Palladium-Catalyzed Carbonylation and Arylation Reactions

Palladium-catalyzed reactions have found widespread use in contemporary organic chemistry due to their impressive range of functional group tolerance and high chemo- and regioselectivity. The pioneering contributions to the development of the Pd-catalyzed C-C bond forming cross-coupling reaction were rewarded with the Nobel Prize in Chemistry in 2010. Today, this is a rapidly growing field, and the development of novel methods, as well as the theoretical understanding of the various processes involved are of immense importance for continued progress in this field. The aim of the work presented in this thesis was to develop novel palladium(0)- and palladium(II)-catalyzed reactions. The work involved in achieving this aim led to the development of a Mo(CO)6-mediated carbonylative Stille cross coupling reaction for the preparation of various deoxybenzoins. The protocol utilized convenient gas-free conditions to facilitate the carbonylative coupling of benzyl bromides and chlorides with aryl and heteroaryl stannanes. Mo(CO)6-assisted conditions were then used in the development of a general protocol suitable for the aminocarbonylation of aryl triflates. Both electron-poor and electron-rich triflates were coupled with primary, secondary and aryl amines. In addition, DMAP was found to be a beneficial additive when using sterically hindered or poorly nucleophilic amines. An efficient and convenient method for the synthesis of styrenes from arylboranes was developed, employing the relatively inexpensive vinyl acetate as the ethene source under Pd(II)-catalyzed conditions. The reaction mechanism was studied using ESI-MS, and a plausible catalytic cycle was proposed. A method for the oxidative Heck reaction employing aryltrifluoroborates and aryl MIDA boronates was also developed. Electron-rich and electron-poor olefins were regioselectively arylated under microwave-assisted conditions. Various arylboron species were identified in an ongoing reaction using ESI-MS.    Further investigations led to the development of a direct method for the synthesis of arylamidines from aryltrifluoroborates and cyanamides. Under Pd(II)-catalyzed conditions it was possible to insert the aryl into primary, secondary and tertiary cyanamides. Finally, a desulfitative method for the synthesis of aryl ketones was developed. A variety of aryl sulfinates were effectively inserted into alkyl- and aryl nitriles. The mechanism was further investigated using ESI-MS and a plausible catalytic cycle was proposed

How to design a digital guide app in Flutter/Firebase with a focus on the group experience and Text-To-Speech

With an emphasis on usability, this paper intends to create a digital museum guide app using the Flutter framework and Firebase web platform. In order to improve the visitor's experience, the app will make use of Geolocation, QR codes, and text-to-speech with translation. It will also provide pertinent audio tracks, activate them based on the user's location, and let users pause and resume audio for those around. The paper will examine how technology may enhance the museum-going experience and analyze the opportunities and challenges associated with developing a digital guide app that seeks to support the group experience

How to design a digital guide app in Flutter/Firebase with a focus on the group experience and Text-To-Speech

With an emphasis on usability, this paper intends to create a digital museum guide app using the Flutter framework and Firebase web platform. In order to improve the visitor's experience, the app will make use of Geolocation, QR codes, and text-to-speech with translation. It will also provide pertinent audio tracks, activate them based on the user's location, and let users pause and resume audio for those around. The paper will examine how technology may enhance the museum-going experience and analyze the opportunities and challenges associated with developing a digital guide app that seeks to support the group experience

Informal caregivers’ experiences of participation in European home health care : A literature review

Bakgrund: Hemsjukvård är en växande och skiftande vårdform i Europa. De närståendes omvårdnadsinsatser är ofta avgörande för en fungerande hemsjukvård. Närståendevård kan samtidigt medföra risker för de närståendes hälsa. Styrdokument för hälso- och sjukvården betonar vikten av patientens och de närståendes delaktighet i vårdens utformning och utförande. Hemmet utgör en speciell vårdkontext, som visats påverka vårdpersonalens och patienternas upplevelser - troligen också de närståendes. Syfte: Att, i en europeisk kontext, beskriva de närståendes upplevelser av delaktighet i hemsjukvård. Metod: Litteraturöversikt av kvalitativa vetenskapsartiklar. Tre elektroniska databaser genomsöktes och elva studier, utgivna mellan 2013 och 2018, inkluderades. Genom kvalitativ dataanalys identifierades teman som präglade de närståendes upplevelser av delaktighet med hemsjukvården. Resultat: Analysen fann tre teman: de närstående utför omvårdnadsprocesser, de närstående griper efter hemsjukvården, samt vårdarnas makt över hopp och förtvivlan. Diskussion: Resultaten diskuterades utifrån Andersheds och Ternestedts teori om närståendes delaktighet. Studier om hopp och fasta vårdkontakter satte resultaten i kontext. De närståendes upplevda ansvar och resurser diskuterades som förutsättningar för delaktighet.Background: Home health care comprises an increasing and diverse range of services throughout Europe. In order to work, these services often rely on care performed by informal caregivers. Informal care can entail risks to the relatives’ health. Legal and policy documents stress the importance of patients’ and relatives’ participation in health care decisions and delivery. The home as a care context has been found to influence the patients’ and health professionals’ experiences, and should be studied also from the relatives’ perspective. Aim: To describe informal caregivers’ experiences of participation in home health care, in a European context. Method: Review of qualitative literature. Three electronic databases were searched, and eleven studies, published between 2013 and 2018, were identified for inclusion. Through qualitative content analysis, themes that defined the informal caregivers’ experiences of participation were identified. Results: Three themes were formulated: relatives perform care processes, relatives grasp at the home health care service, and care professionals mediate hope and despair. Discussion: The results were discussed in relation to Andershed’s and Ternestedt’s theory of relatives’ involvement. Studies of hope and case management contextualized the findings. The informal caregivers’ perceived responsibility and resources were discussed as conditions of participation

Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Aryl Sulfonamides

The insulin-regulated aminopeptidase (IRAP) is a membrane-bound zinc metallopeptidase with many important regulatory functions. It has been demonstrated that inhibition of IRAP by angiotensin IV (Ang IV) and other peptides, as well as more druglike inhibitors, improves cognition in several rodent models. We recently reported a series of aryl sulfonamides as small-molecule IRAP inhibitors and a promising scaffold for pharmacological intervention. We have now expanded with a number of derivatives, report their stability in liver microsomes, and characterize the activity of the whole series in a new assay performed on recombinant human IRAP. Several compounds, such as the new fluorinated derivative <b>29</b>, present submicromolar affinity and high metabolic stability. Starting from the two binding modes previously proposed for the sulfonamide scaffold, we systematically performed molecular dynamics simulations and binding affinity estimation with the linear interaction energy method for the full compound series. The significant agreement with experimental affinities suggests one of the binding modes, which was further confirmed by the excellent correlation for binding affinity differences between the selected pair of compounds obtained by rigorous free energy perturbation calculations. The new experimental data and the computationally derived structure–activity relationship of the sulfonamide series provide valuable information for further lead optimization of novel IRAP inhibitors

Mutations in HECW2 are associated with intellectual disability and epilepsy

BACKGROUND: De novo mutations are a frequent cause of disorders related to brain development. We report the results of screening patients diagnosed with both epilepsy and intellectual disability (ID) using exome sequencing to identify known and new causative de novo mutations relevant to these conditions. METHODS: Exome sequencing was performed on 39 patient-parent trios to identify de novo mutations. Clinical significance of de novo mutations in genes was determined using the American College of Medical Genetics and Genomics standard guidelines for interpretation of coding variants. Variants in genes of unknown clinical significance were further analysed in the context of previous trio sequencing efforts in neurodevelopmental disorders. RESULTS: In 39 patient-parent trios we identified 29 de novo mutations in coding sequence. Analysis of de novo and inherited variants yielded a molecular diagnosis in 11 families (28.2%). In combination with previously published exome sequencing results in neurodevelopmental disorders, our analysis implicates HECW2 as a novel candidate gene in ID and epilepsy. CONCLUSIONS: Our results support the use of exome sequencing as a diagnostic approach for ID and epilepsy, and confirm previous results regarding the importance of de novo mutations in this patient group. The results also highlight the utility of network analysis and comparison to previous large-scale studies as strategies to prioritise candidate genes for further studies. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy and highlights HECW2 as a new candidate gene for neurodevelopmental disorders

Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability

Intellectual Disability (ID) is a clinically heterogeneous condition that affects 2-3% of population worldwide. In recent years, exome sequencing has been a successful strategy for studies of genetic causes of ID, providing a growing list of both candidate and validated ID genes. In this study, exome sequencing was performed on 28 ID patients in 27 patient-parent trios with the aim to identify de novo variants (DNVs) in known and novel ID associated genes. We report the identification of 25 DNVs out of which five were classified as pathogenic or likely pathogenic. Among these, a two base pair deletion was identified in the PUF60 gene, which is one of three genes in the critical region of the 8q24.3 microdeletion syndrome (Verheij syndrome). Our result adds to the growing evidence that PUF60 is responsible for the majority of the symptoms reported for carriers of a microdeletion across this region. We also report variants in several genes previously not associated with ID, including a de novo missense variant in NAA15. We highlight NAA15 as a novel candidate ID gene based on the vital role of NAA15 in the generation and differentiation of neurons in neonatal brain, the fact that the gene is highly intolerant to loss of function and coding variation, and previously reported DNVs in neurodevelopmental disorders