A5062137054- Computational Drug Discovery Methods
- Gut microbiota and health
- Clostridium difficile and Clostridium perfringens research
- Protein Structure and Dynamics
- Gene Regulatory Network Analysis
- Bioinformatics and Genomic Networks
- Genomics and Phylogenetic Studies
- RNA and protein synthesis mechanisms
- Research in Cotton Cultivation
- Monoclonal and Polyclonal Antibodies Research
- Protein Degradation and Inhibitors
- Microbial Metabolic Engineering and Bioproduction
- Cancer Immunotherapy and Biomarkers
- Inflammasome and immune disorders
- Microfluidic and Bio-sensing Technologies
- Signaling Pathways in Disease
- Nonmelanoma Skin Cancer Studies
- Histone Deacetylase Inhibitors Research
- Cancer, Stress, Anesthesia, and Immune Response
- Evolution and Genetic Dynamics
- Receptor Mechanisms and Signaling
- Protist diversity and phylogeny
- Ferrocene Chemistry and Applications
- Advanced Breast Cancer Therapies
- Insect symbiosis and bacterial influences
Novartis (Switzerland)
2022-2025
Novartis Institutes for BioMedical Research
2022-2023
Dana-Farber Cancer Institute
2016-2020
Harvard University
2017-2020
Broad Institute
2018-2020
Center for Systems Biology
2018-2020
Boston University
2018
Memorial Sloan Kettering Cancer Center
2013-2017
University of Chicago
2017
Northwestern University
2017
The intestinal microbiota is a microbial ecosystem of crucial importance to human health. Understanding how the confers resistance against enteric pathogens and antibiotics disrupt that key prevention cure infections. We present novel method infer community ecology directly from time-resolved metagenomics. This extends generalized Lotka-Volterra dynamics account for external perturbations. Data recent experiments on antibiotic-mediated Clostridium difficile infection analyzed quantify...
Predicting dynamics of host-microbial ecosystems is crucial for the rational design bacteriotherapies. We present MDSINE, a suite algorithms inferring dynamical systems models from microbiome time-series data and predicting temporal behaviors. Using simulated data, we demonstrate that MDSINE significantly outperforms existing inference method. then show MDSINE's utility on two new gnotobiotic mice datasets, investigating infection with Clostridium difficile an immune-modulatory probiotic....
Manipulation of the gut microbiota holds great promise for treatment diseases. However, a major challenge is identification therapeutically potent microbial consortia that colonize host effectively while maximizing immunologic outcome. Here, we propose novel workflow to select optimal immune-inducing from microbiome compositicon and immune effectors measurements. Using published newly generated regulatory T-cell (Treg) data germ-free mice, estimate contributions twelve Clostridia strains...
Abstract MAS825, a bispecific IL-1β/IL-18 monoclonal antibody, could improve clinical outcomes in COVID-19 pneumonia by reducing inflammasome-mediated inflammation. Hospitalized non-ventilated patients with (n = 138) were randomized (1:1) to receive MAS825 (10 mg/kg single i.v.) or placebo addition standard of care (SoC). The primary endpoint was the composite Acute Physiology and Chronic Health Evaluation II (APACHE II) score on Day 15 day discharge (whichever earlier) worst-case imputation...
The incorporation of disease-relevant targets in a compound-dependent manner into ternary complexes with an assisting chaperone protein has become common modality. Among the various types complex-forming compounds, molecular glues are particular interest because they do not require significant binary (independent) target affinity. Instead, formed by retrieve part their thermodynamic stability through newly induced chaperone-target or glue-target interactions that occur only complex. These...
Iptacopan, a first‐in‐class complement factor B inhibitor acting proximally in the alternative pathway, has been shown to be safe and effective for patients with complement‐mediated diseases. Iptacopan selectively binds high affinity B, soluble, plasma‐based, hepatically produced protein. Factor is abundant circulation but can saturated at iptacopan clinical dose of 200 mg twice daily. pharmacokinetics (PK) are influenced by target binding. This target‐mediated drug disposition (TMDD)...
The incorporation of disease-relevant targets into ternary complexes in a compound-dependent manner by utilizing an assisting chaperone has become common modality as far bifunctional complex-forming compounds are concerned. In contrast, examples formed molecular glues much rarer. Due to their lack significant binary (independent) target affinity, identification cannot yet be achieved rational methods and is, therefore, more challenging. However, it is precisely for that reason (given the...
Cancer cells have genetic alterations that often directly affect intracellular protein signaling processes allowing them to bypass control mechanisms for cell death, growth and division. drugs targeting these work initially, but resistance is common. Combinations of targeted may overcome or prevent resistance, their selection requires context-specific knowledge pathways including complex interactions such as feedback loops crosstalk. To infer quantitative pathway models, we collected a rich...
While eukaryotes primarily evolve by duplication-divergence expansion (and reduction) of their own gene repertoire with only rare horizontal transfers, prokaryotes appear to under both duplications and widespread transfers over long evolutionary time scales. But, the origin this striking difference in importance remains large a mystery.We propose that abundance free-living is simple but necessary consequence two opposite effects: i) apparent genome size constraint compared typical eukaryote...
Accurate diagnosis of periprosthetic joint infections (PJI) is one the most widely researched areas in modern orthopedic endoprosthesis. However, our understanding immunological basis this severe complication still limited. In study, we developed a flow cytometric approach to precisely characterize immune cell composition joints. Using high-dimensional multi-parametric data, defined, for first time, local populations artificial We identified significant differences cellular distribution...
1052 Background: Aromatase inhibitors (AI) block estrogen synthesis and are effective for the treatment of receptor (ER) positive breast cancer in postmenopausal women. Despite initial benefit, resistance to AIs disease progression occur, at which point cytotoxic chemotherapy is often remaining option. Entinostat, an oral class 1 isoform-selective HDACi, has been shown preclinical studies restore sensitivity acquired AI resistance. The goal this study was determine whether addition...
There is an increasing interest to develop therapeutics that modulate challenging or undruggable target proteins via a mechanism involves ternary complexes. In general, such compounds can be characterized by their direct affinities chaperone and protein degree of cooperativity in the formation complex. As trend, smaller have greater dependency on intrinsic thermodynamic stability relative (or chaperone) binding. This highlights need consider complex-forming early lead optimization,...
We study the expansion of biomolecular networks from view point first evolutionary principles based on duplication and divergence ancestral genes. The gene families subnetworks is analyzed in terms logistic map compositions, which capture varying functional constraints individual genes course evolution. Using a mean-field approach, we then demonstrate existence spontaneous growth-rate variations between discuss relevance such heterogeneous expansions for emergent properties actual networks.
Loss in potency is commonly observed early drug discovery when moving from biochemical to more complex cellular systems. Among other factors, low permeability often considered cause such disconnects.We developed a novel disposition assay MDCK cells determine passive uptake clearance (PSinf), cell-to-medium ratios at steady-state (Kp) and the time reach 90% (TTSS90) single experiment high-throughput format.The was validated using 40 marketed drugs, showing wide distribution of PSinf Kp...
Abstract Reverse phase protein array (RPPA) technology is an antibody-based high-throughput assay for profiling of biological specimens that allows many measurements with very small amounts cell lysate. Here, we report the sensitivity, reproducibility, and accuracy a particular RPPA platform called Zeptosens. We customized protocol our in-house setup, measured more than 80 total phospho-protein levels in various cancer samples, including lines, organoids, tumor chunks, core needle biopsies,...
Data-driven mathematical modeling of biological systems has enormous potential to understand and predict the interplay between molecular phenotypic response perturbation, provides a rational approach nomination therapies in complex diseases such as cancer. Melanoma is particularly debilitating disease for which most eventually fail resistance chemotherapy targeted drugs develop. We have previously applied an iterative experimental-computational approach, termed perturbation biology, test...
Journal Article Association of Two Marker Loci With Chromosome 1 in Cotton: LL and duplicate locus lp1 Get access J. E. ENDRIZZI, ENDRIZZI Department Agronomy Plant Genetics, former statistician the Arizona Agriculture Experiment Station, The University ArizonaTucson, 85721 Search for other works by this author on: Oxford Academic PubMed Google Scholar R. STEIN Heredity, Volume 66, Issue 2, March 1975, Pages 75–78, https://doi.org/10.1093/oxfordjournals.jhered.a108585 Published: 01 1975
Abstract Natural evolution encodes rich information about the structure and function of biomolecules in genetic record. Previously, statistical analysis co-variation patterns natural protein families has enabled accurate computation 3D structures. Here, we explored whether similar can be generated by laboratory evolution, starting from a single gene performing multiple cycles mutagenesis functional selection. We evolved two bacterial antibiotic resistance proteins, β-lactamase PSE1...