Should Artificial Intelligence Play a Durable Role in Biomedical Research and Practice?

During the last decade, artificial intelligence (AI) was applied to nearly all domains of human activity, including scientific research. It is thus warranted to ask whether AI thinking should be durably involved in biomedical research. This problem was addressed by examining three complementary questions (i) What are the major barriers currently met by biomedical investigators? It is suggested that during the last 2 decades there was a shift towards a growing need to elucidate complex systems, and that this was not sufficiently fulfilled by previously successful methods such as theoretical modeling or computer simulation (ii) What is the potential of AI to meet the aforementioned need? it is suggested that recent AI methods are well-suited to perform classification and prediction tasks on multivariate systems, and possibly help in data interpretation, provided their efficiency is properly validated.

Comparison of the Capacity of Several Machine Learning Tools to Assist Immunofluorescence-Based Detection of Anti-Neutrophil Cytoplasmic Antibodies.

The success of artificial intelligence and machine learning is an incentive to develop new algorithms to increase the rapidity and reliability of medical diagnosis. Here we compared different strategies aimed at processing microscope images used to detect anti-neutrophil cytoplasmic antibodies, an important vasculitis marker: (i) basic classifier methods (logistic regression, k-nearest neighbors and decision tree) were used to process custom-made indices derived from immunofluorescence images yielded by 137 sera. (ii) These methods were combined with dimensional reduction to analyze 1733 individual cell images.

Understanding How Cells Probe the World: A Preliminary Step towards Modeling Cell Behavior?

Cell biologists have long aimed at quantitatively modeling cell function. Recently, the outstanding progress of high-throughput measurement methods and data processing tools has made this a realistic goal. The aim of this paper is twofold: First, to suggest that, while much progress has been done in modeling cell states and transitions, current accounts of environmental cues driving these transitions remain insufficient.

Is There a Need for a More Precise Description of Biomolecule Interactions to Understand Cell Function?

An important goal of biological research is to explain and hopefully predict cell behavior from the molecular properties of cellular components. Accordingly, much work was done to build extensive "omic" datasets and develop theoretical methods, including computer simulation and network analysis to process as quantitatively as possible the parameters contained in these resources. Furthermore, substantial effort was made to standardize data presentation and make experimental results accessible to data scientists.

Mechanotransduction as a major driver of cell behaviour: mechanisms, and relevance to cell organization and future research.

How do cells process environmental cues to make decisions? This simple question is still generating much experimental and theoretical work, at the border of physics, chemistry and biology, with strong implications in medicine. The purpose of mechanobiology is to understand how biochemical and physical cues are turned into signals through mechanotransduction. Here, we review recent evidence showing that (i) mechanotransduction plays a major role in triggering signalling cascades following cell-neighbourhood interaction; (ii) the cell capacity to continually generate forces, and biomolecule properties to undergo conformational changes in response to piconewton forces, provide a molecular basis for understanding mechanotransduction; and (iii) mechanotransduction shapes the guidance cues retrieved by living cells and the information flow they generate.

CD8 Co-Receptor Enhances T-Cell Activation without Any Effect on Initial Attachment.

The scanning of surrounding tissues by T lymphocytes to detect cognate antigens requires high speed, sensitivity and specificity. T-cell receptor (TCR) co-receptors such as CD8 increase detection performance, but the exact mechanism remains incompletely understood. Here, we used a laminar flow chamber to measure at the single molecule level the kinetics of bond formation and rupture between TCR- transfected CD8+ and CD8- Jurkat cells and surfaces coated with five peptide-exposing major histocompatibility antigens (pMHCs) of varying activating power.

TCR-pMHC kinetics under force in a cell-free system show no intrinsic catch bond, but a minimal encounter duration before binding.

The T cell receptor (TCR)-peptide-MHC (pMHC) interaction is the only antigen-specific interaction during T lymphocyte activation. Recent work suggests that formation of catch bonds is characteristic of activating TCR-pMHC interactions. However, whether this binding behavior is an intrinsic feature of the molecular bond, or a consequence of more complex multimolecular or cellular responses, remains unclear.

A Rough Energy Landscape to Describe Surface-Linked Antibody and Antigen Bond Formation.

Antibodies and B cell receptors often bind their antigen at cell-cell interface while both molecular species are surface-bound, which impacts bond kinetics and function. Despite the description of complex energy landscapes for dissociation kinetics which may also result in significantly different association kinetics, surface-bound molecule (2D) association kinetics usually remain described by an on-rate due to crossing of a single free energy barrier, and few experimental works have measured association kinetics under conditions implying force and two-dimensional relative ligand-receptor motion. We use a new laminar flow chamber to measure 2D bond formation with systematic variation of the distribution of encounter durations between antigen and antibody, in a range from 0.

The leukocyte-stiffening property of plasma in early acute respiratory distress syndrome (ARDS) revealed by a microfluidic single-cell study: the role of cytokines and protection with antibodies.

Background: Leukocyte-mediated pulmonary inflammation is a key pathophysiological mechanism involved in acute respiratory distress syndrome (ARDS). Massive sequestration of leukocytes in the pulmonary microvasculature is a major triggering event of the syndrome. We therefore investigated the potential role of leukocyte stiffness and adhesiveness in the sequestration of leukocytes in microvessels.

ICARE improves antinuclear antibody detection by overcoming the barriers preventing accreditation.

Background: Antinuclear antibodies (ANA) are useful biomarkers for the diagnosis and the monitoring of rheumatic diseases. The American College of Rheumatology has stated that indirect immunofluorescence (IIF) analysis remains the gold standard for ANA screening. However, IIF is time consuming, subjective, not fully standardized and presents several issues for accreditation which is the process leading to ISO 15189 certification for medical laboratories.

Synchronizing atomic force microscopy force mode and fluorescence microscopy in real time for immune cell stimulation and activation studies.

A method is presented for combining atomic force microscopy (AFM) force mode and fluorescence microscopy in order to (a) mechanically stimulate immune cells while recording the subsequent activation under the form of calcium pulses, and (b) observe the mechanical response of a cell upon photoactivation of a small G protein, namely Rac. Using commercial set-ups and a robust signal coupling the fluorescence excitation light and the cantilever bending, the applied force and activation signals were very easily synchronized. This approach allows to control the entire mechanical history of a single cell up to its activation and response down to a few hundreds of milliseconds, and can be extended with very minimal adaptations to other cellular systems where mechanotransduction is studied, using either purely mechanical stimuli or via a surface bound specific ligand.

Leishmania infection modulates beta-1 integrin activation and alters the kinetics of monocyte spreading over fibronectin.

Contact with Leishmania leads to a decreases in mononuclear phagocyte adherence to connective tissue. In this work, we studied the early stages of bond formation between VLA4 and fibronectin, measured the kinetics of membrane alignment and the monocyte cytoplasm spreading area over a fibronectin-coated surface, and studied the expression of high affinity integrin epitope in uninfected and Leishmania-infected human monocytes. Our results show that the initial VLA4-mediated interaction of Leishmania-infected monocyte with a fibronectin-coated surface is preserved, however, the later stage, leukocyte spreading over the substrate is abrogated in Leishmania-infected cells.

Genotype combinations of two IL4 polymorphisms influencing IL-4 plasma levels are associated with different risks of severe malaria in the Malian population.

We have previously found that children heterozygous for IL4 variable-number tandem repeat (VNTR) (rs8179190) or IL4-33 (rs2070874) variants were at risk for severe malaria (SM), whereas homozygous children were protected suggesting a complex genetic control. Hence, to dissect this complex genetic control of IL4 VNTR and IL4-33, we performed further investigation by conditional logistic regression analysis and found a strong interaction between both markers (p < 10(-6)). The best-fit model revealed three genotype combinations associated with different levels of SM risk.

Early T cell activation: integrating biochemical, structural, and biophysical cues.

T cells carry out the formidable task of identifying small numbers of foreign antigenic peptides rapidly and specifically against a very noisy environmental background of endogenous self-peptides. Early steps in T cell activation have thus fascinated biologists and are among the best-studied models of cell stimulation. This remarkable process, critical in adaptive immune responses, approaches and even seems to exceed the limitations set by the physical laws ruling molecular behavior.

Use of TIRF to Monitor T-Lymphocyte Membrane Dynamics with Submicrometer and Subsecond Resolution.

A key step of adaptive immune responses is the T lymphocyte capacity to detect the presence of foreign antigens on specialized cells with high speed and specificity during contacts lasting a few minutes. Much evidence suggests that there is a deep link between the lifetime of molecular interactions between T cell receptors and ligands and T cell activation, but the precise mechanisms of bond formation and dissociation remain incompletely understood. Previous experiments done with interference reflection microscopy/reflection interference contrast microscopy disclosed transverse motions with several nanometer average amplitude of micrometer size membrane zones.

T lymphocytes need less than 3 min to discriminate between peptide MHCs with similar TCR-binding parameters.

T lymphocytes need to detect rare cognate foreign peptides among numerous foreign and self-peptides. This discrimination seems to be based on the kinetics of TCRs binding to their peptide-MHC (pMHC) ligands, but there is little direct information on the minimum time required for processing elementary signaling events and deciding to initiate activation. Here, we used interference reflection microscopy to study the early interaction between transfected human Jurkat T cells expressing the 1G4 TCR and surfaces coated with five different pMHC ligands of 1G4.

Ara h 2 and Ara h 6 sensitization predicts peanut allergy in Mediterranean pediatric patients.

Background: Peanut allergy (PA) management was improved by the introduction of molecular allergology, but guidelines for Mediterranean patients are lacking. We aimed at evaluating peanut component-resolved diagnosis as a diagnostic and prognostic tool in children from Southern France.

Methods: In 181 pediatric patients, PA diagnosis was founded on medical history, skin prick testing, serum-specific IgE to Arachis hypogea extract and components, Pru p 4, and plant carbohydrates, and oral food challenge.

Contribution of anti-β2glycoprotein I IgA antibodies to the diagnosis of anti-phospholipid syndrome: potential interest of target domains to discriminate thrombotic and non-thrombotic patients.

Objectives: Although the last international guidelines for aPL recommended determination of IgA aCL and anti-β2glycoprotein I (aβ2GPI) antibodies for the evaluation of APS in the absence of conventional IgG or IgM aCL and aβ2GPI antibodies, the clinical value of these antibodies remains controversial. We evaluated the clinical utility of IgA aPL and of the determination of target domains of aβ2GPI IgA antibodies.

Methods: A retrospective analysis was performed on sera from 439 patients referred for routine detection of aPL IgA by in-house ELISA.

Original approach for automated quantification of antinuclear autoantibodies by indirect immunofluorescence.

Introduction: Indirect immunofluorescence (IIF) is the gold standard method for the detection of antinuclear antibodies (ANA) which are essential markers for the diagnosis of systemic autoimmune rheumatic diseases. For the discrimination of positive and negative samples, we propose here an original approach named Immunofluorescence for Computed Antinuclear antibody Rational Evaluation (ICARE) based on the calculation of a fluorescence index (FI).

Methods: We made comparison between FI and visual evaluations on 237 consecutive samples and on a cohort of 25 patients with SLE.

T lymphocytes sense antigens within seconds and make a decision within one minute.

Adaptive immune responses are triggered by the rapid and sensitive detection of MHC-bound peptides by TCRs. The kinetics of early TCR/APC contacts are incompletely known. In this study, we used total internal reflection fluorescence microscopy to image human T cell membranes near model surfaces: contact was mediated by mobile protrusions of <0.

Mechanics of the Toxoplasma gondii oocyst wall.

The ability of microorganisms to survive under extreme conditions is closely related to the physicochemical properties of their wall. In the ubiquitous protozoan parasite Toxoplasma gondii, the oocyst stage possesses a bilayered wall that protects the dormant but potentially infective parasites from harsh environmental conditions until their ingestion by the host. None of the common disinfectants are effective in killing the parasite because the oocyst wall acts as a primary barrier to physical and chemical attacks.

Biophysical description of multiple events contributing blood leukocyte arrest on endothelium.

Blood leukocytes have a remarkable capacity to bind to and stop on specific blood vessel areas. Many studies have disclosed a key role of integrin structural changes following the interaction of rolling leukocytes with surface-bound chemoattractants. However, the functional significance of structural data and mechanisms of cell arrest are incompletely understood.

Immunoglobulin G anticardiolipin antibodies and progression to Q fever endocarditis.

Background: Immunoglobulin G (IgG) anticardiolipin (aCL) antibodies are associated with valvulopathy and endocarditis in patients with lupus and other diseases. During acute Q fever, high IgG aCL prevalence has been reported, but the clinical significance remains unknown.

Methods: To test if increased IgG aCL at acute Q fever diagnosis is associated with an increased risk of progression to endocarditis, all patients diagnosed in the French National Referral Center for Q fever from January 2007 to December 2011 were included and followed regularly until January 2013 in a 5-year prospective cohort study.