A5066637534- RNA Interference and Gene Delivery
- Asthma and respiratory diseases
- Advanced biosensing and bioanalysis techniques
- Lipid Membrane Structure and Behavior
- Cell Image Analysis Techniques
- Image Processing Techniques and Applications
- Immune Cell Function and Interaction
- Advanced Fluorescence Microscopy Techniques
- Receptor Mechanisms and Signaling
- Nanoparticle-Based Drug Delivery
- HIV Research and Treatment
- Chemical Synthesis and Analysis
- T-cell and B-cell Immunology
- Molecular Biology Techniques and Applications
- Graphene and Nanomaterials Applications
- Immune Response and Inflammation
- Innovative Microfluidic and Catalytic Techniques Innovation
- Data Stream Mining Techniques
- Protease and Inhibitor Mechanisms
- Tissue Engineering and Regenerative Medicine
- Galectins and Cancer Biology
- Anodic Oxide Films and Nanostructures
- Research Data Management Practices
- Digital Holography and Microscopy
- Peroxisome Proliferator-Activated Receptors
AstraZeneca (Sweden)
2014-2024
Research Complex at Harwell
2023
AstraZeneca (Australia)
2021
Karolinska Institutet
2004-2015
Lund University
1997-2015
University of Gothenburg
2014-2015
Laboratoire de Biochimie
2015
University of Oxford
2015
Novartis (Sweden)
2014
University of Skövde
2014
Hormone-secreting cells within pancreatic islets of Langerhans play important roles in metabolic homeostasis and disease. However, their transcriptional characterization is still incomplete. Here, we sequenced the transcriptomes thousands human islet from healthy type 2 diabetic donors. We could define specific genetic programs for each individual endocrine exocrine cell type, even rare δ, γ, ε, stellate cells, revealed subpopulations α, β, acinar cells. Intriguingly, δ expressed several...
Delivery of exogenous mRNA using lipid nanoparticles (LNPs) is a promising strategy for therapeutics. However, bottleneck remains in the poor understanding parameters that correlate with endosomal escape versus cytotoxicity. To address this problem, we compared distribution six LNP-mRNA formulations diverse chemical composition and efficacy, similar to those used mRNA-based vaccines, primary human adipocytes, fibroblasts, HeLa cells. Surprisingly, found total uptake not sufficient predictor...
Abstract In terms of lipid nanoparticle (LNP) engineering, the relationship between particle composition, delivery efficacy, and composition biocoronas that form around LNPs, is poorly understood. To explore this we analyze naturally efficacious biocorona compositions using an unbiased screening workflow. First, LNPs are complexed with plasma samples, from individual lean or obese male rats, then functionally evaluated in vitro. Then, a fast, automated, miniaturized method retrieves intact...
B cell-activating factor (BAFF) plays a major role in activation of cells and adaptive humoral immune responses. In chronic obstructive pulmonary disease (COPD), lymphoid follicles have been associated with severity, overexpression BAFF has demonstrated within patients severe COPD.To investigate expression localization the lungs COPD to study by antagonizing mouse model cigarette smoke (CS) exposure.We quantified localized never-smokers, smokers without COPD, air- or CS-exposed mice...
In vivo studies of human brain cellular function face challenging ethical and practical difficulties. Animal models are typically used but display distinct differences. One specific example is astrocytes, recently recognized for contribution to neurological diseases a link the genetic risk factor apolipoprotein E (APOE). Current astrocytic in vitro questioned lack biological characterization. Here, we report induced pluripotent stem cell (hiPSC)-derived astroglia (NES-Astro) developed under...
Abstract RNA-based therapies have great potential to treat many undruggable human diseases. However, their efficacy, in particular for mRNA, remains hampered by poor cellular delivery and limited endosomal escape. Development optimisation of vectors, such as lipid nanoparticles (LNPs), are impeded screening methods probe the intracellular processing LNPs sufficient detail. We developed a high-throughput imaging-based escape assay utilising Galectin-9 reporter fluorescently labelled mRNA...
Lipid nanoparticles (LNPs) have emerged as potent carriers for mRNA delivery, but several challenges remain before this approach can offer broad clinical translation of therapeutics. To improve their efficacy, a better understanding is required regarding how LNPs are trapped and processed at the anionic endosomal membrane prior to release. We used surface-sensitive fluorescence microscopy with single LNP resolution investigate pH dependency binding kinetics ionizable lipid-containing...
Cells use noncanonical autophagy, also called conjugation of ATG8 to single membranes (CASM), label damaged intracellular compartments with ubiquitin-like family proteins in order signal danger caused by pathogens or toxic compounds. CASM relies on E3 complexes sense membrane damage, but so far, only the mechanism activate ATG16L1-containing complexes, associated proton gradient loss, has been described. Here, we show that TECPR1-containing are key mediators cells treated a variety...
Human pluripotent stem cells (hPSC) have the potential to become important tools for establishment of new models in vitro drug testing of, example, toxicity and pharmacological effects. Late-stage attrition pharmaceutical industry is a large extent caused by selection candidates using nonpredictive preclinical that are not clinically relevant. The current hepatic vivo show clear limitations, especially studies chronic hepatotoxicity. For these reasons, we evaluated hPSC-derived hepatocytes...
Abstract Poor understanding of intracellular delivery and targeting hinders development nucleic acid‐based therapeutics transported by nanoparticles. Utilizing a siRNA‐targeting small molecule profiling approach with advanced imaging machine learning biological insights is generated into the mechanism lipid nanoparticle (MC3‐LNP) mRNA. This workflow termed Advanced Cellular Endocytic for Intracellular Delivery (ACE‐ID). A cell‐based assay perturbation 178 targets relevant to trafficking used...
Abstract Cardiac progenitor cells (CPCs), capable of differentiating into multiple cardiac cell types including cardiomyocytes (CMs), endothelial cells, and smooth muscle are promising candidates for repair/regeneration. In vitro model systems where grown in a more vivo-like environment, such as 3D cultures, have been shown to be predictive than 2D culture studying biology disease pathophysiology. this report, we focused on using Wnt inhibitors study the differentiation human iPSC-CPCs under...
Messenger RNA (mRNA) represents a promising next-generation approach for both treatment and vaccination. Lipid based particles are one of the most investigated delivery systems mRNA formulations. Here we explore how complexing lipid affects uptake translation lipoplex-delivered in resident cells human skin explants and, more modular system that utilizes added to pre-formed nanoparticles prior dosing. We prepared formulations lipoplexes with ionizable, cationic or zwitterionic lipids,...
During the last decades, there has been growing interest in using therapeutic messager RNA (mRNA) together with drug delivery systems. Naked, unformulated mRNA is, however, unable to cross cell membrane and is susceptible degradation. Here we use graphene quantum dots (GQDs) functionalized polyethyleneimine (PEI) as a novel system. Our results show that these modified GQDs can be used deliver intact functional Huh-7 hepatocarcinoma cells at low doses and, are not toxic, although cellular...
Background: Early prediction of time-lapse microscopy experiments enables intelligent data management and decision-making. Aim: Using HepG2 cells exposed to lipid nanoparticles loaded with mRNA for expression GFP, the authors hypothesized that it is possible predict in advance whether a cell will express GFP. Methods: The first modeling approach used convolutional neural network extracting per-cell features at early time points. These were then combined explored using either long short-term...
In humans, the antimicrobial peptide LL-37 and potent chemotactic lipid leukotriene B4 (LTB4) are important mediators of innate immunity host defense. Here we show that LTB4, at very low (1 nM) concentrations, strongly promotes release peptides from human neutrophils (PMNs) in a time- dose-dependent manner, as determined by Western blot, enzyme-linked immunoassay (ELISA), antibacterial activity. The LTB4-induced is mediated BLT1 receptor, protein phosphatase-1 (PP-1) inhibits suppressing...
Quantitative analysis of cell structures is essential for biomedical and pharmaceutical research. The standard imaging approach relies on fluorescence microscopy, where interest are labeled by chemical staining techniques. However, these techniques often invasive sometimes even toxic to the cells, in addition being time consuming, labor intensive, expensive. Here, we introduce an alternative deep-learning–powered based bright-field images a conditional generative adversarial neural network...
The recently cloned human chemoattractant receptor-like (CMKRL)1, which is expressed in vivo CD4-positive immune cells, has structural homology with the two chemokine receptors C-C receptor (CCR)5 and C-X-C (CXCR)4, serve as major coreceptors necessary for fusion of HIV-1 envelope target cells. In view similarity, CMKRL1 was tested its possible function another coreceptor after stable expression murine fibroblasts bearing CD4 receptor. cells were infected 10 primary clinical isolates HIV-1,...
Diabetic nephropathy (DN) remains an unmet medical challenge as its prevalence is projected to continue increase and specific medicines for treatment remain undeveloped. Activation of the immune system, in particular T-cells, emerging a possible mechanism underlying DN disease progression humans animal models. We hypothesized that inhibition T-cell activation will ameliorate DN. Interaction B7-1 (CD80) on surface antigen presenting cells with binding partners, CTLA4 (CD152) CD28 essential...
In recent years, there has been an increasing interest in designing delivery systems to enhance the efficacy of RNA-based therapeutics. Here, we have synthesized copolymers comprised dimethylaminoethyl methacrylate (DMAEMA) or diethylaminoethyl (DEAEMA) copolymerized with alkyl monomers ranging from 2 12 carbons, and developed a high throughput workflow for rapid investigation their applicability mRNA delivery. The structure activity relationship revealed that encapsulation efficiency is...
Abstract Development of efficient lipid nanoparticle (LNP) vectors remains a major challenge towards broad clinical translation RNA therapeutics. New lipids will be required, but also better understanding LNP interactions with the biological environment. Herein, we model protein corona formation on PEG-ylated DLin-MC3-DMA LNPs and identify time-dependent maturation steps that critically unlock their cellular uptake mRNA delivery. Uptake requires active serum proteins precedes after...
Abstract The high-affinity leukotriene B4 (LTB4) receptor, BLT1, is a chemotactic receptor involved in inflammatory responses. In this study, we have explored the regulation of BLT1 expression human monocytes by pro- and anti-inflammatory cytokines, lipopolysaccharide (LPS), dexamethasone. We found that proinflammatory mediators, such as interferon-γ (IFN-γ), tumor necrosis factor-α, LPS, down-regulated expression, whereas cytokine, interleukin-10, dexamethasone up-regulated mRNA expression....
Background Type 2 diabetes is associated with macro- and microvascular complications in man. Microvascular dysfunction affects both cardiac renal function now recognized as a main driver of cardiovascular mortality morbidity. However, progression experimental models often obscured by macrovascular pathology consequently demanding to study. The obese type diabetic leptin-deficient (ob/ob) mouse lacks complications, i.e. occlusive atherosclerotic disease, may therefore be potential model for...