| 1. |
- Becker, K., et al.
(författare)
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Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
- 2021
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Ingår i: EBioMedicine. - : Elsevier B.V.. - 2352-3964. ; 73
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Tidskriftsartikel (refereegranskat)abstract
- Background: The clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP). Methods: A combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP. Findings: EBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin. Interpretation: This study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section. © 2021 The Author(s)
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| 2. |
- Arheimer, Berit, et al.
(författare)
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The IAHS Science for Solutions decade, with Hydrology Engaging Local People IN a Global world (HELPING)
- 2024
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Ingår i: Hydrological Sciences Journal. - 0262-6667 .- 2150-3435.
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Tidskriftsartikel (refereegranskat)abstract
- The new scientific decade (2023-2032) of the International Association of Hydrological Sciences (IAHS) aims at searching for sustainable solutions to undesired water conditions - may it be too little, too much or too polluted. Many of the current issues originate from global change, while solutions to problems must embrace local understanding and context. The decade will explore the current water crises by searching for actionable knowledge within three themes: global and local interactions, sustainable solutions and innovative cross-cutting methods. We capitalise on previous IAHS Scientific Decades shaping a trilogy; from Hydrological Predictions (PUB) to Change and Interdisciplinarity (Panta Rhei) to Solutions (HELPING). The vision is to solve fundamental water-related environmental and societal problems by engaging with other disciplines and local stakeholders. The decade endorses mutual learning and co-creation to progress towards UN sustainable development goals. Hence, HELPING is a vehicle for putting science in action, driven by scientists working on local hydrology in coordination with local, regional, and global processes.
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| 3. |
- ASKEBJER, P, et al.
(författare)
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AMANDA - STATUS-REPORT FROM THE 1993-94 CAMPAIGN AND OPTICAL-PROPERTIES OF THE SOUTH-POLE ICE
- 1995
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Ingår i: NUCLEAR PHYSICS B. - : ELSEVIER SCIENCE BV. - 0550-3213. ; , s. 287-292
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- We report the first results of the AMANDA detector. During the antarctic summer 1993-94 four strings were deployed between 0.8 an 1 km depth, each equipped with 20 photomultiplier tubes (PMTs). A laser source was used to investigate the optical properties
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| 4. |
- ASKEBJER, P, et al.
(författare)
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ON THE AGE VS DEPTH AND OPTICAL CLARITY OF DEEP ICE AT THE SOUTH-POLE
- 1995
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Ingår i: JOURNAL OF GLACIOLOGY. - : INT GLACIOL SOC. - 0022-1430. ; 41:139, s. 445-454
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The first four strings of phototubes for the AMANDA high-energy neutrino observatory are now frozen in place at a depth of 800-1000 m in ice at the South Pole. During the 1995-96 season, as many as six more strings will be deployed at greater depths. Prov
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| 5. |
- Askebjer, P, et al.
(författare)
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Optical properties of deep ice at the South Pole: Absorption
- 1997
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Ingår i: APPLIED OPTICS. - : OPTICAL SOC AMER. - 0003-6935. ; 36:18, s. 4168-4180
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- We discuss recent measurements of the wavelength-dependent absorption coefficients in deep South Pole ice. The method uses transit-time distributions of pulses from a variable-frequency laser sent between emitters and receivers embedded in the ice. At dep
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| 6. |
- ASKEBJER, P, et al.
(författare)
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OPTICAL-PROPERTIES OF THE SOUTH-POLE ICE AT DEPTHS BETWEEN 0.8 AND 1 KILOMETER
- 1995
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Ingår i: SCIENCE. - : AMER ASSOC ADVAN SCIENCE. - 0036-8075. ; 267:5201, s. 1147-1150
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The optical properties of the ice at the geographical South Pole have been investigated at depths between 0.8 and 1 kilometer. The absorption and scattering lengths of visible light (similar to 515 nanometers) have been measured in situ with the use of th
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| 7. |
- Jaramillo, Fernando, et al.
(författare)
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Priorities and Interactions of Sustainable Development Goals (SDGs) with Focus on Wetlands
- 2019
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Ingår i: Water. - : MDPI. - 2073-4441. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- Wetlands are often vital physical and social components of a country’s natural capital, as well as providers of ecosystem services to local and national communities. We performed a network analysis to prioritize Sustainable Development Goal (SDG) targets for sustainable development in iconic wetlands and wetlandscapes around the world. The analysis was based on the information and perceptions on 45 wetlandscapes worldwide by 49 wetland researchers of the Global Wetland Ecohydrological Network (GWEN). We identified three 2030 Agenda targets of high priority across the wetlandscapes needed to achieve sustainable development: Target 6.3—“Improve water quality”; 2.4—“Sustainable food production”; and 12.2—“Sustainable management of resources”. Moreover, we found specific feedback mechanisms and synergies between SDG targets in the context of wetlands. The most consistent reinforcing interactions were the influence of Target 12.2 on 8.4—“Efficient resource consumption”; and that of Target 6.3 on 12.2. The wetlandscapes could be differentiated in four bundles of distinctive priority SDG-targets: “Basic human needs”, “Sustainable tourism”, “Environmental impact in urban wetlands”, and “Improving and conserving environment”. In general, we find that the SDG groups, targets, and interactions stress that maintaining good water quality and a “wise use” of wetlandscapes are vital to attaining sustainable development within these sensitive ecosystems.
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| 8. |
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| 9. |
- Nikitidou, Elisabeth, 1987-
(författare)
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Cellular responses to amyloid-beta protofibrils : Focus on astrocytes, extracellular vesicles and antibody treatment
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Knowledge about the cellular mechanisms behind the initiation and propagation of Alzheimer’s disease (AD) is limited. Decades of research have focused on neuronal abnormalities in AD, but recently more attention has been given to the glial cells. Being the most numerous glial cell type in the brain, astrocytes are important for many functions, but their role in AD is poorly understood. The aim with this thesis was to clarify the involvement of astrocytes in AD by using a co-culture system of primary neurons and glia. The co-cultures were exposed to soluble amyloid-beta (Aβ) aggregates, i.e. protofibrils that are known to be particularly harmful.In Paper I, the capacity of astrocytes to ingest and degrade Aβ protofibrils was investigated. We found that astrocytes effectively ingested Aβ, but were ineffective in degrading the material. The intracellular accumulation of Aβ in astrocytes resulted in lysosomal dysfunction, high intracellular load of partly N-terminally truncated Aβ and extracellular vesicle (EV) mediated neuronal cell death.Cells can communicate by releasing cargo into EVs, but the role of EVs in the spreading of Aβ pathology is unclear. In Paper II, the protein content of EVs released specifically following Aβ protofibril exposure was analyzed. We found markedly increased levels of apolipoprotein E (apoE) in EVs from Aβ protofibril exposed co-cultures, suggesting a role for intercellular transfer of apoE in Aβ pathology.Passive immunotherapy has been suggested as a promising therapeutic strategy for AD. In Paper III, we investigated if the Aβ protofibril-selective antibody mAb158 could affect Aβ clearance in the co-culture. The mAb158 treatment reduced Aβ accumulation in astrocytes and rescued neurons from Aβ-induced cell death.In Paper IV, we explored the effect of EVs, isolated from Aβ protofibril exposed co-cultures on cultured neurons. In addition to increased cell death, we found that such EVs had a strong negative impact on the synapses, dendrites and mitochondria of the neurons.Taken together, this thesis contributes with important knowledge about the role of astrocytes in Aβ pathology, the vesicle-mediated spreading of Aβ and the effects of anti-Aβ antibody treatment.
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| 10. |
- Rostami, Jinar, et al.
(författare)
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Prolyl oligopeptidase inhibition by KYP-2407 increases alpha-synuclein fibril degradation in neuron-like cells
- 2020
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Ingår i: Biomedicine and Pharmacotherapy. - : Elsevier BV. - 0753-3322 .- 1950-6007. ; 131
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Tidskriftsartikel (refereegranskat)abstract
- Growing evidence emphasizes insufficient clearance of pathological alpha-synuclein (αSYN) aggregates in the progression of Parkinson's disease (PD). Consequently, cellular degradation pathways represent a potential therapeutic target. Prolyl oligopeptidase (PREP) is highly expressed in the brain and has been suggested to increase αSYN aggregation and negatively regulate the autophagy pathway. Inhibition of PREP with a small molecule inhibitor, KYP-2407, stimulates autophagy and reduces the oligomeric species of αSYN aggregates in PD mouse models. However, whether PREP inhibition has any effects on intracellular αSYN fibrils has not been studied before. In this study, the effect of KYP2407 on αSYN preformed fibrils (PFFs) was tested in SH-SY5Y cells and human astrocytes. Immunostaining analysis revealed that both cell types accumulated αSYN PFFs intracellularly but KYP-2047 decreased intracellular αSYN deposits only in SH-SY5Y cells, as astrocytes did not show any PREP activity. Western blot analysis confirmed the reduction of high molecular weight αSYN species in SH-SY5Y cell lysates, and secretion of αSYN from SH-SY5Y cells also decreased in the presence of KYP-2407. Accumulation of αSYN inside the SH-SY5Y cells resulted in an increase of the auto-lysosomal proteins p62 and LC3BII, as well as calpain 1 and 2, which have been shown to be associated with PD pathology. Notably, treatment with KYP-2407 significantly reduced p62 and LC3BII levels, indicating an increased autophagic flux, and calpain 1 and 2 levels returned to normal in the presence of KYP-2407. Our findings indicate that PREP inhibition can potentially be used as therapy to reduce the insoluble intracellular αSYN aggregates.
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