Genetic studies of neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) constitute a heterogeneous group of disorders that adversely impacts a child’s behavioural and learning processes. Developmental delay (DD) and mental retardation are included among the NDDs and are frequently associated with a wide range of accompanying disabilities such as multiple congenital anomalies and dysmorphic features. Despite extensive clinical and laboratory investigation, the cause of the patient’s symptoms remains unknown in approximately half of the cases. For the children’s families this is often frustrating since an aetiological diagnosis not only gives an explanation of why the child has symptoms but may also provide better prognosis evaluation, adequate genetic counselling and enable prenatal diagnosis. In approximately 20% of patients, a clear genetic cause can be found, including both single-gene disorders and chromosomal disorders. In paper I a NIPBL and SMC1L1 mutation screening by direct sequencing and MLPA was performed in a group of nine index patients diagnosed with Cornelia de Lange syndrome (CdLS), which is characterized by severe mental and growth retardation and distinctive dysmorphic facial features. We identified seven NIPBL mutations and showed that a splice-site mutation lead to skipping of an exon. A clear genotype-phenotype correlation was not found. In paper II sequencing and MLPA analysis revealed 18 CHD7 mutations in 28 index patients with CHARGE syndrome. In addition, inherited variants were identified and clinical interpretation of these are discussed. Our results indicate that hypoplastic semicircular canals is not obligatory for a CHD7 mutation, although we agree that it is the most frequent and specific sign of CHARGE syndrome. A CHD7 mutation was found in a patient not fulfilling clinical criteria showing that also atypical patients benefit from testing. Paper I and II confirm that NIPBL and CHD7 are the main causative genes for CdLS and CHARGE syndrome respectively. However, in >30% of our patients no causal mutation could be detected. Whole genome-/exome sequencing might find new causative genes and/or mutations in non-coding sequences of known genes. The patient described in paper III had an 18.2 Mb de novo deletion of chromosome 11q13.4-q14.3. By comparing his phenotype to the few previously described patients, we show that a common phenotype for patients with deletions in this region might be emerging, comprising mild-moderate DD, a sociable personality and dysmorphic facial features. The implementation of high-resolution array-CGH over the last decade has enabled the genome-wide identification of submicroscopic copy number variations (CNVs) in patients with NDDs. In study IV we wanted to evaluate array-CGH as a diagnostic tool in our clinical laboratory. In the 160 investigated patients, 21 (13,1%) causal CNVs and 15 (9.4%) CNVs of unclear clinical significance were detected. Standard karyotyping had in seven cases failed to detect causal CNVs ≥5 Mb, five of which were ≥10Mb, emphasizing that more reliable methods were needed to exclude CNVs in these patients. Array-CGH proved to be very useful and became recommended as the first step investigation for patients with idiopathic DD. However, increasing the resolution of a whole genome screen in the diagnostic setting has its drawback of detecting an increased number of CNVs of unclear clinical significance. In paper V we report on the clinical and molecular characterization of 16 individuals with distal 22q11.2 duplications. The patients displayed a variable phenotype, and many of the duplications were inherited (83%). The possible pathogenicity of these duplications is discussed and we conclude that it is likely that distal 22q11.2 duplications represent a susceptibility/risk locus for NDDs rather than being causal variants. Additional genetic, epigenetic or environmental factors are likely required to cause a phenotype. Five patients had additional CVNs of unclear clinical significance making a 2-hit event plausible. Paper IV and V illustrate that the identification of CNVs of uncertain clinical significance puts new demands on genetic counselling and continuous research and submission of cases to databases are still important. Future challenges include how to deal with the interpretation of multiple rare variants in one individual and to find ways to estimate how great a risk factor certain CNVs, such as distal 22q11.2 duplications, actually are for a phenotypic effect

Naturalistiska perennplanteringar på gröna tak med biokol i substratet

Gröna tak kan generera många välbehövda ekosystemtjänster och vara en av lösningarna för att hantera de klimatförändringar vi står inför. De kan också ha en positiv och lugnande inverkan på oss människor i den stressade värld vi lever i. Därför är det viktigt att de gröna tak vi skapar är hållbara över tid och klarar av att leverera dess tilltänkta funktion. Syftet med mitt arbete är att ge förslag på vilka perenner som är lämpliga för växtbäddar på gröna tak och den extrema ståndort som ofta råder där. Genom att fördjupa mig inom biokol och dess användning undersöker jag vilka effekter biokol kan ha på växtbäddens tillgång på fukt, näring samt förändring av pH-värde och om detta förändrar antalet potentiella växtarter att plantera på ett grönt tak. För att skapa hållbara och visuellt attraktiva planteringar har jag också undersökt hur ekologi och design kan samverka i dagens naturalistiska planteringar. Målet är att mitt arbete ska kunna användas av andra landskapsarkitekter och liknande professioner. Min metod resulterade i nio olika hypotetiska växtbäddsscenarion fördelat på tre olika substratdjup av 50-, 150- och 300 millimeter. Inom dessa tre typer av växtbäddar har biokol i halterna 0-, 10- och 20 volymprocent tillsatts, vilket har generat nio olika växtlistor som visar hur artdiversiteten förändras med biokolets påverkan. För att illustrera hur arterna från växtlistorna kan användas i planteringar, har tre olika naturalistiska perennplanteringsmixar tagits fram för de olika substratdjupen. Det tunnaste substratdjupet definieras främst av sedumarter, det mittersta av örtartad ängsvegetation och det tjockaste av starkväxande högre perenner. Slutsatser av arbetet visade att biokol genom sin vatten- och näringshållande förmåga kan förbättra förhållandena i växtbäddar på gröna tak och utöka mängden potentiella växtarter. Störst effekt hade biokol i den tunnaste växtbädden där antalet potentiella växtarter ökade med 46 % från växtbädden utan biokol till den innehållande 20 volymprocent biokol. Generellt sett gjorde 20 volymprocent biokol en större påverkan i alla olika substratdjup än 10 volymprocent biokol. Desto tjockare substratdjup hade också en signifikant betydelse för att kunna tillgodose ståndortskraven för fler växter. Viktigt att tänka på när vi gestaltar framtidens gröna tak är att ta hänsyn till växters naturliga ståndort och hur växter interagerar med varandra.Green roofs can help us to provide many imperative ecosystem services and be part of the solutions that combat our ongoing climate crisis. In this stressed world of ours, green space can also yield a positive and calming influence. Therefore, it is essential that the green roofs we´re creating, are sustainable over time and strive to continue their full potential. My aim with my master thesis is to provide suitable examples of perennial plants for green roofs and the high-stress environment in which they create. I wanted to examine the possibility of increasing the amount of suitable plant material by looking at biochar and its effects on green roof substrates regarding water – holding capacity, nutrient cycling, and change in soil pH. To create sustainable and visually attractive green roofs plantings, I’ve also been looking into how ecology and design can co-exist in the concept of naturalistic planting design. My goal with this work is for it to be shared with other landscape architects and similar professions to create future attractive and sustainable green roofs. My studies resulted in nine different hypothetical plant bed scenarios, divided into three different substrate depths of 50, 150, and 300 millimetres. Within these three types of planting beds, the green roof substrate has been mixed with 0%, 10%, and 20% volume per volume (v/v) biochar. This generated nine different lists of plants showing how the species diversity changes over the influence of biochar. To illustrate how the different species from the lists can be used in plantings, I created three different perennial planting mixes, based on naturalistic planting design principles, for the three different substrate depths. The thinnest substrate is mostly defined by species from the Sedum family, the median depth support the growth of herbaceous meadow flowers and the thickest consists of taller and stronger growing perennials. Conclusions of my work indicate that biochar with its ability to store water and nutrients can enhance the environment in green roof substrates and therefor extend the list of potential plant materials. Regarding biochar, 20 % v/v biochar had a larger impact on the variety of plant selection than 10 % v/v. In my hypothetical plant bed scenario of 50 millimetres substrate depth, the list with potential plant species significantly increased by 46 % when comparing the difference between no added biochar and 20 % v/v biochar. Ultimately, when designing green roofs there are several key components needed to achieve long-lasting and more sustainable green roofs. I believe these consist of rich species diversity, consideration of plants natural habitat, and how they interact with other species

Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells

The aryl hydrocarbon receptor (AHR)controls interleukin 22 production by T helper 17 cells (Th17). IL-22contributes to intestinalhomeostasis but has also been implicated inchronic inflammatory disorders and colorectal cancer, highlighting the need for appropriate regulation of IL-22 production. Upon activation, the AHR induces expression of cytochrome P4501 (CYP1) enzymes that in turn play an important feedback role that curtails the duration of AHR signaling by metabolizingAHRligands. Recently we described how agents that inhibit CYP1 function potentiate AHR signalingby disruptingmetabolic clearance of the endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ). In the present study, we investigated the immune-modulating effects of environmental pollutants such as polycyclic aromatic hydrocarbons on Th17 differentiation and IL-22 production. Using Th17 cells deficient in CYP1 enzymes (Cyp1a1/1a2/1b1-/-)we show that these chemicals potentiate AHR activation through inhibition of CYP1 enzymes which leads to increases in intracellular AHR agonists. Our findings demonstrate that IL-22 production by Th17 cellsis profoundly enhanced by impaired CYP1-function and strongly suggest that chemicals able to modify CYP1 function or expression may disrupt AHR-mediated immune regulation by altering the levels of endogenous AHR agonist(s)

The effectiveness of coping strategies used by entrepreneurs and their impact on personal well-being and venture performance

This paper analyzes effectiveness of coping strategies that entrepreneurs use to daily manage work related stress. Coping is the process of expending efforts to solve personal and interpersonal problems and reducing stress induced by unpleasant and stressful situations. Two broad strategies of coping are identified; problem-based coping refers to a cognitively-based response behavior that includes efforts to alleviate stressful circumstances while emotion-based coping involves behavioural responses to regulate the affective consequences of stressful events. The purpose of this research is to analyze relationships among the coping strategies used by entrepreneurs and a set of antecedents influencing the selection of coping strategies. The methodology used is based on structural equation modeling and empirical data of 469 entrepreneurs from two European countries. Our results show that problem based coping facilitates well-being and venture performance. In addition, our findings also support interaction effects of founder centrality and contextual conditions of venturing on the extent entrepreneurs engage in coping. We believe that our insights can help in training entrepreneurs in the development of effective coping strategies that are context dependent. In specific, our results suggest entrepreneurs to engage in problem-focused strategies when they want to effectively address the economic aspects of their lives whereas when they engage in emotion based strategies they seem to increase the self-knowledge they need to start subsequent ventures and facilitate learning from failure. Future studies on coping strategies could study the interplay of coping strategies used to resolve challenging social situations that various stakeholders of practicing entrepreneurs impose

Učinkovitost strategija suočavanja poduzetnika sa stresom i njihov utjecaj na osobnu dobrobit i uspješnost poduzeća

This paper analyzes effectiveness of coping strategies that entrepreneurs use to daily manage work related stress. Coping is the process of expending efforts to solve personal and interpersonal problems and reducing stress induced by unpleasant and stressful situations. Two broad strategies of coping are identified; problem-based coping refers to a cognitively-based response behavior that includes efforts to alleviate stressful circumstances while emotion-based coping involves behavioural responses to regulate the affective consequences of stressful events. The purpose of this research is to analyze relationships among the coping strategies used by entrepreneurs and a set of antecedents influencing the selection of coping strategies. The methodology used is based on structural equation modeling and empirical data of 469 entrepreneurs from two European countries. Our results show that problem based coping facilitates well-being and venture performance. In addition, our findings also support interaction effects of founder centrality and contextual conditions of venturing on the extent entrepreneurs engage in coping. We believe that our insights can help in training entrepreneurs in the development of effective coping strategies that are context dependent. In specific, our results suggest entrepreneurs to engage in problem-focused strategies when they want to effectively address the economic aspects of their lives whereas when they engage in emotion based strategies they seem to increase the self-knowledge they need to start subsequent ventures and facilitate learning from failure. Future studies on coping strategies could study the interplay of coping strategies used to resolve challenging social situations that various stakeholders of practicing entrepreneurs impose.U ovom radu analizira se učinkovitost strategija suočavanja sa stresom koje poduzetnici upotrebljavaju na dnevnoj osnovi radi upravljanja stresom uzrokovanim poslom. Suočavanje sa stresom je proces usmjeren na rješavanje ljudskih i međuljudskih problema i reduciranje stresa kojeg izazivaju neugodne i napete situacije. U širem smislu riječi, identificirane su dvije strategije suočavanja: problemski orijentirano suočavanje, koje se odnosi na kognitivno utemeljene bihevioralne odgovore s ciljem ublažavanja stresnih okolnosti, te suočavanje zasnovano na emocijama, koje uključuje bihevioralne reakcije usmjerene na reguliranje afektivnih posljedica stresnih događaja. Cilj istraživanja je analizirati odnose između poduzetničkih strategija suočavanja te set čimbenika koji utječu na odabir istih. U radu se koristi metoda modeliranja strukturnih jednadžbi i empirijske podatke 469 poduzetnika iz dviju europskih zemalja. Rezultati analize pokazuju pozitivan utjecaj problemski orijentiranih strategija suočavanja na dobrobit poduzetnika i uspješnost njihovih poduzeća. Dobiveni rezultati potvrđuju i interakcijske učinke centralnosti poduzetnika i kontekstualnih odrednica poduzetništva na razinu suočavanja poduzetnika sa stresom. Vjerujemo da će rezultati našeg istraživanja pridonijeti obuci poduzetnika u području razvoja učinkovitih strategija suočavanja ovisnih o kontekstu. Preciznije, dobiveni rezultati sugeriraju poduzetnicima primjenu problemski orijentiranih strategija u slučajevima kada se žele efektivno usmjeriti na ekonomske aspekte svojih života. S druge strane, pokazalo se da suočavanje zasnovano na emocijama povećava poznavanje samog sebe koje je potrebno za poduzimanje budućih poduzetničkih pothvata i olakšavanje učenja iz neuspjeha. Buduća istraživanja strategija suočavanja mogla bi obuhvatiti njihovo međusobno djelovanje u funkciji rješavanja zahtjevnih društvenih situacija koje poduzetnicima nameću različiti dioničari

Učinkovitost strategija suočavanja poduzetnika sa stresom i njihov utjecaj na osobnu dobrobit i uspješnost poduzeća

This paper analyzes effectiveness of coping strategies that entrepreneurs use to daily manage work related stress. Coping is the process of expending efforts to solve personal and interpersonal problems and reducing stress induced by unpleasant and stressful situations. Two broad strategies of coping are identified; problem-based coping refers to a cognitively-based response behavior that includes efforts to alleviate stressful circumstances while emotion-based coping involves behavioural responses to regulate the affective consequences of stressful events. The purpose of this research is to analyze relationships among the coping strategies used by entrepreneurs and a set of antecedents influencing the selection of coping strategies. The methodology used is based on structural equation modeling and empirical data of 469 entrepreneurs from two European countries. Our results show that problem based coping facilitates well-being and venture performance. In addition, our findings also support interaction effects of founder centrality and contextual conditions of venturing on the extent entrepreneurs engage in coping. We believe that our insights can help in training entrepreneurs in the development of effective coping strategies that are context dependent. In specific, our results suggest entrepreneurs to engage in problem-focused strategies when they want to effectively address the economic aspects of their lives whereas when they engage in emotion based strategies they seem to increase the self-knowledge they need to start subsequent ventures and facilitate learning from failure. Future studies on coping strategies could study the interplay of coping strategies used to resolve challenging social situations that various stakeholders of practicing entrepreneurs impose.U ovom radu analizira se učinkovitost strategija suočavanja sa stresom koje poduzetnici upotrebljavaju na dnevnoj osnovi radi upravljanja stresom uzrokovanim poslom. Suočavanje sa stresom je proces usmjeren na rješavanje ljudskih i međuljudskih problema i reduciranje stresa kojeg izazivaju neugodne i napete situacije. U širem smislu riječi, identificirane su dvije strategije suočavanja: problemski orijentirano suočavanje, koje se odnosi na kognitivno utemeljene bihevioralne odgovore s ciljem ublažavanja stresnih okolnosti, te suočavanje zasnovano na emocijama, koje uključuje bihevioralne reakcije usmjerene na reguliranje afektivnih posljedica stresnih događaja. Cilj istraživanja je analizirati odnose između poduzetničkih strategija suočavanja te set čimbenika koji utječu na odabir istih. U radu se koristi metoda modeliranja strukturnih jednadžbi i empirijske podatke 469 poduzetnika iz dviju europskih zemalja. Rezultati analize pokazuju pozitivan utjecaj problemski orijentiranih strategija suočavanja na dobrobit poduzetnika i uspješnost njihovih poduzeća. Dobiveni rezultati potvrđuju i interakcijske učinke centralnosti poduzetnika i kontekstualnih odrednica poduzetništva na razinu suočavanja poduzetnika sa stresom. Vjerujemo da će rezultati našeg istraživanja pridonijeti obuci poduzetnika u području razvoja učinkovitih strategija suočavanja ovisnih o kontekstu. Preciznije, dobiveni rezultati sugeriraju poduzetnicima primjenu problemski orijentiranih strategija u slučajevima kada se žele efektivno usmjeriti na ekonomske aspekte svojih života. S druge strane, pokazalo se da suočavanje zasnovano na emocijama povećava poznavanje samog sebe koje je potrebno za poduzimanje budućih poduzetničkih pothvata i olakšavanje učenja iz neuspjeha. Buduća istraživanja strategija suočavanja mogla bi obuhvatiti njihovo međusobno djelovanje u funkciji rješavanja zahtjevnih društvenih situacija koje poduzetnicima nameću različiti dioničari

Gaturummet - dess roll genom historien och spaning efter framtida potential

Gaturummet har genom historien haft en stor betydelse för oss människor. Ett offentligt rum i staden som används av människor från alla samhällsklasser och till många olika aktiviteter. När den industriella revolutionen påbörjades och bilismen gjorde sitt intåg under början av 1900-talet förändrades människors transportvanor. Vilket resulterade i en radikal förändring i hur gaturummen utformades och användes. Målet med uppsatsen är att undersöka vilken roll gaturummet spelat genom historien, vilken roll den har idag och vilken roll ett framtida gaturum skulle kunna spela för oss människor. Syftet är att fundera på om det går att planera och skapa gaturum som inte bara behöver vara en transportsträcka, utan även bjuder in till övriga mänskliga aktiviteter. Som metod används en litteraturstudie för att beskriva gaturummets historia. För att kunna diskutera gaturummets potentiella framtid har en fallstudie genomförts som beskriver omvandlingar av tre samtida gaturum. Slutsatsen av den historiska tillbakablicken visar att gaturummet tycks ha gått från att vara en relativt oordnad och stökig plats med många olika mänskliga aktiviteter, till att bli en plats allt mer präglad av transportbehov, regler och restriktioner. I framtiden förväntas bilens nuvarande höga prioritet inom planeringen att minska vilket resulterar i mer plats åt övriga mänskliga aktiviteter i gaturummet.Through time the streetscapes in our cities have played many different roles for us humans. As a public space in the city, it´s used by all kinds of people and includes a big variety of human activities. During the beginning of the 20th century the automobile made its entrance as a result of the rapid developing industrialism. People’s habits of transportation was put up for a big change. This led to a radical alteration how the streetscape was designed and therefore used by people. The purpose with this dissertation is to examine which role the streetscape have played for people throughout history, its present role and a potential future one. The aim is to explore the possibilities in planning and design of streetscapes, that’s not necessarily only a way of getting from one place to another, but also invites for other human activities. A literature study has been conducted for describing the history of the streetscape. To be able to discuss the streetscapes possible future, a case study regarding the transformation of three modern streetscapes have been carried out. As a conclusion from the historical background its’ shown that the streetscape seems to have transformed from a relatively disordered place, where a variety of human activities were found, to a place characterized by the need of transportation, rules and restrictions. In future planning, when motoring is no longer a top priority, other human activities is expected to be valued more highly

Developing and validating a multi-dimensional scale for operationalizing industrial service offering

Purpose – The purpose of this paper is to develop a new scale for measuring the scope (i.e. breadth and depth) of industrial service offering. Design/methodology/approach – The scale and its constructs are developed by combining the key insights from prior literature and practitioners gained through expert interviews; validating the constructs by 3 item-construct validation rounds with 9 academic experts; and by testing and further revising the scale, with a sample of 91 manufacturing firms. Findings – The distinct contribution of the study is the construction and validation of a new multi-dimensional scale for operationalizing the scope of industrial service offering. In addition, the identified service categories (i.e. pre-sales services, product support services, product life-cycle services, R&D services and operational services) extend the current literature on service typologies. Research limitations/implications – The data are somewhat biased toward small- and medium-sized industrial firms. Hence, the development of the measurement in the context of large industrial firms provides one fruitful avenue for further research. Practical implications – For managers of industrial firms, the identified service categories provide novel insight on how to develop, bundle and commercialize industrial services to their varying customer segments. Originality/value – This study develops a multi-dimensional, fine-grained, statistical and relationship-level scale for measuring the scope of industrial service business. Moreover, this study tests and further develops the scale with quantitative empirical data.fi=vertaisarvioitu|en=peerReviewed

A survey study of the transitioning towards high-value industrial product-services

Servitization literature suggests that traditional manufacturing companies are increasingly offering industrial services in order to increase their position in the global competition. However, little is known about extent and profit potential of different types of such offers in current industry. This paper offers an overview of such offers and concludes that maintenance based business models are most closely linked to increased revenue generation while add-on services have a negative effect. Future trends, suggest that business models such as R&D services and functional services will be increasingly important in the future.© 2014 Elsevier. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).fi=vertaisarvioitu|en=peerReviewed