A5054209658- Alzheimer's disease research and treatments
- Parkinson's Disease Mechanisms and Treatments
- SARS-CoV-2 and COVID-19 Research
- Microfluidic and Bio-sensing Technologies
- Microfluidic and Capillary Electrophoresis Applications
- Monoclonal and Polyclonal Antibodies Research
- Cholinesterase and Neurodegenerative Diseases
- Lipid Membrane Structure and Behavior
- SARS-CoV-2 detection and testing
- Computational Drug Discovery Methods
- Prion Diseases and Protein Misfolding
- Protein Structure and Dynamics
- RNA modifications and cancer
- Neuroscience and Neuropharmacology Research
- Genetics, Aging, and Longevity in Model Organisms
- COVID-19 Clinical Research Studies
- Cellular transport and secretion
- Genetic Neurodegenerative Diseases
- Advanced Polymer Synthesis and Characterization
- Long-Term Effects of COVID-19
- Heparin-Induced Thrombocytopenia and Thrombosis
- Hippo pathway signaling and YAP/TAZ
- Advanced Fluorescence Microscopy Techniques
- Nanopore and Nanochannel Transport Studies
- S100 Proteins and Annexins
University of Cambridge
2015-2024
Max Planck Institute for the Science of Light
2022-2024
Soochow University
2023
National Institute of Diabetes and Digestive and Kidney Diseases
2022
Toronto Centre for Phenogenomics
2022
Rockefeller University
2016-2017
University of Oklahoma Health Sciences Center
2012-2016
Indiana University Bloomington
2016
University Health Network
2013
OU Health
2012
Abstract The self-assembly of α-synuclein (αS) into intraneuronal inclusion bodies is a key characteristic Parkinson’s disease. To define the nature species giving rise to neuronal damage, we have investigated mechanism action main αS populations that been observed form progressively during fibril growth. fibrils release soluble prefibrillar oligomeric with cross-β structure and solvent-exposed hydrophobic clusters. oligomers are efficient in crossing permeabilize membranes, causing cellular...
Transient oligomeric species formed during the aggregation process of 42-residue form amyloid-β peptide (Aβ42) are key pathogenic agents in Alzheimer's disease (AD). To investigate relationship between Aβ42 and its cytotoxicity influence a potential drug on both phenomena, we have studied effects trodusquemine. This aminosterol enhances rate by promoting monomer-dependent secondary nucleation, but significantly reduces toxicity resulting oligomers to neuroblastoma cells inhibiting their...
RbpA and CarD are essential transcription regulators in mycobacteria. Mechanistic analyses of promoter open complex (RPo) formation establish that cooperatively stimulate an intermediate (RP2) leading to RPo; RP2 is likely a bottleneck step at the majority mycobacterial promoters. Once RPo forms, also disfavors its isomerization back RP2. We determined 2.76 Å-resolution crystal structure initiation (TIC) with as well CarD/RbpA/TIC model. Both bind near upstream edge -10 element where they...
Local replication doubles the number of tau aggregate in Alzheimer’s disease only once every 5 years, limiting overall rate.
Fibrillar protein aggregates are a hallmark of range human disorders, from prion diseases to dementias, but also encountered in several functional contexts. Yet, the fundamental links between assembly mechanisms and their or pathological roles have remained elusive. Here, we analyze aggregation kinetics large set proteins that self-assemble by nucleated-growth mechanism, those associated with disease, over whose fulfill biology, aggregate only under artificial conditions. We find that,...
Sorting cells is an essential primary step in many biological and clinical applications such as high-throughput drug screening, cancer research cell transplantation. Cell sorting based on their mechanical properties has long been considered a promising label-free biomarker that could revolutionize the isolation of from heterogeneous populations. Recent advances microfluidic image-based analysis combined with subsequent by on-chip actuators demonstrated possibility physical properties....
Oligomeric species arising during the aggregation of α-synuclein are implicated as a major source toxicity in Parkinson's disease, and thus potential drug target. However, both their mechanism formation role largely unresolved. Here we show that, at physiological pH absence lipid membranes, aggregates form by secondary nucleation, rather than simple primary that this process is enhanced agitation. Moreover, using combination single molecule bulk level techniques, identify nucleation on...
Abstract Colorectal cancer (CRC) tumors are composed of heterogeneous and plastic cell populations, including a pool stem cells that express LGR5. Whether these distinct populations display different mechanical properties, how properties might contribute to metastasis is poorly understood. Using CRC patient derived organoids (PDOs), we find compared LGR5- cells, LGR5+ stiffer, adhere better the extracellular matrix (ECM), move slower both as single clusters, higher nuclear YAP, show survival...
Phase transitions of protein molecules are central to biological function and malfunction. One such transition commonly encountered in nature is the conversion soluble monomeric states into solid phases, which include crystals amyloid fibrils, latter associated with onset development neurodegenerative diseases. Monitoring aggregate formation phase behavior essential gaining mechanistic insights these fundamental processes. Fluorescence techniques have proven invaluable observing molecules;...
Introducing ThX, a next-generation ThT derivative that allows for the early detection of amyloid aggregates at bulk and single-aggregate levels.
Abstract The onset and progression of numerous protein misfolding diseases are associated with the presence oligomers formed during aberrant aggregation several different proteins, including amyloid-β (Aβ) in Alzheimer’s disease α-synuclein (αS) Parkinson’s disease. These small, soluble aggregates currently major targets for drug discovery. In this study, we show that trodusquemine, a naturally-occurring aminosterol, markedly reduces cytotoxicity αS, Aβ HypF-N to human neuroblastoma cells by...
The aberrant aggregation of proteins is a key molecular event in the development and progression wide range neurodegenerative disorders. We have shown previously that squalamine trodusquemine, two natural products aminosterol class, can modulate amyloid-β peptide (Aβ) α-synuclein (αS), which are associated with Alzheimer’s Parkinson’s diseases. In this work, we expand our previous analyses to derivatives, des-squalamine α-squalamine, obtaining further insights into mechanism by aminosterols...
Parkinson's disease is associated with the aberrant aggregation of α-synuclein. Although causes this process are still unclear, post-translational modifications α-synuclein likely to play a modulatory role. Since constitutively N-terminally acetylated, we investigated how modification alters behavior protein. By applying three-pronged kinetics approach, observed that N-terminal acetylation results in reduced rate lipid-induced and slows down both elongation fibril-catalyzed aggregate...
Recent studies have demonstrated that the COOH-terminal fragment of incretin hormone glucagon-like peptide-1 (GLP-1), a nonapeptide GLP-1(28-36)amide, attenuates diabetes and hepatic steatosis in diet-induced obese mice. However, effect this pancreatic β-cells remains largely unknown. Here, we show streptozotocin-induced mouse model, GLP-1(28-36)amide improved glucose disposal increased β-cell mass proliferation. An vitro investigation revealed stimulates β-catenin (β-cat) Ser(675)...
Abstract Aberrant soluble oligomers formed by the amyloid-β peptide (Aβ) are major pathogenic agents in onset and progression of Alzheimer’s disease. A variety biomolecules can influence formation these brain, although their mechanisms action still largely unknown. Here, we studied effects on Aβ aggregation DOPAL, a reactive catecholaldehyde intermediate dopamine metabolism. We found that DOPAL is able to stabilize oligomeric species, including dimers trimers, exert toxic human neuroblastoma...
Mutations in the SNCA gene, which encodes protein α-synuclein, have been linked with early onset Parkinson's disease. The exact nature of this association, however, is still poorly understood. To investigate problem, we started from observation that α-synuclein constitutively N-terminally acetylated, a post-translational modification alters charge and structure molecules affects their interaction lipid membranes, as well aggregation process. We thus studied five N-terminal acetylated...
Antibody profiling is a fundamental component of understanding the humoral response in wide range disease areas. Most currently used approaches operate by capturing antibodies onto functionalised surfaces. Such measurements surface binding are governed an overall antibody titre, while two molecular parameters, affinity and concentration, challenging to determine individually from such approaches. Here, applying microfluidic diffusional sizing (MDS), we show how can overcome this challenge...
Abstract Effective public-health measures and vaccination campaigns against SARS-CoV-2 require granular knowledge of population-level immune responses. We developed a Tripartite Automated Blood Immunoassay (TRABI) to assess the IgG response ectodomain receptor-binding domain spike protein as well nucleocapsid SARS-CoV-2. used TRABI for continuous seromonitoring hospital patients healthy blood donors (n=72’222) in canton Zurich from December 2019 2020 (pre-vaccine period). Seroprevalence...
Oligomers comprised of misfolded proteins are implicated as neurotoxins in the pathogenesis protein misfolding conditions such Parkinson's and Alzheimer's diseases. Structural, biophysical, biochemical characterization these nanoscale assemblies is key to understanding their pathology design therapeutic interventions, yet it challenging due heterogeneous, transient nature low relative abundance complex mixtures. Here, we demonstrate separation heterogeneous populations oligomeric...
Schizophrenia is a complex psychiatric disorder with genetic and phenotypic heterogeneity. Accumulating rare genome-wide association study (GWAS) common risk variant information has yet to yield robust mechanistic insight. Leveraging large-scale gene deletion mouse phenomic data thus potential functionally interrogate prioritize human disease genes. To this end, we applied cross-species network-based approach parse an extensive set (188 genes) associated disrupted prepulse inhibition (PPI),...
The clinical outcome of SARS-CoV-2 infections, which can range from asymptomatic to lethal, is crucially shaped by the concentration antiviral antibodies and their affinity targets. However, polyclonal antibody responses in plasma difficult measure. Here we used microfluidic profiling (MAAP) determine aggregate affinities concentrations anti-SARS-CoV-2 samples 42 seropositive individuals, 19 were healthy donors, 20 displayed mild symptoms, 3 critically ill. We found that dissociation...
Effective public health measures against SARS-CoV-2 require granular knowledge of population-level immune responses. We developed a Tripartite Automated Blood Immunoassay (TRABI) to assess the IgG response three proteins. used TRABI for continuous seromonitoring hospital patients and blood donors (n = 72′250) in canton Zurich from December 2019 2020 (pre-vaccine period). found that antibodies waned with half-life 75 days, whereas cumulative incidence rose 2.3% June 12.2% mid-December 2020. A...