Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by inflammation and impaired tissue regeneration, and is reported as the fourth leading cause of death ...worldwide by the Centers for Disease Control and Prevention (CDC). Environmental pollution and specifically motor vehicle emissions are known to play a role in the pathogenesis of COPD, but little is still known about the molecular mechanisms that are altered following diesel exhaust particles (DEP) exposure. Here we used lung organoids derived from co-culture of alveolar epithelial progenitors and fibroblasts to investigate the effect of DEP on the epithelial-mesenchymal signaling niche in the distal lung, which is essential for tissue repair. We found that DEP treatment impaired the number as well as the average diameter of both airway and alveolar type of lung organoids. Bulk RNA-sequencing of re-sorted epithelial cells and fibroblasts following organoid co-culture shows that the Nrf2 pathway, which regulates antioxidants' activity, was upregulated in both cell populations in response to DEP; and WNT/β-catenin signaling, which is essential to promote epithelial repair, was downregulated in DEP-exposed epithelial cells. We show that pharmacological treatment with anti-oxidant agents such as N-acetyl cysteine (NAC) or Mitoquinone mesylate (MitoQ) reversed the effect of DEP on organoids growth. Additionally, a WNT/β-catenin activator (CHIR99021) successfully restored WNT signaling and promoted organoid growth upon DEP exposure. We propose that targeting oxidative stress and specific signaling pathways affected by DEP in the distal lung may represent a strategy to restore tissue repair in COPD.
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•Diesel exhaust particles (DEP) impair lung alveolar epithelial progenitors.•DEP increases oxidative stress in lung fibroblasts and epithelial cells.•DEP reduces WNT/β-catenin signaling in the epithelial cells.•Anti-oxidants (NAC, MitoQ) and WNT/β-catenin activation revert the DEP effect.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nonyrast, excited states in neutron-rich 186W were populated via inelastic-scattering reactions using beams of 136Xe nuclei accelerated to 725 and 800 MeV. Levels populated in the reactions were ...investigated via particle-γ coincidence techniques using the Gammasphere array of high-purity germanium detectors and the compact heavy-ion counter, CHICO2. The Kπ = 2+ (γ ), Kπ = 0+ and Kπ = 2– (octupole) rotational side bands were extended to spins 14h¯, 12h¯, and 13h¯, respectively. A staggering pattern observed in the energies of levels in the Kπ = 2+ band was found to be consistent with a potential that gets softer to vibration in the γ degree of freedom with increasing spin. Furthermore, the odd-even staggering of states in the Kπ = 2– band was found to exhibit a phase opposite to that seen in the γ band; an effect most probably associated with Coriolis coupling to other, unobserved octupole vibrational bands in 186W.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Elevated plasma cholesterol and type 2 diabetes (T2D) are associated with coronary artery disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while ...individuals with hypercholesterolemia have reduced T2D risk. We explore the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic, and clinical data, we identify a glucose and lipid determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impact lipid and glucose levels in inverse directions. Experimental inhibition of one of the GLD network master regulators, lanosterol synthase (LSS), in mice confirms the inverse relationships to glucose and lipid levels as predicted by our model and provides mechanistic insights.
Melanoma represents an important public health problem, due to its high case-fatality rate. Identification of individuals at high risk would be of major interest to improve early diagnosis and ...ultimately survival. The aim of this study was to evaluate whether
variants predicted melanoma risk independently of at-risk phenotypic characteristics.
Data were collected within an international collaboration - the M-SKIP project. The present pooled analysis included data on 3,830 single, primary, sporadic, cutaneous melanoma cases and 2,619 controls from seven previously published case-control studies. All the studies had information on
gene variants by sequencing analysis and on hair color, skin phototype, and freckles, ie, the phenotypic characteristics used to define the red hair phenotype.
The presence of any
variant was associated with melanoma risk independently of phenotypic characteristics (OR 1.60; 95% CI 1.36-1.88). Inclusion of
variants in a risk prediction model increased melanoma predictive accuracy (area under the receiver-operating characteristic curve) by 0.7% over a base clinical model (
=0.002), and 24% of participants were better assessed (net reclassification index 95% CI 20%-30%). Subgroup analysis suggested a possibly stronger role of
in melanoma prediction for participants without the red hair phenotype (net reclassification index: 28%) compared to paler skinned participants (15%).
The authors suggest that measuring the
genotype might result in a benefit for melanoma prediction. The results could be a valid starting point to guide the development of scientific protocols assessing melanoma risk prediction tools incorporating the
genotype.
Background
Huntington’s disease (HD) is a genetic, neurodegenerative disease. Due to the progressive nature of HD and the absence of a cure, (health-related) quality of life ((HR)QoL) is an important ...topic. Several studies have investigated (HR)QoL in HD, yet a clear synthesis of the existing literature is lacking to date. We performed a systematic review on self-reported (HR)QoL, and factors and intervention effects associated with (HR)QoL in premanifest and manifest HD gene expansion carriers (pHDGECs and mHDGECs, respectively).
Methods
PubMed, EMBASE, Web of Science, and PsycINFO were searched systematically from September 17th, 2021, up to August 11th, 2022. Methodological and conceptual quality of the included studies was assessed with two appraisal tools.
Results
30 out of 70 eligible articles were included. mHDGECs experienced lower (HR)QoL compared to pHDGECs and controls, whereas mixed findings were reported when compared to other neurological diseases. Several factors were associated with (HR)QoL that might contribute to lower (HR)QoL in mHDGECs, including depressive symptoms, physical and psychological symptoms, lower functional capacity, lower support, and unmet needs. Multidisciplinary rehabilitation programs and a respiratory muscle training were beneficial for (HR)QoL in mHDGECs.
Discussion
(HR)QoL is experienced differently across the course of the disease. Although (HR)QoL is key for understanding the impact of HD and the effect of symptomatic treatment, there is a need to improve the methodological and conceptual shortcomings that were found in most studies, especially regarding the conceptual clarity when reporting on QoL and HRQoL. Suggestions for strengthening these shortcomings are provided in this review.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
According to the spectra in extended data figure 3 of ref. 1, the presence of the 263-keV peak indicates that chance coincidences are not negligible. Considering that only the 268-keV transition ...contributes to isomer depletion, the similar intensity ratios indicate that the peak at 268 keV comes mainly from contamination. ...the deduced excitation probability of P = 0.010(3) should be regarded as an upper limit for isomer depletion. Four transitions at 123, 203, 770 and 963 keV were used to deduce the average ratio (kave). Because these transitions, together with the 268-keV transition, are not visible above the background in spectra g1b2 and b1b2 (see extended data figure 3b, 3d of ref. 1), the definition of k for these transitions can be simplified as k = (g1g2)/(b1g2), without a drastic change in the central value. Furthermore, according to its definition, k is not sufficient to obtain the spectra shown in figure 3 of ref. ·, because the transitions of interest are not in coincidence with both gating transitions without the isomer depletion mechanism. ...the data analysis using k ratios introduced in ref. 1 is adequate for the discussion on figure 2, but not for figure 3 in ref. 1.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Chronic obstructive pulmonary disease (COPD) is characterized by a persistent inflammatory state in the lungs and defective tissue repair. Although the inflammatory response in patients with COPD is ...well characterized and known to be exaggerated during exacerbations, its contribution to lung injury and abnormal repair is still unclear. In this study, we aimed to investigate how the inflammatory microenvironment affects the epithelial progenitors and their supporting mesenchymal niche cells involved in tissue repair of the distal lung. We focused on IL-1β, a key inflammatory mediator that is increased during exacerbations of COPD, and used an organoid model of lung epithelial cells and fibroblasts to assess the effect of IL-1β treatment on these cells' transcriptome and secreted factors. Whereas direct treatment of the lung organoids with IL-1β promoted organoid growth, this switched toward inhibition when it was added as fibroblast pretreatment followed by organoid treatment. We then investigated the IL-1β-driven mechanisms in the fibroblasts and found an inflammatory response related to (C-X-C motif) ligand (CXCL) chemokines; we confirmed that these chemokines were responsible for the impaired organoid growth and found that targeting their C-X-C chemokine receptors 1/2 (CXCR1/2) receptors or the IL-1β intracellular signaling reduced the proinflammatory response and restored organoid growth. These data demonstrate that IL-1β alters the fibroblasts' state by promoting a distinct inflammatory response, switching their supportive function on epithelial progenitors toward an inhibitory one in an organoid assay. These results imply that chronic inflammation functions as a shift toward inhibition of repair, thereby contributing to chronic inflammatory diseases like COPD.
•There is no agreement on the significance of mirror self-recognition test in infancy.•In adults, the DMN has been associated with abstract self-processing.•Recognisers showed greater ...fronto-temporoparietal connectivity than Non-Recognisers.•Self-recognition may reflect a genuine advance in toddlers’ self-awareness.
How and when a concept of the ‘self’ emerges has been the topic of much interest in developmental psychology. Self-awareness has been proposed to emerge at around 18 months, when toddlers start to show evidence of physical self-recognition. However, to what extent physical self-recognition is a valid indicator of being able to think about oneself, is debated. Research in adult cognitive neuroscience has suggested that a common network of brain regions called Default Mode Network (DMN), including the temporo-parietal junction (TPJ) and the medial prefrontal cortex (mPFC), is recruited when we are reflecting on the self. We hypothesized that if mirror self-recognition involves self-awareness, toddlers who exhibit mirror self-recognition might show increased functional connectivity between frontal and temporoparietal regions of the brain, relative to those toddlers who do not yet show mirror self-recognition. Using fNIRS, we collected resting-state data from 18 Recognizers and 22 Non-Recognizers at 18 months of age. We found significantly stronger fronto-temporoparietal connectivity in Recognizers compared to Non-Recognizers, a finding which might support the hypothesized relationship between mirror-self recognition and self-awareness in infancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Genome-wide association studies (GWAS) have identified hundreds of cardiometabolic disease (CMD) risk loci. However, they contribute little to genetic variance, and most downstream gene-regulatory ...mechanisms are unknown. We genotyped and RNA-sequenced vascular and metabolic tissues from 600 coronary artery disease patients in the Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET). Gene expression traits associated with CMD risk single-nucleotide polymorphism (SNPs) identified by GWAS were more extensively found in STARNET than in tissue- and disease-unspecific gene-tissue expression studies, indicating sharing of downstream cis-/trans-gene regulation across tissues and CMDs. In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the low-density lipoprotein cholesterol and coronary artery disease risk gene PCSK9. STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy, and prevention.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
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