A new paradigm for the prediction of antidepressant treatment response

Current treatment of Major Depressive Disorder utilizes a trial-and-error sequential treatment strategy that results in delays in achieving response and remission for a majority of patients. Protracted ineffective treatment prolongs patient suffering and increases health care costs. In addition, long and unsuccessful antidepressant trials may diminish patient expectations, reinforce negative cognitions, and condition patients not to respond during subsequent antidepressant trials, thus contributing to further treatment resistance. For these reasons, it is critical to identify reliable predictors of antidepressant treatment response that can be used to shorten or eliminate lengthy and ineffective trials. Research on possible endophenotypic as well as genomic predictors has not yet yielded reliable predictors. The most reliable predictors identified thus far are symptomatic and physiologic characteristics of patients that emerge early in the course of treatment. We propose here the term “response endophenotypes” (REs) to describe this class of predictors, defined as latent measurable symptomatic or neurobiologie responses of individual patients that emerge early in the course of treatment, and which carry strong predictive power for individual patient outcomes. Use of REs constitutes a new paradigm in which medication treatment trials that are likely to be ineffective could be stopped within 1 to 2 weeks and other medication more likely to be effective could be started. Data presented here suggest that early changes in symptoms, quantitative electroencephalography, and gene expression could be used to construct effective REs. We posit that this new paradigm could lead to earlier recovery from depressive illness and ultimately produce profound health and economic benefits

Cell-Free Synthesis of the Mitochondrial ADP/ATP Carrier Protein of Neurospora crassa

ADP/ATP carrier protein was synthesized in heterologous cell-free systems programmed with Neurospora poly(A)-containing RNA and homologous cell-free systems from Neurospora. The apparent molecular weight of the product obtained in vitro was the same as that of the authentic mitochondrial protein. The primary translation product obtained in reticulocyte lysates starts with formylmethionine when formylated initiator methionyl-tRNA (fMet-tRNAfMet) was present. The product synthesized in vitro was released from the ribosomes into the postribosomal supernatant. The evidence presented indicates that the ADP/ATP carrier is synthesized as a polypeptide with the same molecular weight as the mature monomeric protein and does not carry an additional sequence

Antibody-mediated inhibition of syndecan-4 dimerisation reduces interleukin (IL)-1 receptor trafficking and signalling.

OBJECTIVE: Syndecan-4 (sdc4) is a cell-anchored proteoglycan that consists of a transmembrane core protein and glucosaminoglycan (GAG) side chains. Binding of soluble factors to the GAG chains of sdc4 may result in the dimerisation of sdc4 and the initiation of downstream signalling cascades. However, the question of how sdc4 dimerisation and signalling affects the response of cells to inflammatory stimuli is unknown. METHODS: Sdc4 immunostaining was performed on rheumatoid arthritis (RA) tissue sections. Interleukin (IL)-1 induced extracellular signal-regulated kinases (ERK) phosphorylation and matrix metalloproteinase-3 production was investigated. Il-1 binding to sdc4 was investigated using immunoprecipitation. IL-1 receptor (IL1R1) staining on wild-type, sdc4 and IL1R1 knockout fibroblasts was performed in fluorescence-activated cell sorting analyses. A blocking sdc4 antibody was used to investigate sdc4 dimerisation, IL1R1 expression and the histological paw destruction in the human tumour necrosis factor-alpha transgenic mouse. RESULTS: We show that in fibroblasts, the loss of sdc4 or the antibody-mediated inhibition of sdc4 dimerisation reduces the cell surface expression of the IL-1R and regulates the sensitivity of fibroblasts to IL-1. We demonstrate that IL-1 directly binds to sdc4 and in an IL-1R-independent manner leads to its dimerisation. IL-1-induced dimerisation of sdc4 regulates caveolin vesicle-mediated trafficking of the IL1R1, which in turn determines the responsiveness to IL-1. Administration of antibodies (Ab) against the dimerisation domain of sdc4, thus, strongly reduces the expression IL1R1 on arthritic fibroblasts both in vitro and an animal model of human RA. CONCLUSION: Collectively, our data suggest that Ab that specifically inhibit sdc4 dimerisation may support anti-IL-1 strategies in diseases such as inflammatory arthritis

Biosynthesis of Mitochondrial Porin and Insertion into the Outer Mitochondrial Membrane of Neuruspora crassa

Mitochondrial porin, the major protein of the outer mitochondrial membrane is synthesized by free cytoplasmic polysomes. The apparent molecular weight of the porin synthesized in homologous or heterologous cell-free systems is the same as that of the mature porin. Transfer in vitro of mitochondrial porin from the cytosolic fraction into the outer membrane of mitochondria could be demonstrated. Before membrane insertion, mitochondrial porin is highly sensitive to added proteinase; afterwards it is strongly protected. Binding of the precursor form to mitochondria occurs at 4°C and appears to precede insertion into the membrane. Unlike transfer of many precursor proteins into or across the inner mitochondrial membrane, assembly of the porin is not dependent on an electrical potential across the inner membrane

Enantiorecognition performances of "inherently chiral" film electrodes: a successful first example with planar-chirality probes

Enantiorecognition performances of "inherently chiral" film electrodes: a successful first example with planar-chirality probes Patrizia Mussini,a Serena Arnaboldi,aGiorgio Tomboni,a Mirko Magni?,a Francesco Sannicol\uf2a Heinrich Lang,b Marcus Korbb,Tiziana Benincoric aUniversit\ue0 degli Studi di Milano, Dipartimento di Chimica,Via Golgi 19,20133 Milano, bTechnische Universit\ue4t Chemnitz, Stra fe der Nationen 62, 09111 Chemnitz, Germany cUniv. degli Studi dell\u2019Insubria, Dip. di Scienza e Alta Tecnologia, Via Valleggio 11, 22100 Como, Italy [email protected] Enantiorecognition in voltammetry is a quite attractive target, implying a superior selectivity degree, which necessarily requires the electron transfer to take place in a chiral interphase environment, exploiting a chiral electrode surfaces or a chiral medium. Many approaches have been proposed, but unfortunately however most of them suffer from some drawback, like complex preparation, high cost and/or lack of robustness...., but above all, in most cases, they result in current differences between the two enantiomer of chiral probes, while a difference in peak potentials would be the desirable feature for enantiorecognition purposes.[1,2] In this context, we have recently reported the outstanding performances of "inherently chiral" electrodes prepared by fast and reproducible electrodeposition of a thin film of thiophene-based oligomers from "inherently chiral" monomers like BT2T4 (right) [3-6]. "Inherent chirality" implies that chirality and key functional properties originate from the same structural element; in the cited monomer cases, this is obtained by a tailored torsion in the conjugated electroactive system, with an energy barrier too high to be overcome at room T, so that the monomer exists in two stable enantiomers. Upon electrooligomerization of the (R)- or (S)- enantiomer, electroactive oligomer films are obtained, including linear and cyclic terms of different dimensions, and fully retaining the monomer configuration. Testing such electrode surfaces in chiral CV experiments with chiral probes, neat differences in peak potentials are observed for the enantiomers of chiral probes even of significantly different structure, specular upon inverting the film or probe configuration. The property appears to be of general character, testing a first small series of probes of different structures, even of pharmaceutical interest [3-6] (and also working on achiral electrodes in inherently chiral ionic-liquid based media[7,8]). Of course, it is important to widen the range of investigated cases. One issue concerns testing probes having other stereogenic elements than stereogenic centres (which is the most current occurence, as in our first tested cases), considering for instance axial chirality, helical chirality, and planar chirality. In this presentation we will focus on the latter case, for which convenient, electrochemically reversible model probes are provided by disubstituted ferrocene scaffolds like the one shown on the left (with R1\uf0b9 R2). Successful and reproducible chiral voltammetry tests with a first couple of such planar chirality examples on oligo BT2T4 films nicely confirm the general character of the successful inherent chirality electrode strategy. The current support of Fondazione Cariplo/Regione Lombardia "Avviso congiunto per l\u2019incremento dell\u2019attrattivit\ue0 del sistema di ricerca lombardo e della competitivit\ue0 dei ricercatori candidati su strumenti ERC - edizione 2016\u201d (Project 2016-0923) to our inherently chiral research is gratefully acknowledged- References: 1. Curr.Op. 2018, 7, 188-199 2 Curr. Op. 2018, 8, 60-72 3. Angew. Chem. Int. Ed. 2014, 53, 2623. 4. Chem. Eur. J. 2014, 20, 15298. 5. Chem. Sci. 2015, 6,1706. 6. Chem. Eur.2016 , 22,10839. 7. Anal. Bioanal. Chem. 2016, 408, 7243. 8. Angew Chem.2017 9. Electrochem. Comm. 2018, 89, 57-6

Import of cytochrome c into mitochondria

The import of cytochrome c into mitochondria can be resolved into a number of discrete steps. Here we report on the covalent attachment of heme to apocytochrome c by the enzyme cytochrome c heme lyase in mitochondria from Neurospora crassa. A new method was developed to measure directly the linkage of heme to apocytochrome c. This method is independent of conformational changes in the protein accompanying heme attachment. Tryptic peptides of [35S]cysteine-labelled apocytochrome c, and of enzymatically formed holocytochrome c, were resolved by reverse-phase HPLC. The cysteine-containing peptide to which heme was attached eluted later than the corresponding peptide from apocytochrome c and could be quantified by counting 35S radioactivity as a measure of holocytochrome c formation. Using this procedure, the covalent attachment of heme to apocytochrome c, which is dependent on the enzyme cytochrome c heme lyase, could be measured. Activity required heme (as hemin) and could be reversibly inhibited by the analogue deuterohemin. Holocytochrome c formation was stimulated 5–10-fold by NADH > NADPH > glutathione and was independent of a potential across the inner mitochondrial membrane. NADH was not required for the binding of apocytochrome c to mitochondria and was not involved in the reduction of the cysteine thiols prior to heme attachment. Holocytochrome c formation was also dependent on a cytosolic factor that was necessary for the heme attaching step of cytochrome c import. The factor was a heat-stable, protease-insensitive, low-molecular-mass component of unknown function. Cytochrome c heme lyase appeared to be a soluble protein located in the mitochondrial intermembrane space and was distinct from the previously identified apocytochrome c binding protein having a similar location. A model is presented in which the covalent attachment of heme by cytochrome c heme lyase also plays an essential role in the import pathway of cytochrome c

A Taxonomy of Explainable Bayesian Networks

Artificial Intelligence (AI), and in particular, the explainability thereof, has gained phenomenal attention over the last few years. Whilst we usually do not question the decision-making process of these systems in situations where only the outcome is of interest, we do however pay close attention when these systems are applied in areas where the decisions directly influence the lives of humans. It is especially noisy and uncertain observations close to the decision boundary which results in predictions which cannot necessarily be explained that may foster mistrust among end-users. This drew attention to AI methods for which the outcomes can be explained. Bayesian networks are probabilistic graphical models that can be used as a tool to manage uncertainty. The probabilistic framework of a Bayesian network allows for explainability in the model, reasoning and evidence. The use of these methods is mostly ad hoc and not as well organised as explainability methods in the wider AI research field. As such, we introduce a taxonomy of explainability in Bayesian networks. We extend the existing categorisation of explainability in the model, reasoning or evidence to include explanation of decisions. The explanations obtained from the explainability methods are illustrated by means of a simple medical diagnostic scenario. The taxonomy introduced in this paper has the potential not only to encourage end-users to efficiently communicate outcomes obtained, but also support their understanding of how and, more importantly, why certain predictions were made

A probabilistic analysis of argument cogency

This paper offers a probabilistic treatment of the conditions for argument cogency as endorsed in informal logic: acceptability, relevance, and sufficiency. Treating a natural language argument as a reason-claim-complex, our analysis identifies content features of defeasible argument on which the RSA conditions depend, namely: change in the commitment to the reason, the reason’s sensitivity and selectivity to the claim, one’s prior commitment to the claim, and the contextually determined thresholds of acceptability for reasons and for claims. Results contrast with, and may indeed serve to correct, the informal understanding and applications of the RSA criteria concerning their conceptual dependence, their function as update-thresholds, and their status as obligatory rather than permissive norms, but also show how these formal and informal normative approachs can in fact align