A5053802870- Endoplasmic Reticulum Stress and Disease
- Protein Structure and Dynamics
- Gut microbiota and health
- Advanced NMR Techniques and Applications
- Clostridium difficile and Clostridium perfringens research
- Enzyme Structure and Function
- RNA regulation and disease
- Gastrointestinal motility and disorders
- Microbial Inactivation Methods
- Monoclonal and Polyclonal Antibodies Research
- Toxin Mechanisms and Immunotoxins
- NMR spectroscopy and applications
- Cytokine Signaling Pathways and Interactions
- Autophagy in Disease and Therapy
- HER2/EGFR in Cancer Research
- Transgenic Plants and Applications
- Cancer Research and Treatments
- Pancreatitis Pathology and Treatment
- IL-33, ST2, and ILC Pathways
- Adipose Tissue and Metabolism
- Microscopic Colitis
- Motor Control and Adaptation
- Optical Imaging and Spectroscopy Techniques
- Entomopathogenic Microorganisms in Pest Control
- Signaling Pathways in Disease
Boston Children's Hospital
2015-2024
Harvard University
2008-2024
University of East Anglia
2024
Beth Israel Deaconess Medical Center
2024
National Institute of Diabetes and Digestive and Kidney Diseases
2012
National Institutes of Health
2012
Columbia University
2001-2009
Aalborg University
1999-2008
Harvard Stem Cell Institute
2008
University of Copenhagen
2008
The mechanisms by which signals are transmitted across the plasma membrane to regulate signaling largely unknown for receptors with single-pass transmembrane domains such as epidermal growth factor receptor (EGFR).A crystal structure of extracellular domain EGFR dimerized (EGF) reveals extended, rod-like IV and a small, hydrophobic interface compatible flexibility.The disulfide cross-linking suggest that 7-residue linker between is flexible.Disulfide shows EGF stimulates only moderate...
Abstract Background P-glycoprotein (P-gp) plays a critical role in protection of the intestinal epithelia by mediating efflux drugs/xenobiotics from mucosa into gut lumen. Recent studies bring to light that P-gp also confers link communication between mucosal barrier function and innate immune system. Yet, despite knowledge for over 10 years central gastrointestinal homeostasis, precise molecular mechanism controls its functional expression regulation remains unclear. Here, we assessed how...
Epithelial cells lining mucosal surfaces of the gastrointestinal and respiratory tracts uniquely express ERN2/IRE1β, a paralogue most evolutionarily conserved endoplasmic reticulum stress sensor, ERN1/IRE1α. How ERN2 functions at host-environment interface why second evolved remain incompletely understood. Using conventionally raised germ-free Ern2-/- mice, we found that was required for microbiota-induced goblet cell maturation mucus barrier assembly in colon. This occurred only after...
Conformational changes occurring on the microsecond−millisecond time scale in basic pancreatic trypsin inhibitor (BPTI) are investigated using nuclear magnetic resonance spectroscopy. The rczz CPMG experiment (Wang, C.; Grey, M. J.; Palmer, A. G. J. Biomol. NMR 2001, 21, 361−366) is used to record 15N spin relaxation dispersion data, Rex(1/τcp), which 1/τcp pulsing rate sequence, at two static fields, 11.7 and 14.1 T, three temperatures, 280, 290, 300 K. These data characterize kinetics...
NMR spin relaxation experiments are used to characterize the dynamics of backbone ubiquitin. Chemical exchange processes affecting residues Ile 23, Asn 25, Thr 55, and Val 70 characterized using on- off-resonance rotating-frame 15N R1rho have a kinetic rate constant 25,000 sec(-1) at 280 K. The process 55 appears result from disruption N-cap hydrogen bonds alpha-helix possibly repacking side chain 23. other on surface ubiquitin identified 1H-15N multiple quantum experiments. These located...
IRE1β is an ER stress sensor uniquely expressed in epithelial cells lining mucosal surfaces. Here, we show that intestinal expressing have attenuated unfolded protein response to stress. When modeled HEK293 and with purified protein, diminishes expression inhibits signaling by the closely related IRE1α. can assemble inhibit IRE1α suppress stress-induced XBP1 splicing, a key mediator of response. In comparison IRE1α, has relatively weak splicing activity, largely explained nonconserved amino...
Cellular signaling mediated by the epidermal growth factor receptor (EGFR or ErbB) family of tyrosine kinases plays an important role in regulating normal and oncogenic cellular physiology. While structures isolated EGFR extracellular domains intracellular protein kinase have suggested mechanisms for factor-mediated dimerization allosteric domain activation, understanding how transmembrane juxtamembrane contribute to requires structural studies on intact molecules. In this report,...
IRE1α is an endoplasmic reticulum (ER) sensor that recognizes misfolded proteins to induce the unfolded protein response (UPR). We studied cholera toxin (CTx), which invades ER and activates in host cells, understand how are recognized. Proximity labeling colocalized enzymatic metastable A1 segment of CTx (CTxA1) with live where we also found CTx-induced activation enhanced toxicity. In vitro, CTxA1 bound lumenal domain (IRE1αLD), but global unfolding was not required. Rather, IRE1αLD...
Cholera toxin B subunit (CTB) exhibits broad-spectrum biologic activity upon mucosal administration. Here, we found that a recombinant CTB containing an endoplasmic reticulum (ER) retention motif (CTB-KDEL) induces colon epithelial wound healing in colitis via the activation of unfolded protein response (UPR) cells. In Caco2 cell model, CTB-KDEL, but not or CTB-KDE, facilitated migration interaction with KDEL receptor, localization ER, UPR activation, and subsequent TGF-β signaling....
<h3>Background</h3> SCORES (Screening Cognitive Outcomes after Repetitive head impact Exposure in Sport) is a 10-year longitudinal study investigating the brain health of former athletes as they age, monitoring signs prodromal dementia an online setting. <h3>Objective</h3> To determine acceptability format and early trends performance between contact-sport exposure groups. <h3>Design</h3> Online prospective cohort study. <h3>Participants</h3> Male female (n=288) aged 40+ without diagnosed...
ABSTRACT IRE1β is an ER stress sensor uniquely expressed in epithelial cells lining mucosal surfaces. Here, we show that intestinal expressing have attenuated response to stress. assembles with and blocks activation of the closely related most evolutionarily ancient stress-sensor IRE1α suppress stress-induced xbp1 splicing, a key mediator unfolded protein response. In comparison, has weak splicing activity, largely explained by non-conserved amino acid kinase domain impairs its...