The haloacetonitriles (HANs) is an emerging class of nitrogenous-disinfection byproducts (N-DBPs) present in disinfected drinking, recycled, processed wastewaters, and reuse waters. HANs were ...identified as primary forcing agents that accounted for DBP-associated toxicity. We evaluated the toxic characteristics of iodoacetonitrile (IAN), bromoacetonitrile (BAN), dibromoacetonitrile (DBAN), bromochloroacetonitrile (BCAN), tribromoacetonitrile (TBAN), chloroacetonitrile (CAN), dichloroacetonitrile (DCAN), trichloroacetonitrile (TCAN), bromodichloroacetonitrile (BDCAN), and chlorodibromoacetonitrile (CDBAN). This research generated the first quantitative, comparative analyses on the mammalian cell cytotoxicity, genotoxicity and thiol reactivity of these HANs. The descending rank order for HAN cytotoxicity was TBAN ≈ DBAN > BAN ≈ IAN > BCAN ≈ CDBAN > BDCAN > DCAN ≈ CAN ≈ TCAN. The rank order for genotoxicity was IAN ≈ TBAN ≈ DBAN > BAN > CDBAN ≈ BDCAN ≈ BCAN ≈ CAN ≈ TCAN ≈ DCAN. The rank order for thiol reactivity was TBAN > BDCAN ≈ CDBAN > DBAN > BCAN > BAN ≈ IAN > TCAN. These toxicity metrics were associated with membrane permeability and chemical reactivity. Based on their physiochemical parameters and toxicity metrics, we developed optimized, robust quantitative structure activity relationship (QSAR) models for cytotoxicity and for genotoxicity. These models can predict cytotoxicity and genotoxicity of novel HANs prior to analytical biological evaluation.
The medial temporal lobe (MTL) supports a constellation of memory-related behaviors. Its involvement in perceptual processing, however, has been subject to enduring debate. This debate centers on ...perirhinal cortex (PRC), an MTL structure at the apex of the ventral visual stream (VVS). Here we leverage a deep learning framework that approximates visual behaviors supported by the VVS (i.e., lacking PRC). We first apply this approach retroactively, modeling 30 published visual discrimination experiments: excluding non-diagnostic stimulus sets, there is a striking correspondence between VVS-modeled and PRC-lesioned behavior, while each is outperformed by PRC-intact participants. We corroborate and extend these results with a novel experiment, directly comparing PRC-intact human performance to electrophysiological recordings from the macaque VVS: PRC-intact participants outperform a linear readout of high-level visual cortex. By situating lesion, electrophysiological, and behavioral results within a shared computational framework, this work resolves decades of seemingly inconsistent findings surrounding PRC involvement in perception.
•There is an enduring debate over medial temporal lobe (MTL) involvement in perception•We find that computational models of vision approximate MTL-lesioned visual behaviors•However, MTL-intact participants outperform MTL-lesioned and model performance•These MTL-dependent visual behaviors rely on perirhinal cortex, not the hippocampus
By integrating lesion, electrophysiological, and behavioral results within a deep learning framework, Bonnen et al. find that the medial temporal lobe—specifically, perirhinal cortex—enables visual discrimination behaviors not supported by canonical visual cortex alone.
Blood–biomaterial compatibility is essential for tissue repair especially for endovascular biomaterials where small-diameter vessel patency and endothelium formation is crucial. To address this ...issue, a composite biomaterial termed PFC fabricated from poly (glycerol sebacate), silk fibroin, and collagen was used to determine if functionalization with syndecan-4 (SYN4) would reduce thrombogenesis through the action of heparan sulfate. The material termed, PFC_SYN4, has structure and composition similar to native arterial tissue and has been reported to facilitate the binding and differentiation of endothelial colony-forming cells (ECFCs). In this study, the hemocompatibility of PFC_SYN4 was evaluated and compared with non-functionalized PFC, electrospun collagen, ePTFE, and bovine pericardial patch (BPV). Ultrastructurally, platelets were less activated when cultured on PFC and PFC_SYN4 compared to collagen where extensive platelet degranulation was observed. Quantitatively, 31% and 44% fewer platelets adhered to PFC_SYN4 compared to non-functionalized PFC and collagen, respectively. Functionalization of PFC resulted in reduced levels of complement activation compared to PFC, collagen, and BPV. Whole blood clotting times indicated that PFC_SYN4 was less thrombogenic compared with PFC, collagen, and BPV. These results suggest that syndecan-4 functionalization of blood-contacting biomaterials provides a novel solution for generating a reduced thrombogenic surface.
In Search of a Human Self-Regulation System Kelley, William M; Wagner, Dylan D; Heatherton, Todd F
Annual review of neuroscience,
07/2015, Letnik:
38, Številka:
1
Journal Article
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The capacity for self-regulation allows people to control their thoughts, behaviors, emotions, and desires. In spite of this impressive ability, failures of self-regulation are common and contribute ...to numerous societal problems, from obesity to drug addiction. Such failures frequently occur following exposure to highly tempting cues, during negative moods, or after self-regulatory resources have been depleted. Here we review the available neuroscientific evidence regarding self-regulation and its failures. At its core, self-regulation involves a critical balance between the strength of an impulse and an individual's ability to inhibit the desired behavior. Although neuroimaging and patient studies provide consistent evidence regarding the reward aspects of impulses and desires, the neural mechanisms that underlie the capacity for control have eluded consensus, with various executive control regions implicated in different studies. We outline the necessary properties for a self-regulation control system and suggest that the use of resting-state functional connectivity analyses may be useful for understanding how people regulate their behavior and why they sometimes fail in their attempts.
Clinical management of soft tissue sarcoma (STS) is particularly challenging. Here, we used digital pathology and deep learning (DL) for diagnosis and prognosis prediction of STS.
Our retrospective, ...multicenter study included a total of 506 histopathological slides from 291 patients with STS. The Cancer Genome Atlas cohort (240 patients) served as training and validation set. A second, multicenter cohort (51 patients) served as an additional test set. The use of the DL model (DLM) as a clinical decision support system was evaluated by nine pathologists with different levels of expertise. For prognosis prediction, 139 slides from 85 patients with leiomyosarcoma (LMS) were used. Area under the receiver operating characteristic (AUROC) and accuracy served as main outcome measures.
The DLM achieved a mean AUROC of 0.97 (±0.01) and an accuracy of 79.9% (±6.1%) in diagnosing the five most common STS subtypes. The DLM significantly improved the accuracy of the pathologists from 46.3% (±15.5%) to 87.1% (±11.1%). Furthermore, they were significantly faster and more certain in their diagnosis. In LMS, the mean AUROC in predicting the disease-specific survival status was 0.91 (±0.1) and the accuracy was 88.9% (±9.9%). Cox regression showed the DLM’s prediction to be a significant independent prognostic factor (P = 0.008, hazard ratio 5.5, 95% confidence interval 1.56-19.7) in these patients, outperforming other risk factors.
DL can be used to accurately diagnose frequent subtypes of STS from conventional histopathological slides. It might be used for prognosis prediction in LMS, the most prevalent STS subtype in our cohort. It can also help pathologists to make faster and more accurate diagnoses. This could substantially improve the clinical management of STS patients.
•A DLM was able to classify five of the most common STS subtypes from histology alone.•When aided by the DLM, pathologists were more accurate, faster, and more certain in their diagnosis.•A similar DLM was able to predict the disease-specific survival status in the most common STS subtype.•The DLM's prediction was an independent prognostic factor.•New image features associated with survival could be identified.
Polyploidy is common in the genus
. However, little is known about the origin, parentage and genomic composition of polyploid species because of a lack of suitable molecular markers and analysis ...tools. We established a phylogenomic framework including species of all described sections of Eurasian shrub willows. We analyzed the genomic composition of seven polyploid willow species in comparison to putative diploid parental species to draw conclusions on their origin and the effects of backcrossing and post-origin evolution. We applied recently developed programs like SNAPP, HyDe, and SNiPloid to establish a bioinformatic pipeline for unravelling the complexity of polyploid genomes. RAD sequencing revealed 23,393 loci and 320,010 high quality SNPs for the analysis of relationships of 35 species of Eurasian shrub willows (
subg.
). Polyploid willow species appear to be predominantly of allopolyploid origin. More ancient allopolyploidization events were observed for two hexaploid and one octoploid species, while our data suggested a more recent allopolyploid origin for the included tetraploids and identified putative parental taxa. SNiPloid analyses disentangled the different genomic signatures resulting from hybrid origin, backcrossing, and secondary post-origin evolution in the polyploid species. Our RAD sequencing data demonstrate that willow genomes are shaped by ancient and recent reticulate evolution, polyploidization, and post-origin divergence of species.
Extracellular DNA traps promote thrombosis Fuchs, Tobias A.; Brill, Alexander; Duerschmied, Daniel ...
Proceedings of the National Academy of Sciences - PNAS,
09/2010, Letnik:
107, Številka:
36
Journal Article
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Neutrophil extracellular traps (NETs) are part of the innate immune response to infections. NETs are a meshwork of DNA fibers comprising histones and antimicrobial proteins. Microbes are immobilized ...in NETs and encounter a locally high and lethal concentration of effector proteins. Recent studies show that NETs are formed inside the vasculature in infections and noninfectious diseases. Here we report that NETs provide a heretofore unrecognized scaffold and stimulus for thrombus formation. NETs perfused with blood caused platelet adhesion, activation, and aggregation. DNase or the anticoagulant heparin dismantled the NET scaffold and prevented thrombus formation. Stimulation of platelets with purified histones was sufficient for aggregation. NETs recruited red blood cells, promoted fibrin deposition, and induced a red thrombus, such as that found in veins. Markers of extracellular DNA traps were detected in a thrombus and plasma of baboons subjected to deep vein thrombosis, an example of inflammation-enhanced thrombosis. Our observations indicate that NETs are a previously unrecognized link between inflammation and thrombosis and may further explain the epidemiological association of infection with thrombosis.
How platelets safeguard vascular integrity HO‐TIN‐NOÉ, B.; DEMERS, M.; WAGNER, D. D.
Journal of thrombosis and haemostasis,
July 2011, 2011-Jul, 2011-07-00, 20110701, Letnik:
9, Številka:
Suppl 1
Journal Article
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The haemostatic role of platelets was established in the 1880s by Bizzozero who observed their ability to adhere and aggregate at sites of vascular injury. It was only some 80 years later that the ...function of platelets in maintaining the structural integrity of intact blood vessels was reported by Danielli. Danielli noted that platelets help preserve the barrier function of endothelium during organ perfusion. Subsequent studies have demonstrated further that platelets are continuously needed to support intact mature blood vessels. More recently, platelets were shown to safeguard developing vessels, lymphatics, as well as the microvasculature at sites of leukocyte infiltration, including inflamed organs and tumours. Interestingly, from a mechanistic point of view, the supporting role of platelets in these various vessels does not necessarily involve the well‐understood process of platelet plug formation but, rather, may rely on secretion of the various platelet granules and their many active components. The present review focuses on these nonconventional aspects of platelet biology and function by presenting situations in which platelets intervene to maintain vascular integrity and discusses possible mechanisms of their actions. We propose that modulating these newly described platelet functions may help treat haemorrhage as well as treat cancer by increasing the efficacy of drug delivery to tumours.
Cancer-associated thrombosis often lacks a clear etiology. However, it is linked to a poor prognosis and represents the second-leading cause of death in cancer patients. Recent studies have shown ...that chromatin released into blood, through the generation of neutrophil extracellular traps (NETs), is procoagulant and prothrombotic. Using a murine model of chronic myelogenous leukemia, we show that malignant and nonmalignant neutrophils are more prone to NET formation. This increased sensitivity toward NET generation is also observed in mammary and lung carcinoma models, suggesting that cancers, through a systemic effect on the host, can induce an increase in peripheral blood neutrophils, which are predisposed to NET formation. In addition, in the late stages of the breast carcinoma model, NETosis occurs concomitant with the appearance of venous thrombi in the lung. Moreover, simulation of a minor systemic infection in tumor-bearing, but not control, mice results in the release of large quantities of chromatin and a prothrombotic state. The increase in neutrophil count and their priming is mediated by granulocyte colony-stimulating factor (G-CSF), which accumulates in the blood of tumor-bearing mice. The prothrombotic state in cancer can be reproduced by treating mice with G-CSF combined with low-dose LPS and leads to thrombocytopenia and microthrombosis. Taken together, our results identify extracellular chromatin released through NET formation as a cause for cancer-associated thrombosis and unveil a target in the effort to decrease the incidence of thrombosis in cancer patients.
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