Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular ...coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF; gene name F3) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation. The mechanism of release involves type I IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 is a type I IFN-stimulated gene. Furthermore, F3 induction by lipopolysaccharide (LPS) is inhibited by the anti-inflammatory agents dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI). Mechanistically, inhibition of F3 by DMF and 4-OI involves suppression of Ifnb1 expression. Additionally, they block type I IFN- and caspase-11-mediated macrophage pyroptosis, and subsequent TF release. Thereby, DMF and 4-OI inhibit TF-dependent thrombin generation. In vivo, DMF and 4-OI suppress TF-dependent thrombin generation, pulmonary thromboinflammation, and lethality induced by LPS, E. coli, and S. aureus, with 4-OI additionally attenuating inflammation-associated coagulation in a model of SARS-CoV-2 infection. Our results identify the clinically approved drug DMF and the pre-clinical tool compound 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I IFN-TF axis.
Objectives
To establish the prevalence of pain and functional disability in Irish adults with moderate and severe haemophilia, and to examine demographic and lifestyle influences.
Methods
Males ...≥18 years with moderate or severe haemophilia participated. Pain and function were examined using the PROBE questionnaire.
Results
Of 49 participants median age 44 (IQR 32, 52) years, most had severe haemophilia (Factor VIII = 30; Factor IX = 13) and were on regular prophylaxis (88%). Those with moderate haemophilia (Factor VIII = 5; Factor IX = 1) treated on demand (12%). Acute (72%) and chronic pain (71%), functional difficulties (58%), and analgesic requirements (92%) were prevalent. Age was significantly associated with more advanced haemophilic arthropathy (p = .002), chronic pain (p = .029) and functional difficulties (p = .036). Adults who reported chronic pain commenced prophylaxis significantly later in life 32 (20, 51) vs. 8 (1, 23) years; p = .004. Physical activity was significantly lower in those with functional difficulties (p < .05). A disparity between self‐perceived ‘target joints’ and clinically defined target joints was also identified (76% vs. 23%).
Conclusion
Haemophilic arthropathy, pain and functional disability were prevalent amongst Irish adults with moderate and severe haemophilia. Age‐dependent lifestyle, analgesic and treatment influences on pain and function warrant further investigation.
Introduction
Although the measurement of physical activity (PA) amongst people with haemophilia (PWH) has become increasingly widespread in recent years, the relationship between PA and bleeding ...phenotype remains poorly understood. In addition, the influence of various treatment regimens on this relationship has not been defined.
Aim
This review aimed to systematically assess the data that are available regarding PA levels amongst PWH, as well as the relationship between PA and bleeding.
Methods
A systematic search of the online databases EMBASE, Cochrane, MEDLINE Ovid, CINAHL and Web of Science was conducted by two independent reviewers. Quality assessment was undertaken using the AXIS Critical Appraisal Tool for Cross‐sectional Studies and the STROBE checklist.
Results
Of 1902 sources identified overall, 36 articles were included. Low‐to‐moderate transparency of reporting and various sources of bias were identified. PA levels varied amongst heterogeneous samples of PWH. The relationship between PA and bleeds was inconclusive, although there was evidence that improvements in treatment over recent decades have appeared to enable PWH to become more physically active.
Conclusion
Based upon the limited available evidence, the relationship between PA and bleeding phenotype in PWH remains unclear. However, with the development of improved prophylaxis treatment regimens in recent years, there is evidence that PA levels have increased, especially amongst people with severe haemophilia. The use of validated outcome measures of PA and more robust reporting of bleeds and treatment regimen are warranted in future research, especially in a rapidly evolving era of new treatments for PWH.
Terminal sialylation determines the plasma half-life of von Willebrand factor (VWF). A role for macrophage galactose lectin (MGL) in regulating hyposialylated VWF clearance has recently been ...proposed. In this study, we showed that MGL influences physiological plasma VWF clearance. MGL inhibition was associated with a significantly extended mean residence time and 3-fold increase in endogenous plasma VWF antigen levels (P<0.05). Using a series of VWF truncations, we further demonstrated that the A1 domain of VWF is predominantly responsible for enabling the MGL interaction. Binding of both full-length and VWF-A1-A2-A3 to MGL was significantly enhanced in the presence of ristocetin (P<0.05), suggesting that the MGL-binding site in A1 is not fully accessible in globular VWF. Additional studies using different VWF glycoforms demonstrated that VWF O-linked glycans, clustered at either end of the A1 domain, play a key role in protecting VWF against MGLmediated clearance. Reduced sialylation has been associated with pathological, increased clearance of VWF in patients with von Willebrand disease. Herein, we demonstrate that specific loss of α2-3 linked sialylation from O-glycans results in markedly increased MGL-binding in vitro, and markedly enhanced MGL-mediated clearance of VWF in vivo. Our data further show that the asialoglycoprotein receptor (ASGPR) does not have a significant role in mediating the increased clearance of VWF following loss of O-sialylation. Conversely however, we observed that loss of N-linked sialylation from VWF drives enhanced circulatory clearance predominantly via the ASGPR. Collectively, our data support the hypothesis that in addition to regulating physiological VWF clearance, the MGL receptor works in tandem with ASGPR to modulate enhanced clearance of aberrantly sialylated VWF in the pathogenesis of von Willebrand disease.
There is growing evidence that the imbalance between oxidative stress and the antioxidant defense system may
be associated with the development neuropsychiatric disorders, such as depression and ...anxiety. Major depression and
anxiety are presently correlated with a lowered total antioxidant state and by an activated oxidative stress (OS) pathway.
The classical antidepressants may produce therapeutic effects other than regulation of monoamines by increasing the
antioxidant levels and normalizing the damage caused by OS processes. This chapter provides an overview of recent work
on oxidative stress markers in the animal models of depression and anxiety, as well as patients with the aforementioned
mood disorders. It is well documented that antioxidants can remove the reactive oxygen species (ROS) and reactive
nitrogen species (RNS) through scavenging radicals and suppressing the OS pathway, which further protect against
neuronal damage caused oxidative or nitrosative stress sources in the brain, hopefully resulting in remission of depression
or anxiety symptoms. The functional understanding of the relationship between oxidative stress and depression and
anxiety may pave the way for discovery of novel targets for treatment of neuropsychiatric disorders.
Context.
Strong lenses are extremely useful probes of the distribution of matter on galaxy and cluster scales at cosmological distances, however, they are rare and difficult to find. The number of ...currently known lenses is on the order of 1000.
Aims.
The aim of this study is to use crowdsourcing to carry out a lens search targeting massive galaxies selected from over 442 square degrees of photometric data from the Hyper Suprime-Cam (HSC) survey.
Methods.
Based on the S16A internal data release of the HSC survey, we chose a sample of ∼300 000 galaxies with photometric redshifts in the range of 0.2 <
z
phot
< 1.2 and photometrically inferred stellar masses of log
M
*
> 11.2. We crowdsourced lens finding on this sample of galaxies on the Zooniverse platform as part of the Space Warps project. The sample was complemented by a large set of simulated lenses and visually selected non-lenses for training purposes. Nearly 6000 citizen volunteers participated in the experiment. In parallel, we used Y
ATTA
L
ENS
, an automated lens-finding algorithm, to look for lenses in the same sample of galaxies.
Results.
Based on a statistical analysis of classification data from the volunteers, we selected a sample of the most promising ∼1500 candidates, which we then visually inspected: half of them turned out to be possible (grade C) lenses or better. By including lenses found by Y
ATTA
L
ENS
or serendipitously noticed in the discussion section of the Space Warps website, we were able to find 14 definite lenses (grade A), 129 probable lenses (grade B), and 581 possible lenses. Y
ATTA
L
ENS
found half the number of lenses that were discovered via crowdsourcing.
Conclusions.
Crowdsourcing is able to produce samples of lens candidates with high completeness, when multiple images are clearly detected, and with higher purity compared to the currently available automated algorithms. A hybrid approach, in which the visual inspection of samples of lens candidates pre-selected by discovery algorithms or coupled to machine learning is crowdsourced, will be a viable option for lens finding in the 2020s, with forthcoming wide-area surveys such as LSST,
Euclid
, and WFIRST.
•Bay 60-7550 exhibits antidepressant- and anxiolytic-like effects in mouse behaviors.•Increased cGMP signaling may contribute to the protective effects of Bay 60-7550.•Bay 60-7550 is able to ...antagonize the oxidative damage produced by chronic stress.•Another possible mechanism of Bay 60-7550's function is its anti-apoptotic effects.
Stress occurs in everyday life, but the relationship between stress and the onset or development of depression/anxiety remains unknown. Increasing evidence suggests that the impairment of antioxidant defense and the neuronal cell death are important in the process of emotional disorders. Chronic stress impairs the homeostasis of antioxidants/oxidation, which results in the aberrant stimulation of the cell cycle proteins where cGMP-PKG signaling is thought to have an inhibitory role. Phosphodiesterase 2 (PDE2) is linked to cGMP-PKG signaling and highly expressed in the limbic brain regions including hippocampus and amygdala, which may play important roles in the treatment of depression and anxiety. To address the possible effects of PDE2 inhibitors on depression-/anxiety-like behaviors and the underlying mechanisms, Bay 60-7550 (0.75, 1.5 and 3mg/kg, i.p.) was administered 30min before chronic stress. The results suggested that Bay 60-7550 not only restored the behavioral changes but also regulated Cu/Zn superoxide dismutase (SOD) levels differentially in hippocampus and amygdala, which were increased in the hippocampus while decreased in the amygdala. It was also significant that Bay 60-7550 regulated the abnormalities of pro- and anti-apoptotic components, such as Bax, Caspase 3 and Bcl-2, and the indicator of PKG signaling characterized by pVASPser239, in these two brain regions. The results suggested that Bay 60-7550 is able to alleviate oxidative stress and mediate part of the apoptotic machinery in neuronal cells possibly through SOD-cGMP/PKG-anti-apoptosis signaling and that inhibition of PDE2 may represent a novel therapeutic target for psychiatric disorders, such as depression and anxiety.
Hypertension is the most common cause of left ventricular (LV) hypertrophy. However, multiple causes can lead to LV hypertrophy, each of which has different histological and mechanical properties. To ...assess the value of a novel speckle-tracking echocardiographic measurement of myocardial strain and strain rate in defining the mechanical properties of LV hypertrophy, 20 patients with asymmetric hypertrophic cardiomyopathy, 24 patients with secondary LV hypertrophy, 12 patients with biopsy-proved confirmed cardiac amyloidosis, and 22 age-matched healthy asymptomatic volunteers were studied. Patients with amyloidosis had severe diastolic dysfunction, and myocardial deformation was significantly decreased. The new technique allowed cardiac amyloid to be easily differentiated from the other categories. In patients with hypertrophic cardiomyopathy, there was segmental myocardium dysfunction as assessed by strain imaging. LV global systolic velocity and radial displacement were higher, and abnormal relaxation was more frequent, in the group with secondary LV hypertrophy than in normal controls. In conclusion, the observations from strain parameters derived from speckle tracking were consistent with the known underlying pathology of each condition, which speaks to the value of strain imaging. Cardiac amyloid profoundly alters all strain parameters, and analysis of these parameters could aid in the diagnosis.
Abstract
We investigated brain wiring in chronic schizophrenia and healthy controls in frontostriatal circuits using diffusion magnetic resonance imaging tractography in a novel way.
We extracted ...diffusion streamlines in 27 chronic schizophrenia and 26 healthy controls connecting 4 frontal subregions to the striatum. We labeled the projection zone striatal surface voxels into 2 subtypes: dominant-input from a single cortical subregion, and, functionally integrative, with mixed-input from diverse cortical subregions.
We showed: 1) a group difference for total striatal surface voxel number (P = .045) driven by fewer mixed-input voxels in the left (P = .007), but not right, hemisphere; 2) a group by hemisphere interaction for the ratio quotient between voxel subtypes (P = .04) with a left (P = .006), but not right, hemisphere increase in schizophrenia, also reflecting fewer mixed-input voxels; and 3) fewer mixed-input voxel counts in schizophrenia (P = .045) driven by differences in left hemisphere limbic (P = .007) and associative (P = .01), but not sensorimotor, striatum.
These results demonstrate a less integrative pattern of frontostriatal structural connectivity in chronic schizophrenia. A diminished integrative pattern yields a less complex input pattern to the striatum from the cortex with less circuit integration at the level of the striatum. Further, as brain wiring occurs during early development, aberrant brain wiring could serve as a developmental biomarker for schizophrenia.
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