The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models.

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × âˆ¼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

Functional genomics data: privacy risk assessment and technological mitigation.

The generation of functional genomics data by next-generation sequencing has increased greatly in the past decade. Broad sharing of these data is essential for research advancement but poses notable privacy challenges, some of which are analogous to those that occur when sharing genetic variant data. However, there are also unique privacy challenges that arise from cryptic information leakage during the processing and summarization of functional genomics data from raw reads to derived quantities, such as gene expression values. Here, we review these challenges and present potential solutions for mitigating privacy risks while allowing broad data dissemination and analysis.

Trial of Endovascular Therapy for Acute Ischemic Stroke with Large Infarct.

BACKGROUND: The role of endovascular therapy for acute stroke with a large infarction has not been extensively studied in differing populations. METHODS: We conducted a multicenter, prospective, open-label, randomized trial in China involving patients with acute large-vessel occlusion in the anterior circulation and an Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0 to 10, with lower values indicating larger infarction) or an infarct-core volume of 70 to 100 ml. Patients were randomly assigned in a 1:1 ratio within 24 hours from the time they were last known to be well to undergo endovascular therapy and receive medical management or to receive medical management alone. The primary outcome was the score on the modified Rankin scale at 90 days (scores range from 0 to 6, with higher scores indicating greater disability), and the primary objective was to determine whether a shift in the distribution of the scores on the modified Rankin scale at 90 days had occurred between the two groups. Secondary outcomes included scores of 0 to 2 and 0 to 3 on the modified Rankin scale. The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours after randomization. RESULTS: A total of 456 patients were enrolled; 231 were assigned to the endovascular-therapy group and 225 to the medical-management group. Approximately 28% of the patients in both groups received intravenous thrombolysis. The trial was stopped early owing to the efficacy of endovascular therapy after the second interim analysis. At 90 days, a shift in the distribution of scores on the modified Rankin scale toward better outcomes was observed in favor of endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval, 1.11 to 1.69; P = 0.004). Symptomatic intracranial hemorrhage occurred in 14 of 230 patients (6.1%) in the endovascular-therapy group and in 6 of 225 patients (2.7%) in the medical-management group; any intracranial hemorrhage occurred in 113 (49.1%) and 39 (17.3%), respectively. Results for the secondary outcomes generally supported those of the primary analysis. CONCLUSIONS: In a trial conducted in China, patients with large cerebral infarctions had better outcomes with endovascular therapy administered within 24 hours than with medical management alone but had more intracranial hemorrhages. (Funded by Covidien Healthcare International Trading [Shanghai] and others; ANGEL-ASPECT ClinicalTrials.gov number, NCT04551664.).

A survey of generative AI for de novo drug design: new frontiers in molecule and protein generation.

Artificial intelligence (AI)-driven methods can vastly improve the historically costly drug design process, with various generative models already in widespread use. Generative models for de novo drug design, in particular, focus on the creation of novel biological compounds entirely from scratch, representing a promising future direction. Rapid development in the field, combined with the inherent complexity of the drug design process, creates a difficult landscape for new researchers to enter. In this survey, we organize de novo drug design into two overarching themes: small molecule and protein generation. Within each theme, we identify a variety of subtasks and applications, highlighting important datasets, benchmarks, and model architectures and comparing the performance of top models. We take a broad approach to AI-driven drug design, allowing for both micro-level comparisons of various methods within each subtask and macro-level observations across different fields. We discuss parallel challenges and approaches between the two applications and highlight future directions for AI-driven de novo drug design as a whole. An organized repository of all covered sources is available at https://github.com/gersteinlab/GenAI4Drug.

Predicting recurrent glioblastoma clinical outcome to immune checkpoint inhibition and low-dose bevacizumab with tumor in situ fluid circulating tumor DNA analysis.

OBJECTIVE: Most recurrent glioblastoma (rGBM) patients do not benefit from immune checkpoint inhibition, emphasizing the necessity for response biomarkers. This study evaluates whether tumor in situ fluid (TISF) circulating tumor DNA (ctDNA) could serve as a biomarker for response to low-dose bevacizumab (Bev) plus anti-PD-1 therapy in rGBM patients, aiming to enhance systemic responses to immunotherapy. METHODS: In this phase II trial, 32 GBM patients with first recurrence after standard therapy were enrolled and then received tislelizumab plus low-dose Bev each cycle. TISF samples were analyzed for ctDNA using a 551-gene panel before each treatment. RESULTS: The median progression-free survival (mPFS) and overall survival (mOS) were 8.2 months (95% CI, 5.2-11.1) and 14.3 months (95% CI, 6.5-22.1), respectively. The 12-month OS was 43.8%, and the objective response rate was 56.3%. Patients with more than 20% reduction in the mutant allele fraction and tumor mutational burden after treatment were significantly associated with better prognosis compared to baseline TISF-ctDNA. Among detectable gene mutations, patients with MUC16 mutation, EGFR mutation & amplification, SRSF2 amplification, and H3F3B amplification were significantly associated with worse prognosis. CONCLUSIONS: Low-dose Bev plus anti-PD-1 therapy significantly improves OS in rGBM patients, offering guiding significance for future individualized treatment strategies. TISF-ctDNA can monitor rGBM patients' response to combination therapy and guide treatment. CLINICAL TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT05540275.

Constructing a full, multiple-layer interactome for SARS-CoV-2 in the context of lung disease: Linking the virus with human genes and microbes.

The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in millions of deaths worldwide. The disease presents with various manifestations that can vary in severity and long-term outcomes. Previous efforts have contributed to the development of effective strategies for treatment and prevention by uncovering the mechanism of viral infection. We now know all the direct protein-protein interactions that occur during the lifecycle of SARS-CoV-2 infection, but it is critical to move beyond these known interactions to a comprehensive understanding of the "full interactome" of SARS-CoV-2 infection, which incorporates human microRNAs (miRNAs), additional human protein-coding genes, and exogenous microbes. Potentially, this will help in developing new drugs to treat COVID-19, differentiating the nuances of long COVID, and identifying histopathological signatures in SARS-CoV-2-infected organs. To construct the full interactome, we developed a statistical modeling approach called MLCrosstalk (multiple-layer crosstalk) based on latent Dirichlet allocation. MLCrosstalk integrates data from multiple sources, including microbes, human protein-coding genes, miRNAs, and human protein-protein interactions. It constructs "topics" that group SARS-CoV-2 with genes and microbes based on similar patterns of co-occurrence across patient samples. We use these topics to infer linkages between SARS-CoV-2 and protein-coding genes, miRNAs, and microbes. We then refine these initial linkages using network propagation to contextualize them within a larger framework of network and pathway structures. Using MLCrosstalk, we identified genes in the IL1-processing and VEGFA-VEGFR2 pathways that are linked to SARS-CoV-2. We also found that Rothia mucilaginosa and Prevotella melaninogenica are positively and negatively correlated with SARS-CoV-2 abundance, a finding corroborated by analysis of single-cell sequencing data.

Balloon Angioplasty vs Medical Management for Intracranial Artery Stenosis: The BASIS Randomized Clinical Trial.

Importance: Previous randomized clinical trials did not demonstrate the superiority of endovascular stenting over aggressive medical management for patients with symptomatic intracranial atherosclerotic stenosis (sICAS). However, balloon angioplasty has not been investigated in a randomized clinical trial. Objective: To determine whether balloon angioplasty plus aggressive medical management is superior to aggressive medical management alone for patients with sICAS. Design, Setting, and Participants: A randomized, open-label, blinded end point clinical trial at 31 centers across China. Eligible patients aged 35 to 80 years with sICAS defined as recent transient ischemic attack (<90 days) or ischemic stroke (14-90 days) before enrollment attributed to a 70% to 99% atherosclerotic stenosis of a major intracranial artery receiving treatment with at least 1 antithrombotic drug and/or standard risk factor management were recruited between November 8, 2018, and April 2, 2022 (final follow-up: April 3, 2023). Interventions: Submaximal balloon angioplasty plus aggressive medical management (n = 249) or aggressive medical management alone (n = 252). Aggressive medical management included dual antiplatelet therapy for the first 90 days and risk factor control. Main Outcomes and Measures: The primary outcome was a composite of any stroke or death within 30 days after enrollment or after balloon angioplasty of the qualifying lesion or any ischemic stroke in the qualifying artery territory or revascularization of the qualifying artery after 30 days through 12 months after enrollment. Results: Among 512 randomized patients, 501 were confirmed eligible (mean age, 58.0 years; 158 [31.5%] women) and completed the trial. The incidence of the primary outcome was lower in the balloon angioplasty group than the medical management group (4.4% vs 13.5%; hazard ratio, 0.32 [95% CI, 0.16-0.63]; P < .001). The respective rates of any stroke or all-cause death within 30 days were 3.2% and 1.6%. Beyond 30 days through 1 year after enrollment, the rates of any ischemic stroke in the qualifying artery territory were 0.4% and 7.5%, respectively, and revascularization of the qualifying artery occurred in 1.2% and 8.3%, respectively. The rate of symptomatic intracranial hemorrhage in the balloon angioplasty and medical management groups was 1.2% and 0.4%, respectively. In the balloon angioplasty group, procedural complications occurred in 17.4% of patients and arterial dissection occurred in 14.5% of patients. Conclusions and Relevance: In patients with sICAS, balloon angioplasty plus aggressive medical management, compared with aggressive medical management alone, statistically significantly lowered the risk of a composite outcome of any stroke or death within 30 days or an ischemic stroke or revascularization of the qualifying artery after 30 days through 12 months. The findings suggest that balloon angioplasty plus aggressive medical management may be an effective treatment for sICAS, although the risk of stroke or death within 30 days of balloon angioplasty should be considered in clinical practice. Trial Registration: ClinicalTrials.gov Identifier: NCT03703635.

A critical review of biochar as an environmental functional material in soil ecosystems for migration and transformation mechanisms and ecological risk assessment.

At present, biochar has a large application potential in soil amelioration, pollution remediation, carbon sequestration and emission reduction, and research on the effect of biochar on soil ecology and environment has made positive progress. However, under natural and anthropogenic perturbations, biochar may undergo a series of environmental behaviors such as migratory transformation, mineralization and decomposition, and synergistic transport, thus posing certain potential risks. This paper outlines the multi-interfacial migration pathway of biochar in "air-soil-plant-animal-water", and analyzes the migration process and mechanism at different interfaces during the preparation, transportation and application of biochar. The two stages of the biochar mineralization process (mineralization of easily degradable aliphatic carbon components in the early stage and mineralization of relatively stable aromatic carbon components in the later stage) were described, the self-influencing factors and external environmental factors of biochar mineralization were analyzed, and the mineral stabilization mechanism and positive/negative excitation effects of biochar into the soil were elucidated. The proximity between field natural and artificially simulated aging of biochar were analyzed, and the change of its properties showed a trend of biological aging > chemical aging > physical aging > natural aging, and in order to improve the simulation and prediction, the artificially simulated aging party needs to be changed from a qualitative method to a quantitative method. The technical advantages, application scope and potential drawbacks of different biochar modification methods were compared, and biological modification can create new materials with enhanced environmental application. The stability performance of modified biochar was compared, indicating that raw materials, pyrolysis temperature and modification method were the key factors affecting the stability of biochar. The potential risks to the soil environment from different pollutants carried by biochar were summarized, the levels of pollutants released from biochar in the soil environment were highlighted, and a comprehensive selection of ecological risk assessment methods was suggested in terms of evaluation requirements, data acquisition and operation difficulty. Dynamic tracing of migration decomposition behavior, long-term assessment of pollution remediation effects, and directional design of modified composite biochar materials were proposed as scientific issues worthy of focused attention. The results can provide a certain reference basis for the theoretical research and technological development of biochar.

Impact of soil density on biomineralization using EICP and MICP techniques for earthen sites consolidation.

Enzyme-induced calcium carbonate precipitation (EICP) and microbially-induced calcium carbonate precipitation (MICP) techniques represent emerging trends in soil stabilization. However, the impact of soil density on biomineralization, particularly in historical earthen sites, remains unclear. This study compares the consolidation effects of EICP and MICP on cylindrical samples (10 cm × 5 cm) with three densities (1.5 g/cm3, 1.6 g/cm3, and 1.7 g/cm3) derived from the soil near the UNESCO World Cultural Heritage Site of Suoyang Ancient City, Gansu Province, China. Results showed that calcium carbonate production increased across all densities through bio-cementation, with higher densities producing more calcium carbonate. MICP-treated specimens exhibited larger increases in calcium carbonate production compared to those treated with EICP. Specimens with a density of 1.7 g/cm³ showed a wave velocity increase of 3.26% (EICP) and 7.13% (MICP), and an unconfined compressive strength increase of 8% (EICP) and 26% (MICP). These strength increases correlated with the generation of calcium carbonate. The findings suggest that biomineralization can be effectively utilized for in situ consolidation of earthen sites, emphasizing the importance of considering soil density in biologically-based conservation technologies. Furthermore, MICP shows potential advantages over EICP in providing stronger, compatible and more sustainable soil reinforcement.

Adult mice with noise-induced hearing loss exhibited temporal ordering memory deficits accompanied by microglia-associated neuroplastic changes in the medial prefrontal cortex.

Acquired peripheral hearing loss in midlife is considered the primary modifiable risk factor for dementia, while the underlying pathological mechanism remains poorly understood. Excessive noise exposure is the most common cause of acquired peripheral hearing loss in modern society. This study was designed to investigate the impact of noise-induced hearing loss (NIHL) on cognition, with a focus on the medial prefrontal cortex (mPFC), a brain region that is involved in both auditory and cognitive processes and is highly affected in patients with cognitive impairment. Adult C57BL/6 J mice were randomly assigned to a control group and seven noise groups: 0HPN, 12HPN, 1DPN, 3DPN, 7DPN, 14DPN, and 28DPN, which were exposed to broadband noise at a 123 dB sound pressure level (SPL) for 2 h and sacrificed immediately (0 h), 12 h, or 1, 3, 7, 14, or 28 days post-noise exposure (HPN, DPN), respectively. Hearing assessment, behavioral tests, and neuromorphological studies in the mPFC were performed in control and 28DPN mice. All experimental animals were included in the time-course analysis of serum corticosterone (CORT) levels and mPFC microglial morphology. The results illustrated that noise exposure induced early-onset transient serum CORT elevation and permanent moderate-to-severe hearing loss in mice. 28DPN mice, in which permanent NIHL has been verified, exhibited impaired performance in temporal order object recognition tasks concomitant with reduced structural complexity of mPFC pyramidal neurons. The time-course immunohistochemical analysis in the mPFC revealed significantly higher morphological microglial activation at 14 and 28 DPN, preceded by a remarkably higher amount of microglial engulfed postsynaptic marker PSD95 at 7 DPN. Additionally, lipid accumulation in microglia was observed in 7DPN, 14DPN and 28DPN mice, suggesting a driving role of lipid handling deficits following excessive phagocytosis of synaptic elements in delayed and sustained microglial abnormalities. These findings provide fundamentally novel information concerning mPFC-related cognitive impairment in mice with NIHL and empirical evidence suggesting the involvement of microglial malfunction in the mPFC neurodegenerative consequences of NIHL.

Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke.

BACKGROUND: In acute ischemic stroke, there is uncertainty regarding the benefit and risk of administering intravenous alteplase before endovascular thrombectomy. METHODS: We conducted a trial at 41 academic tertiary care centers in China to evaluate endovascular thrombectomy with or without intravenous alteplase in patients with acute ischemic stroke. Patients with acute ischemic stroke from large-vessel occlusion in the anterior circulation were randomly assigned in a 1:1 ratio to undergo endovascular thrombectomy alone (thrombectomy-alone group) or endovascular thrombectomy preceded by intravenous alteplase, at a dose of 0.9 mg per kilogram of body weight, administered within 4.5 hours after symptom onset (combination-therapy group). The primary analysis for noninferiority assessed the between-group difference in the distribution of the modified Rankin scale scores (range, 0 [no symptoms] to 6 [death]) at 90 days on the basis of a lower boundary of the 95% confidence interval of the adjusted common odds ratio equal to or larger than 0.8. We assessed various secondary outcomes, including death and reperfusion of the ischemic area. RESULTS: Of 1586 patients screened, 656 were enrolled, with 327 patients assigned to the thrombectomy-alone group and 329 assigned to the combination-therapy group. Endovascular thrombectomy alone was noninferior to combined intravenous alteplase and endovascular thrombectomy with regard to the primary outcome (adjusted common odds ratio, 1.07; 95% confidence interval, 0.81 to 1.40; P = 0.04 for noninferiority) but was associated with lower percentages of patients with successful reperfusion before thrombectomy (2.4% vs. 7.0%) and overall successful reperfusion (79.4% vs. 84.5%). Mortality at 90 days was 17.7% in the thrombectomy-alone group and 18.8% in the combination-therapy group. CONCLUSIONS: In Chinese patients with acute ischemic stroke from large-vessel occlusion, endovascular thrombectomy alone was noninferior with regard to functional outcome, within a 20% margin of confidence, to endovascular thrombectomy preceded by intravenous alteplase administered within 4.5 hours after symptom onset. (Funded by the Stroke Prevention Project of the National Health Commission of the People's Republic of China and the Wu Jieping Medical Foundation; DIRECT-MT ClinicalTrials.gov number, NCT03469206.).

Microbial Diversity on the Surface of Historical Monuments in Lingyan Temple, Jinan, China.

Lingyan Temple is an important part of the World Heritage Mixed Property on Mount Taishan, in which numerous cultural heritage monuments, including exquisite painted arhat statues and inscriptions, display the ancient Chinese Buddhist culture. However, these monuments are suffering aesthetic and structural damage due to rich biofilms. In this study, the microbial communities colonized on historical monuments in different microenvironments were characterized through a combination of culture-dependent techniques and high-throughput sequencing. Microbial diversity was significantly different among the historical sites with different microenvironments. For example, Actinobacteria and Ascomycota were the core phyla in the indoor samples, while they were less abundant in the outdoor samples, and phototrophic microorganisms including Cyanobacteria and green algae were only dominant in the samples near springs. The results suggested that environmental factors such as water and airborne microorganisms may be the main causes influencing microbial distribution. Most of the identified dominant species were common on the historical monuments and could contribute to biodeterioration. This analysis of microbiota will provide further information on the biodeterioration processes and preservation strategies of cultural heritage monuments in Lingyan Temple.

Antibacterial metabolites from the beetle-associated fungus Penicillium chrysogenum.

The antibacterial secondary metabolites of the fungus Penicillium chrysogenum associated with the beetle Aspongopus chinensis were investigated through chromatographic fractionation methods of ethyl acetate extracts of the fungal cultures. Five compounds were isolated, and their structures were determined as emodin, 4-(methoxymethyl)benzoic acid, isoochracinic acid, secalonic acid D, and dicerandrol A using mass spectroscopy and nuclear magnetic resonance spectroscopic analyses. Emodin exhibited strong antimicrobial activity, especially against Staphylococcus aureus even when growing on cooked pork, with a minimal inhibitory concentration (MIC) of 6.3 µg/mL. Dimeric tetrahydroxanthones, such as secalonic acid D and dicerandrol A, also exhibited potent activity, with MIC values ranging from 9.5 to 28.5 µg/mL. In summary, P. chrysogenum was isolated as a symbiotic fungus of the beetle A. chinensis for the first time and this strain could generate antibacterial secondary metabolites, which could potently inhibit gram-positive bacteria growth in vitro.

Randomized, prospective, multicenter trial assessing the numen coil embolization system in the endovascular treatment of small intracranial aneurysms: outcomes from the CATCH Trial.

BACKGROUND AND PURPOSE: The CATCH (Coil Application Trial in China) trial was designed to assess the safety and efficacy of the Numen Coil Embolization System in the treatment of intracranial aneurysms in comparison with the Axium coil (ev3/Medtronic). Although the endovascular treatment of small (< 5 mm) intracranial aneurysms has been reported with favorable long-term clinical and angiographic outcomes, randomized trials are still lacking. Data for aneurysms smaller than 5 mm were extracted from the CATCH trial. MATERIALS AND METHODS: A randomized, prospective, multicenter trial was conducted at ten centers throughout China. Enrolled subjects with small intracranial aneurysms were randomly assigned to receive treatment with the Numen Coil or the Axium coil. The primary outcome was successful aneurysm occlusion at the 6-month follow-up. In contrast, the secondary outcomes included complete aneurysm occlusion, recurrence rate, clinical deterioration, and safety data at the 6-month and 12-month follow-ups. RESULTS: A total of 124 patients were enrolled in the study. Overall, 58 patients were assigned to the Numen group, and 66 were assigned to the Axium group. At the 6-month follow-up, the successful aneurysm occlusion rate was 93.1% (54/58) in the MicroPort NeuroTech group and 97.0% (64/66) in the Axium group, with a common odds ratio of 0.208 (95% confidence interval, 0.023-1.914; P = 0.184). Complications were comparable between the groups. CONCLUSIONS: Compared with the Aixum coil, the Numen coil is safe and effective in treating small intracranial aneurysms. TRIAL REGISTRATION: (13/12/2016, NCT02990156).

Effects of biochar and freeze‒thaw cycles on the bacterial community and multifunctionality in a cold black soil area.

Global climate change has altered soil freeze‒thaw cycle events, and little is known about soil microbe response to and multifunctionality regarding freeze‒thaw cycles. Therefore, in this study, biochar was used as a material to place under seasonal freeze-thaw cycling conditions. The purpose of this study was to explore the ability of biochar to regulate the function of freeze-thaw soil cycles to ensure spring sowing and food production. The results showed that biochar significantly increased the richness and diversity of soil bacteria before and after freezing-thawing. In the freezing period, the B50 treatment had the greatest improvement effect (2.6% and 5.5%, respectively), while in the thawing period, the B75 treatment had the best improvement effect. Biochar changed the composition and distribution characteristics of the bacterial structure and enhanced the multifunctionality of freeze-thaw soil and the stability of the bacterial symbiotic network. Compared with the CK treatment, the topological characteristics of the bacterial ecological network of the B50 treatment increased the most. They were 0.89 (Avg.degree), 9.79 (Modularity), 9 (Nodes), and 255 (Links). The freeze-thaw cycle decreased the richness and diversity of the bacterial community and changed the composition and distribution of the bacterial community, and the total bacterial population decreased by 658 (CK), 394 (B25), 644 (B50) and 86 (B75) during the thawing period compared with the freezing period. The soil multifunctionality in the freezing period was higher than that during the thawing period, indicating that the freeze-thaw cycle reduced soil ecological function. From the perspective of abiotic analysis, the decrease in soil multifunctionality was due to the decrease in soil nutrients, enzyme activities, soil basic respiration and other singular functions. From the perspective of bacteria, the decrease in soil multifunctionality was mainly due to the change in the Actinobacteriota group. This work expands the understanding of biochar ecology in cold black soil. These results are conducive to the sustainable development of soil ecological function in cold regions and ultimately ensure crop growth and food productivity.

Metabolome and transcriptome analyses identify the plant immunity systems that facilitate sesquiterpene and lignan biosynthesis in Syringa pinnatifolia Hemsl.

BACKGROUND: Syringa pinnatifolia Hemsl. is a shrub belonging to the Oleaceae family. The peeled woody stems and roots of S. pinnatifolia are used in Chinese traditional medicine. This plant has been used for centuries, and modern pharmacological research has revealed its medicinal value. However, the wild populations of S. pinnatifolia have been decreasing, and it has been listed as an endangered plant in China. To elucidate the molecular mechanism leading to the synthesis of the major components of S. pinnatifolia for its further development and sustainable use, this study compared peeled stems and twigs at the metabolic and molecular levels. RESULTS: Peeled stems with the purple substance visible (SSP) and peeled twigs without the purple substance (TSP) were compared at different levels. Microscopic observation showed resin-like fillers in SSP and wood fiber cell walls approximately 1.0 µm thicker than those in TSP (wood fiber cell thickness approximately 2.7 µm). In addition, 104 volatile organic compounds and 870 non-volatile metabolites were detected in the non-targeted and widely-targeted metabolome analyses, respectively. Among the 76 differentially accumulated metabolites (DAMs) detected, 62 were up-accumulated in SSP. Most of these DAMs were terpenes, of which 90% were identified as sesquiterpenes in the volatile organic compound analysis. In the analysis of the non-volatile metabolites, 21 differentially accumulated lignans were identified, of which 18, including five subtypes, were accumulated in SSP. RNA sequencing revealed 4,421 upregulated differentially expressed genes (DEGs) and 5,522 downregulated DEGs in SSP compared with TSP, as well as 33,452 genes that were not differentially expressed. Analysis of the DEGs suggested that sesquiterpenes and lignans were mostly biosynthesized via the mevalonate and phenylpropanoid pathways, respectively. Additionally, in SSP, the enriched Gene Ontology terms included response to biotic stimulus and defense response, while the enriched Kyoto Encyclopedia of Genes and Genomes pathways included plant-pathogen interaction and many other pathways related to plant immunity. CONCLUSIONS: This study provides metabolome and transcriptome information for S. pinnatifolia, suggesting that biotic stimuli, including pathogens, are potential and valuable approaches to promoting the biosynthesis of the metabolites linked to the medicinal properties of this plant.

Gene Tracer: a smart, interactive, voice-controlled Alexa skill For gene information retrieval and browsing, mutation annotation and network visualization.

MOTIVATION: Traditionally, an individual can only query and retrieve information from a genome browser by using accessories such as a mouse and keyboard. However, technology has changed the way that people interact with their screens. We hypothesized that we could leverage technological advances to use voice recognition as an interactive input to query and visualize genomic information. RESULTS: We developed an Amazon Alexa skill called Gene Tracer that allows users to use their voice to find disease-associated gene information, deleterious mutations and gene networks, while simultaneously enjoy a genome browser-like visualization experience on their screen. As the voice can be well recognized and understood, Gene Tracer provides users with more flexibility to acquire knowledge and is broadly applicable to other scenarios. AVAILABILITYAND IMPLEMENTATION: Alexa skill store (https://www.amazon.com/LT-Gene-tracer/dp/B08HCL1V68/) and a demonstration video (https://youtu.be/XbDbx7JDKmI). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

LncRNA GAS5 promotes abdominal aortic aneurysm formation through regulating the miR-185-5p/ADCY7 axis.

One of the causes of abdominal aortic aneurysm (AAA) is the apoptosis of vascular smooth muscle cells. Many long noncoding RNA (lncRNAs) have been implicated in AAA formation. However, the mechanism of growth arrest-specific 5 (GAS5) in AAA formation is not yet clear. The expression levels of GAS5, microRNA-185-5p (miR-185-5p) and adenylate cyclase 7 (ADCY7) were determined by quantitative real-time PCR. Angiotensin II (ANGII) was used to induce AAA cell models. Cell viability was detected by MTT assay, and cell apoptosis was assessed by flow cytometry. Western blot analysis was used to test the protein expression levels. Besides, a dual-luciferase reporter assay was used to identify the mechanism of GAS5. GAS5 was upregulated in AAA tissues and ANGII-induced human aortic smooth muscle cells (HASMCs). GAS5 overexpression inhibited proliferation and promoted apoptosis and inflammatory response in ANGII-induced HASMCs, while its knockdown had the opposite effects. MiR-185-5p could be absorbed by GAS5, and its inhibitor could invert the effects of GAS5 silencing on proliferation, apoptosis and inflammatory response in ANGII-induced HASMCs. ADCY7 was a target of miR-185-5p. ADCY7 knockdown increased proliferation, while decreased apoptosis and inflammatory response in ANGII-induced HASMCs. Also, overexpressed ADCY7 reversed the effect of miR-185-5p overexpression on proliferation, apoptosis and inflammatory response in ANGII-induced HASMCs. GAS5 positively regulated the ADCY7 expression to inhibit the activity of the AKT signaling pathway by sponging miR-185-5p. LncRNA GAS5 contributed to AAA formation through regulating HASMCs proliferation, apoptosis and inflammatory response, which might provide new ideas for the treatment of AAA.

Complete Endovascular Reconstruction of the Canine Ascending Aorta, Aortic Arch, and Supra-Aortic Vessels by Implanting a New Unibody Outer Double-Branched Stent-Graft.

PURPOSE: We evaluated the feasibility and safety of using a new unibody outer double-branched stent-graft system to reconstruct the canine ascending aorta, aortic arch, and supra-aortic vessels. MATERIALS AND METHODS: The outer-branched stent-graft was a unibody design. The branched stent-graft consisted of a main stent-graft and 2 branches. The introducer system included a tri-channel catheter, 2 detachable sleeves, a front fixing device, a constraining wire, and a curved outer sheath. The branched stent-graft was loaded into the introducer system. Ten adult mongrel dogs underwent general anesthesia, and the branched stent-grafts were deployed into the canine ascending aorta, aortic arch, and supra-aortic vessels by the introducer system. All animals were followed up for 3 months. At the end of the follow-up period, computed tomographic angiography (CTA) was performed to observe the patency of the branched stent-grafts. RESULTS: The mean operation time was 142.7±13.7 minutes. The mean fluoroscopy time was 20.73±2.22 minutes. The mean dosage of contrast agent was 95.9±8.7 mL. During the operation, the tri-channel catheters successfully paralleled the wires in the aorta. All 10 branched stent-grafts were successfully implanted into the canine ascending aorta and aortic arch. There were no symptoms of cerebral embolization and no incision infection during the follow-up period. Computed tomographic angiography and specimens showed that the branched stent-grafts and native vessels were patent, the inner surfaces of the branched stent-grafts were covered by neointima, and there was no retrograde aortic dissection in the ascending aorta. CONCLUSIONS: This animal research demonstrated that the unibody outer double-branched stent-graft system could be applied to reconstruct the canine ascending aorta, aortic arch, and supra-aortic vessels. CLINICAL IMPACT: Thoracic endovascular aortic repair has been the main treatment method for aortic aneurysms or dissections involving the descending thoracic aorta. However, the aortic arch and ascending aorta remain the last segments of the aorta without a validated and routinely used endovascular option. In this research, we designed a new unibody outer branched stent-graft system to reconstruct the distal ascending aorta, aortic arch and supra-aortic vessels. The unibody outer branched stent-graft system could be applied to treat aortic pathologies which involve the middle and distal proximal ascending aorta, aortic arch and proximal descending aorta.