To assess the spectrum of pediatric clinical phenotypes in TJP2 disease, we reviewed records of our seven patients in whom intrahepatic cholestasis was associated with biallelic TJP2 variants (13; 12 ...novel) and correlated clinical manifestations with mutation type. The effect of a splicing variant was analyzed with a minigene assay. The effects of three missense variants were analyzed with protein expression in vitro. Our patients had both remitting and persistent cholestasis. Three exhibited growth retardation. Six responded to treatment with cholestyramine, ursodeoxycholic acid, or both. Two had cholecystolithiasis. None required liver transplantation or developed hepatocellular or cholangiocellular malignancy. None manifested extrahepatic disease not attributable to effects of cholestasis. The variant c.2180‐5T>G resulted in exon 15 skipping with in‐frame deletion of 32 amino acid residues in TJP2. The three missense variants decreased but did not abolish TJP2 expression. Patients with truncating or canonical splice‐site variants had clinically more severe disease. TJP2 disease in children includes a full clinical spectrum of severity, with mild or intermittent forms as well as the severe and minimal forms hitherto described. Biallelic TJP2 variants must be considered in children with clinically intermittent or resolved intrahepatic cholestasis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Impressive progress has been made in the copper‐catalyzed asymmetric propargylic substitution (APS) reaction, but its use in remote asymmetric yne‐allylic substitution remains a challenging topic. ...Herein, we report the first remote enantioselective copper‐catalyzed sulfonylation of yne‐allylic esters with sodium sulfinates. The reaction is assumed to occur via a copper‐vinylvinylidene species as the key reactive intermediate. The use of readily available starting materials, the mild reaction conditions, and the excellent regio‐, enantio‐ and stereoselectivity, as well as broad substrate scope (>70 examples), show the practicality and attractiveness of this method.
An enantioselective copper‐catalyzed reaction was developed for the sulfonylation of yne‐allylic esters with sodium sulfinates. Salient features of this practical method include readily available starting materials, mild reaction conditions, excellent regio‐, enantio‐ and diastereoselectivity, as well as broad substrate scope.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background & Aims
ABCB11 deficiency presenting in infancy is believed generally to manifest as persistent/progressive cholestasis. We describe a group of patients with biallelic ABCB11 variants whose ...disorder manifested as transient neonatal cholestasis (TNC).
Methods
Neonatal intrahepatic cholestasis in 68 children (31 males) with biallelic predictedly pathogenic variants (PPV) in ABCB11 was classified as transient (TNC group, n = 23, 11 males), intermittent (benign recurrent intrahepatic cholestasis BRIC group, n = 3, 1 male) or persistent/ progressive (progressive familial intrahepatic cholestasis PFIC group, n = 42, 19 males). Clinical, genetic and bile salt export pump (BSEP) expression information was correlated with outcomes.
Results
The median onset age of jaundice was 3 days (birth to 2 months) for the TNC group and 10.5 days (birth to 3 months) for the PFIC group (P = .034). The median length of follow‐up of TNC patients was 44 months (12 months‐168 months). At presentation, hepatobiliary‐injury biomarker values were similar between the groups (P > .05). TNC patients (17/23) more often than PFIC patients (20/42, P = .041) harboured biallelic non‐null variants (predicted not to terminate translation prematurely). TNC patient livers (7/7) more often than PFIC patient livers (5/16, P = .005) expressed immunohistochemically detectable BSEP. Kaplan‐Meier analysis showed better prognosis for patients with BSEP expression (P = .009). Too few BRIC patients were available for statistical study.
Conclusions
Neonatal cholestasis associated with biallelic PPV in ABCB11 can resolve temporarily or persistently in one third of cases. Resolution is more likely in patients with biallelic non‐null PPV or with liver BSEP expression.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Background and Aims
Alagille syndrome (ALGS) type 2 caused by mutations in NOTCH2 has genotypic and phenotypic heterogeneity. Diagnosis in some atypical patients with isolated hepatic presentation ...could be missed.
Methods
Using 2087 patients with paediatric liver manifestations, NOTCH2 allele frequencies, in‐silico prediction, protein domains and clinical features were analysed to define the pathogenicity of NOTCH2 variants for diagnosis of ALGS type 2.
Results
Among 2087 patients with paediatric liver manifestations, significantly more NOTCH2 variants were absent in gnomAD in patients with elevated γ‐glutamyltransferase (GGT) (p = .041). Significantly more NOTCH2 variants which were absent in gnomAD were located in protein functional domains (p = .038). When missense variants were absent in gnomAD and predicted to be pathogenic by at least three out of seven in‐silico tools, they were found to be significantly associated with liver manifestations with elevated GGT (p = .003). Comparing this to patients with likely benign (LB) variants, the patients with likely‐pathogenic (LP) variants have significantly more liver manifestations with elevated GGT (p = .0001). Significantly more patients with LP variants had extra‐hepatic phenotypes of ALGS compared with those patients with LB variants (p = .0004).
Conclusion
When NOTCH2 variants are absent in gnomAD, null variants and missense variants which were predicted to be pathogenic by at least three in‐silico tools could be considered pathogenic in patients with high GGT chronic liver diseases.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
N6-methyladenosine (m6A), an epigenetic modification on RNAs, plays an important role in many physiological and pathological processes. However, the involvement of m6A in goat uterus during early ...pregnancy remains largely unknown. In this study, we found that the total m6A level was increasing in goat uterus as early pregnancy progressed. Methyltransferase-like 3 (METTL3) is a core catalytic subunit of the m6A methyltransferase. We thus determined the expression and regulation of METTL3 in goat uterus. METTL3 was highly expressed in the luminal and glandular epithelia from day 16 (D16) to D25 of pregnancy, and it could be up-regulated by estrogen and progesterone in goat uterus and primary endometrial epithelial cells (EECs). In EECs, knockdown or overexpression of METTL3 resulted in a significant decrease or increase of cell proliferation, respectively. METTL3 knockdown reduced the m6A level of not only total RNA but also connective tissue growth factor (CTGF) mRNA. Luciferase assay suggested that METTL3 might target the potential m6A sites in the 3'untranslated region (3'UTR) of CTGF mRNA. Moreover, METTL3 positively regulated CTGF expression, and CTGF knockdown significantly counteracted the promoting effect of METTL3 overexpression on EEC proliferation. Collectively, METTL3 is dynamically expressed in goat uterus and can affect EEC proliferation by regulating CTGF in an m6A-dependent manner. Our results will lay a foundation for further studying the crucial mechanism of METTL3-mediated m6A modification in goat uterus during early pregnancy.
Purpose
To characterize profile of cytokines in aqueous humour of common macular diseases during intravitreal anti‐VEGF therapy.
Methods
Aqueous humour from eyes with central retinal vein occlusion ...(CRVO), branch retinal vein occlusion (BRVO), diabetic macular oedema (DME), neovascular age‐related macular degeneration (nAMD) or pathologic myopia associated choroidal neovascularization (pmCNV) was sampled prior to 1st (n = 144) and 2nd (n = 48) intravitreal anti‐VEGF therapy. Cytokines including vascular endothelium growth factor (VEGF), intercellular adhesion molecule 1 (ICAM‐1) and interleukin 6 (IL‐6) were quantitated and analysed along with retinal thickness data by optical coherence tomography (OCT) across two intravitreal injections and five macular disease types.
Results
ICAM‐1, IL‐6 and VEGF are positively associated in the aqueous humour of naive eyes (r = 0.39–0.77, p = 0.018 to <0.0001). ICAM‐1, VEGF and IL‐6 were significantly higher in CRVO and DME while lowest in pmCNV (p < 0.0001). Reduction of central retinal thickness (CRT) as a favourable response to anti‐VEGF therapy was in the order of CRVO, BRVO, DME and nAMD/pmCNV (p < 0.0001). The strongest predictor for favourable CRT reduction was baseline CRT (p < 0.0001) followed by baseline ICAM‐1 (p = 0.04). After the 1st intravitreal anti‐VEGF therapy, VEGF in aqueous humour lowered significantly but ICAM‐1 and IL‐6 levels remained unchanged. ICAM‐1 was not predictive for CRT reduction following 2nd anti‐VEGF therapy.
Conclusion
Rate of cytokine production is disease‐dependent and higher in CRVO and DME. Anatomical response to intravitreal anti‐VEGF therapy is disease‐specific and best in RVO patients. A combination therapy using both anti‐VEGF and anti‐inflammatory therapeutics may be superior to single anti‐VEGF therapy, at least for RVO and DME.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The goal of this study was to analyze whether mitochondria-associated endoplasmic reticulum membrane (MAMs) dysfunction mediated arsenic (As)-evoked pulmonary ferroptosis and acute lung injury (ALI). ...As exposure led to alveolar structure damage, inflammatory cell infiltration and pulmonary function decline in mice. Ferritin, the marker of iron overload, was increased, GPX4, the index of lipid peroxidation, was decreased in As-exposed lungs and pulmonary epithelial cells (MLE-12). Pretreatment with ferrostatin-1 (Fer-1), the inhibitor of ferroptosis, alleviated As-evoked ALI. In addition, As-induced non-heme iron deposition was inhibited in Fer-1 pretreated-mice. Moreover, As-triggered mitochondria damage and ferroptosis were mitigated in Fer-1 pretreated-MLE-12 cells. Mechanistically, PERK phosphorylation and mitofusin-2 (Mfn-2) reduction was observed in As-exposed MLE-12 cells and mice lungs. Additionally, the interaction between PERK and Mfn-2 was downregulated and MAMs dysfunction was observed in As-exposed MLE-12 cells. Intriguingly, PERK inhibitor and Mfn-2-overexpression all mitigated As-induced ferroptosis in MLE-12 cells. Additionally, CLPP and mtHSP70, the markers of mitochondrial stress, were upregulated, mitochondrial ROS (mtROS) was elevated, mitochondrial membrane potential (MMP) and ATP were decreased in As-exposed MLE-12 cells. Mitoquinone mesylate (MitoQ), a novel mitochondrial-targeted antioxidant, alleviated As-induced excess mtROS, mitochondrial stress, MAMs dysfunction in pulmonary epithelial cells. Similarly, in vivo experiments indicated that MitoQ pretreatment countered As-induced pulmonary ferroptosis and ALI. These data indicated that mtROS-initiated MAMs dysfunction is, at least partially, implicated in As-evoked ferroptosis and ALI.
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•Acute As exposure induced pulmonary function decline and ALI in mice.•Acute As exposure caused ferroptosis, MAMs dysfunction and mitochondrial stress in mice lungs and pulmonary epithelial cells.•Pretreatment with ferrostatin-1 alleviated As-induced pulmonary function decline and ALI.•PERK inhibitor and Mfn-2-overexpression inhibited As-evoked ferroptosis in pulmonary epithelial cells.•MitoQ neutralized As-mediated MAMs dysfunction, mtROS production and ferroptosis in pulmonary epithelial cells.•MitoQ abolished As-induced decline of the interaction between PERK and Mfn-2 in pulmonary epithelial cells.•MitoQ attenuated As-caused ferroptosis and ALI in mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Air pollution epidemiological studies increasingly rely on high-resolution exposure prediction models. However, to date, few models of this type exist for use in China.
We produced a national ...land-use regression model (LUR) to estimate monthly average PM2.5, PM10 and NO2 from 2014 to 2016 in China.
We developed a spatiotemporal semi-parametric model using generalized additive mixed models. A variety of predictor variables were included in model: time varying meteorological data, high resolution land cover data from Globaland30, satellite measures of aerosol optical depth, and Geographic Information System (GIS)-derived predictors. We assessed model performance with two cross-validation (CV) approaches, including hold-out CV, and 10-fold CV.
Over 22,000 monthly observations at 1382 monitoring locations were included to estimate the air pollution exposure. The time-varying spatial terms explained 87%, 71%, and 69% of variability with a hold-out cross-validated R2 of 0.85, 0.62, and 0.62 for PM2.5, PM10 and NO2 models, respectively. Models show that meteorological variables, population density, elevation, distance to road, and land cover types were important predictors for air pollution exposure.
we have developed a new nationwide model to estimate residence-level air pollution exposures, which can be used in studies of the chronic adverse effects of air pollution.
•We developed national scale spatiotemporal land use models to estimate monthly PM2.5, PM10 and NO2 concentrations in China.•For the PM2.5, PM10 and NO2 models, predictors explained 87%, 71%, and 69% of variability of the pollutant distributions.•Meteorological, AOD, and GIS-derived covariates were important predictors for air pollution exposure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Clinical studies on progressive familial intrahepatic cholestasis (PFIC) type 5 caused by mutations in NR1H4 are limited.
New patients with biallelic NR1H4 variants from our center and all patients ...from literature were retrospectively analyzed.
Three new patients were identified to be carrying five new variants. Liver phenotypes of our patients manifests as low-γ-glutamyl transferase cholestasis, liver failure and related complications. One patient underwent liver transplantation (LT) and survived, and two other patients died without LT. Nine other patients were collected through literature review. Twelve out of 13 patients showed neonatal jaundice, with the median age of onset being 7 days after birth. Reported clinical manifestations included cholestasis (13/13, 100%), elevated AFP (11/11, 100%), coagulopathy (11/11, 100%), hypoglycemia (9/13, 69%), failure to thrive (8/13, 62%), splenomegaly (7/13, 54%), hyperammonemia (7/13, 54%), and hepatomegaly (6/13, 46%). Six of 13 patients received LT at a median age of 6.2 months, and only one patient died of acute infection at one year after LT. Other 7 patients had no LT and died with a median age of 5 months (range 1.2-8). There were 8 patients with homozygous genotype and 5 patients with compound heterozygous genotype. In total, 13 different variants were detected, and 5 out of 12 single or multiple nucleotides variants were located in exon 5.
We identified three newly-diagnosed patients and five novel mutations. NR1H4-related PFIC typically cause progressive disease and early death. LT may be the only lifesaving therapy leading to cure.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Biallelic MYO5B variants have been associated with familial intrahepatic cholestasis (FIC) with low serum gamma-glutamyltransferase (GGT). Intronic or synonymous variants outside of canonical splice ...sites (hereinafter referred to as noncanonical variants) with uncertain significance were identified in MYO5B posing a challenge in clinical interpretation. This study is aimed at assessing the effects of these variants on premessenger RNA (pre-mRNA) splicing to improve recognition of pathogenic spliceogenic variants in MYO5B and better characterize the MYO5B genetic variation spectrum. Disease-associated MYO5B noncanonical variants were collected from the literature or newly identified low GGT cholestasis patients. In silico splicing predictions were performed to prioritize potential pathogenic variants. Minigene splicing assays were performed to determine their splicing patterns, with confirmation by blood RNA analysis in one case. Eleven (five novel) noncanonical variants with uncertain significance were identified. Minigene splicing assays revealed that three variants (c.2090+3A>T, c.2414+5G>T, and c.613-11G>A) caused complete aberrations, five variants (c.2349A>G/p.(=), c.4221G>A/p.(=), c.1322+5G>A, c.1669-35A>C, and c.3045+3A>T) caused predominant aberrations, and three variants (c.4852+11A>G, c.455+8T>C, and c.2415-6C>G) had no effect on pre-mRNA splicing. Patient-derived RNA analysis showed consistent results. Based on our results, eight variants were reclassified as likely pathogenic and three as likely benign. Combining the clinical features and the above analysis, the diagnosis of MYO5B-associated FIC could be made in three new patients. In conclusion, we characterized the splicing patterns of MYO5B noncanonical variants and suggest that RNA analysis should be routinely included in clinical diagnostics to provide essential evidence for the interpretation of variants.
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BFBNIB, FZAB, GIS, IJS, KILJ, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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