Ligand dissociation from estrogen receptor is mediated by receptor dimerization: Evidence from molecular dynamics simulations

Estrogen Receptor (ER) is an important target for pharmaceutical design. Like other ligand-dependent transcription factors, hormone binding regulates ER transcriptional activity. Nevertheless, the mechanisms by which ligands enter and leave ERs and other nuclear receptors remain poorly understood. Here, we report results of locally enhanced sampling molecular dynamics simulations to identify dissociation pathways of two ER ligands [the natural hormone 17 beta-estradiol (E-2) and the selective ER modulator raloxifene (RAL)] from the human ER alpha ligand-binding domain in monomeric and dimeric forms. E-2 dissociation occurs via three different pathways in ER monomers. One resembles the mousetrap mechanism (Path I), involving repositioning of helix 12 (H12), others involve the separation of H8 and H11 (Path II), and a variant of this pathway at the bottom of the ligand-binding domain (Path II`). RAL leaves the receptor through Path I and a Path I variant in which the ligand leaves the receptor through the loop region between H11 and H12 (Path I`). Remarkably, ER dimerization strongly suppresses Paths II and II` for E-2 dissociation and modifies RAL escape routes. We propose that differences in ligand release pathways detected in the simulations for ER monomers and dimers provide an explanation for previously observed effects of ER quaternary state on ligand dissociation rates and suggest that dimerization may play an important, and hitherto unexpected, role in regulation of ligand dissociation rates throughout the nuclear receptor family.

Identification of protein-coding and intronic noncoding RNAs down-regulated in clear cell renal carcinoma

The clear cell subtype of renal cell carcinoma (RCC) is the most lethal and prevalent cancer of the urinary system. To investigate the molecular changes associated with malignant transformation in clear cell RCC, the gene expression profiles of matched samples of tumor and adjacent non-neoplastic tissue were obtained from six patients. A custom-built cDNA microarray platform was used, comprising 2292 probes that map to exons of genes and 822 probes for noncoding RNAs mapping to intronic regions. Intronic transcription was detected in all normal and neoplastic renal tissues. A subset of 55 transcripts was significantly down-regulated in clear cell RCC relative to the matched nontumor tissue as determined by a combination of two statistical tests and leave-one-out patient cross-validation. Among the down-regulated transcripts, 49 mapped to untranslated or coding exons and 6 were intronic relative to known exons of protein-coding genes. Lower levels of expression of SIN3B, TRIP3, SYNJ2BP and NDE1 (P<0.02), and of intronic transcripts derived from SND1 and ACTN4 loci (P<0.05), were confirmed in clear cell RCC by Real-time RT-PCR. A subset of 25 transcripts was deregulated in additional six nonclear cell RCC samples, pointing to common transcriptional alterations in RCC irrespective of the histological subtype or differentiation state of the tumor. Our results indicate a novel set of tumor suppressor gene candidates, including noncoding intronic RNAs, which may play a significant role in malignant transformations of normal renal cells. (C) 2008 Wiley-Liss, Inc.

Jämförande analys mellan svenska och portugisiska reklambyråer. : Saker som är bra att veta om man ska arbeta som grafisk formgivare i Sverige eller i Portugal

If you move from Sweden to Portugal to work as an Art Director at an Ad agency, there are certain things you ought to know. Perhaps even before you decide to move. There are a lot of things that are quite different if you compare Portugal to Sweden, not only the language, but also the design, software, working hours and much more. You have for example two month with double salary, you work till six p.m. and when it comes to maternity leave, you have 100% compensation with no taxes the first four months of every pregnancy. The tasks you have to handle as an Art Director in Portugal may, as in Sweden, be various. The difference is more how you solve your task and what the design looks like. As a Swede in Portugal the solution will probably look like a mixture between the Portuguese “expressive” and the Swedish “clean” design. This degree project discusses questions that might turn up when a Swede gets employed as an Art Director in Portugal. What will the salary be? When, in the morning, is it time to show up at the office? How many weeks of vacations are entitled? There are a lot of distinctions, but also a lot of similarities. The report is mainly based upon the author’s own experiences of the Ad agency McCann-Erickson in Lisbon. The history of McCann-Erickson starts in New York, 1930 and grew rapidly into one of the leading corporation with agencies all over the world. It is still today one of the world’s largest Ad company with clients like Coca-Cola and General Motors, and the slogan “truth well told” still lights up all their agencies after almost a century, just like a leading star.

Gender Equality a case study of Sweden : Gender Equality Gender Equity and policies of combating inequality at workplace to make the society equal.

The paper analyses Gender Equality, Gender Equity and policies of combating inequality at workplace to make the society equal as a case study of Sweden. The aim of paper is see the gender equality, gender equity, discrimination against women at workplace and to describe the policies combating inequality in the welfare state of Sweden. This work highlights the gender equality in terms of institutionalizing gender equality, gender equity, gender and pay gap, parental leave, gender and the pension system and sexual behavior directed towards women and policies combating inequality to bring equality in society. For my research I used the secondary data the fact sheets, scientific literature, statistics from eurostate of Sweden and case studies about Swedish society and the theoretical explanation to explain the phenomena. To achieve my aim I used the combination of both qualitative and quantitative methods of research. I showed the empirical evidences of these phenomena from the Swedish society and theoretical analysis about equality and equity of gender in different wakes of life. I found an interesting conclusion that there are good policies and legislation to combat inequality to bring society but there are no policies to change the perception of society about male and female role.

Los asilados de las embajadas de Europa Occidental en Chile tras el golpe militar y sus consecuencias diplomáticas : El caso de Suecia

Given the expectations that western governments had in the reforms being implemented by the Unidad Popular, the September 1973 coup d’état in Chile caused a great international outcry. The violence and repression that accompanied the military coup produced a worldwide repudiation of the military junta. Sweden stood out most consistently among the countries that declared their opposition to Chile during the period of the dictatorship by continuously denouncing the violations to human rights. In this context, Sweden’s Ambassador to Chile, Harald Edelstam, played a very important role in saving the lives of hundreds of Chilean citizens and foreign nationals who sought refuge from the regime’s bloody repression. Making use of the privileges he enjoyed as a diplomat, Edelstam confronted the military authorities to release people wrongfully sentenced to the death penalty. As a result, he was declared persona non grata and forced to leave Chile. This was the beginning of a long and controversial diplomatic relationship that lasted until the return of democracy in Chile in 1990. This article is a first attempt at understanding how human rights violations affected bilateral relations between Chile and Sweden with respect to the diplomatic efforts of Ambassador Harald Edelstam.

Hur retusch påverkar skönhetsannonsers attraktion : En studie om målgruppens åsikter och köplust

Tidigare studier som gjorts inom området visade att kvinnor anser att kvinnors skönhet inte är värderad enligt rimliga normer i vårt samhälle. Hård retuschering motarbetas på många håll, bland annat genom att organisationer som ASA (Advertising Standards Authority) och politiska partier som Liberaldemokraterna i Storbritannien arbetar för att missledande retuschering ska försvinna. En studie har visat att det, för att öka annonsers attraktionskraft, är viktigt att den ökade skönheten hos en modell är relevant för produktens användningsområde, då betraktaren anstränger sig intellektuellt vid betraktandet av bilden. Det finns dock inga tidigare studier som bevisar om en retuscherad modell faktiskt ökar målgruppens köplust av skönhetsprodukter vid rådande samhällsattityder och skönhetsideal. Två enkätundersökningar gjordes därför med sammanlagt 1480 deltagare. Produkten i studien var en fiktiv hudkräm. Genom att i den ena undersökningen låta betraktaren möta modellbilden i en situation som efterliknade verkligheten, på så sätt att de inte fick veta om den var retuscherad, kunde studien svara på om retuschering ökade köplusten. Bilder med bortretuscherade skönhetsfläckar och utväxt prefererades. Att retuschera bort flyghår ökade inte köplusten. I den andra jämförande undersökningen kunde betraktaren jämföra den retuscherade med den oretuscherade modellbilden. Resultaten visade att skönhetsfläckar och flyghår tillåts och prefereras borttagna, men inte utväxt. I intervjuer med fem kvinnor hördes målgruppens attityder om vad som ansågs var tillåtet att retuschera. Svaren tydde på att en relevant och försiktig retuschering prefererades. Att lämna några födelsemärken ökade trovärdigheten.

Förlorad i övergången från aritmetik till algebra : Hur gymnasieelever översätter aritmetik till algebra

The aim of this thesis is to look for signs of students’ understanding of algebra by studying how they make the transition from arithmetic to algebra. Students in an Upper Secondary class on the Natural Science program and Science and Technology program were given a questionnaire with a number of algebraic problems of different levels of difficulty. Especially important for the study was that students leave comments and explanations of how they solved the problems. According to earlier research, transitions are the most critical steps in problem solving. The Algebraic Cycle is a theoretical tool that can be used to make different phases in problem solving visible. To formulate and communicate how the solution was made may lead to students becoming more aware of their thought processes. This may contribute to students gaining more understanding of the different phases involved in mathematical problem solving, and to students becoming more successful in mathematics in general.The study showed that the students could solve mathematical problems correctly, but that they in just over 50% of the cases, did not give any explanations to their solutions.

Inte bara jämställdhet : Beslutet om föräldraledighet, moderskaps- och faderskapsidealoch idéer om barns bästa

More than gender equality. Decisions on parental leave and ideals around motherhood, fatherhood and the best interest of the child On the basis of 40 semi-structured interviews, this study discusses decision making processes regarding parental leave among nascent first-time middle-class parents in Sweden. We analyze motives and ideas behind the couples’ plans and decisions and how decisions on parental leave were made. We furthermore show how the decision making processes can be discussed in relation to the institutional context. The results show that ideals and norms of gender equality are accompanied by gendered divisions of work and care and a partially traditional view on motherhood and fatherhood. Contrary to previous studies, we do not find a clear link between gender equal ideals and explicit negotiations. An equal division of parental leave is, in some couples, taken for granted to such an extent that the decision on how to divide the leave is taken implicitly rather than explicitly. Decisions on division of parental leave are not isolated processes. Rather, ideals and norms around motherhood, fatherhood, gender equality and not least what is ‘in the best interest of the child’ constitute part of the context in which these decision making processes take place.

Lifestyle and health status in a sample of Swedish women four years after pregnancy : a comparison of women with a history of normal pregnancy and women with a history of gestational diabetes mellitus

Background: Despite the recommendations to continue the regime of healthy food and physical activity (PA) postpartum for women with previous gestational diabetes mellitus (GDM), the scientific evidence reveals that these recommendations may not be complied to. This study compared lifestyle and health status in women whose pregnancy was complicated by GDM with women who had a normal pregnancy and delivery. Methods: The inclusion criteria were women with GDM (ICD-10: O24.4 A and O24.4B) and women with uncomplicated pregnancy and delivery in 2005 (ICD-10: O80.0). A random sample of women fulfilling the criteria (n = 882) were identified from the Swedish Medical Birth Register. A questionnaire was sent by mail to eligible women approximately four years after the pregnancy. A total of 444 women (50.8%) agreed to participate, 111 diagnosed with GDM in their pregnancy and 333 with normal pregnancy/ delivery. Results: Women with previous GDM were significantly older, reported higher body weight and less PA before the index pregnancy. No major differences between the groups were noticed regarding lifestyle at the follow-up. Overall, few participants fulfilled the national recommendations of PA and diet. At the follow-up, 19 participants had developed diabetes, all with previous GDM. Women with previous GDM reported significantly poorer self-rated health (SRH), higher level of sick-leave and more often using medication on regular basis. However, a history of GDM or having overt diabetes mellitus showed no association with poorer SRH in the multivariate analysis. Irregular eating habits, no regular PA, overweight/obesity, and regular use of medication were associated with poorer SRH in all participants. Conclusions: Suboptimal levels of PA, and fruit and vegetable consumption were found in a sample of women with a history of GDM as well as for women with normal pregnancy approximately four years after index pregnancy. Women with previous GDM seem to increase their PA after childbirth, but still they perform their PA at lower intensity than women with a history of normal pregnancy. Having GDM at index pregnancy or being diagnosed with overt diabetes mellitus at follow-up did not demonstrate associations with poorer SRH four years after delivery.

Essays on firm dynamics in the Swedish wholesale trade sector

This thesis consists of a summary and five self-contained papers addressing dynamics of firms in the Swedish wholesale trade sector. Paper [1] focuses upon determinants of new firm formation in the Swedish wholesale trade sector, using two definitions of firms’ relevant markets, markets defined as administrative areas, and markets based on a cost minimizing behavior of retailers. The paper shows that new entering firms tend to avoid regions with already high concentration of other firms in the same branch of wholesaling, while right-of-the-center local government and quality of the infrastructure have positive impacts upon entry of new firms. The signs of the estimated coefficients remain the same regardless which definition of relevant market is used, while the size of the coefficients is generally higher once relevant markets delineated on the cost-minimizing assumption of retailers are used. Paper [2] analyses determinant of firm relocation, distinguishing between the role of the factors in in-migration municipalities and out-migration municipalities. The results of the analysis indicate that firm-specific factors, such as profits, age and size of the firm are negatively related to the firm’s decision to relocate. Furthermore, firms seems to be avoiding municipalities with already high concentration of firms operating in the same industrial branch of wholesaling and also to be more reluctant to leave municipalities governed by right-of-the- center parties. Lastly, firms seem to avoid moving to municipalities characterized with high population density. Paper [3] addresses determinants of firm growth, adopting OLS and a quantile regression technique. The results of this paper indicate that very little of the firm growth can be explained by the firm-, industry- and region-specific factors, controlled for in the estimated models. Instead, the firm growth seems to be driven by internal characteristics of firms, factors difficult to capture in conventional statistics. This result supports Penrose’s (1959) suggestion that internal resources such as firm culture, brand loyalty, entrepreneurial skills, and so on, are important determinants of firm growth rates. Paper [4] formulates a forecasting model for firm entry into local markets and tests this model using data from the Swedish wholesale industry. The empirical analysis is based on directly estimating the profit function of wholesale firms and identification of low- and high-return local markets. The results indicate that 19 of 30 estimated models have more net entry in high-return municipalities, but the estimated parameters is only statistically significant at conventional level in one of our estimated models, and then with unexpected negative sign. Paper [5] studies effects of firm relocation on firm profits of relocating firms, employing a difference-in-difference propensity score matching. Using propensity score matching, the pre-relocalization differences between relocating and non-relocating firms are balanced, while the difference-in-difference estimator controls for all time-invariant unobserved heterogeneity among firms. The results suggest that firms that relocate increase their profits significantly, in comparison to what the profits would be had the firms not relocated. This effect is estimated to vary between 3 to 11 percentage points, depending on the length of the analyzed period. 

Hälsofrämjande arbete på SSAB i Borlänge : Hälsofrämjande processer i arbetslivet och ledarskapets betydelse för medarbetarens hälsa

Problem: Arbetsmiljön är viktig för människors välbefinnande. Hälsofrämjande faktorer antas inte bara styrka individens fysiska och psykiska hälsa, utan även företagets konkurrenskraft och lönsamhet. I uppsatsen undersöker vi hur företaget SSAB i Borlänge arbetar med hälsa genom att tillämpa ett hälsofrämjande perspektiv och utgå från teorin om Känslan av sammanhang (KASAM). Ledarskapsvärderingar har betydelse för medarbetares hälsa (Hanson, 2004) och vi undersöker vilken uppfattning ett antal chefer har om sina roller i det hälsofrämjande arbetet och deras syn på medarbetarundersökningen HälsoSAM som företagshälsovården på SSAB bedriver. Arbetsbelastningen på medarbetare och chefer ökar till följd av sparkrav, samtidigt som resurserna minskar (Gatu, 2003). Följden blir en större risk för ohälsa och ett sätt att minska sjukfrånvaron är att genomföra hälsofrämjande insatser (Prevent, 2001). Syfte: Syftet med studien är att utifrån ett hälsofrämjande perspektiv förklara vad chefer har för möjligheter att skapa förutsättningar för att främja medarbetarnas hälsa på SSAB i Borlänge. Metod: Den metod som ligger till grund för uppsatsen baseras på ett kvalitativt angreppssätt där semistrukturerade intervjuer samt litteraturstudier genomförts för att samla information. Analys: Ledarens beteende påverkar medarbetarna. Hög arbetsbelastning på SSABs chefer leder till lägre närvaro bland medarbetarna, vilket i sin tur ger sämre förutsättningar för att främja hälsan. HälsoSAM kartlägger medarbetarnas hälsoläge, både välbefinnande och arbetskapacitet. Resultaten är vägledande i det hälsofrämjande arbetet men överbelastning, tidsbrist och kunskapsbrist hos cheferna bidrar till att uppföljningen inte blir systematisk. För ett väl fungerande hälsoarbete krävs systematik. Slutsats: Hälsofrämjande processer i arbetslivet skapas genom balans mellan krav och resurser. På SSAB i Borlänge hindras hälsoarbetet av tidsbrist och kunskapsbrist hos cheferna. Kostnadsbesparingar påverkar hälsoarbetet negativt och systematiken i uppföljningsarbetet blir lidande. Ansvaret för hälsoarbetet läggs på företagshälsovården, men utan stöd från chefer blir inte hälsoarbetet en naturlig del i verksamheten. Det är viktigt att i rådande situation se vad främjande av hälsa kan ge tillbaka till företaget i både ekonomiska och kvalitativa termer. Insikt om detta ökar chefernas incitament att prioritera hälsofrämjande processer och organisera arbetet så att människor har förutsättningar att hantera, kontrollera och klara av sina uppgifter.

Skilsmässor och separationer : Betydelsen av rollspecialisering och jämställdhet

Divorces and separations: the impact of role specialisation and equality At the same time as women made their large scale entrance on the labour market divorce rates increased in most western societies. This combination of societal trends was widely understood from the perspective of the specialization and trading model, which implies undermined marital stability through decreasing interdependency between husband and wife. We argue the need to acknowledge the new roles, and perceptions of these roles, men and women have in order to explain differences in separation and stability among couples. When both partners are expecting to be in paid labour and share housework responsibilities, specialisation could actually be a risk factor for cohabitational dissolution. This article uses a ten year longitudinal database of all Swedish cohabiting first time parents in 1993. The analyses generally support what could be labelled a role balance model on separation rather than the specialization model. Looking at the father’s participation in childcare this was quite clear, where the man’s outtake of parental leave for the first child was shown to be related to reduced hazards of separation. In the same way equal distribution of the household labour market incomes between the partners was related to lower hazards of separation.

Att bli, att vara och att ha varit - om ingångar i och utgångar ur Jehovas vittnen i Sverige

Summary To become, to be and to have been: about the  Jehovah’s Witnesses The Watchtower Bible and Tract Society, in the following text referred to as the Jehovah’s Witnesses or “the organisation”, is a worldwide Christian organisation with about 6.7 million members. The organisation has many times, without any success so far, proclaimed Armageddon when they expect Jehovah to return to Earth. They interpret the Bible in their own, often very literal way, and require their members to live according to these interpretations. Among the consequences of this, members are forbidden to vote, to do military service or to receive blood transfusions. Apart from attending the three weekly meetings, members are expected to be active in missionary work, known as “publishing”. If a member fails to do a certain number of hours’ publishing, he or she risks being deprived of active membership status Sweden in general is considered to be a society where the population is not very religious. The formerly state-governed Lutheran church has lost its influence and the vast majority of ordinary Swedes do not visit church on other occasions than weddings, funerals or christenings. Expressing one’s own religious values has become somewhat of a private matter where publicity is seldom appreciated, which is contrary to the practice of the Jehovah’s Witnesses. This is one of the reasons why the Jehovah’s Witnesses are commonly perceived by average Swedes as a “suspicious” religious organisation. The aim and methods of the study This dissertation seeks to describe and investigate the entering and leaving of a highly structured and hierarchical religious community, exemplified in this case by the Jehovah’s Witnesses. What are the thoughts and aspirations of someone who is considering becoming a Jehovah’s Witness? What are the priorities and what experiences seem important when a person is going through such a process? And when this person has finally reached his or her goal of becoming a member, is it the same motivation that makes him or her stay in the organisation for longer periods of time, possibly for the rest of their lives, or does it change during the process of entering, or does this motivation change its character during the transition from entering to being a regular member? Why do some of the members change their attitude to the Jehovah’s Witnesses from rejoicing to bitterness? And how does this process of exit manifest itself? In what way is it different from the process of entry? The respondents in this study were chosen from both active members of the Jehovah’s Witnesses in Sweden and those who have left the organisation for personal reasons. Repeated interviews with ten active members of the organisation have been conducted in the course of the study and compared to equal numbers of former members. The interviews have been semi-structured to deal with questions of how a person has come into contact with the organisation; how they retrospectively experienced the process of entry; the reasons for becoming a member. Questions have also been asked about life in the organisation. The group of “exiters” have also been asked about the experience of leaving, why they wanted to leave, and how this process was started and carried out. In addition to this I have analysed a four-year diary describing the time inside and the process of leaving the organisation. This has given me an extra psychological insight into the inner experience of someone who has gone through the whole process. The analysis has been done by categorising the content of the transcribed interviews. An attempt to outline a model of an entry and exit process has been made, based on ideas and interpretations presented in the interviews. The analysis of the diary has involved thorough reading, resulting in a division of it into four different parts, where each part has been given a certain key-word, signifying the author’s emotional state when writing it. A great deal of the information about the Jehovah’s Witnesses has been collected through discussion boards on the Internet, informal talks with members and ex-members, interviews with representatives of the organisations during visits to its different offices (Bethels), such as St. Petersburg, Russia, and Brooklyn, New York, USA. The context Each organisation evolves in its own context with its own norms, roles and stories that would not survive outside it. With this as a starting point, there is a chapter dedicated to the description of the organisation’s history, structure and activities. It has been stated that the organisation’s treatment of its critical members and the strategies for recruiting new members have evolved over the years of its history. At the beginning there was an openness allowing members to be critical. As the structure of the organisation has become more rigid and formalised, the treatment of internal critics has become much less tolerated and exclusion has become a frequent option. As a rule many new members have been attracted to the organisation when (1) the day of Armageddon has been pronounced to be approaching; (2) the members of the organisation have been persecuted or threatened with persecution; and (3) the organisation has discovered a “new market”. The processes for entering and exiting How the entering processes manifest themselves depends on whether the person has been brought up in the organisation or not. A person converting as an adult has to pass six phases before being considered a Jehovah’s Witness by the organisation. These are:  Contact with the Jehovah’s Witnesses, Studying the bible with members of the organisation, Questioning, Accepting, Being active as publisher (spreading the belief), Being baptised.  For a person brought up in the organisation, the process to full membership is much shorter:   Upbringing in the organisation, Taking a stand on the belief, Being baptised. The exit process contains of seven phases:   Different levels of doubts, Testing of doubts, Turning points, Different kinds of decisions, Different steps in executing the decisions, Floating, a period of emotional and cognitive consideration of membership and its experiences, Realtive neutrality.   The process in and the process out are both slow and are accompanied with anguish and doubts. When a person is going through the process in or out of the organisation he or she experiences criticism. This is when people around the adept question the decision to continue in the process. The result of the criticism depends on where in the process the person is. If he or she is at the beginning of the process, the criticism will probably make the person insecure and the process will slow down or stop. If the criticism is pronounced in a later phase, the process will probably speed up. The norms of the organisation affect the behaviour of the members. There are techniques for inclusion that both bind members to the organisation and shield them off from the surrounding society. Examples of techniques for inclusion are the “work situation” and “closed doors”. The work situation signifies that members who do as the organisation recommends – doing simple work – often end up in the same branch of industry as many other Jehovah’s Witnesses. This often means that the person has other witnesses as workmates. If the person is unemployed or moves to another town it is easy to find a new job through connections in the organisation. Doubts and exclusions can lead to problems since they entail a risk of losing one’s job. This can also result in problems getting a new job. Jehovah’s Witnesses are not supposed to talk to excluded members, which of course mean difficulties working together. “Closed doors” means that members who do as the organisation recommends – not pursuing higher education, not engaging in civil society, working with a manual or in other way simple job, putting much time into the organisation – will, after a long life in the organisation, have problems starting a new life outside the Jehovah’s Witnesses. The language used in the organisation shows the community among the members, thus the language is one of the most important symbols. A special way of thinking is created through the language. It binds members to the organisation and sometimes it can work as a way to get back into the normative world of the organisation. Randall Collins’s (1990, 2004) thoughts about “emotional energy” have enabled an understanding of the solidarity and unity in the organisation. This also gives an understanding of the way the members treat doubting and critical members. The members who want to exit have to open up the binding/screening off. A possible way to do that is through language, to become aware of the effect the language might have. Another way is to search for emotional energy in another situation. During the exit process, shame might be of some importance. When members become aware of the shame they feel, because they perceive they are “acting a belief”, the exit process might accelerate.