A5016342562- CRISPR and Genetic Engineering
- RNA and protein synthesis mechanisms
- Machine Learning in Bioinformatics
- Advanced biosensing and bioanalysis techniques
- Pluripotent Stem Cells Research
- Chemical Synthesis and Analysis
- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Reproductive Biology and Fertility
- vaccines and immunoinformatics approaches
- RNA Interference and Gene Delivery
- Glycosylation and Glycoproteins Research
- Virus-based gene therapy research
- Bacterial Genetics and Biotechnology
- Genomics and Phylogenetic Studies
- Protein Structure and Dynamics
- Animal Genetics and Reproduction
- Monoclonal and Polyclonal Antibodies Research
- SARS-CoV-2 and COVID-19 Research
- Ubiquitin and proteasome pathways
- RNA regulation and disease
- Cancer-related gene regulation
- Immune Cell Function and Interaction
- Biosensors and Analytical Detection
- Viral Infectious Diseases and Gene Expression in Insects
Duke University
2022-2025
Massachusetts Institute of Technology
1982-2023
Harvard University
2012-2023
MIT-Harvard Center for Ultracold Atoms
2017-2022
Human Media
2017-2022
Center for Cancer Research
2022
California Institute for Regenerative Medicine
2022
University of Pennsylvania
2022
Cornell University
2022
Massachusetts General Hospital
2022
During activation, T cells undergo metabolic reprogramming, which imprints distinct functional fates. We determined that on PD-1 ligation, activated are unable to engage in glycolysis or amino acid metabolism but have an increased rate of fatty β-oxidation (FAO). promotes FAO endogenous lipids by increasing expression CPT1A, and inducing lipolysis as indicated elevation the lipase ATGL, marker glycerol release acids. Conversely, CTLA-4 inhibits without augmenting FAO, suggesting sustains...
S. canis Cas9 is a natural CRISPR enzyme that uses two motif insertions to enable flexible targeting of DNA sequences.
An in vitro model of human ovarian follicles would greatly benefit the study female reproduction. Ovarian development requires combination germ cells and several types somatic cells. Among these, granulosa play a key role follicle formation support for oogenesis. Whereas efficient protocols exist generating primordial cell-like (hPGCLCs) from induced pluripotent stem (hiPSCs), method has been elusive. Here, we report that simultaneous overexpression two transcription factors (TFs) can direct...
Designing binders to target undruggable proteins presents a formidable challenge in drug discovery. In this work, we provide an algorithmic framework design short, target-binding linear peptides, requiring only the amino acid sequence of protein. To do this, propose process generate naturalistic peptide candidates through Gaussian perturbation peptidic latent space ESM-2 protein language model and subsequently screen these novel sequences for target-selective interaction activity via...
Abstract CRISPR-associated (Cas) DNA-endonucleases are remarkably effective tools for genome engineering, but have limited target ranges due to their protospacer adjacent motif (PAM) requirements. We demonstrate a critical expansion of the targetable sequence space type II-A enzyme through identification natural 5 $$^{\prime}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msup><mml:mrow/><mml:mrow><mml:mo>′</mml:mo></mml:mrow></mml:msup></mml:math> -NAAN-3 PAM preference...
Abstract CRISPR enzymes require a defined protospacer adjacent motif (PAM) flanking guide RNA-programmed target site, limiting their sequence accessibility for robust genome editing applications. In this study, we recombine the PAM-interacting domain of SpRY, broad-targeting Cas9 possessing an NRN > NYN (R = A or G, Y C T) PAM preference, with N-terminus Sc + +, simultaneously broad, efficient, and accurate NNG capabilities, to generate chimeric enzyme highly flexible preference: SpRYc....
Abstract Protein-protein interactions (PPIs) are critical for biological processes and predicting the sites of these is useful both computational experimental applications. We present a S tructure- gnostic L anguage T ransformer Pep tide Pr ioritization (SaLT&PepPr) pipeline to predict interaction interfaces from protein sequence alone subsequent generation peptidic binding motifs. Our model fine-tunes ESM-2 language (pLM) with per-position prediction task identify PPI using data PDB,...
Proteins serve as the workhorses of living organisms, orchestrating a wide array vital functions. Post-translational modifications (PTMs) their amino acids greatly influence structural and functional diversity different protein types uphold proteostasis, allowing cells to swiftly respond environmental changes intricately regulate complex biological processes. To this point, efforts model features proteins have involved training large expressive language models (pLMs) such ESM-2 ProtT5, which...
Abstract Denoising Diffusion Probabilistic Models (DDPMs) have emerged as a potent class of generative models, demonstrating exemplary performance across diverse AI domains such computer vision and natural language processing. In the realm protein design, while there been advances in structure-based, graph-based, discrete sequence-based diffusion, exploration continuous latent space diffusion within models (pLMs) remains nascent. this work, we introduce AMP-Diffusion, model tailored for...
Fusion oncoproteins, a class of chimeric proteins arising from chromosomal translocations, are major drivers various pediatric cancers. These intrinsically disordered and lack druggable pockets, making them highly challenging therapeutic targets for both small molecule-based structure-based approaches. Protein language models (pLMs) have recently emerged as powerful tools capturing physicochemical functional protein features but yet to be trained on fusion oncoprotein sequences. We introduce...
The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has elicited a global health crisis of catastrophic proportions. With only few vaccines approved for early or limited use, there is critical need effective antiviral strategies. In this study, we report unique platform, through computational design ACE2-derived peptides which both target viral spike protein receptor binding domain (RBD) and recruit E3 ubiquitin ligases subsequent intracellular degradation SARS-CoV-2 in...
Interactions among the three adenovirus core polypeptides V, VII, and mu were examined, using reversible chemical cross-linker dithiobis(succinimidyl propionate) two-dimensional polyacrylamide gel electrophoresis. Cross-linked species obtained from gradient-purified type 2 cores well represented cross-linked products of pentonless virions crude preparations. The more efficiently formed also identified with arginine-specific cross-linker, p-azidophenyl glyoxal. In addition to dimers V...
Abstract STUDY QUESTION Can in vitro maturation (IVM) and developmental competence of human oocytes be improved by co-culture with ovarian support cells (OSCs) derived from human-induced pluripotent stem (hiPSCs)? SUMMARY ANSWER OSC-IVM significantly improves the rates metaphase II (MII) formation euploid Day 5 or 6 blastocyst formation, when compared to a commercially available IVM system. WHAT IS KNOWN ALREADY has historically shown highly variable performance maturing generating strong...
Abstract Designing binders to target undruggable proteins presents a formidable challenge in drug discovery, requiring innovative approaches overcome the lack of putative binding sites. Recently, generative models have been trained design via three-dimensional structures proteins, but as result, struggle disordered or conformationally unstable targets. In this work, we provide generalizable algorithmic framework short, target-binding linear peptides, only amino acid sequence protein. To do...
Fusion oncoproteins, a class of chimeric proteins arising from chromosomal translocations, drive and sustain various cancers, particularly those impacting children. Unfortunately, due to their intrinsically disordered nature, large size, lack well-defined, druggable pockets, they have been historically challenging target therapeutically: neither small molecule-based methods nor structure-based approaches for binder design are strong options this molecules. Recently, protein language models...
In vitro expansion of human primordial germ cell-like cells (hPGCLCs), a pluripotent stem cell-derived PGC model, has proved challenging due to rapid loss cell (PGC)-like identity and limited survival/proliferation. Here, we describe long-term culture hPGCLCs (LTC-hPGCLCs), which actively proliferate in serum-free, feeder-free condition without apparent limit as highly homogeneous diploid populations maintaining transcriptomic epigenomic characteristics hPGCLCs. Histone proteomics confirmed...
A bstract Therapeutic modalities targeting pathogenic proteins are the gold standard of treatment for multiple disease indications. Unfortunately, a significant portion these considered “undruggable” by small molecule-based approaches, largely due to their disordered nature and instability. Designing functional peptides undruggable targets, either as standalone binders or fusions effector domains, thus presents unique opportunity therapeutic intervention. In this work, we adapt recent models...
The ability to precisely target specific motifs on disease-related proteins, whether conserved epitopes viral intrinsically disordered regions within transcription factors, or breakpoint junctions in fusion oncoproteins, is essential for modulating their function while minimizing off-target effects. Current methods struggle achieve this specificity without reliable structural information. In work, we introduce a