Dense reinforcement learning for safety validation of autonomous vehicles.

One critical bottleneck that impedes the development and deployment of autonomous vehicles is the prohibitively high economic and time costs required to validate their safety in a naturalistic driving environment, owing to the rarity of safety-critical events1. Here we report the development of an intelligent testing environment, where artificial-intelligence-based background agents are trained to validate the safety performances of autonomous vehicles in an accelerated mode, without loss of unbiasedness. From naturalistic driving data, the background agents learn what adversarial manoeuvre to execute through a dense deep-reinforcement-learning (D2RL) approach, in which Markov decision processes are edited by removing non-safety-critical states and reconnecting critical ones so that the information in the training data is densified. D2RL enables neural networks to learn from densified information with safety-critical events and achieves tasks that are intractable for traditional deep-reinforcement-learning approaches. We demonstrate the effectiveness of our approach by testing a highly automated vehicle in both highway and urban test tracks with an augmented-reality environment, combining simulated background vehicles with physical road infrastructure and a real autonomous test vehicle. Our results show that the D2RL-trained agents can accelerate the evaluation process by multiple orders of magnitude (103 to 105 times faster). In addition, D2RL will enable accelerated testing and training with other safety-critical autonomous systems.

Hemagglutination Inhibition Antibody Titers as Mediators of Influenza Vaccine Efficacy Against Symptomatic Influenza A(H1N1), A(H3N2), and B/Victoria Virus Infections.

BACKGROUND: The hemagglutination inhibition antibody (HAI) titer contributes only a part of vaccine-induced protection against influenza virus infections. Using causal mediation analysis, we quantified the proportion of vaccine efficacy mediated by postvaccination HAI titers. METHODS: We conducted causal mediation analyses using data from a randomized, active-comparator controlled, phase III, trial of an inactivated, split-virion seasonal quadrivalent influenza vaccine in children conducted from October 2010 to December 2011 in 8 countries. Vaccine efficacy was estimated using a weighted Cox proportional hazards model. Estimates were decomposed into the direct and indirect effects mediated by postvaccination HAI titers. RESULTS: The proportions of vaccine efficacy mediated by postvaccination HAI titers were estimated to be 22% (95% confidence interval, 18%--47%) for influenza A(H1N1), 20% (16%-39%) for influenza A(H3N2), and 37% (26%-85%) for influenza B/Victoria. CONCLUSIONS: HAI titers partially mediate influenza vaccine efficacy against influenza A(H1N1), A(H3N2), and B/Victoria. Our estimates were lower than in previous studies, possibly reflecting expected heterogeneity in antigenic similarity between vaccine and circulating viruses across seasons.

PS2MS: A Deep Learning-Based Prediction System for Identifying New Psychoactive Substances Using Mass Spectrometry.

The rapid proliferation of new psychoactive substances (NPS) poses significant challenges to conventional mass-spectrometry-based identification methods due to the absence of reference spectra for these emerging substances. This paper introduces PS2MS, an AI-powered predictive system designed specifically to address the limitations of identifying the emergence of unidentified novel illicit drugs. PS2MS builds a synthetic NPS database by enumerating feasible derivatives of known substances and uses deep learning to generate mass spectra and chemical fingerprints. When the mass spectrum of an analyte does not match any known reference, PS2MS simultaneously examines the chemical fingerprint and mass spectrum against the putative NPS database using integrated metrics to deduce possible identities. Experimental results affirm the effectiveness of PS2MS in identifying cathinone derivatives within real evidence specimens, signifying its potential for practical use in identifying emerging drugs of abuse for researchers and forensic experts.

Epicardial adipose tissue volume and density are associated with heart failure with improved ejection fraction.

BACKGROUND: Heart failure (HF) with improved ejection fraction (EF, HFimpEF) is a distinct HF subtype, characterized by left ventricular (LV) reverse remodeling and myocardial functional recovery. Multiple cardiometabolic factors are implicated in this process. Epicardial adipose tissue (EAT), emerging as an endocrine and paracrine organ, contributes to the onset and progression of HF. However, the relation between EAT and the incidence of HFimpEF is still unclear. METHODS: A total of 203 hospitalized HF patients with reduced EF (HFrEF, LVEF ≤ 40%) who underwent coronary CT angiography (CCTA) during index hospitalization were consecutively enrolled between November 2011 and December 2022. Routine follow-up and repeat echocardiograms were performed. The incidence of HFimpEF was defined as (1) an absolute LVEF improvement ≥ 10% and (2) a second LVEF > 40% (at least 3 months apart). EAT volume and density were semiautomatically quantified on non-enhanced series of CCTA scans. RESULTS: During a median follow-up of 8.6 (4.9 ~ 13.3) months, 104 (51.2%) patients developed HFimpEF. Compared with HFrEF patients, HFimpEF patients had lower EAT volume (115.36 [IQR 87.08 ~ 154.78] mL vs. 169.67 [IQR 137.22 ~ 218.89] mL, P < 0.001) and higher EAT density (-74.92 ± 6.84 HU vs. -78.76 ± 6.28 HU, P < 0.001). Multivariate analysis showed lower EAT volume (OR: 0.885 [95%CI 0.822 ~ 0.947]) and higher density (OR: 1.845 [95%CI 1.023 ~ 3.437]) were both independently associated with the incidence of HFimpEF. Subgroup analysis revealed that the association between EAT properties and HFimpEF was not modified by HF etiology. CONCLUSIONS: This study reveals that lower EAT volume and higher EAT density are associated with development of HFimpEF. Therapies targeted at reducing EAT quantity and improving its quality might provide favorable effects on myocardial recovery in HF patients.

The impact of EID policy and trade on the environmental effects of Chinese paper enterprises from the perspective of financial constraints.

Accompanying China's accession to the World Trade Organization, the rapid development of the Chinese economy has led to increasingly serious environmental issues. However, the inherent mechanisms underlying the impact of Environmental Information Disclosure (EID) policy and trade on the environmental effects of Chinese paper enterprises remain unclear in the context of the era's requirement for a resource-conserving and environmentally-friendly society. The pollution problem in the papermaking industry has received attention worldwide, and how to balance the environmental and development issues of papermaking enterprises is an urgent issue that needs to be solved in the academic community. This study explores the impact mechanisms of EID policy and trade on the environmental effects of enterprises from the perspective of financial constraints. Utilizing the PSM-DID model, the study investigates the moderating effects of financial constraints on the EID policy and import-export trade. The findings reveal that both external and internal financial constraints have negative, detrimental effects on the environmental effects of the EID policy and trade. These constraints impede research and development investment and technological upgrades, hinder productivity improvement, and hamper the realization of "regulatory and trade innovation effects". This study enriches our understanding of the mechanisms by which trade affects the environmental effects of Chinese paper enterprises and further identifies the impacts of Chinese EID policy and trade on pollution emissions by enterprises, providing a theoretical basis and practical foundation for the government in formulating financial, environmental, and trade policies.

Early Drain Removal Versus Routine Drain Removal After Pancreaticoduodenectomy and/or Distal Pancreatectomy: A Meta-Analysis and Systematic Review.

BACKGROUND: Early drain removal (EDR) has been widely accepted, but not been routinely used in patients after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP). This study aimed to evaluate the safety and benefits of EDR versus routine drain removal (RDR) after PD or DP. METHODS: A systematic search was conducted on medical search engines from January 1, 2008 to November 1, 2023, for articles that compared EDR versus RDR after PD or DP. The primary outcome was clinically relevant postoperative pancreatic fistula (CR-POPF). Further analysis of studies including patients with low-drain fluid amylase (low-DFA) on postoperative day 1 and defining EDR timing as within 3 days was also performed. RESULTS: Four randomized controlled trials (RCTs) and eleven non-RCTs with a total of 9465 patients were included in this analysis. For the primary outcome, the EDR group had a significantly lower rate of CR-POPF (OR 0.23; p < 0.001). For the secondary outcomes, a lower incidence was observed in delayed gastric emptying (OR 0.63, p = 0.02), Clavien-Dindo III-V complications (OR 0.48, p < 0.001), postoperative hemorrhage (OR 0.55, p = 0.02), reoperation (OR 0.57, p < 0.001), readmission (OR 0.70, p = 0.003) and length of stay (MD -2.04, p < 0.001) in EDR. Consistent outcomes were observed in the subgroup analysis of low-DFA patients and definite EDR timing, except for postoperative hemorrhage in EDR. CONCLUSION: EDR after PD or DP is beneficial and safe, reducing the incidence of CR-POPF and other postoperative complications. Further prospective studies and RCTs are required to validate this finding.

Identification of potential crucial genes shared in psoriasis and ulcerative colitis by machine learning and integrated bioinformatics.

BACKGROUND: Mounting evidence suggest that there are an association between psoriasis and ulcerative colitis (UC), although the common pathogeneses are not fully understood. Our study aimed to find potential crucial genes in psoriasis and UC through machine learning and integrated bioinformatics. METHODS: The overlapping differentially expressed genes (DEGs) of the datasets GSE13355 and GSE87466 were identified. Then the functional enrichment analysis was performed. The overlapping genes in LASSO, SVM-RFE and key module in WGCNA were considered as potential crucial genes. The receiver operator characteristic (ROC) curve was used to estimate their diagnostic confidence. The CIBERSORT was conducted to evaluate immune cell infiltration. Finally, the datasets GSE30999 and GSE107499 were retrieved to validate. RESULTS: 112 overlapping DEGs were identified in psoriasis and UC and the functional enrichment analysis revealed they were closely related to the inflammatory and immune response. Eight genes, including S100A9, PI3, KYNU, WNT5A, SERPINB3, CHI3L2, ARNTL2, and SLAMF7, were ultimately identified as potential crucial genes. ROC curves showed they all had high confidence in the test and validation datasets. CIBERSORT analysis indicated there was a correlation between infiltrating immune cells and potential crucial genes. CONCLUSION: In our study, we focused on the comprehensive understanding of pathogeneses in psoriasis and UC. The identification of eight potential crucial genes may contribute to not only understanding the common mechanism, but also identifying occult UC in psoriasis patients, even serving as therapeutic targets in the future.

Enhanced tyrosine sulfation is associated with chronic kidney disease-related atherosclerosis.

BACKGROUND: Chronic kidney disease (CKD) accelerates atherosclerosis, but the mechanisms remain unclear. Tyrosine sulfation has been recognized as a key post-translational modification (PTM) in regulation of various cellular processes, and the sulfated adhesion molecules and chemokine receptors have been shown to participate in the pathogenesis of atherosclerosis via enhancement of monocyte/macrophage function. The levels of inorganic sulfate, the essential substrate for the sulfation reaction, are dramatically increased in patients with CKD, which indicates a change of sulfation status in CKD patients. Thus, in the present study, we detected the sulfation status in CKD patients and probed into the impact of sulfation on CKD-related atherosclerosis by targeting tyrosine sulfation function. RESULTS: PBMCs from individuals with CKD showed higher amounts of total sulfotyrosine and tyrosylprotein sulfotransferase (TPST) type 1 and 2 protein levels. The plasma level of O-sulfotyrosine, the metabolic end product of tyrosine sulfation, increased significantly in CKD patients. Statistically, O-sulfotyrosine and the coronary atherosclerosis severity SYNTAX score positively correlated. Mechanically, more sulfate-positive nucleated cells in peripheral blood and more abundant infiltration of sulfated macrophages in deteriorated vascular plaques in CKD ApoE null mice were noted. Knockout of TPST1 and TPST2 decreased atherosclerosis and peritoneal macrophage adherence and migration in CKD condition. The sulfation of the chemokine receptors, CCR2 and CCR5, was increased in PBMCs from CKD patients. CONCLUSIONS: CKD is associated with increased sulfation status. Increased sulfation contributes to monocyte/macrophage activation and might be involved in CKD-related atherosclerosis. Inhibition of sulfation may suppress CKD-related atherosclerosis and is worthy of further study.

New Indole Alkaloids from the Fungus Talaromyces assiutensis JTY2.

Three new indole alkaloids, named talatensindoids A-C (1-3), together with two known biogenetically related indole alkaloids tryptamine (4) and L-tryptophan (5) were isolated from the Talaromyces assiutensis JTY2 based on the guidance of OSMAC approach. The structures of these indole alkaloids were determined by comprehensive spectroscopic analyses. The absolute configuration of 3 was confirmed by X-ray crystallographic analysis. Compound 1 represent the rare example of a chlorine-substituted indole alkaloid from natural products. The inhibitory activity of compounds 1-5 against two phytopathogenic fungi and three phytopathogenic bacteria was evaluated. Compound 1 exhibited broad spectrum antibacterial activities.

Medium- to long-term clinical efficacy of total hip arthroplasty with structural bone grafting for dysplasia of the hip.

BACKGROUND: Patients with dysplasia of the hip (DDH) have different degrees of bone defects above and outside the acetabulum, and anatomically reconstructing the acetabular centre of rotation is difficult in primary total hip arthroplasty (THA). METHODS: From April 2012 to December 2022, 64 patients (64 hips) with DDH treated with THA with structural bone graft in the superolateral acetabulum were selected. The Oxford hip score(OHS), Barthel index (BI), leg length discrepancy, Wibegr central edge-angle(CE), gluteus medius muscle strength, vertical and horizontal distance of the hip rotation center, coverage rate of the bone graft and complications were used to evaluate the clinical effectiveness of the patients. RESULTS: All patients were followed up for an average of 7.3±1.9 years. The OHS improved significantly after the operation (P<0.001). The postoperative BI was significantly greater than that before operation (P<0.001). The postoperative leg length discrepancy was significantly lower than that before the operation (P<0.001). Postoperative bedside photography revealed that the height and horizontal distance to the hip rotation center were significantly lower after surgery than before surgery (P<0.001). The postoperative CE was significantly greater than that before surgery (P<0.001). No acetabular component loosening or bone graft resorption was found during the postoperative imaging examination. CONCLUSIONS: The use of biological acetabular cup combined with structural bone graft in the superolateral acetabulum in THA for DDH can obtain satisfactory medium and long-term clinical and radiological results.

Nomogram for predicting surgical site infections in elderly patients after open lumbar spine surgery: A retrospective study.

The aim of this study is to develop a nomogram to assess the risk of surgical site infection in elderly patients undergoing open lumbar spine surgery and explore related risk factors. We reviewed the records of 578 elderly patients who had undergone open lumbar spine surgery. The clinical parameters were subjected to lasso regression and logistic regression analyses. Subsequently, a nomogram was constructed to predict the risk of postoperative surgical site infection and validated using bootstrap resampling. A total of 578 patients were included in the analysis, of which 17 were diagnosed as postoperative surgical site infection. Following the final logistic regression analysis, obesity, hypoalbuminemia and drinking history were identified as independent risk factors and subsequently incorporated into the nomogram. The nomogram demonstrated excellent discrimination, with an area under the receiver-operating characteristic curve of 0.879 (95% CI 0.769 ~ 0.989) after internal validation. The calibration curve exhibited a high level of consistency. Decision curve analysis revealed that this nomogram had greater clinical value when the risk threshold for surgical site infection occurrence was >1% and <89%. We had developed a nomogram for predicting the risk of postoperative surgical site infection in elderly patients who had undergone open lumbar spine surgery. Validation using bootstrap resampling demonstrated excellent discrimination and calibration, indicating that the nomogram may hold potential clinical utility as a simple predictive tool for healthcare professionals.

[Two new pinophol derivatives from endophytic fungus Penicillium herquei JX4 hosted in Ceriops tagal].

An OSMAC strategy was used to study secondary metabolites and anti-inflammatory activities of the endophytic fungus Penicillium herquei JX4 hosted in Ceriops tagal. The PDB ferment of fungus P. herquei JX4 was isolated, purified, and identified by using silica gel column chromatography, gel column chromatography, octadecylsilyl(ODS) column chromatography, and semi-preparative high-performance liquid chromatography. Two new pinophol derivatives, pinophol H(1) and pinophol I(2) were isolated and identified, and they were evaluated in terms of the inhibitory activities against the nitric oxide(NO) production induced by lipopolysaccharide(LPS) in mouse macrophage RAW264.7 cells. The results showed that compound 1 had significant inhibitory activity on NO production, with an IC_(50) value of 8.12 µmol·L~(-1).

Catalytic Structure Design by AI Generating with Spectroscopic Descriptors.

Generative artificial intelligence has depicted a beautiful blueprint for on-demand design in chemical research. However, the few successful chemical generations have only been able to implement a few special property values because most chemical descriptors are mathematically discrete or discontinuously adjustable. Herein, we use spectroscopic descriptors with machine learning to establish a quantitative spectral structure-property relationship for adsorbed molecules on metal monatomic catalysts. Besides catalytic properties such as adsorption energy and charge transfer, the complete spatial relative coordinates of the adsorbed molecule were successfully inverted. The spectroscopic descriptors and prediction models are generalized, allowing them to be transferred to several different systems. Due to the continuous tunability of the spectroscopic descriptors, the design of catalytic structures with continuous adsorption states generated by AI in the catalytic process has been achieved. This work paves the way for using spectroscopy to enable real-time monitoring of the catalytic process and continuous customization of catalytic performance, which will lead to profound changes in catalytic research.

Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in children aged 6-17 years: a preliminary report of COV006, a phase 2 single-blind, randomised, controlled trial.

BACKGROUND: Vaccination of children and young people against SARS-CoV-2 is recommended in some countries. Scarce data have been published on immune responses induced by COVID-19 vaccines in people younger than 18 years compared with the same data that are available in adults. METHODS: COV006 is a phase 2, single-blind, randomised, controlled trial of ChAdOx1 nCoV-19 (AZD1222) in children and adolescents at four trial sites in the UK. Healthy participants aged 6-17 years, who did not have a history of chronic respiratory conditions, laboratory-confirmed COVID-19, or previously received capsular group B meningococcal vaccine (the control), were randomly assigned to four groups (4:1:4:1) to receive two intramuscular doses of 5 × 1010 viral particles of ChAdOx1 nCoV-19 or control, 28 days or 84 days apart. Participants, clinical investigators, and the laboratory team were masked to treatment allocation. Study groups were stratified by age, and participants aged 12-17 years were enrolled before those aged 6-11 years. Due to the restrictions in the use of ChAdOx1 nCoV-19 in people younger than 30 years that were introduced during the study, only participants aged 12-17 years who were randomly assigned to the 28-day interval group had received their vaccinations at the intended interval (day 28). The remaining participants received their second dose at day 112. The primary outcome was assessment of safety and tolerability in the safety population, which included all participants who received at least one dose of the study drug. The secondary outcome was immunogenicity, which was assessed in participants who were seronegative to the nucleocapsid protein at baseline and received both prime and boost vaccine. This study is registered with ISRCTN (15638344). FINDINGS: Between Feb 15 and April 2, 2021, 262 participants (150 [57%] participants aged 12-17 years and 112 [43%] aged 6-11 years; due to the change in the UK vaccination policy, the study terminated recruitment of the younger age group before the planned number of participants had been enrolled) were randomly assigned to receive vaccination with two doses of either ChAdOx1 nCoV-19 (n=211 [n=105 at day 28 and n=106 at day 84]) or control (n=51 [n=26 at day 28 and n=25 at day 84]). One participant in the ChAdOx1 nCoV-19 day 28 group in the younger age bracket withdrew their consent before receiving a first dose. Of the participants who received ChAdOx1 nCoV-19, 169 (80%) of 210 participants reported at least one solicited local or systemic adverse event up to 7 days following the first dose, and 146 (76%) of 193 participants following the second dose. No serious adverse events related to ChAdOx1 nCoV-19 administration were recorded by the data cutoff date on Oct 28, 2021. Of the participants who received at least one dose of ChAdOx1 nCoV-19, there were 128 unsolicited adverse events up to 28 days after vaccination reported by 83 (40%) of 210 participants. One participant aged 6-11 years receiving ChAdOx1 nCoV-19 reported a grade 4 fever of 40·2°C on day 1 following first vaccination, which resolved within 24 h. Pain and tenderness were the most common local solicited adverse events for all the ChAdOx1 nCoV-19 and capsular group B meningococcal groups following both doses. Of the 242 participants with available serostatus data, 14 (6%) were seropositive at baseline. Serostatus data were not available for 20 (8%) of 262 participants. Among seronegative participants who received ChAdOx1 nCoV-19, anti-SARS-CoV-2 IgG and pseudoneutralising antibody titres at day 28 after the second dose were higher in participants aged 12-17 years with a longer interval between doses (geometric means of 73 371 arbitrary units [AU]/mL [95% CI 58 685-91 733] and 299 half-maximal inhibitory concentration [IC50; 95% CI 230-390]) compared with those aged 12-17 years who received their vaccines 28 days apart (43 280 AU/mL [95% CI 35 852-52 246] and 150 IC50 [95% CI 116-194]). Humoral responses were higher in those aged 6-11 years than in those aged 12-17 years receiving their second dose at the same 112-day interval (geometric mean ratios 1·48 [95% CI 1·07-2·07] for anti-SARS-CoV-2 IgG and 2·96 [1·89-4·62] for pseudoneutralising antibody titres). Cellular responses peaked after a first dose of ChAdOx1 nCoV-19 across all age and interval groups and remained above baseline after a second vaccination. INTERPRETATION: ChAdOx1 nCoV-19 is well tolerated and immunogenic in children aged 6-17 years, inducing concentrations of antibody that are similar to those associated with high efficacy in phase 3 studies in adults. No safety concerns were raised in this trial. FUNDING: AstraZeneca and the UK Department of Health and Social Care through the UK National Institute for Health and Care Research.

Microfluidic Mixer for In Situ Ammonia Analysis of Single Cells in Mass Spectrometry.

Mass spectrometry (MS) is a powerful tool for exploring single-cell heterogeneity. However, due to the ultralow absolute content of most substances in a single cell, existing methods can only analyze high-content substances; conventional methods are incompetent for quantitative analysis of important trace-amount small-molecule metabolites such as ammonia and sulfide. Herein, a method integrating single-cell extraction, online derivatization, and MS for multifunctional and more accurate MS analysis is reported. For application, ammonia content in a single cell was analyzed, where the cellular heterogeneity in ammonia metabolism was revealed. First, the extraction room of a microfluidic probe was covered on the target single cell, and the extraction fluid was allowed to flow through a single cell and dissolve cellular ammonia. Then, the ammonia was mixed and reacted with the pretreatment reagent input from another inlet to achieve the derivatization and signal amplification, enhancing the analysis sensitivity on MS. Finally, the sample was sent to MS, and the ammonia content was successfully quantitatively evaluated by analyzing its derivative urotropine, demonstrating the potential of this method to advance single-cell mass spectrometry analysis to higher sensitivity.

Genomic signals of local adaptation in Picea crassifolia.

BACKGROUND: Global climate change poses a grave threat to biodiversity and underscores the importance of identifying the genes and corresponding environmental factors involved in the adaptation of tree species for the purposes of conservation and forestry. This holds particularly true for spruce species, given their pivotal role as key constituents of the montane, boreal, and sub-alpine forests in the Northern Hemisphere. RESULTS: Here, we used transcriptomes, species occurrence records, and environmental data to investigate the spatial genetic distribution of and the climate-associated genetic variation in Picea crassifolia. Our comprehensive analysis employing ADMIXTURE, principal component analysis (PCA) and phylogenetic methodologies showed that the species has a complex population structure with obvious differentiation among populations in different regions. Concurrently, our investigations into isolation by distance (IBD), isolation by environment (IBE), and niche differentiation among populations collectively suggests that local adaptations are driven by environmental heterogeneity. By integrating population genomics and environmental data using redundancy analysis (RDA), we identified a set of climate-associated single-nucleotide polymorphisms (SNPs) and showed that environmental isolation had a more significant impact than geographic isolation in promoting genetic differentiation. We also found that the candidate genes associated with altitude, temperature seasonality (Bio4) and precipitation in the wettest month (Bio13) may be useful for forest tree breeding. CONCLUSIONS: Our findings deepen our understanding of how species respond to climate change and highlight the importance of integrating genomic and environmental data in untangling local adaptations.

Proline-rich 11 (PRR11) promotes the progression of cutaneous squamous cell carcinoma by activating the EGFR signaling pathway.

Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin malignancies, and its incidence rate is increasing worldwide. Proline-rich 11 (PRR11) has been reported to be involved in the occurrence and development of various tumors. However, the role of PRR11 in cSCC remains unknown. In the present study, we observed upregulated expression of PRR11 in cSCC tissues and cell lines. Knockdown of PRR11 in the cSCC cell lines A431 and SCL-1 inhibited cell proliferation by inducing cell cycle arrest during the G1/S phase transition, promoted cell apoptosis, and reduced cell migration and invasion in vitro. Conversely, overexpression of PRR11 promoted cell proliferation, decreased cell apoptosis, and enhanced cell migration and invasion. PRR11 knockdown also inhibited cSCC tumor growth in a mouse xenograft model. Mechanistic investigations by RNA sequencing revealed that 891 genes were differentially expressed genes between cells with PRR11 knockdown and control cells. Enrichment analysis of different genes showed that the epidermal growth factor receptor (EGFR) signaling pathway was the top enriched pathway. We further validated that PRR11 induced EGFR pathway activity, which contributed to cSCC progression. These data suggest that PRR11 may serve as a novel therapeutic target in cSCC.

IFN-beta and EIF2AK2 are potential biomarkers for interstitial lung disease in anti-MDA5 positive dermatomyositis.

OBJECTIVE: DM with positive anti-melanoma differentiation-related gene 5 (MDA5) antibody is an autoimmune disease with multiple complications. Interstitial lung diseases (ILDs) are significantly associated with DM and are particularly related to MDA5+ DM. This article aims to explore potential molecular mechanisms and develop new diagnostic biomarkers for MDA5+ DM-ILD. METHODS: The series matrix files of DM and non-specific interstitial pneumonia (NSIP) were downloaded from the Gene Expression Omnibus (GEO) database to identify the differentially expressed genes (DEGs). Gene set enrichment analysis (GSEA) was used to screen the common enriched pathways related to DM and NSIP. Next, the co-expressed differential expressed genes (co-DEGs) between MDA5+, MDA5- and NSIP groups were identified by Venn plots, and then selected for different enrichment analyses and protein-protein interaction (PPI) network construction. The mRNA expression levels of IFN-beta and EIF2AK2 were measured by RT-qPCR. The protein expression levels of IFN-beta were measured by ELISA. RESULTS: Using GSEA, the enriched pathway 'herpes simplex virus 1 infection' was both up-regulated in DM and NSIP. Enrichment analysis in MDA5+ DM, MDA5- DM and NSIP reported that the IFN-beta signalling pathway was an important influencing factor in the MDA5+ DM-ILD. We also identified that eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) was an important gene signature in the MDA5+ DM-ILD by PPI analysis. The expression levels of IFN-beta and EIF2AK2 were significantly increased in MDA5+ DM-ILD patients. CONCLUSIONS: IFN-beta and EIF2AK2 contributed to the pathogenesis of MDA5+ DM-ILD, which could be used as potential therapeutic targets.

Transcriptome-based analyses of adaptive divergence between two closely related spruce species on the Qinghai-Tibet plateau and adjacent regions.

Speciation among populations connected by gene flow is driven by adaptation to different environments, but underlying gene-environment associations remain largely unknown. Here, 162 individuals from 32 populations were sampled to obtain 191,648 independent single nucleotide polymorphisms (SNPs) across the genomes of two closely related spruce species, Picea asperata and Picea crassifolia, which occur on the Qinghai-Tibet Plateau and in surrounding regions. Using the SNP data set, genotype-environment associations and demographic modelling were used to examine local adaptation and genetic divergence between these two species. While morphologically similar, the two Picea species were genetically differentiated in multiple analyses. These species diverged despite continuous gene flow, and their initial divergence was dated back to the late Quaternary. The effective population sizes of both species have expanded since their divergence, as confirmed by niche distribution simulations. A total of 6365 genes were associated with the tested environmental variables; of these, 41 were positively selected in P. asperata and were mainly associated with temperature, while 83 were positively selected in P. crassifolia and were primarily associated with precipitation. These results deepen our understanding of the adaptive divergence and demographic histories of these two spruce species and highlight the importance of genomic data in deciphering the environmental selection underlying Quaternary interspecific divergence.

[68Ga]Ga-DOTA-FAPI-04 PET/MR in patients with acute myocardial infarction: potential role of predicting left ventricular remodeling.

PURPOSE: To assess predictive value of 68Ga-labeled fibroblast activation protein inhibitor-04 ([68Ga]Ga-DOTA-FAPI-04) PET/MR for late left ventricular (LV) remodeling in patients with ST-segment elevated myocardial infarction (STEMI). METHODS: Twenty-six patients with STEMI were included in the study. [68Ga]Ga-DOTA-FAPI-04 PET/MR was performed at baseline and at average 12 months after STEMI. LV remodeling was defined as >10% increase in LV end-systolic volume (LVESV) from baseline to 12 months. RESULTS: The LV remodeling group demonstrated higher [68Ga]Ga-DOTA-FAPI-04 uptake volume (UV) at baseline than the non-LV remodeling group (p < 0.001). [68Ga]Ga-DOTA-FAPI-04 UV at baseline was a significant predictor (OR = 1.048, p = 0.011) for LV remodeling at 12 months after STEMI. Compared to clinical information, MR imaging and cardiac function parameters at baseline, [68Ga]Ga-DOTA-FAPI-04 UV demonstrated better predictive ability (AUC = 0.938, p < 0.001) for late LV remodeling, with sensitivity of 100.0% and specificity of 81.3%. CONCLUSIONS: [68Ga]Ga-DOTA-FAPI-04 PET/MR is an effective tool to non-invasively quantify myocardial fibroblasts activation, and baseline [68Ga]Ga-DOTA-FAPI-04 UV may have potential predictive value for late LV remodeling.