Simultaneous evolutionary expansion and constraint of genomic heterogeneity in multifocal lung cancer.

Recent genomic analyses have revealed substantial tumor heterogeneity across various cancers. However, it remains unclear whether and how genomic heterogeneity is constrained during tumor evolution. Here, we sequence a unique cohort of multiple synchronous lung cancers (MSLCs) to determine the relative diversity and uniformity of genetic drivers upon identical germline and environmental background. We find that each multicentric primary tumor harbors distinct oncogenic alterations, including novel mutations that are experimentally demonstrated to be functional and therapeutically targetable. However, functional studies show a strikingly constrained tumorigenic pathway underlying heterogeneous genetic variants. These results suggest that although the mutation-specific routes that cells take during oncogenesis are stochastic, genetic trajectories may be constrained by selection for functional convergence on key signaling pathways. Our findings highlight the robust evolutionary pressures that simultaneously shape the expansion and constraint of genomic diversity, a principle that holds important implications for understanding tumor evolution and optimizing therapeutic strategies.Across cancer types tumor heterogeneity has been observed, but how this relates to tumor evolution is unclear. Here, the authors sequence multiple synchronous lung cancers, highlighting the evolutionary pressures that simultaneously shape the expansion and constraint of genomic heterogeneity

A High-Voltage Serial-In-Parallel-Out Shift Register With Amorphous Silicon TFTs

In this paper, we proposed a high-voltage serial-in-parallel-out (SIPO) shift register based on amorphous silicon thin-film transistors (a-Si TFTs). We provided a detailed introduction of the bootstrap inverter, the key component of the proposed shift register, and presented the simulation and analysis of one-stage and five-stage SIPO shift registers, respectively. Then we fabricated the five-stage SIPO shift registers employing a-Si TFTs. Both the simulation results and experimental results show that the proposed SIPO shift register is capable of transmitting a 50 V high voltage pulse signal with a clock frequency of 20 kHz and is expected to be an important building block for the applications of digital microfluidics

Electrocatalytic degradation of levofloxacin wastewater by Ru-Ti-Ni/CNT electrodes

We synthesized a series of Ru-Ti-Ni/CNT electrodes to degrade levofloxacin in wastewater. The unique structure of Ni single-atom-kernelled Ru nanoparticles regulates the reaction process, producing a notable synergistic effect. The reaction kinetics constant of Ru-Ti-Ni/CNT with a Ru: Ti ratio of 10:0 outperforms Ni/CNT by 3.7 times and CNT alone by 16.4 times. Comprehensive characterizations revealed its morphology and structure nature. Ru nanoparticles can shield Ni, while Ni single-atom facilitates electron transfer in Ru nanoparticles, generating abundant reactive oxygen radicals (ROS) that degrade pollutants

Perovskite CaZrO3 for efficient ozonation treatment of organic pollutants in wastewater

Catalytic ozonation with nano-perovskite oxides is a more efficient and advanced oxidation process for the mineralization of organic pollutants. In this study, by regulating the amount of polyethylene glycol during the synthesis of CaZrO3 perovskite-type oxides by the co-precipitation method, efficient surface oxygen vacancies were formed in CaZrO3. Owing to the presence of abundant oxygen vacancies, CaZrO3 modified by PEG exhibited a much higher catalytic activity than unmodified CaZrO3. It was further discovered from the EPR results that the main active oxygen species depend on the surface structure of CaZrO3. The variation of oxygen vacancies on the surface of the catalyst with PEG addition stimulated ozone decomposition to generate a large number of superoxide radicals. This study not only proposed a method to improve the activity of the catalyst, but also further studied the reaction mechanism of CaZrO3 catalyzed ozonation. It provides a solid theoretical basis for the industrial application of catalytic ozonation technology

Cation deviated stoichiometry Ca1.1ZrO3 perovskite as an efficient ozonation catalyst for m-cresol wastewater degradation

Highly efficient and stable catalysts for continuous catalytic ozonation of organic pollutants are of great significance in industrial applications. Perovskites have been seen as promising environmental catalysts because of their tunable defect structures and electronic properties. This work reports on A-site cation stoichiometry deviation as an effective engineering strategy to improve the crystallinity of perovskite CaZrO3, as well as its catalytic ozonation activity. High pure phase Ca1.1ZrO3 nanocrystals were successfully synthesized using a co-precipitation calcination method and evaluated as ozonation catalysts for m-cresol degradation. Surprisingly, Ca1.1ZrO3 exhibits a higher total organic carbon (TOC) removal rate, ozone utilization rate, and conversion rate of m-cresol than the stoichiometric of CaZrO3 and other conventional transition metal catalysts. In addition, Ca1.1ZrO3 shows an almost constant conversion rate of m-cresol (100%) and TOC removal rate (similar to 82%) during uninterrupted 100-h catalytic ozonation m-cresol degradation, demonstrating its excellent catalytic stability. These outstanding catalytic activity and stability toward ozonation are attributed to the synergistic meliorated oxygen octahedron structure, including Zr cation and contiguous coordinated oxygen, by introducing a non-stoichiometry defect into the perovskite. Thus, Ca1.1ZrO3 presents an advanced oxidation process of reactive oxygen species (.OH, O-2(.)- , O-1(2)). These results were verified by in situ X-ray diffraction, in situ Fourier transform infrared spectroscopy, electron paramagnetic resonance, and density functional theory. This work strongly believes that Ca1.1ZrO3 can be an efficient, stable, and an economic catalyst for catalytic ozonation

ATR-binding lncRNA ScaRNA2 promotes cancer resistance through facilitating efficient DNA end resection during homologous recombination repair

Abstract Background Our previous study first showed that ATR-binding long noncoding RNA (lncRNA) is necessary for ATR function and promotes cancer resistance. However, the specific lncRNAs instrumental in ATR activation remain largely unclear, which limits our comprehensive understanding of this critical biological process. Methods RNA immunoprecipitation (RIP) followed by RNA sequencing was employed to identify ATR-binding lncRNAs, which were further validated using RIP-qPCR assays. Immunofluorescence staining and Western blotting were applied to detect the activation of DNA damage repair factors. After the effect of scaRNA2 on cellular sensitivity to DNA-damaging reagents was determined, the effects of scaRNA2 on radiotherapy were investigated in patient-derived organoids and xenograft preclinical models. The clinical relevance of scaRNA2 was also validated in tissues isolated from rectal cancer patients. Results ScaRNA2 was identified as the most enriched ATR-binding lncRNA and was found to be essential for homologous recombination (HR) mediated DNA damage repair. Furthermore, scaRNA2 knockdown abrogated the recruitment of ATR and its substrates in response to DNA damage. Mechanistically, scaRNA2 was observed to be necessary for Exo1-mediated DNA end resection and bridged the MRN complex to ATR activation. Knockdown of scaRNA2 effectively increased the sensitivity of cancer cells to multiple kinds of DNA damage-related chemoradiotherapy. Preclinically, knockdown of scaRNA2 improved the effects of radiotherapy on patient-derived organoids and xenograft models. Finally, an increase in scaRNA2 colocalized with ATR was also found in clinical patients who were resistant to radiotherapy. Conclusions ScaRNA2 was identified as the most abundant lncRNA bound to ATR and was demonstrated to bridge DNA end resection to ATR activation; thus, it could be applied as a potent target for combined cancer treatments with chemoradiotherapy

SENP5 promotes homologous recombination-mediated DNA damage repair in colorectal cancer cells through H2AZ deSUMOylation

Abstract Background Neoadjuvant radiotherapy has been used as the standard treatment of colorectal cancer (CRC). However, radiotherapy resistance often results in treatment failure. To identify radioresistant genes will provide novel targets for combined treatments and prognostic markers. Methods Through high content screening and tissue array from CRC patients who are resistant or sensitive to radiotherapy, we identified a potent resistant gene SUMO specific peptidase 5 (SENP5). Then, the effect of SENP5 on radiosensitivity was investigated by CCK8, clone formation, comet assay, immunofluorescence and flow cytometric analysis of apoptosis and cell cycle to investigate the effect of SENP5 on radiosensitivity. SUMO-proteomic mass spectrometry combined with co-immunoprecipitation assay were used to identify the targets of SENP5. Patient-derived organoids (PDO) and xenograft (PDX) models were used to explore the possibility of clinical application. Results We identified SENP5 as a potent radioresistant gene through high content screening and CRC patients tissue array analysis. Patients with high SENP5 expression showed increased resistance to radiotherapy. In vitro and in vivo experiments demonstrated that SENP5 knockdown significantly increased radiosensitivity in CRC cells. SENP5 was further demonstrated essential for efficient DNA damage repair in homologous recombination (HR) dependent manner. Through SUMO mass spectrometry analysis, we characterized H2AZ as a deSUMOylation substrate of SENP5, and depicted the SUMOylation balance of H2AZ in HR repair and cancer resistance. By using PDO and PDX models, we found targeting SENP5 significantly increased the therapeutic efficacy of radiotherapy. Conclusion Our findings revealed novel role of SENP5 in HR mediated DNA damage repair and cancer resistance, which could be applied as potent prognostic marker and intervention target for cancer radiotherapy