A5030005612- Bacterial Genetics and Biotechnology
- Biotin and Related Studies
- Microbial Metabolic Engineering and Bioproduction
- Advanced Proteomics Techniques and Applications
- Cancer-related Molecular Pathways
- Advanced biosensing and bioanalysis techniques
- Chemical Synthesis and Analysis
- Bioinformatics and Genomic Networks
- Protein Structure and Dynamics
- Adipokines, Inflammation, and Metabolic Diseases
- Cellular transport and secretion
- DNA Repair Mechanisms
- Asymmetric Hydrogenation and Catalysis
- Gene expression and cancer classification
- Epigenetics and DNA Methylation
- Adipose Tissue and Metabolism
- Glioma Diagnosis and Treatment
- Monoclonal and Polyclonal Antibodies Research
- Microtubule and mitosis dynamics
- PARP inhibition in cancer therapy
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Organoboron and organosilicon chemistry
- Pineapple and bromelain studies
- Telomeres, Telomerase, and Senescence
- Carbohydrate Chemistry and Synthesis
Center for Systems Biology
2020-2025
Harvard University
2020-2025
Boston VA Research Institute
2024
University of Wisconsin–Milwaukee
2024
Harvard University Press
2024
University College Dublin
2018
22q11 Ireland
2018
Trinity College Dublin
2012
Fight-or-flight responses involve β-adrenergic-induced increases in heart rate and contractile force. In the present study, we uncover primary mechanism underlying heart's innate reserve. We show that four protein kinase A (PKA)-phosphorylated residues Rad, a calcium channel inhibitor, are crucial for controlling basal current essential β-adrenergic augmentation of influx cardiomyocytes. Even with intact PKA signaling to other proteins modulating handling, preventing adrenergic activation...
Abstract Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated (MMEJ). Using this method, we show that patient-derived glioblastoma (GBM) samples with acquired temozolomide (TMZ) resistance display elevated HR MMEJ activity, suggesting these contribute to resistance....
Thiouracil catalyzes stereoselective glycosylations with galactals in loadings as low 0.1 mol%.
Loss of the tubulin-binding protein STMN2 is implicated in amyotrophic lateral sclerosis (ALS) but how it protects neurons not known. known to turn over rapidly and accumulate at axotomy sites. We confirmed fast turnover U2OS cells iPSC-derived showed that degradation occurs mainly by ubiquitin-proteasome system. The membrane targeting N-terminal domain promoted turnover, whereas its tubulin binding stathmin-like (SLD) stabilization. Proximity labeling imaging localizes trans-Golgi network...
Abstract Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated (MMEJ) show that HR MMEJ are therapeutically-targetable resistance mechanisms glioblastoma. Using targeted screen of clinically relevant small molecules, we identify ATM kinase inhibitor, AZD1390, as potent...
The Library of Integrated Network-based Cellular Signatures (LINCS), an NIH Common Fund program, has cataloged and analyzed cellular function molecular activity profiles in response to >80,000 perturbing agents that are potentially disruptive cells. Because the importance proteins their modifications specific perturbations, four six LINCS centers have included significant proteomics efforts characterization resulting phenotype. This manuscript aims describe this effort data harmonization...
We have developed a copper-catalyzed process for the coupling of aldehydes, amines, and boronic acids. This allows greater reactivity with simple aryl acids reactions to proceed that previously failed. Initial mechanistic studies support involving transmetalation from boron copper.
Notch signaling relies on ligand-induced proteolysis of the transmembrane receptor to liberate a nuclear effector that drives cell fate decisions. Upon ligand binding, sequential cleavage by protease ADAM10 and intracellular γ-secretase releases domain (NICD), which translocates nucleus forms complex induces target gene transcription. To map location timing individual steps required for movement from plasma membrane nucleus, we used proximity labeling with quantitative, multiplexed mass...
Selective breakdown of proteins and aggregates is crucial for maintaining normal cellular activities involved in the pathogenesis diverse diseases. How cell recognizes tags these targets different structural states degradation by proteasome autophagy pathways has not been well understood. Here, we discovered that a HECT-family ubiquitin ligase HUWE1 broadly required efficient soluble factors clearance protein aggregates/condensates. Underlying this capacity novel Ubiquitin-Directed Ligase...
We performed quantitative proteomics on 60 human-derived breast cancer cell line models to a depth of ~13,000 proteins. The resulting high-throughput datasets were assessed for quality and reproducibility. used the identify characterize subtypes showed that they conform known transcriptional subtypes, revealing molecular are preserved even in under-sampled protein feature sets. All freely available as public resources LINCS portal. anticipate these datasets, either isolation or combination...
Immunoglobulin light chain (AL) amyloidosis is an incurable hematologic disorder typically characterized by the production of amyloidogenic chains clonal plasma cells. These misfold and aggregate in healthy tissues as amyloid fibrils, leading to life-threatening multi-organ dysfunction. Here we show that cells AL are highly primed undergo apoptosis dependent on pro-survival proteins MCL-1 BCL-2. Notably, this dependency indirectly targeted proteasome inhibitor bortezomib, currently standard...
Stathmins are small, unstructured proteins that bind tubulin dimers and implicated in several human diseases, but whose function remains unknown. We characterized a new stathmin, STMND1 (Stathmin Domain Containing 1) as the representative of an ancient subfamily. features N-terminal myristoylated palmitoylated motif which directs it to membranes tubulin-binding stathmin-like domain (SLD) contains internal nuclear localization signal. Biochemistry proximity labeling showed binds tubulin, live...
SUMMARY Neuroinflammation is a pathological feature of many neurodegenerative diseases, including Alzheimer’s disease (AD) 1,2 and amyotrophic lateral sclerosis (ALS) 3 , raising the possibility common therapeutic targets. We previously established that cytoplasmic double-stranded RNA (cdsRNA) spatially coincident with pTDP-43 inclusions in neurons patients C9ORF72-mediated ALS 4 . CdsRNA triggers type-I interferon (IFN-I)-based innate immune response human neural cells, resulting their...
In bacteria, algae, fungi, and plant cells, the wall must expand in concert with cytoplasmic biomass production, otherwise cells would experience toxic molecular crowding 1 , 2 or lyse. But how achieve expansion of this complex biomaterial coordination biosynthesis macromolecules cytoplasm remains unexplained 3 although recent works have revealed that these processes are indeed coupled 4,5 . Here, we report a striking increase turgor pressure growth rate E. coli suggesting speed cell is...
ABSTRACT Normal tissue physiology and repair depends on communication with the immune system. Understanding this at molecular level in intact requires new methods. The consequences of SARS-CoV-2 infection, which can result acute respiratory distress, thrombosis death, has been studied primarily accessible liquid specimens such as blood, sputum bronchoalveolar lavage, all are peripheral to primary site infection lung. Here, we describe combined use multiplexed deep proteomics imaging profile...
In bacteria, algae, fungi, and plant cells, the wall must expand in concert with cytoplasmic biomass production, otherwise cells would experience toxic molecular crowding
Abstract Current treatments for advanced prostate cancer (PCa) primarily target the androgen receptor (AR) pathway. However, emergence of castration-resistant (CRPC) and resistance to AR pathway inhibitors (APSIs) remains ongoing challenges. Here, we present BSJ-5-63, a novel proteolysis-targeting chimera (PROTAC) targeting cyclin-dependent kinases (CDKs) CDK12, CDK7, CDK9, offering multi-pronged approach CRPC therapy. BSJ-5-63 degrades diminishing BRCA1 BRCA2 expression inducing sustained...
The master regulator of the DNA damage response, transcription factor p53, orchestrates multiple downstream responses and coordinates repair processes. In response to double-strand breaks, p53 exhibits pulses expression, but how it achieves temporal coordination remains unclear. Here, we show that p53's posttranslational modification state is altered between its first second expression. We acetylations at two sites, K373 K382, were reduced in pulse, these differentially affected target...