Instrumental Learning Within the Rat Spinal Cord: Localization of the Essential Neural Circuit.

Following spinal transection of the upper thoracic spinal cord, male Sprague-Dawley rats given legshock whenever a hindlimb is extended learn to maintain the leg in a flexed position. The region of the cord that mediates this instrumental learning was isolated using neuroanatomical tracing, localized infusion of lidocaine, and surgical transections. DiI and Fluoro-Gold microinjection at the site of shock application labeled motor neuron bodies of lamina IX in the lower lumbar region. Local application of the Na++ channel blocker lidocaine disrupted learning when it was applied over a region extending from the lower lumbar (L3) to upper sacral (S2) cord. The drug had no effect rostral or caudal to this region. Surgical transections as low as L4 had no effect on learning. Learning also survived a dual transection at L4 and S3, but not L4 and S2. The results suggest that the essential neural circuit lies between L4 and S3. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The face of the patent is not the “Whole Story”: determining effective life of a pharmaceutical patent in the United States

This article provides an overview of the factors that may contribute to the effective term of protection for a pharmaceutical product in the USA––by patent and by FDA market exclusivities, identifies public and commercial sources for collecting relevant patent term and exclusivity data, and provides a strategy for ensuring that the effective term of protection has been calculated accurately.     

Updating Situation Models: Reply to Zwaan and Madden (2004).

E. J. O'Brien, M. L. Rizzella, J. E. Albrecht, and J. G. Halleran (1998) demonstrated that, consistent with the memory-based text processing view, outdated or incorrect information can be reactivated through a passive resonance process. Once reactivated, this outdated information can still influence comprehension. R. A. Zwaan and C. J. Madden (2004) suggested that the O'Brien et al. findings resulted from problems with the materials used. The present authors show that the possible "problems" identified by Zwaan and Madden do not adequately explain the findings of O'Brien et al. and that Zwaan and Madden's Experiment 3 lacks sufficient control or power to support their alternative interpretation of O'Brien et al. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reliability and performance optimization of pipelined real-time systems

We consider pipelined real-time systems that consist of a chain of tasks executing on a distributed platform. The processing of the tasks is pipelined: each processor executes only one interval of consecutive tasks. We are interested in minimizing both the input–output latency and the period of application mapping. For dependability reasons, we are also interested in maximizing the reliability of the system. We therefore assign several processors to each interval of tasks, so as to increase the reliability of the system. Both processors and communication links are unreliable and subject to transient failures. We assume that the arrival of the failures follows a constant parameter Poisson law, and that the failures are statistically independent events. We study several variants of this multiprocessor mapping problem, with several hypotheses on the target platform (homogeneous/heterogeneous speeds and/or failure rates). We provide NP-hardness complexity results, and optimal mapping algorithms for polynomial problem instances. Efficient heuristics are presented to solve the general case, and experimental results are provided.     

A Dynamic Risk Assessment Methodology for Maintenance Decision Support

The failure mode and effect analysis (FMEA) is a widely applied technique for prioritizing equipment failures in the maintenance decision‐making domain. Recent improvements on the FMEA have largely focussed on addressing the shortcomings of the conventional FMEA of which the risk priority number is incorporated as a measure for prioritizing failure modes. In this regard, considerable research effort has been directed towards addressing uncertainties associated with the risk priority number metrics, that is occurrence, severity and detection. Despite these improvements, assigning these metrics remains largely subjective and mostly relies on expert elicitations, more so in instances where empirical data are sparse. Moreover, the FMEA results remain static and are seldom updated with the availability of new failure information. In this paper, a dynamic risk assessment methodology is proposed and based on the hierarchical Bayes theory. In the methodology, posterior distribution functions are derived for risk metrics associated with equipment failure of which the posterior function combines both prior functions elicited from experts and observed evidences based on empirical data. Thereafter, the posterior functions are incorporated as input to a Monte Carlo simulation model from which the expected cost of failure is generated and failure modes prioritized on this basis. A decision scheme for selecting appropriate maintenance strategy is proposed, and its applicability is demonstrated in the case study of thermal power plant equipment failures. Copyright © 2016 John Wiley & Sons, Ltd.     

Reg-1α, a New Substrate of Calpain-2 Depending on Its Glycosylation Status

Reg-1α/lithostathine, a protein mainly associated with the digestive system, was previously shown to be overexpressed in the pre-clinical stages of Alzheimer’s disease. In vitro, the glycosylated protein was reported to form fibrils at physiological pH following the proteolytic action of trypsin. However, the nature of the protease able to act in the central nervous system is unknown. In the present study, we showed that Reg-1α can be cleaved in vitro by calpain-2, the calcium activated neutral protease, overexpressed in neurodegenerative diseases. Using chemical crosslinking experiments, we found that the two proteins can interact with each other. Identification of the cleavage site using mass spectrometry, between Gln⁴ and Thr⁵, was found in agreement with the in silico prediction of the calpain cleavage site, in a position different from the one reported for trypsin, i.e., Arg¹¹-Ile¹² peptide bond. We showed that the cleavage was impeded by the presence of the neighboring glycosylation of Thr⁵. Moreover, in vitro studies using electron microscopy showed that calpain-cleaved protein does not form fibrils as observed after trypsin cleavage. Collectively, our results show that calpain-2 cleaves Reg-1α in vitro, and that this action is not associated with fibril formation.     

Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence,Severity, and Treatment Response

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea–hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke.     

Tumor Infiltration with CD20+CD73+ B Cells Correlates with Better Outcome in Colorectal Cancer

Immunotherapy has become increasingly important in the treatment of colorectal cancer (CRC). Currently, CD73, also known as ecto-5′-nucleotidase (NT5E), has gained considerable interest as a potential therapeutic target. CD73 is one of the key enzymes catalyzing the conversion of extracellular ATP into adenosine, which in turn exerts potent immune suppressive effects. However, the role of CD73 expression on various cell types within the CRC tumor microenvironment remains unresolved. The expression of CD73 on various cell types has been described recently, but the role of CD73 on B-cells in CRC remains unclear. Therefore, we analyzed CD73 on B-cells, especially on tumor-infiltrating B-cells, in paired tumor and adjacent normal tissue samples from 62 eligible CRC patients. The highest expression of CD73 on tumor-infiltrating B-cells was identified on class-switched memory B-cells, followed by naive B-cells, whereas no CD73 expression was observed on plasmablasts. Clinicopathological correlation analysis revealed that higher CD73⁺ B-cells infiltration in the CRC tumors was associated with better overall survival. Moreover, metastasized patients showed a significantly decreased number of tumor-infiltrating CD73⁺ B-cells. Finally, neoadjuvant therapy correlated with reduced CD73⁺ B-cell numbers and CD73 expression on B-cells in the CRC tumors. As promising new immune therapies are being developed, the role of CD73⁺ B-cells and their subsets in the development of colorectal cancer should be further explored to find new therapeutic options.     

Characterization of a Cutibacterium acnes Camp Factor 1-Related Peptide as a New TLR-2 Modulator in In Vitro and Ex Vivo Models of Inflammation

Cutibacterium acnes (C. acnes) has been implicated in inflammatory acne where highly mutated Christie–Atkins–Munch–Petersen factor (CAMP)1 displays strong toll like receptor (TLR)-2 binding activity. Using specific antibodies, we showed that CAMP1 production was independent of C. acnes phylotype and involved in the induction of inflammation. We confirmed that TLR-2 bound both mutated and non-mutated recombinant CAMP1, and peptide array analysis showed that seven peptides (A14, A15, B1, B2, B3, C1 and C3) were involved in TLR-2 binding, located on the same side of the three-dimensional structure of CAMP1. Both mutated and non-mutated recombinant CAMP1 proteins induced the production of C-X-C motif chemokine ligand interleukin (CXCL)8/(IL)-8 in vitro in keratinocytes and that of granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, IL-1β and IL-10 in ex vivo human skin explants. Only A14, B1 and B2 inhibited the production of CXCL8/IL-8 by keratinocytes and that of (GM-CSF), TNF-α, IL-1β and IL-10 in human skin explants stimulated with rCAMP1 and C. acnes. Following pretreatment with B2, RNA sequencing on skin explants identified the 10 genes displaying the strongest differential expression as IL6, TNF, CXCL1, CXCL2, CXCL3, CXCL8, IL-1β, chemokine ligand (CCL)2, CCL4 and colony stimulating factor (CSF)2. We, thus, identified a new CAMP1-derived peptide as a TLR-2 modulator likely to be a good candidate for clinical evaluation.