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Single-cell responses are shaped by the geometry of signalling kinetic trajectories carved in a multidimensional space spanned by signalling protein abundances. It is, however, challenging to assay a large number (more than 3) of signalling species in live-cell imaging, which makes it difficult to probe single-cell signalling kinetic trajectories in large dimensions. Flow and mass cytometry techniques can measure a large number (4 to more than 40) of signalling species but are unable to track single cells. Thus, cytometry experiments provide detailed time-stamped snapshots of single-cell signalling kinetics. Is it possible to use the time-stamped cytometry data to reconstruct single-cell signalling trajectories? Borrowing concepts of conserved and slow variables from non-equilibrium statistical physics we develop an approach to reconstruct signalling trajectories using snapshot data by creating new variables that remain invariant or vary slowly during the signalling kinetics. We apply this approach to reconstruct trajectories using snapshot data obtained from in silico simulations, live-cell imaging measurements, and, synthetic flow cytometry datasets. The application of invariants and slow variables to reconstruct trajectories provides a radically different way to track objects using snapshot data. The approach is likely to have implications for solving matching problems in a wide range of disciplines.

Natural killer (NK) cells perform immunosurveillance of virally infected and transformed cells, and their activation depends on the balance between signaling by inhibitory and activating receptors. Cytokine receptor signaling can synergize with activating receptor signaling to induce NK cell activation. We investigated the interplay between the signaling pathways stimulated by the cytokine interleukin-2 (IL-2) and the activating receptor NKG2D in immature (CD56bright) and mature (CD56dim) subsets of human primary NK cells using mass cytometry experiments and in silico modeling. Our analysis revealed that IL-2 changed the abundances of several key proteins, including NKG2D and the phosphatase CD45. Furthermore, we found differences in correlations between protein abundances, which were associated with the maturation state of the NK cells. The mass cytometry measurements also revealed that the signaling kinetics of key protein abundances induced by NKG2D stimulation depended on the maturation state and the pretreatment condition of the NK cells. Our in silico model, which described the multidimensional data with coupled first-order reactions, predicted that the increase in CD45 abundance was a major enhancer of NKG2D-mediated activation in IL-2-treated CD56bright NK cells but not in IL-2-treated CD56dim NK cells. This dependence on CD45 was verified by measurement of CD107a mobilization to the NK cell surface (a marker of activation). Our mathematical framework can be used to glean mechanisms underlying synergistic signaling pathways in other activated immune cells.

The article focuses on the implications of artificial intelligence, specifically ChatGPT, in graduate medical education applications, including its potential impact on personal statements, letters of recommendation, and program evaluations.

Understanding the movement patterns of an invasive species can be a powerful tool in designing effective management and control strategies. Here, we used a Bayesian multistate model to investigate the movement of two invasive carp species, silver carp (Hypophthalmichthys molitrix) and bighead carp (H. nobilis), using acoustic telemetry. The invaded portions of the Illinois and Des Plaines Rivers, USA, are a high priority management zone in the broader efforts to combat the spread of invasive carps from reaching the Laurentian Great Lakes. Our main objective was to characterize the rates of upstream and downstream movements by carps between river pools that are maintained by navigation lock and dam structures. However, we also aimed to evaluate the efficacy of the available telemetry infrastructure to monitor carp movements through this system. We found that, on a monthly basis, most individuals of both species remained within their current river pools: averaging 76.2% of silver carp and 75.5% of bighead carp. Conversely, a smaller proportion of silver carp, averaging 14.2%, and bighead carp, averaging 13.9%, moved to downstream river pools. Movements towards upstream pools were the least likely for both species, with silver carp at an average of 6.7% and bighead carp at 7.9%. The highest probabilities for upstream movements were for fish originating from the three most downstream river pools, where most of the population recruitment occurs. However, our evaluation of the telemetry array's effectiveness indicated low probability to detect fish in this portion of the river. We provide insights to enhance the placement and use of these monitoring tools, aiming to deepen our comprehension of these species' movement patterns in the system. [ABSTRACT FROM AUTHOR]

Evidence from phase three clinical trials helps shape clinical practice. However, a very small minority of patients with cancer participate in clinical trials and many trials are not completed on time due to slow accrual. Issues with restrictive eligibility criteria can severely limit the patients who can access trials, without any convincing evidence that these restrictions impact patient safety. Similarly, regulatory, organizational, and institutional hurdles can delay trial activation, ultimately making some studies irrelevant. Additional issues during trial conduct (e.g., mandatory in-person visits, central confirmation of standard biomarkers, and inflexible drug dosage modification) contribute to making trials non-patient-centric. These real-life observations from experienced clinical trialists can seem nonsensical to investigators and patients alike, who are trying to bring effective drugs to patients with cancer. In this review, we delve into these issues in detail, and discuss potential solutions to make clinical trials more accessible to patients. [ABSTRACT FROM AUTHOR]