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.
Platelets in Inflammation and Thrombosis Wagner, Denisa D; Burger, Peter C
Arteriosclerosis, thrombosis, and vascular biology,
2003-December, Letnik:
23, Številka:
12
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ABSTRACT—For many years it has been known that platelets play an important role in thrombosis and hemostasis. In recent times, however, it has become evident that platelets also have relevant ...functions in inflammation. It was shown that thrombosis and inflammation share several key molecular mechanisms and in fact are 2 intrinsically linked processes. In this review, we intend to give a short overview with emphasis on work stemming from our laboratory.
•MCE habitat and diversity have been previously underestimated.•The shallow-water reef community overlaps considerably with the upper mesophotic.•The lower mesophotic harbors a distinct community ...with specialized species.•Horizontal connectivity between MCEs remains largely unknown.
While substantial mesophotic coral ecosystem (MCE) habitat (>30–40m) remains uninvestigated, recent investigations show that the extent of both MCE habitat and species diversity is greater than previously thought. The depth distributions and biogeographic ranges for many shallow-water organisms have also been historically underestimated. The upper mesophotic is home to many shallow-water marine organisms and represents a transition zone between shallow-water and lower mesophotic communities. The lower mesophotic represents a distinct community with some species exhibiting special physiological adaptations. Therefore, vertical connectivity is predominantly relevant between the upper mesophotic and shallow-water reefs. In some cases vertical connectivity is restricted due to genetic adaptation to these opposing reef habitats. Horizontal connectivity between MCEs remains largely unknown and represents an important avenue for future research.
Deep vein thrombosis and pulmonary embolism are major health problems associated with high mortality. Recently, DNA-based neutrophil extracellular traps (NETs) resulting from the release of ...decondensed chromatin, were found to be part of the thrombus scaffold and to promote coagulation. However, the significance of nuclear decondensation and NET generation in thrombosis is largely unknown. To address this, we adopted a stenosis model of deep vein thrombosis and analyzed venous thrombi in peptidylarginine deiminase 4 (PAD4)-deficient mice that cannot citrullinate histones, a process required for chromatin decondensation and NET formation. Intriguingly, less than 10% of PAD4 ⁻/⁻ mice produced a thrombus 48 h after inferior vena cava stenosis whereas 90% of wild-type mice did. Neutrophils were abundantly present in thrombi formed in both groups, whereas extracellular citrullinated histones were seen only in thrombi from wild-type mice. Bone marrow chimera experiments indicated that PAD4 in hematopoietic cells was the source of the prothrombotic effect in deep vein thrombosis. Thrombosis could be rescued by infusion of wild-type neutrophils, suggesting that neutrophil PAD4 was important and sufficient. Endothelial activation and platelet aggregation were normal in PAD4 ⁻/⁻ mice, as was hemostatic potential determined by bleeding time and platelet plug formation after venous injury. Our results show that PAD4-mediated chromatin decondensation in the neutrophil is crucial for pathological venous thrombosis and present neutrophil activation and PAD4 as potential drug targets for deep vein thrombosis.
Animals rely on learned associations to make decisions. Associations can be based on relationships between object features (e.g., the three leaflets of poison ivy leaves) and outcomes (e.g., rash). ...More often, outcomes are linked to multidimensional states (e.g., poison ivy is green in summer but red in spring). Feature-based reinforcement learning fails when the values of individual features depend on the other features present. One solution is to assign value to multi-featural conjunctive representations. Here, we test if the hippocampus forms separable conjunctive representations that enables the learning of response contingencies for stimuli of the form: AB+, B-, AC-, C+. Pattern analyses on functional MRI data show the hippocampus forms conjunctive representations that are dissociable from feature components and that these representations, along with those of cortex, influence striatal prediction errors. Our results establish a novel role for hippocampal pattern separation and conjunctive representation in reinforcement learning.
Essentials
Neutrophil extracellular traps (NETs) might play a role in cancer‐related coagulopathy.
We determined NET biomarkers and followed cancer patients for venous thromboembolism (VTE).
We found ...a constant association with VTE for citrullinated histone H3.
Biomarkers of NET formation could reflect a novel pathomechanism of cancer‐related VTE.
Summary
Background
Neutrophil extracellular traps (NETs) are decondensed chromatin fibers that might play a role in the prothrombotic state of cancer patients.
Objectives
To investigate whether the levels of citrullinated histone H3 (H3Cit), a biomarker for NET formation, cell‐free DNA (cfDNA) and nucleosomes predict venous thromboembolism (VTE) in cancer patients.
Patients/Methods
Nine‐hundred and forty‐six patients with newly diagnosed cancer or progression after remission were enrolled in this prospective observational cohort study. H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients were followed for 2 years. VTE occurred in 89 patients; the cumulative 3‐month, 6‐month, 12‐month and 24‐month incidence rates of VTE were 3.7%, 6.0%, 8.1%, and 10.0%, respectively.
Results
Patients with elevated H3Cit levels (> 75th percentile of its distribution, n = 236) experienced a higher cumulative incidence of VTE (2‐year risk of 14.5%) than patients with levels below this cut‐off (2‐year risk of 8.5%, n = 710). In a competing‐risk regression analysis, a 100 ng mL−1 increase in H3Cit level was associated with a 13% relative increase in VTE risk (subdistribution hazard ratio SHR 1.13, 95% confidence interval CI 1.04–1.22). This association remained after adjustment for high VTE risk and very high VTE risk tumor sites, D‐dimer level, and soluble P‐selectin level (SHR 1.13, 95% CI 1.04–1.22). The association of elevated nucleosome and cfDNA levels with VTE risk was time‐dependent, with associations with a higher risk of VTE only during the first 3–6 months.
Conclusion
These data suggest that biomarkers of NET formation are associated with the occurrence of VTE in cancer patients, indicating a role of NETs in the pathogenesis of cancer‐associated thrombosis.
Cognitive control allows stimulus-response processing to be aligned with internal goals and is thus central to intelligent, purposeful behavior. Control is thought to depend in part on the active ...representation of task information in prefrontal cortex (PFC), which provides a source of contextual bias on perception, decision making, and action. In the present study, we investigated the organization, influences, and consequences of context representation as human subjects performed a cued sorting task that required them to flexibly judge the relationship between pairs of multivalent stimuli. Using a connectivity-based parcellation of PFC and multivariate decoding analyses, we determined that context is specifically and transiently represented in a region spanning the inferior frontal sulcus during context-dependent decision making. We also found strong evidence that decision context is represented within the intraparietal sulcus, an area previously shown to be functionally networked with the inferior frontal sulcus at rest and during task performance. Rule-guided allocation of attention to different stimulus dimensions produced discriminable patterns of activation in visual cortex, providing a signature of top-down bias over perception. Furthermore, demands on cognitive control arising from the task structure modulated context representation, which was found to be strongest after a shift in task rules. When context representation in frontoparietal areas increased in strength, as measured by the discriminability of high-dimensional activation patterns, the bias on attended stimulus features was enhanced. These results provide novel evidence that illuminates the mechanisms by which humans flexibly guide behavior in complex environments.
With the explosion of digital media and technologies, scholars, educators and the public have become increasingly vocal about the role that an 'attention economy' has in our lives
. The rise of the ...current digital culture coincides with longstanding scientific questions about why humans sometimes remember and sometimes forget, and why some individuals remember better than others
. Here we examine whether spontaneous attention lapses-in the moment
, across individuals
and as a function of everyday media multitasking
-negatively correlate with remembering. Electroencephalography and pupillometry measures of attention
were recorded as eighty young adults (mean age, 21.7 years) performed a goal-directed episodic encoding and retrieval task
. Trait-level sustained attention was further quantified using task-based
and questionnaire measures
. Using trial-to-trial retrieval data, we show that tonic lapses in attention in the moment before remembering, assayed by posterior alpha power and pupil diameter, were correlated with reductions in neural signals of goal coding and memory, along with behavioural forgetting. Independent measures of trait-level attention lapsing mediated the relationship between neural assays of lapsing and memory performance, and between media multitasking and memory. Attention lapses partially account for why we remember or forget in the moment, and why some individuals remember better than others. Heavier media multitasking is associated with a propensity to have attention lapses and forget.
Summary
Peripheral T‐cell lymphomas (PTCL) comprise a heterogeneous group of aggressive lymphoproliferative disorders almost all of which are associated with poor clinical outcomes. ...Angioimmunoblastic T‐cell lymphoma (AITL) and some peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) have similarities to normal CD4+ T‐cell subsets in their gene expression profiles. A cell of origin model is, therefore, emerging and is likely to be refined in the future. Follicular helper (Tfh) T cells are now established as the cell of origin of AITL and about 20% of PTCL‐NOS. Sequencing studies have identified recurrent genetic alterations in epigenetic modifiers, T‐cell receptor signalling pathway intermediates or RHOA, most commonly a specific mutation leading to RHOA G17V. While PTCL‐NOS remains a diagnosis of exclusion, advances in genomics have identified subgroups expressing transcription factors TBX 21 (Th1‐like origin) and GATA3 (Th2‐like origin). These findings suggest new biomarkers and new therapeutic avenues including the hypomethylating agent azacytidine, or inhibitors of proximal T‐cell receptor (TCR) signalling and potentially certain monoclonal antibodies. The advances over the past few years, therefore, prompt stratified medicine approaches to test biologically based treatments and determine the clinical utility of the new disease classifications.
Forging new memories for facts and events, holding critical details in mind on a moment-to-moment basis, and retrieving knowledge in the service of current goals all depend on a complex interplay ...between neural ensembles throughout the brain. Over the past decade, researchers have increasingly utilized powerful analytical tools (e.g., multivoxel pattern analysis) to decode the information represented within distributed functional magnetic resonance imaging activity patterns. In this review, we discuss how these methods can sensitively index neural representations of perceptual and semantic content and how leverage on the engagement of distributed representations provides unique insights into distinct aspects of memory-guided behavior. We emphasize that, in addition to characterizing the contents of memories, analyses of distributed patterns shed light on the processes that influence how information is encoded, maintained, or retrieved, and thus inform memory theory. We conclude by highlighting open questions about memory that can be addressed through distributed pattern analyses.
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