The bone morphogenetic protein (BMP) signaling pathway, including antagonists, functions in lung development and regeneration of tracheal epithelium from basal stem cells. Here, we explore its role ...in the alveolar region, where type 2 epithelial cells (AT2s) and Pdgfrα
type 2-associated stromal cells (TASCs) are components of the stem cell niche. We use organoids and
alveolar regrowth after pneumonectomy (PNX) - a process that requires proliferation of AT2s and differentiation into type 1 cells (AT1s). BMP signaling is active in AT2s and TASCs, transiently declines post-PNX in association with upregulation of antagonists, and is restored during differentiation of AT2s to AT1s. In organoids, BMP4 inhibits AT2 proliferation, whereas antagonists (follistatin, noggin) promote AT2 self-renewal at the expense of differentiation. Gain- and loss-of-function genetic manipulation reveals that reduced BMP signaling in AT2s after PNX allows self-renewal but reduces differentiation; conversely, increased BMP signaling promotes AT1 formation. Constitutive BMP signaling in Pdgfrα
cells reduces their AT2 support function, both after PNX and in organoid culture. Our data reveal multiple cell-type-specific roles for BMP signaling during alveolar regeneration.
Lungs are composed of a system of highly branched tubes that bring air into the alveoli, where gas exchange takes place. The proximal and distal regions of the lung contain epithelial cells ...specialized for different functions: basal, secretory and ciliated cells in the conducting airways and type II and type I cells lining the alveoli. Basal, secretory and type II cells can be grown in three-dimensional culture, with or without supporting stromal cells, and under these conditions they give rise to self-organizing structures known as organoids. This Review summarizes the different methods for generating organoids from cells isolated from human and mouse lungs, and compares their final structure and cellular composition with that of the airways or alveoli of the adult lung. We also discuss the potential and limitations of organoids for addressing outstanding questions in lung biology and for developing new drugs for disorders such as cystic fibrosis and asthma.
Studies suggest that vitamin D supplementation may reduce cancer and fracture risks.
To examine the benefits and harms of vitamin D with or without calcium supplementation on clinical outcomes of ...cancer and fractures in adults.
English-language studies identified from MEDLINE and the Cochrane Central Register of Controlled Trials through July 2011.
Randomized, controlled trials (RCTs), prospective cohort studies, and nested case-control studies reporting incidence of or death from cancer and fracture outcomes.
Multiple reviewers extracted details about participant characteristics, including baseline vitamin D status and use of supplements; details of statistical analyses, including adjustments for confounding; and methodological quality. Differences were resolved by consensus.
19 RCTs (3 for cancer and 16 for fracture outcomes) and 28 observational studies (for cancer outcomes) were analyzed. Limited data from RCTs suggested that high-dose (1000 IU/d) vitamin D supplementation can reduce the risk for total cancer, and data from observational studies suggested that higher blood 25-hydroxyvitamin D (25-OHD) concentrations might be associated with increased risk for cancer. Mixed-effects dose-response meta-analyses showed that each 10-nmol/L increase in blood 25-(OH)D concentration was associated with a 6% (95% CI, 3% to 9%) reduced risk for colorectal cancer but no statistically significant dose-response relationships for prostate and breast cancer. Random-effects model meta-analysis showed that combined vitamin D and calcium supplementation reduced fracture risk (pooled relative risk, 0.88 CI, 0.78 to 0.99) in older adults, but the effects differed according to study setting: institution (relative risk, 0.71 CI, 0.57 to 0.89) versus community-dwelling (relative risk, 0.89 CI, 0.76 to 1.04). One RCT showed adverse outcomes associated with supplementation, including increased risk for renal and urinary tract stones.
Most trial participants were older (aged≥65 years) postmenopausal women. Observational studies were heterogeneous and were limited by potential confounders.
Combined vitamin D and calcium supplementation can reduce fracture risk, but the effects may be smaller among community-dwelling older adults than among institutionalized elderly persons. Appropriate dose and dosing regimens, however, require further study. Evidence is not sufficiently robust to draw conclusions regarding the benefits or harms of vitamin D supplementation for the prevention of cancer.
Agency for Healthcare Research and Quality.
This paper explores the slowdown in labour productivity growth in the UK and other advanced economies by decomposing its growth into contributions from different sectors of the economy, looking at ...both within‐industry productivity growth and labour reallocation between sectors. We find that the within‐industry contribution is the main source of the slowdown. Comparing trends pre‐ and post‐2008, the aggregate productivity slowdown can be attributed largely to the manufacturing sector and the information and communication (ICT) sector. Disaggregating further, the UK productivity growth slowdown can be attributed mainly to transport equipment and pharmaceuticals within manufacturing, and computer software and telecommunications within ICT. Strikingly, these are advanced, high value‐added sectors considered to be strengths of the UK economy. Looking across other advanced economies, our results confirm that manufacturing and ICT sectors are the main drivers of the slowdown, to differing degrees. Part of the explanation for the slowdown in in these sectors may relate to the underlying question of how to construct deflators for a modern economy when technological and structural changes are leading to large relative price shifts. The structure and supply chains of the key slowdown sectors also merit further investigation.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Pulmonary fibrosis (PF) is a form of chronic lung disease characterized by pathologic epithelial remodeling and accumulation of extracellular matrix (ECM). To comprehensively define the cell types, ...mechanisms, and mediators driving fibrotic remodeling in lungs with PF, we performed single-cell RNA sequencing of single-cell suspensions from 10 nonfibrotic control and 20 PF lungs. Analysis of 114,396 cells identified 31 distinct cell subsets/states. We report that a remarkable shift in epithelial cell phenotypes occurs in the peripheral lung in PF and identify several previously unrecognized epithelial cell phenotypes, including a
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pathologic, ECM-producing epithelial cell population that was highly enriched in PF lungs. Multiple fibroblast subtypes were observed to contribute to ECM expansion in a spatially discrete manner. Together, these data provide high-resolution insights into the complexity and plasticity of the distal lung epithelium in human disease and indicate a diversity of epithelial and mesenchymal cells contribute to pathologic lung fibrosis.
Acetaminophen (APAP) overdose is one of the most common causes of drug-induced acute liver failure in humans. To investigate the hepatoprotective effect of salvianolic acid C (SAC) on APAP-induced ...hepatic damage, SAC was administered by daily intraperitoneal (i.p.) injection for 6 days before the APAP administration in mice. SAC prevented the elevation of serum biochemical parameters and lipid profile including aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-Bil), total cholesterol (TC), and triacylglycerol (TG) against acute liver failure. Additionally, SAC reduced the content of malondialdehyde (MDA), the cytochrome P450 2E1 (CYP2E1), and the histopathological alterations and inhibited the production of proinflammatory cytokines in APAP-induced hepatotoxicity. Importantly, SAC effectively diminished APAP-induced liver injury by inhibiting nuclear factor-kappa B (NF-κB), toll-like receptor 4 (TLR4), and mitogen-activated protein kinases (MAPKs) activation signaling pathway. Moreover, SAC enhanced the levels of hepatic activities of glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, and Kelch-like ECH-associated protein 1 (Keap1)/erythroid 2–related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in APAP-induced mice. SAC mainly inhibited the activation of apoptotic pathways by reduction of cytochrome c, Bax, and caspase-3 protein expression. Taken together, we provide the molecular evidence that SAC protected the hepatocytes from APAP-induced damage by mitigating mitochondrial oxidative stress, inflammatory response, and caspase-mediated antiapoptotic effect through inhibition of the Keap1/Nrf2/HO-1 signaling axis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Periodontal disease, which includes gingivitis and periodontitis, is highly prevalent in adults and disease severity increases with age. The relationship between periodontal disease and oral ...cancer has been examined for several decades, but there is increasing interest in the link between periodontal disease and overall cancer risk, with systemic inflammation serving as the main focus for biological plausibility. Numerous case-control studies have addressed the role of oral health in head and neck cancer, and several cohort studies have examined associations with other types of cancers over the past decade. For this review, we included studies that were identified from either 11 published reviews on this topic or an updated literature search on PubMed (between 2011 and July 2016). A total of 50 studies from 46 publications were included in this review. Meta-analyses were conducted on cohort and case-control studies separately when at least 4 studies could be included to determine summary estimates of the risk of cancer in relation to 1) periodontal disease or 2) tooth number (a surrogate marker of periodontal disease) with adjustment for smoking. Existing data provide support for a positive association between periodontal disease and risk of oral, lung, and pancreatic cancers; however, additional prospective studies are needed to better inform on the strength of these associations and to determine whether other cancers are associated with periodontal disease. Future studies should include sufficiently large sample sizes, improved measurements for periodontal disease, and thorough adjustment for smoking and other risk factors.
The Phalaenopsis orchid produces complex flowers that are commercially valuable, which has promoted the study of its flower development. E‐class MADS‐box genes, SEPALLATA (SEP), combined with B‐, C‐ ...and D‐class MADS‐box genes, are involved in various aspects of plant development, such as floral meristem determination, organ identity, fruit maturation, seed formation and plant architecture. Four SEP‐like genes were cloned from Phalaenopsis orchid, and the duplicated PeSEPs were grouped into PeSEP1/3 and PeSEP2/4. All PeSEPs were expressed in all floral organs. PeSEP2 expression was detectable in vegetative tissues. The study of protein–protein interactions suggested that PeSEPs may form higher order complexes with the B‐, C‐, D‐class and AGAMOUS LIKE6‐related MADS‐box proteins to determine floral organ identity. The tepal became a leaf‐like organ when PeSEP3 was silenced by virus‐induced silencing, with alterations in epidermis identity and contents of anthocyanin and chlorophyll. Silencing of PeSEP2 had minor effects on the floral phenotype. Silencing of the E‐class genes PeSEP2 and PeSEP3 resulted in the downregulation of B‐class PeMADS2‐6 genes, which indicates an association of PeSEP functions and B‐class gene expression. These findings reveal the important roles of PeSEP in Phalaenopsis floral organ formation throughout the developmental process by the formation of various multiple protein complexes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Recent theoretical contributions provide predictions about the effects of core product competence on firms' productivity. However, we know little about the influence of foreign ownership on core ...product competence that might also lead to productivity gains across firms. This paper uses firm-level data for 137 countries to investigate how foreign ownership affects firms' decision to become specialised at core products and the subsequently firm productivity gains. To tackle the possible endogeneity of foreign ownership, the instrumental variable approach and the propensity score matching technique are employed. The results show that foreign ownership has a positive and significant effect on firms' core product competence and this positive effect leads to productivity gains, especially for the most productive firms. We further reveal that foreign competition within an industry encourages firms to become specialised at core products, which could further lead to productivity gains across firms.
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BFBNIB, IZUM, KILJ, NUK, PILJ, SAZU, UL, UM, UPUK
Psychological and health-restorative benefits of mind-body therapies have been investigated, but their impact on the immune system remain less defined.
To conduct the first comprehensive review of ...available controlled trial evidence to evaluate the effects of mind-body therapies on the immune system, focusing on markers of inflammation and anti-viral related immune responses.
Data sources included MEDLINE, CINAHL, SPORTDiscus, and PsycINFO through September 1, 2013. Randomized controlled trials published in English evaluating at least four weeks of Tai Chi, Qi Gong, meditation, or Yoga that reported immune outcome measures were selected. Studies were synthesized separately by inflammatory (n = 18), anti-viral related immunity (n = 7), and enumerative (n = 14) outcomes measures. We performed random-effects meta-analyses using standardized mean difference when appropriate.
Thirty-four studies published in 39 articles (total 2, 219 participants) met inclusion criteria. For inflammatory measures, after 7 to 16 weeks of mind-body intervention, there was a moderate effect on reduction of C-reactive protein (effect size ES, 0.58; 95% confidence interval CI, 0.04 to 1.12), a small but not statistically significant reduction of interleukin-6 (ES, 0.35; 95% CI, -0.04 to 0.75), and negligible effect on tumor necrosis factor-α (ES, 0.21; 95% CI, -0.15 to 0.58). For anti-viral related immune and enumerative measures, there were negligible effects on CD4 counts (ES, 0.15; 95% CI, -0.04 to 0.34) and natural killer cell counts (ES, 0.12, 95% CI -0.21 to 0.45). Some evidence indicated mind-body therapies increase immune responses to vaccination.
Mind-body therapies reduce markers of inflammation and influence virus-specific immune responses to vaccination despite minimal evidence suggesting effects on resting anti-viral or enumerative measures. These immunomodulatory effects, albeit incomplete, warrant further methodologically rigorous studies to determine the clinical implications of these findings for inflammatory and infectious disease outcomes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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