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- Hallberg, Mathias, 1971-, et al.
(författare)
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Small-molecule AT2 receptor agonists
- 2018
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Ingår i: Medicinal research reviews (Print). - : John Wiley & Sons. - 0198-6325 .- 1098-1128. ; 38:2, s. 602-624
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Forskningsöversikt (refereegranskat)abstract
- The discovery of the first selective, small-molecule ATR receptor (AT2R) agonist compound 21 (C21) (8) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8, encompassing a phenylthiofen scaffold is the drug-like agonist with the highest affinity for the AT2R reported to date (K-i = 0.4 nM). Structure-activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8, are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8) or AT2R antagonists (e.g. 9), respectively, are briefly addressed. A summary of the pharmacological actions of C21 (8) is also presented.
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| 2. |
- Hallberg, Magnus, 1974-
(författare)
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Studies of Functional Interactions within Yeast Mediator and a Proposed Novel Mechanism for Regulation of Gene Expression
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The yeast Mediator complex is required for transcriptional regulation both in vivo and in vitro and the identification of similar complexes from metazoans indicates that its function is conserved through evolution. Mediator subunit composition and structure is well characterized both by biochemical, genetic and biophysical methods. In contrast, little is known about the mechanisms by which Mediator operates and how the complex is regulated. The aim of my thesis was to elucidate how Mediator functions at the molecular level and to investigate functional interactions within Mediator. It is possible to recruit RNA polymerase II to a target promoter and thus to activate transcription by fusing Mediator subunits to a DNA binding domain. In order to investigate functional interactions within Mediator, we made such fusion proteins where different Mediator subunits were fused to the DNA binding domain of lexA. The expression of a reporter gene containing binding sites for lexA was subsequently measured in both a wild type strain and in strains where genes encoding specific Mediator subunits had been disrupted. We found that lexA-Med2 and lexA-Gal11 are strong activators that function independently of all Mediator subunits tested. On the other hand, lexA-Srb10 is a weak activator that depends on Srb8 and Srb11 and lexA-Med1 and lexA-Srb7 are both cryptic activators that become active in the absence of Srb8, Srb10, Srb11, or Sin4. Both lexA-Med1 and lexA-Srb7 proteins showed a stable association with the Mediator subunits Med4 and Med8 in wild type cells and in all deletion strains tested, indicating that they were functionally incorporated into the Mediator complex. We also showed that both Med4 and Med8 exist in two forms that differed in electrophoretic mobility and that these forms differed in their ability to associate with Mediator immuno-purified from the LEXA-SRB7 and LEXA-MED1 strains. Dephosphorylation assays of purified Mediator indicated that the two mobility forms of Med4 corresponded to the phosphorylated and unphosphorylated forms of the Med4 protein respectively. Some of the data presented in this study as well as previous genetic and biochemical data obtained in our lab suggested a functional link between the Med1, Med2, Srb10 and Srb11 proteins. We extended these findings by showing that the Srb10 kinase phosphorylates the Med2 protein at residue serine 208, both in vitro and in vivo. We also showed that a point mutation of the single phosphorylation site to an alanine or to an aspartic acid residue altered the gene expression of a specific set of genes. Taken together, these data indicate that posttranslational modification of Mediator subunits is a so far uncharacterized mechanism for regulation of gene expression. In order to study the function of the Srb7 subunit of Mediator, we isolated a temperature sensitive strain where the amino acids 2 to 8 of srb7 were deleted. The Mediator subunits Nut2 and Med7 were isolated as high copy suppressor of srb7-∆(2-8) and we were also able to show that Srb7 interacted with Nut2 and Med7 both in a 2-hybrid system and in co-immuno precipitation experiments using recombinantly expressed proteins. Interestingly, a deletion of amino acids 2 to 8 of Srb7 abolishes its interaction with both Med7 and Nut2 in vitro. Med4 also interacted with Srb7 in the 2-hybrid system and surprisingly, the first eight amino acids of Srb7 were shown to be sufficient for this interaction.
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| 3. |
- Hallberg, Magnus
(författare)
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Suspended solids and metals in highway runoff : implications for treatment systems
- 2006
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It is known that traffic is a source of pollutants and that pollutant loads increase with elevated traffic densities. Studies executed in Stockholm, Sweden advocate that highway runoff from roads with an annual average daily traffic (AADT) exceeding 30,000 vehicles need treatment before discharge to the receiving water. It is common knowledge that sedimentation is the most expedient method for stormwater treatment. However, sedimentation units are area demanding and in highly urbanised watersheds the land use is often restricted. Studies have implied the occurrence of first flush, i.e. an initially higher pollutant load in the beginning of the runoff event, in highway watersheds. With an emphasized first flush it would be possible to treat only a part of the total runoff volume reducing the area needed for a sedimentation basin. In general two methods are used to design stormwater treatment ponds. One method is based on the reduced catchment area and pond surface and the other is based on an average runoff volume and a permanent pond volume. The methods are relaying on data from routine monitoring of various treatment systems and suggest removal efficiencies for pollutants. Applying general removal efficiencies for design it can be intricate to estimate an outlet concentration when the specific removal efficiency may be dependent on the initial concentration of the pollutant. Consequently, knowledge of the removal efficiencies dependence on initial concentration would be helpful to optimise stormwater treatment systems. This research has studied runoff from highly trafficated watersheds. The aim has been to evaluate the mass transport, stormwater quality and sedimentation behaviour and their implications for stormwater treatment. The study sites, Eugenia and Fredhäll, are located along the six-lane highway E4 through Stockholm that has an AADT load of 120,000 vehicles and a speed limit of 70 km/h. In lack of a unified definition of first flush the mass transport was studied using the EU directive 1991/271/EEC discharge demand for TSS of 60 mg/l. It was found that for the majority of the runoff events during winter the event mean concentration exceeded 60 mg/l suggesting that the complete runoff volume should be captured during winter. The dissolved concentration of metals showed significant variations between winter and summer, as did the concentration in the particulate matter (mg/kg). It was possible to correlate total metal concentration to total suspended solids with good correlation (r2 >0.90) for the majority of studied metals in winter and summer. The findings would imply that a successful treatment of the studied metal pollutants could be carried out by sedimentation. However, depending on discharge criteria, the elevated levels of dissolved matter, especially during winter, have to be considered with regards to the selection of the appropriate water treatment process. The sedimentation process could be described by a logarithmical function and initial turbidity. Good correlation (r2 >0.90) was indicated between turbidity and TSS. The sedimentation process of the studied highway runoff varied significantly (p<0.05) when elevated levels of NaCl could be found in the runoff. A significant difference (p<0.05) was shown for turbidity and TSS between summer and winter, which was assumed to be related to the use of studded tires. This study implies that the entire runoff volume must be treated and that the use of first flush as a design criterion is less applicable for the winter period. The study implies good correlation between total metal concentration and TSS. In addition the indicated correlation between turbidity and TSS would point to the possibility to use turbidity as a surrogate measurement for TSS and the studied metals. Moreover, the possibility to describe the sedimentation process by the initial concentration of turbidity would infer the utilisation of turbidity as a tool for process control for stormwater treatment systems. In addition, the novel results for the dependence on the sedimentation process could be incorporated in existing models for design of stormwater treatment systems in similar watersheds.
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| 4. |
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| 7. |
- Hallberg, Margareta, 1948
(författare)
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Veta rätt men handla fel
- 2014
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Ingår i: Antibiotika - Boten och hoten. - Stockholm : Formas fokuserar. - 9789154060825 ; 2014, s. 169-175
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- populärvetenskapligt bidrag till Formas serie Formas Fokuserar om antibiotikaresistens
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| 8. |
- Hallberg, Margareta, 1948
(författare)
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Vetenskapliga kontroverser oundvikliga i dagens samhälle
- 2007
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Ingår i: Läkartidningen. - 0023-7205. ; 104:8, s. 577-581
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Tidskriftsartikel (refereegranskat)abstract
- Vetenskapliga kontroverser tycks öka. En orsak (av flera) kan vara att vetenskapens roll i det moderna samhället förändrats; vetenskaplig kunskap behövs för att hantera dagens samhällsproblem. Många studier av kontroverser har rört det medicinska kunskapsområdet: frågor om hälsa/ohälsa berör de flesta medborgare, medicinska kontroverser blir därför uppmärksammade, och det är också angeläget att lösa dem. Exempel på sådana kontroverser är DAMP/ADHD, utbrändhet, östrogensubstitution i klimakteriet och MPR-vaccin. Vetenskapsteorin bedriver studier av kontroverser, tex inom ramen för forskningsprogrammet »Kontroversstudier«. Syftet med kontroversstudier är snarare att undersöka än att värdera, dvs att belysa processer som leder till att påståenden betraktas som sanna. Risken finns att kontroverser skapar tvivel på forskningens värde – i värsta fall som kunskapsförakt hos allmänheten.
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| 9. |
- Hallberg, Niklas, 1966-, et al.
(författare)
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Framework for C2 Concept Development : Exploring Design Logic and Systems Engineering
- 2018
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Ingår i: 23rd International Command and Control Research & Technology Symposium. - : International Command and Control Institute. - 9780999724613
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Konferensbidrag (refereegranskat)abstract
- The conditions for military operations have changed due to, e.g., globalization, climate change, and nations' ambitions and actions. This has resulted in new demands on command and control (C2) capability. Further, the rapid evolution of information technology has provided vigorous opportunities to enhance the C2 capability, e.g., through advanced communication, information management, and decision support. However, the need to rely on modern technology also causes increased vulnerabilities. The sociotechnical nature of C2 systems means that the development of C2 systems is complex and challenging. Developing C2 concepts requires collaboration between people from different knowledge disciplines, traditions, and perspectives. Therefore, there is a need for elaborated concept development approaches and structures that promote collaborative efforts. The objective of this paper is a framework for the development of C2 concepts that enhance the collaboration of people from different traditions. The study was carried out as case study performed in two steps: theoretical development and formative evaluation. The case study targets the development of C2 concepts for future military operations of the Swedish Armed Forces. The framework includes terminology models, a development process, and system representations. The case study shows that in diverse teams, it is essential to agree upon terminology, development process, and systems representations used for the development to avoid misunderstandings and unnecessary rework. The framework explored in this paper is only in its first version. However, the development and the application of the framework was found to facilitate and focus the work of the multi-disciplinary team.
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| 10. |
- Hallberg, Niklas, 1966-
(författare)
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Incorporating user values in the design of information systems and services in the public sector : a methods approach
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is motivated by the aim of public-sector organizations to become more efficient by quality improvement efforts and the introduction of infonnation systems. The main objective is to explore methods for the design of infonnation systems and information-system-supported services in the public sector, which meet the users' needs.The thesis is based on six connected studies. The first study was to describe the structure of how the staff at public-service units seek advice. Based on data collected through interviews, a quantitative analysis was performed at primary healthcare centers. In the second study, the use of Quality Function Deployment (QFD) for orientation of public services to a quasi-market situation was investigated. The study displayed how clinical-social-medical services can be orientated to better suit the referral institutions' needs. The third study was performed to adjust a QFD model to a method for the design of information systems in the public sector. The development of the model was performed in a blocked-case study. In the fourth study, the model was extended and applied in a case study where it was used for participatory design of information-system supported services. In the fifth study, the possibility of integrating the QFD model with process graph notations was investigated. The study was performed according to a participatory action research methodology. In the final study, an information system was designed using the QFD model developed and implemented for a public sector profession, occupational therapists.The main contribution of the thesis is the QFD model, called Medical Software Quality Deployment (MSQD), for the design of information systems and information-systems-sul)ported services in the public sector. The advantages of MSQD are that it focuses the design work on the users' needs and provides support for active participation of users. Further advantages are that the requirements are traceable and the design features are prioritized.As a support for the efforts being made in the public sector to increase efficiency, MSQD can be used to design appropriate information systems. The prototype implementation illustrated several optional ways of how this support can be implemented using low-cost technology. MSQD can further be used to develop services to better match the users' needs. Hence, it can be used for inter-organizational information systems design and, thereby, positive gains can be made in the collaboration between different public service organizations.
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