Summary
What is Known and Objective: The pathogenic mechanism of antituberculosis drug‐induced hepatotoxicity (ATDH) is thought to involve drug‐metabolizing enzymes including N‐acetyl transferase2 ...(NAT2), cytochrome P4502E1 (CYP2E1) and glutathione S‐transferase (GST) M1, T1. The associations between genetic polymorphisms of those genes and ATDH have been reported but with inconsistent results. Moreover, most studies were hospital‐based retrospective studies and not prospective. We aimed to investigate possible associations of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms with ATDH using a more robust case–control study nested in a population‐based prospective antituberculosis treatment cohort.
Methods: A total of 4304 patients with smear‐positive tuberculosis (TB) who received standard short‐course chemotherapy were monitored for 6–9 months. Incidence density sampling method was adopted to select controls and 4 : 1 matched with each ATDH cases by age (±5 years), sex, treatment history, disease severity and drug dosage. The CYP2E1, GSTM1 and GSTT1 polymorphisms were genotyped using PCR–RFLP and multiplex PCR methods. Conditional logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P‐values.
Results and Discussion: A total of 89 ATDH cases and 356 controls were included in this study. There was no statistically significant association between CYP2E1 RsaI c1/c1 genotype or DraI C/C genotype and ATDH (OR = 0·99, 95% CI:0·62–1·59; OR = 1·13, 95% CI: 0·40–3·20, respectively) compared with CYP2E1 RsaI c1/c2 or c2/c2 genotypes or DraI D/D genotype, or between GSTM1/GSTT1 null genotypes and ATDH (OR = 1·22, 95% CI: 0·76–1·96; OR = 0·96, 95% CI: 0·60–1·52, respectively) compared with non‐null genotypes.
What is new and Conclusion: This is the first study of the involvement of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms in ATDH using a nested case–control population‐based prospective cohort design. We could not confirm positive associations of genetic polymorphisms of CYP2E1 RsaI, CYP2E1 DraI, GSTM1 null and GSTT1 null with ATDH reported by various groups, in our Chinese TB population.
The network of stemness genes and oncogenes in human patient‐specific reprogrammed cancer stem cells (CSCs) remains elusive, especially in liver cancer. HepG2‐derived induced pluripotent stem ...cell‐like cells (HepG2‐iPS‐like cells) were generated by introducing Yamanaka factors and the knockdown vector shTP53. They exhibited features of stemness and a higher tumorigenesis after xenograft transplantation compared with HepG2 cells. The cancerous mass of severe combined immunodeficiency (SCID) mice derived from one colony was dissected and cultured to establish reprogrammed HepG2‐derived CSC‐like cells (designated rG2‐DC‐1C). A single colony exhibited 42% occurrence of tumors with higher proliferation capacities. rG2‐DC‐1C showed continuous expression of the OCT4 stemness gene and of representative tumor markers, potentiated chemoresistance characteristics, and invasion activities. The sphere‐colony formation ability and the invasion activity of rG2‐DC‐1C were also higher than those of HepG2 cells. Moreover, the expression of the OCT4 gene and the c‐JUN oncogene, but not of c‐MYC, was significantly elevated in rG2‐DC‐1C, whereas no c‐JUN expression was observed in HepG2 cells. The positive‐feedback regulation via OCT4‐mediated transactivation of the c‐JUN promoter and the c‐JUN‐mediated transactivation of the OCT4 promoter were crucial for promoting cancer development and maintaining cancer stemness in rG2‐DC‐1C. Increased expression of OCT4 and c‐JUN was detected in the early stage of human liver cancer. Therefore, the positive feedback regulation of OCT4 and c‐JUN, resulting in the continuous expression of oncogenes such as c‐JUN, seems to play a critical role in the determination of the cell fate decision from iPS cells to CSCs in liver cancer. Stem Cells 2016;34:2613–2624
The OCT4/c‐JUN positive feedback loop found in reprogrammed HepG2‐derived cancer stem cell‐like cells (rG2‐DC‐1C) sheds light on the tumorigenesis of liver cancer. 4F, Yamanaka 4 factors; iPS‐like cells, induced pluripotent stem‐like cells.
Background & Aims Perpetuate liver inflammation is crucial in the pathogenesis of non-alcoholic steatohepatitis (NASH). Expression of CXCL10, a pro-inflammatory cytokine, correlates positively with ...obesity and type 2 diabetes. Whether CXCL10 plays a role in NASH was unknown. We aimed to investigate the functional and clinical impact of CXCL10 in NASH. Methods Cxcl10 gene-deleted ( Cxcl10−/− ) and C57BL/6 wild type (WT) mice were fed a methionine- and choline-deficient (MCD) diet for 4 or 8 weeks. In other experiments, we injected neutralizing anti-CXCL10 mAb into MCD-fed WT mice. Human serum was obtained from 147 patients with biopsy-proven non-alcoholic fatty liver disease and 73 control subjects. Results WT mice, fed the MCD diet, developed steatohepatitis with higher hepatic CXCL10 expression. Cxcl10−/− mice were refractory to MCD-induced steatohepatitis. We further revealed that CXCL10 was associated with the induction of important pro-inflammatory cytokines (TNF-α, IL-1β, and MCP-1) and activation of the NF-κB pathway. CXCL10 was linked to steatosis through upregulation of the lipogenic factors SREBP-1c and LXR, and also to oxidative stress (upregulation of CYP2E1 and C/EBPβ). Blockade of CXCL10 protected against hepatocyte injury in vitro and against steatohepatitis development in mice. We further investigated the clinical impact of CXCL10 and found circulating and hepatic CXCL10 levels were significantly higher in human NASH. Importantly, the circulating CXCL10 level was correlated with the degree of lobular inflammation and was an independent risk factor for NASH patients. Conclusions We demonstrate for the first time that CXCL10 plays a pivotal role in the pathogenesis of experimental steatohepatitis. CXCL10 maybe a potential non-invasive biomarker for NASH patients.
The Gap Rock Lighthouse: construction and typhoon damage Deng, K Y; Poon, S W
Philosophical transactions - Royal Society. Mathematical, Physical and engineering sciences/Philosophical transactions - Royal Society. Mathematical, physical and engineering sciences,
10/2019, Letnik:
377, Številka:
2155
Journal Article
Recenzirano
Odprti dostop
This paper focuses on the Gap Rock lighthouse, a legendary maritime infrastructure built 130 years ago in the Chinese territory and an early example of joint venture among the Qing Dynasty, the ...British Empire and the Hong Kong Colonial Government over a course of two decades. Based on 4 years of cross-territorial archival and field research as well as in-depth interviews with descendants of two key stakeholders, the origin of this lasting legacy on the sea is traced, followed by a detailed account of its challenging processes of planning, design and construction, and of the considerable damage to the compound by a severe typhoon in 1893. A qualitative analysis of the key contributing factors of the damage was conducted by taking into consideration the Island's unique topography and the historical records of territorial weather reports. A re-construction of the typhoon impact on the Lighthouse is presented to explain the possible mistakes in its siting and design that eventually caused the severe damage. This serves as a reminder of the significance of a thorough geographical investigation for any infrastructure for all construction professionals in the face of climatic change. This article is part of the theme issue 'Environmental loading of heritage structures'.
The large intestine harbors microorganisms playing unique roles in host physiology. The beneficial or detrimental outcome of host‐microbiome coexistence depends largely on the balance between ...regulators and responder intestinal CD4+ T cells. We found that ulcerative colitis‐like changes in the large intestine after infection with the protist Blastocystis ST7 in a mouse model are associated with reduction of anti‐inflammatory Treg cells and simultaneous expansion of pro‐inflammatory Th17 responders. These alterations in CD4+ T cells depended on the tryptophan metabolite indole‐3‐acetaldehyde (I3AA) produced by this single‐cell eukaryote. I3AA reduced the Treg subset in vivo and iTreg development in vitro by modifying their sensing of TGFβ, concomitantly affecting recognition of self‐flora antigens by conventional CD4+ T cells. Parasite‐derived I3AA also induces over‐exuberant TCR signaling, manifested by increased CD69 expression and downregulation of co‐inhibitor PD‐1. We have thus identified a new mechanism dictating CD4+ fate decisions. The findings thus shine a new light on the ability of the protist microbiome and tryptophan metabolites, derived from them or other sources, to modulate the adaptive immune compartment, particularly in the context of gut inflammatory disorders.
Synopsis
The unicellular eukaryote Blastocystis is a component of intestinal microbiome. Here, Blastocystis‐derived indole‐3‐acetaldehyde (I3AA) is shown to enhance CD4+ T cell reactivity toward gut flora, thus contributing to the pro‐inflammatory response in gut tissue.
Blastocystis ST7 degrades tryptophan to I3AA via a pathway involving aspartate aminotransferase
Exposure to I3AA enhances T cell reactivity through TCR‐dependent mechanisms and inhibits T lymphocyte exhaustion by reducing PD‐1 expression
I3AA compromises peripheral selection and reduces survival of regulatory T cells by suppressing TGFβ signaling and CD103 expression.
I3AA hinders the activity of regulatory T cells by antagonizing the AhR signaling pathway
An intestinal protist Blastocystis ST7 produces indole‐3‐acetaldehyde that modulates the adaptive immune system response in the context of gut inflammation.
To elucidate the relationship between transport properties and phase transformations in mixed-conducting oxides, Sr
0.9Ca
0.1Co
0.89Fe
0.11O
3−
δ
(SCCFO) and SrCoO
3−
δ
(SCO) were chosen as the model ...materials and have been investigated in detail. Oxygen permeation measurements verified that both oxides are well permeable to oxygen at elevated temperatures, e.g., at 900
°C during a cooling procedure, oxygen permeation rates as large as 1.5 and 2.0
mL/min/cm
2 could be obtained with disk-shaped SCCFO and SCO membranes of thickness 1.5
mm, respectively. But when cooled to critical temperatures, the oxygen permeability of these kinds of oxides diminished sharply, which could be recovered by increasing the temperature again to certain values. Abrupt changes on electrical conductivity were also observed for both oxides around the same region of temperature as that of oxygen permeability. As indicated by high-temperature X-ray diffraction and thermal analysis, the SCCFO and SCO systems undergo phase transformation between a low-temperature orthorhombic brownmillerite structure (B) or a hexagonal 2H-type structure (H) and a high-temperature cubic perovskite structure (C), respectively. The present results suggest the observed abrupt changes in transport properties versus temperature are attributed to such phase transformation, which may be directly associated with the order–disorder transition of oxygen vacancies. Moreover, compared to the B/C transformation that mainly involves an order–disorder transition on the oxygen sublattice, the H/C one necessarily also involves the cooperative long-range reorganization on the cation sublattice. Therefore it occurs at a higher temperature and absorbs more heat quantity than those of B/C transformation.
Temperature dependence of oxygen permeation rates through Sr
0.9Ca
0.1Co
0.89Fe
0.11O
3−δ (SCCFO) and SrCoO
3−δ (SCO) membranes with a thickness of 1.5
mm.
Abstract Objective To investigate secondhand smoke exposure (SHS) of children at home and the prevalence of parental smoking after implementation of the new tobacco control law in Macao. This study ...explored whether the smoking ban in public places in Macao has decreased the prevalence of smoking or led to increased SHS exposure of children at home. As smokers cannot smoke in public places any more, they may smoke at home more frequently; a displacement effect of smoke-free legislation. Study design Cross-sectional survey. Methods This study surveyed 337 fathers and 538 mothers. Questions from a subset of key questions from the Global Adult Tobacco Survey (2nd edition) were applied to assess the SHS exposure of children and the prevalence of parental smoking since the smoking ban. A classification tree analysis was used to analyse the factors increasing SHS exposure of children. Results The prevalence of SHS exposure in children at home was 41.3%. The prevalence rates of paternal and maternal smoking were 43.7% and 3.8%, respectively. Compared with data reported by the Health Bureau of Macao SAR in 2011, the prevalence of parental smoking and the prevalence of SHS exposure of children at home have not decreased since the smoking ban. Analysis of the factors increasing the prevalence of SHS exposure of children indicated that fathers with an education level below high school were more likely to contribute to this increase, compared with fathers with a high school education or more (48.2% vs 32.4%, respectively). In addition, fathers represented the majority of smokers at home, accounting for 92.0% of 415 smoking parents. The prevalence of paternal smoking (82.0%) in the group of children with SHS exposure was much higher than that in the unexposed group (16.7%, Chi-squared test = 367.199, P = 0.000). The SHS exposure of children increased consistently with the decrease in paternal education level. This was consistent with the increasing prevalence of paternal smoking as paternal education level decreased. SHS exposure was most common among children whose fathers had an education level below high school and whose mothers were aged ≤29 years (75.0%). Conclusions This study did not find any decline in the prevalence of parental smoking after the smoking ban. These parents were more likely to smoke at home after the ban, leading to more frequent SHS exposure for their children.
Reprogramming of cancer cells into induced pluripotent stem cells (iPSCs) is a compelling idea for inhibiting oncogenesis, especially through modulation of homeobox proteins in this reprogramming ...process. We examined the role of various long noncoding RNAs (lncRNAs)‐homeobox protein HOXA13 axis on the switching of the oncogenic function of bone morphogenetic protein 7 (BMP7), which is significantly lost in the gastric cancer cell derived iPS‐like cells (iPSLCs). BMP7 promoter activation occurred through the corecruitment of HOXA13, mixed‐lineage leukemia 1 lysine N‐methyltransferase, WD repeat‐containing protein 5, and lncRNA HoxA transcript at the distal tip (HOTTIP) to commit the epigenetic changes to the trimethylation of lysine 4 on histone H3 in cancer cells. By contrast, HOXA13 inhibited BMP7 expression in iPSLCs via the corecruitment of HOXA13, enhancer of zeste homolog 2, Jumonji and AT rich interactive domain 2, and lncRNA HoxA transcript antisense RNA (HOTAIR) to various cis‐element of the BMP7 promoter. Knockdown experiments demonstrated that HOTTIP contributed positively, but HOTAIR regulated negatively to HOXA13‐mediated BMP7 expression in cancer cells and iPSLCs, respectively. These findings indicate that the recruitment of HOXA13–HOTTIP and HOXA13–HOTAIR to different sites in the BMP7 promoter is crucial for the oncogenic fate of human gastric cells. Reprogramming with octamer‐binding protein 4 and Jun dimerization protein 2 can inhibit tumorigenesis by switching off BMP7. Stem Cells 2017;35:2115–2128
Regulation of BMP7 promoter on gastric cancer by LncRNA‐HOXA13. In CS12 cancer cells, HOXA13‐HOTTIP‐WDR5/MLL/TrG complexes are recruited to the S1 site to induce H3K4me3 on BMP7 promoter to enhance the BMP7 transcription to develop the tumorigenesis; by contrast, in JDP2/OCT4 reprogrammed CS12iPSLCs, HOXA13‐HOTAIR‐EZH2/SUZ12/PRC2‐JARID2 complexes are recruited to the S2 site to induce H3K27me3 on BMP7 promoter to repress and inhibit the tumorigenesis.
Neuroimaging evidence suggests that the aging brain relies on a more distributed set of cortical regions than younger adults in order to maintain successful levels of performance during demanding ...cognitive tasks. However, it remains unclear how task demands give rise to this age-related expansion in cortical networks. To investigate this issue, functional magnetic resonance imaging was used to measure univariate activity, network connectivity, and cognitive performance in younger and older adults during a working memory (WM) task. Here, individuals performed a WM task in which they held letters online while reordering them alphabetically. WM load was titrated to obtain four individualized difficulty levels with different set sizes. Network integration—defined as the ratio of within-versus between-network connectivity—was linked to individual differences in WM capacity. The study yielded three main findings. First, as task difficulty increased, network integration decreased in younger adults, whereas it increased in older adults. Second, age-related increases in network integration were driven by increases in right hemisphere connectivity to both left and right cortical regions, a finding that helps to reconcile existing theories of compensatory recruitment in aging. Lastly, older adults with higher WM capacity demonstrated higher levels of network integration in the most difficult task condition. These results shed light on the mechanisms of age-related network reorganization by demonstrating that changes in network connectivity may act as an adaptive form of compensation, with older adults recruiting a more distributed cortical network as task demands increase.
The aim of the present study was to investigate the executive function and planning features of students with different types of learning difficulties. Students with mathematics difficulty (MD; n = ...17), reading difficulty (RD; n = 12), and their commonalities (MDRD; n = 22), along with typically academically developing peers (TD; n = 22), were evaluated on an array of cognitive measures (working memory, inhibition, and planning) individually. Results revealed significant differences among groups on various cognitive measures. Students in the MD, RD, and MDRD groups showed poorer performance compared to the TD group on all of the working memory, inhibition, and planning tasks. The MDRD group showed an overall weakness when compared to other groups, indicating severe cognitive deficits in students with MDRD. The RD group showed deficits in inhibition and planning on tasks requiring verbal skills; MD students showed deficits in inhibition and planning on digit-related tasks. However, no salient difference was found among the MD, RD, and TD groups on working memory. Results have implications for understanding the cognitive features of MD, RD, and MDRD. Intervention programs targeting inhibition and planning may be beneficial for improving reading and mathematics achievement in students with learning difficulties.
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