O planejamento de moduladores da dinâmica dos microtúbulos, a partir da ligação à αβ-tubulina, constitui importante estratégia para a terapia do câncer. Os efeitos de inibição da polimerização da tubulina ou de estabilização dos microtúbulos são promovidos pela interação de compostos em cavidades específicas da proteína alvo. A interferência com a dinâmica dos microtúbulos nas células em rápida multiplicação provoca o bloqueio do ciclo celular, disparando sinais bioquímicos que culminam em apoptose. Os taxanos são os agentes antimitóticos mais importantes dentre os estabilizadores de microtúbulos, ao passo que os alcalóides da vinca e a colchicina são membros representativos dos inibidores da polimerização. Entretanto, o aparecimento de resistência, baixa biodisponibilidade e reações adversas graves são fatores que têm impulsionado a pesquisa por novos agentes anticâncer. Dentre os ligantes identificados recentemente para o sítio do taxol, o discodermolídeo e a dictiostatina, produtos naturais de origem marinha, são potentes estabilizadores de microtúbulos que apresentam maior solubilidade que o taxol e atividade contra células de câncer resistentes aos taxanos. Por essa razão, o modo de ligação desses compostos à cavidade de interação da β-tubulina tem sido objeto de investigação. Modelos preditivos de HQSAR foram desenvolvidos para derivados sintéticos do discodermolídeo e utilizados em conjunto com estudos baseados na estrutura do receptor, em concordância com evidências experimentais, para a proposição de modelos de interação para os análogos na cavidade do taxol. Os modelos de conformação bioativa foram utilizados no alinhamento estrutural do conjunto de dados para estudos de QSAR 3D CoMFA e comparação com o alinhamento baseado nas estruturas minimizadas dos ligantes. A caracterização de padrões de reconhecimento molecular foi útil para a proposição de um modelo farmacofórico baseado nas estruturas dos produtos naturais estabilizadores de microtúbulos. Um modelo farmacofórico simplificado foi integrado ao processo de triagem virtual consistindo na aplicação de filtros hierárquicos sucessivos para a identificação de novos estabilizadores de microtúbulos. Caseobliquinas foram ensaiadas como estabilizadoras de microtúbulos, enquanto que intermediários sintéticos da dictiostatina foram avaliados quanto aos seus efeitos na polimerização da tubulina. Nos últimos anos, tem sido intensificada a busca por novos ligantes do sítio da colchicina, dentre os quais os indóis estão entre os mais relevantes. Para quatro conjuntos de dados totalizando 170 derivados de indóis, modelos de HQSAR foram desenvolvidos para a avaliação virtual de uma base de dados. Estudos de QSAR 3D CoMFA e CoMSIA baseados nos farmacóforos foram comparados para 3 conjuntos de dados. Os resultados sugerem que o núcleo indólico pode interagir de maneiras diferentes na cavidade de interação da proteína. Chalconas do tipo 1, inspiradas em ligantes clássicos do sítio da colchicina, foram avaliadas em ensaios celulares e de polimerização da tubulina, levando a síntese e avaliação de uma nova série de chalconas com propriedade antiproliferativa significativa. Por outro lado, derivados de N-acil-hidrazonas apresentaram atividade antimitótica semelhante à colchicina, enquanto as tiosemicarbazonas citotóxicas não interagiram diretamente com a tubulina. / Inhibition of microtubule function is one of the most important approaches to anticancer therapy. Two main effects can be elicited by tubulin/microtubule-interactive agents: inhibition of tubulin assembly or microtubule stabilization. Interference with either the assembly or disassembly of microtubules within the mitotic spindle in rapidly dividing cells disrupts the normal process of cell division and provokes chemical signals that induce apoptosis. On one hand, taxanes are the most prominent among the microtubule-stabilizing antimitotic agents, while on the other hand, colchicine and the vinca alkaloids are representative members of the tubulin polymerization inhibitors. However, due to poor pharmacokinetic properties, high toxicity and resistance, their clinical utility has been limited, generating new opportunities for the development of novel anticancer agents. In recent years, structurally diverse taxoid-site ligands have been identified, including the potent microtubule-stabilizers discodermolide and dictyostatin. These marine sponge-derived natural products have higher water solubility than taxol and exhibit activity against taxane-resistant cell lines. Therefore, the elucidation of their binding modes is important in drug design. Predictive conformation-independent hologram QSAR models were developed for a series of synthetic discodermolide analogs as antiproliferative agents. Receptor-based studies were integrated with molecular recognition patterns, in agreement with experimental evidences, leading to ligand-binding conformations for discodermolide analogs in the taxol-site. The bioactive conformation models were used to the structural alignment of the data set for the development of 3D QSAR CoMFA models, and for comparison with the models constructed with the rigid-body alignment based on minimized structures of the ligands. A set of structural features related to the interaction with the taxol cavity was identified and the molecular recognition patterns were employed to the construction of pharmacophore models based on the microtubule-stabilizing natural products. A final simplified pharmacophore model was integrated in a virtual screening procedure consisting of consecutive hierarchical filters targeting the identification of novel microtubule-stabilizers. Caseobliquins were screened as microtubule-stabilizers, while intermediates for the synthesis of dictyostatin were evaluated by their effects on tubulin assembly. Recently, the search for more simple anti-tubulin agents has renewed the interest in the development of colchicine analogs, often discarded for their high toxicity. Considering the structurally diverse ligands of the colchicine site, the indole derivatives are among the most important ones. Hologram QSAR models were developed for four data sets consisting of 170 indole derivatives, and used to evaluate a data set of commercially available compounds. Pharmacophore-based 3D QSAR CoMFA and CoMSIA models were constructed and compared to three of the individual data sets. The results indicated that the indole nucleus bind to the protein cavity in different ways. Type 1 chalcones, designed based on classical colchicine site ligands, have been screened for their anti-proliferative activity and tubulin assembly inhibition, leading to the synthesis and assessment of a novel series of chalcone analogs with substantial antiproliferative properties. Some N-acylhydrazone derivatives behaved as mitotic arresters in a way similar to that of colchicine, while cytotoxic thiosemicarbazones did not exhibit tubulin-interacting properties.

Bakgrund: Suicid är ett globalt folkhälsoproblem. I Sverige vårdades 2021 cirka 11 000 patienter som försökt begå suicid. Intensivvårdssjuksköterskor har en betydelsefull roll i vården och mötet med patienten som utfört ett suicidförsök. Människor som försökt begå suicid har ett lidande och behöver bemötas utifrån en helhet av kropp, själ och ande. Syfte: Att beskriva intensivvårdssjuksköterskors erfarenheter av att på en intensivvårdsavdelning vårda patienter som försökt begå suicid. Metod: Kvalitativ innehållsanalys med induktiv ansats. Tio intensivvårdssjuksköterskor med erfarenhet av att vårda patient efter suicidförsök intervjuades. Resultat: Analysen resulterade i fyra kategorier, Väcker känslor, Vårda både kropp och själ, Att skapa en trygg miljö och Att bemöta anhöriga. De fyra kategorierna är sedan uppdelade i nio subkategorier. Konklusion: Studiens resultat visar att intensivvårdssjuksköterskor erfar att omvårdnaden av patienter som försökt begå suicid är komplex. Olika uppfattningar framkommer angående om det ingår i intensivvårdssjuksköterskans roll att prata med patienten om suicidförsöket. Att intensivvårdssjuksköterskor har olika syn på detta kan eventuellt leda till att patienter inte får jämlik vård. Vidare forskning av ämnet behövs för att skapa riktlinjer och tydliggöra om det är intensivvårdssjuksköterskans uppgift att initiera samtal om suicidförsöket. / Background: Suicide is a global public health problem. In Sweden, approximately 11,000 patients who attempted suicide were treated in 2021. Intensive care nurses have an important role in the care and meeting with the patient who has attempted suicide. People who have attempted to commit suicide are suffering and the whole person needs to be treated, body, soul and spirit. Aim: To describe intensive care nurses' experiences of caring for patients who have attempted suicide in an intensive care unit. Method: A qualitative content analyses with an inductive approach. Ten intensive care nurses with experience from caring for patients after suicide attempt, where interviewed. Result: The analysis resulted in four categories, Evokes emotions, Caring for both body and soul, Creating a safe environment and Dealing with relatives. Conclusion: Intensive care nurses experience that the care of patients who have attempted suicide is complex. Different opinions emerge regarding whether it is part of the intensive care nurse's role to talk to the patient about the suicide attempt. Different views on this could potentially lead to patients not receiving equal care. Further research on the subject is needed to create guidelines and clarify whether it is the intensive care nurse's task to initiate conversations about the suicide attempt.

TITLE: Content analyses of the textbooks of biology (natural history) for pupils with hearing impairment as a starting point for creating workbooks AUTHOR: RNDr. Jana Skýbová DEPARTMENT: Biology and Environmental Studies, Faculty of Education, Charles University in Prague TUTOR: doc. RNDr. Vasilis Teodoridis, Ph.D. ABSTRACT: The main aim of the dissertation thesis was to perform content analyses textbooks of biology (natural history) for elementary schools dedicated for pupils with hearing impairment as a base for the special workbooks creation in accordance with curricular and legislative documents. The next aim of thesis was the realization of educational research in all elementary schools for pupils with hearing impairment in the Czech Republic that focusing on teaching process of natural sciences and work with existing (author's) special textbooks for these pupils with accent on analysis of requirements of teachers and pupils for newly created workbooks. Methods of the mentioned pedagogic research was qualitative and quantitative, i.e. questionnaire complemented by interviews. The results of empirical research using textbooks of biology (natural history) in elementary schools dedicated for pupils with hearing impairment in the Czech Republic derived from the current requirements of the teacher-...

Sammanfattning:Introduktion: Vuxna personer med intellektuell funktionsnedsättning är merstillasittande, mindre fysiskt aktiva med ökade hälsorisker jämfört med övriga befolkningen.De har behov av personalens stöttning för att öka sin aktivitetsgrad och utföra fysiskaaktiviteter/träning men även vid andra hälsofrämjande insatser.Syfte: Att belysa fysioterapeuters erfarenheter av, strategier och förutsättningar för atterbjuda hälsofrämjande insatser för vuxna personer med intellektuell funktionsnedsättning,som bor på LSS boende.Metod: Elva fysioterapeuter som arbetar med målgruppen har intervjuats via digitalavideomöten. Intervjuerna har analyserats med kvalitativ innehållsanalys.Resultat: Analysen resulterade i ett tema, fyra kategorier och tolv underkategorier.Temat ”Hälsofrämjande aktiviteter för vuxna personer med IF- ur ett fysioterapeutiskperspektiv- kommer med utmaningar på olika nivåer” grundar sig på de följandekategorierna: Organisatoriska förutsättningar sätter ramar, tillgång till stöd och anpassadträning bidrar till bättre hälsa, personalen är nyckeln till fysisk aktivitet och utarbetadestrategier motiverar hälsofrämjande arbete. Dessa kategorier handlar om attorganisationens utformning och personalresurser påverkar prioriteringen förhälsofrämjande insatser och medför att fysioterapeuterna upplever att de har en drivanderoll i arbetet. Målgruppen behöver tillgång till anpassad träning och anpassadeträningslokaler. Personalens engagemang, egna tränings vana och syn på hälsa är viktigtmen även utarbetade strategier för att motivera personal och målgruppen och att det finnsstrukturerade teammöten.Slutsats: Studiens resultat indikerar att hur långt fysioterapeuterna har kommit i dethälsofrämjande arbetet varierar mellan kommuner och att de har olika förutsättningar förvilka insatser som kan erbjudas. Det finns utmaningar för hälsofrämjande arbetet påindivid-, grupp-, organisations- och samhällsnivå. Det hälsofrämjande arbetet är dock mer iropet nu och det satsas mer på målgruppen, men många utmaningar kvarstår. / Abstract:Introduction: Adults with intellectual disabilities (ID) are more sedentary, less physicallyactive with increased health risks compared to the rest of the population. They are in needof support from the staff to be able to increase their level of activity and to perform physicalactivities/exercise or engage in other health promotion interventions.Aims: To highlight physiotherapists´ experiences of, strategies and conditions to offerhealth promotion efforts for adults´with intellectual disabilities, living at LSS residence.Methods: Eleven physiotherapists working with the target group have been interviewed,using digital video meetings.Results: The analyses resulted in one theme, four categories and twelve subcategories.The theme ”Health promotion activities for adults with ID- from a physiotherapeuticperspective- come with challenges on different levels” is grounded in the followingcategories: Organizational conditions set the framework, access to support and adaptedtrainging contributes to better health, the staff are the key to able fysical activity andestablished stategies motivates heath promontion activities. Theese categories meens thatorganizational conditions and staffresoures affects priorities for health promotion effortsand contributes to physiotherapists feelings that they have a driving role in the work. Thetarget group needs access to adapted training and adapted training facilities. The staff´scommitment, their own training habits and their own views of healh are important, evento have established strategies to motivate staff and the target group but also structuredteam meetings.Conclusion: The results of the study indicate that how far the physiotherapists have comein the health promotion work varies between municipalities and that they have differentconditions to witch efforts they can offer.There are challenges för health promotion work atthe individual, group , organizational and societal level. However healthpromotion work ismore popual now and there is more focus on the target group, but more challenges remain.

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