Amelogenesis imperfecta (AI) is a diverse group of inherited diseases featured by various presentations of enamel malformations that are caused by disturbances at different stages of enamel ...formation. While hypoplastic AI suggests a thickness defect of enamel resulting from aberrations during the secretory stage of amelogenesis, hypomaturation AI indicates a deficiency of enamel mineralization and hardness established at the maturation stage. Mutations in ENAM, which encodes the largest enamel matrix protein, enamelin, have been demonstrated to cause generalized or local hypoplastic AI. Here, we characterized 2 AI families with disparate hypoplastic and hypomaturation enamel defects and identified 2 distinct indel mutations at the same location of ENAM, c588+1del and c.588+1dup. Minigene splicing assays demonstrated that they caused frameshifts and truncation of ENAM proteins, p.Asn197Ilefs*81 and p.Asn197Glufs*25, respectively. In situ hybridization of Enam on mouse mandibular incisors confirmed its restricted expression in secretory stage ameloblasts and suggested an indirect pathogenic mechanism underlying hypomaturation AI. In silico analyses indicated that these 2 truncated ENAMs might form amyloid structures and cause protein aggregation with themselves and with wild-type protein through the added aberrant region at their C-termini. Consistently, protein secretion assays demonstrated that the truncated proteins cannot be properly secreted and impede secretion of wild-type ENAM. Moreover, compared to the wild-type, overexpression of the mutant proteins significantly increased endoplasmic reticulum stress and upregulated the expression of unfolded protein response (UPR)–related genes and TNFRSF10B, a UPR-controlled proapoptotic gene. Caspase, terminal deoxynucleotidyl transferase UTP nick-end labeling (TUNEL), and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays further revealed that both truncated proteins, especially p.Asn197Ilefs*81, induced cell apoptosis and decreased cell survival, suggesting that the 2 ENAM mutations cause AI through ameloblast cell pathology and death rather than through a simple loss of function. This study demonstrates that an ENAM mutation can lead to generalized hypomaturation enamel defects and suggests proteinopathy as a potential pathogenesis for ENAM-associated AI.
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CMK, NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Summary
Background
Aspirin increases the risk of gastrointestinal bleeding.
Aim
To investigate the risk of lower gastrointestinal bleeding (LGIB) in aspirin users.
Methods
Low‐dose (75‐325 mg daily) ...aspirin users and controls matched by age, gender and enrollment time in a 1:5 ratio were selected from 1 million randomly sampled subjects in the National Health Insurance Research Database of Taiwan. Cox proportional hazard regression models were developed to evaluate the predictors of LGIB with adjustments for age, gender, comorbidities including coronary artery disease, ischaemic stroke, diabetes, hypertension, chronic kidney disease, liver cirrhosis, chronic obstructive pulmonary disease, dyslipidemia, uncomplicated peptic ulcer disease, history of peptic ulcer bleeding, and concomitant use of clopidogrel, ticlopidine, warfarin, nonsteroidal anti‐inflammatory drugs (NSAIDs), cyclooxygenase‐2 inhibitors, steroids, proton pump inhibitors (PPIs), histamine‐2 receptor antagonists (H2RAs), nitrates, alendronate, selective serotonin reuptake inhibitors (SSRIs) and calcium channel blockers.
Results
A total of 53 805 aspirin users and 269 025 controls were included. Aspirin group had a higher incidence of LGIB within 1 year than control group (0.20% vs 0.06%, P<.0001). Aspirin (hazard ratio HR: 2.75, 95% confidence interval CI: 2.06‐3.65), NSAIDs (HR: 8.61, 95% CI: 3.28‐22.58), steroids (HR: 10.50, 95% CI: 1.98‐55.57), SSRIs (HR: 11.71, 95% CI: 1.40‐97.94), PPIs (HR: 8.47, 95% CI: 2.26‐31.71), and H2RAs (HR: 10.83, 95% CI: 2.98‐39.33) were significantly associated with LGIB.
Conclusions
The risk of LGIB was higher in low‐dose aspirin users than in aspirin nonusers in this nationwide cohort. Low‐dose aspirin, NSAIDs, steroids, SSRIs, PPIs and H2RAs were independent risk factors for LGIB.
Linked ContentThis article is linked to Taha and Chen et al papers. To view these articles visit https://doi.org/10.1111/apt.14114 and https://doi.org/10.1111/apt.14138.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
There are inconsistencies in the literature regarding the prevalence and assessment of chemotherapy-induced peripheral neuropathy (CIPN). This study explored CIPN natural history and its ...characteristics in patients receiving taxane- and platinum-based chemotherapy.
Multi-country multisite prospective longitudinal observational study. Patients were assessed before commencing and three weekly during chemotherapy for up to six cycles, and at 6,9, and 12 months using clinician-based scales (NCI-CTCAE; WHO-CIPN criterion), objective assessments (cotton wool test;10 g monofilament); patient-reported outcome measures (FACT/GOG-Ntx; EORTC-CIPN20), and Nerve Conduction Studies.
In total, 343 patients were recruited in the cohort, providing 2399 observations. There was wide variation in CIPN prevalence rates using different assessments (14.2-53.4%). Prevalence of sensory neuropathy (and associated symptom profile) was also different in each type of chemotherapy, with paclitaxel (up to 63%) and oxaliplatin (up to 71.4%) showing the highest CIPN rates in most assessments and a more complex symptom profile. Peak prevalence was around the 6-month assessment (up to 71.4%). Motor neurotoxicity was common, particularly in the docetaxel subgroup (up to 22.1%; detected by NCI-CTCAE). There were relatively moderately-to-low correlations between scales (r
= 0.15,p < 0.05-r
= 0.48 p < 0.001), suggesting that they measure different neurotoxicity aspects from each other. Cumulative chemotherapy dose was not associated with onset and course of CIPN.
The historical variation reported in CIPN incidence and prevalence is possibly confounded by disagreement between assessment modalities. Clinical practice should consider assessment of motor neuropathy for neurotoxic chemotherapy. Current scales may not be all appropriate to measure CIPN in a valid way, and a combination of scales are needed.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aims
We investigated the role of transient receptor potential vanilloid receptor type 1 (TRPV1) in simvastatin‐mediated activation of endothelial nitric oxide synthase (eNOS) and angiogenesis.
...Methods
Fluo‐8 NW assay was for Ca2+ detection; Griess's assay was for NO bioavailability; Western blotting and immunoprecipitation were for protein phosphorylation and interaction; tube formation and Matrigel plug assay were for angiogenesis.
Results
In endothelial cells (ECs), treatment with simvastatin time‐dependently increased intracellular level of Ca2+. Pharmacological inhibition or genetic disruption of TRPV1 abrogated simvastatin‐mediated elevation of intracellular Ca2+ in ECs or TRPV1‐transfected HEK293 cells. Loss of TRPV1 function abolished simvastatin‐induced NO production and phosphorylation of eNOS and calmodulin protein kinase II (CaMKII) in ECs and in aortas of mice. Inhibition of TRPV1 activation prevented the simvastatin‐elicited increase in the formation of TRPV1–Akt–CaMKII–AMPK–eNOS complex. In mice, Matrigel plug assay showed that simvastatin‐evoked angiogenesis was abolished by TRPV1 antagonist and genetic ablation of TRPV1. Additionally, our results demonstrated that TRP ankyrin 1 (TRPA1) is the downstream effector in the simvastatin‐activated TRPV1‐Ca2+ signalling and in the consequent NO production and angiogenesis as evidence by that re‐expression of TRPA1 further augmented simvastatin‐elicited Ca2+ influx in TRPV1‐expressed HEK293 cells and ablation of TRPA1 function profoundly inhibited the simvastatin‐induced increase in the phosphorylation of eNOS and CaMKII, formation of TRPV1–Akt–CaMKII–AMPK–eNOS complex, NO bioavailability, tube formation and angiogenesis in ECs or mice.
Conclusion
Simvastatin‐induced Ca2+ influx may through the activation of TRPV1–TRPA1 signalling, which leads to phosphorylation of CaMKII, increases in the formation of TRPV1–CaMKII–AMPK–eNOS complex, eNOS activation, NO production and, ultimately, angiogenesis in ECs.
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DOBA, FSPLJ, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
•There is a major environmental issue about the printed circuit boards throughout the world.•Different physical and chemical recycling techniques have been reviewed.•Nonmetallic fraction of PCBs is ...the unwanted face of this waste stream.•Several applications of the nonmetallic fraction of waste PCBs have been introduced.
E-waste, in particular waste PCBs, represents a rapidly growing disposal problem worldwide. The vast diversity of highly toxic materials for landfill disposal and the potential of heavy metal vapors and brominated dioxin emissions in the case of incineration render these two waste management technologies inappropriate. Also, the shipment of these toxic wastes to certain areas of the world for eco-unfriendly “recycling” has recently generated a major public outcry. Consequently, waste PCB recycling should be adopted by the environmental communities as an ultimate goal.
This article reviews the recent trends and developments in PCB waste recycling techniques, including both physical and chemical recycling. It is concluded that the physical recycling techniques, which efficiently separate the metallic and nonmetallic fractions of waste PCBs, offer the most promising gateways for the environmentally-benign recycling of this waste. Moreover, although the reclaimed metallic fraction has gained more attention due to its high value, the application of the nonmetallic fraction has been neglected in most cases. Hence, several proposed applications of this fraction have been comprehensively examined.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We demonstrate synthetic azimuthal gauge potentials for Bose-Einstein condensates from engineering atom-light couplings. The gauge potential is created by adiabatically loading the condensate into ...the lowest energy Raman-dressed state, achieving a coreless vortex state. The azimuthal gauge potentials act as effective rotations and are tunable by the Raman coupling and detuning. We characterize the spin textures of the dressed states, in agreements with the theory. The lowest energy dressed state is stable with a 4.5-s half-atom-number-fraction lifetime. In addition, we exploit the azimuthal gauge potential to demonstrate the Hess-Fairbank effect, the analogue of Meissner effect in superconductors. The atoms in the absolute ground state has a zero quasiangular momentum and transits into a polar-core vortex when the synthetic magnetic flux is tuned to exceed a critical value. Our demonstration serves as a paradigm to create topological excitations by tailoring atom-light interactions where both types of SO(3) vortices in the |⟨Fover →⟩|=1 manifold, coreless vortices and polar-core vortices, are created in our experiment. The gauge field in the stationary Hamiltonian opens a path to investigating rotation properties of atomic superfluids under thermal equilibrium.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
Improving our understanding of the genes regulating grain yield can contribute to the development of more productive wheat varieties. Previously, a highly significant QTL affecting spikelet number ...per spike (SNS), grain number per spike (GNS) and grain yield was detected on chromosome arm 7AL in multiple genome-wide association studies. Using a high-resolution genetic map, we established that the A-genome homeolog of WHEAT ORTHOLOG OF APO1 (WAPO-A1) was a leading candidate gene for this QTL. Using mutants and transgenic plants, we demonstrate in this study that WAPO-A1 is the causal gene underpinning this QTL. Loss-of-function mutants wapo-A1 and wapo-B1 showed reduced SNS in tetraploid wheat, and the effect was exacerbated in wapo1 combining both mutations. By contrast, spikes of transgenic wheat plants carrying extra copies of WAPO-A1 driven by its native promoter had higher SNS, a more compact spike apical region and a smaller terminal spikelet than the wild type. Taken together, these results indicate that WAPO1 affects SNS by regulating the timing of terminal spikelet formation. Both transgenic and wapo1 mutant plants showed a wide range of floral abnormalities, indicating additional roles of WAPO1 on wheat floral development. Previously, we found three widespread haplotypes in the QTL region (H1, H2 and H3), each associated with particular WAPO-A1 alleles. Results from this and our previous study show that the WAPO-A1 allele in the H1 haplotype (115-bp deletion in the promoter) is expressed at significantly lower levels in the developing spikes than the alleles in the H2 and H3 haplotypes, resulting in reduced SNS. Field experiments also showed that the H2 haplotype is associated with the strongest effects in increasing SNS and GNS (H2>H3>H1). The H2 haplotype is already present in most modern common wheat varieties but is rare in durum wheat, where it might be particularly useful to improve grain yield.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18-21 and are established driver mutations in non-small cell lung cancer (NSCLC)
. Targeted therapies are approved for ...patients with 'classical' mutations and a small number of other mutations
. However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown
. Here we characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC, and establish the structure-function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR-mutant NSCLC and suggest that a structure-function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Information regarding the size-dependent distribution of per- and polyfluoroalkyl substances (PFAS) in atmospheric particulate matter (PM) is very limited. In this study, 248 size-specific PM samples ...were collected from 9 Asian cities using a portable 4-stage cascade impactor for the analysis of PFAS. Of the 34 investigated PFAS, perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) were the major compounds. In particular, the emerging PFAS, hexafluoropropylene oxide dimer acid, was quantified in the PM for the first time, with concentrations ranging from <0.086 to 21.5 pg/m3. Spatially, PFOA and PFOS were the predominant compounds in China, while precursors, emerging PFAS, and short-chain PFAS dominated in India, Japan, and South Korea, respectively. Seasonal variations of PFAS may be controlled by regional climate, local or seasonal emission sources, and long-range transport of air masses. Size-dependent distribution was investigated, showing that the majority of PFAS predominantly affiliated in fine particles, while PFOS and its alternatives tended to attach on coarser particles. Moreover, PFOS distributed on specific sizes exhibited seasonal and regional dependency, while no such patterns were observed for PFOA. These findings will provide useful information on the geographical and size-dependent distribution of PFAS in the atmospheric PM.
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IJS, KILJ, NUK, PNG, UL, UM
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