Collaborating Authors

Constraint-Based Reasoning

The nucleus acts as a ruler tailoring cell responses to spatial constraints


Single cells continuously experience and react to mechanical challenges in three-dimensional tissues. Spatial constraints in dense tissues, physical activity, and injury all impose changes in cell shape. How cells can measure shape deformations to ensure correct tissue development and homeostasis remains largely unknown (see the Perspective by Shen and Niethammer). Working independently, Venturini et al. and Lomakin et al. now show that the nucleus can act as an intracellular ruler to measure cellular shape variations. The nuclear envelope provides a gauge of cell deformation and activates a mechanotransduction pathway that controls actomyosin contractility and migration plasticity. The cell nucleus thereby allows cells to adapt their behavior to the local tissue microenvironment. Science , this issue p. [eaba2644][1], p. [eaba2894][2]; see also p. [295][3] ### INTRODUCTION The human body is a crowded place. This crowding is even more acute when the regulation of cell growth and proliferation fails during the formation of a tumor. Dealing with the lack of space in crowded environments presents cells with a challenge. This is especially true for immune cells, whose task is to patrol tissues, causing them to experience both acute and sustained deformation as they move. Although changes in tissue crowding and associated cell shape alterations have been known by pathologists to be key diagnostic traits of late-stage tumors since the 19th century, the impact of these changes on the biology of cancer and immune cells remains unclear. Moreover, it is not known whether cells can detect and adaptively respond to deformations in densely packed spaces. ### RATIONALE To test the hypothesis that cells possess an ability to detect and respond to environmentally induced changes in their shape, we fabricated artificial microenvironments that mimic the conditions experienced by tumor and immune cells in a crowded tissue. By combining dynamic confinement, force measurements, and live cell imaging, we were able to quantify cell responses to precisely controlled physical perturbations of their shape. ### RESULTS Our results show that, although cells are surprisingly resistant to compressive forces, they monitor their own shape and develop an active contractile response when deformed below a specific height. Notably, we find that this is achieved by cells monitoring the deformation of their largest internal compartment: the nucleus. We establish that the nucleus provides cells with a precise measure of the extent of their deformation. Once cell compression exceeds the size of the nucleus, it causes the bounding nuclear envelope (NE) to unfold and stretch. The onset of the contractile response occurs when the NE reaches a fully unfolded state. This transition in the mechanical state of the NE and its membranes permits calcium release from internal membrane stores and activates the calcium-dependent phospholipase cPLA2, an enzyme known to operate as a molecular sensor of nuclear membrane tension and a critical regulator of signaling and metabolism. Activated cPLA2 catalyzes the formation of arachidonic acid, an omega-6 fatty acid that, among other processes, potentiates the adenosine triphosphatase activity of myosin II. This induces contractility of the actomyosin cortex, which produces pushing forces to resist physical compression and to rapidly squeeze the cell out of its compressive microenvironment in an “evasion reflex” mechanism. ### CONCLUSION Although the nucleus has traditionally been considered a passive storehouse for genetic material, our work identifies it as an active compartment that rapidly convers mechanical inputs into signaling outputs, with a critical role of its envelope in this sensing function. The nucleus is able to detect environmentally imposed compression and respond to it by generating a signal that is used to change cell behaviors. This phenomenon plays a critical role in ensuring that cells, such as the immune cells within a tumor, can adapt, survive, and efficiently move through a crowded and mechanically heterogeneous microenvironment. Characterizing the full spectrum of signals triggered by nuclear compression has the potential to elucidate mechanisms underlying signaling, epigenetic, and metabolic adaptations of cells to their mechanoenvironment and is thus an exciting avenue for future research. ![Figure][4] The nuclear ruler and its contribution to the “life cycle” of a confined cell. (1) Cell confinement below resting nucleus size, leading to nuclear deformation and to unfolding, and stretching of the nuclear envelope. (2) Nuclear membrane tension increase, which triggers calcium release, cPLA2 activation, and arachidonic acid (ARA) production. (3) Actomyosin force ( F ) generation. (4) Increased cell migratory capacity and escape from confinement. The microscopic environment inside a metazoan organism is highly crowded. Whether individual cells can tailor their behavior to the limited space remains unclear. In this study, we found that cells measure the degree of spatial confinement by using their largest and stiffest organelle, the nucleus. Cell confinement below a resting nucleus size deforms the nucleus, which expands and stretches its envelope. This activates signaling to the actomyosin cortex via nuclear envelope stretch-sensitive proteins, up-regulating cell contractility. We established that the tailored contractile response constitutes a nuclear ruler–based signaling pathway involved in migratory cell behaviors. Cells rely on the nuclear ruler to modulate the motive force that enables their passage through restrictive pores in complex three-dimensional environments, a process relevant to cancer cell invasion, immune responses, and embryonic development. [1]: /lookup/doi/10.1126/science.aba2644 [2]: /lookup/doi/10.1126/science.aba2894 [3]: /lookup/doi/10.1126/science.abe3881 [4]: pending:yes

A New Basis for Spreadsheet Computing: Interval Solver for Microsoft Excel

AI Magazine

There is a fundamental mismatch between the computational basis of spreadsheets and our knowledge of the real world. In spreadsheets, numeric data are represented as exact numbers and their mutual relations as functions, whose values (output) are computed from given argument values (input). However, in the real world, data are often inexact and uncertain in many ways, and the relationships, that is, constraints, between input and output are far more complicated. This article shows that interval constraint solving, an emerging AI-based technology, provides a more versatile and useful foundation for spreadsheets. The new computational basis is 100-percent downward compatible with the traditional spreadsheet paradigm.

Optimizing Limousine Service with AI

AI Magazine

A common problem for companies with strong business growth is that it is hard to find enough experienced staff to support expansion needs. This problem is particular pronounced for operations planners and controllers who must be very highly knowledgeable and experienced with the business domain. This article is a case study of how one of the largest travel agencies in Hong Kong alleviated this problem by using AI to support decision-making and problem-solving so that their planners and controllers can work more effectively and efficiently to sustain business growth while maintaining consistent quality of service. AI is used in a mission critical fleet management system (FMS) that supports the scheduling and management of a fleet of luxury limousines for business travelers. The AI problem was modeled as a constraint satisfaction problem (CSP).

Using Global Constraints to Automate Regression Testing

AI Magazine

Nowadays, any communicating or autonomous systems rely on high-quality software-based components. To ensure a sufficient level of quality, these components must be thoroughly verified before being released and being deployed in operational settings. Regression testing is a crucial verification process that executes any new release of a software-based component against previous versions of the component, with existing test cases. However, the selection of test cases in regression testing is challenging as the time available for testing is limited and some selection criteria must be respected. This problem, coined as Test Suite Reduction (TSR), is usually addressed by validation engineers through manual analysis or by using approximation techniques.

Intel inks agreement with Sandia National Laboratories to explore neuromorphic computing


As a part of the U.S. Department of Energy's Advanced Scientific Computing Research program, Intel today inked a three-year agreement with Sandia National Laboratories to explore the value of neuromorphic computing for scaled-up AI problems. Sandia will kick off its work using a 50-million-neuron Loihi-based system recently delivered to its facility in Albuquerque, New Mexico. As the collaboration progresses, Intel says the labs will receive systems built on the company's next-generation neuromorphic architecture. Along with Intel, researchers at IBM, HP, MIT, Purdue, and Stanford hope to leverage neuromorphic computing -- circuits that mimic the nervous system's biology -- to develop supercomputers 1,000 times more powerful than any today. Chips like Loihi excel at constraint satisfaction problems, which require evaluating a large number of potential solutions to identify the one or few that satisfy specific constraints.

The Scheduling Job-Set Optimization Problem: A Model-Based Diagnosis Approach Artificial Intelligence

A common issue for companies is that the volume of product orders may at times exceed the production capacity. We formally introduce two novel problems dealing with the question which orders to discard or postpone in order to meet certain (timeliness) goals, and try to approach them by means of model-based diagnosis. In thorough analyses, we identify many similarities of the introduced problems to diagnosis problems, but also reveal crucial idiosyncracies and outline ways to handle or leverage them. Finally, a proof-of-concept evaluation on industrial-scale problem instances from a well-known scheduling benchmark suite demonstrates that one of the two formalized problems can be well attacked by out-of-the-box model-based diagnosis tools.

Efficient Incremental Modelling and Solving Artificial Intelligence

In various scenarios, a single phase of modelling and solving is either not sufficient or not feasible to solve the problem at hand. A standard approach to solving AI planning problems, for example, is to incrementally extend the planning horizon and solve the problem of trying to find a plan of a particular length. Indeed, any optimization problem can be solved as a sequence of decision problems in which the objective value is incrementally updated. Another example is constraint dominance programming (CDP), in which search is organized into a sequence of levels. The contribution of this work is to enable a native interaction between SAT solvers and the automated modelling system Savile Row to support efficient incremental modelling and solving. This allows adding new decision variables, posting new constraints and removing existing constraints (via assumptions) between incremental steps. Two additional benefits of the native coupling of modelling and solving are the ability to retain learned information between SAT solver calls and to enable SAT assumptions, further improving flexibility and efficiency. Experiments on one optimisation problem and five pattern mining tasks demonstrate that the native interaction between the modelling system and SAT solver consistently improves performance significantly.

A Constraint Programming-based Job Dispatcher for Modern HPC Systems and Applications Artificial Intelligence

Constraint Programming (CP) is a well-established area in AI as a programming paradigm for modelling and solving discrete optimization problems, and it has been been successfully applied to tackle the on-line job dispatching problem in HPC systems including those running modern applications. The limitations of the available CP-based job dispatchers may hinder their practical use in today's systems that are becoming larger in size and more demanding in resource allocation. In an attempt to bring basic AI research closer to a deployed application, we present a new CP-based on-line job dispatcher for modern HPC systems and applications. Unlike its predecessors, our new dispatcher tackles the entire problem in CP and its model size is independent of the system size. Experimental results based on a simulation study show that with our approach dispatching performance increases significantly in a large system and in a system where allocation is nontrivial.

Solving Sudoku With AI or Quantum?


"History is called the mother of all subjects", said Marc Bloch. So, let's talk about how the famous Sudoku even came into existence. The story dates back to the late 19th Century and it originated from France. Le Siecle, a French daily published a 9x9 puzzle that required arithmetic calculations to solve rather than logic and had double-digit numbers instead of 1-to-9 with similar game properties like Sudoku where the digits across rows, columns, and diagonals if added, will result in the same number. In 1979 a retired architect and puzzler named Howard Garns is believed to be the creator behind the modern Sudoku which was first published by Dell Magazines in the name of Number Place.