A5050379643- Global Maritime and Colonial Histories
- Islamic Studies and History
- Antibiotic Resistance in Bacteria
- Bacterial biofilms and quorum sensing
- Cystic Fibrosis Research Advances
- RNA and protein synthesis mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Eicosanoids and Hypertension Pharmacology
- Pneumocystis jirovecii pneumonia detection and treatment
- Pharmacogenetics and Drug Metabolism
- Neonatal Respiratory Health Research
- Biochemical and Structural Characterization
- Enzyme Catalysis and Immobilization
- Bacterial Genetics and Biotechnology
- Historical and Linguistic Studies
- Archaeology and Historical Studies
- Protein Structure and Dynamics
- Asian Studies and History
- Acute Myeloid Leukemia Research
- Colonialism, slavery, and trade
- SARS-CoV-2 and COVID-19 Research
- Enzyme Structure and Function
- Evolution and Genetic Dynamics
- Genomics and Phylogenetic Studies
- Inhalation and Respiratory Drug Delivery
Durham University
2021-2025
Institute for Protein Innovation
2018-2024
Boston Children's Hospital
2019-2024
Harvard University
2019-2024
Dartmouth College
2009-2024
Dana-Farber Cancer Institute
2020
Orient-Institut Beirut
2019-2020
SOAS University of London
2017-2018
University of London
2017-2018
University of Washington
2013-2018
Abstract To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. define mechanistic basis clonal hematopoiesis in SDS, investigate somatic mutations acquired by patients SDS followed longitudinally. Here report multiple independent hematopoietic clones arise life, most commonly harboring heterozygous EIF6 or...
Carbohydrates and glycoproteins modulate key biological functions. However, experimental structure determination of sugar polymers is notoriously difficult. Computational approaches can aid in carbohydrate prediction, determination, design. In this work, we developed a glycan-modeling algorithm, GlycanTreeModeler, that computationally builds glycans layer-by-layer, using adaptive kernel density estimates (KDE) common glycan conformations derived from data the Protein Data Bank (PDB) quantum...
Abstract A major challenge in protein design is to augment existing functional proteins with multiple property enhancements. Altering several properties likely necessitates numerous primary sequence changes, and novel methods are needed accurately predict combinations of mutations that maintain or enhance function. Models co-variation (e.g., EVcouplings), which leverage extensive information about various activities from homologous sequences, have proven effective for many applications...
Significance Pseudomonas aeruginosa pulmonary infections cause prolonged and destructive inflammation for cystic fibrosis patients. Despite vigorous neutrophilic responses, P. persists in a chronic hyperinflammatory environment. We show that the virulence factor, transmembrane conductance regulator inhibitory factor (Cif), promotes sustained airway by reducing host pro-resolving lipid mediators. Cif hydrolyzes epithelial-derived 14,15-epoxyeicosatrienoic acid, disrupting transcellular...
Stéphane Pradines and Farouk Topan (eds): Muslim Cultures of the Indian Ocean: Diversity Pluralism, Past Present (Exploring Contexts.) x, 356 pp. Edinburgh: Edinburgh University Press, 2023. ISBN 978 1 47448649 1.
Abstract A definitive cure for acute myeloid leukemia (AML) remains elusive. Inter and Intra-patient heterogeneity in antigen expression profiles is a major challenge AML treatment. Adapter CAR-T cell therapies utilize chimeric receptor (CAR) which binds to non-natural small molecule, turn can be attached soluble affinity domain that the tumor antigen. Decoupling cancer binding CAR engagement provides flexibility control directing therapy through dosing of adapter, improve safety decrease T...
Cystic fibrosis transmembrane conductance regulator (CFTR) inhibitory factor (Cif) is a virulence secreted by Pseudomonas aeruginosa that reduces the quantity of CFTR in apical membrane human airway epithelial cells. Initial sequence analysis suggested Cif an epoxide hydrolase (EH), but its violates two strictly conserved EH motifs and also compatible with other alpha/beta family members diverse substrate specificities. To investigate mechanistic basis activity, we have determined structure...
Each year vast international resources are wasted on irreproducible research. The scientific community has been slow to adopt standard software engineering practices, despite the increases in high-dimensional data, complexities of workflows, and computational environments. Here we show how applications can be created a reproducible manner when simple design goals for reproducibility met. We describe implementation test server framework 40 benchmarks, covering numerous Rosetta...
Despite SARS-CoV-2 being a "novel" virus, early detection of anti-spike IgG in severe COVID-19 patients may be caused by the amplification humoral memory responses against seasonal coronaviruses. Here, we examine this phenomenon characterizing non-hospitalized convalescent individuals across spectrum severity. We observe that disease severity positively correlates with levels, cross-reactivity other betacoronaviruses (β-CoVs), and FcγR activation. Analysis targeting β-CoV-conserved...
Abstract Carbohydrates and glycoproteins modulate key biological functions. Computational approaches inform function to aid in carbohydrate structure prediction, determination, design. However, experimental determination of sugar polymers is notoriously difficult as glycans can sample a wide range low energy conformations, thus limiting the study glycan-mediated molecular interactions. In this work, we expanded RosettaCarbohydrate framework, developed benchmarked effective tools for glycan...
Abstract Designing optimized proteins is important for a range of practical applications. Protein design rapidly developing field that would benefit from approaches enable many changes in the amino acid primary sequence, rather than small number mutations, while maintaining structure and enhancing function. Homologous protein sequences contain extensive information about various properties activities have emerged over billions years evolution. Evolutionary models sequence co-variation,...
Abstract Understanding how proteins evolve under selective pressure is a longstanding challenge. The immensity of the search space has limited efforts to systematically evaluate impact multiple simultaneous mutations, so mutations have typically been assessed individually. However, epistasis, or way in which interact, prevents accurate prediction combinatorial based on measurements individual mutations. Here, we use artificial intelligence define entire functional sequence landscape protein...
The Gram-negative bacterium Pseudomonas aeruginosa is an opportunistic pathogen that secretes a multitude of virulence factors during the course infection. Among these Cif, epoxide hydrolase (EH) reduces functional localization cystic fibrosis transmembrane conductance regulator in epithelial cells. In addition to being first reported EH factor, Cif possesses unique sequence deviations from canonical motifs. Foremost among substitution histidine for ring-opening tyrosine active site. To test...
The opportunistic pathogen Pseudomonas aeruginosa colonizes the lungs of susceptible individuals by deploying virulence factors targeting host defenses. secreted factor Cif (cystic fibrosis transmembrane conductance regulator inhibitory factor) dysregulates endocytic recycling CFTR and thus reduces abundance in epithelial membranes. We have postulated that decrease ion secretion mediated would slow mucociliary transport bacterial clearance from lungs. To test this hypothesis, we explored...
Endocytic recycling of the cystic fibrosis transmembrane conductance regulator (CFTR) is blocked by CFTR inhibitory factor (Cif). Originally discovered in Pseudomonas aeruginosa, Cif a secreted epoxide hydrolase that transcriptionally regulated CifR, an epoxide-sensitive repressor. In this report, we investigate homologous protein found strains emerging nosocomial pathogens Acinetobacter nosocomialis and baumannii ("aCif"). Like Cif, aCif carries N-terminal secretion signal can be purified...
Disulfide-rich peptides represent an important protein family with broad pharmacological potential. Recent advances in computational methods have made it possible to design new which adopt a stable conformation de novo. Here, we describe system produce disulfide-rich novo using Escherichia coli as the expression host. The advantage of this is that enables production uniformly
Abstract Superantigens are toxins produced by Staphylococcus aureus, called staphylococcal enterotoxins (abbreviated SEA to SEU). They can cross-link the T cell receptor (TCR) and major histocompatibility complex class II, triggering a massive activation hence disease. Due high stability toxicity, superantigens potential agents of bioterrorism. Hence, antagonists may not only be useful in treatment disease but also serve as countermeasures biological warfare. Of particular interest...
Pseudomonas aeruginosa secretes an epoxide hydrolase virulence factor that reduces the apical membrane expression of ABC transporters such as cystic fibrosis transmembrane conductance regulator (CFTR). This factor, named CFTR inhibitory (Cif), is regulated by a TetR-family, epoxide-responsive repressor known CifR via direct binding and repression. We identified two sites in intergenic space between cifR morB, first gene operon containing cif gene. have mapped these found they are 27 bp...
The Rosetta software suite for macromolecular modeling is a powerful computational toolbox protein design, structure prediction, and analysis. development of novel Rosetta-based scientific tools requires two orthogonal skill sets: deep domain-specific expertise in biochemistry technical development, deployment, analysis molecular simulations. Furthermore, the demands simulation necessitate large scale cluster-based or distributed solutions nearly all scientifically relevant tasks. To reduce...