Geographic variation of mutagenic exposures in kidney cancer genomes.

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden1. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.

The landscape of somatic mutation in normal colorectal epithelial cells.

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.

Realization of chiral two-mode Lipkin-Meshkov-Glick models via acoustics.

Thechirality-controlled two-mode Lipkin-Meshkov-Glick (LMG) modelsare mimicked in a potential hybrid quantum system, involving two ensembles of solid-state spins coupled to a pair of interconnected surface-acoustic-wave cavities. With the assistance of dichromatic classical optical drives featuring chiral designs, it can simulate two-mode LMG-type long-range spin-spin interactions with left-right asymmetry. For applications, this unconventional LMG model can not only engineer both ensembles of collective spins into two-mode spin-squeezed states but also simulate novel quantum critical phenomena and time crystal behaviors, among others. Since this acoustic-based system can generate ion-trap-like interactions without requiring any additional trapping techniques, our work is considered a fresh attempt at realizing chiral quantum manipulation of spin-spin interactions using acoustic hybrid systems.

TMEM56 deficiency impairs the haem metabolism and cell cycle progression during human erythropoiesis.

TMEM56, a gene coding a transmembrane protein, is abundantly expressed in erythroid cells. Despite this, its role in erythropoiesis has not been well characterized. In this study, we sought to clarify the function of TMEM56 in erythroid development, focusing specifically on its involvement in haem biosynthesis and cell cycle progression. To do this, we used CD34+ haematopoietic stem cells derived from umbilical cord blood and differentiated them into erythroid cells in an ex vivo model. Our results indicate that the loss of TMEM56 disrupts haem biosynthesis and impairs erythroid differentiation. Furthermore, deletion of Tmem56 in the erythroid lineage in murine models using erythropoietin receptor (EpoR)-Cre revealed defects in erythroid progenitors within the bone marrow under both normal conditions and during haemolytic anaemia. These observations underscore the regulatory role of TMEM56 in maintaining erythroid lineage homeostasis. Taken together, our results unveil a previously unrecognized function of TMEM56 in erythroid differentiation and suggest its potential as an unfounded target for therapeutic strategies in the treatment of erythropoietic disorders.

Resolidified Chalcogen-Assisted Growth of Bilayer Semiconductors with Controlled Stacking Orders.

Bilayer semiconductors have attracted much attention due to their stacking-order-dependent properties. However, as both 3R- and 2H-stacking are energetically stable at high temperatures, most of the high-temperature grown bilayer materials have random 3R- or 2H-stacking orders, leading to non-uniformity in optical and electrical properties. Here, a chemical vapor deposition method is developed to grow bilayer semiconductors with controlled stacking order by modulating the resolidified chalcogen precursors supply kinetics. Taking tungsten disulfide (WS2 ) as an example, pure 3R-stacking (100%) and 2H-stacking dominated (87.6%) bilayer WS2 are grown by using this method and both show high structural and optical quality and good uniformity. Importantly, the bilayer 3R-stacking WS2 shows higher field effect mobility than 2H-stacking samples, due to the difference in stacking order-dependent surface potentials. This method is universal for growing other bilayer semiconductors with controlled stacking orders including molybdenum disulfide and tungsten diselenide, paving the way to exploit stacking-order-dependent properties of these family of emerging bilayer materials.

Ampere-Level Current Density CO2 Reduction with High C2+ Selectivity on La(OH)3-Modified Cu Catalysts.

The carbon dioxide reduction reaction (CO2RR) driven by electricity can transform CO2 into high-value multi-carbon (C2+) products. Copper (Cu)-based catalysts are efficient but suffer from low C2+ selectivity at high current densities. Here La(OH)3 in Cu catalyst is introduced to modify its electronic structure towards efficient CO2RR to C2+ products at ampere-level current densities. The La(OH)3/Cu catalyst has a remarkable C2+ Faradaic efficiency (FEC2+) of 71.2% which is 2.2 times that of the pure Cu catalyst at a current density of 1,000 mA cm-2 and keeps stable for 8 h. In situ spectroscopy and density functional theory calculations both show that La(OH)3 modifies the electronic structure of Cu. This modification favors *CO adsorption, subsequent hydrogenation, *CO─*COH coupling, and consequently increases C2+ selectivity. This work provides a guidance on facilitating C2+ product formation, and suppressing hydrogen evolution by La(OH)3 modification, enabling efficient CO2RR at ampere-level current densities.

The heterogeneity of erythroid cells: insight at the single-cell transcriptome level.

Erythroid cells, the most prevalent cell type in blood, are one of the earliest products and permeate through the entire process of hematopoietic development in the human body, the oxygen-transporting function of which is crucial for maintaining overall health and life support. Previous investigations into erythrocyte differentiation and development have primarily focused on population-level analyses, lacking the single-cell perspective essential for comprehending the intricate pathways of erythroid maturation, differentiation, and the encompassing cellular heterogeneity. The continuous optimization of single-cell transcriptome sequencing technology, or single-cell RNA sequencing (scRNA-seq), provides a powerful tool for life sciences research, which has a particular superiority in the identification of unprecedented cell subgroups, the analyzing of cellular heterogeneity, and the transcriptomic characteristics of individual cells. Over the past decade, remarkable strides have been taken in the realm of single-cell RNA sequencing technology, profoundly enhancing our understanding of erythroid cells. In this review, we systematically summarize the recent developments in single-cell transcriptome sequencing technology and emphasize their substantial impact on the study of erythroid cells, highlighting their contributions, including the exploration of functional heterogeneity within erythroid populations, the identification of novel erythrocyte subgroups, the tracking of different erythroid lineages, and the unveiling of mechanisms governing erythroid fate decisions. These findings not only invigorate erythroid cell research but also offer new perspectives on the management of diseases related to erythroid cells.

DNA methylation of IFI44L as a potential blood biomarker for childhood-onset systemic lupus erythematosus.

BACKGROUND: IFN-induced protein 44-like (IFI44L) promoter methylation has been demonstrated to serve as an effective blood diagnostic biomarker for adult-onset SLE. However, its utility as a diagnostic marker for childhood-onset SLE (cSLE) remains to be verified. METHODS: Initially, we conducted a differential analysis of gene methylation and mRNA expression patterns in cSLE whole blood samples obtained from the public GEO database to determine IFI44L gene expression and assess the methylation status at its CpG sites. Subsequently, we collected clinical whole blood samples from 49 cSLE patients and 12 healthy children, employing an HRM-qPCR-based IFI44L methylation detection technique to evaluate its diagnostic efficacy in pediatric clinical practice. RESULTS: A total of 26 hypomethylated, highly expressed genes in cSLE were identified by intersecting differentially expressed genes (DEGs) and differentially methylation genes (DMGs). GO enrichment analysis for these 26 genes indicated a robust association with type I IFN. Among the overlapping genes, IFI44L exhibited the most pronounced differential expression and methylation. In subsequent clinical validation experiments, IFI44L methylation was confirmed as an effective blood-based diagnostic biomarker for cSLE, achieving an AUC of 0.867, a sensitivity of 0.753, and a specificity of 1.000. CONCLUSIONS: IFI44L methylation is a promising blood biomarker for cSLE. IMPACT: IFI44L promoter methylation was reported to serve as a highly sensitive and specific diagnostic marker for adult-onset SLE. However, the diagnostic efficacy of IFI44L in childhood-onset SLE (cSLE) still remains to be confirmed. In this study, we utilized bioinformatics analysis and conducted clinical experiments to demonstrate that IFI44L methylation can also serve as a promising blood biomarker for cSLE. The findings of this study can facilitate the diagnosis of cSLE and broaden our understanding of its molecular mechanisms, with a particular focus on those related to type I interferons.

Added value of arterial enhancement fraction derived from dual-energy computed tomography for preoperative diagnosis of cervical lymph node metastasis in papillary thyroid cancer: initial results.

OBJECTIVES: To explore the added value of arterial enhancement fraction (AEF) derived from dual-energy computed tomography CT (DECT) to conventional image features for diagnosing cervical lymph node (LN) metastasis in papillary thyroid cancer (PTC). METHODS: A total of 273 cervical LNs (153 non-metastatic and 120 metastatic) were recruited from 92 patients with PTC. Qualitative image features of LNs were assessed. Both single-energy CT (SECT)-derived AEF (AEFS) and DECT-derived AEF (AEFD) were calculated. Correlation between AEFD and AEFS was determined using Pearson's correlation coefficient. Multivariate logistic regression analysis with the forward variable selection method was used to build three models (conventional features, conventional features + AEFS, and conventional features + AEFD). Diagnostic performances were evaluated using receiver operating characteristic (ROC) curve analyses. RESULTS: Abnormal enhancement, calcification, and cystic change were chosen to build model 1 and the model provided moderate diagnostic performance with an area under the ROC curve (AUC) of 0.675. Metastatic LNs demonstrated both significantly higher AEFD (1.14 vs 0.48; p < 0.001) and AEFS (1.08 vs 0.38; p < 0.001) than non-metastatic LNs. AEFD correlated well with AEFS (r = 0.802; p < 0.001), and exhibited comparable performance with AEFS (AUC, 0.867 vs 0.852; p = 0.628). Combining CT image features with AEFS (model 2) and AEFD (model 3) could significantly improve diagnostic performances (AUC, 0.865 vs 0.675; AUC, 0.883 vs 0.675; both p < 0.001). CONCLUSIONS: AEFD correlated well with AEFS, and exhibited comparable performance with AEFS. Integrating qualitative CT image features with both AEFS and AEFD could further improve the ability in diagnosing cervical LN metastasis in PTC. CLINICAL RELEVANCE STATEMENT: Arterial enhancement fraction (AEF) values, especially AEF derived from dual-energy computed tomography, can help to diagnose cervical lymph node metastasis in patients with papillary thyroid cancer, and complement conventional CT image features for improved clinical decision making. KEY POINTS: • Metastatic cervical lymph nodes (LNs) demonstrated significantly higher arterial enhancement fraction (AEF) derived from dual-energy computed tomography (DECT) and single-energy CT (SECT)-derived AEF (AEFS) than non-metastatic LNs in patients with papillary thyroid cancer. • DECT-derived AEF (AEFD) correlated significantly with AEFS, and exhibited comparable performance with AEFS. • Integrating qualitative CT images features with both AEFS and AEFD could further improve the differential ability.

CCL25 contributes to the pathogenesis of D-Gal/LPS-induced acute liver failure.

BACKGROUND AND AIM: Acute liver failure (ALF) is a fatal clinical syndrome of severe hepatic dysfunction. Chemokines promote liver diseases by recruiting and activating immune cells. We aimed to investigate the role of C-C chemokine ligand 25 (CCL25) in ALF. METHODS: An ALF mouse model induced by D-galactosamine/lipopolysaccharide was evaluated through liver hematoxylin and eosin staining and serum transaminase and cytokine measurement. CCL25 expression in serum was analyzed by ELISA and in liver by immunohistochemical staining and western blot. C-C chemokine receptor 9 (CCR9)-expressing cells in the liver were identified by immunofluorescence staining. The effects of anti-CCL25 on ALF were evaluated in vivo. Cytokine expression and migration of CCL25-stimulated RAW264.7 macrophages were studied. We also investigated the role of anti-CCL25 and BMS-345541, an NF-κB signaling inhibitor, in vitro. NF-κB activation was assessed via western blot, and p65 nuclear translocation was detected using cellular immunofluorescence. RESULTS: ALF mice showed severe histological damage and high serum levels of aminotransferase and inflammatory cytokines. Elevated CCL25 and NF-κB activation was observed in vivo. CCR9 was expressed on macrophages in ALF mouse liver. ALF was suppressed after anti-CCL25 treatment, with significant NF-κB inhibition. In vitro, CCL25 induced strong migration and cytokine release in RAW264.7 macrophages, which were eliminated by anti-CCL25 and BMS-345541. Furthermore, the NF-κB activation and p65 nuclear translocation induced by CCL25 were also inhibited by anti-CCL25 and BMS-345541. CONCLUSION: CCL25 contributes to ALF development by inducing macrophage-mediated inflammation via activation of the NF-κB signaling.

Inflammation mediates the association between furan exposure and the prevalence and mortality of chronic obstructive pulmonary disease: National Health and Nutrition Examination Survey 2013-2018.

BACKGROUND: Although extensive research has established associations between chronic obstructive pulmonary disease (COPD) and environmental pollutants, the connection between furan and COPD remains unclear. This study aimed to explore the association between furan and COPD while investigating potential mechanisms. METHODS: The study involved 7,482 adults from the National Health and Nutrition Examination Survey 2013-2018. Exposure to furan was assessed using blood furan levels. Participants were categorized into five groups based on quartiles of log10-transformed blood furan levels. Logistic regression and restricted cubic spline regression models were used to assess the association between furan exposure and COPD risk. Mediating analysis was performed to assess the contribution of inflammation to the effects of furan exposure on COPD prevalence. Cox regression was used to assess the association between furan exposure and the prognosis of COPD. RESULTS: Participants with COPD exhibited higher blood furan levels compared to those without COPD (P < 0.001). Log10-transformed blood furan levels were independently associated with an increased COPD risk after adjusting for all covariates (Q5 vs. Q1: OR = 4.47, 95% CI = 1.58-12.66, P = 0.006, P for trend = 0.001). Inflammatory cells such as monocytes, neutrophils, and basophils were identified as mediators in the relationship between furan exposure and COPD prevalence, with mediated proportions of 8.73%, 20.90%, and 10.94%, respectively (all P < 0.05). Moreover, multivariate Cox regression analysis revealed a positive correlation between log10-transformed blood furan levels and respiratory mortality in COPD patients (HR = 41.00, 95% CI = 3.70-460.00, P = 0.003). CONCLUSIONS: Exposure to furan demonstrates a positive correlation with both the prevalence and respiratory mortality of COPD, with inflammation identified as a crucial mediator in this relationship.

In-plane ESPI with unlimited angle of view for multi-object rotation angle determination.

The in-plane electronic speckle pattern interferometry (ESPI), implemented in a Michelson stellar interferometer-like configuration, offers high sensitivity and dynamic measurement. However, its limited angle of view (AOV) remains a major challenge for the rotation angle determination of multiple objects. In this Letter, we analyze the main factors that influence the AOV of the in-plane ESPI and propose an "image transmitting" approach to enlarge the AOV. With the aid of a folded dual-telescope imaging system, we develop an AOV-unlimited interferometer that can determine multi-object rotation angles in real time. The practicability of the interferometer is demonstrated by the application in real-time measuring of the rotation angles of the disks within a 2D granular system.

Heparanase-mediated histone 3 acetylation regulates VEGF gene transcription in the hyperglycemia and hypoxia human retinal endothelial cells.

Heparanase (HPA) is believed that might mediate histone 3 lysine 9 acetylation (H3K9ac) to regulate vascular endothelial growth factor (VEGF) gene expressions in the hyperglycemia and hypoxia human retinal endothelial cells (HRECs). Cultured human retinal endothelial cells (HRECs) in hyperglycemia, hypoxia, siRNA, and normal medium, respectively. Distributions of H3K9ac and HPA in HRECs were analyzed by immunofluorescence. Western blot and real-time PCR were respectively used to evaluate the expression of HPA, H3K9ac, and VEGF. The differences in occupancies of H3K9ac and RNA polymerase II at VEGF gene promoter among three groups were studied by Chromatin immunoprecipitation (ChIP) combined with real-time PCR. Co-immunoprecipitation (Co-IP) was used to measure the status of HPA and H3K9ac. Re-ChIP was used to verify whether HPA and H3K9ac associate to the transcription of VEGF gene. HPA was consistent with that of H3K9ac in the hyperglycemia and hypoxia groups. And the fluorescent lights of H3K9ac and HPA in siRNA groups were similar to the control group, fainter than that of hyperglycemia, hypoxia, and non-silencing groups. Western blot results showed that the expressions of HPA, H3K9ac, and VEGF in hyperglycemia and hypoxia HRECs were statistically higher than that of the control. HPA, H3K9ac, and VEGF expressions in siRNA groups were statistically lower than hyperglycemia and hypoxia HRECs. The same trends also were found in real-time PCR. ChIP exhibited the occupancies of H3K9ac and RNA Pol II at VEGF gene promoter in hyperglycemia and hypoxia groups were significantly more increased than in the control group. Co-IP revealed that HPA combined with H3K9ac in hyperglycemia and hypoxia groups; while it was not discovered in the control group. Re-ChIP showed that HPA combined with H3K9ac at VEGF gene promoter in the hyperglycemia and hypoxia HRECs nuclear. In our study HPA can influence expressions of H3K9ac and VEGF in the hyperglycemia and hypoxia HRECs. HPA can probably combine with H3K9ac and regulate the transcription of the VEGF gene in the hyperglycemia and hypoxia HRECs.

Associations of Wnt5a expression with liver injury in chronic hepatitis B virus infection.

BACKGROUND: Aberrant Wnt5a expression contributes to immunity, inflammation and tissue damage. However, it remains unknown whether Wnt5a is associated with liver injury in chronic hepatitis B virus (HBV) infection. We aimed to explore the potential role of Wnt5a expression in liver injury caused by chronic HBV infection. METHODS: Wnt5a mRNA levels in peripheral blood mononuclear cells (PBMCs) were analyzed in 31 acute-on-chronic hepatitis B liver failure (ACHBLF) patients, 82 chronic hepatitis B (CHB) patients, and 20 healthy controls using quantitative real-time polymerase chain reaction. Intrahepatic Wnt5a protein expression from 32 chronic HBV infection patients and 6 normal controls was evaluated by immunohistochemical staining. RESULTS: Wnt5a mRNA expression was increased in CHB patients and ACHBLF patients compared to healthy controls and correlated positively with liver injury markers. Additionally, there was a significant correlation between Wnt5a mRNA expression and HBV DNA load in all patients and CHB patients but not in ACHBLF patients. Furthermore, intrahepatic Wnt5a protein expression was elevated in chronic HBV infection patients compared to that in normal controls. Moreover, chronic HBV infection patients with higher hepatic inflammatory grades had increased intrahepatic Wnt5a protein expression compared with lower hepatic inflammatory grades. In addition, the cut-off value of 12.59 for Wnt5a mRNA level was a strong indicator in predicting ACHBLF in CHB patients. CONCLUSIONS: We found that Wnt5a expression was associated with liver injury in chronic HBV infection patients. Wnt5a might be involved in exacerbation of chronic HBV infection.

MMP19 Variants in Familial and Sporadic Idiopathic Pulmonary Fibrosis.

BACKGROUND: Gene variants have been identified in patients with familial or sporadic idiopathic pulmonary fibrosis (IPF). These variants may partially account for the genetic risk of IPF. The aim of this study was to identify potential genes involved in both familial and sporadic IPF. METHODS: A Han family in northern China with four members diagnosed with IPF was investigated in this observational study. Whole-exome sequencing (WES) was used to identify germline variants underlying disease phenotypes in five members of this family. Candidate rare variants were validated by Sanger sequencing in samples from 16 family members and 119 patients with sporadic IPF. The plasma levels of proteins encoded by the above candidate genes were also examined in 16 family members, 119 other patients with sporadic IPF and 120 age- and sex-matched healthy controls. RESULTS: In a Chinese Han family, MMP19 c.1222 C > T was identified in all familial IPF patients and six offspring from generations III and IV. This variant introduces a premature stop codon, which may damage protein function. Sanger sequencing revealed that 7.6% (9/119) of sporadic IPF patients harbored three MMP19 variants. The genetic risk analysis for pulmonary fibrosis showed that MMP19 c.1499 C > T and c.1316G > A were significantly associated with an increased risk of IPF (OR 3.66, p = 0.028 and OR 8.64, p < 0.001, respectively). The plasma levels of MMP19 were significantly higher in patients with sporadic or familial IPF than in healthy controls (all p < 0.001). CONCLUSIONS: MMP19 variants were identified in familial or sporadic IPF, thus providing a potential new clue into IPF pathogenesis.

Cerebral Gray Matter Volume Changes in Patients with Neuropathic Pain from Total Brachial Plexus Injury.

INTRODUCTION: Total brachial plexus injury not only significantly affects the motor and sensory function of the affected upper limbs but also causes further physical and mental damage to patients with long-term intractable pain. Previous studies mainly focused on the surgical treatment, while only a few paid attention to the intractable neuropathic pain caused by this injury. Changes in the volume of gray matter in the brain are thought to be associated with chronic neuropathic pain. METHODS: Voxel-based morphometry analysis was used to compare the difference in cerebral gray matter volume between total brachial plexus injury patients with neuropathic pain and healthy controls. Correlations between pain duration, pain severity, and GM changes were analyzed. RESULTS: The volume of cerebral gray matter in the patient group was decreased significantly in multiple regions, including the parahippocampal gyrus, paracentric lobule, inferior frontal gyrus, auxiliary motor cortex, middle occipital gyrus, right middle temporal gyrus, while it was increased in the insular, pons, middle frontal gyrus, cingulate gyrus, inferior parietal lobule, bilateral thalamus, and globus pallidus. There were no significant correlations between pain duration and rGMV changes, while a positive correlation was observed between pain severity and rGMV changes in one specific region, involving the anterior cingulate cortex. CONCLUSION: Total brachial plexus injury patients with chronic pain have widespread regions of gray matter atrophy and hypertrophy. The only positive correlation was observed between pain severity and rGMV changes in one specific region, suggesting that nociceptive stimuli trigger a variety of nonpain-specific processes, which confirms the multidimensional nature of pain.

Cluster features in fibrosing interstitial lung disease and associations with prognosis.

BACKGROUND: Clustering is helpful in identifying subtypes in complex fibrosing interstitial lung disease (F-ILD) and associating them with prognosis at an early stage of the disease to improve treatment management. We aimed to identify associations between clinical characteristics and outcomes in patients with F-ILD. METHODS: Retrospectively, 575 out of 926 patients with F-ILD were eligible for analysis. Four clusters were identified based on baseline data using cluster analysis. The clinical characteristics and outcomes were compared among the groups. RESULTS: Cluster 1 was characterized by a high prevalence of comorbidities and hypoxemia at rest, with the worst lung function at baseline; Cluster 2 by young female patients with less or no smoking history; Cluster 3 by male patients with highest smoking history, the most noticeable signs of velcro crackles and clubbing of fingers, and the severe lung involvement on chest image; Cluster 4 by male patients with a high percentage of occupational or environmental exposure. Clusters 1 (median overall survival [OS] = 7.0 years) and 3 (OS = 5.9 years) had shorter OS than Clusters 2 (OS = not reached, Cluster 1: p < 0.001, Cluster 3: p < 0.001) and 4 (OS = not reached, Cluster 1: p = 0.004, Cluster 3: p < 0.001). Clusters 1 and 3 had a higher cumulative incidence of acute exacerbation than Clusters 2 (Cluster 1: p < 0.001, Cluster 3: p = 0.014) and 4 (Cluster 1: p < 0.001, Cluster 3: p = 0.006). Stratification by using clusters also independently predicted acute exacerbation (p < 0.001) and overall survival (p < 0.001). CONCLUSIONS: The high degree of disease heterogeneity of F-ILD can be underscored by four clusters based on clinical characteristics, which may be helpful in predicting the risk of fibrosis progression, acute exacerbation and overall survival.

Transcriptomic profiling reveals the molecular responses of Rhodococcus aetherivorans DMU1 to skatole stress.

Skatole is a typical malodor compound in animal wastes. Several skatole-degrading bacterial strains have been obtained, whereas the molecular response of strains to skatole stress has not been well elucidated. Herein, the skatole degradation by a Gram-positive strain Rhodococcus aetherivorans DMU1 was investigated. Strain DMU1 showed high efficiency in skatole degradation under the conditions of 25-40 °C and pH 7.0-10.0. It could utilize various aromatics, including cresols, phenol, and methylindoles, as the sole carbon source for growth, implying its potential in the bioremediation application of animal wastes. Transcriptomic sequencing revealed that 328 genes were up-regulated and 640 genes were down-regulated in strain DMU1 when grown in the skatole-containing medium. Skatole increased the gene expression levels of antioxidant defense systems and heat shock proteins. The expression of ribosome-related genes was significantly inhibited which implied the growth inhibition of skatole. A rich set of oxidoreductases were changed, and a novel gene cluster containing the flavoprotein monooxygenase and ring-hydroxylating oxygenase genes was highly up-regulated, which was probably involved in skatole upstream degradation. The upregulation pattern of this gene cluster was further verified by qRT-PCR assay. Furthermore, skatole should be mainly degraded via the catechol ortho-cleavage pathway with cat25170 as the functional gene. The gene cat25170 was cloned and expressed in E. coli BL21(DE3). Pure enzyme assays showed that Cat25170 could catalyze catechol with Km 9.96 µmol/L and kcat 12.36 s-1.

Three-dimensional analysis of root changes after orthodontic treatment for patients at different stages of root development.

INTRODUCTION: We investigated changes in the roots of maxillary incisors at different stages of root development after fixed-appliance treatment using cone-beam computed tomography. METHODS: Data from 52 subjects receiving fixed-appliance treatment were collected retrospectively. The subjects were divided into 3 groups: mixed dentition group (aged 7-10 years; root development stage: Nolla eighth-10th; n = 16), early permanent dentition group (aged 12-18 years; root development stage: Nolla 10th; n = 20), and adult group (aged 18-35 years; root development stage: Nolla 10th; n = 16). Changes in root lengths and volume of the maxillary central incisors were measured using pretreatment and posttreatment cone-beam computed tomography. RESULTS: The root lengths and volumes of maxillary central incisors in the mixed dentition group significantly increased after orthodontic treatment (P >0.05). No significant differences were found when comparing the final root length and volume of the mixed dentition group with the pretreatment maxillary incisor values of the early permanent dentition group (P >0.05). The early permanent dentition group showed a significant decrease in root length (P <0.05), and both the root length and volume of the adult group significantly decreased after treatment (P <0.05). The differences in root length and volume reduction between the 2 groups were not significant (P >0.05). CONCLUSIONS: Orthodontic treatment had no significant negative impact on the continued root development of incomplete roots with two-thirds root formation. Both the early permanent dentition and adult groups exhibited root resorption after orthodontic treatment. It seemed age was not a factor that resulted in significant root resorption during routine orthodontic leveling and alignment treatment once the roots were fully developed.

Unraveling the skatole biodegradation process in an enrichment consortium using integrated omics and culture-dependent strategies.

3-Methylindole (skatole) is regarded as one of the most offensive compounds in odor emission. Biodegradation is feasible for skatole removal but the functional species and genes responsible for skatole degradation remain enigmatic. In this study, an efficient aerobic skatole-degrading consortium was obtained. Rhodococcus and Pseudomonas were identified as the two major and active populations by integrated metagenomic and metatranscriptomic analyses. Bioinformatic analyses indicated that the skatole downstream degradation was mainly via the catechol pathway, and upstream degradation was likely catalyzed by the aromatic ring-hydroxylating oxygenase and flavin monooxygenase. Genome binning and gene analyses indicated that Pseudomonas, Pseudoclavibacter, and Raineyella should cooperate with Rhodococcus for the skatole degradation process. Moreover, a pure strain Rhodococcus sp. DMU1 was successfully obtained which could utilize skatole as the sole carbon source. Complete genome sequencing showed that strain DMU1 was the predominant population in the consortium. Further crude enzyme and RT-qPCR assays indicated that strain DMU1 degraded skatole through the catechol ortho-cleavage pathway. Collectively, our results suggested that synergistic degradation of skatole in the consortium should be performed by diverse bacteria with Rhodococcus as the primary degrader, and the degradation mainly proceeded via the catechol pathway.