In the past years, mass univariate statistical analyses of neuroimaging data have been complemented by the use of multivariate pattern analyses, especially based on machine learning models. While ...these allow an increased sensitivity for the detection of spatially distributed effects compared to univariate techniques, they lack an established and accessible software framework. The goal of this work was to build a toolbox comprising all the necessary functionalities for multivariate analyses of neuroimaging data, based on machine learning models. The “Pattern Recognition for Neuroimaging Toolbox” (PRoNTo) is open-source, cross-platform, MATLAB-based and SPM compatible, therefore being suitable for both cognitive and clinical neuroscience research. In addition, it is designed to facilitate novel contributions from developers, aiming to improve the interaction between the neuroimaging and machine learning communities. Here, we introduce PRoNTo by presenting examples of possible research questions that can be addressed with the machine learning framework implemented in PRoNTo, and cannot be easily investigated with mass univariate statistical analysis.
Summary
Background
Acute pulmonary embolism (PE) can worsen quality of life due to persistent dyspnea or exercise intolerance.
Objective
Test if tenecteplase increases the probability of a favorable ...composite patient‐oriented outcome after submassive PE.
Methods
Normotensive patients with PE and right ventricular (RV) strain (by echocardiography or biomarkers) were enrolled from eight hospitals. All patients received low‐molecular‐weight heparin followed by random assignment to either a single weight‐based bolus of tenecteplase or placebo, administered in a double‐blinded fashion. The primary composite outcome included: (i) death, circulatory shock, intubation or major bleeding within 5 days or (ii) recurrent PE, poor functional capacity (RV dysfunction with either dyspnea at rest or exercise intolerance) or an SF36® Physical Component Summary (PCS) score < 30 at 90‐day follow‐up.
Results
Eighty‐three patients were randomized; 40 to tenecteplase and 43 to placebo. The trial was terminated prematurely. Within 5 days, adverse outcomes occurred in three placebo‐treated patients (death in one and intubation in two) and one tenecteplase‐treated patient (fatal intracranial hemorrhage). At 90 days, adverse outcomes occurred in 13 unique placebo‐treated patients and five unique tenecteplase‐treated patients Thus, 16 (37%) placebo‐treated and six (15%) tenecteplase‐treated patients had at least one adverse outcome (exact two‐sided P = 0.017).
Conclusions
Treatment of patients with submassive pulmonary embolism with tenecteplase was associated with increased probability of a favorable composite outcome.
Summary
Platelets are generated from nucleated precursors referred to as megakaryocytes. The formation of platelets is one of the most elegant and unique developmental processes in eukaryotes. ...Because they enter the circulation without nuclei, platelets are often considered simple, non‐complex cells that have limited functions beyond halting blood flow. However, emerging evidence over the past decade demonstrates that platelets are more sophisticated than previously considered. Platelets carry a rich repertoire of messenger RNAs (mRNAs), microRNAs (miRNAs), and proteins that contribute to primary (adhesion, aggregation, secretion) and alternative (immune regulation, RNA transfer, translation) functions. It is also becoming increasingly clear that the ‘genetic code’ of platelets changes with race, genetic disorders, or disease. Changes in the ‘genetic code’ can occur at multiple points including megakaryocyte development, platelet formation, or in circulating platelets. This review focuses on regulation of the ‘genetic code’ in megakaryocytes and platelets and its potential contribution to health and disease.
Clinical research based on neuroimaging data has benefited from machine learning methods, which have the ability to provide individualized predictions and to account for the interaction among units ...of information in the brain. Application of machine learning in structural imaging to investigate diseases that involve brain injury presents an additional challenge, especially in conditions like stroke, due to the high variability across patients regarding characteristics of the lesions. Extracting data from anatomical images in a way that translates brain damage information into features to be used as input to learning algorithms is still an open question. One of the most common approaches to capture regional information from brain injury is to obtain the lesion load per region (i.e. the proportion of voxels in anatomical structures that are considered to be damaged). However, no systematic evaluation has yet been performed to compare this approach with using patterns of voxels (i.e. considering each voxel as a single feature). In this paper we compared both approaches applying Gaussian Process Regression to decode motor scores in 50 chronic stroke patients based solely on data derived from structural MRI. For both approaches we compared different ways to delimit anatomical areas: regions of interest from an anatomical atlas, the corticospinal tract, a mask obtained from fMRI analysis with a motor task in healthy controls and regions selected using lesion-symptom mapping. Our analysis showed that extracting features through patterns of voxels that represent lesion probability produced better results than quantifying the lesion load per region. In particular, from the different ways to delimit anatomical areas compared, the best performance was obtained with a combination of a range of cortical and subcortical motor areas as well as the corticospinal tract. These results will inform the appropriate methodology for predicting long term motor outcomes from early post-stroke structural brain imaging.
Summary
Essentials
Phosphoinositide 3‐kinase and MAPK pathways crosstalk via PDK1.
PDK1 is required for adenosine diphosphate‐induced platelet activation and thromboxane generation.
PDK1 regulates ...RAF proto‐oncogene Ser/Thr kinase (Raf1) activation in the MAPK pathway.
Genetic ablation of PDK1 protects against platelet‐dependent thrombosis in vivo.
Summary
Background
Platelets are dynamic effector cells with functions that span hemostatic, thrombotic and inflammatory continua. Phosphoinositide‐dependent protein kinase 1 (PDK1) regulates protease‐activated receptor 4‐induced platelet activation and thrombus formation through glycogen synthase kinase3β. However, whether PDK1 also signals through the ADP receptor and its functional importance in vivo remain unknown.
Objective
To establish the mechanism of PDK1 in ADP‐induced platelet activation and thrombosis.
Methods
We assessed the role of PDK1 on 2MeSADP‐induced platelet activation by measuring aggregation, thromboxane generation and phosphorylation events in the presence of BX‐795, which inhibits PDK1, or by using platelet‐specific PDK1 knockout mice and performing western blot analysis. PDK1 function in thrombus formation was assessed with an in vivo pulmonary embolism model.
Results
PDK1 inhibition with BX‐795 reduced 2‐methylthio‐ADP (2MeSADP)‐induced aggregation of human and murine platelets by abolishing thromboxane generation. Similar results were observed in pdk1−/− mice. PDK1 was also necessary for the phosphorylation of mitogen‐activated protein kinase kinase 1/2 (MEK1/2), extracellular signal‐regulated kinase 1/2, and cytosolic phospholipase A2, indicating that PDK1 regulates an upstream kinase in the mitogen‐activated protein kinase (MAPK) pathway. We next determined that this upstream kinase is Raf‐1, a serine/threonine kinase that is necessary for the phosphorylation of MEK1/2, as pharmacological inhibition and genetic ablation of PDK1 were sufficient to prevent Raf1 phosphorylation. Furthermore, in vivo inhibition or genetic ablation of PDK1 protected mice from collagen/epinephrine‐induced pulmonary embolism.
Conclusion
PDK1 governs thromboxane generation and thrombosis in platelets that are stimulated with 2MeSADP by regulating activation of the MAPK pathway.
Essentials
Platelets express retinoic acid receptor (RAR)α protein, specifically binding target mRNAs.
mRNAs under RARα control include MAP1LC3B2, SLAIN2, and ANGPT1.
All‐trans retinoic acid (atRA) ...releases RARα from its target mRNA.
RARα expressed in human platelets exerts translational control via direct mRNA binding.
Summary
Background
Translational control mechanisms in platelets are incompletely defined. Here, we determined whether the nuclear transcription factor RARα controls protein translational events in human platelets.
Methods
Isolated human platelets were treated with the pan‐RAR agonist all‐trans‐retinoic acid (atRA). Global and targeted translational events were examined.
Results
Stimulation of platelets with atRA significantly increased global protein expression. RARα protein bound to a subset of platelet mRNAs, as measured by next‐generation RNA‐sequencing. In‐depth analyses of 5′ and 3′‐untranslated regions of the RARα‐bound mRNAs revealed consensus RARα binding sites in microtubule‐associated protein 1 light chain 3 beta 2 (MAP1LC3B2), SLAIN motif‐containing protein 2 (SLAIN2) and angiopoietin‐1 (ANGPT1) transcripts. When platelets were treated with atRA, binding interactions between RARα protein and mRNA for MAP1LC3B2, SLAIN2 and ANGPT1 were significantly decreased. Consistent with the release of bound RARα protein from MAP1LCB2mRNA, we observed an increase in the synthesis of MAP1LC3B2 protein.
Conclusions
These findings provide the first evidence that RARα, a nuclear transcriptional factor, regulates synthetic events in anucleate human platelets. They also reveal an additional non‐genomic role for RARα in platelets that may have implications for the vitamin A‐dependent signaling in humans.
Background: Activated platelets have previously‐unrecognized mechanisms of post‐transcriptional gene expression that may influence hemostasis and inflammation. A novel pathway involves splicing of ...pre‐mRNAs in resting platelets to mature, translatable mRNAs in response to cellular activation. Objectives: We asked if bacterial products and host agonists present in the septic milieu induce tissue factor pre‐mRNA splicing in platelets from healthy subjects. In parallel, we asked if spliced tissue factor (TF) mRNA is present in platelets from septic patients in a proof‐of‐principle analysis. Patients/methods: TF pre‐mRNA and mRNA expression patterns were characterized in platelets from septic patients and in platelets isolated from healthy subjects activated with bacteria, toxins and inflammatory agonists. Procoagulant activity was also measured. Results and conclusions: Live bacteria, staphylococcal α‐toxin and lipopolysaccharide (LPS) induced TF pre‐mRNA splicing in platelets isolated from healthy subjects. Toxin‐stimulated platelets accelerated plasma clotting, a response that was blocked by a previously‐characterized splicing inhibitor and by an anti‐tissue factor antibody. Platelets from septic patients expressed spliced TF mRNA, whereas it was absent from unselected and age‐matched control subjects. Tissue factor‐dependent procoagulant activity was elevated in platelets from a subset of septic patients. Thus, bacterial and host factors induce splicing of TF pre‐mRNA, expression of TF mRNA and tissue factor‐dependent clotting activity in human platelets. TF mRNA is present in platelets from some septic patients, indicating that it may be a marker of altered platelet phenotype and function in sepsis and that splicing pathways are induced in this syndrome.
Essentials Platelets express retinoic acid receptor (RAR)alpha protein, specifically binding target mRNAs. mRNAs under RARalpha control include MAP1LC3B2, SLAIN2, and ANGPT1. All-trans retinoic acid ...(atRA) releases RARalpha from its target mRNA. RARalpha expressed in human platelets exerts translational control via direct mRNA binding. Summary Background Translational control mechanisms in platelets are incompletely defined. Here, we determined whether the nuclear transcription factor RARalpha controls protein translational events in human platelets. Methods Isolated human platelets were treated with the pan-RAR agonist all-trans-retinoic acid (atRA). Global and targeted translational events were examined. Results Stimulation of platelets with atRA significantly increased global protein expression. RARalpha protein bound to a subset of platelet mRNAs, as measured by next-generation RNA-sequencing. In-depth analyses of 5' and 3'-untranslated regions of the RARalpha-bound mRNAs revealed consensus RARalpha binding sites in microtubule-associated protein 1 light chain 3 beta 2 (MAP1LC3B2), SLAIN motif-containing protein 2 (SLAIN2) and angiopoietin-1 (ANGPT1) transcripts. When platelets were treated with atRA, binding interactions between RARalpha protein and mRNA for MAP1LC3B2, SLAIN2 and ANGPT1 were significantly decreased. Consistent with the release of bound RARalpha protein from MAP1LCB2mRNA, we observed an increase in the synthesis of MAP1LC3B2 protein. Conclusions These findings provide the first evidence that RARalpha, a nuclear transcriptional factor, regulates synthetic events in anucleate human platelets. They also reveal an additional non-genomic role for RARalpha in platelets that may have implications for the vitamin A-dependent signaling in humans.
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