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The pathogenesis of Crohn's disease (CD), an idiopathic inflammatory bowel disease, is attributed, in part, to intestinal bacteria that may initiate and perpetuate mucosal inflammation in genetically susceptible individuals. Paneth cells (PC) are the major source of antimicrobial peptides in the small intestine, including human alpha-defensins HD5 and HD6. We tested the hypothesis that reduced expression of PC alpha-defensins compromises mucosal host defenses and predisposes patients to CD of the ileum. We report that patients with CID of the ileum have reduced antibacterial activity in their intestinal mucosal extracts. These specimens also showed decreased expression of PC alpha-defensins, whereas the expression of eight other PC products either remained unchanged or increased when compared with controls. The specific decrease of alpha-defensins was independent of the degree of inflammation in the specimens and was not observed in either CD of the colon, ulcerative colitis, or pouchitis. The functional consequence of alpha-defensin expression levels was examined by using a transgenic mouse model, where we found changes in HD5 expression levels, comparable to those observed in CD, had a pronounced impact on the luminal microbiota. Thus, the specific deficiency of PC defensins that characterizes ileal CD may compromise innate immune defenses of the ileal mucosa and initiate and/or perpetuate this disease.

Study Question: What is the transcriptome signature associated with poor performance of rescue IVM (rIVM) oocytes and how can we rejuvenate them?Summary Answer: The GATA-1/CREB1/WNT signalling axis was repressed in rIVM oocytes, particularly those of poor quality; restoration of this axis may produce more usable rIVM oocytes.What Is Known Already: rIVM aims to produce mature oocytes (MII) for IVF through IVM of immature oocytes collected from stimulated ovaries. It is not popular due to limited success rate in infertility treatment. Genetic aberrations, cellular stress and the absence of cumulus cell support in oocytes could account for the failure of rIVM.Study Design, Size, Duration: We applied single-cell RNA sequencing (scRNA-seq) to capture the transcriptomes of human in vivo oocytes (IVO) (n = 10) from 7 donors and rIVM oocytes (n = 10) from 10 donors. The effects of maternal age and ovarian responses on rIVM oocyte transcriptomes were also studied. In parallel, we studied the effect of gallic acid on the maturation rate of mouse oocytes cultured in IVM medium with (n = 84) and without (n = 85) gallic acid.Participants/materials, Setting, Methods: Human oocytes were collected from donors aged 28-41 years with a body mass index of <30. RNA extraction, cDNA generation, library construction and sequencing were performed in one preparation. scRNA-seq data were then processed and analysed. Selected genes in the rIVM versus IVO comparison were validated by quantitative real-time PCR. For the gallic acid study, we collected immature oocytes from 5-month-old mice and studied the effect of 10-μM gallic acid on their maturation rate.Main Results and the Role Of Chance: The transcriptome profiles of rIVM/IVO oocytes showed distinctive differences. A total of 1559 differentially expressed genes (DEGs, genes with at least 2-fold change and adjusted P < 0.05) were found to be enriched in metabolic processes, biosynthesis and oxidative phosphorylation. Among these DEGs, we identified a repression of WNT/β-catenin signalling in rIVM when compared with IVO oocytes. We found that oestradiol levels exhibited a significant age-independent correlation with the IVO mature oocyte ratio (MII ratio) for each donor. rIVM oocytes from women with a high MII ratio were found to have over-represented cellular processes such as anti-apoptosis. To further identify targets that contribute to the poor clinical outcomes of rIVM, we compared oocytes collected from young donors with a high MII ratio with oocytes from donors of advanced maternal age and lower MII ratio, and revealed that CREB1 is an important regulator. Thus, our study identified that GATA-1/CREB1/WNT signalling was repressed in both rIVM oocytes versus IVO oocytes and in rIVM oocytes of lower versus higher quality. Consequently we investigated gallic acid, as a potential antioxidant substrate in human rIVM medium, and found that it increased the mouse oocyte maturation rate by 31.1%.Large Scale Data: Raw data from this study can be accessed through GSE158539.Limitations, Reasons For Caution: In the rIVM oocytes of the high- and low-quality comparison, the number of samples was limited after data filtering with stringent selection criteria. For the oocyte stage identification, we were unable to predict the presence of oocyte spindle, so polar body extrusion was the only indicator.Wider Implications Of the Findings: This study showed that GATA-1/CREB1/WNT signalling was repressed in rIVM oocytes compared with IVO oocytes and was further downregulated in low-quality rIVM oocytes, providing us the foundation of subsequent follow-up research on human oocytes and raising safety concerns about the clinical use of rescued oocytes.Study Funding/competing Interest(s): This work was supported by the Collaborative Research Fund, Research Grants Council, C4054-16G, and Research Committee Funding (Research Sustainability of Major RGC Funding Schemes), The Chinese University of Hong Kong. The authors have no conflicts of interest to declare. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this study was to investigate the correlation between microRNA- 136 levels and biochemical markers of renin-angiotensin-aldosterone system (RAAS) in patients with essential hypertension (EH). PATIENTS AND METHODS: The subjects were divided into EH group (n=110) and healthy control group (n=110). MicroRNA-136 expression, angiotensin-converting enzyme (ACE) activity, and expression of renin (RA) and angiotensin II (Ang II), and aldosterone (ALD) in peripheral blood serum were examined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), equine glycylglycine glycine method, magnetic particle chemistry, and radioimmunoassay, respectively. In addition, the correlation between microRNA-136 and RAAS biochemical markers was estimated by Pearson linear regression. Meanwhile, ROC curve analysis was carried out to evaluate the potential of microRNA-136 for the diagnosis of EH. Follow-up data were recorded for assessing the influence of microRNA-136 on the prognosis in patients with EH. RESULTS: It was found that microRNA-136 expression was remarkably elevated in peripheral blood serum of patients with EH, and the expression levels of biochemical markers of RASS, such as ACE, RA, Ang II, and ALD were also found higher than those in healthy controls. Meanwhile, a significant positive correlation was confirmed between microRNA-136 level and ACE activity, RA, Ang II, as well as ALD levels in patients with EH. In addition, the area under the ROC curve (AUC) was calculated as 0.8662, with a sensitivity of 82.73% and a specificity of 80.91%. After two-months medication intervention, patients with EH expressing a high level of microRNA-136 had better therapeutic efficacy than those with a low level. CONCLUSIONS: In peripheral blood serum, microRNA- 136 expression was dramatically negatively correlated with biochemical markers of RASS. High level of microRNA-136 predicts a good prognosis in patients with EH following medication. Therefore, microRNA-136 can be used as a potential biomarker for the diagnosis of EH. [ABSTRACT FROM AUTHOR]

Various tectonic models have been proposed to account for the widely distributed igneous activities in the southeastern part of the South China Block (SCB) during the Triassic–Jurassic period. One of the major contending debates is on the timing of initiation of the palaeo-Pacific plate subduction under the SCB, due to lack of unequivocal evidence for arc magmatism during the period in this region. The 191 ± 10 Ma (N = 5, MSWD = 12) calc-alkalic high-K I-type Talun metagranite occurs in the southern Tailuko belt of the Tananao metamorphic complex, Taiwan. In terms of age, this metagranite belongs to the Early Yanshanian igneous activity in the southeastern part of the SCB. However, its geographic position does not accord with the well-known general oceanward younging trend of the Yansnanian igneous rocks. In view of the large age uncertainty reported, this metagranite is redated in this study. Some zircons of this metagranite are high in U content and are metamict. Zircons with low U contents are analysed by SHRIMP yielding a more precise age of 200 ± 2 Ma (N = 10, MSWD = 4). In particular, theεHf(t) of these dated zircons ranges from +4.5 to +12.9. The metagranite mainly consists of quartz, K-feldspar, plagioclase, with minor amounts of garnet, biotite, zircon, apatite, and pyrrhotite. Chlorite and calcite are secondary phases overprinted by the later tectonic event(s). Its initial Sr isotope compositional range is 0.70473–0.70588, andεNd(t), +2.4 to +3.6. The results demonstrate that the genesis of this metagranite could be attributed to the assimilation-fractionation of a depleted mantle-derived basaltic magma, which was most likely related to arc magmatism. The present study therefore offers key evidence that during the Mesozoic, the palaeo-Pacific plate subduction underneath the SCB would have taken place no later than the very early Jurassic. [ABSTRACT FROM PUBLISHER]

OBJECTIVE: Both miR-21 and miR-183 are upregulated in hepatocellular carcinoma (HCC) and are considered as oncomiR. However, their oncogenic roles are still not fully understood. This study aimed to explore the regulative role of miR-21 and miR-183 over suppressors of cytokine signaling 6 (SOCS6), a negative regulator of cytokine receptor signaling. MATERIALS AND METHODS: qRT-PCR analysis was performed to assess miR-21 and miR-183 expression in tumor tissues obtained from HCC patients and in HCC cell lines HepG2 and Hep3B. Their regulation over SOCS6 is verified using dual luciferase assay and Western blot analysis. The function of miR-21/miR-183-SOCS6 axis in cell growth, invasion and apoptosis was studied. RESULTS: MiR-21 and miR-183 expression in HCC tissues than in adjacent normal tissues. Knockdown of miR-21 and miR-183 in HepG2 and Hep3B cells could decrease cell viability, increase cell apoptosis and decrease cell invasion. Based on the dual luciferase assay and Western blot analysis, we confirmed that both miR-21 and miR-183 can simultaneously target SOCS6 and modulate its expression at protein level. Overexpression of SOCS6 without 3'UTR could significantly lower cell growth rate and invasion capability, but increase relative cas- pase 3/7 activity and the ratio of apoptotic cells. However, these effects could not be blocked by miR-21 or miR-183 mimics. CONCLUSIONS: This study revealed a novel miR-21/miR-183-SOCS6 axis that might play an important role in modulating cell growth and invasion of HCC cells. [ABSTRACT FROM AUTHOR]

Regularly oriented orthopyroxene (opx) and forsterite (fo) inclusions occur as opx + rutile (rt) or fo + rt inclusion domains in garnet (grt) from Otrøy peridotite. Electron diffraction characterization shows that forsterite inclusions do not have any specific crystallographic orientation relationships (COR) with the garnet host. In contrast, orthopyroxene inclusions have two sets of COR, that is, COR-I: <111>grt//<001>opx and {110}grt∼//∼{100}opx (∼13° off) and COR-II: <111>grt//<011>opx and {110}grt∼//∼{100}opx (∼14° off), in four garnet grains analysed. Both variants of orthopyroxene have a blade-like habit with one pair of broad crystal faces parallel/sub-parallel to {110}grt plane and the long axis of the crystal, <001>opx for COR-I and <011>opx for COR-II, along <111>grt direction. Whereas the lack of specific COR between forsterite and garnet, along with the presence of abundant infiltrating trails/veinlets decorated by fo + rt at garnet edges, provide compelling evidence for the formation of forsterite inclusions in garnet through the sequential cleaving-infiltrating-precipitating-healing process at low temperatures, the origin of the epitaxial orthopyroxene inclusions in garnet is not so obvious. In this connection, the reported COR, the crystal habit and the crystal growth energetics of the exsolved orthopyroxene in relict majoritic garnet were reviewed/clarified. The exsolved orthopyroxene in a relict majoritic garnet follows COR-III: {112}grt//{100}opx and <111>grt//<001>opx. Based on the detailed trace analysis on published SEM images, these exsolved orthopyroxene inclusions are shown to have the crystal habit with one pair of broad crystal faces parallel to {112}grt//{100}opx and the long crystal axis along <111>grt//<001>opx. Such a crystal habit can be rationalized by the differences in oxygen sub-lattices of both structures and represents the energetically favoured crystal shape of orthopyroxene inclusions in garnet formed by solid-state exsolution mechanism. Considering the very different COR, crystal habit, as well as crystal growth direction, the orthopyroxene inclusions in garnet of the present sample most likely had been formed by mechanism(s) other than solid-state exsolution, regardless of their regularly oriented appearance in garnet and the COR specification between orthopyroxene and garnet. In fact, the crystallographic characteristics of orthopyroxene and the similar chemical compositions of garnet at opx + rt inclusion domains, fo + rt inclusion domains/trails and garnet rim suggest that the orthopyroxene inclusions in the garnet are most likely formed by similar cleaving-infiltration process as forsterite inclusions, though probably at an earlier stage of metamorphism. This work demonstrates that the oriented inclusions in host minerals, with or without specific COR, can arise from mechanism(s) other than solid-state exsolution. Caution is thus needed in the interpretation of such COR, so that an erroneous identification of exhumation from UHP depths would not be made. [ABSTRACT FROM AUTHOR]

In Taiwan, efficient climate-driven strong erosion processes are the leading cause for low preservation of geomorphic landforms. Despite the absence of present-day glaciers, glacial relicts have been reported in high altitude areas. These scarce landforms provide opportunities for reconstructing the timing of the last deglaciation in a region where glacial history is poorly documented. We have collected boulders and striated bedrocks in the Nanhutashan area and calculated surface exposure ages based on in-situ produced 10Be concentrations. The oldest glacial remains, dated at 11.1 ± 3.3 ka, correspond to the last glacial advance. The Holocene is characterized by a continuous retreat of the ice-cap until at least 7.2 ± 1.0 ka. Our results are in agreement with a scenario where changes of monsoon regimes lead to a strong reduction of the winter monsoon during the early Holocene, causing a decrease of snow supply and disequilibrium of the hydrological budget. [ABSTRACT FROM AUTHOR]

A new mechanism of cleaving-healing of garnet in metamorphic rocks during exhumation is reported. Almandine garnet with submicron multiple-phase inclusions characteristic of the GRAIL reaction, garnet + rutile = kyanite + ilmenite + low-quartz, was found by analytical electron microscopy to have non-epitaxial rutile nanoparticles distributed along internal {110} microcrack trails at the acute corner of submicron multiple-phase inclusions defined by the intersecting (110) and (011) mould surfaces. Such garnet microcracks were formed during lithostatic decompression due to a relatively high compressibility of quartz in the inclusion pockets and stress concentration at the acute corner. Spontaneous healing with accompanied formation of non-epitaxial rutile nanoparticles was activated predominantly via the GRAIL reaction due to high surface tension at the tip of microcracks and, to a lesser extent, decreasing lithostatic pressure or increasing inclusion pressure upon exhumation. This new mechanism of microcracking and healing involves stress build up, fracture propagation, mineral reaction, transport of elements to the reaction site and lowering of reaction boundaries by capillarity effect, all under the influence of thermodynamic and kinetic factors at the submicron-scale. Thus, TiO2 nanoparticle trails in garnet provide additional information on the P–T path and may shed light on exhumation rates/mechanisms and metamorphic reactions/processes. Careful scrutiny of host minerals on the submicron scale is required to tell whether there are other metamorphic-reaction facilitated healing processes being overlooked by inappropriate techniques or being obliterated by the predominant healing processes of fluid infiltration and resorption zoning. [ABSTRACT FROM AUTHOR]