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I write to put the imagined threats and horrors of the very early days of motherhood into words on paper rather than leaving them as self-depleting, snowballing, internal echoes bounding within a recently emptied body. My contribution to this publication consists of four poems. Poetry provides a space for honesty. It can be pretty and seductive but just as often grimy and fearful and, in all honesty, it is most likely neither fully but a messy mix of it all. For me, the fear and worry that took place within the domestic in the very first part of motherhood was particularly connected to breastfeeding and the perceived pressures of extended family. The poems might highlight difficult feelings that seem less than ideal. But through bringing these to the fore, I want my poetic work to challenge ideals that surround the maternal role. The aim is to give mothers some much-needed recognition at a time when it is so easy to feel alienated and strange. I am also so aware that I am writing for my growing daughter. My most valued future reader. At the time of writing, the poems provide a welcome, an introduction and an important lesson that dog food is inedible. Which brings about another priority of mine, extending across all my work. Though the core matter of my work is so serious, humour and light heartedness provide an amazing tool to reach towards the audience and bring it close.

The purpose of this scoping review was to identify studies where young children’s engagement in early childhood education and care (ECEC) settings was measured and to investigate conceptualizations and operationalizations of child engagement. The literature search conducted in March 2021 included ERIC, PsychInfo, Scopus and Web of Science databases and it resulted in 5965 articles, of which 286 were included in this review. Eligibility criteria were measurements of child engagement in any formal ECEC setting before starting first grade. Data was extracted about engagement conceptualization, theoretical frameworks, study population, study design, and engagement measurement tools and methods. The results showed variations both in the definitions and in the measurement of child engagement. The most common method of measuring children’s engagement in ECEC was observations by an external observer, followed by teacher surveys. Measures of general child engagement in ECEC have a focus on behavioral aspects of engagement while measures that focus on academic activities are more likely to include additional cognitive and emotional aspects of engagement. Child self-reports were rarely used and only present in measures of academic engagement of young children. About one-third of the identified studies relied on unestablished measures of child engagement. Seventy-seven unique established measures of child engagement were identified.

The author has a crackly relationship with photography. In fact, they have at times struggled to see eye to eye. Photography has seemed awkward, with its sharp, obvious, physical boundaries and flat, printed surface. Yet, as an artist, the author has come back to photography again and again. When making autobiographical work, the author brought the camera with me to places where there has been pain. But the author has often wondered if photography cannot offer enough. In this chapter, autobiography is fragmented and messy. It includes sexual violence, and moreover, the folding of these experiences into the self. The aim is to discover if and how these experiences alter interactions with hierarchy but also influence artistic vision and methodology.

Purpose At the outbreak of the COVID-19 pandemic, health care was at the centre of the crisis. New demands made existing organizational practices and services obsolete. Primary health care had a great deal of responsibility for COVID-19-related care. The pandemic demanded effective leadership to manage the new difficulties. This paper aims to explore experiences and perceptions of managers in primary health care in relation to their efforts to manage the COVID-19 crisis in their everyday work. Design/methodology/approach The authors used a qualitative approach based on 14 semi-structured interviews with managers in primary health care from four regions in Sweden. The interviews were conducted during September to December 2020. Data were analysed using conventional qualitative content analysis. Findings Data analysis yielded three categories: lonely in decision-making; stretched to the limit; and proud to have coped. The participants felt lonely in their decision-making, and they were stretched to the limit of their own and the organization’s capacity. The psychosocial working conditions in primary care worsened considerably during the pandemic because demands on leaders increased while their ability to control the work situation decreased. However, they also expressed pride that they and their employees had managed the situation by being flexible and having a common focus. Originality/value Looking ahead and using lessons learnt, and apart from making wise decisions under pressure, an important implication for primary health-care leaders is to not underestimate the power of acknowledging the virtues of humanity and justice during a crisis. Continuing professional education for leaders focusing on crisis leadership could help prepare leaders for future crises.

Background The initial responses to the COVID-19 pandemic in Denmark and Sweden differed markedly. Balancing disparate concerns was crucial to generate trust in the COVID-19 restrictions. Political trust is public support for core political institutions. The aim was to investigate the extent to which there was trust in the handling of the pandemic by the Danish and Swedish governments and trust in the handling of the pandemic by the leading public health authorities in each country. A further aim was also to investigate the characteristics of those in Denmark and Sweden who expressed the lowest degree of trust. Methods Cross-sectional surveys were conducted in 2021, using web panels that are nationally representative of the socio-demographic characteristics. The population consisted of 2619 individuals from Denmark and 2633 from Sweden, representative of the age, sex and region of residence of the populations aged ≥ 18 years. Trust was captured in two questions: trust in how the government and the public health authority in each country had handled the pandemic. Responses on the two trust items were on a five-point Likert scale. Those who expressed “very small trust” or “moderately small trust” were labelled “low trusters”. Results Approximately 61% of the Danish respondents expressed moderately large or very large trust in the government’s handling of the pandemic. The corresponding proportion for Sweden was 42%. The proportion of low trusters was 11% in Denmark and 34% in Sweden. Moderately large or very large trust in the public health authority’s handling was expressed by 83% of the Danish respondents and 74% of the Swedes. The proportion of low trusters was 5% in Denmark and 17% in Sweden. In both countries, trust was lower among men than among women and among those aged 65 years. Conclusions Danes expressed significantly higher trust in their government’s handling of the pandemic than Swedes. In both countries, trust in the public health authority’s handling of the pandemic was higher than that for the government’s handling. Several socio-demographic characteristics were associated with lower trust in handling the pandemic by the government and public health authority.

BACKGROUND: Studies of the social validity of work ability evaluations are rare, although the concept can provide valuable information about the acceptability, comprehensibility and importance of procedures. OBJECTIVE: The aim of this study was to explore clients’ perceptions of social validity of work ability evaluations and the following official decisions concerning sickness benefits within the Swedish sickness insurance system. MATERIALS AND METHODS: This was a longitudinal qualitative study based on interviews with 30 clients on sick leave, analyzed through deductive content analysis. RESULTS: Clients’ understanding of the evaluation was dependent on whether the specific tests were perceived as clearly related to the clients’ situation and what information they received. For a fair description of their work ability, clients state that the strict structure in the evaluation is not relevant to everyone. CONCLUSION: The work ability evaluations indicate low acceptability due to lack of individual adaptation, the comprehensibility varied depending on the applicability of the evaluation and information provided, while the dimension ‘importance’ indicated as higher degree of social validity. The official decision about sickness benefits however was considered unrelated to the evaluation results, lacking solid arguments and sometimes contradictory to other stakeholders’ recommendations indicating poor social validity.

Purpose of review Ambulatory surgery is increasing, more procedures as well as more complex procedures are transferred to ambulatory surgery. Patients of all ages including elderly and more fragile are nowadays scheduled for ambulatory surgery. Enhanced recovery after surgery (ERAS) protocols are now developed for further facilitating readily recovery, ambulation, and discharge. Thus, to secure safety, a vigilant planning and preparedness for adverse events and emergencies is mandatory. Recent findings Proper preoperative assessment, preparation/optimization and collaboration between anaesthetist and surgeon to plan for the optimal perioperative handling has become basic to facilitate well tolerated perioperative course. Standard operating procedures for rare emergencies must be in place. These SOPs should be trained and retrained on a regular basis to secure safety. Check lists and cognitive aids are tools to help improving safety. Audit and analysis of adverse outcomes and deviations is likewise of importance to continuously analyse and implement corrective activity plans whenever needed. Summary The present review will provide an oversight of aspects that needs to be acknowledged around planning handling of rare but serious emergencies to secure quality and safety of care in freestanding ambulatory settings.

Recognition motifs that mediate protein-protein interactions are usually embedded within longer intrinsically disordered regions. While binding interfaces involving the recognition motif in such interactions are well studied, less is known about the role of disordered regions flanking the motifs. The interaction between the transcriptional co-activators NCOA3 (ACTR) and CBP is mediated by coupled binding and folding of the two domains CID and NCBD. Here, we used circular dichroism and kinetics to directly quantify the contribution of the adjacent flanking regions of CID to its interaction with NCBD. Using N-and C terminal combinatorial variants we found that the flanking regions promote binding in an additive fashion while retaining a large degree of disorder in the complex. Experiments at different ionic strengths demonstrated that the increase in affinity is not mediated by electrostatic interactions from the flanking regions. Instead, site-directed mutagenesis and molecular dynamics simulations suggest that binding is promoted by short-lived non-specific hydrophobic contacts between the flanking regions and NCBD. Our findings are consistent with highly frustrated interactions outside of the canonical binding interface resulting in a slightly energetically favorable fuzzy binding. Modulation of affinity via flanking regions could represent a general mechanism for functional regulation by intrinsically disordered protein regions.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Evolution of proteins is constrained by their structure and function. While there is a consensus that the plasticity of intrinsically disordered proteins relaxes the structural constraints on evolution there is a paucity of data on the molecular details of these processes. The Nuclear co-activator binding domain (NCBD) from CREB-binding protein is a protein-protein interaction domain, which contains a hydrophobic core but is not behaving as a typical globular domain, and has been desribed as ‘molten-globule like’. The highly dynamic properties of NCBD makes it an interesting model system for evolutionary structure-function investigation of intrinsically disordered proteins. We have here compared the structure and biophysical properties of an ancient version of NCBD present in a bilaterian animal ancestor living around 600 million years ago with extant human NCBD. Using a combination of NMR spectroscopy, circular dichroism and kinetic methods we show that although NCBD has increased its thermodynamic stability, it has retained its dynamic biophysical properties in the ligand-free state in the evolutionary lineage leading from the last common bilaterian ancestor to humans. Our findings suggest that the dynamic properties of NCBD have been maintained by purifying selection and thus are important for its function, which includes mediating several distinct protein-protein interactions.

PurposeThe protein tyrosine phosphatase PTPN2 dephosphorylates several tyrosine kinases in cancer-related signalling pathways and is thought to be a tumour suppressor. As PTPN2 is not frequently studied in breast cancer, we aimed to explore the role of PTPN2 and the effects of its loss in breast cancer.MethodsProtein expression and gene copy number of PTPN2 were analysed in a cohort of pre-menopausal breast cancer patients with immunohistochemistry and droplet digital PCR, respectively. PTPN2 was knocked down in three cell lines, representing different breast cancer subtypes, with siRNA transfection. Several proteins related to PTPN2 were analysed with Western blot.ResultsLow PTPN2 protein expression was found in 50.2% of the tumours (110/219), gene copy loss in 15.4% (33/214). Low protein expression was associated with a higher relapse rate in patients with Luminal A and HER2-positive tumours, but not triple-negative tumours. In vitro studies further suggested a subtype-specific role of PTPN2. Knockdown of PTPN2 had no effect on the triple-negative cell line, whilst knockdown in MCF7 inhibited phosphorylation of Met and promoted that of Akt. Knockdown in SKBR3 led to increased Met phosphorylation and decreased Erk phosphorylation as well as EGF-mediated STAT3 activation.ConclusionWe confirm previous studies showing that the PTPN2 protein is lost in half of the breast cancer cases and gene deletion occurs in 15-18% of the cases. Furthermore, the results suggest that the role of PTPN2 is subtype-related and should be further investigated to assess how this could affect breast cancer prognosis and treatment response. Funding Agencies|Swedish Cancer Society; ALF Grants, Region Ostergotland; LiU Cancer Foundation; Cancer Research Foundations of Radiumhemmet; Onkologiska Klinikernas i Linkoping Forskningsfond

Purpose The protein tyrosine phosphatase, non-receptor type 2 (PTNP2) regulates receptor tyrosine kinase signalling, preventing downstream activation of intracellular pathways like the PI3K/Akt pathway. The gene encoding the protein is located on chromosome 18p11; the 18p region is commonly deleted in breast cancer. In this study, we aimed to evaluate PTPN2 protein expression in a large breast cancer cohort, its possible associations to PTPN2 gene copy loss, Akt activation, and the potential use as a clinical marker in breast cancer. Methods PTPN2 protein expression was analysed by immunohistochemistry in 664 node-negative breast tumours from patients enrolled in a randomised tamoxifen trial. DNA was available for 146 patients, PTPN2 gene copy number was determined by real-time PCR. Results PTPN2 gene loss was detected in 17.8% of the tumours. Low PTPN2 protein expression was associated with higher levels of nuclear-activated Akt (pAkt-n). Low PTPN2 as well as the combination variable low PTPN2/high pAkt-n could be used as predictive markers of poor tamoxifen response. Conclusion PTPN2 negatively regulates Akt signalling and loss of PTPN2 protein along with increased pAkt-n is a new potential clinical marker of endocrine treatment efficacy, which may allow for further tailored patient therapies. Funding Agencies|Swedish Cancer Society; Cancer Research Foundations of Radiumhemmet; Cancer Society in Stockholm; King Gustav V Jubilee Clinical Research Foundation; ALF grants Region Ostergotland; Onkologiska Klinikernas i Linkoping Forskningsfond

There are multiple examples of protein-protein interactions involving one intrinsically disordered protein region binding to an ordered protein domain in a coupled binding and folding reaction. Similarly to protein folding studies, much effort has been devoted to understanding the mechanisms of such coupled binding and folding reactions. In this chapter, we describe how kinetics can be used to assess binding mechanisms with focus on fluorescence-monitored stopped-flow experiments. The approach can be applied more generally to any protein interaction with or without a coupled conformational change and to other kinetic techniques. Determining binding mechanisms is a great challenge and while "proving" a mechanism may be futile, it is possible to deduce the simplest scenarios, which are consistent with experimental data.

Objective: To investigate and summarize the literature on the validation of International classification of functioning, disability and health (ICF) core sets from 2001 to 2019 and explore what res...

Background-\ud \ud Tinnitus is one of the most frequent chronic conditions in adults with wide range of consequences.\ud \ud Aims/Objectives-\ud \ud The aim of the current study was to determine the problems and life effects reported by individuals with tinnitus using the International Classification of Functioning, Disability and Health (ICF) framework.\ud \ud Material and Methods-\ud \ud The study used a cross-sectional survey design. A total of 344 individuals with tinnitus completed a series of questionnaires. The responses to open-ended questions were linked to ICF categories.\ud \ud Results-\ud \ud Activity limitations and participation restrictions were most dominant consequence of tinnitus followed by effect on the body function with limited emphasis on the contextual factors. Frequently reported responses to body function involved emotional functions (b152), attention function (b140), and sleep functions (b134). Commonly reported responses to activity limitations and participation restrictions were recreation and leisure (d920), conversation (d350), communicating with—receiving—spoken messages (d310), listening (d115), and remunerative employment (d850). Sound intensity (e2500) and sound quality (e2501) were the frequently reported responses to environmental factors. Coping styles, past and present experiences, and lifestyle were the most frequently occurring personal factors.\ud \ud Conclusions and significance-\ud \ud The study highlighted some key influencing factors of tinnitus in different ICF domains which can be helpful in rehabilitation planning.

Purpose: Sickness insurance and workers’ compensation systems decide on peoples’ eligibility for benefits, and are commonly based on medical certificates and assessments of work ability. Systems differ in the extent to which they preserve clients’ dignity and right to fair assessments. In this article, we define a new concept for studying interactions between individuals and systems: social insurance literacy, which concerns how well people understand the different procedures and regulations in social insurance systems, and how well systems communicate with clients in order to help them understand the system. Methods: The concept was defined through a scoping literature review of related concepts, a conceptual re-analysis in relation to the social insurance field, and a following workshop. Results: Five related concepts were reviewed for definitions and operationalizations: health literacy, financial/economic literacy, legal capability/ability, social security literacy, and insurance literacy. Conclusions: Social insurance literacy is defined as the extent to which individuals can obtain, understand and act on information in a social insurance system, related to the comprehensibility of the information provided by the system. This definition is rooted in theories from sociology, social medicine and public health. In the next step, a measure for the concept will be developed based on this review.Implications for rehabilitationSocial insurance literacy is a new concept that is based on theories in sociology, social medicine and public health.It provides conceptual orientation for analyzing factors that may influence different outcomes of peoples’ contacts with social insurance systems.The concept is of relevance for rehabilitation professionals since it focuses on how interactions between individuals and systems can influence the rehabilitation process.The study will in the next step develop a measure of social insurance literacy which will have practical applications for rehabilitation professionals. Social insurance literacy is a new concept that is based on theories in sociology, social medicine and public health. It provides conceptual orientation for analyzing factors that may influence different outcomes of peoples’ contacts with social insurance systems. The concept is of relevance for rehabilitation professionals since it focuses on how interactions between individuals and systems can influence the rehabilitation process. The study will in the next step develop a measure of social insurance literacy which will have practical applications for rehabilitation professionals.

There are multiple examples of protein-protein interactions involving one intrinsically disordered protein region binding to an ordered protein domain in a coupled binding and folding reaction. Similarly to protein folding studies, much effort has been devoted to understanding the mechanisms of such coupled binding and folding reactions. In this chapter, we describe how kinetics can be used to assess binding mechanisms with focus on fluorescence-monitored stopped-flow experiments. The approach can be applied more generally to any protein interaction with or without a coupled conformational change and to other kinetic techniques. Determining binding mechanisms is a great challenge and while "proving" a mechanism may be futile, it is possible to deduce the simplest scenarios, which are consistent with experimental data.

Syfte: Klimatförändringarna bidrar till att Sverige kommer att få ett förändrat regnmönster. Vilket leder till att större krav ställs på dagvattenhaneringen och dess funktion. När grönytor bebyggs ökar risken för översvämningar vid stora skyfall. Det är därför viktigt att anpassa städerna efter de framtida skyfallen samt att dagvattenhanteringen utvecklas och inte nedprioriteras. Syftet med studien är att ge svar på vilka lösningar som används mest och är framgångsrika i kommunerna, vilka faktorer som påverkar kommunernas beslut vid val av dagvattenlösning och hur kommunerna tar hänsyn till klimatförändringarna när det väljer dagvattenlösning. Metod: Litteraturstudien har gett rapporten forskningsfronten inom ämnet och en bra vetenskaplig grund att baseras på. Sex olika interjuver har utförts med respondenter från VA- och samhällsbyggnadsavdelningen på tre kommuner i Skaraborg. Studiens deltagande kommuner är Lidköpings kommun, Skövde kommun och Falköpings kommun. Intervjuerna var indelade i olika huvudkategorier för att kunna besvara studiens frågeställningar. En dokumentanalys har gjorts utifrån ritningar och dokument på nyexploaterade bostadsområden från kommunernas hemsidor. Resultat: Den dagvattenhantering som används mest i kommunerna är öppna dagvattenlösningar så som öppna diken, fördröjningsytor och dammar. Vilket gör lösningarna till de mest framgångsrikaste. Genom öppna dagvattenlösningar säkras samhället från översvämningar då lösningen kan reglera vatten. Faktorer som påverkar kommuners val av lösning är kunskap om dagvatten, samarbetet mellan avdelningarna, teknisk funktion, tid, kapital, lagar och rekommendationer. Utformning av vägar, vattenvägar och höjdsättning i nyexploaterade bostadsområden är viktiga faktorer som kommunerna tar hänsyn till för att klara av de pågående klimatförändringarna. Konsekvenser: Slutsatser som kan tas av studien är att öppna dagvattenlösningar är det som kommunerna strävar efter att använda. Dessutom är lösningen bäst tillämpningsbar för att klara av klimatförändringarna. Genom att använda öppna dagvattenlösningar behöver inte avkall på funktion göras för att använda den billigaste lösningen. Bostadsområdena utformas med vattenvägar, strategiska utlopp och utefter klimatfaktorn. För att uppnå bra dagvattenhantering är personalens kunskapsläge och samarbete mellan avdelningar en viktig del. Rekommendationer som kommunerna kan arbeta vidare med för att få en bättre hållbar dagvattenhantering är utöka kunskap bland de anställda, förbättra samarbetet, granska konsulternas arbete och öka tillsyn samt uppföljningen i produktionen. Begränsningar: Studien har avgränsats till tre kommuner med samma geografiska läge i Sverige. Det går att generalisera studien för att det finns städer i Sverige som har liknande antal invånare. Purpose: The climate changes contribute to Sweden’s future change in rain pattern. This leads to a higher demand on the stormwater management and its function. When green areas are built upon the risk for flooding increase when heavy rains occur. It is therefore important to adapt the cities according to future heavy rains and the stormwater management should not be downgraded. The goal of this study is to answer what solutions are used the most and are successful in the municipalities, what factors that affect the municipalities choice of stormwater solution and how the municipalities account for climate changes when choosing stormwater solutions. Method: The literature review has given the report the research front within the subject and a good scientific base to be based upon. Six different interviews have been held with respondents from the water and plant-department and the community building department withing three municipalities in Skaraborg. The participating municipalities are Lidköpings municipality, Skövdes municipality and Falköpings municipality. The interviews are split into different main categories to answer the questions at issue. A document analysis has been done based upon blueprints and document of newly exploited residential areas from the municipalities’ websites. Findings: The stormwater management solution that is used the most in the municipalities are open stormwater solutions, such as trenches, delay surfaces and ponds. This makes these solutions the most successful. Through open stormwater solutions the society is secured from flooding since the solution can regulate the water. Factors that affect the municipalities choice of solution are knowledge of stormwater, the cooperation between departments, technical function, time, money, laws, and recommendations. The design of roads, waterways, and elevation in newly exploited residential areas are important factors that the municipalities consider, in order to manage the ongoing climate changes. Implications: Conclusions that can be drawn from the study is that open stormwater solutions are what the municipalities strive towards using. In addition, the solution is best suited to manage the climate changes. Through using open stormwater solutions, a need to waiver on function is not needed to use the cheapest solution. The residentials areas are designed with waterways, strategic outlets and along the climate factor. To achieve good stormwater management the level of knowledge within the staff and the cooperation between departments are important. Recommendations that the municipalities could continue to work with to get a more sustainable stormwater management is to expand the knowledge between the staff, improve the cooperation, review the consultants work, increase supervision and to follow up in production. Limitations: The study has been delimited to three municipalities with the same geographic location in Sweden. It is possible to generalize the study since there are cities in Sweden with similar a amount of residents.

Objective: Hearing loss (HL) affects the everyday functioning of millions of people worldwide. The Brief International Classification of Functioning Disability and Health (ICF) core sets for HL was developed to meet the complex health care needs of adults with HL. Because the brief core set for HL has not yet been validated internationally, this study aimed to investigate its validity from an international perspective. Design: A cross-sectional validation study based on data from structured interviews with adults with HL. Study sample: Participants (n ¼ 571) from India, South Africa, Sweden and the US were included. Results: A six-factor solution explained 71% of the variance, focussing on issues related to communication, the social environment, participation in society, health care services, support, relationships and emotions (a ¼ 0.915). Three ICF categories demonstrated low reliability – temperament and personality functions, seeing functions and school education. Conclusion: The Brief ICF core set for HL is valid for adults with HL internationally. However, to further increase its international validity, we recommend adding the categories d920 recreation and leisure and replacing d850 school education with the more inclusive block, d810-d839 education.

Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low affinity to a higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we map native contacts in the transition states of the low-affinity ancestral and high-affinity human NCBD/CID interactions. We show that the coupled binding and folding mechanism is overall similar but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. Adaptation to new binding partners may be facilitated by this ability to exploit multiple alternative transient interactions while retaining the overall binding and folding pathway.

Intrinsically disordered protein (IDP) domains often have multiple binding partners. Little is known regarding molecular changes in the binding mechanism when a new interaction evolves from low to high affinity. Here we compared the degree of native contacts in the transition state of the interaction of two IDP domains, low-affinity ancestral and high-affinity human NCBD and CID. We found that the coupled binding and folding mechanism of the domains is overall similar, but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex while more heterogenous transient interactions, including electrostatic, and an increased disorder characterize the human complex. From an evolutionary perspective, adaptation to new binding partners for IDPs may benefit from this ability to exploit multiple alternative transient interactions while retaining the overall pathway.

Purpose: The purpose of this study was to investigate how communication within the Swedish sickness insurance system differs between cases of sick leave and how this may affect clients’ cases. Materials and methods: This was a document study using 30 client files from the Swedish Social Insurance Agency (SIA). The clients included had been on a work ability evaluation during their sick leave spell and were aged 32–64 years. The material was analyzed using qualitative document analysis. Results: The results show different approaches to communication, characterized by emotional argumentation, matter-of-fact driven argumentation and information exchange, which have diverse success in affecting official decisions. Arguments characterized by emotions such as frustration or desperation are to a larger extent neglected by the authorities compared to those characterized by a matter-of-fact driven approach and referring to regulations and medical certificates. Conclusion: There are differences regarding how clients and stakeholders communicate the clients’ needs and pre-requisites, and how this affects official decisions. Further research must be carried out in order to establish social insurance literacy, initially for individuals on sick leave within the sickness insurance system, and whether there are differences between diverse groups that could lead to injustices. Implications for rehabilitation Within a social insurance context, professionals need to provide clients with adequate and individually adapted information in order for procedures to be perceived as comprehensible and manageable by the clients. The support from stakeholders such as the treating physician and/or employer can affect clients’ sick-leave process. Clients’ treating medical professionals can contribute to ensuring that clients rights are met by communicating the clients’ needs to other stakeholders in a formal way.

The interaction between the transcriptional coactivators CREBBP/p300 and NCOA is governed by two intrinsically disordered domains called NCBD and CID, respectively. The CID domain emerged within the NCOA protein in deuterostome animals (including vertebrates) after their split from the protostomes (molluscs, worms, and arthropods). However, it has not been clear at which point a high affinity interaction evolved within the deuterostome clade and whether all present‐day deuterostome animals have a high affinity NCBD:CID interaction. We have here expressed and measured affinity for NCBD and CID domains from animal species representing different evolutionary branches of the deuterostome tree. While all vertebrate species have high‐affinity NCBD:CID interactions we found that the interaction in the echinoderm purple sea urchin is of similar affinity as that of the proposed ancestral domains. Our findings demonstrate that the high‐affinity NCBD:CID interaction likely evolved in the vertebrate branch and question whether the interaction between CREBBP/p300 and NCOA is essential in nonvertebrate deuterostomes. The data provide an example of evolution of transcriptional regulation through protein‐domain based inventions.

Background Professionals need to be able to express what is at stake during the decision-making process and the discrepancy between formal rules and practical rationality need to be bridgeable and transparent for outsiders. Investigations of social validity for work ability assessments are rare. However, the concept can provide valuable information upon the acceptability and comprehensibility of procedures and how professionals can increase clients’ participation. The purpose of this study was to investigate social validity for work ability evaluations within the sickness insurance system and the official decisions they lead to. Methods This was a longitudinal qualitative study using telephone interviews and files from the Swedish Social Insurance Agency. Clients (n = 30) were interviewed after their participation in a work ability evaluation as well as after receiving an official decision upon eligibility for sickness benefits. Data was analyzed using a deductive content analysis. Results Preliminary findings show that clients’ comprehensibility of the different tests and their composition were depending on whether the specific tests were perceived as clearly related to the clients’ difficulties and what information they had received. In order to receive a fair description of the client’s work ability, clients state that the work ability evaluation needs to be individually adapted and that the standardized structure is not relevant for all. What is acceptable and fair to one client could be unacceptable to another, depending on what arguments and information case-managers and evaluation professionals provided. Conclusions Authorities need to express and motivate the reasons for a diverse range of steps during clients sick-leave process, not only regarding official decisions. Social validity for work ability evaluations is depending on the provided information and the applicability to the clients’ situation. Key messages Social validity is depending on the provided information and the applicability to the clients’ situation. Authorities need to communicate clearly with clients through the whole sick-leave process.

Intrinsically disordered proteins organize interaction networks in the cell in many regulation and signaling processes. These proteins often gain structure upon binding to their target proteins in multistep reactions involving the formation of both secondary and tertiary structure. To understand the interactions of disordered proteins, we need to understand the mechanisms of these coupled folding and binding reactions. We studied helix formation in the binding of the molten globule-like nuclear coactivator binding domain and the disordered interaction domain from activator of thyroid hormone and retinoid receptors. We demonstrate that helix formation in a rapid binding reaction can be followed by stopped-flow synchrotron-radiation circular dichroism (CD) spectroscopy and describe the design of such a beamline. Fluorescence-monitored binding experiments of activator of thyroid hormone and retinoid receptors and nuclear coactivator binding domain display several kinetic phases, including one concentration-independent phase, which is consistent with an intermediate stabilized at high ionic strength. Time-resolved CD experiments show that almost all helicity is formed upon initial association of the proteins or separated from the encounter complex by only a small energy barrier. Through simulation of mechanistic models, we show that the intermediate observed at high ionic strength likely involves a structural rearrangement with minor overall changes in helicity. Our experiments provide a benchmark for simulations of coupled binding reactions and demonstrate the feasibility of using synchrotron-radiation CD for mechanistic studies of protein-protein interactions.

Intrinsically disordered proteins organize interaction networks in the cell in many regulation and signalling processes. These proteins often gain structure upon binding to their target proteins in multi-step reactions involving the formation of both secondary and tertiary structure. To understand the interactions of disordered proteins, we need to understand the mechanisms of these coupled folding and binding reactions. We studied helix formation in the binding of the molten globule-like nuclear coactivator binding domain (NCBD) and the disordered interaction domain from activator of thyroid hormone and retinoid receptors (ACTR). We demonstrate that helix formation in a rapid binding reaction can be followed by stopped flow synchrotron-radiation circular dichroism spectroscopy, and describe the design of such a beamline. Fluorescence-monitored binding experiments of ACTR and NCBD display several kinetic phases including one concentration-independent phase, which is consistent with an intermediate stabilized at high ionic strength. Time resolved circular dichroism experiments show that almost all helicity is formed upon initial association of the proteins, or separated from the encounter complex by only a small energy barrier. Through simulation of mechanistic models, we show that the intermediate observed at high ionic strength likely involves a structural rearrangement with minor overall changes in helicity. Our experiments provide a benchmark for simulations of coupled binding reactions and demonstrate the feasibility of using synchrotron radiation circular dichroism for mechanistic studies of protein-protein interactions.

Structural snapshots characterize six hundred million years of evolution of intrinsically disordered proteins., In every established species, protein-protein interactions have evolved such that they are fit for purpose. However, the molecular details of the evolution of new protein-protein interactions are poorly understood. We have used nuclear magnetic resonance spectroscopy to investigate the changes in structure and dynamics during the evolution of a protein-protein interaction involving the intrinsically disordered CREBBP (CREB-binding protein) interaction domain (CID) and nuclear coactivator binding domain (NCBD) from the transcriptional coregulators NCOA (nuclear receptor coactivator) and CREBBP/p300, respectively. The most ancient low-affinity “Cambrian-like” [540 to 600 million years (Ma) ago] CID/NCBD complex contained less secondary structure and was more dynamic than the complexes from an evolutionarily younger “Ordovician-Silurian” fish ancestor (ca. 440 Ma ago) and extant human. The most ancient Cambrian-like CID/NCBD complex lacked one helix and several interdomain interactions, resulting in a larger solvent-accessible surface area. Furthermore, the most ancient complex had a high degree of millisecond-to-microsecond dynamics distributed along the entire sequences of both CID and NCBD. These motions were reduced in the Ordovician-Silurian CID/NCBD complex and further redistributed in the extant human CID/NCBD complex. Isothermal calorimetry experiments show that complex formation is enthalpically favorable and that affinity is modulated by a largely unfavorable entropic contribution to binding. Our data demonstrate how changes in structure and motion conspire to shape affinity during the evolution of a protein-protein complex and provide direct evidence for the role of structural, dynamic, and frustrational plasticity in the evolution of interactions between intrinsically disordered proteins.

Purpose: The Swedish Social Insurance Administration has developed a new assessment tool for sickness insurance. This study is a part of the initial evaluation of the application, called the Assessment of Work Performance, Structured Activities, and focuses on evaluation of the psychometric properties of social validity, content validity, and utility. Materials and methods: This was a qualitative study using semi-structured telephone interviews with occupational therapists. A convenience sample was used and participants who fulfilled inclusion criteria (n = 15) were interviewed. Data were analyzed using content analysis with a directed approach. Results: The results indicate that the application provides valuable information and that it is socially valid. Assessors found work tasks suitable for a diverse group of clients and reported that clients accepted the assessments. Improvements were suggested, for example, expanding the application with more work tasks. Conclusion: The instrument has benefits; however, further development is desired. The use of a constructed environment in assessments may be a necessary option to supplement a real environment. But depending on organizational factors such as time and other resources, the participants had different opportunities to do so. Further evaluations regarding ecological validity are essential to ensure that assessments are fair and realistic when using constructed environments. Implications for rehabilitation This study indicates that assessment in a constructed environment can provide a secure and protected context for clients being assessed. Psychometric evaluations are a never-ending process and this assessment instrument needs further development. However, this initial evaluation provides guidance in development of the instrument but also what studies to give priority to. It is important to evaluate social validity in order to ensure that clients and assessors perceive assessment methods fair and meaningful. In this study, participants found the work tasks appropriate and usable when assessing their clients but client’s perspective must also be included in following studies. This assessment instrument is the only activity-based assessment instrument within the Swedish Social Security Insurance. Psychometric evaluations are important since it affects so many individuals in Sweden.

SUMMARY Overactivation of the PI3K/AKT signaling pathway is frequently reported in breast cancer, consequently inhibitors targeting this pathway are clinically useful. AKT constitutes a hub in the regulation of several cancer hallmarks, such as proliferation, survival and migration. Three AKT isoforms, named AKT1, AKT2 and AKT3, are identified in humans. AKT alterations, mainly upregulation of phosphorylated AKT in tumors may have prognostic and predictive value. Moreover, the AKT isoforms may possess partly divergent cellular functions and be upregulated in certain breast cancer subtypes, suggesting the importance of isoform-specific analyses. In conclusion, AKT isoform-specific detection and targeting in different tumor subtypes will hopefully result into a further developed personalized medicine.

Secondary frequency control plays a vital role inpower systems and has therefore been the focus of muchresearch. Recent focus is being targeted towards developingdistributed solutions. This paper p ...

// Cynthia Veenstra 1 , Gizeh Perez-Tenorio 1 , Anna Stelling 1 , Elin Karlsson 1 , Sanam Mirwani Mirwani 1 , Bo Nordenskoljd 1 , Tommy Fornander 2 , Olle Stal 1 1 Department of Clinical and Experimental Medicine and Department of Oncology, Linkoping University, Linkoping, Sweden 2 Department of Oncology-Pathology, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden Correspondence to: Cynthia Veenstra, email: cynthia.veenstra@liu.se Keywords: radiation, copy number variation, droplet digital PCR, triple-negative breast cancer, radiotherapy Received: February 24, 2016 Accepted: April 26, 2016 Published: May 10, 2016 ABSTRACT Few biomarkers exist to predict radiotherapy response in breast cancer. In vitro studies suggest a role for Met and its ligand HGF. To study this suggested role, MET and HGF gene copy numbers were determined by droplet digital PCR in tumours from 205 pre-menopausal and 184 post-menopausal patients, both cohorts randomised to receive either chemo- or radiotherapy. MET amplification was found in 8% of the patients in both cohorts and HGF amplification in 7% and 6% of the patients in the pre- and post-menopausal cohort, respectively. Met, phosphorylated Met (pMet), and HGF protein expression was determined by immunohistochemistry in the pre-menopausal cohort. Met, pMet, and HGF was expressed in 33%, 53%, and 49% of the tumours, respectively. MET amplification was associated with increased risk of distant recurrence for patients receiving chemotherapy. For the pre-menopausal patients, expression of cytoplasmic pMet and HGF significantly predicted benefit from radiotherapy in terms of loco-regional recurrence. Similar trends were seen for MET and HGF copy gain. In the post-menopausal cohort, no significant association of benefit from radiotherapy with neither genes nor proteins was found. The present results do not support that inhibition of Met prior to radiotherapy would be favourable for pre-menopausal breast cancer, as previously suggested.

The chromosomal region 11q13 is amplified in 15-20% of breast cancers; an event not only associated with estrogen receptor (ER) expression but also implicated in resistance to endocrine therapy. Coamplifications of the 11q13 and 8p12 regions are common, suggesting synergy between the amplicons. The aim was to identify candidate oncogenes in the 11q13 region based on recurrent amplification patterns and correlations to mRNA expression levels. Furthermore, the 11q13/8p12 coamplification and its prognostic value, was evaluated at the DNA and the mRNA levels. Affymetrix 250K NspI arrays were used for whole-genome screening of DNA copy number changes in 29 breast tumors. To identify amplicon cores at 11q13 and 8p12, genomic identification of significant targets in cancer (GISTIC) was applied. The mRNA expression levels of candidate oncogenes in the amplicons [ RAD9A, RPS6KB2 (S6K2), CCND1, FGF19, FGF4, FGF3, PAK1, GAB2 (11q13); EIF4EBP1 (4EBP1), PPAPDC1B, and FGFR1 (8p12)] were evaluated using real-time PCR. Resulting data revealed three main amplification cores at 11q13. ER expression was associated with the central 11q13 amplification core, encompassing CCND1, whereas 8p12 amplification/gene expression correlated to S6K2 in a proximal 11q13 core. Amplification of 8p12 and high expression of 4EBP1 or FGFR1 was associated with a poor outcome in the group. In conclusion, single nucleotide polymorphism arrays have enabled mapping of the 11q13 amplicon in breast tumors with high resolution. A proximal 11q13 core including S6K2 was identified as involved in the coamplification/coexpression with 8p12, suggesting synergy between the mTOR targets S6K2 and 4EBP1 in breast cancer development and progression. Funding Agencies|Swedish Cancer Foundation||Swedish Research Council

Detection of signals in the mammalian target of rapamycin (mTOR) and the estrogen receptor (ER) pathways may be a future clinical tool for the prediction of adjuvant treatment response in primary breast cancer. Using immunohistological staining, we investigated the value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen benefit in two independent clinical trials comparing adjuvant tamoxifen with no tamoxifen or 5 years versus 2 years of tamoxifen treatment. In addition, the prognostic value of the S6Ks was evaluated. We found that S6K1 correlated with proliferation, HER2 status, and cytoplasmic AKT activity, whereas high protein expression levels of S6K2 and phosphorylated (p) S6K were more common in ER-positive, and low-proliferative tumors with pAKT-s473 localized to the nucelus. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen effect (hazard ratio (HR): 1.07, 95% CI: 0.53–2.81,P=0.84), compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation (HR: 0.42, 95% CI: 0.29–0.62,PP=0.92). In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis in a multivariate analysis,P=0.00041 (cytoplasm),P=0.016 (nucleus). In conclusion, the mTOR-activated kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity and intracellular localization may provide biomarkers for breast cancer treatment, allowing the identification of a group of patients less likely to benefit from tamoxifen and thus in need of an alternative or additional targeted treatment.

Background The AKT/mTORC1/S6K pathway is frequently overstimulated in breast cancer, constituting a promising therapeutic target. The benefit from mTOR inhibitors varies, likely as a consequence of tumour heterogeneity, and upregulation of several compensatory feed-back mechanisms. The mTORC1 downstream effectors S6K1, S6K2, and 4EBP1 are amplified and overexpressed in breast cancer, associated with a poor outcome and divergent endocrine treatment benefit. S6K1 and S6K2 share high sequence homology, but evidence of partly distinct biological functions is emerging. The aim of this work was to explore possible different roles and treatment target potentials of S6K1 and S6K2 in breast cancer. Materials and methods Whole-genome expression profiles were compared for breast tumours expressing high levels of S6K1, S6K2 or 4EBP1, using public datasets, as well as after in vitro siRNA downregulation of S6K1 and/or S6K2 in ZR751 breast cancer cells. In silico homology modelling of the S6K2 kinase domain was used to evaluate its possible structural divergences to S6K1. Results Genome expression profiles were highly different in S6K1 and S6K2 high tumours, whereas S6K2 and 4EBP1 profiles showed significant overlaps, both correlated to genes involved in cell cycle progression, among these the master regulator E2F1. S6K2 and 4EBP1 were inversely associated with IGF1 levels, and their prognostic value was shown to be restricted to tumours positive for IGFR and/or HER2. In vitro, S6K1 and S6K2 silencing resulted in upregulation of genes in the mTORC1 and mTORC2 complexes. Isoform-specific silencing also showed distinct patterns, e.g. S6K2 downregulation lead to upregulation of several cell cycle associated genes. Structural analyses of the S6K2 kinase domain showed unique structure patterns, deviating from those of S6K1, facilitating the development of isoform-specific inhibitors. Our data support emerging proposals of distinct biological features of S6K1 and S6K2, suggesting their importance as separate oncogenes and clinical markers, where specific targeting in different breast cancer subtypes could facilitate further individualised therapies. At the time for thesis presentation publication was in status: ManuscriptFunding Agencies|Swedish Research Council [2012-5136, 2007-3475]; Swedish Cancer Foundation; LiU Cancer; LiU Cancer Foundation

Breast cancer is a heterogeneous disease and new clinical markers are needed to individualise disease management and therapy further. Alterations in the PI3K/AKT pathway, mainly PIK3CA mutations, have been shown frequently especially in the luminal breast cancer subtypes, suggesting a cross-talk between ER and PI3K/AKT. Aberrant PI3K/AKT signalling has been connected to poor response to anti-oestrogen therapies. In vitro studies have shown protein tyrosine phosphatase, non-receptor type 2 (PTPN2) as a previously unknown negative regulator of the PI3K/AKT pathway. Here, we evaluate possible genomic alterations in the PTPN2 gene and its potential as a new prognostic and treatment predictive marker for endocrine therapy benefit in breast cancer. PTPN2 gene copy number was assessed by real-time PCR in 215 tumour samples from a treatment randomised study consisting of postmenopausal patients diagnosed with stage II breast cancer 1976-1990. Corresponding mRNA expression levels of PTPN2 were evaluated in 86 available samples by the same methodology. Gene copy loss of PTPN2 was detected in 16 % (34/215) of the tumours and this was significantly correlated with lower levels of PTPN2 mRNA. PTPN2 gene loss and lower mRNA levels were associated with activation of AKT and a poor prognosis. Furthermore, PTPN2 gene loss was a significant predictive marker of poor benefit from tamoxifen treatment. In conclusion, genomic loss of PTPN2 may be a previously unknown mechanism of PI3K/AKT upregulation in breast cancer. PTPN2 status is a potential new clinical marker of endocrine treatment benefit which could guide further individualised therapies in breast cancer. Funding Agencies|Swedish Cancer Society [13 0435]; Swedish Research Council [A0346701]

The prognosis of patients diagnosed with breast cancer has been considerably improved in the latest 25 years, as a result of continuous development of diagnostics and treatment regimens. Though, tu ...