Kremens are high-affinity receptors for Dickkopf 1 (Dkk1) and regulate the Wnt/β-catenin signaling pathway by down-regulating the low-density lipoprotein receptor-related protein 6 (LRP6). Dkk1 ...competes with Wnt for binding to LRP6; binding of Dkk1 inhibits canonical signaling through formation of a ternary complex with Kremen. The majority of down-regulated clathrin-mediated endocytic receptors contain short conserved regions that recognize tyrosine or dileucine sorting motifs. In this study, we found that Kremen1 is internalized from the cell surface in a clathrin-dependent manner. Kremen1 contains an atypical dileucine motif with the sequence DXXXLV. Mutation of LV to AA in this motif blocked Kremen1 internalization; as reported previously for other proteins, the aspartic acid residue in Kremen1 is not critical. Inhibition of expression of the adaptor protein 2 (AP-2) or inhibition of clathrin by pitstop 2 also blocked Kremen1 internalization. The novel amino acid sequence identified in Kremen1 is similar to the motif previously identified in hydra, yeast, and other organisms known to signal from the trans-Golgi network to the endosomal compartment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We present a new method to photometrically delineate between various sub-types of Type Ia supernovae (SNe Ia). Using the color-stretch parameters, sBV or sgr, and the time of i-band primary maximum ...relative to the B-band ( ) or g-band ( ) maximum it is demonstrated that 2003fg-like, 1991bg-like, and 2002cx-like SNe Ia can be identified readily. In the cases of these extreme SNe Ia, their primary i-band maximum occurs after the time of the B- or g-band maxima. We suggest that the timing of the i-band maximum can reveal the physical state of the SN Ia explosion as it traces: (i) the speed of the recombination front of iron group elements in the ejecta, (ii) the temperature evolution and rate of adiabatic cooling in the ejecta and, (iii) the presence of interaction with a stellar envelope. This photometric sub-typing can be used in conjunction with other SNe analysis, such as the Branch diagram, to examine the physics and diversity of SNe Ia. The results here can also be used to screen out non-Ia SNe from cosmological samples that do not have complete spectroscopic typing. Finally, as future surveys like that of the Vera C. Rubin Observatory (previously referred to as the Large Synoptic Survey Telescope) create large databases of light curves of many objects this photometric identification can be used to readily identify and study the rates and bulk properties of peculiar SNe Ia.
Subependymal nodules (SENs) and subependymal giant cell astrocytomas (SEGAs) are common brain lesions found in patients with tuberous sclerosis complex (TSC). These brain lesions present a mixed ...glioneuronal phenotype and have been hypothesized to originate from neural stem cells. However, this hypothesis has not been tested empirically. Here, we report that loss of Tsc1 in mouse subventricular zone (SVZ) neural stem/progenitor cells (NSPCs) results in formation of SEN- and SEGA-like structural abnormalities in the lateral ventricle, the consequence of abnormal migration of NSPCs following Tsc1 loss.
•Pressure-mediated reflection spectroscopy correlates with 3-day intake of fruit and vegetables.•This method correlates with carotenoids in free living, healthy older adults.•Skin carotenoid content ...may be influenced in a carotenoid-specific manner.•Dark green vegetables are strongly associated with higher skin carotenoid scores.•Revision to dietary supplement data in databases is required for analysis.
Pressure-mediated reflection spectroscopy (RS) measures skin carotenoid content (SCC). Continued validation of this method is pertinent to validate its use as an objective measure of fruit and vegetable intake. This study aimed to assess relationships between SCC scores and self-reported dietary carotenoid intake from 3-day food records in community dwelling older adults. This was a cross-sectional analysis of baseline data among cognitively normal older adults (n = 95) participating in the Nutrition Interventions for Cognitive Enhancement (NICE) study. Food-derived vitamin A (R = 0.24, p < 0.05) and food plus supplemental vitamin A (R = 0.29, p < 0.01) were correlated with SCC. All food-derived carotenoids (R: 0.20−0.39, p < 0.05) except beta-cryptoxanthin and lycopene were correlated with SCC. Lutein + zeaxanthin from food more strongly correlated with SCC (R = 0.38, p < 0.001) than combined food plus supplemental intake (R = 0.31, p = 0.002). Correlations for total fruit and SCC (R = 0.23, p = 0.02), total vegetable and SCC (R = 0.31, p = 0.002), and combined total fruit and vegetable and SCC (R = 0.35, p < 0.001) were significant; no sub-categories of fruit or vegetables except dark green vegetables (Rho = 0.4, p < 0.001) had significant correlations with SCC. The current study demonstrates RS-derived SCC scores correlate with 3-day self-reported intakes of F/V and certain carotenoids in community dwelling older adults.
Traumatic brain injury (TBI) is a leading cause of global morbidity and mortality, partially due to the lack of sensitive diagnostic methods and efficacious therapies. Panels of protein biomarkers ...have been proposed as a way of diagnosing and monitoring TBI. To measure multiple TBI biomarkers simultaneously, we present a variable height microfluidic device consisting of a single channel that varies in height between the inlet and outlet and can passively multiplex bead-based immunoassays by trapping assay beads at the point where their diameter matches the channel height. We developed bead-based quantum dot-linked immunosorbent assays (QLISAs) for interleukin-6 (IL-6), glial fibrillary acidic protein (GFAP), and interleukin-8 (IL-8) using Dynabeads
M-450, M-270, and MyOne
, respectively. The IL-6 and GFAP QLISAs were successfully multiplexed using a variable height channel that ranged in height from ~7.6 µm at the inlet to ~2.1 µm at the outlet. The IL-6, GFAP, and IL-8 QLISAs were also multiplexed using a channel that ranged in height from ~6.3 µm at the inlet to ~0.9 µm at the outlet. Our system can keep pace with TBI biomarker discovery and validation, as additional protein biomarkers can be multiplexed simply by adding in antibody-conjugated beads of different diameters.
Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive ...component of marijuana, binds to cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis was an risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells were used to model Δ9-THC-induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of Δ9-THC. In mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. Genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis.
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•Marijuana use is associated with MI in UK Biobank database•Δ9-THC caused inflammation and oxidative stress in endothelial cells•Δ9-THC caused vascular dysfunction in mice models•Genistein, a CB1 antagonist, attenuated Δ9-THC-induced atherosclerosis
Marijuana use is on the rise and is associated with cardiovascular disease. Δ9-tetrahydrocannabinol (Δ9-THC), the psychedelic component of marijuana, causes vascular inflammation, oxidative stress, and atherosclerosis via cannabinoid receptor 1. Genistein, a soybean isoflavone, blocks harmful cardiovascular effects of Δ9-THC while preserving clinically useful effects such as sedation and analgesia.
To investigate the major organelles of the retinal pigment epithelium (RPE) in wild-type (WT, control) mice and their changes in pigmented Abca4 knockout (Abca4-/-) mice with in situ morphologic, ...spatial, and spectral characterization of live ex vivo flat-mounted RPE using multicolor confocal fluorescence microscopy (MCFM).
In situ imaging of RPE flat-mounts of agouti Abca4-/- (129S4), agouti WT (129S1/SvlmJ) controls, and B6 albino mice (C57BL/6J-Tyrc-Brd) was performed with a Nikon A1 confocal microscope. High-resolution confocal image z-stacks of the RPE cell mosaic were acquired with four different excitation wavelengths (405 nm, 488 nm, 561 nm, and 640 nm). The autofluorescence images of RPE, including voxel-by-voxel emission spectra, were acquired and processed with Nikon NIS-AR Elements software.
The 3-dimensional multicolor confocal images provided a detailed visualization of the RPE cell mosaic, including its melanosomes and lipofuscin granules, and their varying characteristics in the different mice strains. The autofluorescence spectra, spatial distribution, and morphologic features of melanosomes and lipofuscin granules were measured. Increased numbers of lipofuscin and reduced numbers of melanosomes were observed in the RPE of Abca4-/- mice relative to controls.
A detailed assessment of the RPE autofluorescent granules and their changes ex vivo was possible with MCFM. For all excitation wavelengths, autofluorescence from the RPE cells was predominantly contributed by lipofuscin granules, while melanosomes were found to be essentially nonfluorescent. The red shift of the emission peak confirmed the presence of multiple chromophores within lipofuscin granules. The elevated autofluorescence levels in Abca4-/- mice correlated well with the increased number of lipofuscin granules.
Abstract
Background
Inflammatory Bowel Disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC) is a chronic, lifelong illness that has multiple impacts on patients’ physical ...and mental health. Approximately 40,000 individuals in Ireland have IBD and the burden on quality of life is expected to be substantial. Health-related quality of life (HRQoL) utilises quality weights (utilities), measured on a ‘0’ to ‘1’ scale where ‘0’ is defined as a health state equivalent to being dead and ‘1’ is full health, and is often used as a measure of population health status to inform public health and health care policy. Previous evidence has shown that a reduced HRQoL in patients with IBD is associated with higher disease activity, increased medication use, increased sick leave, decreased work participation, smoking, rheumatic symptoms, female gender, and having CD. Despite this evidence, there is a paucity of data on the impact of IBD on the HRQoL of IBD patients in Ireland.
Methods
A cross-sectional, online study was developed aimed at IBD Patients in Ireland and patients were recruited through study invites advertised on The Crohn's and Colitis Ireland social media channels and among patient representatives of INITIative IBD. Information on quality of life was collected using the EuroQol EQ-5D-5L questionnaire. Descriptive statistics describe sociodemographic and clinical characteristics. Categorical variables are summarized as frequencies and percentages. Utility scores are presented as the mean and standard deviation (SD). To evaluate factors correlating with HRQoL in IBD patients, a univariate regression model was applied. Significant variables (p<0.05) were further included in a multivariable ordinal least squares regression model.
Results
A total of 161 IBD patients were recruited. The average EQ-5D-5L utility score was 0.76. Average utility scores were similar for UC (0.76) and CD (0.75) patients, with IBDU patients scoring slightly higher (0.80). Average utility scores were highest for those aged 50-59 years (0.93), with an average utility score for those aged 30-39 of 0.71. Average utility scores were higher in males (0.78). Utility scores ranged from .133 to 1. When compared with those in remission, patients with severe disease severity had significantly lower utility scores (β=-.261; p=0.000).
Conclusion
Findings suggest that HRQoL in IBD patients in Ireland varies according to disease severity. These findings may indicate that follow-up care should include generic HRQoL measurements along with disease-specific as an objective tool for monitoring IBD disease course. This research offers important information for policy-makers for developing better strategies for IBD patients, as well as clinicians, academics and IBD patients.
Breastfeeding is important for infants, and fathers are influential in supporting their partner in their decision to breastfeed and how long they breastfeed for. Fathers can feel excluded from ...traditional antenatal education and support opportunities but highly value social support from peers. Online health forums can be a useful source of social support, yet little is known about how fathers would use a conversation forum embedded in a breastfeeding-focused app. Milk Man is a mobile app that aimed to increase paternal support for breastfeeding using a range of strategies, including a conversation forum.
The aim of this study was to examine how fathers used a breastfeeding-focused conversation forum contained within a mobile app throughout the perinatal period.
A qualitative analysis of comments posted by users in the online forum contained within the Milk Man app was conducted. The app contained a library of information for fathers, as well as a conversation forum. Thematic analysis was used to organize and understand the data. The NVivo 11 software package was used to code comments into common nodes, which were then organized into key themes.
In all, 208 contributors (35.5% 208/586 of those who had access to the app) posted at least once within the forum. In total, 1497 comments were included for analysis. These comments were coded to 3799 individual nodes and then summarized to 54 tree nodes from which four themes emerged to describe how fathers used the app. Themes included seek and offer support, social connection, informational support provision, and sharing experiences. Posting in the forum was concentrated in the antenatal period and up to approximately 6 weeks postpartum.
These data show that fathers are prepared to use a breastfeeding-focused online forum in a variety of ways to facilitate social support. Fathers can be difficult to reach in the perinatal period, yet engaging them and increasing social support is important. This research demonstrates the acceptability of an innovative way of engaging new and expecting fathers.
Epithelial tumor metastasis is preceded by an accumulation of collagen cross-links that heighten stromal stiffness and stimulate the invasive properties of tumor cells. However, the biochemical ...nature of collagen cross-links in cancer is still unclear. Here, we postulated that epithelial tumorigenesis is accompanied by changes in the biochemical type of collagen cross-links. Utilizing resected human lung cancer tissues and a p21CIP1/WAF1-deficient, K-rasG12D-expressing murine metastatic lung cancer model, we showed that, relative to normal lung tissues, tumor stroma contains higher levels of hydroxylysine aldehyde-derived collagen cross-links (HLCCs) and lower levels of lysine aldehyde-derived cross-links (LCCs), which are the predominant types of collagen cross-links in skeletal tissues and soft tissues, respectively. Gain- and loss-of-function studies in tumor cells showed that lysyl hydroxylase 2 (LH2), which hydroxylates telopeptidyl lysine residues on collagen, shifted the tumor stroma toward a high-HLCC, low-LCC state, increased tumor stiffness, and enhanced tumor cell invasion and metastasis. Together, our data indicate that LH2 enhances the metastatic properties of tumor cells and functions as a regulatory switch that controls the relative abundance of biochemically distinct types of collagen cross-links in the tumor stroma.
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