| 1. |
- Andersson, Niklas, et al.
(author)
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Methodology for fast development of digital solutions in integrated continuous downstream processing
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In: Biotechnology and Bioengineering. - 0006-3592.
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Journal article (peer-reviewed)abstract
- The methodology for production of biologics is going through a paradigm shift from batch-wise operation to continuous production. Lot of efforts are focused on integration, intensification, and continuous operation for decreased foot-print, material, equipment, and increased productivity and product quality. These integrated continuous processes with on-line analytics become complex processes, which requires automation, monitoring, and control of the operation, even unmanned or remote, which means bioprocesses with high level of automation or even autonomous capabilities. The development of these digital solutions becomes an important part of the process development and needs to be assessed early in the development chain. This work discusses a platform that allows fast development, advanced studies, and validation of digital solutions for integrated continuous downstream processes. It uses an open, flexible, and extendable real-time supervisory controller, called Orbit, developed in Python. Orbit makes it possible to communicate with a set of different physical setups and on the same time perform real-time execution. Integrated continuous processing often implies parallel operation of several setups and network of Orbit controllers makes it possible to synchronize complex process system. Data handling, storage, and analysis are important properties for handling heterogeneous and asynchronous data generated in complex downstream systems. Digital twin applications, such as advanced model-based and plant-wide monitoring and control, are exemplified using computational extensions in Orbit, exploiting data and models. Examples of novel digital solutions in integrated downstream processes are automatic operation parameter optimization, Kalman filter monitoring, and model-based batch-to-batch control.
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| 2. |
- Schwarz, Hubert, et al.
(author)
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Integrated continuous biomanufacturing on pilot scale for acid-sensitive monoclonal antibodies
- 2022
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In: Biotechnology and Bioengineering. - : Wiley. - 0006-3592 .- 1097-0290.
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Journal article (peer-reviewed)abstract
- In this study, we demonstrated the first, to our knowledge, integrated continuous bioprocess (ICB) designed for the production of acid-sensitive monoclonal antibodies, prone to aggregate at low pH, on pilot scale. A high cell density perfusion culture, stably maintained at 100 × 106 cells/ml, was integrated with the downstream process, consisting of a capture step with the recently developed Protein A ligand, ZCa; a solvent/detergent-based virus inactivation; and two ion-exchange chromatography steps. The use of a mild pH in the downstream process makes this ICB suitable for the purification of acid-sensitive monoclonal antibodies. Integration and automation of the downstream process were achieved using the Orbit software, and the same equipment and control system were used in initial small-scale trials and the pilot-scale downstream process. High recovery yields of around 90% and a productivity close to 1 g purified antibody/L/day were achieved, with a stable glycosylation pattern and efficient removal of impurities, such as host cell proteins and DNA. Finally, negligible levels of antibody aggregates were detected owing to the mild conditions used throughout the process. The present work paves the way for future industrial-scale integrated continuous biomanufacturing of all types of antibodies, regardless of acid stability.
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| 3. |
- Ahnlund, Petra, 1973-, et al.
(author)
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Prevalence and correlates of sexual, physical, and psychological violence against women and men of 60 to 74 years in Sweden
- 2020
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In: Journal of Interpersonal Violence. - Thousand Oaks : Sage Publications. - 0886-2605 .- 1552-6518. ; 35:5-6, s. 1539-1561
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Journal article (peer-reviewed)abstract
- Past-year sexual, physical, and psychological violence against women and men aged 60 to 74 years was studied. The data derived from a nationally representative survey on violence in which approximately 2,800 women and men aged 60 to 74 years in Sweden participated. Women were significantly more likely to have been subjected to at least one form of violence in the past year. The prevalence of sexual violence as well as systematic and repeated psychological violence was found to be significantly higher for women than for men. Sexual violence was the most common form of violence against women. Systematic and repeated psychological violence was the most common form of violence against men. Additional gender differences were found in relation to victim characteristics. While associations among women were found between violence victimization and sociodemographic characteristics, health as well as social capital, only health-related characteristics were found to be associated with past-year violence victimization among men. Among women, economic problems, posttraumatic stress disorder (PTSD) symptoms, lack of trust in other people, and not having anyone to talk to were associated with violence victimization. Poor psychological health and an at-risk consumption of alcohol were found to be associated with violence victimization among men. The results highlight the importance of research on violence victimization to assess gender differences also when inquiring into the situation among persons in older generations. The results also indicate practical implications for caring professions; the need to inquire into the experiences of violence among older persons and to pay particular attention to these characteristics when encountering women and men in this age interval.
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| 4. |
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| 5. |
- Andersson, Erik, et al.
(author)
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Ambio fit for the 2020s
- 2022
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In: Ambio. - : Springer Nature. - 0044-7447 .- 1654-7209. ; 51:5, s. 1091-1093
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Journal article (peer-reviewed)
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| 6. |
- Andersson, Madelene, et al.
(author)
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Development of an experimental ex vivo wound model to evaluate antimicrobial efficacy of topical formulations
- 2021
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In: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:9
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Journal article (peer-reviewed)abstract
- Wound infections are considered a major cause for wound-associated morbidity. There is a high demand for alternative, robust, and affordable methods that can provide relatable and repro-ducible results when testing topical treatments, both in research and in the pharmaceutical industry. Here we present an ex vivo wound infection model using porcine skin and a burn wounding method, allowing for the efficacy evaluation of topical antimicrobial formulations. Utilizing this model, we demonstrate the potential of topical treatments after infecting the wounds with clinically significant bacteria, P. aeruginosa and S. aureus. We show that the method is compatible with several analytical tools used to analyze infection and antimicrobial effects. Both bacterial strains success-fully infected the wound surface, as well as deeper regions of the tissue. Quantification of viable bacteria on the wound surface and in the tissue, longitudinal measurements of bioluminescence, fluorescence microscopy, and scanning electron microscopy were used to confirm the effects of an-tibacterial treatments. Furthermore, we show that biofilms are formed on the wound surface, indi-cating that the demonstrated method mirrors typical in vivo infections.
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| 7. |
- Balldin, Jan, 1935, et al.
(author)
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Inverse relationship between central serotonergic neurotransmission and blood pressure in alcohol-dependent male subjects
- 2006
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In: Journal of Neural Transmission. ; 113, s. 1511-1517
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Journal article (peer-reviewed)abstract
- Data has accumulated indicating an inverse relation between central serotonergic (5-HT) neurotransmission and blood pressure in hypertensive rats and in healthy individuals. The present study aimed to elucidate whether an inverse relation exists between systolic (SBP) and diastolic (DBP) blood pressure levels and central 5-HT neurotransmission also in a group of alcohol-dependent individuals. Central 5-HT neurotransmission was assessed by using the maximum prolactin (PRL) responses to the 5-HT probe DL-fenfluramine (DL-FEN; 60 mg po.) in 17 alcohol-dependent male subjects investigated during a period of on-going alcohol intake. BP was measured immediately before all time points for blood sampling, and readings before DL-FEN administration were used as the subjects resting BP. Results showed that there were inverse correlations between the maximum PRL responses to DL-FEN and the SBP levels (r = -0.57, p < 0.002) and with the DBP levels (r = -0.52, p < 0.05), respectively. The present study suggests the existence of an association between central 5-HT neurotransmission and blood pressure regulation also in alcohol-dependent individuals.
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| 8. |
- Ek, Fredrik, et al.
(author)
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Behavioral Analysis of Dopaminergic Activation in Zebrafish and Rats Reveals Similar Phenotypes
- 2016
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In: Acs Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 7:5, s. 633-646
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Journal article (peer-reviewed)abstract
- Zebrafish is emerging as a complement to mammals in behavioral studies; however, there is a lack of comparative studies with rodents and humans to establish the zebrafish as a predictive translational model. Here we present a detailed phenotype evaluation of zebrafish larvae, measuring 300-3000 variables and analyzing them using multivariate analysis to identify the most important ones for further evaluations. The dopamine agonist apomorphine has previously been shown to have a complex U-shaped dose response relationship in the variable distance traveled. In this study, we focused on breaking down distance traveled into more detailed behavioral phenotypes for both zebrafish and rats and identified in the multivariate analysis low and high dose phenotypes with characteristic behavioral features. Further analysis of single parameters also identified an increased activity at the lowest concentration indicative of a U-shaped dose response. Apomorphine increased the distance of each swim movement (bout) at both high and low doses, but the underlying behavior of this increase is different; at high dose, both bout duration and frequency increased whereas bout max speed was higher at low dose. Larvae also displayed differences in place preference. The low dose phenotype spent more time in the center, indicative of an anxiolytic effect, while the high-dose phenotype had a wall preference. These dose-dependent effects corroborated findings in a parallel rat study and previous observations in humans. The translational value of pharmacological zebrafish studies was further evaluated by comparing the amino acid sequence of the dopamine receptors (D-1-D-4), between zebrafish, rats and humans. Humans and zebrafish share 100% of the amino acids in the binding site for D-1 and D-3 whereas D-2 and D-4 receptors share 85-95%. Molecular modeling of dopamine D2 and D4 receptors indicated that nonconserved amino acids have limited influence on important ligand receptor interactions.
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| 9. |
- Ericsson, Madelene, et al.
(author)
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Exercise training before cardiac-specific Serca2 disruption attenuates the decline in cardiac function in mice
- 2010
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In: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 109:6, s. 1749-1755
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Journal article (peer-reviewed)abstract
- In the heart, function of the sarco(endo)plasmic Ca(2+)-ATPase (SERCA2) is closely linked to contractility, cardiac function, and aerobic fitness. SERCA2 function can be increased by high-intensity interval training, whereas reduced SERCA2 abundance is associated with impaired cardiac function. The working hypothesis was, therefore, that exercise training before cardiomyocyte-specific disruption of the Serca2 gene would delay the onset of cardiac dysfunction in mice. Before Serca2 gene disruption by tamoxifen, untreated SERCA2 knockout mice (Serca2(flox/flox) Tg-αMHC-MerCreMer; S2KO), and SERCA2 FF control mice (Serca2(flox/flox), S2FF) were exercise trained by high-intensity interval treadmill running for 6 wk. Both genotypes responded to training, with comparable increases in maximal oxygen uptake (Vo(2max); 17%), left ventricle weight (15%), and maximal running speed (40%). After exercise training, cardiac-specific Serca2 gene disruption was induced in both exercise trained and sedentary S2KO mice. In trained S2KO, cardiac function decreased less rapidly than in sedentary S2KO. Vo(2max) remained higher in trained S2KO the first 15 days after gene disruption. Six weeks after Serca2 disruption, cardiac output was higher in trained compared with sedentary S2KO mice. An exercise-training program attenuates the decline in cardiac performance induced by acute cardiac Serca2 gene disruption, indicating that mechanisms other than SERCA2 contribute to the favorable effect of exercise training.
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| 10. |
- Ericsson, Madelene, et al.
(author)
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High-intensity exercise training in mice with cardiomyocyte-specific disruption of Serca2
- 2010
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In: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 108:5, s. 1311-1320
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Journal article (peer-reviewed)abstract
- Several lines of evidence indicate that the sarco(endo)plasmic reticulum ATPase type 2 (SERCA2) is essential for maintaining myocardial calcium handling and cardiac pump function. Hence, a reduction in SERCA2 abundance is expected to reduce work performance and maximal oxygen uptake (VO2max) and to limit the response to exercise training. To test this hypothesis, we compared VO2max and exercise capacity in mice with cardiac disruption of Serca2 (SERCA2 KO) with control mice (SERCA2 FF). We also determined whether the effects on VO2max and exercise capacity could be modified by high-intensity aerobic exercise training. Treadmill running at 85-90% of VO2max started 2 wk after Serca2 gene disruption and continued for 4 wk. VO2max and maximal running speed were measured weekly in a metabolic chamber. Cardiac function was assessed by echocardiography during light anesthesia. In sedentary SERCA2 KO mice, the aerobic capacity was reduced by 50% and running speed by 28%, whereas trained SERCA2 KO mice were able to maintain maximal running speed despite a 36% decrease in VO2max. In SERCA2 FF mice, both VO2max and maximal running speed increased by training, while no changes occurred in the sedentary group. Left ventricle dimensions remained unchanged by training in both genotypes. In contrast, training induced right ventricle hypertrophy in SERCA2 KO mice. In conclusion, the SERCA2 protein is essential for sustaining cardiac pump function and exercise capacity. Nevertheless, SERCA2 KO mice were able to maintain maximal running speed in response to exercise training despite a large decrease in VO2max.
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