| 1. |
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| 2. |
- Andersson, C. David, et al.
(författare)
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Divergent Structure-Activity Relationships of Structurally Similar Acetylcholinesterase Inhibitors
- 2013
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:19, s. 7615-7624
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Tidskriftsartikel (refereegranskat)abstract
- The molecular interactions between the enzyme acetylcholinesterase (AChE) and two compound classes consisting of N-[2-(diethylamino)ethyl]benzenesulfonamides and N-[2-(diethylamino)ethyl]benzenemethanesulfonamides have been investigated using organic synthesis, enzymatic assays, X-ray crystallography, and thermodynamic profiling. The inhibitors' aromatic properties were varied to establish structure activity relationships (SAR) between the inhibitors and the peripheral anionic site (PAS) of AChE. The two structurally similar compound classes proved to have distinctly divergent SARs in terms of their inhibition capacity of AChE. Eight X-ray structures revealed that the two sets have different conformations in PAS. Furthermore, thermodynamic profiles of the binding between compounds and AChE revealed class-dependent differences of the entropy/enthalpy contributions to the free energy of binding. Further development of the entropy-favored compound class resulted in the synthesis of the most potent inhibitor and an extension beyond the established SARs. The divergent SARs will be utilized to develop reversible inhibitors of AChE into reactivators of nerve agent-inhibited AChE.
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| 3. |
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| 4. |
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| 5. |
- Edsman, Lennart, et al.
(författare)
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Detection of crayfish plague spores in large freshwater systems
- 2014
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Ingår i: Journal of Applied Ecology. - : Wiley. - 0021-8901 .- 1365-2664. ; 51, s. 544-553
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Tidskriftsartikel (refereegranskat)abstract
- Our study demonstrates a low amount of pathogen spores are present in aquatic environments with non-indigenous crayfish species, emphasizing the need for large-volume filtering techniques for successful detection. The approach can be used for risk assessments and to improve conservation and management strategies of crayfish in Europe. Applications of this method include targeted disease surveillance, habitat evaluation prior to crayfish re-stockings and water monitoring that can minimize disease transmission and spread, for example in crayfish farms and prior to fish movements for stocking purposes.
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| 6. |
- Engdahl, Cecilia, et al.
(författare)
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Acetylcholinesterases from the Disease Vectors Aedes aegypti and Anopheles gambiae : Functional Characterization and Comparisons with Vertebrate Orthologues
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:10
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Tidskriftsartikel (refereegranskat)abstract
- Mosquitoes of the Anopheles (An.) and Aedes (Ae.) genus are principal vectors of human diseases including malaria, dengue and yellow fever. Insecticide-based vector control is an established and important way of preventing transmission of such infections. Currently used insecticides can efficiently control mosquito populations, but there are growing concerns about emerging resistance, off-target toxicity and their ability to alter ecosystems. A potential target for the development of insecticides with reduced off-target toxicity is the cholinergic enzyme acetylcholinesterase (AChE). Herein, we report cloning, baculoviral expression and functional characterization of the wild-type AChE genes (ace-1) from An. gambiae and Ae. aegypti, including a naturally occurring insecticide-resistant (G119S) mutant of An. gambiae. Using enzymatic digestion and liquid chromatography-tandem mass spectrometry we found that the secreted proteins were post-translationally modified. The Michaelis-Menten constants and turnover numbers of the mosquito enzymes were lower than those of the orthologous AChEs from Mus musculus and Homo sapiens. We also found that the G119S substitution reduced the turnover rate of substrates and the potency of selected covalent inhibitors. Furthermore, non-covalent inhibitors were less sensitive to the G119S substitution and differentiate the mosquito enzymes from corresponding vertebrate enzymes. Our findings indicate that it may be possible to develop selective non-covalent inhibitors that effectively target both the wild-type and insecticide resistant mutants of mosquito AChE.
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| 7. |
- Engdahl, Cecilia, et al.
(författare)
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Discovery of selective inhibitors targeting acetylcholinesterase 1 from disease-transmitting mosquitoes
- 2016
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:20, s. 9409-9421
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Vector control of disease-transmitting mosquitoes is increasingly important due to the re-emergence and spread of infections such as malaria and dengue. We have conducted a high throughput screen (HTS) of 17,500 compounds for inhibition of the essential AChE1 enzymes from the mosquitoes Anopheles gambiae and Aedes aegypti. In a differential HTS analysis including the human AChE, several structurally diverse, potent, and selective noncovalent AChE1 inhibitors were discovered. For example, a phenoxyacetamide-based inhibitor was identified with a 100-fold selectivity for the mosquito over the human enzyme. The compound also inhibited a resistance conferring mutant of AChE1. Structure-selectivity relationships could be proposed based on the enzymes' 3D structures; the hits' selectivity profiles appear to be linked to differences in two loops that affect the structure of the entire active site. Noncovalent inhibitors of AChE1, such as the ones presented here, provide valuable starting points toward insecticides and are complementary to existing and new covalent inhibitors.
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| 8. |
- Engdahl, Cecilia, 1987-
(författare)
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Selective inhibition of acetylcholinesterase 1 from disease-transmitting mosquitoes : design and development of new insecticides for vector control
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acetylcholinesterase (AChE) is an essential enzyme with an evolutionary conserved function: to terminate nerve signaling by rapid hydrolysis of the neurotransmitter acetylcholine. AChE is an important target for insecticides. Vector control by the use of insecticide-based interventions is today the main strategy for controlling mosquito-borne diseases that affect millions of people each year. However, the efficiency of many insecticides is challenged by resistant mosquito populations, lack of selectivity and off-target toxicity of currently used compounds. New selective and resistance-breaking insecticides are needed for an efficient vector control also in the future. In the work presented in this thesis, we have combined structural biology, biochemistry and medicinal chemistry to characterize mosquito AChEs and to develop selective and resistance-breaking inhibitors of this essential enzyme from two disease-transmitting mosquitoes.We have identified small but important structural and functional differences between AChE from mosquitoes and AChE from vertebrates. The significance of these differences was emphasized by a high throughput screening campaign, which made it evident that the evolutionary distant AChEs display significant differences in their molecular recognition. These findings were exploited in the design of new inhibitors. Rationally designed and developed thiourea- and phenoxyacetamide-based non-covalent inhibitors displayed high potency on both wild type and insecticide insensitive AChE from mosquitoes. The best inhibitors showed over 100-fold stronger inhibition of mosquito than human AChE, and proved insecticide potential as they killed both adult and larvae mosquitoes.We show that mosquito and human AChE have different molecular recognition and that non-covalent selective inhibition of AChE from mosquitoes is possible. We also demonstrate that inhibitors can combine selectivity with sub-micromolar potency for insecticide resistant AChE.
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| 9. |
- Engdahl, Fredrik, et al.
(författare)
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A Trial of Natural Habitat Enclosure Traps as a Sampling Tool for Juvenile Crayfish
- 2013
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Ingår i: Freshwater Crayfish. - 2076-4324 .- 2076-4332. ; 2, s. 137-144
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Tidskriftsartikel (refereegranskat)abstract
- Recruitment is a vital factor in the assessment, management and population dynamics of decapods. Since the juvenile stages of crayfish often prefer heterogeneous habitats, sampling with quantitative and reproducible methods have so far been challenging. We evaluate a new quantitative sampling method for juvenile crayfish; the enclosure trap. A field test was carried out during two consecutive years on a population of signal crayfish, Pacifastacus leniusculus, in littoral areas of Swedish Lake Erken. The densities of 0+ crayfish varied substantially with year, sampling date and substrate type. As expected, juvenile crayfish densities decreased over time in both study years, indicating a high mortality rate during their first year of life. Juveniles preferred gravel and stone over soft and sand substrates. Mean growth rate varied from 0.15 to 0.22 mm day-1. We evaluate this method and present recommendations for how to design and optimize field studies using enclosure traps. We conclude that enclosure traps can be used to collect valuable data on density, growth and habitat preference of juvenile crayfish, thus providing useful information for studies on population dynamics and increasing the understanding of crayfish recruitment processes.
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| 10. |
- Engdahl, Fredrik
(författare)
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Air - for Health and Comfort, An Analysis of HVAC Systems' Performance in Theory and Practice
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One part of the objective is to analyze how different ventilation systems perform in practice when it comes to supplying and exhausting designed air flow in different outdoor and indoor conditions. The other part is to analyze the design criterias and the energy use of a variable air volume system based on controlled static pressure at the branch duct level and supplying outdoor air only. To investigate the technical status of ventilation systems, the result from the compulsory testing and examination of ventilation systems (OVK) is used. A multi-zone model (COMIS) is used to study the air flow in a multi-family building. Two ventilation systems are analyzed with the same building; the mechanical exhaust and the mechanical supply and exhaust system. Fundamental pressure loss equations, measurements and a computer program are used to determine how much the air flow at the air terminals on a branch with controlled static pressure differs. A model is developed to determine the optimal supply air temperature with respect to energy use. An average of 34% of the studied ventilation systems performed as intended. Both the mechanical exhaust and the mechanical supply and exhaust air system showed sensitiveness to outdoor temperature, building airtightness and wind. When the static pressure is controlled to be constant at the branch duct level it is possible to vary the air flow to different zones without measuring the individual flow and without significantly influence the air flow to other zones. When using 100% outdoor air the indoor air quality will be improved during most of the year. There is a great potential in controlling the supply air temperature optimally to reduce the energy use.
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| 11. |
- Engdahl, Fredrik, et al.
(författare)
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Optimal supply air temperature with respect to energy use in a variable air volume system
- 2004
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Ingår i: Energy and Buildings. - : Elsevier BV. - 1872-6178 .- 0378-7788. ; 36:3, s. 205-218
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Tidskriftsartikel (refereegranskat)abstract
- In a variable air volume (VAV) system with 100% outdoor air, the cooling need in the building is satisfied with a certain air flow at a certain supply air temperature. To minimize the system energy use, an optimal supply air temperature can be set dependent on the load, specific fan power (SFP), chiller coefficient of performance, outdoor temperature and the outdoor relative humidity. The theory for an optimal supply air temperature is presented and the heating, ventilation and air-conditioning (HVAC) energy use is calculated depending on supply air temperature control strategy, average U-value of the building envelope and two outdoor climates. The analyses show that controlling the supply air temperature optimally results in a significantly lower HVAC energy use than with a constant supply air temperature. The optimal average U-value of the building envelope is in practise mostly zero. (C) 2003 Elsevier B.V. All rights reserved.
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| 12. |
- Engdahl, Fredrik, et al.
(författare)
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Pressure controlled variable air volume system
- 2003
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Ingår i: Energy and Buildings. - : Elsevier BV. - 1872-6178 .- 0378-7788. ; 35:11, s. 1161-1172
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Tidskriftsartikel (refereegranskat)abstract
- There is one primary goal and several secondary goals to fulfill when designing a heating, ventilation and air conditioning (HVAC) system. The main goal is to create an indoor climate that satisfies the user and this should be achieved in the most energy efficient way and with a system that also function in a long-term perspective. Higher supply air flow have the potential of increasing office workers performance and decreasing short-term sick leave. To increase the supply air flow, a cooling function is added to the air and 100% outdoor air is supplied. The main objective of this paper is to give the fundamentals for a system design that takes good indoor climate, energy efficiency and long-term operation into account. When controlling the static pressure at branch level, it is possible to vary the air flow to different zones without measuring the individual flow and without affecting the air flow to other zones. An equation for the placement of the pressure sensor is shown and the relative flow difference between the diffusers on the branch is calculated and measured. These principals are the fundamentals for a pressure controlled variable air volume (VAV) system. The fan pressure set point is optimized resulting in a decreased fan power requirement and sound generation. The flow to each zone is controlled at the diffuser outlet which prevents draft and therefore a wide range in supply air temperature can be used. (C) 2003 Elsevier B.V. All rights reserved.
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| 13. |
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| 14. |
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| 15. |
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| 16. |
- Hellsén, Gustaf, et al.
(författare)
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Predicting recurrent cardiac arrest in individuals surviving Out-of-Hospital cardiac arrest
- 2023
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Ingår i: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 184
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite improvements in short-term survival for Out-of-Hospital Cardiac Arrest (OHCA) in the past two decades, long-term survival is still not well studied. Furthermore, the contribution of different variables on long-term survival have not been fully investigated. Aim: Examine the 1-year prognosis of patients discharged from hospital after an OHCA. Furthermore, identify factors predicting re-arrest and/or death during 1-year follow-up. Methods: All patients 18 years or older surviving an OHCA and discharged from the hospital were identified from the Swedish Register for Car-diopulmonary Resuscitation (SRCR). Data on diagnoses, medications and socioeconomic factors was gathered from other Swedish registers. A machine learning model was constructed with 886 variables and evaluated for its predictive capabilities. Variable importance was gathered from the model and new models with the most important variables were created. Results: Out of the 5098 patients included, 902 (-18%) suffered a recurrent cardiac arrest or death within a year. For the outcome death or re-arrest within 1 year from discharge the model achieved an ROC (receiver operating characteristics) AUC (area under the curve) of 0.73. A model with the 15 most important variables achieved an AUC of 0.69. Conclusions: Survivors of an OHCA have a high risk of suffering a re-arrest or death within 1 year from hospital discharge. A machine learning model with 15 different variables, among which age, socioeconomic factors and neurofunctional status at hospital discharge, achieved almost the same predictive capabilities with reasonable precision as the full model with 886 variables.
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| 17. |
- Hessulf, Fredrik, 1986, et al.
(författare)
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Adherence to Guidelines is Associated With Improved Survival Following In-hospital Cardiac Arrest in Sweden
- 2020
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Ingår i: Resuscitation. - : Lippincott Williams & Wilkins. - 0300-9572 .- 1873-1570. ; 155, s. -21
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Tidskriftsartikel (refereegranskat)abstract
- Background: Most resuscitation guidelines have recommendations regarding maximum delay times from collapse to calling for the rescue team and initiation of treatment following cardiac arrest. The aim of the study was to investigate the association between adherence to guidelines for cardiopulmonary resuscitation (CPR) after in-hospital cardiac arrest (IHCA) and survival with a focus on delay to treatment.Methods: We used the Swedish Registry for CPR to study 3212 patients with a shockable rhythm and 9113 patients with non-shockable rhythm from January 1, 2008 to December 31, 2017. Adult patients older than or equal to 18 years with a witnessed IHCA where resuscitation was initiated were included. We assessed trends in adherence to guidelines and their associations with 30-day survival and neurological function. Adherence to guidelines was defined as follows: time from collapse to calling for the rescue team and CPR within 1 min for non-shockable rhythms. For shockable rhythms, adherence was defined as the time from collapse to calling for the rescue team and CPR within 1 min and defibrillation within 3 min.Results: In patients with a shockable rhythm, the 30-day survival for those treated according to guidelines was 66.1%, as compared to 46.5% among those not treated according to guidelines on one or more parameters, adjusted odds ratio 1.84 (95% CI 1.52-2.22). Among patients with a non-shockable rhythm the 30-day survival for those treated according to guidelines was 22.8%, as compared to 16.0% among those not treated according to guidelines on one or more parameters, adjusted odds ratio 1.43 (95% CI 1.24-1.65). Neurological function (cerebral performance category 1-2) among survivors was better among patients treated in accordance with guidelines for both shockable (95.7% vs 91.1%, <0.001) and non-shockable rhythms (91.0% vs 85.5%, p < 0.008). Adherence to the Swedish guidelines for CPR increased slightly 2008-2017.Conclusions: Adherence to guidelines was associated with increased probability of survival and improved neurological function in patients with a shockable and non-shockable rhythm, respectively. Increased adherence to guidelines could increase cardiac arrest survival.
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| 18. |
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| 19. |
- Hessulf, Fredrik, 1986, et al.
(författare)
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Campylobacter jejuni-associated perimyocarditis: two case reports and review of the literature
- 2016
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Ingår i: Bmc Infectious Diseases. - : Springer Science and Business Media LLC. - 1471-2334. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Campylobacter spp. are among the most common bacterial causes of gastroenteritis world-wide and mostly follow a benign course. We report two cases of Campylobacter jejuni-associated perimyocarditis, the first two simultaneous cases published to date and the third and fourth cases over all in Sweden, and a review of the literature. Case presentation: A previously healthy 24-yo male (A) presented at the Emergency Department(ED) with recent onset of chest pain and a 3-day history of abdominal pain, fever and diarrhoea. The symptoms began within a few hours of returning from a tourist visit to a central European capital. Vital signs were stable, the Electrocardiogram(ECG) showed generalized ST-elevation, laboratory testing showed increased levels of C-reactive protein(CRP) and high-sensitive Troponin T(hsTnT). Transthoracic echocardiogram (TTE) was normal, stool cultures were positive for C Jejuni and blood cultures were negative. Two days after patient A was admitted to the ED his travel companion (B), also a previously healthy male (23-yo), presented at the same ED with almost identical symptoms: chest pain precipitated by a few days of abdominal pain, fever and diarrhoea. Patient B declared that he and patient A had ingested chicken prior to returning from their tourist trip. Laboratory tests showed elevated CRP and hsTnT but the ECG and TTE were normal. In both cases, the diagnosis of C jejuni-associated perimyocarditis was set based on the typical presentation and positive stool cultures with identical strains. Both patients were given antibiotics, rapidly improved and were fully recovered at 6-week follow up. Conclusion: Perimyocarditis is a rare complication of C jejuni infections but should not be overlooked considering the risk of heart failure. With treatment, the prognosis of full recovery is good but several questions remain to be answered regarding the pathophysiology and the male preponderance of the condition.
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| 20. |
- Hessulf, Fredrik, 1986, et al.
(författare)
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Factors of importance to 30-day survival after in-hospital cardiac arrest in Sweden - A population-based register study of more than 18,000 cases.
- 2017
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754.
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVE: In-hospital cardiac arrest (IHCA) constitutes a major contributor to cardiovascular mortality. The aim of the present study was to investigate factors of importance to 30-day survival after IHCA in Sweden.METHODS: A retrospective register study based on the Swedish Register of Cardiopulmonary Resuscitation (SRCPR) 2006-2015. Sixty-six of 73 hospitals in Sweden participated. The inclusion criterion was a confirmed cardiac arrest in which resuscitation was attempted among patients aged >18years.RESULTS: In all, 18,069 patients were included, 39% of whom were women. The median age was 75years. Thirty-day survival was 28.3%, 93% with a CPC score of 1-2. One-year survival was 25.0%. Overall IHCA incidence in Sweden was 1.7 per 1000 hospital admissions. Several factors were found to be associated with 30-day survival in a multivariable analysis. They included cardiac arrest (CA) at working days during the daytime (08-20) compared with weekends and night-time (20-08) (OR 1.51 95% CI 1.39-1.64), monitored CA (OR 2.18 95% CI 1.99-2.38), witnessed CA (OR 2.87 95% CI 2.48-3.32) and if the first recorded rhythm was ventricular fibrillation/tachycardia, especially in combination with myocardial ischemia/infarction as the assumed aetiology of the CA (OR for interaction 4.40 95% CI 3.54-5.46).CONCLUSION: 30-day survival after IHCA is associated with the time of the event, the aetiology of the CA and the degree of monitoring and this should influence decisions regarding the appropriate level of monitoring and care.
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| 21. |
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| 22. |
- Hessulf, Fredrik, 1986, et al.
(författare)
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Predicting survival and neurological outcome in out-of-hospital cardiac arrest using machine learning: the SCARS model
- 2023
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Ingår i: eBioMedicine. - : Elsevier BV. - 2352-3964. ; 89
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Tidskriftsartikel (refereegranskat)abstract
- Background: A prediction model that estimates survival and neurological outcome in out-of-hospital cardiac arrest patients has the potential to improve clinical management in emergency rooms.Methods: We used the Swedish Registry for Cardiopulmonary Resuscitation to study all out-of-hospital cardiac arrest (OHCA) cases in Sweden from 2010 to 2020. We had 393 candidate predictors describing the circumstances at cardiac arrest, critical time intervals, patient demographics, initial presentation, spatiotemporal data, socioeconomic status, medications, and comorbidities before arrest. To develop, evaluate and test an array of prediction models, we created stratified (on the outcome measure) random samples of our study population. We created a training set (60% of data), evaluation set (20% of data), and test set (20% of data). We assessed the 30-day survival and cerebral performance category (CPC) score at discharge using several machine learning frameworks with hyperparameter tuning. Parsimonious models with the top 1 to 20 strongest predictors were tested. We calibrated the decision threshold to assess the cut-off yielding 95% sensitivity for survival. The final model was deployed as a web application.Findings: We included 55,615 cases of OHCA. Initial presentation, prehospital interventions, and critical time intervals variables were the most important. At a sensitivity of 95%, specificity was 89%, positive predictive value 52%, and negative predictive value 99% in test data to predict 30-day survival. The area under the receiver characteristic curve was 0.97 in test data using all 393 predictors or only the ten most important predictors. The final model showed excellent calibration. The web application allowed for near-instantaneous survival calculations.Interpretation: Thirty-day survival and neurological outcome in OHCA can rapidly and reliably be estimated during ongoing cardiopulmonary resuscitation in the emergency room using a machine learning model incorporating widely available variables.
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| 23. |
- Hessulf, Fredrik, 1986, et al.
(författare)
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Temporal variation in survival following in-hospital cardiac arrest in Sweden.
- 2023
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Ingår i: International journal of cardiology. - 0167-5273 .- 1874-1754. ; 381, s. 112-119
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to investigate what characterizes IHCAs that take place during the "day" (Monday-Friday 7am-3pm), "evening" (Monday-Friday 3pm-9pm) and "night" (Monday-Friday 9pm-7am and Saturday-Sunday 12am- 11.59pm).We used the Swedish Registry for CPR (SRCR) to study 26,595 patients from January 1, 2008 to December 31, 2019. Adult patients ≥18years with a IHCA where resuscitation was initiated were included. Uni- and multivariable logistic regression was used to investigate associations between temporal factors and survival to 30days.30-day survival and Return of Spontaneous Circulation (ROSC) was 36.8% and 67.9% following CA during the day and decreased during the evening (32.0% and 66.3%) and night (26.2% and 60.2%) (p<0.001 and p=0.028). When comparing the survival rates between the day and the night, survival decreased more (change in relative survival rates) in small (<99 beds) compared to large (<400) hospitals (35.9% vs 25%), in non-academic vs academic hospitals (33.5% vs 22%) and on non-Electro Cardiogram (ECG)-monitored wards vs ECG-monitored wards (46.2% vs 20.9%) (p<0.001 for all). IHCAs that took place during the day (adjusted Odds Ratio (aOR) 1.47 95% CI 1.35-1.60), in academic hospitals (aOR 1.14 95% CI 1.02-1.27) and in large (>400 beds) hospitals (aOR 1.31 95% CI 1.10-1.55) were independently associated with an increased chance of survival.Patients suffering an IHCA have an increased chance of survival during the day vs the evening vs night, and the difference in survival is even more pronounced when cared for at smaller, non-academic hospitals, general wards and wards without ECG-monitoring capacity.
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| 24. |
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| 25. |
- Knutsson, Sofie, et al.
(författare)
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N-Aryl-N'-ethyleneaminothioureas effectively inhibit acetylcholinesterase 1 from disease-transmitting mosquitoes
- 2017
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 134, s. 415-427
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Tidskriftsartikel (refereegranskat)abstract
- Vector control of disease-transmitting mosquitoes by insecticides has a central role in reducing the number of parasitic- and viral infection cases. The currently used insecticides are efficient, but safety concerns and the development of insecticide-resistant mosquito strains warrant the search for alternative compound classes for vector control. Here, we have designed and synthesized thiourea-based compounds as non-covalent inhibitors of acetylcholinesterase 1 (AChE1) from the mosquitoes Anopheles gambiae (An. gambiae) and Aedes aegypti (Ae. aegypti), as well as a naturally occurring resistant-conferring mutant. The N-aryl-N'-ethyleneaminothioureas proved to be inhibitors of AChE1; the most efficient one showed submicromolar potency. Importantly, the inhibitors exhibited selectivity over the human AChE (hAChE), which is desirable for new insecticides. The structure-activity relationship (SAR) analysis of the thioureas revealed that small changes in the chemical structure had a large effect on inhibition capacity. The thioureas showed to have different SAR when inhibiting AChE1 and hAChE, respectively, enabling an investigation of structure-selectivity relationships. Furthermore, insecticidal activity was demonstrated using adult and larvae An. gambiae and Ae. aegypti mosquitoes.
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| 26. |
- Knutsson, Sofie, et al.
(författare)
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Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency
- 2018
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:23, s. 10545-10557
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Tidskriftsartikel (refereegranskat)abstract
- Resistance development in insects significantly threatens the important benefits obtained by insecticide usage in vector control of disease-transmitting insects. Discovery of new chemical entities with insecticidal activity is highly desired in order to develop new insecticide candidates. Here, we present the design, synthesis, and biological evaluation of phenoxyacetamide-based inhibitors of the essential enzyme acetylcholinesterase 1 (AChE1). AChE1 is a validated insecticide target to control mosquito vectors of, e.g., malaria, dengue, and Zika virus infections. The inhibitors combine a mosquito versus human AChE selectivity with a high potency also for the resistance-conferring mutation G122S; two properties that have proven challenging to combine in a single compound. Structure activity relationship analyses and molecular dynamics simulations of inhibitor protein complexes have provided insights that elucidate the molecular basis for these properties. We also show that the inhibitors demonstrate in vivo insecticidal activity on disease-transmitting mosquitoes. Our findings support the concept of noncovalent, selective, and resistance-breaking inhibitors of AChE1 as a promising approach for future insecticide development.
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| 27. |
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| 28. |
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| 29. |
- Sandström, Alfred, et al.
(författare)
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Fiskets fångster och trender för Vätterns kommersiella fisk- och kräftarter
- 2015
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Ingår i: Rapport nr 119 från Vätternvårdsförbundet. ; :27, s. 119-132
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Bokkapitel (populärvet., debatt m.m.)abstract
- Vättern har en av Sveriges och även Europas allra längsta tidsserier med fiskestatistik. Ända se-dan 1914 har fångsterna i det yrkesmässiga fisket registrerats. Fiskets inriktning har förändrats markant under senare år. Tidigare riktades fisket mot sik och röding, numera är det istället signal-kräfta som är den viktigaste arten för fisket. Efter tre år med vikande fångster har fångsten åter ökat de två senaste åren och år 2013 var kräftfångsten cirka 107 ton. Signalkräftan står därmed fortfarande för merparten av värdet i fisket, drygt 90 % av intäkterna i första handelsled. De sen-aste tre åren har det dock skett ett visst trendbrott med ökade fångster av främst röding, öring, sik och lake. För flertalet arter är numera fritidsfiskets fångster relativt omfattande och i vissa fall sannolikt större än i yrkesfisket. Om man summerar de skattade fångsterna i fritidsfisket med de som sker i yrkesfisket så är det tydligt att de totala fångsterna av många arter ökat på senare år. Särskilt för röding, öring, lake och sik är fångsttrenden positiv. Under året har bestånden överva-kats med bottensatta provfiskenät. Resultaten visar att beståndet av sik är fortsatt starkt. Fångsten av sik var den högsta hittills under de tio år som provfisken bedrivits. De flesta fiskätande arter fortsätter också att öka, särskilt tydliga positiva trender finns för röding och öring men även för lake.
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| 30. |
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| 31. |
- Sandström, Alfred, et al.
(författare)
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Fiskets fångster och trender för Vätterns kommersiella fisk- och kräftarter
- 2016
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Ingår i: Årsskrift 2015. ; :124, s. 104-116
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Bokkapitel (populärvet., debatt m.m.)abstract
- Vättern har en av Sveriges och även Europas allra längsta tidsserier med fiskestatistik. ända se-dan 1914 har fångsterna i det yrkesmässiga fisket registrerats. Fiskets inriktning har förändrats markant under de senare åren. Tidigare riktades fisket mot sik och röding, numera är det istället signalkräfta som är den viktigaste arten för fisket. Efter tre år med vikande fångster har fångsten åter ökat de tre senaste åren och år 2014 var kräftfångsten cirka 108 ton. Signalkräftan står där-med fortfarande för merparten av värdet i fisket, drygt 90 % av intäkterna i första handelsled. De senaste fyra åren har det dock skett ett visst trendbrott med ökade fångster av främst röding, öring, sik och lake. För flertalet arter är numera fritidsfiskets fångster relativt omfattande och i vissa fall sannolikt större än i yrkesfisket. Om man summerar de skattade fångsterna i fritidsfisket med de som sker i yrkesfisket så är det tydligt att de totala fångsterna av många arter ökat på se-nare år. Särskilt för röding, öring, lake och sik är fångsttrenden positiv. Under året har bestånden övervakats med bottensatta provfiskenät. Resultaten visar att beståndet av sik var den högsta hittills under de tio år som provfisken bedrivits. De flesta fiskätande arter fortsätter också att öka, särskilt tydliga positiva trender finns för röding och öring men även i viss mån för lake. Provfisken under 2015 visar att medelstorleken hos signalkräfta minskat i några av de områden som är viktiga för fisket. Fångsten per bur i fisket har gått upp något de senaste två åren men är forftarande väsentligt lägre än toppåren 2005-2008.
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| 32. |
- Sandström, Alfred, et al.
(författare)
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Fiskfångster och utsättningar av fisk
- 2014
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Ingår i: Årsskrift 2014. ; :84, s. 77-83
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Totalfångsten i yrkesfisket i Vänern var oförändrad jämfört med 2012. Den viktigaste arten för yrkesfisket var gös, vilken stod för cirka 38 % av totala fångstens värde. Den näst viktigaste arten är siklöja (35 % av värdet). Fångsten av övriga viktiga arter som gädda, gös, lax, signalkräfta, öring och ål var på samma nivå som 2012. Fångsten av abborre minskade från 41 till 33 ton. De registrerade fritidsfiskarna fångade under 2013 totalt 69 ton, vilket är ungefär på samma nivå som 2012 men en minskning sett över längre tid. Totalt 267 276 smolt sattes ut vilket är över medelvärdet för den föregående femårsperioden. Även utsättningen av ål har ökat på senare år, 600 000 försträckta alternativt karantäniserade ålyngel sattes ut under både 2013 och 2014.
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| 33. |
- Sandström, Alfred, et al.
(författare)
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Förvaltning av signalkräfta i sjöar : en litteraturstudie
- 2013
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Fisket efter signalkräfta har fått allt större ekonomisk och social betydelse i Sverige. Trots detta saknas väl underbyggda råd för hur ett hållbart fiske ska bedrivas. Projektet ”Utveckling av fisket efter signalkräfta – hur ska man optimera fiske och förutsäga risken för populationskollapser?” är ett projekt som delfinansieras av Europeiska fiskerifonden 2009-2013. Som en inledande del i detta projekt gjordes en litteratursammanställning, och baserat på denna har planeringen av det framtida arbetet kunnat konkretiseras. Målsättningen med litteraturgenomgången var att identifiera vilken information om signalkräftans biologi och ekologi som behövdes för att kunna ta fram bra fiskerimodeller för hur ett hållbart fiske bör bedrivas. Dessutom var det viktigt att förstå varför vissa bestånd av signalkräfta har kollapsat. Fångsterna av signalkräfta varierar mellan sjöar. Denna variation kan, i sjöar som inte är försurade, till stor del förklaras med hur stor andel av sjöns botten som är täckt med sten. Finns det mycket sten i en sjö finns det också mycket signalkräftor. Det finns några få studier i Sverige på signalkräftan där populationer har följts under en längre tid (minst 15 år). Dessa visar att fångst per mjärde och uttag av konsumtionskräftor varierar mellan olika år inom en sjö. Dessa variationer kan till viss del förklaras med temperaturen under föregående år, men mekanismen bakom detta är inte känd. Studier av andra arter sötvattenskräftor och en del marina skaldjur (t.ex. hummer) tyder på att rekryteringen (reproduktionsframgången) till viss del kan förklara variationerna i fångstnivåer mellan olika år. Denna litteraturgenomgång visar att det saknas väsentlig information om signalkräftans ekologi och biologi för att kunna ta fram teoretiska modeller som ska ligga till grund för rekommendationer om hur ett hållbart fiske ska bedrivas. De beståndsanalyser som bedömts vara intressanta för signalkräfta kräver vissa dataunderlag för att ge tillförlitliga resultat. De enskilt viktigaste faktorerna är rekryteringsframgång, tillväxt, naturlig dödlighet, och detaljerad fiskeristatistik (ansträngning, selektivitet, fångster etc.). Med anledning av resultaten från denna litteraturgenomgång bedömdes följande insatser som prioriterade: • undersöka betydelsen av honans storlek för rekryteringsframgång • utveckla tekniken för märkning av kräftor i olika typer av bestånd för att sedan kunna använda återfångstdata för att bestämma individuell tillväxt, naturlig dödlighet och fiskeridödlighet • uppskatta ytan tillgängligt kräfthabitat för olika kräftbestånd och bedöma i vilken mån det påverkar potentiellt fiskeuttag • analysera ett flertal sjöar med och utan populationskollapser och undersöka vilka miljöfaktorer som kan förklara uppkomsten av kollapser • analysera såväl pestfrekvens som infektionsgrad i enskilda kräftor och utvärdera om det finns en koppling mellan populationskollapser och ökade pestangrepp i sjöar
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| 34. |
- Sandström, Alfred, et al.
(författare)
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Population collapses in introduced non-indigenous crayfish
- 2014
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Ingår i: Biological Invasions. - : Springer Science and Business Media LLC. - 1387-3547 .- 1573-1464. ; 16:9, s. 1961-1977
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Tidskriftsartikel (refereegranskat)abstract
- Invasive species often have instable population dynamics and are known to collapse or oscillate heavily after passing through the initial lag/growth phases. Long-term data-series documenting these fluctuations are however rare. We use long-term (starting in the early 1960s), semi-quantitative data on the invasive signal crayfish (Pacifastacus leniusculus), capturing its population development after introduction in 44 Swedish lakes. In total 18 (41 %) of these populations had experienced a collapse. A stepwise discriminant function analysis including 20 different ecological or physicochemical characteristics identified three variables explaining collapses in the following order: stocking year, population age and mean air temperature. Populations stocked in the 1980s were more likely to collapse than populations stocked in the 1970s. Lakes with collapses were located in areas with 0.4 A degrees C higher yearly mean air temperatures than the still viable populations. Collapses also depended on the time phase of the population and started to occur 12 years after stocking and were most frequent in the interval 16-20 years after stocking and after 11-15 years duration of the established phase with harvestable densities. An analysis of prevalence and pathogen load of Aphanomyces astaci was conducted in eight of the studied populations. A. astaci was present in all populations but neither the level of prevalence nor the pathogen load in infested specimens differed significantly between lakes with collapses and lakes without. Our results highlight the potential sensitivity and instability of introduced crayfish. The importance of density-dependence and temperature suggest that both climate variability and/or fisheries can influence these processes.
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| 35. |
- Sjögren, Klara, 1970, et al.
(författare)
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The gut microbiota regulates bone mass in mice
- 2012
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 27:6, s. 1357-1367
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Tidskriftsartikel (refereegranskat)abstract
- The gut microbiota modulates host metabolism and development of immune status. Here we show that the gut microbiota is also a major regulator of bone mass in mice. Germ-free (GF) mice exhibit increased bone mass associated with reduced number of osteoclasts per bone surface compared with conventionally raised (CONV-R) mice. Colonization of GF mice with a normal gut microbiota normalizes bone mass. Furthermore, GF mice have decreased frequency of CD4+ T cells and CD11b+/GR 1 osteoclast precursor cells in bone marrow, which could be normalized by colonization. GF mice exhibited reduced expression of inflammatory cytokines in bone and bone marrow compared with CONV-R mice. In summary, the gut microbiota regulates bone mass in mice, and we provide evidence for a mechanism involving altered immune status in bone and thereby affected osteoclast-mediated bone resorption. Further studies are required to evaluate the gut microbiota as a novel therapeutic target for osteoporosis. (C) 2012 American Society for Bone and Mineral Research.
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| 36. |
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| 37. |
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| 41. |
- Torabzadeh-Tari, Mohsen
(författare)
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Analysis of Electro-Meachanical Actuator Systems in More Electric Aircraft Applications
- 2005
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Conventional hydraulic actuators in aircraft are demanding regarding maintenance which implies high operation costs. In recent years the focus therefore has been set on electro-hydrostatic and electro-mechanical actuators. The aim of this work is to analyze and evaluate the possibility of introducing electro-mechanical actuators (EMAs) in more electric aircraft applications. The major goal is to optimize the weight of such actuator systems including the electro-machine (electric motor) gear mechanism and power converter, without loss of reliability. Other optimisation criteria on such solutions are low losses and good thermal properties. A quasi-static model approach of EMAs is used here in order to decrease the simulation time. It is possible because the low (mechanical) and high (electrical) frequency components are separated in the model, see [1]. The inverters and converters are described as fictive DC-DC transformers with corresponding efficiencies, see [2]. By introducing an object oriented approach the model is flexible and re-usable and can be used as a framework in the future build-up of models of entire MEA aircrafts, see [3]. Power density, cost and weight of the actuator systems are some of the important key factors for comparing purpose and as a platform for the dimensioning of the aircraft. The next issue becomes the scalability of the model and the key factors, because of the diversity of the actuators used in different parts of the MEA aircraft. Therefore the ambition is set to build up a database of different scalable actuator solutions which among others returns these key factors as output.
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| 42. |
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