Summary
Background
Pemphigus is a group of rare life‐threatening mucocutaneous autoimmune diseases, presenting mainly as two subtypes: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Inherited ...predispositions to pemphigus have long been speculated but they remain poorly understood.
Objectives
To identify common and specific nongenetic and genetic factors associated with pemphigus and its subtypes in the Chinese population.
Methods
A genome‐wide association study (GWAS) was performed in 496 unrelated patients with pemphigus (including 365 with PV and 104 with PF) and 1105 controls without pemphigus.
Results
A sex preference was observed only in PV (57·5% female) and not in PF (47·1% female). For male patients only, the mean age at diagnosis was significantly lower for PV than for PF (P < 0·001). The strongest associated single‐nucleotide polymorphisms are in the human leucocyte antigen (HLA) region: rs70993900 (PV; P = 1·5 × 10−45) and rs9469220 (PF; P = 1·1 × 10−8). HLA‐DQB1*05:03 ranks at the top (P = 4·7 × 10−40; odds ratio 12·4) in both subtypes, with significantly different risk allele frequency (RAFPV = 34·2% vs. RAFPF = 18·8% vs. RAFcontrol = 4·4%), whereas HLA‐DRB1*14:01 and HLA‐DRB1*04:06 are PV specific. HLA‐DQB1*03:03 and HLA‐DQB1*03:02 show significant subtype specificity in opposite directions. All of these associations were validated in the replication series with 147 cases of pemphigus and 604 controls. Multiple novel non‐HLA susceptibility loci were also identified in the GWAS.
Conclusions
This study represents the largest GWAS on pemphigus in the Chinese population published to date, and has allowed us to identify HLA haplotypes significantly shared between or specific to the two main subtypes of pemphigus.
What's already known about this topic?
Pemphigus is a group of autoimmune mucocutaneous diseases.
It has multiple subtypes associated with certain human leucocyte antigen (HLA) haplotypes in an ethnicity‐specific manner.
What does this study add?
This is the largest genome‐wide association study published on pemphigus to date.
We identified, for the first time, more than 100 single‐nucleotide polymorphisms (SNPs; six independent) at the HLA locus, with associations reaching genome‐wide significance.
Some of these SNPs are strongly associated with specific subtypes of pemphigus.
What is the translational message?
The identified new haplotypes can potentially serve as genetic markers to improve investigation of the epidemiology and pathogenesis of pemphigus and its specific subtypes.
Linked Comment: Geller. Br J Dermatol 2019; 180:713–714.
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Metastasis significantly reduces the survival rate of osteosarcoma (OS) patients. Therefore, identification of novel targets remains extremely important to prevent metastasis and treat OS. In this ...report, we show that SPARCL1 is downregulated in OS by epigenetic methylation of promoter DNA. In vitro and in vivo experiments revealed that SPARCL1 inhibits OS metastasis. We further demonstrated that SPARCL1-activated WNT/β-catenin signaling by physical interaction with various frizzled receptors and lipoprotein receptor-related protein 5/6, leading to WNT-receptor complex stabilization. Activation of WNT/β-catenin signaling contributes to the SPARCL1-mediated inhibitory effects on OS metastasis. Furthermore, we uncovered a paracrine effect of SPARCL1 on macrophage recruitment through activated WNT/β-catenin signaling-mediated secretion of chemokine ligand5 from OS cells. These findings suggest that the targeting of SPARCL1 as a new anti-metastatic strategy for OS patients.
Abstract
An ordinary Hall effect in a conductor arises due to the Lorentz force acting on the charge carriers. In ferromagnets, an additional contribution to the Hall effect, the anomalous Hall ...effect (AHE), appears proportional to the magnetization. While the AHE is not seen in a collinear antiferromagnet, with zero net magnetization, recently it has been shown that an intrinsic AHE can be non-zero in non-collinear antiferromagnets as well as in topological materials hosting Weyl nodes near the Fermi energy. Here we report a large anomalous Hall effect with Hall conductivity of 27 Ω
−1
cm
−1
in a chiral-lattice antiferromagnet, CoNb
3
S
6
consisting of a small intrinsic ferromagnetic component (≈0.0013
μ
B
per Co) along
c
-axis. This small moment alone cannot explain the observed size of the AHE. We attribute the AHE to either formation of a complex magnetic texture or the combined effect of the small intrinsic moment on the electronic band structure.
Occult peritoneal metastasis (PM) in advanced gastric cancer (AGC) patients is highly possible to be missed on computed tomography (CT) images. Patients with occult PMs are subject to late detection ...or even improper surgical treatment. We therefore aimed to develop a radiomic nomogram to preoperatively identify occult PMs in AGC patients.
A total of 554 AGC patients from 4 centers were divided into 1 training, 1 internal validation, and 2 external validation cohorts. All patients’ PM status was firstly diagnosed as negative by CT, but later confirmed by laparoscopy (PM-positive n = 122, PM-negative n = 432). Radiomic signatures reflecting phenotypes of the primary tumor (RS1) and peritoneum region (RS2) were built as predictors of PM from 266 quantitative image features. Individualized nomograms of PM status incorporating RS1, RS2, or clinical factors were developed and evaluated regarding prediction ability.
RS1, RS2, and Lauren type were significant predictors of occult PM (all P < 0.05). A nomogram of these three factors demonstrated better diagnostic accuracy than the model with RS1, RS2, or clinical factors alone (all net reclassification improvement P < 0.05). The area under curve yielded was 0.958 95% confidence interval (CI) 0.923–0.993, 0.941 (95% CI 0.904–0.977), 0.928 (95% CI 0.886–0.971), and 0.920 (95% CI 0.862–0.978) for the training, internal, and two external validation cohorts, respectively. Stratification analysis showed that this nomogram had potential generalization ability.
CT phenotypes of both primary tumor and nearby peritoneum are significantly associated with occult PM status. A nomogram of these CT phenotypes and Lauren type has an excellent prediction ability of occult PM, and may have significant clinical implications on early detection of occult PM for AGC.
Growth performance, digestive and absorptive capacities and target of rapamycin (TOR), ribosomal protein S6 kinase 1 (S6K1) and eIF4E‐binding protein (4E‐BP) gene expression in the hepatopancreas and ...intestine of juvenile grass carp (Ctenopharyngodon idellus) fed graded ratios of dietary alpha‐linolenic acid/linoleic acid (ALA/LNA) (0.01, 0.34, 0.68, 1.03, 1.41, 1.76 and 2.15) for 60 days were investigated. The results showed that ALA/LNA ratio of 1.03 significantly improved (i) per cent weight gain (PWG) and feed efficiency, (ii) hepatopancreatic trypsin, chymotrypsin, lipase, amylase and intestinal creatine kinase (CK) activities, (iii) hepatopancreatic trypsinogen‐2 and chymotrypsinogen mRNA levels. Meanwhile, fish fed with ALA/LNA ratio of 0.68 significantly enhanced, (iv) Na+/K+‐ATPase and γ‐glutamyl transpeptidase activities in whole intestine, and alkaline phosphatase activities in the proximal intestine (PI) and distal intestine, (v) amylase, intestinal Na+/K+‐ATPase alpha‐subunit isoform 1, Na+/K+‐ATPase alpha‐subunit isoform 8 and CK mRNA abundances, (vi) TOR and S6K1 gene expression in the hepatopancreas and intestine of juvenile grass carp. Based on the quadratic regression analysis of PWG, cholecystokinin and leptin contents in the PI, optimal dietary ALA/LNA ratio of juvenile grass carp (8.78–72.00 g) was estimated to be 1.08, 1.19 and 1.05, respectively.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Constrained by the Nielsen-Ninomiya no-go theorem, in all so-far experimentally determined Weyl semimetals (WSMs) the Weyl points (WPs) always appear in pairs in the momentum space with no ...exception. As a consequence, Fermi arcs occur on surfaces which connect the projections of the WPs with opposite chiral charges. However, this situation can be circumvented in the case of unpaired WP, without relevant surface Fermi arc connecting its surface projection, appearing singularly, while its Berry curvature field is absorbed by nontrivial charged nodal walls. Here, combining angle-resolved photoemission spectroscopy with density functional theory calculations, we show experimentally that a singular Weyl point emerges in PtGa at the center of the Brillouin zone (BZ), which is surrounded by closed Weyl nodal walls located at the BZ boundaries and there is no Fermi arc connecting its surface projection. Our results reveal that nontrivial band crossings of different dimensionalities can emerge concomitantly in condensed matter, while their coexistence ensures the net topological charge of different dimensional topological objects to be zero. Our observation extends the applicable range of the original Nielsen-Ninomiya no-go theorem which was derived from zero dimensional paired WPs with opposite chirality.
The plastic deformation and fracture behavior of two different types of Cu/X (X=Nb, Zr) nanostructured multilayered films (NMFs) were systematically investigated over wide ranges of modulation period ...(λ) and modulation ratio (η, the ratio of X layer thickness to Cu layer thickness). It was found that both the ductility and fracture mode of the NMFs were predominantly related to the constraining effect of ductile Cu layers on microcrack-initiating X layers, which showed a significant length-scale dependence on λ and η. Experimental observations and theoretical analyses also revealed a transition in strengthening mechanism, from single dislocation slip in confined layers to a load-bearing effect, when the Cu layer thickness was reduced to below ∼15nm by either decreasing λ or increasing η. This is due to the intense suppression of dislocation activities in the thin Cu layers, which causes a remarkable reduction in the deformability of the Cu layers. Concomitantly, the constraining effect of Cu layers on microcrack propagation is weakened, which can be used to explain the experimentally observed λ and η-dependent fracture mode transition from shear mode to an opening mode. Furthermore, the fracture toughness of the NMFs is also found to be sensitive to both λ and η. A fracture mechanism-based micromechanical model is developed to quantitatively assess the length-scale-dependent fracture toughness, and these calculations are in good agreement with experimental findings.
The comparison between relatively intact nanoscale extracellular vesicle-derived DNA (nEV-DNA) and fragmented circulating cell-free DNA (cfDNA) in mutation detection among patients with ...non-small-cell lung cancer (NSCLC) has not been carried out yet, and thus deserves investigation.
Both nEV-DNA and cfDNA was obtained from 377 NSCLC patients with known EGFR mutation status and 69 controls. The respective EGFRE19del/T790M/L858R mutation status was interrogated with amplification-refractory-mutation-system-based PCR assays (ARMS-PCR).
Neither nEV-DNA nor cfDNA levels show a strong correlation with tumor volumes. There is no correlation between cfDNA and nEV-DNA levels either. The detection sensitivity of nEV-DNA and cfDNA using ARMS-PCR in early-stage NSCLC was 25.7% and 14.2%, respectively, with 96.6% and 91.7% specificity, respectively. In late-stage NSCLC, both nEV-DNA and cfDNA show ∼80% sensitivity and over 95% specificity.
nEV-DNA is superior to cfDNA for mutation detection in early-stage NSCLC using ARMS-PCR. However, the advantages vanish in late-stage NSCLC.
Nitrification is a series of processes that oxidizes ammonia to nitrate, which contributes to hypoxia development in coastal oceans, especially in eutrophicated regions. The nitrification rate of ...bulk water (NRb) and particle free water (NRpf, particle > 3 μm eliminated) were determined along the Chang Jiang River plume in August 2011 by nitrogen isotope tracer technique. Measurements of dissolved oxygen (DO), community respiration rate (CR), nutrients, dissolved organic nitrogen (DON), total suspended matter (TSM), particulate organic carbon/nitrogen (POC / PON), acid-leachable iron and manganese on suspended particles and both archaeal and β-proteobacterial ammonia monooxygenase subunit A gene (amoA) abundance on size-fractioned particles (> 3 μm and 0.22–3 μm) were conducted. The NRb ranged from undetectable up to 4.6 μmol L−1 day−1, peaking at a salinity of ~ 29. NRb values were positively correlated with ammonium concentration, suggesting the importance of substrate in nitrification. In the river mouth and the inner plume, NRb was much higher than NRpf, indicating that the nitrifying microorganism is mainly particle associated, which was supported by its significant correlation with amoA gene abundance and TSM concentration. The estimated oxygen demands of nitrification accounted for 0.32 to 318% of CR, in which 50% samples demanded more oxygen than that predicted by by the Redfield model (23%), indicating that oxygen might not be the sole oxidant though DO was sufficient (> 58 μmol kg−1) throughout the observation period. The excess nitrification-associated oxygen demand (NOD) showed a tendency to occur at lower DO samples accompanied by higher acid-leachable Fe / Mn, which implied reactive Fe3+ / Mn4+ may play a role as oxidant in the nitrification process. Stoichiometric calculation suggested that reactive Fe on particles was 10 times the oxidant demand required to complete ammonia oxidation in the entire plume. The potential involvement of reactive iron and manganese in the nitrification process in oxygenated water further complicated nitrogen cycling in the turbid river plume.
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