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Microorganisms evolved adaptive responses to survive stressful challenges in ever-changing environments. Understanding the relationships between the physiological/metabolic adjustments allowing cellular stress adaptation and gene expression changes being used by organisms to achieve such adjustments may significantly impact our ability to understand and/or guide evolution. Here, we studied those relationships during adaptation to various stress challenges in Saccharomyces cerevisiae, focusing on heat stress responses. We combined dozens of independent experiments measuring whole-genome gene expression changes during stress responses with a simplified kinetic model of central metabolism. We identified alternative quantitative ranges for a set of physiological variables in the model (production of ATP, trehalose, NADH, etc.) that are specific for adaptation to either heat stress or desiccation/rehydration. Our approach is scalable to other adaptive responses and could assist in developing biotechnological applications to manipulate cells for medical, biotechnological, or synthetic biology purposes., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background Aims: The PR1 peptide, derived from the leukemia-associated antigens proteinase 3 and neutrophil elastase, is overexpressed on HLA-A2 in acute myeloid leukemia (AML). We developed a T-cell receptor (TCR)-like monoclonal antibody (8F4) that binds the PR1/HLA-A2 complex on the surface of AML cells, efficiently killing them in vitro and eliminating them in preclinical models. Humanized 8F4 (h8F4) with high affinity for the PR1/HLA-A2 epitope was used to construct an h8F4- chimeric antigen receptor (CAR) that was transduced into T cells to mediate anti-leukemia activity., Methods: Human T cells were transduced to express the PR1/HLA-A2-specific CAR (h8F4-CAR-T cells) containing the scFv of h8F4 fused to the intracellular signaling endo-domain of CD3 zeta chain through the transmembrane and intracellular costimulatory domain of CD28., Results: Adult human normal peripheral blood (PB) T cells were efficiently transduced with the h8F4-CAR construct and predominantly displayed an effector memory phenotype with a minor population (12%) of central memory cells in vitro. Umbilical cord blood (UCB) T cells could also be efficiently transduced with the h8F4-CAR. The PB and UCB-derived h8F4-CAR-T cells specifically recognized the PR1/HLA-A2 complex and were capable of killing leukemia cell lines and primary AML blasts in an HLA-A2-dependent manner., Conclusions: Human adult PB and UCB-derived T cells expressing a CAR derived from the TCR-like 8F4 antibody rapidly and efficiently kill AML in vitro. Our data could lead to a new treatment paradigm for AML in which targeting leukemia stem cells could transfer long-term immunity to protect against relapse., (Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Two Component Systems and Phosphorelays (TCS/PR) are environmental signal transduction cascades in prokaryotes and, less frequently, in eukaryotes. The internal domain organization of proteins and the topology of TCS/PR cascades play an important role in shaping the responses of the circuits. It is thus important to maintain updated censuses of TCS/PR proteins in order to identify the various topologies used by nature and enable a systematic study of the dynamics associated with those topologies. To create such a census, we analyzed the proteomes of 7,609 organisms from all domains of life with fully sequenced and annotated genomes. To begin, we survey each proteome searching for proteins containing domains that are associated with internal signal transmission within TCS/PR: Histidine Kinase (HK), Response Regulator (RR) and Histidine Phosphotranfer (HPt) domains, and analyze how these domains are arranged in the individual proteins. Then, we find all types of operon organization and calculate how much more likely are proteins that contain TCS/PR domains to be coded by neighboring genes than one would expect from the genome background of each organism. Finally, we analyze if the fusion of domains into single TCS/PR proteins is more frequently observed than one might expect from the background of each proteome. We find 50 alternative ways in which the HK, HPt, and RR domains are observed to organize into single proteins. In prokaryotes, TCS/PR coding genes tend to be clustered in operons. 90% of all proteins identified in this study contain just one of the three domains, while 8% of the remaining proteins combine one copy of an HK, a RR, and/or an HPt domain. In eukaryotes, 25% of all TCS/PR proteins have more than one domain. These results might have implications for how signals are internally transmitted within TCS/PR cascades. These implications could explain the selection of the various designs in alternative circumstances.

Signal transduction systems mediate the response and adaptation of organisms to environmental changes. In prokaryotes, this signal transduction is often done through Two Component Systems (TCS). These TCS are phosphotransfer protein cascades, and in their prototypical form they are composed by a kinase that senses the environmental signals (SK) and by a response regulator (RR) that regulates the cellular response. This basic motif can be modified by the addition of a third protein that interacts either with the SK or the RR in a way that could change the dynamic response of the TCS module. In this work we aim at understanding the effect of such an additional protein (which we call "third component") on the functional properties of a prototypical TCS. To do so we build mathematical models of TCS with alternative designs for their interaction with that third component. These mathematical models are analyzed in order to identify the differences in dynamic behavior inherent to each design, with respect to functionally relevant properties such as sensitivity to changes in either the parameter values or the molecular concentrations, temporal responsiveness, possibility of multiple steady states, or stochastic fluctuations in the system. The differences are then correlated to the physiological requirements that impinge on the functioning of the TCS. This analysis sheds light on both, the dynamic behavior of synthetically designed TCS, and the conditions under which natural selection might favor each of the designs. We find that a third component that modulates SK activity increases the parameter space where a bistable response of the TCS module to signals is possible, if SK is monofunctional, but decreases it when the SK is bifunctional. The presence of a third component that modulates RR activity decreases the parameter space where a bistable response of the TCS module to signals is possible.

Most aspects of molecular biology can be understood in terms of biological design principles. These principles can be loosely defined as qualitative and quantitative features that emerge in evolution and recur more frequently than one would expect by chance alone in biological systems that perform a given type of process or function. Furthermore, such recurrence can be rationalized in terms of the functional advantage that the design provides to the system when compared with possible alternatives. This paper focuses on those design features that can be related to improved functional effectiveness of molecular and regulatory networks. We begin by reviewing assumptions and methods that underlie the study of such principles in molecular networks. We follow by discussing many of the design principles that have been found in genetic, metabolic, and signal transduction circuits. We concentrate mainly on results in the context of Biochemical Systems Theory, although we also briefly discuss other work. We conclude by discussing the importance of these principles for both, understanding the natural evolution of complex networks at the molecular level and for creating artificial biological systems with specific features., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: Autistic spectrum disorders (ASD) is a term that is not included in DSM IV or in ICD 10, which are the diagnostic tools most commonly used by clinical professionals but can offer problems in research when it comes to finding homogenous groups., Development: From a neuropaediatric point of view, there is a need for a classification of the generalised disorders affecting development and for this purpose we used Wing's triad, which defines the continuum of the autistic spectrum, and the information provided by magnetoencephalography (MEG) as grouping elements. Specific generalised developmental disorders were taken as being those syndromes that partially expressed some autistic trait, but with their own personality so that they could be considered to be a specific disorder. ASD were classified as being primary, cryptogenic or secondary. The primary disorders, in turn, express a continuum that ranges from Savant syndrome to Asperger's syndrome and the different degrees of early infantile autism. MEG is a functional neuroimaging technique that has enabled us to back up this classification.