Therapeutic Strategies for RB1-Deficient Cancers: Intersecting Gene Regulation and Targeted Therapy.

The retinoblastoma (RB) transcriptional corepressor 1 (RB1) is a critical tumor suppressor gene, governing diverse cellular processes implicated in cancer biology. Dysregulation or deletion in RB1 contributes to the development and progression of various cancers, making it a prime target for therapeutic intervention. RB1's canonical function in cell cycle control and DNA repair mechanisms underscores its significance in restraining aberrant cell growth and maintaining genomic stability. Understanding the complex interplay between RB1 and cellular pathways is beneficial to fully elucidate its tumor-suppressive role across different cancer types and for therapeutic development. As a result, investigating vulnerabilities arising from RB1 deletion-associated mechanisms offers promising avenues for targeted therapy. Recently, several findings highlighted multiple methods as a promising strategy for combating tumor growth driven by RB1 loss, offering potential clinical benefits in various cancer types. This review summarizes the multifaceted role of RB1 in cancer biology and its implications for targeted therapy.

Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study.

BACKGROUND: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma. METHODS: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881. FINDINGS: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups. INTERPRETATION: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting. FUNDING: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

In Situ Spectroscopic Elucidation of the Electrochemical Potential Drop at Polyelectrolytes/Au Interfaces.

Polyelectrolytes have been widely applied in electrochemical devices. Understanding the polyelectrolyte/electrode interfaces is pivotal for polyelectrolyte-based applications. Here, we measured the electrochemical potential drop and the local activity of the mobile ion of H+ or OH- at the polyelectrolytes/Au interfaces by in situ electrochemical surface-enhanced Raman spectroscopy and voltammetry in three-electrode cells. We found that the potential dependences of the electrochemical potential drop in polyelectrolytes were smaller than that in conventional electrolyte solutions. The interfacial activity of H+ or OH- was much lower than that of bulk polyelectrolytes. The potential-dependent molecular dynamics simulations showed that the mobility of ionomers of polyelectrolytes in an electrostatic field was limited by a polymer matrix. These results suggested a characteristically thicker compact layer in the electrical double layer of a polyelectrolyte/electrode interface due to the accumulation of mobile H+ or OH- with a thicker hydration layer and immobile ionomers.

Statistical Interpretation and Comparison of Waterfall Plots.

Waterfall plots have gained popularity as a visualization tool to present antitumor activity of treatments in oncology, especially for phase I and II trials. The typical waterfall plot in oncology is a bar plot with each bar representing the best percent tumor size reduction from baseline for a patient sorted in descending order along the x-axis. As new therapies are routinely developed in combination with standard of care or other investigational treatments, waterfall plot comparison between combination therapy and monotherapy may facilitate development decisions in addition to overall response rate or duration of response. However, waterfall plots are often assessed heuristically in practice with lack of statistical rigor. In this work, we examine the correspondence between the waterfall plot and the empirical cumulative distribution function. We demonstrate how to derive key summary statistics directly from the waterfall plot. Using real examples from published waterfall plots, we show how comparisons of waterfall plots can elucidate clinically meaningful information, such as treatment effect patterns in progression-free survival and overall survival.

Wearable Biosensor with Molecularly Imprinted Conductive Polymer Structure to Detect Lentivirus in Aerosol.

The coronavirus disease (COVID-19) pandemic has increased pressure to develop low-cost, compact, user-friendly, and ubiquitous virus sensors for monitoring infection outbreaks in communities and preventing economic damage resulting from city lockdowns. As proof of concept, we developed a wearable paper-based virus sensor based on a molecular imprinting technique, using a conductive polyaniline (PANI) polymer to detect the lentivirus as a test sample. This sensor detected the lentivirus with a 4181 TU/mL detection limit in liquid and 0.33% to 2.90% detection efficiency in aerosols at distances ranging from 30 cm to 60 cm. For fabrication, a mixture of a PANI monomer solution and virus were polymerized together to form a conductive PANI sensing element on a polyethylene terephthalate (PET) paper substrate. The sensing element exhibited formation of virus recognition sites after the removal of the virus via ultrasound sonication. A dry measurement technique was established that showed aerosol virus detection by the molecularly imprinted sensors within 1.5 h of virus spraying. This was based on the mechanism via which dispensing virus droplets on the PANI sensing element induced hybridization of the virus and molecularly imprinted virus recognition templates in PANI, influencing the conductivity of the PANI film upon drying. Interestingly, the paper-based virus sensor was easily integrated with a wearable face mask for the detection of viruses in aerosols. Since the paper sensor with molecular imprinting of virus recognition sites showed excellent stability in dry conditions for long periods of time, unlike biological reagents, this wearable biosensor will offer an alternative approach to monitoring virus infections in communities.

Antifungal mechanism of volatile compounds emitted by Actinomycetota Paenarthrobacter ureafaciens from a disease-suppressive soil on Saccharomyces cerevisiae.

Increasing evidence suggests that in disease-suppressive soils, microbial volatile compounds (mVCs) released from bacteria may inhibit the growth of plant-pathogenic fungi. However, the antifungal activities and molecular responses of fungi to different mVCs remain largely undescribed. In this study, we first evaluated the responses of pathogenic fungi to treatment with mVCs from Paenarthrobacter ureafaciens. Then, we utilized the well-characterized fungal model organism Saccharomyces cerevisiae to study the potential mechanistic effects of the mVCs. Our data showed that exposure to P. ureafaciens mVCs leads to reduced growth of several pathogenic fungi, and in yeast cells, mVC exposure prompts the accumulation of reactive oxygen species. Further experiments with S. cerevisiae deletion mutants indicated that Slt2/Mpk1 and Hog1 MAPKs play major roles in the yeast response to P. ureafaciens mVCs. Transcriptomic analysis revealed that exposure to mVCs was associated with 1,030 differentially expressed genes (DEGs) in yeast. According to gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses, many of these DEGs are involved in mitochondrial dysfunction, cell integrity, mitophagy, cellular metabolism, and iron uptake. Genes encoding antimicrobial proteins were also significantly altered in the yeast after exposure to mVCs. These findings suggest that oxidative damage and mitochondrial dysfunction are major contributors to the fungal toxicity of mVCs. Furthermore, our data showed that cell wall, antioxidant, and antimicrobial defenses are induced in yeast exposed to mVCs. Thus, our findings expand upon previous research by delineating the transcriptional responses of the fungal model. IMPORTANCE Since the use of bacteria-emitted volatile compounds in phytopathogen control is of considerable interest, it is important to understand the molecular mechanisms by which fungi may adapt to microbial volatile compounds (mVCs). Paenarthrobacter ureafaciens is an isolated bacterium from disease-suppressive soil that belongs to the Actinomycetota phylum. P. ureafaciens mVCs showed a potent antifungal effect on phytopathogens, which may contribute to disease suppression in soil. However, our knowledge about the antifungal mechanism of mVCs is limited. This study has proven that mVCs are toxic to fungi due to oxidative stress and mitochondrial dysfunction. To deal with mVC toxicity, antioxidants and physical defenses are required. Furthermore, iron uptake and CAP proteins are required for antimicrobial defense, which is necessary for fungi to deal with the thread from mVCs. This study provides essential foundational knowledge regarding the molecular responses of fungi to inhibitory mVCs.

Dynamics of Droplet Coalescence on Hydrophobic Fibers in Oil: Morphology and Liquid Bridge Evolution.

Although droplet self-jumping on hydrophobic fibers is a well-known phenomenon, the influence of viscous bulk fluids on this process is still not fully understood. In this work, two water droplets' coalescence on a single stainless-steel fiber in oil was investigated experimentally. Results showed that lowering the bulk fluid viscosity and increasing the oil-water interfacial tension promoted droplet deformation, reducing the coalescence time of each stage. While the total coalescence time was more influenced by the viscosity and under-oil contact angle than the bulk fluid density. For water droplets coalescing on hydrophobic fibers in oils, the expansion of the liquid bridge can be affected by the bulk fluid, but the expansion dynamics exhibited similar behavior. The drops begin their coalescence in an inertially limited viscous regime and transition to an inertia regime. Larger droplets did accelerate the expansion of the liquid bridge but had no obvious influence on the number of coalescence stages and coalescence time. This study can provide a more profound understanding of the mechanisms underlying the behavior of water droplet coalescence on hydrophobic surfaces in oil.

Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation.

N6-methyladenosine (m6A), one of the most prevalent mRNA modifications in eukaryotes, plays a critical role in modulating both biological and pathological processes. However, it is unknown whether mutant p53 neomorphic oncogenic functions exploit dysregulation of m6A epitranscriptomic networks. Here, we investigate Li-Fraumeni syndrome (LFS)-associated neoplastic transformation driven by mutant p53 in iPSC-derived astrocytes, the cell-of-origin of gliomas. We find that mutant p53 but not wild-type (WT) p53 physically interacts with SVIL to recruit the H3K4me3 methyltransferase MLL1 to activate the expression of m6A reader YTHDF2, culminating in an oncogenic phenotype. Aberrant YTHDF2 upregulation markedly hampers expression of multiple m6A-marked tumor-suppressing transcripts, including CDKN2B and SPOCK2, and induces oncogenic reprogramming. Mutant p53 neoplastic behaviors are significantly impaired by genetic depletion of YTHDF2 or by pharmacological inhibition using MLL1 complex inhibitors. Our study reveals how mutant p53 hijacks epigenetic and epitranscriptomic machinery to initiate gliomagenesis and suggests potential treatment strategies for LFS gliomas.

Phase 1b study of pan-AKT inhibitor vevorisertib alone or with paclitaxel or fulvestrant in PIK3CA/AKT/PTEN-mutated advanced solid tumors.

BACKGROUND: In this first-in-human phase 1b study (ClinicalTrials.gov identifier NCT02761694) of advanced solid tumors with PIK3CA/AKT/PTEN mutations, the authors investigated the safety and efficacy of the pan-AKT inhibitor vevorisertib (MK-4440; ARQ 751) as monotherapy or with paclitaxel or fulvestrant. METHODS: Patients with histologically confirmed, advanced or recurrent, PIK3CA/AKT/PTEN-mutated solid tumors, measurable disease according to Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status ≤1 received vevorisertib (dose range, 5-100 mg) alone or with paclitaxel 80 mg/m2 or fulvestrant 500 mg. The primary end point was safety and tolerability. Secondary end points included pharmacokinetics and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Of 78 patients enrolled, 58 received vevorisertib monotherapy, 10 received vevorisertib plus paclitaxel, and nine received vevorisertib plus fulvestrant. Dose-limiting toxicity occurred in three patients (vevorisertib monotherapy, n = 2 [grade 3 pruritic and maculopapular rashes]; vevorisertib plus paclitaxel, n = 1 [grade 1 asthenia]). Across doses, treatment-related AEs occurred in 46 patients (79%) with vevorisertib monotherapy, in 10 patients (100%) with vevorisertib plus paclitaxel, and in nine patients (100%) with vevorisertib plus fulvestrant; and grade 3 treatment-related AEs occurred in 13 (22%), 7 (70%), and 3 (33%) patients, respectively. No grade 4/5 treatment-related AEs occurred. Maximum vevorisertib concentrations were reached 1-4 hours after dosing; the elimination half-life ranged from 8.8 to 19.3 hours. The objective response rate was 5% with vevorisertib monotherapy (three partial responses), 20% with vevorisertib plus paclitaxel (two partial responses), and 0% with vevorisertib plus fulvestrant. CONCLUSIONS: Vevorisertib alone or with paclitaxel or fulvestrant had a manageable safety profile, and vevorisertib alone or with paclitaxel had minimal to modest antitumor activity in this patient population with PIK3CA/AKT/PTEN-mutated advanced solid tumors. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02761694.

Bcl11b and Atoh8 Coordinate Cellular Plasticity for Reprogramming and Transformation.

By dissecting and comparing the transcriptional trajectories and epigenomic traits of reprogramming and transforming cells at the single-cell resolution, Huyghe et al discovered Bcl11b and Atoh8, two key transcription factors controlling cell plasticity during pluripotent reprogramming and oncogenic transformation.

Hereditary retinoblastoma iPSC model reveals aberrant spliceosome function driving bone malignancies.

The RB1 gene is frequently mutated in human cancers but its role in tumorigenesis remains incompletely defined. Using an induced pluripotent stem cell (iPSC) model of hereditary retinoblastoma (RB), we report that the spliceosome is an up-regulated target responding to oncogenic stress in RB1-mutant cells. By investigating transcriptomes and genome occupancies in RB iPSC­derived osteoblasts (OBs), we discover that both E2F3a, which mediates spliceosomal gene expression, and pRB, which antagonizes E2F3a, coregulate more than one-third of spliceosomal genes by cobinding to their promoters or enhancers. Pharmacological inhibition of the spliceosome in RB1-mutant cells leads to global intron retention, decreased cell proliferation, and impaired tumorigenesis. Tumor specimen studies and genome-wide TCGA (The Cancer Genome Atlas) expression profile analyses support the clinical relevance of pRB and E2F3a in modulating spliceosomal gene expression in multiple cancer types including osteosarcoma (OS). High levels of pRB/E2F3a­regulated spliceosomal genes are associated with poor OS patient survival. Collectively, these findings reveal an undiscovered connection between pRB, E2F3a, the spliceosome, and tumorigenesis, pointing to the spliceosomal machinery as a potentially widespread therapeutic vulnerability of pRB-deficient cancers.

Pembrolizumab plus dinaciclib in patients with hematologic malignancies: the phase 1b KEYNOTE-155 study.

Preclinical data demonstrated that combining an anti-programmed cell death 1 (PD-1) inhibitor with a cyclin-dependent kinase 9 (CDK9) inhibitor provided enhanced antitumor activity with no significant toxicities, suggesting this combination may be a potential therapeutic option. The multicohort, phase 1 KEYNOTE-155 study evaluated the safety and antitumor activity of the PD-1 inhibitor pembrolizumab plus the CDK9 inhibitor dinaciclib in patients with relapsed or refractory (rr) chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Patients enrolled were ≥18 years of age with a confirmed diagnosis of CLL, DLBCL, or MM. The study included 2 phases: a dose-evaluation phase to determine dose-limiting toxicities and a signal-detection phase. Patients received pembrolizumab 200 mg every 3 weeks plus dinaciclib 7 mg/m2 on day 1 and 10 mg/m2 on day 8 of cycle 1 and 14 mg/m2 on days 1 and 8 of cycles 2 and later. Primary endpoint was safety, and a key secondary endpoint was objective response rate (ORR). Seventy-two patients were enrolled and received ≥1 dose of study treatment (CLL, n = 17; DLBCL, n = 38; MM, n = 17). Pembrolizumab plus dinaciclib was generally well tolerated and produced no unexpected toxicities. The ORRs were 29.4% (5/17, rrCLL), 21.1% (8/38, rrDLBCL), and 0% (0/17, rrMM), respectively. At data cutoff, all 72 patients had discontinued treatment, 38 (52.8%) because of progressive disease. These findings demonstrate activity with combination pembrolizumab plus dinaciclib and suggest that a careful and comprehensive approach to explore anti-PD-1 and CDK9 inhibitor combinations is warranted. This trial was registered at www.clinicaltrials.gov as NCT02684617.

Assessment of Two Commercial Comprehensive Gene Panels for Personalized Cancer Treatment.

(1) Background: Analysis of tumor DNA by next-generation sequencing (NGS) plays various roles in the classification and management of cancer. This study aimed to assess the performance of two similar and large, comprehensive gene panels with a focus on clinically relevant variant detection and tumor mutation burden (TMB) assessment; (2) Methods: DNA from 19 diagnostic small cell lung cancer biopsies and an AcroMetrix™ assessment sample with >500 mutations were sequenced using Oncomine™ Comprehensive Assay Plus (OCAP) on the Ion Torrent platform and TruSight Oncology 500 Assay (TSO500) on the Illumina platform; (3) Results: OCAP and TSO500 achieved comparable NGS quality, such as mean read coverage and mean coverage uniformity. A total of 100% of the variants in the diagnostic samples and 80% of the variants in the AcroMetrix™ assessment sample were detected by both panels, and the panels reported highly similar variant allele frequency. A proportion of 14/19 (74%) samples were classified in the same TMB category; (4) Conclusions: Comparable results were obtained using OCAP and TSO500, suggesting that both panels could be applied to screen patients for enrolment in personalized cancer treatment trials.

Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies.

Cardiotoxicity of Antineoplastic Therapies and Applications of Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

The therapeutic landscape for the treatment of cancer has evolved significantly in recent decades, aided by the development of effective oncology drugs. However, many cancer drugs are often poorly tolerated by the body and in particular the cardiovascular system, causing adverse and sometimes fatal side effects that negate the chemotherapeutic benefits. The prevalence and severity of chemotherapy-induced cardiotoxicity warrants a deeper investigation of the mechanisms and implicating factors in this phenomenon, and a consolidation of scientific efforts to develop mitigating strategies. Aiding these efforts is the emergence of induced pluripotent stem cells (iPSCs) in recent years, which has allowed for the generation of iPSC-derived cardiomyocytes (iPSC-CMs): a human-based, patient-derived, and genetically variable platform that can be applied to the study of chemotherapy-induced cardiotoxicity and beyond. After surveying chemotherapy-induced cardiotoxicity and the associated chemotherapeutic agents, we discuss the use of iPSC-CMs in cardiotoxicity modeling, drug screening, and other potential applications. Improvements to the iPSC-CM platform, such as the development of more adult-like cardiomyocytes and ongoing advances in biotechnology, will only enhance the utility of iPSC-CMs in both basic science and clinical applications.

Classification Method of Uniform Circular Array Radar Ground Clutter Data Based on Chaotic Genetic Algorithm.

The classification and recognition of radar clutter is helpful to improve the efficiency of radar signal processing and target detection. In order to realize the effective classification of uniform circular array (UCA) radar clutter data, a classification method of ground clutter data based on the chaotic genetic algorithm is proposed. In this paper, the characteristics of UCA radar ground clutter data are studied, and then the statistical characteristic factors of correlation, non-stationery and range-Doppler maps are extracted, which can be used to classify ground clutter data. Based on the clustering analysis, results of characteristic factors of radar clutter data under different wave-controlled modes in multiple scenarios, we can see: in radar clutter clustering of different scenes, the chaotic genetic algorithm can save 34.61% of clustering time and improve the classification accuracy by 42.82% compared with the standard genetic algorithm. In radar clutter clustering of different wave-controlled modes, the timeliness and accuracy of the chaotic genetic algorithm are improved by 42.69% and 20.79%, respectively, compared to standard genetic algorithm clustering. The clustering experiment results show that the chaotic genetic algorithm can effectively classify UCA radar's ground clutter data.

Topography of transcriptionally active chromatin in glioblastoma.

Molecular profiling of the most aggressive brain tumor glioblastoma (GBM) on the basis of gene expression, DNA methylation, and genomic variations advances both cancer research and clinical diagnosis. The enhancer architectures and regulatory circuitries governing tumor-intrinsic transcriptional diversity and subtype identity are still elusive. Here, by mapping H3K27ac deposition, we analyze the active regulatory landscapes across 95 GBM biopsies, 12 normal brain tissues, and 38 cell line counterparts. Analyses of differentially regulated enhancers and super-enhancers uncovered previously unrecognized layers of intertumor heterogeneity. Integrative analysis of variant enhancer loci and transcriptome identified topographies of transcriptional enhancers and core regulatory circuitries in four molecular subtypes of primary tumors: AC1-mesenchymal, AC1-classical, AC2-proneural, and AC3-proneural. Moreover, this study reveals core oncogenic dependency on super-enhancer-driven transcriptional factors, long noncoding RNAs, and druggable targets in GBM. Through profiling of transcriptional enhancers, we provide clinically relevant insights into molecular classification, pathogenesis, and therapeutic intervention of GBM.

Two-Stage Fast DOA Estimation Based on Directional Antennas in Conformal Uniform Circular Array.

In conformal array radar, due to the directivity of antennas, the responses of the echo signals between different antennas are distinct, and some antennas cannot even receive the target echo signal. These phenomena significantly affect the accuracy of direction-of-arrival (DOA) estimation. To implement accurate DOA estimation in a conformal uniform circular array (UCA) composed of directional antennas, the two-stage fast DOA estimation algorithm is proposed. In the pre-processing stage, multi-target decoupling and target detection are mainly used to obtain the targets' range bin indexes set; in the rough-precise DOA estimation stage, the amplitude and phase information of each antenna are used for rough DOA estimation and precise DOA estimation, respectively. Based on simulation and actual anechoic chamber radar experiments, and through quantitative analyses of the accuracy, validity and elapsed time of the two-stage fast DOA estimation algorithm compared with the directional antenna MUSIC (DA-MUSIC), sub-array MUSIC (S-MUSIC) and Capon-like algorithms, results indicate that the two-stage fast DOA estimation algorithm can rapidly and accurately estimate DOAs in a multi-target scenario without the range-angle pair-matching procedure. Lower computational complexity and superior estimation accuracy provide the two-stage fast DOA estimation algorithm a broader application prospect in the practical engineering field.

MicrobiomeExplorer: an R package for the analysis and visualization of microbial communities.

SUMMARY: We developed the MicrobiomeExplorer R package to facilitate the analysis and visualization of microbial communities. The MicrobiomeExplorer R package allows a user to perform typical microbiome analytic workflows and visualize their results, either through the command line or an interactive Shiny application included with the package. In addition to applying common analytical workflows, the application enables automated analysis report generation. AVAILABILITY AND IMPLEMENTATION: Available at https://github.com/zoecastillo/microbiomeExplorer. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Discovery of novel N-aryl pyrrothine derivatives as bacterial RNA polymerase inhibitors.

Bacterial RNA polymerase (RNAP) is a validated drug target for broad-spectrum antibiotics, and its "switch region" is considered as the promising binding site for novel antibiotics. Based on the core scaffold of dithiolopyrrolone, a series of N-aryl pyrrothine derivatives was designed, synthesized, and evaluated for their antibacterial activity. Compounds generally displayed more active against Gram-positive bacteria, but less against Gram-negative bacteria. Among them, compound 6e exhibited moderate antibacterial activity against clinical isolates of rifampin-resistant Staphylococcus aureus with minimum inhibition concentration value of 1-2 µg/ml and inhibited Escherichia coli RNAP with IC50 value of 12.0 ± 0.9 µM. In addition, compound 6e showed certain degree of cytotoxicity against HepG2 and LO2 cells. Furthermore, molecular docking studies suggested that compound 6e might interact with the switch region of bacterial RNAP in a similar conformation to myxopyronin A. Together, the N-aryl pyrrothine scaffold is a promising lead for discovery of antibacterial drugs acting against bacterial RNAP.