Dark Matter In Minimal Trinification

We study an example of Grand Unified Theory (GUT), known as trinification, which was first introduced in 1984 by S.Glashow. This model has the GUT gauge group as $[SU(3)]^3$ with a discrete $\mathbb{Z}_3$ to ensure the couplings are unified at the GUT scale. In this letter we consider this trinification model in its minimal formulation and investigate its robustness in the context of cosmology. In particular we show that for a large set of the parameter space the model doesn't seem to provide a Dark Matter candidate compatible with cosmological data.Comment: To appear in the LXXXVI session of the "Les Houches" summer school. 9 pages, 2 graph

Continuous bioprocessing and process analytical technologies: A path towards quality by design

Recent success in monoclonal antibody based immuno-oncology therapeutics such as Keytruda® has initiated a revolution within the Biopharmaceutical Industry. Development efforts to support this class of molecules include single-use technology, continuous production, process analytical technology (PAT), information technology (IT), multivariate data analysis (MVDA), and efforts towards real time release testing (RTRT). Merck’s vision for a next-generation large molecule production facility aligns with these six key principles, as demonstrated by the construction of a continuous monoclonal antibody (mAb) production pilot plant named the Protein Refinery Operations lab (PROLab) within Merck Bioprocess Development. Quality-by-Design (QbD) principles are maturing for the development of standard batch-based therapeutic protein manufacturing processes. Outside of the insight gained through similar techniques applied to unit operations run in a continuous mode, similar approaches for the dependencies created by connected and continuous processes are still in their infancy. Previously, a methodology for characterizing holistic downstream process performance through real time perturbation analysis, where the response to an upstream stimulus is monitored at several unit operations simultaneously was presented to start applying QbD principles to continuous bioprocessing. Here, the authors build upon the concept of perturbation analysis by presenting case studies where advanced PAT tools have been embedded in PROLab operation. At-line and off-line process and product quality data from continuous upstream and downstream production will be presented over the course of long term perfusion cell culture with variable production rates. Specific emphasis will be placed on the performance of bioreactor cell retention and clarification trains, and post-chromatographic ultrafiltration unit operations. This process understanding can then be utilized to place PAT tools at the appropriate locations in the process to achieve product attribute control and ultimately to assure uninterrupted supply of therapeutic proteins to patient

Monomeric C-reactive protein: a novel biomarker predicting neurodegenerative disease and vascular dysfunction

Circulating C-reactive protein (pCRP) concentrations rise dramatically during both acute (e.g., following stroke) or chronic infection and disease (e.g., autoimmune conditions such as lupus), providing complement fixation through C1q protein binding. It is now known, that on exposure to the membranes of activated immune cells (and microvesicles and platelets), or damaged/dysfunctional tissue, it undergoes lysophosphocholine (LPC)-phospholipase-C-dependent dissociation to the monomeric form (mCRP), concomitantly becoming biologically active. We review histological, immunohistochemical, and morphological/topological studies of post-mortem brain tissue from individuals with neuroinflammatory disease, showing that mCRP becomes stably distributed within the parenchyma, and resident in the arterial intima and lumen, being “released” from damaged, hemorrhagic vessels into the extracellular matrix. The possible de novo synthesis via neurons, endothelial cells, and glia is also considered. In vitro, in vivo, and human tissue co-localization analyses have linked mCRP to neurovascular dysfunction, vascular activation resulting in increased permeability, and leakage, compromise of blood brain barrier function, buildup of toxic proteins including tau and beta amyloid (Aβ), association with and capacity to “manufacture” Aβ-mCRP-hybrid plaques, and, greater susceptibility to neurodegeneration and dementia. Recently, several studies linked chronic CRP/mCRP systemic expression in autoimmune disease with increased risk of dementia and the mechanisms through which this occurs are investigated here. The neurovascular unit mediates correct intramural periarterial drainage, evidence is provided here that suggests a critical impact of mCRP on neurovascular elements that could suggest its participation in the earliest stages of dysfunction and conclude that further investigation is warranted. We discuss future therapeutic options aimed at inhibiting the pCRP-LPC mediated dissociation associated with brain pathology, for example, compound 1,6-bis-PC, injected intravenously, prevented mCRP deposition and associated damage, after temporary left anterior descending artery ligation and myocardial infarction in a rat model

Clinical risk scores for predicting stroke-associated pneumonia: A systematic review:A systematic review

Purpose Several risk stratification scores for predicting stroke-associated pneumonia have been derived. We aimed to evaluate the performance and clinical usefulness of such scores for predicting stroke-associated pneumonia. Method A systematic literature review was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, with application of the Quality Assessment of Diagnostic Accuracy-2 tool. Published studies of hospitalised adults with ischaemic stroke, intracerebral haemorrhage, or both, which derived and validated an integer-based clinical risk score, or externally validated an existing score to predict occurrence of stroke-associated pneumonia, were considered and independently screened for inclusion by two reviewers. Findings We identified nine scores, from eight derivation cohorts. Age was a component of all scores, and the NIHSS score in all except one. Six scores were internally validated and five scores were externally validated. The A2DS2 score (Age, Atrial fibrillation, Dysphagia, Severity [NIHSS], Sex) was the most externally validated in 8 independent cohorts. Performance measures were reported for eight scores. Discrimination tended to be more variable in the external validation cohorts (C statistic 0.67–0.83) than the derivation cohorts (C statistic 0.74–0.85). Discussion Overall, discrimination and calibration were similar between the different scores. No study evaluated influence on clinical decision making or prognosis. Conclusion The clinical prediction scores varied in their simplicity of use and were comparable in performance. Utility of such scores for preventive intervention trials and in clinical practice remains uncertain and requires further study

Prediction of Cognitive States During Flight Simulation Using Multimodal Psychophysiological Sensing

The Commercial Aviation Safety Team found the majority of recent international commercial aviation accidents attributable to loss of control inflight involved flight crew loss of airplane state awareness (ASA), and distraction was involved in all of them. Research on attention-related human performance limiting states (AHPLS) such as channelized attention, diverted attention, startle/surprise, and confirmation bias, has been recommended in a Safety Enhancement (SE) entitled "Training for Attention Management." To accomplish the detection of such cognitive and psychophysiological states, a broad suite of sensors was implemented to simultaneously measure their physiological markers during a high fidelity flight simulation human subject study. Twenty-four pilot participants were asked to wear the sensors while they performed benchmark tasks and motion-based flight scenarios designed to induce AHPLS. Pattern classification was employed to predict the occurrence of AHPLS during flight simulation also designed to induce those states. Classifier training data were collected during performance of the benchmark tasks. Multimodal classification was performed, using pre-processed electroencephalography, galvanic skin response, electrocardiogram, and respiration signals as input features. A combination of one, some or all modalities were used. Extreme gradient boosting, random forest and two support vector machine classifiers were implemented. The best accuracy for each modality-classifier combination is reported. Results using a select set of features and using the full set of available features are presented. Further, results are presented for training one classifier with the combined features and for training multiple classifiers with features from each modality separately. Using the select set of features and combined training, multistate prediction accuracy averaged 0.64 +/- 0.14 across thirteen participants and was significantly higher than that for the separate training case. These results support the goal of demonstrating simultaneous real-time classification of multiple states using multiple sensing modalities in high fidelity flight simulators. This detection is intended to support and inform training methods under development to mitigate the loss of ASA and thus reduce accidents and incidents

mCRP-Induced Focal Adhesion Kinase-Dependent Monocyte Aggregation and M1 Polarization, which was partially blocked by the C10M Inhibitor

Monomeric C-reactive protein (mCRP) has recently been implicated in the abnormal vascular activation associated with development of atherosclerosis, but it may act more specifically through mechanisms perpetuating damaged vessel inflammation and subsequent aggregation and internalization of resident macrophages. Whilst the direct effects of mCRP on endothelial cells have been characterized, the interaction with blood monocytes has, to our knowledge, not been fully defined. Here we showed that mCRP caused a strong aggregation of both U937 cell line and primary peripheral blood monocytes (PBMs) obtained from healthy donors. Moreover, this increase in clustering was dependent on focal adhesion kinase (FAK) activation (blocked by a specific inhibitor), as was the concomitant adhesive attachment to the plate, which was suggestive of macrophage differentiation. Confocal microscopy confirmed the increased expression and nuclear localization of p-FAK, and cell surface marker expression associated with M1 macrophage polarization (CD11b, CD14, and CD80, as well as iNOS) in the presence of mCRP. Inclusion of a specific CRP dissociation/mCRP inhibitor (C10M) effectively inhibited PBMs clustering, as well as abrogating p-FAK expression, and partially reduced the expression of markers associated with M1 macrophage differentiation. mCRP also increased the secretion of pro-inflammatory cytokines Interleukin-8 (IL-8) and Interleukin-1β (IL-1β), without notably affecting MAP kinase signaling pathways; inclusion of C10M did not perturb or modify these effects. In conclusion, mCRP modulates PBMs through a mechanism that involves FAK and results in cell clustering and adhesion concomitant with changes consistent with M1 phenotypical polarization. C10M has potential therapeutic utility in blocking the primary interaction of mCRP with the cells—for example, by protecting against monocyte accumulation and residence at damaged vessels that may be predisposed to plaque development and atherosclerosis

Nanoparticle “switch-on” by tetrazine triggering

This work describes how a small-molecule chemical trigger, reacting through the mediatory of an inverse electron demand Diels–Alder reaction, results in enhanced cellular uptake and selective nanoparticle disintegration and cargo liberation, via gross polymeric morphological alterations. The power of these responsive nanoparticles is demonstrated through encapsulation of the anti-cancer agent doxorubicin and its triggered release, allowing controlled cell death in response to a small-molecule chemical trigger

On looking into words (and beyond): Structures, Relations, Analyses

On Looking into Words is a wide-ranging volume spanning current research into word structure and morphology, with a focus on historical linguistics and linguistic theory. The papers are offered as a tribute to Stephen R. Anderson, the Dorothy R. Diebold Professor of Linguistics at Yale, who is retiring at the end of the 2016-2017 academic year. The contributors are friends, colleagues, and former students of Professor Anderson, all important contributors to linguistics in their own right. As is typical for such volumes, the contributions span a variety of topics relating to the interests of the honorand. In this case, the central contributions that Anderson has made to so many areas of linguistics and cognitive science, drawing on synchronic and diachronic phenomena in diverse linguistic systems, are represented through the papers in the volume. The 26 papers that constitute this volume are unified by their discussion of the interplay between synchrony and diachrony, theory and empirical results, and the role of diachronic evidence in understanding the nature of language. Central concerns of the volume include morphological gaps, learnability, increases and declines in productivity, and the interaction of different components of the grammar. The papers deal with a range of linked synchronic and diachronic topics in phonology, morphology, and syntax (in particular, cliticization), and their implications for linguistic theory

On looking into words (and beyond): Structures, Relations, Analyses

On Looking into Words is a wide-ranging volume spanning current research into word structure and morphology, with a focus on historical linguistics and linguistic theory. The papers are offered as a tribute to Stephen R. Anderson, the Dorothy R. Diebold Professor of Linguistics at Yale, who is retiring at the end of the 2016-2017 academic year. The contributors are friends, colleagues, and former students of Professor Anderson, all important contributors to linguistics in their own right. As is typical for such volumes, the contributions span a variety of topics relating to the interests of the honorand. In this case, the central contributions that Anderson has made to so many areas of linguistics and cognitive science, drawing on synchronic and diachronic phenomena in diverse linguistic systems, are represented through the papers in the volume. The 26 papers that constitute this volume are unified by their discussion of the interplay between synchrony and diachrony, theory and empirical results, and the role of diachronic evidence in understanding the nature of language. Central concerns of the volume include morphological gaps, learnability, increases and declines in productivity, and the interaction of different components of the grammar. The papers deal with a range of linked synchronic and diachronic topics in phonology, morphology, and syntax (in particular, cliticization), and their implications for linguistic theory