Zachary Sethna

Princeton University | PU · Department of Physics

Deciphering individual cell phenotypes from cell-specific transcriptional processes requires high dimensional single cell RNA sequencing. However, current dimensionality reduction methods aggregate sparse gene information across cells, without directly measuring the relationships that exist between genes. By performing dimensionality reduction with...

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients¹, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA–lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time fr...

Missense driver mutations in cancer are concentrated in a few hotspots1. Various mechanisms have been proposed to explain this skew, including biased mutational processes2, phenotypic differences3–6 and immunoediting of neoantigens7,8; however, to our knowledge, no existing model weighs the relative contribution of these features to tumour evolutio...

2516 Background: Pancreas ductal adenocarcinoma (PDAC) is a lethal cancer that claims ̃90% of patients in <24 months of diagnosis. PDAC is also refractory to immunotherapy as most tumors exhibit an immune excluded/desert phenotype. However, although characterized by low mutation rates, most PDACs harbor mutations that can generate immunogenic neoan...

Background Cancer immunoediting predicts that T cells selectively kill tumor cells expressing immunogenic mutations (neoantigens) resulting in less immunogenic clones to outgrow in tumors. ¹ Although established through longitudinal studies of how tumors evolve in immune-proficient and -deficient mice, 1 2 whether the human immune system naturally...

Cancer immunoediting, a hallmark of cancer, predicts that lymphocytes recognize tumor-specific mutations (neoantigens) to kill immunogenic tumor cells and select less immunogenic clones to survive in immunocompetent hosts. Yet, though proven in mice, whether immunoediting governs how human tumors evolve naturally, and the principles of how the immu...

The diversity of T-cell receptor (TCR) repertoires is achieved by a combination of two intrinsically stochastic steps: random receptor generation by VDJ recombination, and selection based on the recognition of random self-peptides presented on the major histocompatibility complex. These processes lead to a large receptor variability within and betw...

T-cell receptors (TCR) are key proteins of the adaptive immune system, generated randomly in each individual, whose diversity underlies our ability to recognize infections and malignancies. Modeling the distribution of TCR sequences is of key importance for immunology and medical applications. Here, we compare two inference methods trained on high-...

The diversity of T-cell receptor (TCR) repertoires is achieved by a combination of two intrinsically stochastic steps: random receptor generation by VDJ recombination, and selection based on the recognition of random self-peptides presented on the major histocompatibility complex. These processes lead to a large receptor variability within and betw...

T-cell receptors (TCR) are key proteins of the adaptive immune system, generated randomly in each individual, whose diversity underlies our ability to recognize infections and malignancies. Modeling the distribution of TCR sequences is of key importance for immunology and medical applications. Here, we compare two inference methods trained on high-...

Motivation: High-throughput sequencing of large immune repertoires has enabled the development of methods to predict the probability of generation by V(D)J recombination of T- and B-cell receptors of any specific nucleotide sequence. These generation probabilities are very non-homogeneous, ranging over 20 orders of magnitude in real repertoires. S...

Motivation High-throughput sequencing of large immune repertoires has enabled the development of methods to predict the probability of generation by V(D)J recombination of T- and B-cell receptors of any specific nucleotide sequence. These generation probabilities are very non-homogeneous, ranging over 20 orders of magnitude in real repertoires. Sin...

Motivation: High-throughput sequencing of large immune repertoires has enabled the de- velopment of methods to predict the probability of generation by V(D)J recombination of T- and B-cell receptors of any specific nucleotide sequence. These generation probabilities are very non-homogeneous, ranging over 20 orders of magnitude in real repertoires....

Despite the extreme diversity of T cell repertoires, many identical T-cell receptor (TCR) sequences are found in a large number of individual mice and humans. These widely-shared sequences, often referred to as `public', have been suggested to be over-represented due to their potential immune functionality or their ease of generation by V(D)J recom...

Despite the extreme diversity of T cell repertoires, many identical T cell receptor (TCR) sequences are found in a large number of individual mice and humans. These widely-shared sequences, often referred to as ‘public‘, have been suggested to be over-represented due to their potential immune functionality or their ease of generation by V(D)J recom...

Significance The immune system defends against pathogens in part via a diverse population of T cells that display different surface receptor proteins [T-cell receptors (TCRs)] designed to recognize MHC-presented foreign peptides. Receptor diversity is produced by an initial random gene recombination process, followed by selection for proteins that...

The ability of the adaptive immune system to respond to arbitrary pathogens stems from the broad diversity of immune cell surface receptors (TCRs). This diversity originates in a stochastic DNA editing process (VDJ recombination) that acts each time a new immune cell is created from a stem cell. By analyzing T cell sequence repertoires taken from t...

We quantify the VDJ recombination and somatic hypermutation processes in human B-cells using probabilistic inference methods on high-throughput DNA sequence repertoires of human B-cell receptor heavy chains. Our analysis captures the statistical properties of the naive repertoire, first after its initial generation via VDJ recombination and then af...

We quantify the VDJ recombination and somatic hypermutation processes in human B-cells using probabilistic inference methods on high-throughput DNA sequence repertoires of human B-cell receptor heavy chains. Our analysis captures the statistical properties of the naive repertoire, first after its initial generation via VDJ recombination and then af...

Techniques that accelerate data acquisition without sacrificing the advantages of fast Fourier transform (FFT) reconstruction could benefit a wide variety of magnetic resonance experiments. Here we discuss an approach for reconstructing multidimensional nuclear magnetic resonance (NMR) spectra and MR images from sparsely-sampled time domain data, b...

Probing the internal composition of bone on the sub-100 μm length scale is important to study normal features and to look for signs of disease. However, few useful non-destructive techniques are available to evaluate changes in the bone mineral chemical structure and functional micro-architecture on the interior of bones. MRI would be an excellent...

Typically, in 2D NMR (or 2D MRI), only one ``row'' of the time-dependent (or k-dependent) signal is sampled N times per ˜T1 (spin-lattice relaxation time). Thus, filling a 2D Cartesian grid of M xN data points requires M additional experiments, for a total spectral acquisition time Tacq M xT1. Measuring fewer ``rows'' than required for Fourier reco...

We discuss here an approach for reconstructing spectra from sparse time domain data, by way of iterated projections, and more specifically by alternating projections or by use of the difference map algorithm developed by Veit Elser. This is done in a purely deterministic way, by reformulating any a priori knowledge or constraints into projections,...

Recent fundamental research in quantum computing gave rise to a new NMR pulse sequence - the quadratic echo - that can be used to narrow the broad MR spectrum of solids by orders of magnitude. This advance enables high spatial resolution, 3D MRI of hard and soft solids (e.g., the ^31P MRI of bone and soft tissues, which has recently been demonstrat...

Deformation fabrics (lattice-preferred orientation: LPO) and the water content in the deep upper mantle are among the controversial issues on deep upper mantle dynamics. For example, there are some reports suggesting the ``pressure-induced'' fabric transitions in olivine where the dominant slip direction in olivine is proposed to change from [100]...