T-cell tolerant fraction as a predictor of immune-related adverse events.

Background: Immune checkpoint inhibitor (ICI) therapies may cause unpredictable and potentially severe autoimmune toxicities termed immune-related adverse events (irAEs). Because T cells mediate ICI effects, T cell profiling may provide insight into the risk of irAEs. Here we evaluate a novel metric-the T-cell tolerant fraction-as a predictor of future irAEs.

Dynamic kernel matching for non-conforming data: A case study of T cell receptor datasets.

Most statistical classifiers are designed to find patterns in data where numbers fit into rows and columns, like in a spreadsheet, but many kinds of data do not conform to this structure. To uncover patterns in non-conforming data, we describe an approach for modifying established statistical classifiers to handle non-conforming data, which we call dynamic kernel matching (DKM). As examples of non-conforming data, we consider (i) a dataset of T-cell receptor (TCR) sequences labelled by disease antigen and (ii) a dataset of sequenced TCR repertoires labelled by patient cytomegalovirus (CMV) serostatus, anticipating that both datasets contain signatures for diagnosing disease.

Reconstituting T cell receptor selection in-silico.

Each T cell receptor (TCR) gene is created without regard for which substances (antigens) the receptor can recognize. T cell selection culls developing T cells when their TCRs (i) fail to recognize major histocompatibility complexes (MHCs) that act as antigen presenting platforms or (ii) recognize with high affinity self-antigens derived from healthy cells and tissue. While T cell selection has been thoroughly studied, little is known about which TCRs are retained or removed by this process.

Association between body mass index, dosing strategy, and efficacy of immune checkpoint inhibitors.

Background: Increased body mass index (BMI) has been associated with improved response to immune checkpoint inhibitors (ICIs) in multiple cancer types. We evaluated associations between BMI, ICI dosing strategy, and clinical outcomes.

Methods: We abstracted clinical data on patients with cancer treated with ICI, including age, sex, cancer type, BMI, ICI type, dosing strategy (weight-based or fixed), radiographic response, overall survival (OS), and progression-free survival (PFS).

T Cell Receptor Repertoires Acquired Routine Pap Testing May Help Refine Cervical Cancer and Precancer Risk Estimates.

Cervical cancer is the fourth most common cancer and fourth leading cause of cancer death among women worldwide. In low Human Development Index settings, it ranks second. Screening and surveillance involve the cytology-based Papanicolaou (Pap) test and testing for high-risk human papillomavirus (hrHPV).

Biophysicochemical motifs in T cell receptor sequences as a potential biomarker for high-grade serous ovarian carcinoma.

We previously showed, in a pilot study with publicly available data, that T cell receptor (TCR) repertoires from tumor infiltrating lymphocytes (TILs) could be distinguished from adjacent healthy tissue repertoires by the presence of TCRs bearing specific, biophysicochemical motifs in their antigen binding regions. We hypothesized that such motifs might allow development of a novel approach to cancer detection. The motifs were cancer specific and achieved high classification accuracy: we found distinct motifs for breast versus colorectal cancer-associated repertoires, and the colorectal cancer motif achieved 93% accuracy, while the breast cancer motif achieved 94% accuracy.

Machine Learning on Sequential Data Using a Recurrent Weighted Average.

Recurrent Neural Networks (RNN) are a type of statistical model designed to handle sequential data. The model reads a sequence one symbol at a time. Each symbol is processed based on information collected from the previous symbols.

Biophysicochemical Motifs in T-cell Receptor Sequences Distinguish Repertoires from Tumor-Infiltrating Lymphocyte and Adjacent Healthy Tissue.

Immune repertoire deep sequencing allows comprehensive characterization of antigen receptor-encoding genes in a lymphocyte population. We hypothesized that this method could enable a novel approach to diagnose disease by identifying antigen receptor sequence patterns associated with clinical phenotypes. In this study, we developed statistical classifiers of T-cell receptor (TCR) repertoires that distinguish tumor tissue from patient-matched healthy tissue of the same organ.

Rapid constriction of the selectivity filter underlies C-type inactivation in the KcsA potassium channel.

C-type inactivation is a time-dependent process observed in many K channels whereby prolonged activation by an external stimulus leads to a reduction in ionic conduction. While C-type inactivation is thought to be a result of a constriction of the selectivity filter, the local dynamics of the process remain elusive. Here, we use molecular dynamics (MD) simulations of the KcsA channel to elucidate the nature of kinetically delayed activation/inactivation gating coupling.

VDJServer: A Cloud-Based Analysis Portal and Data Commons for Immune Repertoire Sequences and Rearrangements.

Background: Recent technological advances in immune repertoire sequencing have created tremendous potential for advancing our understanding of adaptive immune response dynamics in various states of health and disease. Immune repertoire sequencing produces large, highly complex data sets, however, which require specialized methods and software tools for their effective analysis and interpretation.

Results: VDJServer is a cloud-based analysis portal for immune repertoire sequence data that provide access to a suite of tools for a complete analysis workflow, including modules for preprocessing and quality control of sequence reads, V(D)J gene segment assignment, repertoire characterization, and repertoire comparison.

Chemical substitutions in the selectivity filter of potassium channels do not rule out constricted-like conformations for C-type inactivation.

In many K channels, prolonged activating stimuli lead to a time-dependent reduction in ion conduction, a phenomenon known as C-type inactivation. X-ray structures of the KcsA channel suggest that this inactivated state corresponds to a "constricted" conformation of the selectivity filter. However, the functional significance of the constricted conformation has become a matter of debate.

Statistical classifiers for diagnosing disease from immune repertoires: a case study using multiple sclerosis.

Background: Deep sequencing of lymphocyte receptor repertoires has made it possible to comprehensively profile the clonal composition of lymphocyte populations. This opens the door for novel approaches to diagnose and prognosticate diseases with a driving immune component by identifying repertoire sequence patterns associated with clinical phenotypes. Indeed, recent studies support the feasibility of this, demonstrating an association between repertoire-level summary statistics (e.

Probing the Effects of Gating on the Ion Occupancy of the K Channel Selectivity Filter Using Two-Dimensional Infrared Spectroscopy.

The interplay between the intracellular gate and the selectivity filter underlies the structural basis for gating in potassium ion channels. Using a combination of protein semisynthesis, two-dimensional infrared (2D IR) spectroscopy, and molecular dynamics (MD) simulations, we probe the ion occupancy at the S1 binding site in the constricted state of the selectivity filter of the KcsA channel when the intracellular gate is open and closed. The 2D IR spectra resolve two features, whose relative intensities depend on the state of the intracellular gate.

Instantaneous ion configurations in the K+ ion channel selectivity filter revealed by 2D IR spectroscopy.

Potassium channels are responsible for the selective permeation of K ions across cell membranes. K ions permeate in single file through the selectivity filter, a narrow pore lined by backbone carbonyls that compose four K binding sites. Here, we report on the two-dimensional infrared (2D IR) spectra of a semisynthetic KcsA channel with site-specific heavy (CO) isotope labels in the selectivity filter.

Quantitative analysis of the water occupancy around the selectivity filter of a K+ channel in different gating modes.

Recovery in K(+) channels, that is, the transition from the inactivated nonconductive selectivity filter conformation toward the conductive conformation, occurs on a time scale of the order of seconds, which is astonishingly long, given that the structural differences among the filter conformations are faint (<1 Å). Computational studies and electrophysiological measurements suggested that buried water molecules bound behind the selectivity filter are at the origin of the slowness of recovery in K(+) channels. Using a combination of solid-state NMR spectroscopy (ssNMR) and long molecular dynamics simulations, we sketch a high-resolution map of the spatial and temporal distribution of water behind the selectivity filter of a membrane-embedded K(+) channel in two different gating modes.

Recovery from slow inactivation in K+ channels is controlled by water molecules.

Application of a specific stimulus opens the intracellular gate of a K(+) channel (activation), yielding a transient period of ion conduction until the selectivity filter spontaneously undergoes a conformational change towards a non-conductive state (inactivation). Removal of the stimulus closes the gate and allows the selectivity filter to interconvert back to its conductive conformation (recovery). Given that the structural differences between the conductive and inactivated filter are very small, it is unclear why the recovery process can take up to several seconds.

Heuristically optimal path scanning for high-speed multiphoton circuit imaging.

Population dynamics of patterned neuronal firing are fundamental to information processing in the brain. Multiphoton microscopy in combination with calcium indicator dyes allows circuit dynamics to be imaged with single-neuron resolution. However, the temporal resolution of fluorescent measures is constrained by the imaging frequency imposed by standard raster scanning techniques.