Apoptotic cells are rapidly engulfed and removed by phagocytes after displaying cell surface eat-me signals. Among many phospholipids, only phosphatidylserine (PS) is known to act as an eat-me signal ...on apoptotic cells. Using unbiased proteomics, we identified externalized phosphatidylinositides (PIPs) as apoptotic eat-me signals recognized by CD14
phagocytes. Exofacial PIPs on the surfaces of early and late-apoptotic cells were observed in patches and blebs using anti-PI(3,4,5)P
antibody, AKT- and PLCδ PH-domains, and CD14 protein. Phagocytosis of apoptotic cells was blocked either by masking exofacial PIPs or by CD14 knockout in phagocytes. We further confirmed that exofacial PIP
thymocytes increased dramatically after in vivo irradiation and that exofacial PIP
cells represented more significant populations in tissues of Cd14
than WT mice, especially after induction of apoptosis. Our findings reveal exofacial PIPs to be previously unknown cell death signals recognized by CD14
phagocytes.
•Brain age prediction from routine clinical T2-weighted images is feasible.•We built and evaluated a prediction model with institutional clinical imaging data.•A greater white matter hyperintensity ...resulted in a higher predicted age difference.•Diabetes mellitus was associated with a higher predicted age difference.
Our study investigated the feasibility and clinical relevance of brain age prediction using axial T2-weighted images (T2-WIs) with a deep convolutional neural network (CNN) algorithm. The CNN model was trained by 1,530 scans in our institution. The performance was evaluated by the mean absolute error (MAE) between the predicted brain age and the chronological age based on an internal test set (n=270) and an external test set (n=560). The ensemble CNN model showed an MAE of 4.22 years in the internal test set and 9.96 years in the external test set. Participants with grade 2–3 white matter hyperintensity (WMH) showed a higher corrected predicted age difference (PAD) than grade 0 WMH (posthoc p<0.001). Participants diagnosed with diabetes mellitus also had a higher corrected PAD than those without diabetes (adjusted p=0.048), although it showed no significant differences according to the diagnosis of hypertension or dyslipidemia. We suggest that routine clinical T2-WIs are feasible to predict brain age, and it might be clinically relevant according to the WMH grade and the presence of diabetes mellitus.
Surface-templated evaporation driven (STED) method is a promising method to fabricate supraparticles with various sizes, porosities, and shapes by drying colloidal dispersion drops on liquid ...repellent surfaces. Until now, for the method, only spherical shaped colloidal particles have been used as primary colloids. Here, we introduce six different shapes of nano-colloidal dispersions for the STED method: nanocubics, nanoplates, nanosheets, coffin-shaped nanoparticles (NPs), spherical NPs, and aggregates of NPs. It is confirmed that the shape and size of the primary colloids have little effect for drying the dispersion drop when a single component colloidal dispersion is dried. For heterogeneous supraparticles with composite material assembly, still the shape of the colloids has no influences, while the size and dispersity play roles for tuning the morphology of the supraparticles. From the results, we propose a way to fabricate homogeneous mixture, core/shell, and Janus core/shell structures of the supraparticles depending on the size and dispersity of the mixture colloidal dispersion. Indeed, knowledge on the effects of types of colloids would be of great importance for tailoring supraparticles.
Grain filling is an important trait of rice that affects the yield of grain-oriented crop species with sink capacity-related traits. Here, we used a doubled haploid (DH) population derived from a ...cross between 93-11 (P1, indica) and Milyang352 (P2, japonica) to investigate quantitative traits loci (QTLs) controlling grain filling in rice employing the Kompetitive allele-specific PCR (KASP) markers. The mapping population was grown under early-, normal-, and late-cultivation periods. The phenotypic evaluation revealed that spikelet number per panicle positively correlated with the grain-filling ratio under early cultivation conditions. Notably, three significant QTLs associated with the control of grain filling, qFG3, qFG5-1, and qFG5-2, were identified. Genes harbored by these QTLs are linked with diverse biological processes and molecular functions. Likewise, genes associated with abiotic stress response and transcription factor activity and redox homeostasis were detected. Genes such as MYB, WRKY60, and OsSh1 encoding transcription factor, β-catenin, and the tubulin FtsZ, as well as those encoding cytochrome P450, would play a forefront role in controlling grain filling under early cultivation conditions. Our results suggest that qFG3-related genes could mediate the transition between grain filling and abiotic stress response mechanisms. Fine-mapping these QTLs would help identify putative candidate genes for downstream functional characterization.
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•EBV positivity in CD20-positive tumor-infiltrating lymphocytes was present in over 70% of HCC-IS.•HCC-IS lacked CTNNB1 mutations and exhibited increased global DNA ...hypermethylation.•Both PD-1 and PD-L1 in tumor-infiltrating lymphocytes, and PD-L1 in tumor cells were overexpressed in HCC-IS.•HCCs with high EBV positivity, paradoxically, were associated with a poor prognosis.•HCCs with high EBV positivity exhibited increased levels of functionally exhausted CD8 T cells.
The immunogenomic characteristics of hepatocellular carcinomas (HCCs) with immune cell stroma (HCC-IS), defined histologically, have not been clarified. We investigated the clinical and molecular features of HCC-IS and the prognostic impact of Epstein-Barr virus (EBV) infection.
We evaluated 219 patients with conventional HCC (C-HCC) and 47 with HCC-IS using in situ hybridization for EBV, immunohistochemistry, multiplex immunofluorescence staining, and whole exome and transcriptome sequencing. Human leukocyte antigen types were also extracted from the sequencing data. Genomic and prognostic parameters were compared between HCC-IS and C-HCC. Results: CD8 T cell infiltration was more frequent in HCC-IS than C-HCC (mean fraction/sample, 22.6% vs. 8.9%, false discovery rate q <0.001), as was EBV positivity in CD20-positive tumor-infiltrating lymphocytes (TILs) (74.5% vs. 4.6%, p <0.001). CTNNB1 mutations were not identified in any HCC-IS, while they were present in 24.1% of C-HCC (p = 0.016). Inhibitory and stimulatory immune modulators were expressed at similar levels in HCC-IS and EBV-positive C-HCC. Global hypermethylation, and expression of PD-1 and PD-L1 in TILs, and PD-L1 in tumors, were also associated with HCC-IS (p <0.001), whereas human leukocyte antigen type did not differ according to HCC type or EBV positivity. HCC-IS was an independent factor for favorable recurrence-free survival (adjusted hazard ratio aHR 0.23; p = 0.002). However, a subgroup of tumors with a high density of EBV-positive TILs had poorer recurrence-free (aHR 25.48; p <0.001) and overall (aHR 9.6; p = 0.003) survival, and significant enrichment of CD8 T cell exhaustion signatures (q = 0.0296).
HCC-IS is a distinct HCC subtype associated with a good prognosis and frequent EBV-positive TILs. However, paradoxically, a high density of EBV-positive TILs in tumors is associated with inferior prognostic outcomes. Patients with HCC-IS could be candidates for immunotherapy.
Hepatocellular carcinomas with histologic evidence of abundant immune cell infiltration are characterized by frequent activation of Epstein-Barr virus in tumor-infiltrating lymphocytes and less aggressive clinical behavior. However, a high density of Epstein-Barr virus-positive tumor-infiltrating lymphocytes is associated with inferior prognostic outcomes, possibly as a result of immune escape due to significant CD8 T cell exhaustion.
In rice, high radial oxygen loss (ROL) has been associated with the reduction in the activity of methanogens, therefore reducing the formation of methane (CH
) due to the abundance in application of ...nitrogen (N)-rich fertilizers. In this study, we evaluated the root growth behavior and ROL rate of a doubled haploid (DH) population (
= 117) and parental lines 93-11 (P1,
) and Milyang352 (P2,
) in response to iron (II) sulfide (FeS). In addition, we performed a linkage mapping and quantitative trait locus (QTL) analysis on the same population for the target traits. The results of the phenotypic evaluation revealed that parental lines had distinctive root growth and ROL patterns, with 93-11 (
) and Milyang352 (
) showing low and high ROL rates, respectively. This was also reflected in their derived population, indicating that 93.2% of the DH lines exhibited a high ROL rate and about 6.8% had a low ROL pattern. Furthermore, the QTL and linkage map analysis detected two QTLs associated with the control of ROL and root area on chromosomes 2 (
, 127 cM, logarithm of the odds (LOD) 3.04, phenotypic variation explained (PVE) 11.61%) and 8 (
, 97 cM, LOD 4.394, PVE 15.95%), respectively. The positive additive effect (2.532) of
indicates that the allele from 93-11 contributed to the observed phenotypic variation for ROL. The breakthrough is that the
harbors genes proposed to be involved in stress signaling, defense response mechanisms, and transcriptional regulation, among others. The qPCR results revealed that the majority of genes harbored by the
recorded a higher transcript accumulation level in Milyang352 over time compared to 93-11. Another set of genes exhibited a high transcript abundance in P1 compared to P2, while a few were differentially regulated between both parents. Therefore,
and
,
genes encoding transcription factors (TFs), coupled with
,
and
are suggested to play important roles in the positive regulation of ROL in rice. However, the recorded differential expression of
and
, and the decrease in
,
, and
TF expression between parental lines proposes them as being involved in the control of oxygen flux level in rice roots.
There are a few studies about the relationship between inflammatory bowel disease (IBD) and atopic dermatitis (AD). It is implied that both diseases have common pathophysiologic mechanisms and can ...affect each other. However, little information is available on the effect of AD on the clinical course of patients with IBD.
This is a multi-center, retrospective, observational study. We define AD as a chronic eczematoid dermatosis diagnosed by dermatologists. Patients with concurrent IBD and AD were defined as a case group. Age, gender, and IBD subtype-matched patients without AD were included as a reference group.
The numbers of patients in the case and reference groups were 61 and 122 respectively. There was a significantly shorter biologics-free survival in the case group than that in the reference group according to the multivariable-adjusted Cox regression analysis with the onset age, disease duration, smoking status, use of steroid, use of immunomodulator, initial C-reactive protein, initial erythrocyte sedimentation rate, presence of other allergic diseases and initial disease severity hazard ratio (HR) 1.828, 95% confidence interval (CI) 1.022-3.271, p = .042. The trend was consistent in the subgroup analysis with ulcerative colitis (HR 3.498, 95% CI 1.066-11.481, p = .039), but not with Crohn's disease (HR 1.542, 95% CI 0.720-3.301, p = .265).
AD showed a significant effect on the biologics-free survival of patients with IBD and especially the UC subtype. Further mechanistic research is required to elucidate the pathogenesis of AD on the clinical course of IBD.
Abstract
Objective
The aim of this study was to find peripheral biomarkers and central metabolites affecting neuroinflammation in complex regional pain syndrome (CRPS) patients using 11C-(R)-PK11195 ...positron emission tomography (PET) and magnetic resonance spectroscopy (MRS).
Methods
Using MRS and PET, we measured associations between neurometabolites and neuroinflammation in 12 CRPS patients and 11 healthy controls. Also, we investigated various peripheral parameters that may affect neuroinflammation in CRPS.
Results
We found positive correlations of Lipid (Lip)13a/total creatine (tCr) and Lip09/tCr with neuroinflammation, the distribution volume ratio (DVR) of 11C-(R)-PK11195 in the right and left insula in CRPS patients. However, these correlations were not found in controls. High hemoglobin levels correlated with decreased neuroinflammation (the DVR of 11C-(R)-PK11195) in the right thalamus and left insula in healthy controls. We found that high levels of glucose and pH correlated with increased neuroinflammation, but high levels of CO2, basophil, and creatinine were associated with decreased neuroinflammation in the left thalamus and the right and left insula in CRPS patients.
Conclusions
This is the first report indicating that elevated neuroinflammation levels are associated primarily with lipids in the brain and pH, glucose, CO2, basophil, and creatinine in the peripheral parameters in CRPS patients. Our results suggest that characterizing the peripheral biomarkers and central metabolites affecting neuroinflammation is essential to understanding the pathophysiology of CRPS.
This study aimed to investigate distinct neurometabolites in the anterior cingulate cortex (ACC), right and left thalamus, and insula of patients with fibromyalgia (FM) compared with healthy controls ...using proton magnetic resonance spectroscopy (MRS). Levels of N-acetylaspartate (NAA), N-acetylaspartylglutamate (NAAG), total NAA (tNAA = NAA + NAAG), myo-inositol (ml), glutamine (Gln), glutamate (Glu), Glx (Glu + Gln), glycerophosphocholine (GPC), total choline (tCho = GPC + phosphocholine) and glutathione (GSH) levels relative to total creatine (tCr) levels including creatine (Cr) and phosphocreatine (PCr) and relative to Cr levels were determined in the ACC, right and left thalamus, and insula in 12 patients with FM and 13 healthy controls using MRS. In the ACC, NAA/tCr (P = 0.028) and tCho/tCr (P = 0.047) were higher in patients with FM. In the right and left insula, tNAA/tCr (P = 0.019, P = 0.007, respectively) was lower in patients with FM. Patients with FM showed lower levels of ml/Cr (P = 0.037) in the right insula than healthy controls. These findings are paramount to understand decisive pathophysiological mechanisms related to abnormal features in the brain and parasympathetic nervous systems in FM. We suggest that the results presented herein may be essential to understand hidden pathological mechanisms and also life system potential as protective and recovering metabolic strategies in patients with FM.
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