The ensemble photometric variability of over 10510^5 quasars in the Dark Energy Camera Legacy Survey and the Sloan Digital Sky Survey

We present the ensemble variability analysis results of quasars using the Dark Energy Camera Legacy Survey (DECaLS) and the Sloan Digital Sky Survey (SDSS) quasar catalogs. Our dataset includes 119,305 quasars with redshifts up to 4.89. Combining the two datasets provides a 15-year baseline and permits analysis of the long timescale variability. Adopting a power-law form for the variability structure function, $V=A(t/1yr)^{\gamma}$, we use the multi-dimensional parametric fitting to explore the relationships between the quasar variability amplitude and a wide variety of quasar properties, including redshift (positive), bolometric luminosity (negative), rest-frame wavelength (negative), and black hole mass (uncertain). We also find that $\gamma$ can be also expressed as a function of redshift (negative), bolometric luminosity (positive), rest-frame wavelength (positive), and black hole mass (positive). Tests of the fitting significance with the bootstrap method show that, even with such a large quasar sample, some correlations are marginally significant. The typical value of $\gamma$ for the entire dataset is $\gtrsim 0.25$, consistent with the results in previous studies on both the quasar ensemble variability and the structure function. A significantly negative correlation between the variability amplitude and the Eddington ratio is found, which may be explained as an effect of accretion disk instability.Comment: 13 pages, 8 figures, 4 tables, accepted for publication in Ap

Systematical identification of splicing regulatory cis-elements and cognate trans-factors

The majority of human genes undergo alternative splicing to generate multiple isoforms with distinct functions. This process is generally controlled by cis-acting splicing regulatory elements (SREs) that recruit trans-acting factors to promote or inhibit the use of nearby splice sites. The growing interest in understanding the regulatory rules of splicing necessitates the systematic identification of these SREs and their cognate protein factors using experimental and computational approaches. Here we describe a strategy to identify and analyze both cis-acting SREs and trans-acting splicing factors. This strategy involves a cell-based screen to identify SREs from a random sequences library and a modified RNA affinity purification approach to unbiasedly identify the splicing factors. These methods can be adopted to identify splicing enhancers or silencers in both exons and introns, and can be extended to different cultured cells. The resulting SREs and splicing factors can be further analyzed with a series of computational and experimental approaches. This approach will help us to collect a molecular part-list for splicing regulation, providing a rich data source that enables a better understanding of the “splicing code”

Efficient backsplicing produces translatable circular mRNAs

While the human transcriptome contains a large number of circular RNAs (circRNAs), the functions of most circRNAs remain unclear. Sequence annotation suggests that most circRNAs are generated from splicing in reversed orders across exons. However, the mechanisms of this backsplicing are largely unknown. Here we constructed a single exon minigene containing split GFP, and found that the pre-mRNA indeed produces circRNA through efficient backsplicing in human and Drosophila cells. The backsplicing is enhanced by complementary introns that form double-stranded RNA structure to bring splice sites in proximity, but such structure is not required. Moreover, backsplicing is regulated by general splicing factors and cis-elements, but with regulatory rules distinct from canonical splicing. The resulting circRNA can be translated to generate functional proteins. Unlike linear mRNA, poly-adenosine or poly-thymidine in 3′ UTR can inhibit circular mRNA translation. This study revealed that backsplicing can occur efficiently in diverse eukaryotes to generate circular mRNAs

An extensive program of periodic alternative splicing linked to cell cycle progression

Progression through the mitotic cell cycle requires periodic regulation of gene function at the levels of transcription, translation, protein-protein interactions, post-translational modification and degradation. However, the role of alternative splicing (AS) in the temporal control of cell cycle is not well understood. By sequencing the human transcriptome through two continuous cell cycles, we identify ~1300 genes with cell cycle-dependent AS changes. These genes are significantly enriched in functions linked to cell cycle control, yet they do not significantly overlap genes subject to periodic changes in steady-state transcript levels. Many of the periodically spliced genes are controlled by the SR protein kinase CLK1, whose level undergoes cell cycle-dependent fluctuations via an auto-inhibitory circuit. Disruption of CLK1 causes pleiotropic cell cycle defects and loss of proliferation, whereas CLK1 over-expression is associated with various cancers. These results thus reveal a large program of CLK1-regulated periodic AS intimately associated with cell cycle control

Genomic analysis and characterization of phages infecting the marine Roseobacter CHAB-I-5 lineage reveal a globally distributed and abundant phage genus

Marine phages play an important role in marine biogeochemical cycles by regulating the death, physiological metabolism, and evolutionary trajectory of bacteria. The Roseobacter group is an abundant and important heterotrophic bacterial group in the ocean, and plays an important role in carbon, nitrogen, sulfur and phosphorus cycling. The CHAB-I-5 lineage is one of the most dominant Roseobacter lineages, but remains largely uncultured. Phages infecting CHAB-I-5 bacteria have not yet been investigated due to the lack of culturable CHAB-I-5 strains. In this study, we isolated and sequenced two new phages (CRP-901 and CRP-902) infecting the CHAB-I-5 strain FZCC0083. We applied metagenomic data mining, comparative genomics, phylogenetic analysis, and metagenomic read-mapping to investigate the diversity, evolution, taxonomy, and biogeography of the phage group represented by the two phages. The two phages are highly similar, with an average nucleotide identity of 89.17%, and sharing 77% of their open reading frames. We identified several genes involved in DNA replication and metabolism, virion structure, DNA packing, and host lysis from their genomes. Metagenomic mining identified 24 metagenomic viral genomes closely related to CRP-901 and CRP-902. Genomic comparison and phylogenetic analysis demonstrated that these phages are distinct from other known viruses, representing a novel genus-level phage group (CRP-901-type). The CRP-901-type phages do not contain DNA primase and DNA polymerase genes, but possess a novel bifunctional DNA primase-polymerase gene with both primase and polymerase activities. Read-mapping analysis showed that the CRP-901-type phages are widespread across the world’s oceans and are most abundant in estuarine and polar waters. Their abundance is generally higher than other known roseophages and even higher than most pelagiphages in the polar region. In summary, this study has greatly expanded our understanding of the genetic diversity, evolution, and distribution of roseophages. Our analysis suggests that the CRP-901-type phage is an important and novel marine phage group that plays important roles in the physiology and ecology of roseobacters

Engineered proteins with Pumilio/ fem-3 mRNA binding factor scaffold to manipulate RNA metabolism

Pumilio/fem-3 mRNA binding factor (FBF) proteins are characterized by a sequence-specific RNA-binding domain. This unique single-stranded RNA recognition module, whose sequence specificity can be reprogrammed, has been fused with functional modules to engineer protein factors with various functions. Here we summarize the advancement in developing RNA regulatory tools and opportunities for the future

Jailbreaker: Automated Jailbreak Across Multiple Large Language Model Chatbots

Large Language Models (LLMs) have revolutionized Artificial Intelligence (AI) services due to their exceptional proficiency in understanding and generating human-like text. LLM chatbots, in particular, have seen widespread adoption, transforming human-machine interactions. However, these LLM chatbots are susceptible to "jailbreak" attacks, where malicious users manipulate prompts to elicit inappropriate or sensitive responses, contravening service policies. Despite existing attempts to mitigate such threats, our research reveals a substantial gap in our understanding of these vulnerabilities, largely due to the undisclosed defensive measures implemented by LLM service providers. In this paper, we present Jailbreaker, a comprehensive framework that offers an in-depth understanding of jailbreak attacks and countermeasures. Our work makes a dual contribution. First, we propose an innovative methodology inspired by time-based SQL injection techniques to reverse-engineer the defensive strategies of prominent LLM chatbots, such as ChatGPT, Bard, and Bing Chat. This time-sensitive approach uncovers intricate details about these services' defenses, facilitating a proof-of-concept attack that successfully bypasses their mechanisms. Second, we introduce an automatic generation method for jailbreak prompts. Leveraging a fine-tuned LLM, we validate the potential of automated jailbreak generation across various commercial LLM chatbots. Our method achieves a promising average success rate of 21.58%, significantly outperforming the effectiveness of existing techniques. We have responsibly disclosed our findings to the concerned service providers, underscoring the urgent need for more robust defenses. Jailbreaker thus marks a significant step towards understanding and mitigating jailbreak threats in the realm of LLM chatbots

Extensive translation of circular RNAs driven by N6-methyladenosine

Extensive pre-mRNA back-splicing generates numerous circular RNAs (circRNAs) in human transcriptome. However, the biological functions of these circRNAs remain largely unclear. Here we report that N6-methyladenosine (m6A), the most abundant base modification of RNA, promotes efficient initiation of protein translation from circRNAs in human cells. We discover that consensus m6A motifs are enriched in circRNAs and a single m6A site is sufficient to drive translation initiation. This m6A-driven translation requires initiation factor eIF4G2 and m6A reader YTHDF3, and is enhanced by methyltransferase METTL3/14, inhibited by demethylase FTO, and upregulated upon heat shock. Further analyses through polysome profiling, computational prediction and mass spectrometry reveal that m6A-driven translation of circRNAs is widespread, with hundreds of endogenous circRNAs having translation potential. Our study expands the coding landscape of human transcriptome, and suggests a role of circRNA-derived proteins in cellular responses to environmental stress

Engineering splicing factors with designed specificities

Alternative splicing is generally regulated by trans-acting factors that specifically bind pre-mRNA to activate or inhibit the splicing reaction. This regulation is critical for normal gene expression, and dysregulation of splicing is closely associated with human diseases. Here we engineer artificial splicing factors by combining sequence-specific RNA-binding domains of human Pumilio1 with functional domains that regulate splicing. We applied these factors to modulate different types of alternative splicing in selected targets, examine the activity of effector domains from natural splicing factors, and modulate splicing of an endogenous gene, Bcl-x, an anti-cancer target. The designer factor targeted to Bcl-x increased the pro-apoptotic Bcl-xS splicing isoform, thus promoting apoptosis and increasing chemosensitivity of cancer cells to common anti-tumor drugs. Our approach permits the creation of artificial factors to target virtually any pre-mRNA, providing a new strategy to study splicing regulation and manipulate disease-associated splicing events