A5025528538- Prion Diseases and Protein Misfolding
- Alzheimer's disease research and treatments
- Trace Elements in Health
- Neurological diseases and metabolism
- Protein Structure and Dynamics
- Enzyme Structure and Function
- Glycosylation and Glycoproteins Research
- Heat shock proteins research
- Monoclonal and Polyclonal Antibodies Research
- Immunodeficiency and Autoimmune Disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- Neuroscience and Neuropharmacology Research
- Influenza Virus Research Studies
- Neurological Disease Mechanisms and Treatments
- HIV Research and Treatment
- vaccines and immunoinformatics approaches
- Respiratory viral infections research
- Mass Spectrometry Techniques and Applications
- Nerve injury and regeneration
- Cell Adhesion Molecules Research
- HIV/AIDS drug development and treatment
- Receptor Mechanisms and Signaling
- Computational Drug Discovery Methods
- RNA and protein synthesis mechanisms
- Cholinesterase and Neurodegenerative Diseases
Janssen (Netherlands)
2015-2020
Johnson & Johnson (Netherlands)
2017-2020
Johnson & Johnson (Sweden)
2018
Janssen (Belgium)
2018
Yale University
2009
Howard Hughes Medical Institute
2008-2009
Case Western Reserve University
2002-2008
Fox Chase Cancer Center
2006
The identification of human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem revitalized hopes developing a universal influenza vaccine. Using rational design and library approach, we engineered stable HA antigens ("mini-HAs") based on an H1 subtype sequence. Our most advanced candidate exhibits structural bnAb binding properties comparable to those full-length HA, completely protects mice in lethal heterologous heterosubtypic challenge models, reduces fever...
The original experiments reconstituting GroEL-GroES-mediated protein folding were carried out under "nonpermissive" conditions, where the chaperonin system was absolutely required and substrate proteins could not achieve native state if diluted directly from denaturant into solution. Under "permissive" however, employing lower concentration temperature, some can be refolded both by while free in For several of these, refolds more rapidly inside GroEL-GroES cis chamber than solution,...
One of the arguments in favor protein-only hypothesis transmissible spongiform encephalopathies is link between inherited prion diseases and specific mutations PRNP gene. such mutation (Asp178 --> Asn) associated with two distinct disorders: fatal familial insomnia or Creutzfeldt-Jakob disease, depending upon presence Met Val at position 129, respectively. In this study, we have characterized biophysical properties recombinant human proteins (huPrP90-231) corresponding to polymorphic...
An important step toward understanding the mechanism of PrPC-to-PrPSc conversion is to elucidate folding pathway(s) prion protein. On basis stopped-flow measurements, we recently proposed that protein folds via a transient intermediate formed on submillisecond time scale, and mutations linked familial diseases result in pronounced increase population this intermediate. Here, have extended these studies continuous-flow measurements using capillary mixing system with resolution ∼100 μs. This...
Transmissible spongiform encephalopathies are associated with conformational conversion of the cellular prion protein, PrP(C), into a proteinase K-resistant, amyloid-like aggregate, PrP(Sc). Although structure PrP(Sc) remains enigmatic, recent studies have afforded increasingly detailed characterization recombinant PrP amyloid. However, all previous were performed using amyloid fibrils formed in presence denaturing agents that significantly alter folding state(s) precursor monomer. Here we...
Several reports have described the presence of antibodies against Alzheimer's disease-associated hyperphosphorylated forms tau in serum healthy individuals. To characterize specificities that can be found, we interrogated peripheral IgG+ memory B cells from asymptomatic blood donors for reactivity to a panel phosphorylated peptides using single-cell screening assay. Antibody sequences were recovered, cloned, and expressed as full-length IgGs. In total, 52 somatically mutated tau-binding...
Deposition of α-synuclein into Lewy bodies and neurites is the hallmark Parkinson's disease (PD). It hypothesized that pathology spreads by a "prion-like" mechanism (i.e., seeded aggregation or templated misfolding). Therefore, various extracellular conformers and/or posttranslational modifications may serve as biomarkers potential targets for novel interventions. To explore whether antibody repertoires PD patients contain anti-α-synuclein antibodies can potentially be used markers...
Abstract Epitope characterization is critical for elucidating the mechanism of action drug candidates. However, traditional high-resolution epitope mapping techniques are not well suited screening numerous candidates recognizing a similar target. Here, we use Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) to explore conformational impact diverse molecules binding on Hemagglutinin (HA), major surface antigen influenza viruses. We optimized semi-automated HDX-MS workflow systematically...
ABSTRACT The extraordinary diversity of the human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein poses a major challenge for development an HIV-1 vaccine. One strategy to circumvent this problem utilizes bioinformatically optimized mosaic antigens. However, Env proteins expressed as trimers have not been previously evaluated their stability, antigenicity, and immunogenicity. Here, we report production characterization stable M gp140 trimer. trimer bound CD4 well multiple...
Misfolding and aggregation of tau protein are closely associated with the onset progression Alzheimer's Disease (AD). By interrogating IgG+ memory B cells from asymptomatic donors peptides, we have identified two somatically mutated VH5–51/VL4–1 antibodies. One these, CBTAU-27.1, binds to motif in R3 repeat domain blocks into paired helical filaments (PHFs) by sequestering monomeric tau. The other, CBTAU-28.1, N-terminal insert region inhibits spreading seeds mediates uptake aggregates...
Aggregation of tau protein and spreading aggregates are pivotal pathological processes in a range neurological disorders. Accumulating evidence suggests that immunotherapy targeting may be viable therapeutic strategy. We have previously described the isolation antibody CBTAU-22.1 from memory B-cell repertoire healthy human donors. was shown to specifically bind disease-associated phosphorylated epitope C-terminus (Ser422) able inhibit P301S spinal cord lysates vitro, albeit with limited...
Aggregation of tau protein and formation paired helical filaments is a hallmark Alzheimer's disease other tauopathies. Compared to proteins associated with neurodegenerative diseases, the reported in vitro aggregation kinetics for are less consistent presenting relatively high variability. Here we describe development an assay that mimics expected steps misfolding vivo. The uses longest isoform (huTau441) which contains both N-terminal acidic inserts as well four microtubule binding domains...
Alzheimer's disease (AD) is a progressive neurodegenerative condition in which aggregated tau and amyloid proteins accumulate the brain causing neuronal dysfunction eventually leads to cognitive decline. Hyperphosphorylated aggregates neuron are believed cause most of pathology associated with AD. These assumed be released into extracellular compartment taken up by adjacent healthy neurons where they induce further aggregation. This "prion-like" spreading can interrupted antibodies capable...
Abstract Background Although several studies demonstrate prion-like properties of Tau fibrils, the effect size in seeding capacity these aggregates is not fully understood. The aim this study to characterize seeds by their and capacity. Methods were isolated from postmortem AD brain tissue separated low molecular weight species sucrose gradient ultracentrifugation. Biochemical characterization different fractions was done non-reducing Western blotting aggregate-specific immuno-assays using...
ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionORIGINAL ARTICLEThis notice is a correctionThe Emerging Principles of Mammalian Prion Propagation and Transmissibility Barriers: Insight from Studies in VitroWitold K. Surewicz, Eric M. Jones, Adrian C. ApetriCite this: Acc. Chem. Res. 2006, 39, 11, 879–880Publication Date (Web):September 27, 2006Publication History Published online27 September 2006Published inissue 1 November 2006https://doi.org/10.1021/ar068279xCopyright © 2006 American...
The chaperonin system assists the folding of a large variety proteins by two actions: binding in hydrophobic central cavity an open ring and mediated subsequently GroES‐encapsulated hydrophilic chamber. We have been studying GroEL both vivo vitro, report on recent results. In one experiment we used hydrogen‐deuterium exchange NMR spectroscopy to compare trajectories human DHFR while free solution inside stable GroEL‐GroES complex formed single version GroEL, SR1, GroES. observe that...
ABSTRACT Misfolding and aggregation of tau protein are closely associated with the onset progression Alzheimer’s Disease (AD). By interrogating IgG + memory B cells from asymptomatic donors peptides, we have identified two somatically mutated V H 5-51/V L 4-1 antibodies. One these, CBTAU-27.1, binds to motif in R3 repeat domain blocks into paired helical filaments (PHFs) by sequestering monomeric tau. The other, CBTAU-28.1, N-terminal insert region inhibits spreading seeds mediates uptake...
Alzheimer's disease (AD) is a progressive neurodegenerative condition in which aggregated tau and amyloid proteins accumulate the brain causing neuronal dysfunction eventually leads to cognitive decline. Hyperphosphorylated aggregates neuron are believed cause most of pathology associated with AD. These assumed be released into extracellular compartment taken up by adjacent healthy neurons where they induce further aggregation. This "prion-like" spreading can interrupted antibodies capable...