Human iPSC derived neural cells as models of brain development and as tools in pharmaceutical drug discovery

Human brain evolution has resulted in a cognitive superiority compared to all other animals. Unique cortical structures and expanding progenitor populations have been associated with the possibility for developing a highly folded neocortex and expanded surface area, which is linked to cognitive function. Alongside the development of the neuronal population there has been a remarkable evolution of a second population of brain cells called astrocytes. Astrocytes, which historically have been viewed as the glue of the brain, are now considered as a major regulator of brain homeostasis and neuron communication. Hypothesized to meet the increased complexity of neuronal sub-populations astrocytes have become highly diversified. Specific astrocytes can only be observed in higher primates and generally comprises a more advance form and structure enabling a single astrocyte to support a higher number of neurons. Additionally, it has been shown that human astrocytes can improve cognitive function in mice, an observation signifying the importance of astrocytes in human brain evolution. However, increased complexity is accompanied by biological errors resulting in human specific diseases. Disease mechanisms linked to human biological traits poses challenges when trying to uncover and develop treatments against its pathological conditions using animal models. With decreasing drug developmental programs in the pharmaceutical industry targeting neurological and psychiatric diseases there is a need to improve and accelerate drug discovery in this area. Studying cellular functions of the human brain is challenging partly due to limited accessibility of brain tissue. Historically, the main source of cells was derived from healthy tissue following surgical procedures as well as post-mortem and fetal tissue. However, since the discovery of induced pluripotent stem cells, having the potential to generate any cell type in the body, accessibility to neural like cells has changed dramatically. Common strategies for acquiring neurons and astrocytes from pluripotent stem cells are to try and mimic the naturally occurring embryonic development. However, this requires the establishment of defined and detailed protocols instructing the cells how to develop and becoming the cell type of interest. Neurons follow a step-wise development program which have been uncovered and in great parts mimicked in the lab. However, whether this step-wise developmental progression holds true for astrocytes is yet to be defined. The aim of this thesis was to develop a protocol to derive astrocytes from human induced pluripotent stem cells (hiPSC) and benchmark them against current models available for the pharmaceutical industry. Moreover, the project aimed to establish hiPSC derived neuronal and astrocyte models in a pharmaceutical setting to investigate their potential contribution in drug development. The characterization of four astrocytic models in comparison to a neural stem cell and nonneural model showed expected astrocyte specific characteristics. However, large differences in gene expression and astrocyte associated functions indicated a large heterogeneity among models which was also demonstrated in drug response stimulations. This clearly implies that discovery of new chemical compounds for further drug development will be context dependent, having identification bias towards the model of choice. Moreover, thorough characterization and diverse applications demonstrated a very robust and reproducible protocol for the generation of hiPSC derived astrocytes, a feature naturally critical if utilized in pharmaceutical assays. Finally, in addition to improved functionality compared to conventional models, hiPSC derived astrocytes show developmental traits linked to embryonic development increasing translability and model relevance. Furthermore, in a proof of principle study hiPSC derived neurons were shown to be able to predict unwanted side effect of a drug used to prevent excessive blood loss from major trauma or surgery. The drug is believed to affect specific neurons resulting in involuntary seizures. Besides demonstrating receptor activity of the drug, human iPSC derived neurons were shown to be applicable in the development of new drugs lacking this side effect. Finally, this was performed using a label-free and simple method which is highly applicable for drug screening. In conclusion this thesis presents a protocol for the derivation of an astrocytic model having translatability to the embryonic development and possesses several cellular functions observed by astrocytes in vivo. The application of hiPSC derived neurons and astrocytes in a pharmaceutical setting demonstrate that they can make a significant contribution in drug discovery

Overregulation of Health Care: Musings on Disruptive Innovation Theory

Disruptive innovation theory provides one lens through which to describe how regulations may stifle innovation and increase costs. Basing their discussion on this theory, Curtis and Schulman consider some of the effects that regulatory controls may have on innovation in the health sector

Wood in psychiatric in-patient rooms may reduce the length of stay for patients

Objective – To outline a study of healthcare outcomes for psychiatric patients within an in-patient psychiatric ward. The planned study was initiated as a follow-up of the design process, where emphasis was made to use interior surfaces of wood in a new Swedish psychiatric building. Background –The influence of the physical environment for treatment outcomes within somatic care has been acknowledge for decades. Today there is also a growing amount of research within the field of psychiatric health facilities. View of, and access to, nature have shown to be of major importance. Recent research suggests that wood in patient rooms may have a healing effect. Research question – Does the use of wood in psychiatric in-patient rooms have positive health outcomes, such as reduced length of stay for patients and reduced stress levels? Method – The quantitative study will be executed in a new Swedish psychiatric building with 96 in-patient rooms in 4 wards. Each ward is divided into modules (6 patients/module). The study has a comparative approach: treatment outcomes in a module where patient rooms with wood covered facade-walls (n=2) will be compared to rooms with painted plaster façade-walls (n=2) and artificial wood panels (n=2). Patients in the module, intended for a special but general diagnosis, will be placed randomly in rooms with or without wood surfaces. All patient rooms are én-suite rooms. The staff is identical between rooms. All patient rooms have identical orientation. Results – An outline of a study in a psychiatric hospital is presented. This includes aspects related to research design, participation from patients, ethical considerations and statistical power of the planned experiment. Final outcomes from the study will be carried out after the new psychiatric building is inaugurated in 2020. Conclusion – Choice of building material can be an important measure to include in the design of health facilities. The study will provide new insights into what materials can be used and how they should be used to maximise possible beneficial health effects. Several aspects of architectural design can influence users in the built environment. Thus, there can be confounding factors influencing patients´ health and psychological well-being.publishedVersio

KARAKTERISASI PENAMPILAN BIBIT KAKAO BERPRODUKSI TINGGI

Understanding and explaining perception of touch is a non-trivial task. Even seemingly trivial differences in exploration may potentially have a significant impact on perception and levels of discrimination. In this study, we explore different aspects of contact related to stiffness perception and their effects on the just noticeable difference (JND) of stiffness are surveyed. An experiment has been performed on non-deformable, compliant objects in a virtual environment with three different types of contact: Discontinuous pressure, continuous pressure and continuous lateral motion. The result shows a significantly better discrimination performance in the case of continuous pressure (a special case of nonlinearity), which can be explained by the concept of haptic memory. Moreover, it is found that the perception is worse for the changes that occur along the lateral axis than the normal axis

Detection of breast cancer lymph node metastases in frozen sections with a point-of care low-cost microscope scanner

Background Detection of lymph node metastases is essential in breast cancer diagnostics and staging, affecting treatment and prognosis. lntraoperative microscopy analysis of sentinel lymph node frozen sections is standard for detection of axillary metastases but requires access to a pathologist for sample analysis. Remote analysis of digitized samples is an alternative solution but is limited by the requirement for high-end slide scanning equipment. Objective To determine whether the image quality achievable with a low-cost, miniature digital microscope scanner is sufficient for detection of metastases in breast cancer lymph node frozen sections. Methods Lymph node frozen sections from 79 breast cancer patients were digitized using a prototype miniature microscope scanner and a high-end slide scanner. Images were independently reviewed by two pathologists and results compared between devices with conventional light microscopy analysis as ground truth. Results Detection of metastases in the images acquired with the miniature scanner yielded an overall sensitivity of 91% and specificity of 99% and showed strong agreement when compared to light microscopy (k = 0.91). Strong agreement was also observed when results were compared to results from the high-end slide scanner (k = 0.94). A majority of discrepant cases were micrometastases and sections of which no anticytokeratin staining was available. Conclusion Accuracy of detection of metastatic cells in breast cancer sentinel lymph node frozen sections by visual analysis of samples digitized using low-cost, point-of-care microscopy is comparable to analysis of digital samples scanned using a high-end, whole slide scanner. This technique could potentially provide a workflow for digital diagnostics in resource-limited settings, facilitate sample analysis at the point-of-care and reduce the need for trained experts on-site during surgical procedures.Peer reviewe

Tuning the photochemical properties of the fulvalene-tetracarbonyl-diruthenium system

In a Molecular Solar-Thermal Energy Storage (MOST) system, solar energy is converted to chemical energy using a compound that undergoes reversible endothermic photoisomerization. The high-energy photoisomer can later be converted back to the parent compound and the excess energy is released as heat. One of the most studied MOST systems is based on fulvalene-tetracarbonyl-diruthenium, and this paper demonstrates, for the first time, the possibility to tune the photochemical properties of this system by positive steric hindrance working on the fulvalene unit

Nätverk för ingenjörsutbildningar för samverkan vid införande av ny examens- och utbildningsstruktur

I föreliggande arbete beskrivs arbetet med att skapa ett nätverk med det övergripande syftet att stärka svensk ingenjörsutbildning. Under 2007 har nätverket finansierats av NSHU, som tillhandahållit medel för att stödja svenska högskolors arbete med Bolognaprocessen. Nätverket Ingenjörsutbildningarna har under året anordnat ett antal välbesökta workshopar. Ett antal grupperingar som inte tidigare haft regelbundna träffar har därmed skapats. Deltagarnas omdömen har varit positiva. Det är tydligt att det finns ett behov av ämnesbaserade nätverk, och där diskussionerna inte bara handlar om Bolognafrågor utan även om ämnesinnehåll, rekrytering, varumärken med mera. Projektet kan sägas ha startat ett nätverkande mellan ingenjörsutbildningar men det krävs mer arbete för att nå kontinuitet

Phylogenetic Signals of Salinity and Season in Bacterial Community Composition Across the Salinity Gradient of the Baltic Sea

Understanding the key processes that control bacterial community composition has enabled predictions of bacterial distribution and function within ecosystems. In this study, we used the Baltic Sea as a model system to quantify the phylogenetic signal of salinity and season with respect to bacterioplankton community composition. The abundances of 16S rRNA gene amplicon sequencing reads were analyzed from samples obtained from similar geographic locations in July and February along a brackish to marine salinity gradient in the Baltic Sea. While there was no distinct pattern of bacterial richness at different salinities, the number of bacterial phylotypes in winter was significantly higher than in summer. Bacterial community composition in brackish vs. marine conditions, and in July vs. February was significantly different. Non-metric multidimensional scaling showed that bacterial community composition was primarily separated according to salinity and secondly according to seasonal differences at all taxonomic ranks tested. Similarly, quantitative phylogenetic clustering implicated a phylogenetic signal for both salinity and seasonality. Our results support that global patterns of bacterial community composition with respect to salinity and season are the result of phylogenetically clustered ecological preferences with stronger imprints from salinity

Inventering och utveckling för uppföljning av gräsmarks- och hällmarksnaturtyper 2017 (reviderad rapport)

I denna rapport beskrivs resultat från arbetet med biogeografisk uppföljning av några naturtyper med sparsam eller aggregerad fördelning i landskapet. För hällmarkstorrängar (naturtyp 8230) redovisas här resultat från tredje året av det sexåriga inventeringsvarv, där polygoner större än 100 m2 (d.v.s. 0,01 hektar) har avgränsats med flygbildstolkning och därefter inventerats med tätt utlagda provytor, med minsta avstånd 10 m. En stor andel av hällmarkstorrängarna ligger utanför skyddade områden och TUVA-objekt, men förekomsten av hällmarkstorrängsarter är likartad i olika regioner och inom resp. utanför skyddade områden. För rapportering till EU för Art- och habitatdirektivet skulle det vara värdefullt med en utökad uppföljning av hällmarkstorrängar inom skyddade områden, med samma metodik som i det befintliga utlägget. Även för kalkhällmarksnaturtyperna finns en stor andel av ytorna utanför skyddade områden, förutom på Stora alvaret, som är väl täckt av TUVA och Natura 2000-områden. För dessa – basiska berghällar (6110), alvar och prekambriska kalkhällmarker (6280) samt karsthällmarker (8240) – har inventeringen genomförts med ett kraftigt förtätat stickprov av mindre landskapsrutor på Öland och Gotland. En utvidgad flygbildstolkning med heltäckande polygonavgränsning av naturtyper har använts, i kombination med provytor med en utökad lista av arter och andra variabler (t.ex. vittringsmaterial på kalksten, och en särskild grupp av variabler har tagits fram för karstsprickor och karstlevande snäckor. På Gotland har preliminärt, utifrån de provytor som inventerats hittills, ungefär en tredjedel av de fältbesökta provytorna någon förekomst av karstsprickor, och många av dem har ett stort antal hällsnäckor. Utgångspunkten är att denna design och metodik ska utgöra första året av ett tänkt sexårigt inventeringsvarv. För svämängar (6450) har en komplett inventering med avgränsning i flygbilder och stickprov av provytor utförts längs med hela Vindelälven. Under 2017 har omfattningen varit hälften av den tänkta inom ett sexårigt inventeringsvarv, där ambitionen är att samtliga svämängar från Dalälven och norrut ska karteras längs med alla vattendrag i Sverige som finns med i kartskiktet för naturtypen större vattendrag (3210). Att använda infraröda flygfoton från olika tidpunkter för att bedöma översvämningspåverkan ger mycket god träffsäkerhet, och vegetationens sammansättning har överensstämt mycket väl med den förväntade i de fältbesökta ytorna. Svämängar och högörtängar (6430) kan också finnas vid vissa mindre vattendrag, om vattenfluktuationen är tillräckligt stor för att bibehålla en lagom stor störning och förhindra igenväxning med träd och buskar. Vi har därför tagit fram en metodik för att kartera förekomster av de naturtyperna samordnat med den biogeografiska uppföljningen av mindre vattendrag (3260). Inga objekt påträffades 2017, men från 2018 görs uppföljningen i full skala i hela landet, vilket vi hoppas ger goda förutsättningarna för att ändå få användbara resultat till en rimlig kostnad. Metodtesterna för slåtterängar har framför allt fokuserat på naturtyperna slåtterängar i låglandet (6510) och höglänta slåtterängar (6520), men även objekt av lövängar har besökts (6530), för att få en bra helhetsbild över slåtterpräglade värden. För att belysa den frågan har fokus dock varit på markvegetationen, men inte på hävdpåverkade träd, som är en viktig del av lövängarnas värden. Slåtterängarna i alla regioner kännetecknas av stor andel örter i fältskiktet och en relativt enhetlig grupp av kärlväxter som verkar tydligt slåttergynnade i alla de besökta regionerna. Vårt förslag är att man även i fortsättningen utgår ifrån befintliga kartskikt över skyddsvärda slåtterängar, t.ex. från TUVA-databasen och miljöersättningen till slåtterängar. För trädanknutna värden i lövängar behövs dock andra typer av inventeringsmoment än de som har används hittills i detta projekt. Som komplement till t.ex. den klassning av vanliga gräsmarksnaturtyper som görs i Jordbruksverkets kvalitetsuppföljning av ängs- och betesmarker, så har en naturtypsklassning testats även för de gräsmarker som inventeras inom Remiil (Regional miljöövervakning i landskapsrutor), på uppdrag av 18 län. Eftersom denna inventering fokuserar på alla gräsmarkstyper i landskapet, så tillhör endast en mindre andel av fältytorna någon skyddsvärd naturtyp enligt EU:s klassificering, men eftersom totalantalet provytor är stort, så kan det ändå ge ett betydelsefullt och kostnadseffektivt bidrag, om bestämda åtgärder vidtas för att förbättra samordningen mellan de gräsmarksinventeringar som finns