About 25% of patients with chronic obstructive pulmonary disease (COPD) will develop cachexia (fat-free body mass index <17 kg.m(-2) (males) or <14 kg.m(-2) (females)). This is associated with ...approximately 50% reduction in median survival. The pathogenetic mechanism has been variously suggested to result from the following: 1) energy imbalance; 2) disuse atrophy; 3) tissue hypoxia from arterial hypoxaemia; 4) systemic inflammation; and 5) anabolic hormonal insufficiency. Genetic polymorphisms implicate inflammatory cytokines, especially interleukin (IL)-1beta, but IL-6 and tumour necrosis factor (TNF)-alpha do not show polymorphisms in these patients. Early reports of elevated TNF-alpha levels suggested a role for inflammation, but recent studies have not shown elevated levels of either IL-6 or TNF-alpha. Therapeutic trials of nutritional support, hormonal supplementation, anti-TNF-alpha immunotherapy, ghrelin and antioxidants have been conducted, but only a few have shown any benefits in muscle structure and function. Considerably more mechanistic knowledge is needed before therapeutic recommendations can be made. At this time, it is not possible to attribute cachexia in COPD unequivocally to inflammation or any other cause, and much more research is needed. To date, studies have been predominantly cross-sectional, with measurements made only after cachexia has developed. Future research should target prospective observation, studying patients as cachexia progresses, since once cachexia is established, inflammatory cytokine levels may not be abnormal.
Essentials
Neutrophil elastase (NE) plays a role in extracellular trap formation (NETosis) triggered by microbes.
The contribution of NE was evaluated in mouse NETosis models of sterile inflammation ...and thrombosis.
NE is not required for mouse neutrophil NET production in vitro with non‐infectious stimuli.
NE deficiency had no significant effect on thrombosis in the inferior vena cava stenosis model.
Summary
Background
Neutrophil serine proteases have been implicated in coagulation and neutrophil extracellular trap (NET) formation. In human neutrophils, neutrophil elastase (NE) translocates to the nucleus during NETosis and cleaves histones, thus aiding in chromatin decondensation. NE−/− mice were shown not to release NETs in response to microbes. However, mouse studies evaluating the role of NE in NET formation in sterile inflammation and thrombosis are lacking.
Objective
We wished to establish if neutrophils from NE−/− mice have a defect in NETosis, similar to peptidylarginine deiminase 4 (PAD4−/−) mice, and how this might have an impact on venous thrombosis, a model where NETs are produced and are crucial to thrombus development.
Methods
We performed in vitro NET assays using neutrophils from wild‐type (WT), NE−/−, SerpinB1 (SB1)−/− and NE−/−SB1−/− mice. We compared WT and NE−/− animals using the inferior vena cava stenosis model of deep vein thrombosis (DVT).
Results
Neutrophil elastase deficiency resulted in a small reduction in ionomycin‐induced NET formation in vitro without affecting histone citrullination. However, NET production in response to phorbol 12‐myristate 13‐acetate or platelet activating factor was normal in neutrophils from two independent NE‐deficient mouse lines, and in NE−/−SB1−/− as compared with SB1−/− neutrophils. NE deficiency or inhibition did not prevent NETosis in vivo or DVT outcome.
Conclusions
Neutrophil elastase is not required for NET formation in mice. NE−/− mice, which form pathological venous thrombi containing NETs, do not phenocopy PAD4−/− mice in in vitro NETosis assays or experimental venous thrombosis. Our study suggests that NET‐targeted therapies need to be highly effective to have an impact on DVT.
Background: Upon activation, neutrophils can release nuclear material known as neutrophil extracellular traps (NETs), which were initially described as a part of antimicrobial defense. Extracellular ...chromatin was recently reported to be prothrombotic in vitro and to accumulate in plasma and thrombi of baboons with experimental deep vein thrombosis (DVT). Objective: To explore the source and role of extracellular chromatin in DVT. Methods: We used an established murine model of DVT induced by flow restriction (stenosis) in the inferior vena cava (IVC). Results: We demonstrate that the levels of extracellular DNA increase in plasma after 6 h IVC stenosis, compared with sham‐operated mice. Immunohistochemical staining revealed the presence of Gr‐1‐positive neutrophils in both red (RBC‐rich) and white (platelet‐rich) parts of thrombi. Citrullinated histone H3 (CitH3), an element of NETs’ structure, was present only in the red part of thrombi and was frequently associated with the Gr‐1 antigen. Immunofluorescent staining of thrombi showed proximity of extracellular CitH3 and von Willebrand factor (VWF), a platelet adhesion molecule crucial for thrombus development in this model. Infusion of Deoxyribonuclease 1 (DNase 1) protected mice from DVT after 6 h and also 48 h IVC stenosis. Infusion of an unfractionated mixture of calf thymus histones increased plasma VWF and promoted DVT early after stenosis application. Conclusions: Extracellular chromatin, likely originating from neutrophils, is a structural part of a venous thrombus and both the DNA scaffold and histones appear to contribute to the pathogenesis of DVT in mice. NETs may provide new targets for DVT drug development.
This article is a summary of the Sol Sherry Lecture of the Council on Arteriosclerosis, Thrombosis, and Vascular Biology, which was presented at the Scientific Sessions of the American Heart ...Association in November 2004. It highlights work from our laboratory, focusing mainly on new aspects of P-selectin and CD40L (CD154) biology and on the interplay of platelets and leukocytes in thrombosis and inflammation.
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.
The vast majority of people worldwide have been impacted by coronavirus disease (COVID-19). In addition to the millions of individuals who have been infected with the disease, billions of individuals ...have been asked or required by local and national governments to change their behavioral patterns. Previous research on epidemics or traumatic events suggests that this can lead to profound behavioral and mental health changes; however, researchers are rarely able to track these changes with frequent, near-real-time sampling or compare their findings to previous years of data for the same individuals.
By combining mobile phone sensing and self-reported mental health data among college students who have been participating in a longitudinal study for the past 2 years, we sought to answer two overarching questions. First, have the behaviors and mental health of the participants changed in response to the COVID-19 pandemic compared to previous time periods? Second, are these behavior and mental health changes associated with the relative news coverage of COVID-19 in the US media?
Behaviors such as the number of locations visited, distance traveled, duration of phone usage, number of phone unlocks, sleep duration, and sedentary time were measured using the StudentLife smartphone sensing app. Depression and anxiety were assessed using weekly self-reported ecological momentary assessments of the Patient Health Questionnaire-4. The participants were 217 undergraduate students, with 178 (82.0%) students providing data during the Winter 2020 term. Differences in behaviors and self-reported mental health collected during the Winter 2020 term compared to previous terms in the same cohort were modeled using mixed linear models.
During the first academic term impacted by COVID-19 (Winter 2020), individuals were more sedentary and reported increased anxiety and depression symptoms (P<.001) relative to previous academic terms and subsequent academic breaks. Interactions between the Winter 2020 term and the week of the academic term (linear and quadratic) were significant. In a mixed linear model, phone usage, number of locations visited, and week of the term were strongly associated with increased amount of COVID-19-related news. When mental health metrics (eg, depression and anxiety) were added to the previous measures (week of term, number of locations visited, and phone usage), both anxiety (P<.001) and depression (P=.03) were significantly associated with COVID-19-related news.
Compared with prior academic terms, individuals in the Winter 2020 term were more sedentary, anxious, and depressed. A wide variety of behaviors, including increased phone usage, decreased physical activity, and fewer locations visited, were associated with fluctuations in COVID-19 news reporting. While this large-scale shift in mental health and behavior is unsurprising, its characterization is particularly important to help guide the development of methods to reduce the impact of future catastrophic events on the mental health of the population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Histones are released from dying cells and contribute to antimicrobial defense during infection. However, extracellular histones are a double-edged sword because they also damage host tissue and may ...cause death. We studied the interactions of histones with platelets. Histones bound to platelets, induced calcium influx, and recruited plasma adhesion proteins such as fibrinogen to induce platelet aggregation. Hereby fibrinogen cross-linked histone-bearing platelets and triggered microaggregation. Fibrinogen interactions with αIIbβ3 integrins were not required for this process but were necessary for the formation of large platelet aggregates. Infused histones associated with platelets in vivo and caused a profound thrombocytopenia within minutes after administration. Mice lacking platelets or αIIbβ3 integrins were protected from histone-induced death but not from histone-induced tissue damage. Heparin, at high concentrations, prevented histone interactions with platelets and protected mice from histone-induced thrombocytopenia, tissue damage, and death. Heparin and histones are evolutionary maintained. Histones may combine microbicidal with prothrombotic properties to fight invading microbes and maintain hemostasis after injury. Heparin may provide an innate counter mechanism to neutralize histones and diminish collateral tissue damage.
Humans display a strong tendency to make spontaneous inferences concerning the thoughts and intentions of others. Although this ability relies upon the concerted effort of multiple brain regions, the ...dorsal medial prefrontal cortex (DMPFC) is most closely associated with the ability to reason about other people's mental states and form impressions of their character. Here, we investigated this region's putative social category preference using fMRI as 34 participants engaged in uninstructed viewing of a complex naturalistic stimulus. Using a data-driven "reverse correlation" approach, we characterize the DMPFC's stimulus response profile from ongoing neural responses to a dynamic movie stimulus. Results of this analysis demonstrate that the DMPFC's response profile is dominated by the presence of scenes involving social interactions between characters. Subsequent content analysis of video clips created from this response profile confirmed this finding. In contrast, regions of the inferotemporal and parietal cortex were selectively tuned to faces and actions, both features that often covary with social interaction but may be difficult to disentangle using standard event-related approaches. Together, these findings suggest that the DMPFC is finely tuned for processing social interaction above other categories and that this preference is maintained during unrestricted viewing of complex natural stimuli such as movies.
Recently, studies have brought into question whether the dorsal medial prefrontal cortex (DMPFC), a region long associated with social cognition, is specialized for the processing of social information. We examine the response profile of this region during natural viewing of a reasonably naturalistic stimulus (i.e., a Hollywood movie) using a data-driven reverse correlation technique. Our findings demonstrate that, during natural viewing, the DMPFC is strongly tuned to the social features of the stimulus above other categories. Moreover, this response differs from other areas with previously well characterized response profiles such as the lateral and medial fusiform gyrus. These findings suggest that this region's dominant function in everyday situations is to support reasoning about the thoughts and intentions of conspecifics.
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.
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