Usually the dense extracellular structure in fibrotic tissues is described as extracellular matrix (ECM) or simply as collagen. However, fibrosis is not just fibrosis, which is already exemplified by ...the variant morphological characteristics of fibrosis due to viral versus cholestatic, autoimmune or toxic liver injury, with reticular, chicken wire and bridging fibrosis. Importantly, the overall composition of the ECM, especially the relative amounts of the many types of collagens, which represent the most abundant ECM molecules and which centrally modulate cellular functions and physiological processes, changes dramatically during fibrosis progression.
We hypothesize that there are good and bad collagens in fibrosis and that a change of location alone may change the function from good to bad. Whereas basement membrane collagen type IV anchors epithelial and other cells in a polarized manner, the interstitial fibroblast collagens type I and III do not provide directional information. In addition, feedback loops from biologically active degradation products of some collagens are examples of the importance of having the right collagen at the right place and at the right time controlling cell function, proliferation, matrix production and fate. Examples are the interstitial collagen type VI and basement membrane collagen type XVIII. Their carboxyterminal propeptides serve as an adipose tissue hormone, endotrophin, and as a regulator of angiogenesis, endostatin, respectively.
We provide an overview of the 28 known collagen types and propose that the molecular composition of the ECM in fibrosis needs careful attention to assess its impact on organ function and its potential to progress or reverse. Consequently, to adequately assess fibrosis and to design optimal antifibrotic therapies, we need to dissect the molecular entity of fibrosis for the molecular composition and spatial distribution of collagens and the associated ECM.
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p62/SQSTM1 is an autophagy receptor and signaling adaptor with an N-terminal PB1 domain that forms the scaffold of phase-separated p62 bodies in the cell. The molecular determinants that govern PB1 ...domain filament formation in vitro remain to be determined and the role of p62 filaments inside the cell is currently unclear. We here determine four high-resolution cryo-EM structures of different human and Arabidopsis PB1 domain assemblies and observed a filamentous ultrastructure of p62/SQSTM1 bodies using correlative cellular EM. We show that oligomerization or polymerization, driven by a double arginine finger in the PB1 domain, is a general requirement for lysosomal targeting of p62. Furthermore, the filamentous assembly state of p62 is required for autophagosomal processing of the p62-specific cargo KEAP1. Our results show that using such mechanisms, p62 filaments can be critical for cargo uptake in autophagy and are an integral part of phase-separated p62 bodies.
Summary
Background
Activation of Kupffer cells may be involved in the pathogenesis of portal hypertension by release of vasoconstrictive substances and fibrosis due to co‐activation of hepatic ...stellate cells.
Aim
To study soluble plasma (s) CD163, a specific marker of activated macrophages, as a biomarker for portal hypertension in patients with liver cirrhosis.
Methods
We measured sCD163 concentration and the hepatic venous pressure gradient (HVPG) by liver vein catheterisation in 81 cirrhosis patients (Child–Pugh CP‐A: n = 26, CP‐B: n = 29, CP‐C: n = 26) and 22 healthy subjects. We also measured their cardiac output (CO), cardiac index and systemic vascular resistance (SVR). Liver status was examined by Child–Pugh and MELD‐score.
Results
In cirrhosis, sCD163 concentration was nearly three times higher than in controls (4.7 ± 2.5 vs. 1.6 ± 0.5 mg/L, P < 0.001). sCD163 was also higher, as measured in steps by CP‐score (P < 0.001). The HVPG rose steeply to an asymptote of 22 mmHg with sCD163 up to about 5 mg/L and not to higher values with higher sCD163. In a multivariate analysis, sCD163 was the only independent predictor of the HVPG but did not predict any of the systemic circulatory findings. sCD163 > 3.95 mg/L (upper normal limit) predicted HVPG ≥ 10 mmHg with a positive predictive value of 0.99.
Conclusions
Circulating sCD163 originating from activated Kupffer cells is increased in cirrhosis with increasing Child–Pugh score and with increasing HVPG, and it is an independent predictor for HVPG. These findings support a primary role of macrophage activation in portal hypertension, and may indicate a target for biological intervention.
Recent research suggests that prenatal exposure to nonviral infection may be associated with increased risk of schizophrenia, and we hypothesized an association between maternal bacterial infection ...during pregnancy and elevated offspring risk of schizophrenia. Data on maternal infections from the Copenhagen Perinatal Cohort were linked with the Danish National Psychiatric Register. Offspring cases of narrowly defined schizophrenia (International Classification of Diseases, Eighth Revision ICD-8) and more broadly defined schizophrenia (ICD-8 and ICD-10) were identified before the ages of 32-34 and 45-47 years, respectively. The effect of prenatal exposure to bacterial infections was adjusted for prenatal exposure to analgesics and parental social status. In a risk set of 7941 individuals, 85 cases (1.1%) of ICD-8 schizophrenia were identified by the age of 32-34 years and 153 cases (1.9%) of more broadly defined schizophrenia by the age of 45-47 years. First-trimester exposure conferred an elevated risk of ICD-8 schizophrenia (odds ratio 2.53; 95% confidence interval CI 1.07-5.96) and also of broadly defined schizophrenia (odds ratio 2.14; 95% CI 1.06-4.31). Second-trimester exposure also conferred a significantly elevated risk of schizophrenia but only in unadjusted analyses. These findings suggest a relationship between maternal bacterial infection in pregnancy and offspring risk of schizophrenia, and this effect was somewhat stronger for ICD-8 schizophrenia with earlier onset. Post hoc analyses showed that upper respiratory tract and gonococcal infections were associated with elevated risk of the disease. An association between risk of schizophrenia and prenatal exposure to bacterial infections might be mediated through transplacental passage of maternally produced cytokines in response to bacterial infections.
Freshwater runoff to fjords with marine-terminating glaciers along the Greenland Ice Sheet margin has an impact on fjord circulation and potentially ice sheet mass balance through increasing heat ...transport to the glacier front. Here, the authors use the high-resolution (5.5 km) HIRHAM5 regional climate model, allowing high detail in topography and surface types, to estimate freshwater input to Godthåbsfjord in southwest Greenland. Model output is compared to hydrometeorological observations and, while simulated daily variability in temperature and downwelling radiation shows high correlation with observations (typically >0.9), there are biases that impact the results. In particular, overestimated albedo leads to underestimation of melt and runoff at low elevations.
In the model simulation (1991–2012), the ice sheet experiences increasing energy input from the surface turbulent heat flux (up to elevations of 2000 m) and shortwave radiation (at all elevations). Southerly wind anomalies and declining cloudiness due to an increase in atmospheric pressure over north Greenland contribute to increased summer melt. This results in declining surface mass balance (SMB), increasing surface runoff, and upward shift of the equilibrium line altitude.
SMB is reconstructed back to 1890 though regression between simulated SMB and observed temperature and precipitation, with added uncertainty in the period 1890–1952 because of possible inhomogeneity in the precipitation record. SMB as low as in recent years appears to have occurred before, most notably around 1930, 1950, and 1960. While previous low SMBs were mainly caused by low accumulation, those around 1930 and in the 2000s are mainly due to warming.
Cardiovascular (CV) co-morbidity is one of the major modifiable risk factors driving the excess mortality in individuals with schizophrenia or bipolar disorder. Population-based studies in this area ...are sparse.
We used Danish population registers to calculate incidence rate ratios (IRRs) for CV drug use, and mortality rate ratios comparing subjects with schizophrenia or bipolar disorder with subjects with no prior psychiatric hospitalization.
IRRs for CV prescriptions were significantly decreased in patients with schizophrenia or bipolar disorder compared with the general population. Among persons without previous myocardial infarction (MI) or cerebrovascular disease, persons with schizophrenia or bipolar disorder had an up to 6- and 15-fold increased mortality from all causes or unnatural causes, respectively, compared with the general population, being most pronounced among those without CV treatment (16-fold increase). Among those with previous MI or cerebrovascular disease, excess all-cause and unnatural death was lower (up to 3-fold and 7-fold increased, respectively), but was similar in CV-treated and -untreated persons.
The present study shows an apparent under-prescription of most CV drugs among patients with schizophrenia or bipolar disorder compared with the general population in Denmark. The excess of mortality by unnatural deaths in the untreated group suggests that the association between CV treatment and mortality may be confounded by severity of illness. However, our results also suggest that treatment of CV risk factors is neglected in these patients.
MicroRNAs can promote translation of specific mRNAs in quiescent (G0) mammalian cells and immature Xenopus laevis oocytes. We report that microRNA-mediated upregulation of target mRNAs in oocytes is ...dependent on nuclear entry of the microRNA; cytoplasmically-injected microRNA repress target mRNAs. Components of the activation microRNP, AGO, FXR1 (FXR1-iso-a) and miR16 are present in the nucleus and cytoplasm. Importantly, microRNA target mRNAs for upregulation, Myt1, TNFα and a reporter bearing the TNFα AU-rich, microRNA target sequence, are associated with AGO in immature oocyte nuclei and AGO2 in G0 human nuclei, respectively. mRNAs that are repressed or lack target sites are not associated with nuclear AGO. Crosslinking-coupled immunopurification revealed greater association of AGO2 with FXR1 in the nucleus compared to cytoplasm. Consistently, overexpression of FXR1-iso-a rescues activation of cytoplasmically-injected RNAs and in low density, proliferating cells. These data indicate the importance of a compartmentalized AGO2-FXR1-iso-a complex for selective recruitment for microRNA-mediated upregulation.
: Extracellular matrix (ECM) remodeling of the intestinal tissue is important in inflammatory bowel disease (IBD) due to the extensive mucosal remodeling. There are still gaps in our knowledge as to ...how ECM remodeling is related to intestinal epithelium homeostasis and healing of the intestinal mucosa.
: The aim of this review is to highlight the importance of the ECM in relation to the pathogenesis of IBD, while addressing basement membrane and interstitial matrix remodeling, and the processes of wound healing of the intestinal tissue in IBD.
: In IBD, basement membrane remodeling may reflect the integrity of the intestinal epithelial-cell homeostasis. The interstitial matrix remodeling is associated with deep inflammation such as the transmural inflammation as seen in fistulas and intestinal fibrosis leading to fibrostenotic strictures, in patients with CD. The interplay between wound healing processes and ECM remodeling also affects the tissue homeostasis in IBD. The interstitial matrix, produced by fibroblasts, holds a very different biology as compared to the epithelial basement membrane in IBD. In combination with integration of wound healing, quantifying the interplay between damage and repair to these sub compartments may provide essential information in IBD patient profiling, mucosal healing and disease management.
Summary
Background
Misbalances in extracellular matrix turnover are key factors in the development of stricturing (Montreal B2) and penetrating (Montreal B3) Crohn's disease.
Aim
To determine whether ...serological markers for collagen formation and degradation could serve as biomarkers for complications of Crohn's disease.
Methods
Serum biomarkers for type I, III, V and VI collagen formation (P1NP, Pro‐C3, Pro‐C5, Pro‐C6) and matrix metalloproteinase mediated degradation (C1M, C3M, C5M and C6M) were measured in a retrospective, single centre cohort of 112 patients with Crohn's disease in the terminal ileum (nonstricturing/nonpenetrating: n=40, stricturing: n=55, penetrating: n=17) and 24 healthy controls. Active inflammation was defined as CRP >5 mg/L.
Results
C3M and Pro‐C5 levels were higher in penetrating vs nonpenetrating/nonstricturing and stricturing disease (33.6±5 vs 25.8±2.2 P=.004 and 27.2±2.3 P=.018 nmol/L C3M, 1262.7±259.4 vs 902.9±109.9 P=.005 and 953.0±106.4 P=.015 nmol/L Pro‐C5). C1M (71.2±26.1 vs 46.2±6.2 nmol/L P<.001), C3M (31.6±3.9 vs 26.1±1.6 nmol/L P=.002 and Pro‐C5 levels (1171.7±171.5 vs 909.6±80.4 nmol/L P=.002) were higher in patients with active inflammation vs without active inflammation. Pro‐C3/C3M‐ratios were best to differentiate between penetrating vs nonstricturing/nonpenetrating and stricturing disease with area under the curves of 0.815±0.109 (P<.001) and 0.746±0.114 (P=.002) respectively.
Conclusions
Serological biomarkers show that penetrating Crohn's disease is characterised by increased matrix metalloproteinase‐9 degraded type III collagen and formation of type V collagen. Active inflammation in Crohn's disease is characterised by increased formation of type V collagen and increased matrix metalloproteinase mediated breakdown of type I, III collagen. Pro‐C3/C3M ratios are superior in differentiating between penetrating Crohn's disease vs inflammatory and stricturing Crohn's disease.
Phthalates adversely affect the male reproductive system in animals. We investigated whether phthalate monoester contamination of human breast milk had any influence on the postnatal surge of ...reproductive hormones in newborn boys as a sign of testicular dysgenesis. Design: We obtained biologic samples from a prospective Danish-Finnish cohort study on cryptorchidism from 1997 to 2001. We analyzed individual breast milk samples collected as additive aliquots 1-3 months postnatally (n = 130; 62 cryptorchid/68 healthy boys) for phthalate monoesters mono-methyl phthalate (mMP), mono-ethyl phthalate (mEP), mono-n-butyl phthalate (mBP), mono-benzyl phthalate (mBzP), mono-2-ethylhexyl phthalate (mEHP), mono-isononyl phthalate (miNP). We analyzed serum samples (obtained in 74% of all boys) for gonadotropins, sex-hormone binding globulin (SHBG), testosterone, and inhibin B. Results: All phthalate monoesters were found in breast milk with large variations medians (minimum-maximum): mMP 0.10 (< 0.01-5.53 μg/L), mEP 0.95 (0.07-41.4 μg/L), mBP 9.6 (0.6-10,900 μg/L), mBzP 1.2 (0.2-26 μg/L), mEHP 11 (1.5-1,410 μg/L), miNP 95 (27-469 μg/L). Finnish breast milk had higher concentrations of mBP, mBzP, mEHP, and Danish breast milk had higher values for miNP (p = 0.0001-0.056). No association was found between phthalate monoester levels and cryptorchidism. However, mEP and mBP showed positive correlations with SHBG (r = 0.323, p = 0.002 and r = 0.272, p = 0.01, respectively); mMP, mEP, and mBP with LH:free testosterone ratio (r = 0.21-0.323, p = 0.002-0.044) and miNP with luteinizing hormone (r = 0.243, p = 0.019). mBP was negatively correlated with free testosterone (r = -0.22, p = -0.033). Other phthalate monoesters showed similar but nonsignificant tendencies. Conclusions: Our data on reproductive hormone profiles and phthalate exposures in newborn boys are in accordance with rodent data and suggest that human Leydig cell development and function may also be vulnerable to perinatal exposure to some phthalates. Our findings are also in line with other recent human data showing incomplete virilization in infant boys exposed to phthalates prenatally.
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