Intracellular chloride channel protein 1 (CLIC1) is a 241 amino acid protein of the glutathione S transferase fold family with redox- and pH-dependent membrane association and chloride ion channel ...activity. Whilst CLIC proteins are evolutionarily conserved in Metazoa, indicating an important role, little is known about their biology. CLIC1 was first cloned on the basis of increased expression in activated macrophages. We therefore examined its subcellular localisation in murine peritoneal macrophages by immunofluorescence confocal microscopy. In resting cells, CLIC1 is observed in punctate cytoplasmic structures that do not colocalise with markers for endosomes or secretory vesicles. However, when these macrophages phagocytose serum-opsonised zymosan, CLIC1 translocates onto the phagosomal membrane. Macrophages from CLIC1(-/-) mice display a defect in phagosome acidification as determined by imaging live cells phagocytosing zymosan tagged with the pH-sensitive fluorophore Oregon Green. This altered phagosomal acidification was not accompanied by a detectable impairment in phagosomal-lysosomal fusion. However, consistent with a defect in acidification, CLIC1(-/-) macrophages also displayed impaired phagosomal proteolytic capacity and reduced reactive oxygen species production. Further, CLIC1(-/-) mice were protected from development of serum transfer induced K/BxN arthritis. These data all point to an important role for CLIC1 in regulating macrophage function through its ion channel activity and suggest it is a suitable target for the development of anti-inflammatory drugs.
Echocardiographic studies indicate South Asian people have smaller ventricular volumes, lower mass and more concentric remodelling than White European people, but there are no data using cardiac MRI ...(CMR). We aimed to compare CMR quantified cardiac structure and function in White European and South Asian people.
Healthy White European and South Asian participants in the UK Biobank Imaging CMR sub-study were identified by excluding those with a history of cardiovascular disease, hypertension, obesity or diabetes. Ethnic groups were matched by age and sex. Cardiac volumes, mass and feature tracking strain were compared.
121 matched pairs (77 male/44 female, mean age 58 ± 8 years) of South Asian and White European participants were included. South Asian males and females had smaller absolute but not indexed left ventricular (LV) volumes, and smaller absolute and indexed right ventricular volumes, with lower absolute and indexed LV mass and lower LV mass:volume than White European participants. Although there were no differences in ventricular or atrial ejection fractions, LV global longitudinal strain was higher in South Asian females than White European females but not males, and global circumferential strain was higher in both male and South Asian females than White European females. Peak early diastolic strain rates were higher in South Asian versus White European males, but not different between South Asian and White European females.
Contrary to echocardiographic studies, South Asian participants in the UK Biobank study had less concentric remodelling and higher global circumferential strain than White European subjects. These findings emphasise the importance of sex- and ethnic- specific normal ranges for cardiac volumes and function.
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Cerebrovascular reactivity (CVR) is inversely related to white matter hyperintensity severity, a marker of cerebral small vessel disease (SVD). Less is known about the relationship between CVR and ...other SVD imaging features or cognition. We aimed to investigate these cross-sectional relationships.
Between 2018 and 2021 in Edinburgh, we recruited patients presenting with lacunar or cortical ischemic stroke, whom we characterized for SVD features. We measured CVR in subcortical gray matter, normal-appearing white matter, and white matter hyperintensity using 3T magnetic resonance imaging. We assessed cognition using Montreal Cognitive Assessment. Statistical analyses included linear regression models with CVR as outcome, adjusted for age, sex, and vascular risk factors. We reported regression coefficients with 95% CIs.
Of 208 patients, 182 had processable CVR data sets (median age, 68.2 years; 68% men). Although the strength of association depended on tissue type, lower CVR in normal-appearing tissues and white matter hyperintensity was associated with larger white matter hyperintensity volume (B
=-0.0073 95% CI, -0.0133 to -0.0014 %/mm Hg per 10-fold increase in percentage intracranial volume), more lacunes (B
=-0.00129 95% CI, -0.00215 to -0.00043 %/mm Hg per lacune), more microbleeds (B
=-0.00083 95% CI, -0.00130 to -0.00036 %/mm Hg per microbleed), higher deep atrophy score (B
=-0.00218 95% CI, -0.00417 to -0.00020 %/mm Hg per score point increase), higher perivascular space score (B
=-0.0034 95% CI, -0.0066 to -0.0002 %/mm Hg per score point increase in basal ganglia), and higher SVD score (B
=-0.0048 95% CI, -0.0075 to -0.0021 %/mm Hg per score point increase). Lower CVR in normal-appearing tissues was related to lower Montreal Cognitive Assessment without reaching convention statistical significance (B
=0.00065 95% CI, -0.00007 to 0.00137 %/mm Hg per score point increase).
Lower CVR in patients with SVD was related to more severe SVD burden and worse cognition in this cross-sectional analysis. Longitudinal analysis will help determine whether lower CVR predicts worsening SVD severity or vice versa.
URL: https://www.isrctn.com; Unique identifier: ISRCTN12113543.
ABSTRACT Using the Submillimeter Array (SMA) on Mauna Kea, the H 2 16 O 10 2,9 -9 3,6 transition ( E up = 1863 K) at 321.2 GHz has been detected toward the embedded low-mass protostar HL Tau. The ...line centroid is blueshifted by 20 km s−1 with respect to the source velocity, and it has a FWHM of 25 km s−1. The emission is tentatively resolved and extends ∼3″-4″ over the sky (∼2 beams), or ∼500 au at the distance of Taurus. The velocity offset, and to a lesser degree the spatial extent of the emission, show that the line originates in the protostellar jet or wind. This result suggests that at least some water emission observed with Herschel and Spitzer toward embedded sources, and perhaps also disk sources, contains a wind or jet component, which is crucial for interpreting these data. These pathfinder observations done with the SMA open a new window into studying the origin of water emission with e.g., ALMA, thus providing new insights into where water is in protostellar systems.
Understanding how disks dissipate is essential to studies of planet formation. However, identifying exactly how dust and gas dissipate is complicated due to the difficulty of finding objects that are ...clearly in the transition phase of losing their surrounding material. We use Spitzer Infrared Spectrograph (IRS) spectra to examine 35 photometrically selected candidate cold disks (disks with large inner dust holes). The infrared spectra are supplemented with optical spectra to determine stellar and accretion properties and 1.3 mm photometry to measure disk masses. Based on detailed spectral energy distribution modeling, we identify 15 new cold disks. The remaining 20 objects have IRS spectra that are consistent with disks without holes, disks that are observed close to edge-on, or stars with background emission. Based on these results, we determine reliable criteria to identify disks with inner holes from Spitzer photometry, and examine criteria already in the literature. Applying these criteria to the c2d surveyed star-forming regions gives a frequency of such objects of at least 4% and most likely of order 12% of the young stellar object population identified by Spitzer. We also examine the properties of these new cold disks in combination with cold disks from the literature. Hole sizes in this sample are generally smaller than in previously discovered disks and reflect a distribution in better agreement with exoplanet orbit radii. We find correlations between hole size and both disk and stellar masses. Silicate features, including crystalline features, are present in the overwhelming majority of the sample, although the 10 mu m feature strength above the continuum declines for holes with radii larger than similar to 7 AU. In contrast, polycyclic aromatic hydrocarbons are only detected in 2 out of 15 sources. Only a quarter of the cold disk sample shows no signs of accretion, making it unlikely that photoevaporation is the dominant hole-forming process in most cases.
Background and Purpose- Perivascular spaces (PVS) around venules may help drain interstitial fluid from the brain. We examined relationships between suspected venules and PVS visible on brain ...magnetic resonance imaging. Methods- We developed a visual venular quantification method to examine the spatial relationship between venules and PVS. We recruited patients with lacunar stroke or minor nondisabling ischemic stroke and performed brain magnetic resonance imaging and retinal imaging. We quantified venules on gradient echo or susceptibility-weighted imaging and PVS on T2-weighted magnetic resonance imaging in the centrum semiovale and then determined overlap between venules and PVS. We assessed associations between venular count and patient demographic characteristics, vascular risk factors, small vessel disease features, retinal vessels, and venous sinus pulsatility. Results- Among 67 patients (69% men, 69.0±9.8 years), only 4.6% (range, 0%-18%) of venules overlapped with PVS. Total venular count increased with total centrum semiovale PVS count in 55 patients after accounting for venule-PVS overlap (β=0.468 95% CI, 0.187-0.750) and transverse sinus pulsatility (β=0.547 95% CI, 0.309-0.786) and adjusting for age, sex, and systolic blood pressure. Conclusions- Despite increases in both visible PVS and suspected venules, we found minimal spatial overlap between them in patients with sporadic small vessel disease, suggesting that most magnetic resonance imaging-visible centrum semiovale PVS are periarteriolar rather than perivenular.
Background: The emergence of new SARS-CoV-2 variants calls for more data on SARS-CoV-2 mRNA vaccine response. Aims: We aimed to assess the response to a third mRNA vaccine dose against SARS-CoV-2 in ...inflammatory bowel disease (IBD) patients. Methods: This was a single-center, observational prospective study of IBD patients who received a third mRNA vaccine dose against SARS-CoV-2. Antibody titers were taken post-third-dose at one and three months using the Roche Elecsys anti-SARS-CoV-2-S enzyme immunoassay. Titers less than 0.8 units/mL were considered negative according to the manufactures. Titers between 0.8 units/mL and 250 units/mL were considered non-neutralizing. Titers greater than 250 units/mL were considered neutralizing. Results: Eighty-three patients were included, all of whom had detectable antibodies at 3 months post-third dose. A total of 89% showed neutralizing and 11% non-neutralizing titers. Participants with non-neutralizing titers were more likely to be on systemic corticosteroids (p = 0.04). Two participants seroconverted from negative to positive, whereas 86% with non-neutralizing titers boosted to neutralizing levels. Only one participant with neutralizing titers after a third dose had a decrease to a non-neutralizing level within 3 months. Conclusions: Our findings support the ongoing recommendations for additional doses in immunocompromised individuals. However, longitudinal studies with a greater-sized patient population are needed.
The detrimental effects of invasive lionfishes (
Pterois volitans
and
Pterois miles
) on western Atlantic shallow reefs are well documented, including declines in coral cover and native fish ...populations, with disproportionate predation on critically endangered reef fish in some locations. Yet despite individuals reaching depths >100 m, the role of mesophotic coral ecosystems (MCEs; reefs 30–150 m) in lionfish ecology has not been addressed. With lionfish control programs in most invaded locations limited to 30 m by diving restrictions, understanding the role of MCEs in lionfish distributions remains a critical knowledge gap potentially hindering conservation management. Here we synthesise unpublished and previously published studies of lionfish abundance and body length at paired shallow reef (0–30 m) and MCE sites in 63 locations in seven western Atlantic countries and eight sites in three Indo-Pacific countries where lionfish are native. Lionfish were found at similar abundances across the depth gradient from shallow to adjacent MCEs, with no difference between invaded and native sites. Of the five invaded countries where length data were available three had larger lionfish on mesophotic than shallow reefs, one showed no significant difference, while the fifth represented a recently invaded site. This suggests at least some mesophotic populations may represent extensions of natural ontogenetic migrations. Interestingly, despite their shallow focus, in many cases culling programs did not appear to alter abundance between depths. In general, we identify widespread invasive lionfish populations on MCE that could be responsible for maintaining high densities of lionfish recruits despite local shallow-biased control programs. This study highlights the need for management plans to incorporate lionfish populations below the depth limit of recreational diving in order to address all aspects of the local population and maximise the effectiveness of control efforts.
Enlarged perivascular spaces (PVS) and white matter hyperintensities (WMH) are features of cerebral small vessel disease which can be seen in brain magnetic resonance imaging (MRI). Given the ...associations and proposed mechanistic link between PVS and WMH, they are hypothesized to also have topological proximity. However, this and the influence of their spatial proximity on WMH progression are unknown. We analyzed longitudinal MRI data from 29 out of 32 participants (mean age at baseline = 71.9 years) in a longitudinal study of cognitive aging, from three waves of data collection at 3-year intervals, alongside semi-automatic segmentation masks for PVS and WMH, to assess relationships. The majority of deep WMH clusters were found adjacent to or enclosing PVS (waves-1: 77%; 2: 76%; 3: 69%), especially in frontal, parietal, and temporal regions. Of the WMH clusters in the deep white matter that increased between waves, most increased around PVS (waves-1-2: 73%; 2-3: 72%). Formal statistical comparisons of severity of each of these two SVD markers yielded no associations between deep WMH progression and PVS proximity. These findings may suggest some deep WMH clusters may form and grow around PVS, possibly reflecting the consequences of impaired interstitial fluid drainage
PVS. The utility of these relationships as predictors of WMH progression remains unclear.
Growing interest surrounds perivascular spaces (PVS) as a clinical biomarker of brain dysfunction given their association with cerebrovascular risk factors and disease. Neuroimaging techniques ...allowing quick and reliable quantification are being developed, but, in practice, they require optimisation as their limits of validity are usually unspecified.
We evaluate modifications and alternatives to a state-of-the-art (SOTA) PVS segmentation method that uses a vesselness filter to enhance PVS discrimination, followed by thresholding of its response, applied to brain magnetic resonance images (MRI) from patients with sporadic small vessel disease acquired at 3 T.
The method is robust against inter-observer differences in threshold selection, but separate thresholds for each region of interest (i.e., basal ganglia, centrum semiovale, and midbrain) are required. Noise needs to be assessed prior to selecting these thresholds, as effect of noise and imaging artefacts can be mitigated with a careful optimisation of these thresholds. PVS segmentation from T1-weighted images alone, misses small PVS, therefore, underestimates PVS count, may overestimate individual PVS volume especially in the basal ganglia, and is susceptible to the inclusion of calcified vessels and mineral deposits. Visual analyses indicated the incomplete and fragmented detection of long and thin PVS as the primary cause of errors, with the Frangi filter coping better than the Jerman filter.
Limits of validity to a SOTA PVS segmentation method applied to 3 T MRI with confounding pathology are given.
Evidence presented reinforces the STRIVE-2 recommendation of using T2-weighted images for PVS assessment wherever possible. The Frangi filter is recommended for PVS segmentation from MRI, offering robust output against variations in threshold selection and pathology presentation.
•Practical evaluations on filter and threshold selection to a SOTA MRI-visible PVS segmentation method.•Practical recommendations on compensating noise impact in SOTA PVS segmentation method.•Comparison PVS segmentation performance on T1-weighted vs. T2-weighted MRI.
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