis pathway produces neuroactive products. Given the scope and importance of Trp metabolic pathways,we developed and validated a robust, sensitive and selective bioanalytical method by high performance liquid chromatography (HPLC) coupled mass spectrometry (MS) for simultaneous determination of TRP and its 16 metabolites. Therefore, we chose to evaluate the three routes, glioma cell lines. The initial choice of this type of cell was due to the great interest in Trp metabolism studies in tumor cells, which glioma cells has been a model. In assays with glioma cells, we followed the effects of an inductor and inhibitors of the first stage of Trp metabolism, via the kynurenine pathway, or IFN -γ (IDO inducer) 1- methyltryptophane (1- MT; competitive IDO inhibitor) and 680C91 (selective TDO inhibitor). We could observe the first step induction or inhibition impact had over the further metabolites and the metabolism differences between the two studied strains, A172 and T98G. The T98G glioma cell has only IDO activity, while the A172 has both IDO and TDO activity as well. The IFN-γ indution showed that this cytokine not only acts in the formation of QUIN route, but has a modest impact on the others routes. Inhibition of IDO showed that the competitive inhibitor has activity in itself than a simple Trp-QUIN relationship. However, our results allow us to show the first time the complete description of these pathways, in particular, in these cell lines that can assume therapeutic strategies in these routes that are related or not with tumor progression.

Tryptophan 2,3-dioxygenase (TDO), along with indoleamine 2,3-dioxygenase (IDO) and indoleamine 2,3-dioxygenase-2 (IDO2) are the three enzymes that catalyse oxidation of L-tryptophan (L-Trp) in the first step of the kynurenine pathway. Despite the fact that all three catalyse the same reaction, they were detected and characterized in different chronological periods; TDO, IDO and IDO2 were discovered in 1936, 1967 and 2007 respectively. Years of studies showed that abnormal regulation of L-Trp, in the first step of kynurenine pathway, is related with several disorders, including cancer. Regardless of their distinct dissimilarities, TDO, IDO and IDO2 were all detected in various cancers, supporting tumour escape and survival. The early identification of IDO immunomodulatory action (1990s) led to intense research for the development of IDO inhibitors, but not TDO. Despite this effort, the most pharmacologically suitable IDO inhibitor, 1-methyltryptophan (1- MT), appears to be ineffective as monotherapeutic drug. Discovery of IDO2 showed that 1-MT action is not fully understood, raising questions about the biological significance of IDO2. The ultimate goal of the current study was to address the problems outlined above. Because TDO and IDO are two druggable molecular targets, the discovery of a new class of effective inhibitors was pursued. Plate screening of ~2800 potential inhibitor compounds obtained from National Cancer Institute (NCI), USA, indicated seven promising compounds that inhibit both TDO and IDO in either nanomolar or low micromolar range. Interestingly, of these seven inhibitors, six have been identified to have cytotoxic action against several types of tumour cell lines (NCI data). NSC 26326, known as b-lapachone, is a natural occurring quinone and the strongest inhibitor of all seven. This NCI compound inhibits both TDO and IDO with inhibition constants of ~30-70 nM and 97 ± 14 nM respectively. Like NSC 26326, NSC 36398 is another natural occurring product and the only compound that showed selectivity against TDO with inhibition constant of 16.3 ± 3.8 μM. Among the seven compounds that displayed promise as inhibitors of TDO and IDO was mitomycin C. Mitomycin C, which is an approved oncology drug and a known inhibitor of IDO (Ki = 24.2 ± 1.2 μM), is also inhibitor of TDO with inhibition constant of 2.86 ± 0.03 μM. Another major goal of the current work was the discovery of isatin derivatives as inhibitors of TDO and IDO. Using the tryptophan-like structure of isatin as starting point, a number of structural modifications were carried out (structureactivity relationship (SAR)) succeeding the optimization of their inhibition activity. This new family of TDO and IDO inhibitors demonstrated inhibition potencies in the low micromolar range with 5,7-dicholoisatin to reach the nanomolar range (in the case of TDO). Halogenation of isatin and its derivatives was found to increase noticeably the inhibition potencies of these molecules by 12fold and 6fold for TDO and IDO respectively while breakdown of isatin’s pyrrolidine ring had a disastrous result on the inhibition of both enzymes. Combinations of 1-MT with either the newly-identified NCI inhibitors or the isatin derivatives were also examined. The in vitro combinations of 1-MT with either the NCI inhibitors or the isatin derivatives revealed an additive effect without though excluding the possibility of synergistic effect in vivo. The specificity of TDO, IDO and IDO2 against the two stereoisomers of 1- MT was also investigated, with interesting results. While IDO is inhibited only by the L-isoform of 1-MT (Ki = 18.0 ± 3.4 μM), IDO2 is inhibited by both 1-Me-L-Trp and 1-Me-D-Trp with inhibition constants of 306 ± 17 μM and 3419 ± 259 μM respectively. Biochemical characterization of human IDO2 was another goal of the current thesis, which completed successfully. Kinetic, redox and inhibition study of human IDO2 indicated significant differences in comparison with human IDO something which suggests the potential implication of IDO2 in an identified biological pathway (other than tryptophan catabolism function).The findings presented herein help to solve the mystery of 1-MT action, at least in vitro, give answers in regards to IDO2 function, and provide a number of new, promising inhibitors for TDO and IDO.

Darbe atskleidžiama kolektyvinių derybų samprata, principai ir reikšmė ir tarptautinės ir Europos bendrijos darbo teisės pagrindiniai teisės aktai šiais klausimais. Kolektyvinėmis derybomis yra ginami darbuotojų, kaip silpnesnės darbo santykių šalies, interesai, siekiama pagerinti darbo sąlygas ir socialines garantijas. Kolektyvinių derybų šalys yra darbdaviai, jų grupės arba organizacijos ir darbuotojų organizacijos arba jų atstovai. Labai svarbūs yra kolektyvinių derybų principai, ypatingai teisės jungtis į organizacijas ir vesti kolektyvines derybas. Kolektyvinės derybos yra labai svarbios norint išlaikyti darbo santykių stabilumą ir išspręsti kolektyvinius ginčus. Darbe ieškoma atsakymo, ar streikai yra vienintelis būdas patenkinti darbuotojų reikalavimus. Kolektyvinės derybos yra reglamentuojamos tarptautiniais teisės aktais, Europos bendrijos teisės aktais ir nacionalinais teisės aktais. Tarptautinės darbo organizacijos (TDO) priimtos konvencijos ir rekomendacijos yra vienas iš svarbiausių šaltinių kolektyvinių derybų klausimais tarptautinėje teisėje. Šiose konvencijose įtvirtintos pagrindinės nuostatos ir kryptis minėtų derybų atžvilgiu. Kolektyvinės derybos Europos darbo teisėje yra įtvirtintos keliuose pagrindiniuose teisės aktuose. Europos socialinė chartija detaliai reglamentuoja valstybės pareigą skatinti kolektyvines derybas ir suteikia derybų šalims teisę jas vesti. Tiek tarptautiniai teisės aktai, tiek ir Europos bendrijos kuriama teisė šiuo klausimu įtvirtina... [toliau žr. visą tekstą] / The collective bargaining is necessary to protect the employee‘s, as a weeker part of labour relationships, interests and to make working conditions and social guarantees better. The parties of the collective bargaining are employers, their groups or organizations and employees‘ organizations or their representatives. The procedure of collective bargaining is regulated by national law, depending on each state conditions and expirience concerning collective bargaining. Very important are principles of collective bargaining, because collective bargaining are iniciated freely, voluntary and independent and about the content parties decide themselves without the intervention of the state. One of the most important principle is right to organise collective bargaining. This principle fixes employers and employees rights. Collective bargaining is very important to make labour relationships steady and to solve collective disputes. Collective bargaining is regulated bu international law, European community international law and national law. International labour organisation (ILO) adopted Conventions and recommendations are one of the most important source in International labour law concerning collective bargaining. In these conventions and recommendations are fixed most important provisions and and directions to the member states concerning above-mentioned bargaining. Lithuanian has ratified these Convenctions and must keep their provisions. The European law the most important is... [to full text]

Magistriniame darbe analizuojamas poilsio laiko tarptautinis teisinis reguliavimas ir jo įgyvendinimo ypatumai Lietuvos darbo teisėje atskleidžiant teisinę poilsio laiko sampratą, apžvelgiant poilsio laiko reguliavimo pasauliniu ir regioniniu mastu prielaidas ir tarptautinius teisės aktus poilsio laiko reguliavimo klausimais, išskiriant ir aptariant atskirus poilsio laiko reguliavimo Lietuvos darbo teisėje poinstitučius. Darbe taip pat atskleidžiamos esminės poilsio laiko reguliavimo kryptys Lietuvoje. Išanalizavus minėtas nuostatas bei tendencijas darytinos išvados, jog poilsio laikas glaudžiai siejasi su darbo laiko sąvoka. Lietuvos darbo kodekse pasinaudota Rytų bei Vidurio Europos valstybių patirtimi, Tarptautinės darbo organizacijos konvencijų bei rekomendacijų ir Europos socialinės chartijos (pataisytos) nuostatomis, perkelta didžioji dalis Europos Sąjungos direktyvų nuostatų, nors poilsio laikas labai priklauso nuo nacionalinių valstybių ypatumų ir yra net tam tikros kultūros dalis. Darbuotojai dažnai dėl per didelio darbo krūvio išnaudoja tik dalį jiems priklausančio poilsio laiko - esant tokiai situacijai darbdavys turėtų imtis priemonių darbuotojų poilsiui užtikrinti. Deja, nesant aiškios atostogų suteikimo ir atšaukimo iš jų tvarkos, kyla rizika, kad darbdavys gali piktnaudžiauti atostogų suteikimo diskrecijos teise ir padaryti tai savotiška „skatinimo – baudimo“ priemone. Siūlytina koreguoti DK 184 str., įtvirtinant darbuotojų teisę į nemokamas atostogas dėl kitų... [toliau žr. visą tekstą] / Master thesis analyzes international legal regulation of rest period and peculiarities of its implementation in Lithuanian labour law, revealing the legal concept of rest period, reviewing assumptions about regulation of rest period at international and regional level, international legal acts on issues regarding regulation of rest period, highlighting and discussing the different sub-institutes of regulation of rest period in Lithuanian labour law. The paper also reveals key directions of regulation of rest period in Lithuania. The analysis of these provisions and trends draws the conclusion that the rest period is closely related to the concept of working time. Experience of East and Central European countries, conventions and recommendations of International Labour Organisation and provisions of European Social Charter (revised) were used and majority of European Union directives provisions were incorporated in Lithuania Labour Code, although the rest period is very dependent on the characteristics of nation-states and is even some part of the culture. Due to excessive workload employees often use only part of rest period that belongs to them - in such situations the employer should take measures to ensure the rest period of employees. Unfortunately, due to the absence of clear order for issues of granting leave and recalling it, there is a risk that employers may abuse its discretion rights in granting annual leave by making it a kind of devise for “promotion or... [to full text]

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Darbo jėgą sudaro apie 45 % pasaulio gyventojų. Profesinės traumos, su darbu susijusios ligos turi didelę reikšmę darbuotojų sveikatai. Ligos, kurios nesusijusios su darbu, gali taip pat turėti įtakos darbo našumui. Darbuotojų saugos ir sveikatos tarnybos plačiai pripažįstamos kaip esminis sveikesnės ir saugesnės darbo aplinkos kūrimo elementas. Darbo tikslas – įvertinti Darbuotojų saugos ir sveikatos tarnybų veiklą Lietuvos energetikos sektoriaus įmonėse. Darbo tikslui pasiekti buvo iškelti šie uždaviniai: įvertinti Lietuvos Darbuotojų saugos ir sveikatos tarnybų funkcijų atitikimą TDO 161 (ILO 161) konvencijai; nustatyti vykdomas Lietuvos energetikos sektoriaus įmonių Darbuotojų saugos ir sveikatos tarnybų funkcijas; įvertinti Lietuvos energetikos sektoriaus įmonių Darbuotojų saugos ir sveikatos žmogiškųjų resursų atitikimą Lietuvos Respublikos teisės aktams. Lietuvos DSS tarnybų funkcijų atitikimas TDO 161 konvencijai buvo vertinamas pagal 11 funkcijų, reglamentuotų konvencijoje. DSS tarnybų funkcijos ir žmogiškieji resursai nustatyti atlikus anketinė apklausą, kuri atlikta 2009 m. lapkričio – gruodžio mėnesiais. Naudota anketa sudaryta remiantis Pasaulinės sveikatos organizacijos rekomendacijomis: „Regioninės rekomendacijos: Sveikos darbo vietos plėtra“ ir „Pagrindinės profesinės sveikatos tarnybos“. Tyrimo metu atlikus anketinę apklausą ištirta 14 (53,8 proc.) energetikos sektoriaus DSS tarnybų. Lietuvos DSS tarnybų funkcijų atitikimas parodė, kad šių tarnybų veiklos... [toliau žr. visą tekstą] / Labour force is constituted of some 45 per cent of the world population. Occupational injuries, as well as work related diseases have a lot of influence on health of the labour force. Diseases, which are not related to work, may also have an impact on efficiency of work. Occupational health and safety (OHS) services are widely recognized as the essential element of healthier and more secure labour environment. The aim of the work is to evaluate activities of OHS services in energy sector companies in Lithuania. The following tasks were raised in order to achieve the aim: to assess the conformity of functions performed by Lithuanian OHS services with ILO Convention No. 161; to identify functions of OHS services in energy sector companies in Lithuania; to identify and evaluate the conformity of human resources of OHS services in energy sector companies in Lithuania with the legislation of the Republic of Lithuania. Conformity of functions of Lithuanian OHS services with ILO Convention No. 161 was assessed on the basis of 11 functions regulated in the Convention. Functions and human resources of the Occupational health and safety services were detected having performed a questionnaire survey in November – December 2009. Questionnaire was drawn up following the guidelines of the World Health Organization (WHO): Regional Guidelines for the Development of Healthy Workplaces and Basic Occupational Health Services. During the research a questionnaire survey was performed, which... [to full text]

While the free electron model can often be surprisingly successful in describing properties of solids, there are plenty of materials in which interactions between electrons are too significant to be neglected. These strongly correlated systems sometimes exhibit rather unexpected, unusual and useful phenomena, understanding of which is one of the aims of condensed matter physics. Heat capacity measurements of paramagnetic YFe$_{2}$Ge$_{2}$ give a Sommerfeld coefficient of about 100 mJ mol$^{−1}$ K$^{−2}$, which is about an order of magnitude higher than the value predicted by band structure calculations. This suggests the existence of strong electronic correlations in the compound, potentially due to proximity to an antiferromagnetic quantum critical point (QCP). Existence of the latter is also indicated by the non-Fermi liquid T$^{3/2}$ behaviour of the low temperature resistivity. Below 1.8 K a superconducting phase develops in the material, making it a rare case of a non-pnictide and non-chalcogenide iron based superconductor with the 1-2-2 structure. This thesis describes growth and study of a new generation of high quality YFe$_{2}$Ge$_{2}$ samples with residual resistance ratios reaching 200. Measurements of resistivity, heat capacity and magnetic susceptibility confirm the intrinsic and bulk character of the superconductivity, which is also argued to be of an unconventional nature. In order to test the hypothesis of the nearby QCP, resistance measurements under high pressure of up to 35 kbar have been conducted. Pressure dependence of the critical temperature of the superconductivity has been found to be rather weak. μSR measurements have been performed, but provided limited information due to sample inhomogeneity resulting in a broad distribution of the critical temperature. While the superconductivity is the result of an effective attraction between electrons, under different circumstances the electronic properties of a system can instead be dictated by the Coulomb repulsion. This is the case for another transition metal based compound NiS$_{2}$, which is a Mott insulator. Applying hydrostatic pressure of about 30 kbar brings the material across the Mott metal-insulator transition (MIT) into the metallic phase. We have used the tunnel diode oscillator (TDO) technique to measure quantum oscillations in the metallised state of NiS$_{2}$, making it possible to track the evolution of the principal Fermi surface and the associated effective mass as a function of pressure. New results are presented which access a wider pressure range than previous studies and provide strong evidence that the effective carrier mass diverges close to the Mott MIT, as expected within the Brinkman-Rice scenario and predicted in dynamical mean field theory calculations. Quantum oscillations have been measured at pressures as close to the insulating phase as 33 kbar and as high as 97 kbar. In addition to providing a valuable insight into the mechanism of the Mott MIT, this study has also demonstrated the potential of the TDO technique for studying materials at high pressures.