Understanding the genetic effects on non-coding RNA (ncRNA) expression facilitates functional characterization of disease-associated genetic loci. Among several classes of ncRNAs, microRNAs (miRNAs) ...are key post-transcriptional gene regulators. Despite its biological importance, previous studies on the genetic architecture of miRNA expression focused mostly on the European individuals, underrepresented in other populations. Here, we mapped miRNA expression quantitative trait loci (miRNA-eQTL) for 343 miRNAs in 141 Japanese using small RNA sequencing and whole-genome sequencing, identifying 1275 cis-miRNA-eQTL variants for 40 miRNAs (false discovery rate < 0.2). Of these, 25 miRNAs having eQTL were unreported in the European studies, including 5 miRNAs with their lead variant monomorphic in the European populations, which demonstrates the value of miRNA-eQTL analysis in diverse ancestral populations. MiRNAs with eQTL effect showed allele-specific expression (ASE; e.g. miR-146a-3p), and ASE analysis further detected cis-regulatory variants not captured by the conventional miRNA-eQTL mapping (e.g. miR-933). We identified a copy number variation associated with miRNA expression (e.g. miR-570-3p, P = 7.2 × 10-6), which contributes to a more comprehensive landscape of miRNA-eQTLs. To elucidate a post-transcriptional modification in miRNAs, we created a catalog of miRNA-editing sites, including 10 canonical and 6 non-canonical sites. Finally, by integrating the miRNA-eQTLs and Japanese genome-wide association studies of 25 complex traits (mean n = 192 833), we conducted a transcriptome-wide association study, identifying miR-1908-5p as a potential mediator for adult height, colorectal cancer and type 2 diabetes (P < 9.1 × 10-5). Our study broadens the population diversity in ncRNA-eQTL studies and contributes to functional annotation of disease-associated loci found in non-European populations.
The incidence and prevalence of non-tuberculous mycobacteria (NTM) infections are steadily increasing worldwide, partially due to the increased incidence of immunocompromised conditions, such as the ...post-transplantation state. The importance of proper diagnosis and management of NTM infection has been recently recognized. Host immunological responses play integral roles in vulnerability to NTM infections, and may contribute to the onset of specific types of NTM infection. Furthermore, distinct NTM species are known to affect and attenuate these host immune responses in unique manners. Therefore, host immune responses must be understood with respect to each causative NTM species. Here, we review innate, cellular-mediated, and humoral immunity to NTM and provide perspectives on novel diagnostic approaches regarding each NTM species.
The efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small-cell lung cancer (NSCLC) might depend on the presence of emphysema, but this association is not established. We ...aimed to investigate if quantitively and automatically measuring emphysema can predict the effect of ICIs. We retrospectively analyzed 56 patients with NSCLC who underwent immunotherapy at our hospital. We used the Goddard scoring system (GS) to evaluate the severity of emphysema on baseline CT scans using three-dimensional image analysis software. The emphysema group (GS ≥ 1) showed better progression-free survival (PFS) than the non-emphysema group (GS = 0) (6.5 vs. 2.3 months, respectively, p < 0.01). Multivariate analyses revealed that good performance status, GS of ≥ 1, and high expression of PD-L1 were independently associated with better PFS, while smoking status was not. In conclusion, quantitative evaluation of emphysema can be an objective parameter for predicting the therapeutic effects of ICIs in patients with NSCLC. Our findings can be used to generate hypotheses for future studies.
Nanoparticles, i.e., particles with a diameter of ≤100 nm regardless of their composing material, are added to various foods as moisturizers, coloring agents, and preservatives. Silicon dioxide ...(SiO2, silica) nanoparticles in particular are widely used as food additives. However, the influence of SiO2 nanoparticle oral consumption on intestinal homeostasis remains unclear. The daily intake of 10-nm-sized SiO2 nanoparticles exacerbates dextran sulfate sodium (DSS)-induced colitis, whereas the daily intake of 30-nm-sized SiO2 nanoparticles has no influence on intestinal inflammation. The exacerbation of colitis induced by consuming 10-nm-sized SiO2 nanoparticles was abolished in mice deficient in apoptosis-associated speck-like protein containing a CARD (ASC). Our study indicates that the oral intake of small SiO2 nanoparticles poses a risk for worsening intestinal inflammation through activation of the ASC inflammasome.
•Silica nanoparticles activate ASC-inflammasome in macrophages.•Oral intake of silica nanoparticles exacerbates DSS-induced colitis.•Smaller silica nanoparticles have harmful effects on intestinal inflammation.
To evaluate tumor blood flow using
O-water positron emission tomography (PET) in patients with non-small cell lung cancer (NSCLC) before and after chemotherapy with bevacizumab, and to investigate ...the effects of bevacizumab on tumor blood flow changes and progression-free survival (PFS). Twelve patients with NSCLC were enrolled. Six patients underwent chemotherapy with bevacizumab and the other six without bevacizumab.
O-water dynamic PET scans were performed within 1 week before the start of chemotherapy and within 1 week after the first day of chemotherapy. Tumor blood flow was analyzed quantitatively using a single one-tissue compartment model with the correction of pulmonary circulation blood volume and arterial blood volume via an image-derived input function. In the bevacizumab group, mean tumor blood flow was statistically significantly reduced post-chemotherapy (pre-chemotherapy 0.27 ± 0.14 mL/cm
/min, post-chemotherapy 0.18 ± 0.12 mL/cm
/min). In the no bevacizumab group, there was no significant difference between mean tumor perfusion pre-chemotherapy (0.42 ± 0.42 mL/cm
/min) and post-chemotherapy (0.40 ± 0.27 mL/cm
/min). In the bevacizumab group, there was a positive correlation between the blood flow ratio (tumor blood flow post-chemotherapy/tumor blood flow pre-chemotherapy) and PFS (correlation coefficient 0.94). Mean tumor blood flow decreases after bevacizumab administration and was positively correlated with longer PFS.
Abstract
The immunological basis of the clinical heterogeneity in autoimmune vasculitis remains poorly understood. In this study, we conduct single-cell transcriptome analyses on peripheral blood ...mononuclear cells (PBMCs) from newly-onset patients with microscopic polyangiitis (MPA). Increased proportions of activated CD14
+
monocytes and CD14
+
monocytes expressing interferon signature genes (ISGs) are distinctive features of MPA. Patient-specific analysis further classifies MPA into two groups. The MPA-MONO group is characterized by a high proportion of activated CD14
+
monocytes, which persist before and after immunosuppressive therapy. These patients are clinically defined by increased monocyte ratio in the total PBMC count and have a high relapse rate. The MPA-IFN group is characterized by a high proportion of ISG
+
CD14
+
monocytes. These patients are clinically defined by high serum interferon-alpha concentrations and show good response to immunosuppressive therapy. Our findings identify the immunological phenotypes of MPA and provide clinical insights for personalized treatment and accurate prognostic prediction.
Abstract
Objective
B-cell activating factor (BAFF) is implicated in SLE pathogenesis. Blocking BAFF signalling has contributed to reducing glucocorticoid dosage and preventing organ damage. However, ...clinical characteristics of patients who may benefit from this therapy are not yet fully elucidated. Therefore, we identified patients with high BAFF-bioactivity to investigate their clinical characteristics and BAFF-producing cells.
Methods
We established the reporter cell for BAFF and investigated the clinical characteristics of SLE patients with high BAFF-bioactivity. We identified BAFF-expressing kidney cells using publicly available scRNA-seq data and immunohistological analysis. SLE patients were stratified based on the bioactivity of BAFF and type-I IFN (IFN-I) to identify associated characteristic clinical manifestations.
Results
SLE patients, especially patients with LN, had significantly higher serum BAFF-bioactivity than healthy controls (HC) and non-LN patients. Additionally, single-cell-RNA-seq data and immunohistological analysis of kidney samples from LN patients revealed that BAFF is expressed in glomerular macrophages and mesangial cells. Notably, BAFF bioactivity was elevated in the urine of LN patients compared with that of non-LN patients, while no IFN-I bioactivity was detected in the urine. Furthermore, SLE stratification based on bioactivities of serum BAFF and IFN-I revealed the clinical characteristics of patients: high BAFF represented patients with LN and high IFN-I represented patients with blood and skin manifestations.
Conclusions
Monitoring urinary BAFF-bioactivity may be valuable in diagnosing LN. Furthermore, stratification based on serum BAFF and IFN-I bioactivities may allow the identification of appropriate patients for biologics targeting BAFF and IFN-I.
Superior manual dexterity in higher primates emerged together with the appearance of cortico-motoneuronal (CM) connections during the evolution of the mammalian corticospinal (CS) system. Previously ...thought to be specific to higher primates, we identified transient CM connections in early postnatal mice, which are eventually eliminated by Sema6D-PlexA1 signaling. PlexA1 mutant mice maintain CM connections into adulthood and exhibit superior manual dexterity as compared with that of controls. Last, differing PlexA1 expression in layer 5 of the motor cortex, which is strong in wild-type mice but weak in humans, may be explained by FEZF2-mediated cis-regulatory elements that are found only in higher primates. Thus, species-dependent regulation of PlexA1 expression may have been crucial in the evolution of mammalian CS systems that improved fine motor control in higher primates.
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