Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells

The success of adoptive T-cell therapies for the treatment of cancer patients depends on transferred T-lymphocytes finding and infiltrating cancerous tissues. For intravenously transferred T-cells, this means leaving the bloodstream (extravasation) from tumour blood vessels. In inflamed tissues, a key event in extravasation is the capture, rolling and arrest of T-cells inside blood vessels which precedes transmigration across the vessel wall and entry into tissues. This depends on co-ordinated signalling of selectins, integrins and chemokine receptors on T-cells by their respective ligands which are up-regulated on inflamed blood vessels. Clinical data and experimental studies in mice suggest that tumour blood vessels are anergic to inflammatory stimuli and the recruitment of cytotoxic CD8(+) T-lymphocytes is not very efficient. Interestingly, and somewhat counter-intuitively, anti-angiogenic therapy can promote CD8(+) T-cell infiltration of tumours and increase the efficacy of adoptive CD8(+) T-cell therapy. Rather than inhibit tumour angiogenesis, anti-angiogenic therapy ‘normalizes’ (matures) tumour blood vessels by promoting pericyte recruitment, increasing tumour blood vessel perfusion and sensitizing tumour blood vessels to inflammatory stimuli. A number of different approaches are currently being explored to increase recruitment by manipulating the expression of homing-associated molecules on T-cells and tumour blood vessels. Future studies should address whether these approaches improve the efficacy of adoptive T-cell therapies for solid, vascularized cancers in patients

The bird species diversity in the wintering season is negatively associated with precipitation, tree species diversity and stand density in the Sierra Madre Occidental, Durango, Mexico

Bird migration constitutes a redistribution of bird diversity that radically changes the composition of the bird community worldwide. It comprises about 19% of the world’s bird species. Several studies have indicated that changes in avian community structure and differences in bird richness in different seasons are mainly driven by seasonality and by winter harshness, and that the associated costs increase with the distance involved. Western Mexico is an important wintering area for most passerines that breed in western North America, and that travel long on the long-distance Central and Pacific migration routes. In this study, we examined bird species richness and diversity during the breeding and wintering seasons in the Central Sierra Madre Occidental (SMO), North Durango (Mexico) in relation to i) tree species diversity, ii) tree dimension, iii) forest stand density and site quality, iv) density and dimension of snag trees, and v) various climate variables. The overall aim of the study was to determine how the observed associations between bird species diversity and variables i-v are affected by the season considered (breeding or wintering). The diversity of bird species in the breeding season was not affected by any of the climate and forest stand variables considered. In contrast, bird species diversity in the wintering season was significantly and weakly to moderately associated with climate variables, tree species diversity and stand density, although not with density or dimension of snag trees. Bird species diversity was higher at lower elevations and in drier and warmer locations of the SMO. The association detected is therefore mainly a local migratory phenomenon. | Supporting Information Supporting Information </supplementary-material

Random subwindows and extremely randomized trees for image classification in cell biology

Background: With the improvements in biosensors and high-throughput image acquisition technologies, life science laboratories are able to perform an increasing number of experiments that involve the generation of a large amount of images at different imaging modalities/scales. It stresses the need for computer vision methods that automate image classification tasks. Results: We illustrate the potential of our image classification method in cell biology by evaluating it on four datasets of images related to protein distributions or subcellular localizations, and red-blood cell shapes. Accuracy results are quite good without any specific pre-processing neither domain knowledge incorporation. The method is implemented in Java and available upon request for evaluation and research purpose. Conclusion: Our method is directly applicable to any image classification problems. We foresee the use of this automatic approach as a baseline method and first try on various biological image classification problems

HistoWeb - Etudier l'histologie dans une nouvelle écologie d'apprentissage

HistoWeb targets the transformation of the professional tool Cytomineinto a comprehensive and innovative teaching platform, valuing the notions of learning ecology and new learning dimensions seeking for lifelong competencies. The poster was released at the Digital Learning round table, organized by the European Commission around H2020 funding instruments and call 2 "ICT-20 Technologies for better human learning"Appel Germaine Tillio

ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells

L-selectin on T-cells is best known as an adhesion molecule that supports recruitment of blood-borne naïve and central memory cells into lymph nodes. Proteolytic shedding of the ectodomain is thought to redirect activated T-cells from lymph nodes to sites of infection. However, we have shown that activated T-cells re-express L-selectin before lymph node egress and use L-selectin to locate to virus-infected tissues. Therefore, we considered other roles for L-selectin proteolysis during T cell activation. In this study, we used T cells expressing cleavable or non-cleavable L-selectin and determined the impact of L-selectin proteolysis on T cell activation in virus-infected mice. We confirm an essential and non-redundant role for ADAM17 in TCR-induced proteolysis of L-selectin in mouse and human T cells and show that L-selectin cleavage does not regulate T cell activation measured by CD69 or TCR internalisation. Following virus infection of mice, L-selectin proteolysis promoted early clonal expansion of cytotoxic T cells resulting in an 8-fold increase over T cells unable to cleave L-selectin. T cells unable to cleave L-selectin showed delayed proliferation in vitro which correlated with lower CD25 expression. Based on these results, we propose that ADAM17-dependent proteolysis of L-selectin should be considered a regulator of T-cell activation at sites of immune activity

Scenario trees and policy selection for multistage stochastic programming using machine learning

We propose a hybrid algorithmic strategy for complex stochastic optimization problems, which combines the use of scenario trees from multistage stochastic programming with machine learning techniques for learning a policy in the form of a statistical model, in the context of constrained vector-valued decisions. Such a policy allows one to run out-of-sample simulations over a large number of independent scenarios, and obtain a signal on the quality of the approximation scheme used to solve the multistage stochastic program. We propose to apply this fast simulation technique to choose the best tree from a set of scenario trees. A solution scheme is introduced, where several scenario trees with random branching structure are solved in parallel, and where the tree from which the best policy for the true problem could be learned is ultimately retained. Numerical tests show that excellent trade-offs can be achieved between run times and solution quality

Photoabsorption and photoion spectroscopy of atomic uranium in the region of 6p and 5d excitations

The photoabsorption process in atomic uranium has been investigated experimentally and theoretically in the 15–150-eV region. Using the dual laser plasma technique, the 6p photoabsorption spectrum has been recorded while for the first time the 5d region has been remeasured photoelectrically using both photoabsorption and photoion spectroscopy. Interpretation of the photoabsorption spectra is supported by Hartree-Fock calculations which take into account spin-flip decay and the interaction of many discrete states with many continua. The 6p spectrum is entirely dominated by spin-orbit split 6p⃗6d transitions. The 5d-subshell photoabsorption is shown to consist predominantly of discrete 5d⃗5f excitations; here the electrostatic and spin-orbit interactions are comparable in strength

Novel Role of Phosphorylation-Dependent Interaction between FtsZ and FipA in Mycobacterial Cell Division

The bacterial divisome is a multiprotein complex. Specific protein-protein interactions specify whether cell division occurs optimally, or whether division is arrested. Little is known about these protein-protein interactions and their regulation in mycobacteria. We have investigated the interrelationship between the products of the Mycobacterium tuberculosis gene cluster Rv0014c-Rv0019c, namely PknA (encoded by Rv0014c) and FtsZ-interacting protein A, FipA (encoded by Rv0019c) and the products of the division cell wall (dcw) cluster, namely FtsZ and FtsQ. M. smegmatis strains depleted in components of the two gene clusters have been complemented with orthologs of the respective genes of M. tuberculosis. Here we identify FipA as an interacting partner of FtsZ and FtsQ and establish that PknA-dependent phosphorylation of FipA on T77 and FtsZ on T343 is required for cell division under oxidative stress. A fipA knockout strain of M. smegmatis is less capable of withstanding oxidative stress than the wild type and showed elongation of cells due to a defect in septum formation. Localization of FtsQ, FtsZ and FipA at mid-cell was also compromised. Growth and survival defects under oxidative stress could be functionally complemented by fipA of M. tuberculosis but not its T77A mutant. Merodiploid strains of M. smegmatis expressing the FtsZ(T343A) showed inhibition of FtsZ-FipA interaction and Z ring formation under oxidative stress. Knockdown of FipA led to elongation of M. tuberculosis cells grown in macrophages and reduced intramacrophage growth. These data reveal a novel role of phosphorylation-dependent protein-protein interactions involving FipA, in the sustenance of mycobacterial cell division under oxidative stress

Proteins with Complex Architecture as Potential Targets for Drug Design: A Case Study of Mycobacterium tuberculosis

Lengthy co-evolution of Homo sapiens and Mycobacterium tuberculosis, the main causative agent of tuberculosis, resulted in a dramatically successful pathogen species that presents considerable challenge for modern medicine. The continuous and ever increasing appearance of multi-drug resistant mycobacteria necessitates the identification of novel drug targets and drugs with new mechanisms of action. However, further insights are needed to establish automated protocols for target selection based on the available complete genome sequences. In the present study, we perform complete proteome level comparisons between M. tuberculosis, mycobacteria, other prokaryotes and available eukaryotes based on protein domains, local sequence similarities and protein disorder. We show that the enrichment of certain domains in the genome can indicate an important function specific to M. tuberculosis. We identified two families, termed pkn and PE/PPE that stand out in this respect. The common property of these two protein families is a complex domain organization that combines species-specific regions, commonly occurring domains and disordered segments. Besides highlighting promising novel drug target candidates in M. tuberculosis, the presented analysis can also be viewed as a general protocol to identify proteins involved in species-specific functions in a given organism. We conclude that target selection protocols should be extended to include proteins with complex domain architectures instead of focusing on sequentially unique and essential proteins only

Portrait of a Pathogen: The Mycobacterium tuberculosis Proteome In Vivo

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a facultative intracellular pathogen that can persist within the host. The bacteria are thought to be in a state of reduced replication and metabolism as part of the chronic lung infection. Many in vitro studies have dissected the hypothesized environment within the infected lung, defining the bacterial response to pH, starvation and hypoxia. While these experiments have afforded great insight, the picture remains incomplete. The only way to study the combined effects of these environmental factors and the mycobacterial response is to study the bacterial response in vivo.We used the guinea pig model of tuberculosis to examine the bacterial proteome during the early and chronic stages of disease. Lungs were harvested thirty and ninety days after aerosol challenge with Mtb, and analyzed by liquid chromatography-mass spectrometry. To date, in vivo proteomics of the tubercle bacillus has not been described and this work has generated the first large-scale shotgun proteomic data set, comprising over 500 unique protein identifications. Cell wall and cell wall processes, and intermediary metabolism and respiration were the two major functional classes of proteins represented in the infected lung. These classes of proteins displayed the greatest heterogeneity indicating important biological processes for establishment of a productive bacterial infection and its persistence. Proteins necessary for adaptation throughout infection, such as nitrate/nitrite reduction were found at both time points. The PE-PPE protein class, while not well characterized, represented the third most abundant category and showed the most consistent expression during the infection.Cumulatively, the results of this work may provide the basis for rational drug design - identifying numerous Mtb proteins, from essential kinases to products involved in metal regulation and cell wall remodeling, all present throughout the course of infection