Strain prioritization and genome mining for enediyne natural products

The enediyne family of natural products has had a profound impact on modern chemistry, biology, and medicine, and yet only 11 enediynes have been structurally characterized to date. Here we report a genome survey of 3,400 actinomycetes, identifying 81 strains that harbor genes encoding the enediyne polyketide synthase cassettes that could be grouped into 28 distinct clades based on phylogenetic analysis. Genome sequencing of 31 representative strains confirmed that each clade harbors a distinct enediyne biosynthetic gene cluster. A genome neighborhood network allows prediction of new structural features and biosynthetic insights that could be exploited for enediyne discovery. We confirmed one clade as new C-1027 producers, with a significantly higher C-1027 titer than the original producer, and discovered a new family of enediyne natural products, the tiancimycins (TNMs), that exhibit potent cytotoxicity against a broad spectrum of cancer cell lines. Our results demonstrate the feasibility of rapid discovery of new enediynes from a large strain collection. IMPORTANCE Recent advances in microbial genomics clearly revealed that the biosynthetic potential of soil actinomycetes to produce enediynes is underappreciated. A great challenge is to develop innovative methods to discover new enediynes and produce them in sufficient quantities for chemical, biological, and clinical investigations. This work demonstrated the feasibility of rapid discovery of new enediynes from a large strain collection. The new C-1027 producers, with a significantly higher C-1027 titer than the original producer, will impact the practical supply of this important drug lead. The TNMs, with their extremely potent cytotoxicity against various cancer cells and their rapid and complete cancer cell killing characteristics, in comparison with the payloads used in FDA-approved antibody-drug conjugates (ADCs), are poised to be exploited as payload candidates for the next generation of anticancer ADCs. Follow-up studies on the other identified hits promise the discovery of new enediynes, radically expanding the chemical space for the enediyne family

Construction of Bio-Engineering Comprehensive Experimental Teaching Innovation System

Analysis of the current situation and development prospects of need of bio-engineering professionals to build the education idea of social demand-oriented, “all for students, the whole process for educating people, all-round education,” take CDIO engineering education philosophy as the guiding ideology, practice curriculum system for the carrier, developing ability as the main line, to build an “innovative educational concept - Research theory Teaching - entrepreneurial practice Teaching - specialized personnel training,” experimental zone training model, developed with the appropriate professional teaching programs, course syllabus, experiments and practical syllabus. Talents experimental area constructed has achieved good teaching results

ECGMamba: Towards Efficient ECG Classification with BiSSM

Electrocardiogram (ECG) signal analysis represents a pivotal technique in the diagnosis of cardiovascular diseases. Although transformer-based models have made significant progress in ECG classification, they exhibit inefficiencies in the inference phase. The issue is primarily attributable to the secondary computational complexity of Transformer's self-attention mechanism. particularly when processing lengthy sequences. To address this issue, we propose a novel model, ECGMamba, which employs a bidirectional state-space model (BiSSM) to enhance classification efficiency. ECGMamba is based on the innovative Mamba-based block, which incorporates a range of time series modeling techniques to enhance performance while maintaining the efficiency of inference. The experimental results on two publicly available ECG datasets demonstrate that ECGMamba effectively balances the effectiveness and efficiency of classification, achieving competitive performance. This study not only contributes to the body of knowledge in the field of ECG classification but also provides a new research path for efficient and accurate ECG signal analysis. This is of guiding significance for the development of diagnostic models for cardiovascular diseases.Comment: 6 pages, 2 figures. arXiv admin note: text overlap with arXiv:2404.17858 by other author

Characterization of Small Interfering RNAs Derived from the Geminivirus/Betasatellite Complex Using Deep Sequencing

BACKGROUND: Small RNA (sRNA)-guided RNA silencing is a critical antiviral defense mechanism employed by a variety of eukaryotic organisms. Although the induction of RNA silencing by bipartite and monopartite begomoviruses has been described in plants, the nature of begomovirus/betasatellite complexes remains undefined. METHODOLOGY/PRINCIPAL FINDINGS: Solanum lycopersicum plant leaves systemically infected with Tomato yellow leaf curl China virus (TYLCCNV) alone or together with its associated betasatellite (TYLCCNB), and Nicotiana benthamiana plant leaves systemically infected with TYLCCNV alone, or together with TYLCCNB or with mutant TYLCCNB were harvested for RNA extraction; sRNA cDNA libraries were then constructed and submitted to Solexa-based deep sequencing. Both sense and anti-sense TYLCCNV and TYLCCNB-derived sRNAs (V-sRNAs and S-sRNAs) accumulated preferentially as 22 nucleotide species in infected S. lycopersicum and N. benthamiana plants. High resolution mapping of V-sRNAs and S-sRNAs revealed heterogeneous distribution of V-sRNA and S-sRNA sequences across the TYLCCNV and TYLCCNB genomes. In TYLCCNV-infected S. lycopersicum or N. benthamiana and TYLCCNV and βC1-mutant TYLCCNB co-infected N. benthamiana plants, the primary TYLCCNV targets were AV2 and the 5' terminus of AV1. In TYLCCNV and betasatellite-infected plants, the number of V-sRNAs targeting this region decreased and the production of V-sRNAs increased corresponding to the overlapping regions of AC2 and AC3, as well as the 3' terminal of AC1. βC1 is the primary determinant mediating symptom induction and also the primary silencing target of the TYLCCNB genome even in its mutated form. CONCLUSIONS/SIGNIFICANCE: We report the first high-resolution sRNA map for a monopartite begomovirus and its associated betasatellite using Solexa-based deep sequencing. Our results suggest that viral transcript might act as RDR substrates resulting in dsRNA and secondary siRNA production. In addition, the betasatellite affected the amount of V-sRNAs detected in S. lycopersicum and N. benthamiana plants

A new multi-step BDF energy stable technique for the extended Fisher-Kolmogorov equation

The multi-step backward difference formulas of order k (BDF-k) for 3 ≤ k ≤ 5 are proposed for solving the extended Fisher–Kolmogorov equation. Based upon the careful discrete gradient structures of the BDF-k formulas, the suggested numerical schemes are proved to preserve the energy dissipation laws at the discrete levels. The maximum norm priori estimate of the numerical solution is established by means of the energy stable property. With the help of discrete orthogonal convolution kernels techniques, the L2 norm error estimates of the implicit BDF-k schemes are established. Several numerical experiments are included to illustrate our theoretical results

Vessel co-option: a unique vascular-immune niche in liver cancer

Tumor vasculature is pivotal in regulating tumor perfusion, immune cell infiltration, metastasis, and invasion. The vascular status of the tumor is intricately linked to its immune landscape and response to immunotherapy. Vessel co-option means that tumor tissue adeptly exploits pre-existing blood vessels in the para-carcinoma region to foster its growth rather than inducing angiogenesis. It emerges as a significant mechanism contributing to anti-angiogenic therapy resistance. Different from angiogenic tumors, vessel co-option presents a distinctive vascular-immune niche characterized by varying states and distribution of immune cells, including T-cells, tumor-associated macrophages, neutrophils, and hepatic stellate cells. This unique composition contributes to an immunosuppressive tumor microenvironment that is crucial in modulating the response to cancer immunotherapy. In this review, we systematically reviewed the evidence and molecular mechanisms of vessel co-option in liver cancer, while also exploring its implications for anti-angiogenic drug resistance and the immune microenvironment, to provide new ideas and clues for screening patients with liver cancer who are effective in immunotherapy

Adverse renal outcomes following targeted therapies in renal cell carcinoma: a systematic review and meta-analysis

Introduction: To clarify the prevalence of adverse renal outcomes following targeted therapies in renal cell carcinoma (RCC).Methods: A systematic search was performed in MEDLINE, EMBASE, and Cochrane Central Library. Studies that had reported adverse renal outcomes following targeted therapies in RCC were eligible. Outcomes included adverse renal outcomes defined as either renal dysfunction as evidenced by elevated serum creatinine levels or the diagnosis of acute kidney injury, or proteinuria as indicated by abnormal urine findings. The risk of bias was assessed according to Cochrane handbook guidelines. Publication bias was assessed using Funnel plot analysis and Egger Test.Results: The occurrences of the examined outcomes, along with their corresponding 95% confidence intervals (CIs), were combined using a random-effects model. In all, 23 studies including 10 RCTs and 13 observational cohort studies were included. The pooled incidence of renal dysfunction and proteinuria following targeted therapies in RCC were 17% (95% CI: 12%–22%; I2 = 88.5%, p < 0.01) and 29% (95% CI: 21%–38%; I2 = 93.2%, p < 0.01), respectively. The pooled incidence of both types of adverse events varied substantially across different regimens. Occurrence is more often in polytherapy compared to monotherapy. The majority of adverse events were rated as CTCAE grades 1 or 2 events. Four studies were assessed as having low risk of bias.Conclusion: Adverse renal outcomes reflected by renal dysfunction and proteinuria following targeted therapies in RCC are not uncommon and are more often observed in polytherapy compared to monotherapy. The majority of the adverse events were of mild severity.Systematic Review Registration: Identifier CRD42023441979

Construction of nZVI@PES metal-organic frameworks to catalyze peroxymonosulfate for removal of naproxen

Naproxen, as one of the typical drugs and personal care products, has been widely detected in the environment due to its extensive production and use. Heterogeneous advanced oxidation technology based on persulfate activation has been more and more applied in the degradation of toxic and harmful pollutants in recent years. In particular, iron based catalytic materials are widely used in persulfate activation because of their environmental protection, low cost and high reactivity, but there are some defects in the application process such as easy oxidation and agglomeration. In this work, polymeric polyether sulfone (PES) material was introduced as organic framework, and the nZVI@PES metal-organic frameworks (MOFs) was constructed by solvent surface dissolution, phase conversion and surface reduction loading methods. Peroxymonosulfate (PMS) was further activated to degrade naproxen in aqueous environment. The synergic degradation performance of the nZVI@PES MOFs /PMS system on naproxen was evaluated