Transcriptional inhibition after irradiation occurs preferentially at highly expressed genes in a manner dependent on cell cycle progression.

In response to DNA double-strand damage, ongoing transcription is inhibited to facilitate accurate DNA repair while transcriptional recovery occurs after DNA repair is complete. However, the mechanisms at play and the identity of the transcripts being regulated in this manner are unclear. In contrast to the situation following UV damage, we found that transcriptional recovery after ionizing radiation (IR) occurs in a manner independent of the HIRA histone chaperone. Sequencing of the nascent transcripts identified a programmed transcriptional response, where certain transcripts and pathways are rapidly downregulated after IR, while other transcripts and pathways are upregulated. Specifically, most of the loss of nascent transcripts occurring after IR is due to inhibition of transcriptional initiation of the highly transcribed histone genes and the rDNA. To identify factors responsible for transcriptional inhibition after IR in an unbiased manner, we performed a whole genome gRNA library CRISPR/Cas9 screen. Many of the top hits on our screen were factors required for protein neddylation. However, at short times after inhibition of neddylation, transcriptional inhibition still occurred after IR, even though neddylation was effectively inhibited. Persistent inhibition of neddylation blocked transcriptional inhibition after IR, and it also leads to cell cycle arrest. Indeed, we uncovered that many inhibitors and conditions that lead to cell cycle arrest in G1 or G2 phase also prevent transcriptional inhibition after IR. As such, it appears that transcriptional inhibition after IR occurs preferentially at highly expressed genes in cycling cells.

ROI constrained optimal online allocation in sponsored search.

Sponsored search plays a major role in the revenue contribution of e-commerce platforms. Advertising systems are designed to maximize platform revenue, but other goals also need to be considered, such as user experience, advertiser utility, and how to achieve the long-term revenue goal. A key component of a sponsored search system is online allocation, which makes real-time decisions to match users' search requests with relevant ad campaigns to maximize platform revenue within constraints such as campaign budgets. Although much progress has been made, most of the research work on allocation problem has focused on satisfying guaranteed deals for display ads, and those challenges for allocation problems in sponsored search are not properly addressed. In this paper, we develop a framework to solve the large-scale sponsored search ad allocation problem, consisting of two main parts. One is an optimization problem solved offline by a parameter-server based architecture, and the other is an online strategy to alleviate the conflict with the auction mechanism during online service. Comprehensive offline evaluation on real production data and online A/B testing on real production system have been made. The experimental results demonstrate that through better allocating user queries to appropriate ads, the proposed model can significantly increase the platform's revenue without sacrificing advertisers' ROI.

Transcriptional inhibition after irradiation occurs preferentially at highly expressed genes in a manner dependent on cell cycle progression.

In response to DNA double strand damage, ongoing transcription is inhibited to facilitate accurate DNA repair while transcriptional recovery occurs after DNA repair is complete. However, the mechanisms at play and identity of the transcripts being regulated in this manner are unclear. In contrast to the situation following UV damage, we found that transcriptional recovery after ionizing radiation (IR) occurs in a manner independent of the HIRA histone chaperone. Sequencing of the nascent transcripts identified a programmed transcriptional response, where certain transcripts and pathways are rapidly downregulated after IR, while other transcripts and pathways are upregulated. Specifically, most of the loss of nascent transcripts occurring after IR is due to inhibition of transcriptional initiation of the highly transcribed histone genes and the rDNA. To identify factors responsible for transcriptional inhibition after IR in an unbiased manner, we performed a whole genome gRNA library CRISPR / Cas9 screen. Many of the top hits in our screen were factors required for protein neddylation. However, at short times after inhibition of neddylation, transcriptional inhibition still occurred after IR, even though neddylation was effectively inhibited. Persistent inhibition of neddylation blocked transcriptional inhibition after IR, and it also leads to cell cycle arrest. Indeed, we uncovered that many inhibitors and conditions that lead to cell cycle arrest in G1 or G2 phase also prevent transcriptional inhibition after IR. As such, it appears that transcriptional inhibition after IR occurs preferentially at highly expressed genes in cycling cells.

Comprehensive Analysis of Glutamate Receptor-like Genes in Rice (Oryza sativa L.): Genome-Wide Identification, Characteristics, Evolution, Chromatin Accessibility, gcHap Diversity, Population Variation and Expression Analysis.

Glutamate receptors (GLR) are widely present in animals and plants, playing essential roles in regulating plant growth, development and stress response. At present, most studies of GLRs in plants are focused on Arabidopsis thaliana, while there have been few studies on rice. In this study, we identified 26 OsGLR genes in rice (Oryza sativa L.). Then, we analyzed the chromosomal location, physical and chemical properties, subcellular location, transmembrane (TM) helices, signal peptides, three-dimensional (3D) structure, cis-acting elements, evolution, chromatin accessibility, population variation, gene-coding sequence haplotype (gcHap) and gene expression under multiple abiotic stress and hormone treatments. The results showed that out of the 26 OsGLR genes, ten genes had the TM domain, signal peptides and similar 3D structures. Most OsGLRs exhibited high tissue specificity in expression under drought stress. In addition, several OsGLR genes were specifically responsive to certain hormones. The favorable gcHap of many OsGLR genes in modern varieties showed obvious differentiation between Xian/indica and Geng/japonica subspecies. This study, for the first time, comprehensively analyzes the OsGLR genes in rice, and provides an important reference for further research on their molecular function.

The Chromatin Landscape Channels DNA Double-Strand Breaks to Distinct Repair Pathways.

DNA double-strand breaks (DSBs), the most deleterious DNA lesions, are primarily repaired by two pathways, namely homologous recombination (HR) and non-homologous end joining (NHEJ), the choice of which is largely dependent on cell cycle phase and the local chromatin landscape. Recent studies have revealed that post-translational modifications on histones play pivotal roles in regulating DSB repair pathways including repair pathway choice. In this review, we present our current understanding of how these DSB repair pathways are employed in various chromatin landscapes to safeguard genomic integrity. We place an emphasis on the impact of different histone post-translational modifications, characteristic of euchromatin or heterochromatin regions, on DSB repair pathway choice. We discuss the potential roles of damage-induced chromatin modifications in the maintenance of genome and epigenome integrity. Finally, we discuss how RNA transcripts from the vicinity of DSBs at actively transcribed regions also regulate DSB repair pathway choice.

DNA-PK promotes DNA end resection at DNA double strand breaks in G0 cells.

DNA double-strand break (DSB) repair by homologous recombination is confined to the S and G2 phases of the cell cycle partly due to 53BP1 antagonizing DNA end resection in G1 phase and non-cycling quiescent (G0) cells where DSBs are predominately repaired by non-homologous end joining (NHEJ). Unexpectedly, we uncovered extensive MRE11- and CtIP-dependent DNA end resection at DSBs in G0 murine and human cells. A whole genome CRISPR/Cas9 screen revealed the DNA-dependent kinase (DNA-PK) complex as a key factor in promoting DNA end resection in G0 cells. In agreement, depletion of FBXL12, which promotes ubiquitylation and removal of the KU70/KU80 subunits of DNA-PK from DSBs, promotes even more extensive resection in G0 cells. In contrast, a requirement for DNA-PK in promoting DNA end resection in proliferating cells at the G1 or G2 phase of the cell cycle was not observed. Our findings establish that DNA-PK uniquely promotes DNA end resection in G0, but not in G1 or G2 phase cells, which has important implications for DNA DSB repair in quiescent cells.

Bibliometrics research on radiomics of lung cancer.

BACKGROUND: Lung cancer is currently the most commonly diagnosed malignant tumor worldwide. Exploring ways to improve the accuracy and timeliness of diagnosis has important clinical significance. Radiomics transforms images into high-dimensional data, and uses deep learning and artificial intelligence to improve the accuracy and efficiency of disease diagnosis. There is an increasing amount of research on radiomics in the diagnosis of lung cancer. This study analyzes the relevant literature in the Science Citation Index Expanded (SCI-E) database to understand the current research status and future development direction of lung cancer radiomics. METHODS: This study is based on the SCI-E database. The first search formula is topic = Lung cancer OR Lung neoplasms (#1), the second search formula is topic = Radiomics (#2), and the third search formula is #1 and #2, that is, literature that meets both the first and second search results. CiteSpace software was used to analyze lung cancer radiomics from the annual distribution of articles, countries, institutions, journals, and authors and keywords. HistCite software was used to visualize the citation chronology of the lung cancer radiomics literature, and Pajek software was used to analyze the main path of the citation chronology. RESULTS: There were a total of 749 publications, of which most were original articles (529, 70.63%) and reviews (109, 14.55%). The citation frequency is 21,676 times, the h-index is 66, and the average number of citations per publication is 28.94. The research mainly comes from the United States of America, China and other countries. The research institutions are mainly medical centers such as Moffitt Cancer Center, Maastricht University and Harvard Medical School. The authors are also mainly from these institutions. The literature was published in many related journals, mainly imaging and oncology journals. Keyword analysis shows that in recent years, research has focused on deep learning and artificial intelligence. CONCLUSIONS: The field of lung cancer radiomics is developing rapidly, and the main focuses of research are deep learning and artificial intelligence.

Autophagic death induced by thermo­chemotherapy in gastric cancer cells results from the reactive oxygen species pathway.

Gastric cancer is the third leading type of cancer and has the third leading cancer­associated mortality in China. The mechanism of thermo­chemotherapy in gastric cancer cells remains to be elucidated. The present study aimed to investigate the role of autophagic cell death in the thermo­chemotherapy of gastric cancer. The current study included four groups: An empty control group, a hyperthermia group, a chemotherapy (oxaliplatin) group, and a thermo­chemotherapy group. Cell viability was analyzed by the MTS assay. Production of intracellular reactive oxygen species (ROS) was quantified by flow cytometry. Autophagy­associated proteins, Beclin 1, microtubule­associated protein 1A/1B­light chain (LC3B) and mammalian target of rapamycin (mTOR), were determined by western blot analysis. The results indicated that thermo­chemotherapy markedly increased intracellular ROS production, and decreased mitochondrial membrane potential. The transmission electron microscopy results indicated that thermo­chemotherapy induced production of autophagic bodies. In addition, thermo­chemotherapy­induced cell damage at the cellular and animal levels indicated a notable increase in the expression of the autophagy­associated genes, LC3B and Beclin 1. A negative correlation between mTOR expression and autophagy was also identified, which demonstrates that thermo­chemotherapy induces autophagic cell death by activating the autophagy­associated signaling pathways. The results of the present study demonstrated that the ROS level is important in autophagic death of the gastric carcinoma cells, and the increased ROS level, induced by thermo­chemotherapy treatment, induced autophagy in gastric carcinoma cells.

Efficacy and safety of ultrasound-guided continuous hyperthermic intraperitoneal perfusion chemotherapy for the treatment of malignant ascites: a midterm study of 36 patients.

BACKGROUND: This study aimed to evaluate the efficacy and safety of ultrasound-guided continuous hyperthermic intraperitoneal perfusion chemotherapy (CHIPC) for the treatment of malignant ascites (MA). METHODS: Between July 2011 and June 2013, 36 MA patients were prospectively and consecutively hospitalized for three cycles of elective CHIPC under ultrasound guidance, maintained at a constant flow rate of 400-600 mL/min normal saline containing 5-fluorouracil plus mitomycin or carboplatin and at a constant temperature of 43°C±0.2°C, for 90 minutes. Main outcome measures were ascites resolution, Karnofsky performance status (KPS), and serum tumor biomarkers at 2 weeks after the last cycle of CHIPC. All the patients underwent uneventful CHIPC as scheduled, and vital signs remained stable over CHIPC. RESULTS: At 2 weeks after the last cycle of CHIPC, MA completely and partially resolved in 26 (72.2%) patients and eight (22.2%) patients, respectively; mean KPS score increased from pretreatment 61±9 to posttreatment 76±9 (P<0.001), and serum carcinoembryonic antigen and carbohydrate antigens 12-5 and 19-9 significantly decreased (all P<0.01). CONCLUSION: The current study indicated that ultrasound-guided CHIPC is an effective and safe palliative treatment modality for MA with respect to MA resolution, patient's general well-being, and systemic disease control. The long-term benefit of CHIPC on overall survival remains to be investigated in MA patients.

A Dicer-Independent Route for Biogenesis of siRNAs that Direct DNA Methylation in Arabidopsis.

DNA methylation directed by 24-nucleotide (nt) small interfering RNAs (siRNAs) plays critical roles in gene regulation and transposon silencing in Arabidopsis. 24-nt siRNAs are known to be processed from double-stranded RNAs by Dicer-like 3 (DCL3) and loaded into the effector Argonaute 4 (AGO4). Here we report a distinct class of siRNAs independent of DCLs (sidRNAs). sidRNAs are present as ladders of ∼ 20-60 nt in length, often having the same 5' ends but differing in 3' ends by 1-nt steps. We further show that sidRNAs are associated with AGO4 and capable of directing DNA methylation. Finally we show that sidRNA production depends on distributive 3'-5' exonucleases. Our findings suggest an alternative route for siRNA biogenesis. Precursor transcripts are bound by AGO4 and subsequently subjected to 3'-5' exonucleolytic trimming for maturation. We propose that sidRNAs generated through this route are the initial triggers of de novo DNA methylation.

CMA33/XCT Regulates Small RNA Production through Modulating the Transcription of Dicer-Like Genes in Arabidopsis.

Small RNAs (sRNAs) play important regulatory roles in various aspects of plant biology. They are processed from double-stranded RNA precursors by Dicer-like (DCL) proteins. There are three major classes of sRNAs in Arabidopsis: DCL1-dependent microRNA (miRNA), DCL3-dependent heterochromatic siRNA (hc-siRNA), and DCL4-dependent trans-acting siRNA (ta-siRNA). We have previously isolated a mutant with compromised miRNA activity, cma33. Here we show that CMA33 encodes a nuclear localized protein, XAP5 CIRCADIAN TIMEKEEPER (XCT). The cma33/xct mutation led to reduced accumulation of not only miRNAs but also hc-siRNAs and ta-siRNAs. Intriguingly, we found that the expression of DCL1, DCL3, and DCL4, but not other genes in the sRNA biogenesis pathways, was decreased in cma33/xct. Consistent with this, the occupancy of Pol II at DCL1, DCL3, and DCL4 genes was reduced upon the loss of CMA33/XCT. Collectively, our data suggest that CMA33/XCT modulates sRNA production through regulating the transcription of DCLs.