| 1. |
- Kambugyiro, Doris Kwesiga, 1981-
(författare)
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Exploring the Under Reporting of Pregnancy and Adverse Pregnancy Outcomes in Population and Health Surveys : A Multi-Country Qualitative Study
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Globally in 2021, an estimated 2.3 million newborn deaths and 1.9 million stillbirths occurred, with highest mortality in sub-Saharan Africa and southern Asia. True mortality is likely higher due to under reporting of pregnancies and Adverse Pregnancy Outcomes (APOs). Accurate data are critical for monitoring and preventing these events but many countries rely on Demographic and Health Surveys (DHS), despite measurement challenges. Few studies have explored reasons for under reporting pregnancy and APOs in low income countries, within surveys and surveillance settings.Objective: To explore enablers and barriers to reporting pregnancy and APOs during population and health surveys in multi-country contexts, informing measurement improvements.Methods: The study was conducted in Uganda, Guinea-Bissau, Ghana, Ethiopia and Bangladesh between 2018 and 2021. Focus group discussions (Study I and II), narratives (Study III) and cognitive interviews (Study IV) were undertaken. Thematic analysis was done for the first three studies and qualitative description for Study IV.Results: Methodological challenges included question framing, where double barrelled questions resulted in wrong answers. There were incorrect definitions for miscarriages and stillbirths. Enablers were mostly around interviewers’ skills like building rapport, probing and empathy. Community barriers comprised socio-cultural factors that encouraged silence, including fear of witchcraft. Stigma towards APOs was common, with some foetal deaths viewed as not human, thus less reported. Informal reporting of APOs within social networks sometimes resulted in social support. Individually, APOs left women and men with negative psychosocial effects like depression, thus their reluctance to report. Nevertheless, some respondents said interviews left them feeling better, especially if the interviewer comforted them. Respondents accepted interviews hoping to receive health education about pregnancy loss.Conclusions: Many adverse pregnancy outcomes are avoidable, but they must be accurately measured before designing appropriate interventions. Surveys like the DHS are globally trusted but this study demonstrates that they have weaknesses and sometimes inaccurate data. Improving measurement requires precise questions, strengthened interviewer training, embedded counseling and health education. Supportive policies encouraging reporting are critical, alongside sensitizing citizens on its importance. Otherwise, APOs shall remain invisible and a continued burden to the mental health of those who experience them.
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| 2. |
- Alogheli, Hiba
(författare)
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Computational Studies of Macrocycles and Molecular Modeling of Hepatitis C Virus NS3 Protease Inhibitors
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Computational tools are utilized in the drug discovery process to discover, design, and optimize new therapeutics. One important approach is structure-based drug design which relies on knowledge about the 3D structure of the biological target. The first part of this work focuses on applying structure-based drug design for binding mode prediction of HCV NS3 protease inhibitors. The NS3 protease is a challenging target from a computational perspective as it contains an extended binding site. Binding mode predictions were performed for various classes of new acyclic and macrocyclic HCV NS3 protease inhibitors and was used in the design of new inhibitors. None of the synthetized inhibitors have been co-crystallized yet, which has made the evaluation of the suggested binding mode predictions challenging.Macrocycles are an interesting compound class in drug discovery due to their unique structural architecture, which can enable access to new chemical space. Macrocycles can successfully modulate difficult therapeutic targets, as exemplified in the development of protease inhibitors. Furthermore they can improve drug-like properties, such as cell permeability and bioavailability. The second part of this thesis focuses on macrocycles from a computational point of view. A data set of 47 clinically relevant macrocycles was compiled and used in these studies. First, two different docking protocols rigid docking of pre-generated conformers and flexible docking in Glide were evaluated and compared. The results showed that flexible docking in Glide was sufficient for docking of macrocycles with respect to accuracy and speed.The aim of the second study was to evaluate and compare the performance of the more general conformational analysis tools, MCMM and MTLMOD, with the recently developed macrocycle-specialized conformational sampling tools, Prime-MCS and MMBS. In most cases, the general conformational analysis tools (with enhanced parameter settings) performed equally well as compared to the macrocycle-specialized conformational sampling techniques. However, MMBS was superior at locating the global energy minimum conformation.Finally, calculation of the conformational energy penalty of protein-bound macrocycles was performed. The macrocycle data set was complemented with linear analogues that are similar either with respect to physicochemical properties or 2D fingerprints. The conformational energy penalties of these linear analogues were calculated and compared to the conformational energy penalties of the macrocycles. The complete data set of macrocycles and non-macrocycles in this study differ from previously published work addressing conformational energy penalties, since it covers a more extended area of chemical space. Furthermore, there was a weak correlation between the calculated conformational energy penalties and the flexibility of the structures.
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| 3. |
- Duc, Duong, 1984-
(författare)
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Healthcare context for knowledge translation in Vietnam : Development and application of the Context Assessment for Community Health (COACH) tool
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The failure to translate evidence into clinical practice has been repeatedly highlighted. This failure is partly attributed to disregarding the context within which healthcare is delivered. The aim of this thesis was to develop and psychometrically evaluate the Context Assessment for Community Health (COACH) tool, and, through that process, provide opportunities to measure aspects of context perceived to be important for Knowledge Translation (KT) interventions in low- and middle-income countries (LMIC).All four studies in this thesis were mainly undertaken in Quang Ninh province, Vietnam during 2008–2014. Study II, however, was also conducted in four other LMICs (Bangladesh, Nicaragua, South Africa, and Uganda). Study I employed inductive content analysis of 16 focus group discussions to explore the influence of context in a community-based facilitation intervention in Vietnam. Studies II and III reported on the development of the COACH tool and assessment of its psychometric properties. Study IV used the COACH tool in a survey among health workers in Vietnam.To date, three sources of evidence regarding validity of the COACH tool have been provided, that is, test content, response processes, and internal instrument structure, with promising psychometric characteristics. The COACH tool could be used as means of characterizing aspects of context ahead of KT interventions, for tailoring KT strategies, and for further understanding of the results of KT interventions.
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| 4. |
- Eriksson, Leif
(författare)
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Knowledge Translation in Vietnam : Evaluating facilitation as a tool for improved neonatal health and survival
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neonatal mortality remains a problem worldwide, despite the existence of low-cost and evidence-based interventions. Unfortunately, the translation of these interventions into practice is deficient.The aim of this thesis was to study aspects of knowledge translation (KT) before and during the Neonatal Knowledge Into Practice (NeoKIP) trial in Quang Ninh, Vietnam. Over a period of three years, this trial evaluated the use of facilitators from the Women’s Union who supported maternal and newborn health groups (MNHG) comprised of eight local stakeholders, as an intervention for improved neonatal survival.In the first two studies (before intervention) we assessed primary health care staff’s knowledge and material preparedness regarding evidence-based neonatal care and explored how primary health care staff translated knowledge into practice. The last two studies (during intervention) were process evaluations aimed at describing the implementation, process and mechanism of the NeoKIP intervention.Primary health care workers achieved 60% of the maximum score in the knowledge survey. Two separate geographical areas were identified with differences in staff levels of knowledge and concurrent disparities in neonatal survival, antenatal care and post-natal home visits. Staff perceived formal training to be the best way to acquire knowledge but asked for more interaction between colleagues within the healthcare system. Traditional medicine, lack of resources, low workload and poorly paid staff constituted barriers for the development of staff knowledge and skills.Eleven facilitators were trained to cover eight facilitator positions. Of the 44 MNHGs, 43 completed their activities to the end of the study. In total, 95% of the monthly meetings with a MNHG and a facilitator were conducted with attendance at 86%. MNHGs identified 32 unique problems, mainly families’ knowledge/behavior, and implemented 39 unique actions, mostly regarding communication. MNHGs experienced that the group was strategically composed to influence change in the communes and facilitators were identified as being important to sustaining activities over time. The facilitators’ lack of health knowledge was regarded as a deficit in assisting the MNHGs, but their performance and skills increased over time.This low-cost model, building on local stakeholder involvement, has the capacity to be scaled up within existing healthcare structures.
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| 5. |
- Eriksson, Rickard
(författare)
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Structural Changes in Lithium Battery Materials Induced by Aging or Usage
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Li-ion batteries have a huge potential for use in electrification of the transportation sector. The major challenge to be met is the limited energy storage capacity of the battery pack: both the amount of energy which can be stored within the space available in the vehicle (defining its range), and the aging of the individual battery cells (determining how long a whole pack can deliver sufficient energy and power to drive the vehicle). This thesis aims to increase our knowledge and understanding of structural changes induced by aging and usage of the Li-ion battery materials involved.Aging processes have been studied in commercial-size Li-ion cells with two different chemistries. LiFePO4/graphite cells were aged under different conditions, and thereafter examined at different points along the electrodes by post mortem characterisation using SEM, XPS, XRD and electrochemical characterization in half-cells. The results revealed large differences in degradation behaviour under different aging conditions and in different regions of the same cell. The aging of LiMn2O4-LiCoO2/Li4Ti5O12 cells was studied under two different aging conditions. Post mortem analysis revealed a high degree of Mn/Co mixing within individual particles of the LiMn2O4-LiCoO2 composite electrode.Structural changes induced by lithium insertion were studied in two negative electrode materials: in Li0.5Ni0.25TiOPO4 using in situ XRD, and in Ni0.5TiOPO4 using EXAFS, XANES and HAXPES. It was shown that Li0.5Ni0.25TiOPO4 lost most of its long-range-order during lithiation, and that both Ni and Ti were involved in the charge compensation mechanism during lithiation/delithiation of Ni0.5TiOPO4, with small clusters of metal-like Ni forming during lithiation.Finally, in situ XRD studies were also made of the reaction pathways to form LiFeSO4F from two sets of reactants: either FeSO4·H2O and LiF, or Li2SO4 and FeF2. During the heat treatment, Li2SO4 and FeF2 react to form FeSO4·H2O and LiF in a first step. In a second step LiFeSO4F is formed. This underlines the importance of the structural similarities between LiFeSO4F and FeSO4·H2O in the formation process of LiFeSO4F.
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| 6. |
- Phoosuwan, Nitikorn, 1982-
(författare)
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Perinatal Depressive Symptoms among Women in North-Eastern Thailand : Risk Factors, Support and Prevention
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Perinatal depressive symptoms among women remain a global burden. Improvements in self-efficacy among public health professionals (PHPs) in primary healthcare settings to detect and manage perinatal depressive symptoms among women are needed.The aims of this thesis were to: identify prevalence and risk factors associated with perinatal depressive symptoms among women; to explore and describe life situation and support among women with antenatal depressive symptoms (ADS) and their partners; and to improve self-efficacy of PHPs in detection and management of perinatal depressive symptoms in Sakonnakhon province in Thailand. Qualitative and quantitative studies with different types of data collection methods were used.Study I determined prevalence of ADS and associated risk factors among 449 Thai women in late pregnancy using the Edinburgh Postnatal Depression Scale (EPDS). The prevalence was 46.8% and associated risk factors were insufficient money, being a teenager, low psychological well-being, low self-esteem and low sense of coherence.Study II explored and described life situation and support during pregnancy among women with ADS and their partners using semi-structured interviews. Four categories emerged: Having obstacles in life, Facing life situation, Enhancing confidence and Dissatisfaction with help.Study III determined risk factors associated with postpartum depressive symptoms at one month among 319 women and at three months among 276 women. Risk factors at one month were antenatal psychological well-being, non-exclusive breastfeeding, low personal income and caregiver not a mother; risk factors at three months were unintended pregnancy, low personal income/month, low self-esteem, low psychological well-being and low maternal competence.Study IV evaluated a self-efficacy improvement programme (SIP) intended to increase PHPs’ self-efficacy in efforts to detect and manage perinatal depressive symptoms among women. After the SIP, PHPs in the intervention group (n=33) had higher self-efficacy scores than PHPs in the control group (n=33). Four categories emerged in qualitative evaluation: Having confidence, Changing knowledge and attitudes, Increasing perception of an important role, and Increasing awareness of performed function.Women who are at increased risk for perinatal depressive symptoms should be screened using the EPDS. Health care professionals should involve expectant fathers in ANC process. The SIP enhances PHPs’ ability to detect and manage perinatal depressive symptoms.
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| 7. |
- Quennerstedt, Mikael, 1966-
(författare)
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Att lära sig hälsa
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this dissertation is to contribute to an understanding of the subject content in Physical Education (PE) foremost from a health perspective. By using an approach deriving from John Dewey’s transactional perspective on meaningmaking (Bentley & Dewey 1949), and a discourse theoretical position, the discourses identified in the dissertation’s studies are consequently regarded as participants in pupils’ meaning-making. This makes it possible to discuss the results of the studies in terms of the institutional content and conditions of meaning-making in PE. The thesis consists of three different discourse analyses, where the institutionalised aspect of meaning-making in PE is examined by analysing local curriculum documents from 72 Swedish compulsory schools. The results of the dissertation show that in the study of subject content in PE a dominance of an activity discourse can be identified, although a social development discourse is also identified as being important in the documents. The results, thus, suggest that the subject content of PE can be characterised by a wide variety of activities, where pupils are expected to be active participants in the sense of being physically active. The content is also characterised by actions promoting good relationships, co-operation and consideration for others. Actions privileged within the discourses in PE are movement, physical activity, trying many different activities together, active participation, good relations and enjoyment. The results also show that health is explicitly constituted as fitness training, life-long physical activity and knowledge about physical training based on scientific facts from physiology and anatomy. Learning health in PE thus mainly consists of a pathogenic health discourse. But from a salutogenic perspective, health is also constituted as the possibility to participate in movement, physical leisure activities and social relations, and enjoy a life-long engagement in different movement and sport activities. The analysis also shows, however, that within the frame of the subject content of PE, it is also possible to regard health in terms of a commitment to health- and environmental issues, a sense of well-being in ongoing activities and an active involvement in subject content matters within PE. Health can therefore be constituted in different ways within PE, although this is not always made explicit in the local curriculum documents.
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| 8. |
- Ristilä, Mikael
(författare)
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Vitamin B6 as a potential antioxidant : a study emanating from UV-B-stressed plants
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Increased influx of solar UV-B radiation (280-320 nm), due to a decreasing stratospheric ozone layer, impacts severely on plants. Some of the UV-B effects on plants are related to stress induced by produced reactive oxygen species (ROS). Pyridoxine (vitamin B6) has been reported to be a potential quencher of ROS.Previous studies have shown that the PDX1.3 gene (encoding a key enzyme in vitamin B6 biosynthesis) is up-regulated by UV-B. We showed that this up-regulation also occurs at the protein level in UV-B exposed Col-0 wild-type plants. Studies performed using pdx1 knock-out mutants of Arabidopsis thaliana showed elevated transcripts levels for LHCB1*3 and PR-5 compared with the Col-0 wild-type. The pdx1 knock-out mutants showed an increased sensitivity towards H2O2-stress, but no increased sensitivity towards low dose UV-B-stress.To study the postulated role of pyridoxine as quencher of ROS in more detail, both theoretical and experimental studies were performed. Theoretical and experimental UV absorption spectra obtained at different protonation/deprotonation states of pyridoxine showed a very close resemblance at low and high pH. However, for the computational studies at physiological pH addition of counterions were required to accurately describe the experimental spectra.When theoretically studying the reactivity of pyridoxine towards three different ROS, .OH, .OOH and .O2-, the hydroxyl radical (.OH) was shown to be the most reactive species, while the superoxide radical (.O2-) showed no reactivity towards pyridoxine.In order to study the role of G-proteins in UV-B signal transduction pathways, UV-B irradiated G-protein mutants of Arabidopsis thaliana were studied. The regulation of the PDX1.3 gene was not affected in the G-protein mutants, regardless of the developmental stage of the plant. However, the expression of CHS was affected in the Ga subunit mutants.
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| 9. |
- Rudbeck, Maria, 1979-
(författare)
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The Beauty of the Bitter Devils : A Theoretical Study on Phosphate Molecules
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Phosphate transfer reactions are catalyzed by a large number of enzymes comprising kinases, mutases and phosphatases. These enzymes play a fundamental role in controlling numerous life processes and it is therefore important to understand the origin of their potent catalytic power. An example is the Ca2+-ATPase. In the E2P-state, this enzyme hydrolyses the phosphorylated amino acid, Asp351, 106 to 107 fold faster than when the model compound, acetyl phosphate, is hydrolyzed in in water.This thesis explores the catalytic power of Ca2+-ATPase using theoretical method based on quantum mechanics. The studies of this protein were made by performing quantum chemical calculations on models of phosphoric monoesters as well as on the explicit reaction pathway of the hydrolysis. The studies show the importance of electrostatic interactions as well as the role of the specific active site residue Glu183, a residue that acts as a base in the catalytic pathway. Furthermore, based on the calculations, the interpretation of the experimental infrared spectrum of the E2P-state of Ca2+-ATPase, could be further elucidated as well as modified.The experimental infrared spectrum of phosphoenol pyruvate in water has also been elucidated through calculations. This molecule is converted into pyruvate in the last step of the glycolytic pathway, a reaction that is catalyzed by pyruvate kinase (PK). These results further enabled the interpretation of the experimental spectrum of the PK's catalytic reaction.These two processes, the transport of Ca2+ into the sarcoplasmatic reticulum against a concentration gradient and the glycolysis, are two important actions of a muscle cell.
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| 10. |
- Sequeira, Movin
(författare)
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Decision support for multi-criteria evaluation of manufacturing reshoring decisions
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Reshoring decisions in the manufacturing sector have received increasing attention due to their potential to improve overall quality, flexibility, or reduce risk. Contemporary events such as the pandemic and the supply crisis have made manufacturing reshoring decisions a timely and important topic to study. Particularly, the decision support deserves attention as there is limited knowledge on tools for reshoring decisions. The purpose of this study is to investigate the feasibility of decision support for reshoring decisions. The purpose is addressed through three research questions (RQ). The first question (RQ1) is “What criteria should be considered in evaluating a manufacturing reshoring decision?” and should guide companies in identifying factors in a reshoring decision. The second one (RQ2) is “How do decision-makers reason with respect to criteria in manufacturing reshoring decisions?” and describes the importance of the identified criteria that come into play during the decision. The third one (RQ3) is “How can the criteria be modeled in decision-support tools for evaluating manufacturing reshoring decisions?” and explores the feasibility of decision support. The research methods involve systematic literature review, multiple case study, modeling, and archival research. The findings show that reshoring is a multi-criteria decision with cost, quality, and delivery time criteria are considered to be more important (high weight) than sustainability criteria (low weight). The reasoning is manifested by inference rules pertaining to the important criteria. Multi-criteria decision-making techniques such as fuzzy inference, AHP, fuzzy-AHP and fuzzy-TOPSIS are feasible for evaluating manufacturing reshoring decisions. While these techniques rely on decision-makers’ ability to specify weights and rules, rule mining is used to extract rules from large datasets. This research contributes through increased knowledge regarding the criteria, reasoning, and modeling of reshoring decisions. Furthermore, the research extrapolates on the theories that are required to move forward when investigating this topic. For practitioners, this research develops tools that can be used in different stages of the decision-making process. For society, the support tools mean making rational decisions on reshoring rather than emotional or politically motivated ones.
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| 11. |
- Erdtman, Edvin, 1981-
(författare)
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5-Aminolevulinic acid and derivatives thereof : properties, lipid permeability and enzymatic reactions
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 5-aminolevulinic acid (5-ALA) and derivatives thereof are widely usedprodrugs in treatment of pre-malignant skin diseases of the cancer treatmentmethod photodynamic therapy (PDT). The target molecule in 5-ALAPDTis protoporphyrin IX (PpIX), which is synthesized endogenously from5-ALA via the heme pathway in the cell. This thesis is focused on 5-ALA,which is studied in different perspectives and with a variety of computationalmethods. The structural and energetic properties of 5-ALA, itsmethyl-, ethyl- and hexyl esters, four different 5-ALA enols, and hydrated5-ALA have been investigated using Quantum Mechanical (QM) first principlesdensity functional theory (DFT) calculations. 5-ALA is found to bemore stable than its isomers and the hydrolysations of the esters are morespontaneous for longer 5-ALA ester chains than shorter. The keto-enoltautomerization mechanism of 5-ALA has been studied, and a self-catalysismechanism has been proposed to be the most probable. Molecular Dynamics(MD) simulations of a lipid bilayer have been performed to study themembrane permeability of 5-ALA and its esters. The methyl ester of 5-ALAwas found to have the highest permeability constant (PMe-5-ALA = 52.8 cm/s).The mechanism of the two heme pathway enzymes; Porphobilinogen synthase(PBGS) and Uroporphyrinogen III decarboxylase (UROD), have beenstudied by DFT calculations and QM/MM methodology. The rate-limitingstep is found to have a barrier of 19.4 kcal/mol for PBGS and 13.7kcal/mol for the first decarboxylation step in UROD. Generally, the resultsare in good agreement with experimental results available to date.
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| 12. |
- Eriksson, Jonas
(författare)
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Genetic and Genomic Studies in Chicken : Assigning Function to Vertebrate Genes
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A major challenge in the post-genomic era is to understand how genome sequence variants (genotype) give rise to the enormous diversity observed in terms of morphology, physiology and behavior (phenotype) among living organisms. Domestic animals—with their tremendous phenotypic variation—are excellent model organisms for determining the relationships between genotype and phenotype. In this thesis, I describe the utilization of the chicken, in combination with modern genetic and genomic approaches, in developing our understanding of the genetic mechanisms underlying phenotypic variation. These studies provide novel information on the genetics behind variation in carotenoid- and melanin-based pigmentation—observed in many organisms—and also cast light on the genetic basis of chicken domestication. In paper I, we report that the yellow skin phenotype—observed in most commercial chickens—is caused by one or several tissue-specific mutations altering the expression of beta-carotene oxygenase 2 (BCO2 or BCDO2) in skin. In addition, we present the first conclusive evidence of a hybrid origin of the domestic chicken, since the allele causing yellow skin most likely originates from the grey jungle fowl (Gallus sonneratii) and not from the previously described sole ancestor, the red jungle fowl (Gallus gallus). In paper II, we detect a number of loci that were likely important during the domestication process of chicken and the later specialization into meat (broiler) and egg (layer) producing lines. One of the major findings was that worldwide, almost all domestic chickens carry a missense mutation in TSHR (thyroid stimulating hormone receptor) in a position that is completely conserved amongst vertebrates. We speculate that this “domestication-mutation” has played an important role in the transformation of the wild red jungle fowl ancestor into the modern domestic chicken. In paper III, we demonstrate that the dilution of red (pheomelanin) pigmentation—observed in the plumage of the Inhibitor of Gold chicken—is caused by a frame-shift mutation in the catechol-O-methyltransferase domain containing 1 (COMTD1) gene. The production and regulation of pheomelanin is poorly understood and this discovery advances our current knowledge of this pathway.
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| 13. |
- Johansson, Lars, 1961-
(författare)
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Teenager fatalities : epidemiology and implications for prevention
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A significant number of teenagers are killed each year by unintentional or intentional injuries. A teenager is in a vulnerable phase of her/his life, going from being a child to adult. This transition often includes testing the limits of their capabilities, which can include, e.g., high speed driving, testing alcohol and other drugs, including drinking and driving. The development from child to adult includes different psychological stress factors, such as, e.g., school problems, broken love affairs and bullying. The demands – perceived or real – also increases over time and vulnerable individuals can turn to self-harm and in the most extreme case suicide.The aim of this thesis was to investigate teenager fatalities in the northern half of Sweden and to suggest preventive measures.A survey of teenager fatalities during a twenty-year period revealed that the incidence of unintentional (n=248) deaths decreased, while intentional (n=102) deaths were unaffected over time. Most unintentional deaths were transportation related (n=204) while most of the intentional deaths were suicides (n=88). Twenty-eight percent of the decedents were test-positive for alcohol at autopsy.In a series of three studies, teenager suicides were investigated in depth, firstly through an interview study with the investigating police officer in charge of the investigation of a teenager suicide. Most of the suicides occurred in rural and depopulated areas despite the fact that most teenagers live in the larger cities along the coastline. A majority of the suicides appeared to be planned. Females, contrary to males, often had a psychiatric history. One of the conclusions was that police officers provide essential information concerning the circumstances around a teenager suicide.Parents who had lost a child through suicide, and in some cases siblings, were interviewed 15-25 months after the suicide. It was striking how the life of the surviving family members were still affected by the devastating trauma of the suicide; most parents testified that they were still struggling with the question “why?” and that they were thinking of their lost child every day. Post suicide support was often badly timed and insufficient, especially for the younger siblings. The family doctor has an important role as a co-ordinator of a long-term individually formulated support scheme for the bereaved.Evidence of suicide contagion and suicide cluster formation, i.e., one teenager suicide led to another suicide, was found in these studies, and two suicide clusters were identified, with links between the victims in each cluster. Both clusters occurred within a geographical and timely proximity. Everyone involved in the well-being of the young should be aware of the risk of contagion and suicide cluster formation.The fifth study concerned 12,812 teenagers who visited the Emergency Room at Umeå University Hospital due to an injury during 1993 through 2006. Sixty-one of these were found dead through 2007, 49 by unnatural (of which 38 were included) and 12 by natural causes. The standard mortality rate for unnatural death was calculated to 1.44 (1.02-1.98), confirming an increased risk of premature death. In many of these deaths, alcohol and drugs may have contributed. By increasing the awareness among health professionals that injury can predict a premature death - primarily among those who develop substance abuse - some premature deaths may be prevented by early intervention.This thesis confirms that most teenagers die from unnatural causes, mostly in transportation-related events and by suicide. By studying these deaths, preventive measures that could save lives have been suggested.
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| 14. |
- Musa, Klefah Abrahem Klefah
(författare)
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Computational studies of photodynamic drugs, phototoxic reactions and drug design
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The most important criterion when designing new drugs or improving old ones in order to prevent side effects or at least diminish them is drug safety. Treatment of all diseases generally needs use of either topical application or systemic medications (transported in the blood) during a certain period of time. These treatments are associated with a number of adverse effects. Photosensitivity is one of those side effects, with phototoxicity as one of the photosensitivity disorders. This adverse side effect arises because of a reaction between UV or visible-light and the drug molecule, its active form or photoproduct(s). Due to phototoxic side effect, unexpected symptoms varying from just a simple rash to severe cutaneous affectations can appear. Furthermore, biomolecular damage occurs once the drug-light interaction takes place persistently and ends with cell death.Several drug families, such as over-the-counter drugs in the non-steroidal anti-inflammatory drug family of 2-arylpropionic acid derivatives, or prescription required fluoroquinolone drugs, have the capability to absorb mainly UV light radiation which in turn causes different phototoxic reactions by forming radical derivatives, reactive oxygen species or both. These may effect DNA, protein and lipid cell components leading to photogenotoxicity, photoallergy and lipid peroxidation, respectively. The photodegradation mechanisms of drugs belonging to the above mentioned families including ketoprofen, ibuprofen, flurbiprofen, naproxen, the active form of nabumetone, diclofenac and its main photoproduct, suprofen, tiaprofenic acid, naphazoline, norfloxacin and lomefloxacin are investigated in more detail in this thesis.The results obtained by computational density functional theory (DFT) and time-dependent-DFT (TD-DFT) are in line with experimental data available to date. The studies provide detailed insight into the molecular basis and understanding of the full photodegradation mechanisms of drugs mentioned above. This also plays an important role in preventing or at least reducing the phototoxic adverse effects by enabling the development of safe drugs in this area. Hence, new modified non-steroid anti-inflammatory molecules were designed by computational techniques. Obtained results suggest possibility of their future usage as pharmaceuticals with reduced photodegradation and cyclooxygenase 1 induced adverse side effects compared to the parent compounds.
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| 15. |
- Öhman, Marie, 1958-
(författare)
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Kropp och makt i rörelse
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Body and Power in MotionThis dissertation is concerned with body and politics, or, more specifi cally body, power and governance. The central question is how specifi c individuals and bodies are constituted in the teaching of Physical Education (PE) in school. Inspired by Foucault’s work and the research fi eld that emanates from the concept of governmentality, one of the ambitions is to develop a method that facilitates the study of power and governance processes in teachers’ and students’ interactive actions and dealings. With the aid of this approach, 15 video-recorded physical education lessons in 5 Swedish nine-year compulsory schools are analysed in order to demonstrate how governance processes are included in the work and activities in terms of how the processes of governance–self-governance are staged, and the direction this takes. In using the term direction I am here referring to the content the governance is aiming towards, where the question of which subjects and bodies are constituted is of substantial interest. This means that the study not only focuses on what is done, but also on the way in which it is done, i.e. it analyses both process and content.The results show that physical exertion and the desire for physical work is a thread that runs though the analysed material. It is mainly scientifi c knowledge about the body that is referred to in actual teaching practice. This is displayed through the use of a scientifi cally inspired language when talking about the body, where effects on muscles and degrees of oxygen intake are considered in connection with the physical activities. In connection with physical exertion, pupils are encouraged to do their best, try the activities on offer, cooperate with others and face challenges. In line with the governmentality perspective’s problematisation of the process governance–self-governance, the study highlights a governance mentality that is not characterised by coercion, but is rather directed towards different components of willingness where the students are expected to be participatory, take responsibility and govern their own actions in the direction of that which is most desirable and reasonable. The willingness component appears as the actual hub of character-building, were the students ought to be physically active, should want to do their best, be willing to try, should want to show solidarity and should want to defeat the others. The process of governance–self-governance is staged as different ways of appealing to one’s willingness in the activities studied. Specifi c governance techniques are used to support and promote self-governance work, i.e. different forms of encouragement strengthen the correct action, emphasising physical exertion as pleasurable and focuses on the fact that we are all involved in a common project. In the dissertation it is shown how the body is included in a socio-political context. Through the body the individual is turned into a participant of physical projects concerned with becoming a certain kind of social citizen. The body thus symbolises the complex encounter between the individual and society. In this way the study demonstrates and highlights tendencies that are evident in modern society. It is thus a narrative that indicates how we all become part of a discourse system.
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| 16. |
- Bergquist, Filip, et al.
(författare)
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Pharmacokinetics of Intravenously (DIZ101), Subcutaneously (DIZ102), and Intestinally (LCIG) Infused Levodopa in Advanced Parkinson Disease
- 2022
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Ingår i: Neurology. - : Lippincott, Williams & Wilkins. - 0028-3878 .- 1526-632X. ; 99:10, s. E965-E976
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Intestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson disease. The primary objective of this trial was to investigate whether continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady-state plasma concentrations of levodopa that are equivalent in magnitude, and noninferior in variability, to those obtained with LCIG in patients with advanced Parkinson disease. Methods A concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved LCIG in a randomized, 3-period crossover, open-label, multicenter trial. Formulations were infused for 16 hours to patients with Parkinson disease who were using LCIG as their regular treatment. Patients were recruited from several university neurology clinics but came to the same phase I unit for treatment. Pharmacokinetic variables and safety including dermal tolerance are reported. The primary outcomes were bioequivalence and noninferior variability of DIZ101 and DIZ102 vs LCIG with respect to levodopa plasma concentrations. Results With dosing adjusted to estimated bioavailability, DIZ101 and DIZ102 produced levodopa plasma levels within standard bioequivalence limits compared with LCIG in the 18 participants who received all treatments. Although the levodopa bioavailability for DIZ102 was complete, it was 80% for LCIG. Therapeutic concentrations of levodopa were reached as quickly with subcutaneous administration of DIZ102 as with LCIG and remained stable throughout the infusions. Owing to poor uptake of LCIG, carbidopa levels in plasma were higher with DIZ101 and DIZ102 than with the former. All individuals receiving any of the treatments (n = 20) were included in the evaluation of safety and tolerability. Reactions at the infusion sites were mild and transient. Discussion It is feasible to rapidly achieve high and stable levodopa concentrations by means of continuous buffering of a subcutaneously administered acidic levodopa/carbidopa-containing solution.
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| 17. |
- Durbeej, Bo, 1973-
(författare)
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Quantum Chemical Studies of Protein-Bound Chromophores, UV-Light Induced DNA Damages, and Lignin Formation
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Quantum chemical methods have been used to provide a better understanding of the photochemistry of astaxanthin and phytochromobilin; the photoenzymic repair of UV-light induced DNA damages; and the formation of lignin. The carotenoid astaxanthin (AXT) is responsible for the colouration of lobster shell. In solution, the electronic absorption spectra of AXT peak in the 470-490 nm region, corresponding to an orange-red colouration. Upon binding to the lobster-shell protein-complex α-crustacyanin, the absorption maximum is shifted to 632 nm, yielding a slate-blue colouration. Herein, the structural origin of this bathochromic shift is investigated on the basis of recent experimental work.The tetrapyrrole phytochromobilin (PΦB) underlies the photoactivation of the plant photoreceptor phytochrome. Upon absorption of 660-nm light, PΦB isomerizes from a C15-Z,syn configuration (in the inactive form of the protein) to C15-E,anti (in the active form). In this work, a reaction mechanism for this isomerization is proposed. DNA photolyases are enzymes that repair DNA damages resulting from far-UV-light induced [2+2] cycloaddition reactions involving pyrimidine nucleobases. The catalytic activity of these enzymes is initiated by near-UV and visible light, and is governed by electron transfer processes between a catalytic cofactor of the enzyme and the DNA lesions. Herein, an explanation for the experimental observation that the repair of cyclobutane pyrimidine dimers (CPD) – the major type of lesion – proceeds by electron transfer from the enzyme to the dimer is presented. Furthermore, the formation of CPD is studied.Lignin is formed by dehydrogenative polymerization of hydroxycinnamyl alcohols. A detailed understanding of the polymerization mechanism and the factors controlling the outcome of the polymerization is, however, largely missing. Quantum chemical calculations on the initial dimerization step have been performed in order to gain some insight into these issues.
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| 18. |
- Enström, Johanna
(författare)
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A Systems View of Advancements in Biomass Supply Chains
- 2022
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Forest fuel is an important source of energy with potential for increased use in the Nordic countries. Profitable forest operations are dependent on logistics as the forest is a natural resource with varying conditions over widespread areas. In comparison to saw log and pulp wood supply, forest fuel supply has to face challenges like low product value, seasonality and irregularity of customer demand, low bulk density and the need to process the biomass prior to delivery. In order to utilize both the economic potential and societal benefits from replacing fossil-based fuels with renewable forest fuels these challenges must be managed. This requires efficient long distance transports, with changes of transport mode typically required.This thesis examines preconditions necessary for logistic planning to achieve cost and energy efficient long distance transports within supply chains for forest fuel. The thesis has an explorative approach, including both qualitative and quantitative techniques. Paper I provides a review of the development within forestry logistics in Sweden and Finland since the beginning of the century, with focus on transports, terminal usage and storage related aspects. Paper II uses qualitative interviews to deepen the understanding of a specific forest fuel supply chain by focusing on communications and relations between the actors. Paper III is a study of the influence of a terminal before maritime transport of wood chips using simulation. Paper I shows that forestry logistics faces challenges, primarily related to increased variations in field conditions caused by climate change. The importance of terminal storage for the supply of forest products will likely increase as an effect. Also the entrepreneurs interviewed in Paper II stressed the benefits of terminals in the supply chain, e.g. enhanced planning opportunities and a more even workflow over the year. Paper III puts cost for extra terminal handling in relation to storage costs in a port and demonstrates the importance of including variation in logistic planning. The terminal flows were not profitable in the case of a small port. In order to make a well-founded decision gains in other parts of the supply chain must also be considered, even when they are harder to quantify. This deserves attention in future research.
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| 19. |
- Eriksson, Leif A., 1964-, et al.
(författare)
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Tetrazole derivatives as cytochrome p450 inhibitors
- 2019
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Patent (populärvet., debatt m.m.)abstract
- According to the invention there is provided a compound of formula I, wherein R1 and R2 have meanings given in the description, which compounds are useful in the treatment of skin disorders and other diseases.
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| 20. |
- Jansson, Emil, 1980-
(författare)
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Electronic characterization of molecules with application to organic light emitting diodes
- 2007
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The presented thesis is devoted to the field of organic light emittingdiodes (OLEDs). Time-dependent Kohn-Sham density functional theory(TDDFT) is applied in order to eludicate optical properties such as fluorescence andphosphorescence for some of the most important materials. The accuracy of TDDFTis evaluated with respect to the calculated absorption and emission spectra forcommonly used light emitting polymers. A continuation of this work is devoted toPolyfluorene as this polymer has proven to be very promising. In this study thechain length dependence of its singlet and triplet excited states is analyzed as wellas the excited state structures.Understanding the phosphorescence mechanism of tris(2-phenylpyridine)Iridium isof importance in order to interpret the high efficiency of OLEDscontaining these specimens. The mechanism is analyzed by calculatingthe electric transition dipole moments by means of TDDFT usingquadratic response functions. As not only the optical properties are essential foreffective devices, electron transfer properties are addressed. The electrontransfer capability of the sulfur and nitrogen analogues of Oxadiazoleis evaluated through their internal reorganization energy.
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| 21. |
- Liljenberg, Magnus, 1962-
(författare)
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Quantum Chemical Studies of Aromatic Substitution Reactions
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, density functional theory (DFT) is used to investigate the mechanisms and reactivities of electrophilic and nucleophilic aromatic substitution reactions (SEAr and SNAr respectively). For SEAr, the σ-complex intermediate is preceded by one (halogenation) or two (nitration) π-complex intermediates. Whereas the rate-determining transition state (TS) for nitration resembles the second π-complex, the corresponding chlorination TS is much closer to the σ-complex. The last step, the expulsion of the proton, is modeled with an explicit solvent molecule in combination with PCM and confirmed to be a nearly barrierless process for nitration/chlorination and involves a substantial energy barrier for iodination. It is also shown for nitration that the gas phase structures and energetics are very different from those in polar solvent. The potential energy surface for SNAr reactions differs greatly depending on leaving group; the σ-complex intermediate exist for F-/HF, but for Cl-/HCl or Br-/HBr the calculations indicate a concerted mechanism. These mechanistic results form a basis for the investigations of predictive reactivity models for aromatic substitution reactions. For SEAr reactions, the free energy of the rate-determining TS reproduces both local (regioselectivity) and global reactivity (substrate selectivity) with good to excellent accuracy. For SNAr reactions good accuracies are obtained for Cl-/HCl or Br-/HBr as leaving group, using TS structures representing a one-step concerted mechanism. The σ-complex intermediate can be used as a reactivity indicator for the TS energy, and for SEAr the accuracy of this method varies in a way that can be rationalized with the Hammond postulate. It is more accurate the later the rate-determining TS, that is the more deactivated the reaction. For SNAr reactions with F-/HF as leaving group, the same method gives excellent accuracy for both local and global reactivity irrespective of the degree of activation.
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| 22. |
- Nash, Peppi, 1969-
(författare)
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Experimental and Clinical Studies of Oxidative Stress in Pre-Eclampsia
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Impaired placentation and oxidative stress are proposed to play major roles in the pathogenesis of pre-eclampsia (PE). It has recently been pointed out that PE might be more than one disease and may have several different pathogeneses. This thesis describes a new animal model for PE and examines the role of oxidative stress in early respective late onset PE.The effects of Suramin injections on day 10 and 11 of pregnancy were investigated in normal and diabetic rats of two strains (U and H), with or without additional vitamin E treatment. Suramin caused placental dysfunction in both rat strains: foetal growth restriction, increased resorption rate, reduced placental blood flow, and decreased maternal blood volume in the placenta. In the U strain Suramin also caused maternal hypertension and reduced renal blood flow. Oxidative stress in the Suramin treated rats was indicated by increased levels of isoprostane 8-iso-PGF2α in the placenta. Antioxidative treatment with vitamin E partly protected against the effects of Suramin. Streptozotocin-induced diabetes seemed to cause similar placental effects as Suramin, and in the diabetic rats the additional effects of Suramin were only moderate. In conclusion, Suramin-injected pregnant rats constitute a valid animal model for placental dysfunction (U and H rats) and PE (U rats).Oxidative stress was estimated in women with early onset (≤ 32 weeks) or late onset (≥ 35 weeks) PE, in normotensive pregnant women of respective gestational length, and in healthy non-pregnant women. The ratio of PAI-1/PAI-2 was measured in serum, and the amount of isoprostane 8-iso-PGF2α was measured in placenta, serum, and urine. The ratio of PAI-1/PAI-2 and placental isoprostane levels were higher in women with early onset PE compared with all other groups. Serum levels of isoprostane were similar between groups. Urinary levels of isoprostane were similar in all pregnant women, but lower in non-pregnant women. These data indicate that pregnancy increases general oxidative stress, and that early onset, but not late onset PE, causes increased oxidative stress also in placental tissue. The pathogeneses of early and late onset PE are, therefore, not likely to be identical.
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| 23. |
- Näslund Eriksson, Lisa, 1972-
(författare)
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Forest-Fuel Systems : Comparative Analyses in a Life Cycle Perspective
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Forest fuels can be recovered, stored and handled in several ways and these different ways have different implications for CO2 emissions. In this thesis, comparative analyses were made on different forest-fuel systems. The analyses focused on the recovery and transport systems. Costs, primary energy use, CO2 emissions, storage losses and work environment associated with the use of forest fuel for energy were examined by using systems analysis methodology in a life cycle perspective. The bundle system showed less dry-matter losses and lower costs than the chip system. The difference was mainly due to more efficient forwarding, hauling and large-scale chipping. The potential of allergic reactions by workers did not differ significantly between the systems. In difficult terrain types, the loose material and roadside bundling systems become as economical as the clearcut bundle system. The stump and small roundwood systems showed the greatest increase in costs when the availability of forest fuel decreased. Stumps required the greatest increase in primary energy use. Forest fuels are a limited resource. A key factor is the amount of biomass recovered per hectare. Combined recovery of logging residues, stumps and small roundwood from thinnings from the same forest area give a high potential of reduced net CO2 emissions per hectare of forest land. Compensation fertilization becomes more cost-effective and the primary energy use for ash spreading becomes low – about 0,25‰. The total amount of available forest fuel in Sweden is 66 TWh per year. This would cost 1 billion €2007 to recover and would avoid 6.9 Mtonne carbon if fossil coal were replaced. In southern Sweden almost all forest fuel is obtainable in high-concentration areas where it is easy to recover. When determining potential CO2 emissions avoidance, the transportation distance was found to be less important than the other factors considered in this work. The type of transportation system did not have a significant influence over the CO2 avoided per hectare of forest land. The most important factor analysed here was the type of fossil fuel (coal, oil or natural gas) replaced together with the net amount of biomass recovered per hectare of forest land. Large-scale, long-distance transportation of biofuels from central Sweden has the potential to be cost-effective and also attractive in terms of CO2 emissions. A bundle recovery system meant that more biomass per hectare could be delivered to end-users than a pellet system due to conversion losses when producing pellets.
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| 24. |
- van de Vegte, Yordi, et al.
(författare)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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| 25. |
- Wu, Min, 1986, et al.
(författare)
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Proline 411 biases the conformation of the intrinsically disordered plant UVR8 photoreceptor C27 domain altering the functional properties of the peptide
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- UVR8 (UV RESISTANCE LOCUS 8) is a UV-B photoreceptor responsible for initiating UV-B signalling in plants. UVR8 is a homodimer in its signalling inactive form. Upon absorption of UV radiation, the protein monomerizes into its photoactivated state. In the monomeric form, UVR8 binds the E3 ubiquitin ligase COP1 (CONSTITUTIVELY PHOTOMORPHOGENIC 1), triggering subsequent UV-B-dependent photomorphogenic development in plants. Recent in vivo experiments have shown that the UVR8 C-terminal region (aa 397-423; UVR8(C27)) alone is sufficient to regulate the activity of COP1. In this work, CD spectroscopy and NMR experiments showed that the UVR8(C27) domain was non-structured but gained secondary structure at higher temperatures leading to increased order. Bias-exchange metadynamics simulations were also performed to evaluate the free energy landscape of UVR8(C27). An inverted free energy landscape was revealed, with a disordered structure in the global energy minimum. Flanking the global energy minimum, more structured states were found at higher energies. Furthermore, stabilization of the low energy disordered state was attributed to a proline residue, P411, as evident from P411A mutant data. P411 is also a key residue in UVR8 binding to COP1. UVR8(C27) is therefore structurally competent to function as a molecular switch for interaction of UVR8 with different binding partners since at higher free energies different structural conformations are being induced in this peptide. P411 has a key role for this function.
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| 26. |
- Zou, Rongfeng
(författare)
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Computational Studies of Protein-ligand Systems Using Enhanced Sampling Methods
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on studies of protein-ligand systems using enhanced sampling methods. In chapter I, I give a brief introduction to the time-scale problem and some enhanced sampling methods. In chapter II, the basics of MD simulation are reviewed. In chapter III, the theoretical backgrounds of umbrella sampling, bias-exchange metadynamics and infrequent metadynamics are presented. In chapter IV, the 5 papers included in this thesis are summarized. In paper 1, we studied the relationship between the antibacterial activities of antimicrobial peptides and their aggregation propensities. We found that an increasing aggregation propensity increases the free energy cost of peptide embedding into the bacterial membrane and decreases antibacterial activity. In paper 2, we employed the umbrella sampling approach to obtain the free energy landscape of Pittsburgh compound-B penetrating into the core binding sites of amyloid βfibrils. Our study suggested that, for the design of probes binding to fibril like proteins, other than the binding affinity, the dynamics of probes in the fibrils should also be considered. In paper 3, we studied the coupled folding and binding process of the intrinsically disordered protein p53 to MDM2 with bias-exchange metadynamics and infrequent metadynamics. We reconstructed the free energy landscape and built a kinetic network for this process. In paper 4, we studied the binding modes of ASEM with a chimera structure of α7 nicotinic acetylcholine receptor with well-tempered metadynamics. We found that an important residue, Trp53, can significantly affect the stabilities of the binding modes. In paper 5, we proposed an efficient method to estimate the transition times of rare events in biomolecular systems. In chapter V, I present a conclusion of this thesis and propose an outlook related to the selection of collective variables for enhanced sampling methods.
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