Regulations of m6A and other RNA modifications and their roles in cancer.

RNA modification is an essential component of the epitranscriptome, regulating RNA metabolism and cellular functions. Several types of RNA modifications have been identified to date; they include N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), N6,2'-O-dimethyladenosine (m6Am), N4-acetylcytidine (ac4C), etc. RNA modifications, mediated by regulators including writers, erasers, and readers, are associated with carcinogenesis, tumor microenvironment, metabolic reprogramming, immunosuppression, immunotherapy, chemotherapy, etc. A novel perspective indicates that regulatory subunits and post-translational modifications (PTMs) are involved in the regulation of writer, eraser, and reader functions in mediating RNA modifications, tumorigenesis, and anticancer therapy. In this review, we summarize the advances made in the knowledge of different RNA modifications (especially m6A) and focus on RNA modification regulators with functions modulated by a series of factors in cancer, including regulatory subunits (proteins, noncoding RNA or peptides encoded by long noncoding RNA) and PTMs (acetylation, SUMOylation, lactylation, phosphorylation, etc.). We also delineate the relationship between RNA modification regulator functions and carcinogenesis or cancer progression. Additionally, inhibitors that target RNA modification regulators for anticancer therapy and their synergistic effect combined with immunotherapy or chemotherapy are discussed.

Identification of odorant-binding proteins and functional analysis of antenna-specific BhorOBP28 in Batocera horsfieldi (Hope).

BACKGROUND: The important wood-boring pest Batocera horsfieldi has evolved a sensitive olfactory system to locate host plants. Odorant-binding proteins (OBPs) are thought to play key roles in olfactory recognition. Therefore, exploring the physiological function of OBPs could facilitate a better understanding of insect chemical communications. RESULTS: In this research, 36 BhorOBPs genes were identified via transcriptome sequencing of adults' antennae from B. horsfieldi, and most BhorOBPs were predominantly expressed in chemosensory body parts. Through fluorescence competitive binding and fluorescence quenching assays, the antenna-specific BhorOBP28 was investigated and displayed strong binding affinities forming stable complexes with five volatiles, including (+)-α-Pinene, (+)-Limonene, ß-Pinene, (-)-Limonene, and (+)-Longifolene, which could also elicit conformation changes when they were interacting with BhorOBP28. Batocera horsfieldi females exhibited a preference for (-)-Limonene, and a repellent response to (+)-Longifolene. Feeding dsOBP19 produced by a bacteria-expressed system with a newly constructed vector could lead to the knockdown of BhorOBP28, and could further impair B. horsfieldi attraction to (-)-Limonene and repellent activity of (+)-Longifolene. The analysis of site-directed mutagenesis revealed that Leu7, Leu72, and Phe121 play a vital role in selectively binding properties of BhorOBP28. CONCLUSION: By modeling the molecular mechanism of olfactory recognition, these results demonstrate that BhorOBP28 is involved in the chemoreception of B. horsfieldi. The bacterial-expressed dsRNA delivery system gains new insights into potential population management strategies. Through the olfactory process concluded that discovering novel behavioral regulation and environmentally friendly control options for B. horsfieldi in the future. © 2024 Society of Chemical Industry.

K235 acetylation couples with PSPC1 to regulate the m6A demethylation activity of ALKBH5 and tumorigenesis.

N6-methyladenosine (m6A) modification plays important roles in bioprocesses and diseases. AlkB homolog 5 (ALKBH5) is one of two m6A demethylases. Here, we reveal that ALKBH5 is acetylated at lysine 235 (K235) by lysine acetyltransferase 8 and deacetylated by histone deacetylase 7. K235 acetylation strengthens the m6A demethylation activity of ALKBH5 by increasing its recognition of m6A on mRNA. RNA-binding protein paraspeckle component 1 (PSCP1) is a regulatory subunit of ALKBH5 and preferentially interacts with K235-acetylated ALKBH5 to recruit and facilitate the recognition of m6A mRNA by ALKBH5, thereby promoting m6A erasure. Mitogenic signals promote ALKBH5 K235 acetylation. K235 acetylation of ALKBH5 is upregulated in cancers and promotes tumorigenesis. Thus, our findings reveal that the m6A demethylation activity of ALKBH5 is orchestrated by its K235 acetylation and regulatory subunit PSPC1 and that K235 acetylation is necessary for the m6A demethylase activity and oncogenic roles of ALKBH5.

[Treatment of stable degenerative lumbar spondylolisthesis with percutaneous endoscopic surgery through two different approaches].

OBJECTIVE: To assess the clinical effects of percutaneous endoscopic surgery through two different approaches for stable degenerative lumbar spondylolisthesis. METHODS: Sixty-four patients with stable degenerative lumbar spondylolisthesis who underwent percutaneous endoscopic procedures between January 2016 and December 2019 were divided into transforaminal approach group and interlaminar approach group according to surgical approaches, 32 patients in each group. There were 16 males and 16 females in transforaminal approach group, aged from 52 to 84 years old with an average of (66.03±9.60) years, L2 slippage in 4 cases, L3 slippage in 5, and L4 slippage in 23. There were 17 males and 15 females in interlaminar approach group, aged from 46 to 81 years old with an average of (61.38±9.88) years, L3 slippage in 3 cases, L4 slippage in 15, and L5 slippage in 14. Operative time, intraoperative fluoroscopy times, and postoperative bedtime were compared between two groups. Anteroposterior displacement values, interbody opening angles, and the percentage of slippage were measured on preoperative and postoperative 12-month dynamic radiographs. Visual analogue scale (VAS) of low back pain and lower extremity pain, and the Japanese Orthopaedic Association (JOA) score before and after surgery were observed, and clinical effects were evaluated according to the modified MACNAB criteria. RESULTS: All operations were successfully completed, and patients in both groups were followed up for more than 1 year, and without complications during follow-up period. ①There was no significant difference in operation time between two groups(P>0.05). Intraoperative fluoroscopy times were longer in transforaminal approach group than that in intervertebral approach group(P<0.05). Postoperative bedtime was shorter in transforaminal approach group than that in intervertebral approach group (P<0.05).② No lumbar instability was found on dynamic radiography at 12 months postoperatively in both groups. There were no significant differences in anteroposterior displacement values, interbody opening angles, and the percentage of slippage between two groups postoperative 12 months and preoperative 1 day(P>0.05). ③There was no significant difference between two groups in VAS of low back pain at 3 days and 1, 12 months after the operation compared with the preoperative(P>0.05), but the VAS of the lower extremity pain was significantly improved compared with the preoperative(P<0.05). Both of groups showed significant improvement in JOA score at 12 months compared with preoperatively(P<0.05). There was no significant difference in VAS of low back pain, lower extremity pain and JOA scores between two groups during the same period after surgery(P>0.05). According to modified Macnab criteria, excellent, good, fair and poor outcomes were 21, 7, 3 and 1 in transforaminal approach group respectively, and which in intervertebral approach group were 20, 7, 5 and 0, there was no significant difference in clinical effect between the groups(P>0.05). CONCLUSION: Intervertebral approach may reduce intraoperative fluoroscopy times and transforaminal approach can shorten postoperative bedtime, both approaches achieve satisfactory results in the treatment of stable degenerative lumbar spondylolisthesis with no progression of short-term slippage.

New material of Euroleptochromus tuberculatus Yin & Cai (Coleoptera: Staphylinidae: Scydmaeninae) in Eocene Baltic amber.

The extinct members of the ant-like stone beetle supertribe Mastigitae are among the best studied groups of all fossil Scydmaeninae, and their evolutionary history can be traced from the latest Albian to the earliest Cenomanian through Miocene/Oligocene, with seven extinct genera being described (summarized in Jaoszyski, 2016; Jaoszyski & Perkovsky, 2016; Jaoszyski et al., 2018; Ross, 20192022 (list of Burmese amber taxa)).

Small Protein Hidden in lncRNA LOC90024 Promotes "Cancerous" RNA Splicing and Tumorigenesis.

Conventional therapies for late-stage colorectal cancer (CRC) have limited effects because of chemoresistance, recurrence, and metastasis. The "hidden" proteins/peptides encoded by long noncoding RNAs (lncRNAs) may be a novel resource bank for therapeutic options for patients with cancer. Here, lncRNA LOC90024 is discovered to encode a small 130-amino acid protein that interacts with several splicing regulators, such as serine- and arginine-rich splicing factor 3 (SRSF3), to regulate mRNA splicing, and the protein thus is named "Splicing Regulatory Small Protein" (SRSP). SRSP, but not LOC90024 lncRNA itself, promotes CRC tumorigenesis and progression, while silencing of SRSP suppresses CRC tumorigenesis. Mechanistically, SRSP increases the binding of SRSF3 to exon 3 of transcription factor Sp4, resulting in the inclusion of Sp4 exon 3 to induce the formation of the "cancerous" long Sp4 isoform (L-Sp4 protein) and inhibit the formation of the "noncancerous" short Sp4 isoform (S-Sp4 peptide), which lacks the transactivation domain. The upregulated SRSP level is positively associated with malignant phenotypes and poor prognosis in patients with CRC. Collectively, the findings uncover that a lncRNA-encoded small protein SRSP induces "cancerous" Sp4 splicing variant formation and may be a potential prognostic biomarker and therapeutic target for patients with CRC.

An oncopeptide regulates m6A recognition by the m6A reader IGF2BP1 and tumorigenesis.

N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic RNAs. The biological importance of m6A relies on m6A readers, which control mRNA fate and function. However, it remains unexplored whether additional regulatory subunits of m6A readers are involved in the m6A recognition on RNAs. Here we discover that the long noncoding RNA (lncRNA) LINC00266-1 encodes a 71-amino acid peptide. The peptide mainly interacts with the RNA-binding proteins, including the m6A reader IGF2BP1, and is thus named "RNA-binding regulatory peptide" (RBRP). RBRP binds to IGF2BP1 and strengthens m6A recognition by IGF2BP1 on RNAs, such as c-Myc mRNA, to increase the mRNA stability and expression of c-Myc, thereby promoting tumorigenesis. Cancer patients with RBRPhigh have a poor prognosis. Thus, the oncopeptide RBRP encoded by LINC00266-1 is a regulatory subunit of m6A readers and strengthens m6A recognition on the target RNAs by the m6A reader to exert its oncogenic functions.

Theoretical insight into the multiple interactions of quinazoline inhibitors with breast cancer resistance protein (BCRP/ABCG2).

Communicated by Ramaswamy H. Sarma.

Fragment-centric topographic mapping method guides the understanding of ABCG2-inhibitor interactions.

Understanding protein-ligand interactions is crucial to drug discovery and design. However, it would be extremely difficult for the proteins which only have one available apo structure but multiple binding sites. To address this constraint, a fragment-centric topographic mapping method (AlphaSpace software) was employed to map out concave interaction pockets at the assigned protein region. These pockets are used as complementary spaces to screen the known inhibitors for this specific binding site and to guide the molecular docking pose selection as well as protein-ligand interaction analysis. By mapping the shape of central cavity surface, we have tested the strategy against a multi-drug resistant transmembrane protein-ABCG2 to assist in generating a pharmacophore model for its inhibitors that is based on the structure of apo. Classical molecular simulation and accelerated molecular simulation are used to verify the accuracy of inhibitor screening and binding pose selection. Our study not only has gained insight for the development of novel specific ABCG2 inhibitors, but also has provided a general strategy in describing protein-ligand interactions.

A univariate ternary logic and three-valued multiplier implemented in a nano-columnar crystalline zinc oxide memristor.

Memristors, which feature small sizes, fast speeds, low power, CMOS compatibility and nonvolatile modulation of device resistance, are promising candidates for next-generation data storage and in-memory computing paradigms. Compared to the binary logics enabled by memristor devices, ternary logics with larger information-carrying capacity can provide higher computation efficiency with simple operation schemes, reduced circuit complexity and smaller chip areas. In this study, we report the fabrication of memristor devices based on nano-columnar crystalline ZnO thin films; they show symmetric and reliable multi-level resistive switching characteristics over three hundred cycles, which benefits the implementation of univariate ternary logic operations. Experimental results demonstrate that a three-valued logic complete set can be realized by the univariate operations of the present ZnO memristor device, and a ternary multiplier unit circuit is designed for potential applications. The present methodology can be beneficial for constructing future high-performance computation architectures.