A5007250467- Cancer, Hypoxia, and Metabolism
- Growth Hormone and Insulin-like Growth Factors
- Alzheimer's disease research and treatments
- Protease and Inhibitor Mechanisms
- Bacterial Genetics and Biotechnology
- Bacteriophages and microbial interactions
- Escherichia coli research studies
- Porphyrin Metabolism and Disorders
- Blood Coagulation and Thrombosis Mechanisms
- Advanced biosensing and bioanalysis techniques
- Cancer Research and Treatments
- RNA Interference and Gene Delivery
- Antibiotic Resistance in Bacteria
- Antimicrobial Peptides and Activities
- Retinoids in leukemia and cellular processes
- Folate and B Vitamins Research
- Microtubule and mitosis dynamics
- Iron Metabolism and Disorders
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Immune Response and Inflammation
- Metabolism, Diabetes, and Cancer
- Cell Adhesion Molecules Research
- Glycosylation and Glycoproteins Research
- Glycogen Storage Diseases and Myoclonus
McGill University
2015-2024
Concordia University
2024
University of Helsinki
2020
Jewish General Hospital
2020
Université de Montréal
2011
Queen's University
1997-2004
University of Pennsylvania
1999
University of Toronto
1998
University of Washington
1997-1998
Packaging DNA into condensed structures is integral to the transmission of genomes. The mammalian mitochondrial genome (mtDNA) a high copy, maternally inherited in which mutations cause variety multisystem disorders. In all eukaryotic cells, multiple mtDNAs are packaged with protein spheroid bodies called nucleoids, fundamental units mtDNA segregation. mechanism nucleoid formation, however, remains unknown. Here, we show that transcription factor TFAM, an abundant and highly conserved High...
DNA death grip Poly(ADP-ribose) polymerase–1 (PARP-1) binds to breaks and recruits repair components. Cancer-killing PARP-1 inhibitor (PARPi) compounds all block the same catalytic site but exhibit vastly different efficacy. Zandarashvili et al. investigated molecular impact of PARPi binding (see Perspective by Slade Eustermann). Different molecules perturb allostery in diverse manners: Some drive promote release from DNA, others retention. These insights help explain efficacies clinic...
Based on its clinical benefits, Trikafta — the combination of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor), and gating potentiator VX-770 (ivacaftor) was FDA approved for treatment patients with cystic fibrosis (CF) carrying deletion phenylalanine at position 508 (F508del) CF transmembrane conductance regulator (CFTR) least 1 allele. Neither mechanism action nor susceptibility rare mutants to are known. Here, we show that, in human bronchial epithelial cells, synergistically...
Streptococcus suis is an important swine pathogen that causes meningitis, endocarditis, arthritis and septicaemia. As a zoonotic agent, S. also similar diseases in humans. Binding of pathogenic bacteria to extracellular matrix components enhances their adhesion invasion host cells. In the present study we isolated identified novel fibronectin-binding protein from suis. The native (designated SsEno) possessed not only high homology with other bacterial enolases but enolase activity. We...
The development of nucleic acid therapeutics has been hampered by issues associated with their stability and in vivo delivery. To address these challenges, we describe a new strategy to engineer DNA structures strong binding affinity human serum albumin (HSA). HSA is the most abundant protein blood long circulation half-life (19 days). It shown hinder phagocytosis, retained tumors, aids cellular penetration. Indeed, already successfully used for delivery small-molecule drugs nanoparticles....
Similarity between the apolipoprotein(a) (apo(a)) moiety of lipoprotein(a) (Lp(a)) and plasminogen suggests a potentially important link atherosclerosis thrombosis. Lp(a) may interfere with tissue activator (tPA)-mediated activation in fibrinolysis, thereby generating hypercoagulable state vivo. A fluorescence-based system was employed to study effect apo(a) on presence native fibrin degraded cofactors absence positive feedback reactions catalyzed by plasmin. Human physiologically relevant,...
Apoptotic cells trigger immune tolerance in engulfing phagocytes. This poorly understood process is believed to contribute the severe immunosuppression and increased susceptibility nosocomial infections observed critically ill sepsis patients. Extracellular high mobility group box 1 (HMGB1) an important mediator of both lethality induction by apoptotic cells. We have found that HMGB1 sensitive processing caspase-1, resulting production a fragment within its N-terminal DNA-binding domain (the...
NRF2 (nuclear factor erythroid 2-related 2) is a master regulator of protective responses in healthy tissues. However, when it active tumor cells, can result drug resistance. KEAP1, the endogenous inhibitor, binds and redirects to proteasomal degradation, so KEAP1/NRF2 interaction critical for maintaining at basal level. A number clinically relevant KEAP1 mutations were shown disrupt this interaction, leading elevated levels Here, we describe small-molecule R16, that selectively mutants...
Abstract The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which ultimately leads to generation Aβ peptides. Here, we provide evidence that altered BACE1 levels and activity impact degradation Aβ40 Aβ42 into a common Aβ34 intermediate. Using human cerebrospinal fluid (CSF) samples from Amsterdam Dementia Cohort, show elevated in individuals with mild cognitive impairment who later progressed dementia. Furthermore,...
A compound that binds to tubulin in an unusual way has superior antitumor efficacy and safety a distinctive impact on microtubule curvature dynamics.
The IGFI receptor promotes malignant progression and has been recognized as a target for cancer therapy. Clinical trials with anti-IGFIR antibodies provided evidence of therapeutic efficacy but exposed limitations due in part to effects on, the compensatory function of, insulin system. Here, we report on production, characterization, biologic activity novel, IGF-targeting protein (the IGF-Trap) comprising soluble form hIGFIR Fc portion hIgG1. IGF-Trap high affinity hIGFI hIGFII low insulin,...
Abstract —Elevated levels of lipoprotein(a) [Lp(a)] are correlated with an increased risk atherosclerotic disease. We examined the effect recombinant apolipoprotein(a) [r-apo(a)] and Lp(a) on responses washed human platelets, prelabeled in dense granules [ 14 C]serotonin suspended Tyrode’s solution, to ADP thrombin receptor–activating peptide SFLLRN. No 17 kringle (K), 12K, or 6K r-apo(a) derivatives (at concentrations 0.35 0.7 μmol/L) (up 0.1 primary ADP-induced platelet aggregation was...
Mutations in human LMBRD1 and ABCD4 prevent lysosomal export of vitamin B12 to the cytoplasm, impairing B12-dependent enzymes methionine synthase methylmalonyl-CoA mutase. The gene products are implicated transport at membrane proposed act complex. To address mechanism for transport, we report novel recombinant production LMBD1 detailed biophysical analyses. Using blue native PAGE, chemical crosslinking, size exclusion chromatography coupled multi-angle light scattering (SEC-MALS), show that...
ABSTRACT Actinobacillus pleuropneumoniae is a Gram-negative bacterium belonging to the Pasteurellaceae family and causative agent of porcine pleuropneumonia, highly contagious lung disease causing important economic losses. Surface polysaccharides, including lipopolysaccharides (LPS) capsular polysaccharides (CPS), are implicated in adhesion virulence A. , but their role biofilm formation still unclear. In this study, we investigated requirement for these surface by serotype 1....
There is increasing evidence suggesting that amyloidogenic proteins might form deposits in non-neuronal tissues neurodegenerative disorders such as Alzheimer's or Parkinson's diseases. However, the detection of these aggregation-prone within human skin has been controversial. Using immunohistochemistry (IHC) and mass spectrometry tissue imaging (MALDI-MSI), fresh frozen samples were analyzed for expression localization disease-related proteins. While α-synuclein was detected throughout...
Transforming growth factor-β (TGF-β) is a multifunctional cytokine implicated in many diseases, including tissue fibrosis and cancer. TGF-β mediates diverse biological responses by signalling through type I II receptors (TβRI TβRII). We have previously identified CD109, glycosylphosphatidylinositol (GPI)-anchored protein, as novel co-receptor that negatively regulates demonstrated membrane-anchored CD109 promotes receptor degradation via SMAD7/Smurf2-mediated mechanism. To determine whether...
Abstract The amyloid-β42 (Aβ42) peptide is believed to be the main culprit in pathogenesis of Alzheimer disease (AD), impairing synaptic function and initiating neuronal degeneration. Soluble Aβ42 oligomers are highly toxic contribute progressive dysfunction, loss spine density affect long-term potentiation (LTP). We have characterized a short, L-amino acid Aβ-oligomer Interacting Peptide (AIP) that targets relatively well-defined population low-n oligomers, rather than simply inhibiting...