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SPECT imaging of distribution and retention of a brain-penetrating bispecific amyloid-β antibody in a mouse model of Alzheimer's disease

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Translational Neurodegeneration 2020年第3期9卷 473-483页

作者： tobias gustavsson Stina Syvänen Paul O'Callaghan Dag Sehlin Department of Public Health and Caring Sciences Uppsala UniversityUppsalaSweden Department of Medical Cell Biology Uppsala UniversityUppsalaSweden

Background:Alzheimer's disease(AD)immunotherapy with antibodies targeting amyloid-B(AB)has been extensively explored in clinical *** aim of this study was to study the long-term brain distribution of two radiolabeled monoclonal Aβ antibody variants-RmAb158,the recombinant murine version of BAN2401,which has recently demonstrated amyloid removal and reduced cognitive decline in AD patients,and the bispecific RmAb158-scFv8D3,which has been engineered for enhanced brain uptake via transferrin receptor-mediated ***:A single intravenous injection of iodine-125(251)-labeled RmAb158-scFv8D3 or RmAb158 was administered to AD transgenic mice(tg-ArcSwe).In vivo single photon emission computed tomography was used to investigate brain retention and intrabrain distribution of the antibodies over a period of 4 *** in blood and brain tissue was measured ex vivo and autoradiography was performed in combination with Aβand CD31 immunostaining to investigate the intrabrain distribution of the antibodies and their interactions with ***:Despite faster blood clearance,[125]RmAb158-scFv8D3 displayed higher brain exposure than[25]RmAb158 throughout the *** brain distribution of[l25]RmAb158-scFv8D3 was more uniform and coincided with parenchymal Aβ pathology,while[2 I]RmAb158 displayed a more scattered distribution pattern and accumulated in central parts of the brain at later *** vivo autoradiography indicated greater vascular escape and parenchymal Aβ interactions for[25]RmAb158-scFv8D3,whereas[25]RmAb158 displayed retention and Aβ interactions in lateral ***:The high brain uptake and uniform intrabrain distribution of RmAb158-scFv8D3 highlight the benefits of receptor-mediated transcytosis for antibody-based brain ***,it suggests that the alternative transport route of the bispecific antibody contributes to improved efficacy of brain-directed immunotherapy.

关键词： Alzheimer's disease Amyloid beta SPECT Immunotherapy Bispecific antibody Transferrin receptor

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Novel multivalent design of a monoclonal antibody improves binding strength to soluble aggregates of amyloid beta

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Translational Neurodegeneration 2021年第3期10卷 502-517页

作者： Fadi Rofo Jos Buijs Ronny Falk Ken Honek Lars Lannfelt Anna M.Lilja Nicole G.Metzendorf tobias gustavsson Dag Sehlin Linda Söderberg Greta Hultqvist Protein Drug Design Faculty of PharmacyUppsala University75124 UppsalaSweden Department of Immunology Genetics and PathologyUppsala University75185 UppsalaSweden Ridgeview Instruments 75237 UppsalaSweden BioArctic AB 11251 StockholmSweden Department of Public Health and Caring Sciences Uppsala University75185 UppsalaSweden

Background:Amyloid-β(Aβ)immunotherapy is a promising therapeutic strategy in the fght against Alzheimer’s disease(AD).A number of monoclonal antibodies have entered clinical trials for *** of them have failed due to the lack of efcacy or side-efects,two antibodies are currently in phase 3,and one has been approved by *** soluble intermediate aggregated species of Aβ,termed oligomers and protofbrils,are believed to be key pathogenic forms,responsible for synaptic and neuronal degeneration in ***,antibodies that can strongly and selectively bind to these soluble intermediate aggregates are of great diagnostic and therapeutic ***:We designed and recombinantly produced a hexavalent antibody based on mAb158,an Aβprotofbrilselective *** humanized version of mAb158,lecanemab(BAN2401),is currently in phase 3 clinical trials for the treatment of *** new designs involved recombinantly fusing single-chain fragment variables to the N-terminal ends of mAb158 ***-time interaction analysis with LigandTracer and surface plasmon resonance were used to evaluate the kinetic binding properties of the generated antibodies to Aβ*** ELISA setups were applied to demonstrate the binding strength of the hexavalent antibody to Aβaggregates of diferent ***,the ability of the antibodies to protect cells from Aβ-induced efects was evaluated by MTT ***:Using real-time interaction analysis with LigandTracer,the hexavalent design promoted a 40-times enhanced binding with avidity to protofbrils,and most of the added binding strength was attributed to the reduced rate of ***,ELISA experiments demonstrated that the hexavalent design also had strong binding to small oligomers,while retaining weak and intermediate binding to monomers and insoluble *** hexavalent antibody also reduced cell death induced by a mixture of soluble Aβ***:We provide a new antibody design with i

关键词： Multivalent antibodies Alzheimer’s disease Aβ Avidity Oligomers Protofbrils

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Comparison of emergency surgical cricothyroidotomy and percutaneous cricothyroidotomy by experienced airway providers in an obese,in vivo porcine hemorrhage airway model

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Military Medical Research 2023年第4期10卷 421-430页

作者： Tomas Karlsson Andreas Brännström Mikael Gellerfors Jenny gustavsson Mattias Günther Department of Clinical Science and Education Section of Anesthesiology and Intensive CareKarolinska Institutet11883 StockholmSweden Department of Neuroscience Karolinska Institutet17177 StockholmSweden Department of Physiology and Pharmacology Section of Anesthesiology and Intensive CareKarolinska Institutet11883 StockholmSweden Department of Perioperative Medicine and Intensive Care Karolinska University Hospital17177 StockholmSweden Swedish Air Ambulance(SLA) 79291 MoraSweden Rapid Response Cars 18233 StockholmSweden.

Background: Emergency front-of-neck airway(eFONA) is a life-saving procedure in “cannot intubate, cannot oxygenate”(CICO). The fastest and most reliable method of eFONA has not been determined. We compared two of the most advocated approaches: surgical cricothyroidotomy and percutaneous cricothyroidotomy, in an obese, in vivo porcine hemorrhage model, designed to introduce real-time physiological feedback, relevant and high provider stress. The primary aim was to determine the fastest method to secure airway. Secondary aims were arterial saturation and partial pressure of oxygen, proxy survival and influence of ***: Twelve pigs [(60.3±4.1) kg] were anesthetized and exposed to 25%–35% total blood volume hemorrhage before extubation and randomization to Seldinger technique “percutaneous cricothyroidotomy”(n=6) or scalpelbougie-tube technique “surgical cricothyroidotomy”(n=6). Specialists in anesthesia and intensive care in a tertiary referral hospital performed the eFONA, simulating an actual ***: In surgical cricothyroidotomy vs. percutaneous cricothyroidotomy, the median(interquartile range, IQR) times to secure airway were 109(IQR 71–130) s and 298(IQR 128–360) s(P=0.0152), arterial blood saturation(SaO2) were 74.7(IQR 46.6–84.2)% and 7.9(IQR 4.1–15.6)%(P=0.0167), PaO_(2) were 7.0(IQR 4.7–7.7) kPa and 2.0(IQR 1.1–2.9) kPa(P=0.0667), and times of cardiac arrest(proxy survival) were 137–233 s, 190(IQR 143–229) s, from CICO. All six animals survived surgical cricothyroidotomy, and two of six(33%) animals survived percutaneous cricothyroidotomy. Years in anesthesia, 13.5(IQR 7.5–21.3), did not influence time to secure ***: eFONA by surgical cricothyroidotomy was faster and had increased oxygenation and survival, when performed under stress by board certified anesthesiologists, and may be an indication of preferred method in situations with hemorrhage and CICO, in obese patients.

关键词： Emergency front-of-neck airway “Cannot intubate cannot oxygenate”(CICO) Surgical cricothyroidotomy,Percutaneous cricothyroidotomy Porcine model

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飞行时间-电感耦合等离子体质谱法测定钢、镍基合金及锆锡合金中痕量元素(英文)

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冶金分析 2007年第2期27卷 8-12页

作者： gustavsson Ingemar GRANFORS Michael Swedish Corrosion and Metals Research Institute Drottning Kristinas vg 48 SE 114 28 Stockholm Sweden Studsvik Nuclear AB Hot Cell Laboratory SE 611 82 Nykping Sweden

在微波辅助系统中对屑状的样品进行湿法消解,采用飞行时间电感耦合等离子体质谱测定钢、镍基合金及锆锡合金中9种痕量和超痕量元素元素。所建立的工作曲线的线性跨度达多个数量级。对一些稀有元素如Ga,Ta,Ir,Pt和,U和较常见的元素如Sn,S... 详细信息

在微波辅助系统中对屑状的样品进行湿法消解,采用飞行时间电感耦合等离子体质谱测定钢、镍基合金及锆锡合金中9种痕量和超痕量元素元素。所建立的工作曲线的线性跨度达多个数量级。对一些稀有元素如Ga,Ta,Ir,Pt和,U和较常见的元素如Sn,Sb,Pb和Bi一起进行测定,检测的含量范围从0.046μg/g(锆锡合金中的U)至45μg/g(低合金钢中的Sn),并测定了镍基合金中的微量元素Sn。对于所分析的样品中μg/g级和次-μg/g级的元素,获得了较好的精密度和准确度。

关键词：飞行时间电感耦合等离子体质谱微波消解痕量元素钢镍基合金锆锡合金

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GENERATION OF TRANSGENIC MICE FOR IN VIVO DETECTION OF INSULIN-CONTAINING GRANULE EXOCYTOSIS AND QUANTIFICATION OF INSULIN SECRETION

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Journal of Innovative Optical Health Sciences 2009年第4期2卷 397-405页

作者： JINLING LU NATALIA gustavsson QIMING LI GEORGE KRADDA THOMAS C.SUUDHOF WEIPING HAN Laboratory of Metabolic Medicine Singapore Bioimaging Consortium A*STAR Singapore 138667 Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute Stanford University School of Medicine Palo Alto CA 94304USA Department of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore 117597

Insulin secretion is a complex and highly regulated *** much progress has been made in understanding the cellular mechanisms of insulin secretion and regulation,it remains unclear how conclusions from these studies apply to living *** few studies have been done to address these issues is largely due to the lack of suitable tools in detecting secretory events at high spatial and temporal resolution in *** combined with genetically encoded biosensor,optical imaging is a powerful tool for visualization of molecular events in *** this study,we generated a DNA construct encoding a secretory granule resident protein that is linked with two spectrally separate fluorescent proteins,a highly pH-sensitive green pHluorin on the intra-granular side and a red mCherry in the *** exocytosis of secretory granules,the dim pHluorin inside the acidic secretory granules became highly fluorescent outside the cells at neutral pH,while mCherry fluorescence remained constant in the process,thus allowing ratiometric quantification of insulin secretory ***,mCherry fluorescence enabled tracking the movement of secretory granules in living *** validated this approach in insulin-secreting cells,and generated a transgenic mouse line expressing the optical sensor specifically in pancreaticβ-*** transgenic mice will be a useful tool for future investigations of molecular mechanism of insulin secretion in vitro and in vivo.

关键词： Insulin secretion diabetes optical imaging secretory granule exocytosis.

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High-angle deflection of metagrating-integrated laser emission for high-contrast microscopy

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Light(Science & Applications) 2023年第11期12卷 2434-2442页

作者： Mindaugas Juodėnas Erik Strandberg Alexander Grabowski Johan gustavsson HanaŠípová-Jungová Anders Larsson Mikael Käll Department of Physics Chalmers University of Technology41296 GothenburgSweden Department of Microtechnology and Nanoscience Chalmers University of Technology41296 GothenburgSweden

Flat metaoptics components are looking to replace classical optics elements and could lead to extremely compact biophotonics devices if integrated with on-chip light sources and ***,using metasurfaces to shape light into wide angular range wavefronts with high efficiency,as is typically required in high-contrast microscopy applications,remains a *** we demonstrate curved GaAs metagratings integrated on vertical-cavity surface-emitting lasers(VCSELs)that enable on-chip illumination in total internal reflection and dark field *** on an unconventional design that circumvents the aspect ratio dependent etching problems in monolithic integration,we demonstrate off-axis emission centred at 60°in air and 63°in glass with>90%and>70%relative deflection efficiency,*** resulting laser beam is collimated out-of-plane but maintains Gaussian divergence in-plane,resulting in a long and narrow illumination *** show that metagrating-integrated VCSELs of different kinds can be combined to enable rapid switching between dark-field and total internal reflection *** approach provides a versatile illumination solution for high-contrast imaging that is compatible with conventional microscopy setups and can be integrated with biophotonics devices,such as portable microscopy,NIR-II range bioimaging,and lab-on-a-chip devices.

关键词： illumination deflection optics

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Stage and size using magnetic resonance imaging and endosonography in neoadjuvantly-treated rectal cancer

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World Journal of Gastroenterology 2013年第21期19卷 3263-3271页

作者： Torbjrn Swartling Peter Klebo Kristoffer Derwinger Bengt gustavsson Gran Kurlberg Department of Surgery Institute of Clinical SciencesSahlgrenska University Hospital/stra41685 GothenburgSweden Sahlgrenska Academy Department of RadiologySahlgrenska University Hospital/stra41685 GothenburgSweden

AIM: To assess the stage and size of rectal tumours using 1.5 Tesla (1.5T) magnetic resonance imaging (MRI) and three-dimensional (3D) endosonography (ERUS). METHODS: In this study, patients were recruited in a phaseⅠ/Ⅱ trial of neoadjuvant chemotherapy for biopsy-proven rectal cancer planned for surgical resection with or without preoperative radiotherapy. The feasibility and accuracy of 1.5T MRI and 3D ERUS were compared with the histopathology of the fixed surgical specimen (pathology) to determine the stage and size of the rectal cancer before and after neoadjuvant chemotherapy. A Philips Intera 1.5T with a cardiac 5-channel synergy surface coil was used for the MRI, and a B-K Medical Falcon 2101 EXL 3D-Probe was used at 13 MHz for the ERUS. Our hypothesis was that the staging accuracy would be the same when using MRI, ERUS and a combination of MRI and ERUS. For the combination, MRI was chosen for the assessment of the lymph nodes, and ERUS was chosen for the assessment of perirectal tissue penetration. The stage was dichotomised into stageⅠ and stage Ⅱ or greater. The size was measured as the supero-inferior length and the maximal transaxial area of the tumour. RESULTS: The staging feasibility was 37 of 37 for the MRI and 29 of 36 for the ERUS, with stenosis as a limiting factor. Complete sets of investigations were available in 18 patients for size and 23 patients for stage. The stage accuracy by MRI, ERUS and the combination of MRI and ERUS was 0.65, 0.70 and 0.74, respectively, before chemotherapy and 0.65, 0.78 and 0.83, respectively, after chemotherapy. The improvement of the post-chemotherapy staging using the combination of MRI and ERUS compared with the staging using MRI alone was significant (P = 0.046). The post-chemotherapy understaging frequency by MRI, ERUS and the combination of MRI and ERUS was 0.18, 0.14 and 0.045, respectively, and these differences were non-significant. The measurements of the supero-inferior length by ERUS compared with MRI w

关键词： Rectal cancer Magnetic resonance imaging Endosonography Predictive value of tests Neoadjuvant treatment

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Genetic Diversity and Structure of Tunisian Local Pear Germplasm as Revealed by SSR Markers

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Horticultural Plant Journal 2020年第2期6卷 61-70页

作者： Rim Ouni Anna Zborowska Jasna Sehic Sarra Choulak JInaki Hormaza Larisa Garkava-gustavsson Messaoud Mars Research Unit on Agrobiodiversity(UR13AGR05) Higher Agronomic InstituteIRESA-University of SousseChott-Mariem 4042Tunisia Department of Plant Breeding Swedish University of Agricultural Sciences23053 AlnarpSweden Department of Plant Breeding-Balsgd Swedish University of Agricultural SciencesFjkestadsven 459SE-29194 KristianstadSweden Laboratory of Genetics Biodiversity and Bioresources Valorisation(LR11ES41)ISBMUniversity of MonastirMonastir 5000Tunisia Instituto de Hortofruticultura Subtropical Mediterránea La Mayora(IHSM-UMA-CSIC)Estaci on Experimental La MayoraAlgarrobo-CostaMálaga 29750Spain

Growing pear has a long tradition in Tunisia, and numerous local cultivars possessing an excellent adaptability and resilience potential to climatic variation are present. This large adaptability is associated with an important genetic diversity, which is threatened to *** measures have to be taken in order to properly evaluate and conserve this local material. Microsatellite markers were used to assess the level of genetic diversity among Tunisian pear germplasm, and compare it with some European varieties and wild pear species. 61 pear accessions representing eight groups(six groups from Tunisia, one from Northern Europe and another group composed of wild pear) have been genotyped using SSR markers derived from apple and pear. The pear accessions showed a significant polymorphism and 95 polymorphic alleles were found. The number of alleles per locus varied from 5 for CH04e03 locus to 14 for CH01d09 locus with an average of 9.4 alleles per ***, the mean gene diversity(H_e) per locus ranged from 0.192 to 0.752. Genetic distance values and cluster analyses revealed high genetic similarities among the Tunisian groups. Factorial correspondence analysis(FCA) categorized the accessions into three independent groups where Tunisian local accessions agglomerated together distantly from European and wild pear accessions. Additionally, UPGMA dendrogram grouped accessions into two clusters, confirmed thereafter by the Bayesian model-based Structure analysis. The results showed 16 putative triploid accessions found in the local germplasm. This study provides valuable information to develop strategies of local pear conservation and use.

关键词： Pyrus communis molecular marker genetic diversity local accession

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Correlative optical photothermal infrared and X-ray fluorescence for chemical imaging of trace elements and relevant molecular structures directly in neurons

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Light(Science & Applications) 2021年第8期10卷 1536-1545页

作者： Nadja gustavsson Agnes Paulus Isak Martinsson Anders Engdahl Kadda Medjoubi Konstantin Klementiev Andrea Somogyi Tomas Deierborg Ferenc Borondics Gunnar K Gouras Oxana Klementieva Medical Microspearoscopy Department of Experimental Medical ScienceLund University22180 LundSweden. Experimental Neuroinflammation Lab Department of Experimental Medical ScienceLund University22180 LundSweden. Experimental Dementia Research Department of Experimental Medical ScienceLund University22180 LundSweden. Synchrotron SOLEIL L'Orme des Merisiers91192 Gif Sur Yvette CedexFrance. MAX IV Laboratory 22100 LundSweden. Lund Institute for advanced Neutron and X-ray Science(LINXS) 22370 LundSweden

Alzheimer's disease(AD)is the most common cause of dementia,costing about 1%of the global *** of clinical trials targeting amyloid-βprotein(Aβ),a key trigger of AD,have been explained by drug inefficiency regardless of the mechanisms of amyloid neurotoxicity,which are very difficult to address by available ***,we combine two imaging modalities that stand at opposite ends of the electromagnetic spectrum,and therefore,can be used as complementary tools to assess structural and chemical information directly in a single *** label-free super-resolution microspectroscopy for sub-cellular imaging based on novel optical photothermal infrared(O-PTIR)and synchrotron-based X-ray fluorescence(S-XRF)nano-imaging techniques,we capture elemental distribution and fibrillary forms of amyloid-βproteins in the same neurons at an unprecedented *** results reveal that in primary AD-like neurons,iron clusters co-localize with elevated amyloidβ-sheet structures and oxidized ***,our O-PTIR/S-XRF results motivate using high-resolution multimodal microspectroscopic approaches to understand the role of molecular structures and trace elements within a single neuronal cell.

关键词： elevated elements complementary

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THE EVOLUTION OF FIBERLINE TECHNOLOGY IN AN ENVIRONMENTAL LIGHT

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天津科技大学学报 2004年第S1期 156-164页

作者： Catrin gustavsson,Martin Ragnar Kvaerner Pulping AB R&D Box 1033 SE-651 15 Karlstad Sweden Kvaerner Pulping AB R&D Box 1033 SE-651 15 Karlstad Sweden

With the environment in focus three different fiberlines ranging over a 20-year-period are compared. It is concluded that the environmental operation has significantly been boosted over the years. Today's challenges in the R&D activities relating to fiberline technology include e.g. improved pulp yields and prevention of yellowing of fully bleached pulp. A method for determination of mill pulp yield is presented, and the latest modified cooking concept briefly discussed in relation to the higher yields obtained. The topic of yellowing is discussed and hot chlorine dioxide bleaching is presented as a tool to reduce the yellowing tendency.

关键词： THE EVOLUTION OF FIBERLINE TECHNOLOGY IN AN ENVIRONMENTAL LIGHT

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