Genome-Wide Identification of TLP Gene Family in Populus trichocarpa and Functional Characterization of PtTLP6, Preferentially Expressed in Phloem.

Thaumatin-like proteins (TLPs) in plants are involved in diverse biotic and abiotic stresses, including antifungal activity, low temperature, drought, and high salinity. However, the roles of the TLP genes are rarely reported in early flowering. Here, the TLP gene family was identified in P. trichocarpa. The 49 PtTLP genes were classified into 10 clusters, and gene structures, conserved motifs, and expression patterns were analyzed in these PtTLP genes. Among 49 PtTLP genes, the PtTLP6 transcription level is preferentially high in stems, and GUS staining signals were mainly detected in the phloem tissues of the PtTLP6pro::GUS transgenic poplars. We generated transgenic Arabidopsis plants overexpressing the PtTLP6 gene, and its overexpression lines showed early flowering phenotypes. However, the expression levels of main flowering regulating genes were not significantly altered in these PtTLP6-overexpressing plants. Our data further showed that overexpression of the PtTLP6 gene led to a reactive oxygen species (ROS) burst in Arabidopsis, which might advance the development process of transgenic plants. In addition, subcellular localization of PtTLP6-fused green fluorescent protein (GFP) was in peroxisome, as suggested by tobacco leaf transient transformation. Overall, this work provides a comprehensive analysis of the TLP gene family in Populus and an insight into the role of TLPs in woody plants.

Evaluation of Fermented Soybean Meal to Replace a Portion Fish Meal on Growth Performance, Antioxidant Capacity, Immunity, and mTOR Signaling Pathway of Coho Salmon (Oncorhynchus kisutch).

In this study, we evaluated the effects of fermented soybean meal (FSBM) or/and unfermented SBM replacing a portion of fish meal (FM) on the growth performance, antioxidant capacity, immunity, and mechanistic target of rapamycin (mTOR) signaling pathway of juvenile coho salmon (Oncorhynchus kisutch). Four groups of juvenile coho salmon (initial weight 152.23 ± 3.21 g) in triplicate were fed for 12 weeks on four different iso-nitrogen and iso-lipid experimental diets: G0 diet (28% FM protein, control group), G1 diet (18% FM protein and 10% SBM protein), G2 diet (18% FM protein, 5% SBM protein, and 5% FSBM protein), and G3 diet (18% FM protein and 10% FSBM protein). The main results were compared with the G0 diet; the weight gain rate, specific growth rate, and condition factor of juveniles in G3 were increased significantly (p < 0.05). The content of muscle crude protein, the total protein, glucose, albumin, total cholesterol in serum, and the total antioxidant capacity in the liver of juveniles in G3 was increased significantly (p < 0.05). The activities of pepsin, trypsin, α-amylase, and lipase in the intestine, the superoxide dismutase, catalase, and alkaline phosphatase in the liver of juveniles in G3 were increased significantly (p < 0.05). The expression levels of phosphatidylinositide 3-kinases, serine/threonine kinase, mTOR, and ribosomal protein S6 kinase 1 genes in the liver of juveniles in G3 were upregulated significantly (p < 0.05). The feed coefficient ratio, viscerosomatic index, the contents of muscle moisture, and malondialdehyde in the liver of juveniles in G3 were decreased significantly (p < 0.05). The expression levels of tumor necrosis factor α, interleukin 1ß, and interleukin 6 genes in the liver of juveniles in G3 were downregulated significantly (p < 0.05). However, there was no significant effect (p > 0.05) on the survival rate, food intake, and muscle crude lipid and ash of juveniles among the experimental groups. In conclusion, FSBM to replace a portion FM had a positive effect on the growth performance, protein deposition, antioxidant enzyme activity, digestive enzyme activity, protein synthesis, and immune-related genes of juvenile coho salmon.

Aspartic proteases modulate programmed cell death and secondary cell wall synthesis during wood formation in poplar.

Programmed cell death (PCD) is essential for wood development in trees. However, the determination of crucial factors involved in xylem PCD of wood development is still lacking. Here, two Populus trichocarpa typical aspartic protease (AP) genes, AP17 and AP45, modulate xylem maturation, especially fibre PCD, during wood formation. AP17 and AP45 were dominantly expressed in the fibres of secondary xylem, as suggested by GUS expression in APpro::GUS transgenic plants. Cas9/gRNA-induced AP17 or AP45 mutants delayed secondary xylem fibre PCD, and ap17ap45 double mutants showed more serious defects. Conversely, AP17 overexpression caused premature PCD in secondary xylem fibres, indicating a positive modulation in wood fibre PCD. Loss of AP17 and AP45 did not alter wood fibre wall thickness, whereas the ap17ap45 mutants showed a low lignin content in wood. However, AP17 overexpression led to a significant decrease in wood fibre wall thickness and lignin content, revealing the involvement in secondary cell wall synthesis during wood formation. In addition, the ap17ap45 mutant and AP17 overexpression plants resulted in a significant increase in saccharification yield in wood. Overall, AP17 and AP45 are crucial modulators in xylem maturation during wood development, providing potential candidate genes for engineering lignocellulosic wood for biofuel utilization.

Efficient Synthesis of Multiply Seven-Membered-Ring Fused Porphyrins by Rhodium-Catalyzed [5+2] Annulation.

Rhodium-catalyzed reaction of meso-pyrrol-2-yl NiII porphyrins with internal alkynes proceeded smoothly to give singly, doubly, and quadruply seven-membered-ring fused NiII porphyrins as the first example of [5+2] annulation reaction for porphyrin substrates, where the meso-appended pyrrole unit serves as a directing group. These reactions are operationally quite simple and easy. A plausible reaction mechanism was proposed on the basis of the isolation of a key intermediate. The structures of the representative products have been revealed to be considerably bent owing to the implemented seven-membered rings. Doubly fused ZnII and NiII porphyrins possessing an unsubstituted meso-position were dimerized to meso-meso linked dimers by aerobic oxidation with Zn(OAc)2 ⋅2 H2 O and electrochemical oxidation, respectively. The optical and electrochemical highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) gaps, as well as the aromatic characters of the fused porphyrins decrease as the fusion parts increases.

CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is still incurable and characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche. METHODS: Cell proliferation, drug resistance, and chromosomal instability (CIN) induced by CHEK1 were confirmed by Giemsa staining, exon sequencing, immunofluorescence and xenograft model in vivo. Bone lesion was evaluated by Tartrate-resistant acid phosphatase (TRAP) staining. The existence of circCHEK1_246aa was evaluated by qPCR, Sanger sequencing and Mass Spectrometer. RESULTS: We demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. Increased CHEK1 expression induced MM cellular proliferation and evoked drug-resistance in vitro and in vivo. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced CIN. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by upregulating NFATc1 expression. Intriguingly, we discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation. CONCLUSIONS: Our findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and BM niche.

Genome-wide characterization of aspartic protease (AP) gene family in Populus trichocarpa and identification of the potential PtAPs involved in wood formation.

BACKGROUND: Aspartic protease (AP) is one of four large proteolytic enzyme families that are involved in plant growth and development. Little is known about the AP gene family in tree species, although it has been characterized in Arabidopsis, rice and grape. The AP genes that are involved in tree wood formation remain to be determined. RESULTS: A total of 67 AP genes were identified in Populus trichocarpa (PtAP) and classified into three categories (A, B and C). Chromosome mapping analysis revealed that two-thirds of the PtAP genes were located in genome duplication blocks, indicating the expansion of the AP family by segmental duplications in Populus. The microarray data from the Populus eFP browser demonstrated that PtAP genes had diversified tissue expression patterns. Semi-qRT-PCR analysis further determined that more than 10 PtAPs were highly or preferentially expressed in the developing xylem. When the involvement of the PtAPs in wood formation became the focus, many SCW-related cis-elements were found in the promoters of these PtAPs. Based on PtAPpromoter::GUS techniques, the activities of PtAP66 promoters were observed only in fiber cells, not in the vessels of stems as the xylem and leaf veins developed in the transgenic Populus tree, and strong GUS signals were detected in interfascicular fiber cells, roots, anthers and sepals of PtAP17promoter::GUS transgenic plants. Intensive GUS activities in various secondary tissues implied that PtAP66 and PtAP17 could function in wood formation. In addition, most of the PtAP proteins were predicted to contain N- and (or) O-glycosylation sites, and the integration of PNGase F digestion and western blotting revealed that the PtAP17 and PtAP66 proteins were N-glycosylated in Populus. CONCLUSIONS: Comprehensive characterization of the PtAP genes suggests their functional diversity during Populus growth and development. Our findings provide an overall understanding of the AP gene family in trees and establish a better foundation to further describe the roles of PtAPs in wood formation.

Examining the evidence for mutual modulation between m6A modification and circular RNAs: current knowledge and future prospects.

The resistance of cancer cells to treatment significantly impedes the success of therapy, leading to the recurrence of various types of cancers. Understanding the specific mechanisms of therapy resistance may offer novel approaches for alleviating drug resistance in cancer. Recent research has shown a reciprocal relationship between circular RNAs (circRNAs) and N6-methyladenosine (m6A) modification, and their interaction can affect the resistance and sensitivity of cancer therapy. This review aims to summarize the latest developments in the m6A modification of circRNAs and their importance in regulating therapy resistance in cancer. Furthermore, we explore their mutual interaction and exact mechanisms and provide insights into potential future approaches for reversing cancer resistance.

Synergistic reduction of air pollutants and carbon dioxide emissions in Shanxi Province, China from 2013 to 2020.

Synergistic reduction of air pollutants and carbon dioxide (CO2) emissions is currently a key environmental policy in China, yet provincial-level studies remain scarce. To fill the gap, this study developed a coupled emission inventory from 2013 to 2020 in Shanxi, a coal-dependent province critical to China's energy security. This facilitated the investigation of emission trends, primary sources, synergistic effects, and spatial distribution. The results show that, while air pollutant emissions decreased significantly during the study period, CO2 emissions increased slightly. The main emitters of SO2, NOx, and CO2 were identified as power, heating, industrial boilers, and residential coal combustion. The iron and steel industry contributed significantly to PM2.5 emissions, coke production to VOCs, and vehicles to NOx and VOCs. NH3 emissions were mainly attributed to fertilizer use and livestock. Synergistic reductions were evident in coal-related sources, especially industrial boilers and residential coal combustion, underlining the importance of optimizing the energy structure. Anthropogenic emissions were concentrated in basins with poor dispersion conditions. Taiyuan, Yuncheng, and Linfen emerged as key areas for synergistic reduction efforts. This study provides important insights for environmental policy development in Shanxi and other coal-dependent regions.

Association between sleep quality and living environment among Chinese older persons: a cross-sectional study.

Sleep quality significantly affects the quality of life of older persons. Therefore, this study explored the relationship between sleep quality and living environment of older persons in China to provide a theoretical basis for therapies to alleviate sleep disorders in older persons. A total of 6211 subjects > 60 years of age in Anhui Province, China, were evaluated using the Pittsburgh Sleep Quality Index and a self-reported questionnaire. Multivariate logistic regression analysis revealed that living alone (OR = 1.26, 95% CI 1.09-1.46) and living in a rural area (OR = 1.19, 95% CI 1.06-1.34) were significantly associated with a high incidence of sleep disorders in older persons. Living near a park or foot paths suitable for exercise or walking was significantly associated with a lower incidence of sleep disorders in older persons (OR = 0.87, 95% CI 0.77-0.96). Individual factors such as female sex (OR = 1.30, 95% CI 1.14-1.48) and depression (OR = 2.80, 95% CI 2.47-3.19) were also associated with sleep quality in older persons. These data indicate a correlation exists between living environment and sleep quality.

Crystalline lens nuclear age prediction as a new biomarker of nucleus degeneration.

BACKGROUND: The crystalline lens is a transparent structure of the eye to focus light on the retina. It becomes muddy, hard and dense with increasing age, which makes the crystalline lens gradually lose its function. We aim to develop a nuclear age predictor to reflect the degeneration of the crystalline lens nucleus. METHODS: First we trained and internally validated the nuclear age predictor with a deep-learning algorithm, using 12 904 anterior segment optical coherence tomography (AS-OCT) images from four diverse Asian and American cohorts: Zhongshan Ophthalmic Center with Machine0 (ZOM0), Tomey Corporation (TOMEY), University of California San Francisco and the Chinese University of Hong Kong. External testing was done on three independent datasets: Tokyo University (TU), ZOM1 and Shenzhen People's Hospital (SPH). We also demonstrate the possibility of detecting nuclear cataracts (NCs) from the nuclear age gap. FINDINGS: In the internal validation dataset, the nuclear age could be predicted with a mean absolute error (MAE) of 2.570 years (95% CI 1.886 to 2.863). Across the three external testing datasets, the algorithm achieved MAEs of 4.261 years (95% CI 3.391 to 5.094) in TU, 3.920 years (95% CI 3.332 to 4.637) in ZOM1-NonCata and 4.380 years (95% CI 3.730 to 5.061) in SPH-NonCata. The MAEs for NC eyes were 8.490 years (95% CI 7.219 to 9.766) in ZOM1-NC and 9.998 years (95% CI 5.673 to 14.642) in SPH-NC. The nuclear age gap outperformed both ophthalmologists in detecting NCs, with areas under the receiver operating characteristic curves of 0.853 years (95% CI 0.787 to 0.917) in ZOM1 and 0.909 years (95% CI 0.828 to 0.978) in SPH. INTERPRETATION: The nuclear age predictor shows good performance, validating the feasibility of using AS-OCT images as an effective screening tool for nucleus degeneration. Our work also demonstrates the potential use of the nuclear age gap to detect NCs.

The association between influenza vaccination and the perception of COVID-19 as well as COVID-19 vaccination behavior among community residents in Anhui province, China.

Influenza is a significant public health threat associated with high morbidity and mortality globally. This study investigated the influenza vaccination rate (IVR) among community residents in Anhui province, China, and explored the association between participants' influenza vaccination and their key sociodemographic characteristics, perception of COVID-19 as well as COVID-19 vaccination behavior. We found that the IVR among respondents in Anhui province was 27.85% in 2020. Regression analyses revealed that males (OR = 1.41, 95% CI: 1.01 ~ 1.96), residents with above middle school education (OR = 1.88, 95% CI: 1.04 ~ 3.39), considered themselves likely to be infected with COVID-19 (OR = 1.53, 95% CI: 1.04 ~ 2.24), had received the COVID-19 vaccine (OR = 9.85, 95% CI: 3.49 ~ 27.78), did not plan to receive COVID-19 vaccine in the future (OR = 1.70, 95% CI: 1.17 ~ 2.47), and had no adverse reactions after COVID-19 vaccination (OR = 1.54, 95% CI: 1.04 ~ 2.27) were associated with a higher IVR. The acceptance of influenza vaccination was mainly associated with respondents' gender, education, perception of COVID-19, history of COVID-19 vaccination in city and countryside community residents in Anhui province.

Growth Performance, Antioxidant and Immunity Capacity Were Significantly Affected by Feeding Fermented Soybean Meal in Juvenile Coho Salmon (Oncorhynchus kisutch).

This study aims to investigate the effects of partial dietary replacement of fish meal with unfermented and/or fermented soybean meal (fermented by Bacillus cereus) supplemented on the growth performance, whole-body composition, antioxidant and immunity capacity, and their related gene expression of juvenile coho salmon (Oncorhynchus kisutch). Four groups of juveniles (initial weight 159.63 ± 9.54 g) at 6 months of age in triplicate were fed for 12 weeks on four different iso-nitrogen (about 41% dietary protein) and iso-lipid (about 15% dietary lipid) experimental diets. The main results were: Compared with the control diet, the diet with replaced 10% fish meal protein with fermented soybean meal protein supplementation can significantly (p < 0.05) influence the expression of superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, nuclear factor erythroid 2-related factor 2, tumor necrosis factor α and interleukin-6 genes, the growth performance, the serum biochemical indices, and the activity of antioxidant and immunity enzymes. However, there was no significant effect (p > 0.05) on the survival rate (SR) and whole-body composition in the juveniles among the experimental groups. In conclusion, the diet with replaced 10% fish meal protein with fermented soybean meal protein supplementation could significantly increase the growth performance, antioxidant and immunity capacity, and their related gene expression of juveniles.

Rhodium-Catalyzed [5 + 2] Annulation of Pyrrole Appended BODIPYs: Access to Azepine-Fused BODIPYs.

Rhodium-catalyzed C-H/N-H [5 + 2] annulations of 8-(pyrrol-2-yl)-appended boron-complexed dipyrromethenes (BODIPYs) with internal alkynes have been established to afford a series of azepine-fused BODIPYs with good yields and excellent regioselectivity, in which the pyrrol-2-yl unit serves as the directing group as a rare example. A RhI intermediate was obtained to indicate a RhI/RhIII catalytic process involved in this reaction. Importantly, the [5 + 2] C-H annulation is demonstrated as a concise strategy to change the optical properties of BODIPY.

[Synergistic Benefits of Pollution and Carbon Reduction from Air Pollution Control in Hebei Province from 2013 to 2020].

Recently, China has been facing the dual challenges of air pollution control and carbon emission reduction. Pollution and carbon reduction have become a breakthrough point for green socio-economic transformation. Air pollutant and CO2 emission inventories provide a tool for monitoring pollution and carbon reduction; however, there have been some problems in previous studies, including incomplete species coverage, different source classifications, and narrow time scales. Based on the unified emission source classification system and estimation method, an emission inventory was developed for Hebei Province from 2013 to 2020, and the emission trends, structure change, driving force, synergistic benefits, and spatial distribution were analyzed. Hebei Province achieved a balance during the study period in socio-economic development and anthropogenic emission control. SO2 emissions decreased rapidly during the "Ten Atmospheric Measures" period. VOCs and NH3 emissions reduction were more significant during the "Blue Sky Defense War" period. The decrease rates of NOx and PM2.5 emissions were relatively stable, and CO2 emissions increased slightly. The coal-fired treatment effectively reduced the air pollutant and CO2 emissions and strengthening the emission standards for key industries reduced SO2, NOx, and PM2.5 emissions; however, the VOCs emission control requires improvement. Power and residential sources achieved co-reduction of air pollutants and CO2 and reducing residential coal optimized the energy structure, thereby leading to greater synergistic benefits in the residential source. The key pollution and carbon reduction areas in Hebei Province were Shijiazhuang, Tangshan, Handan, Baoding, and Langfang. The methods and conclusions in this study can provide technical and decision-making references for regional pollution and carbon reduction efforts.

YTHDF2 promotes multiple myeloma cell proliferation via STAT5A/MAP2K2/p-ERK axis.

Multiple myeloma (MM) is still incurable partially due to lacking effective therapeutic targets. Aberrant N6-methyladenosine (m6A) RNA modification plays a vital role in many cancers, however few researches are executed in MM. We first screened the m6A-related genes in MM patient cohorts and correlated these genes with patient outcomes. We found that YTHDF2, a well-recognized m6A reader, was increased in MM patients and associated with poor outcomes. Decreased YTHDF2 expression hampered MM cell proliferation in vitro and in vivo, while enforced YTHDF2 expression reversed those effects. The analyses of m6A-RIP-seq and RIP-PCR indicated that STAT5A was the downstream target of YTHDF2, which was binding to the m6A modification site of STAT5A to promote its mRNA degradation. ChIP-seq and PCR assays revealed that STAT5A suppressed MM cell proliferation by occupying the transcription site of MAP2K2 to decrease ERK phosphorylation. In addition, we confirmed that YTHDF2 mediated the unphosphorylated form of STAT5A to inhibit the expression of MAP2K2/p-ERK. In conclusion, our study highlights that YTHDF2/STAT5A/MAP2K2/p-ERK axis plays a key role in MM proliferation and targeting YTHDF2 may be a promising therapeutic strategy.

DAZAP1 facilitates the alternative splicing of KITLG to promote multiple myeloma cell proliferation via ERK signaling pathway.

Multiple myeloma (MM) is an incurable plasma cell malignancy, in which alternative pre-mRNA splicing (AS) acts as one of the key transcriptome modifier. The Deleted in Azoospermia-Associated Protein 1 (DAZAP1) is a splicing factor that has been identified as an oncogene in multiple cancers, yet its role in MM proliferation remains unclear. We first analyzed MM clinical databases and found that MM patients with elevated DAZAP1 had a poor survival. Furthermore, we overexpressed DAZAP1 by lentiviral transfection and utilized siRNA silencing the expression of DAZAP1 in MM cells. DAZAP1 promoted MM cell proliferation in vitro and accelerated MM xenograft tumor growth in vivo. KEGG pathway enrichment analysis showed that ERK signaling pathway was activated in DAZAP1-OE MM cells. The analyses of RIP-seq and RIP-qPCR revealed that DAZAP1 activated alternative splicing of KIT proto-oncogene ligand (KITLG) mRNA. Further study validated that DAZAP1 increased ERK phosphorylation via modulating alternative splicing of KITLG mRNA to promote MM cell proliferation. In conclusion, we establish DAZAP1 as a tumor-promoting gene with therapeutic potential and provide mechanistic insights into targeting DAZAP1 as a new strategy for the diagnosis and treatment of MM.

Effects of Dietary Riboflavin Supplementation on the Growth Performance, Body Composition and Anti-Oxidative Capacity of Coho Salmon (Oncorhynchus kisutch) Post-Smolts.

The present study investigated the effects of dietary riboflavin on growth performance, body composition and anti-oxidative capacity of coho salmon (Oncorhynchus kisutch) post-smolts. Seven experimental diets were formulated with graded riboflavin levels of 0.00, 3.96, 8.07, 16.11, 31.81, 63.67 and 126.69 mg/kg, respectively. Each diet was fed to triplicate groups of 10 fish with an individually initial mean body weight of 186.22 ± 0.41 g in 21 cages (water volume, 1000-L/cage) and fed three times daily (7:30, 12:30 and 17:30) to apparent satiation for 12 weeks. Fish fed a diet with 31.81 mg/kg riboflavin had the highest specific growth rate (SGR), which was significantly higher than fish-fed diets with 0.00, 3.96, 8.07 and 126.69 mg/kg riboflavin (p < 0.05). Feed conversion ratio showed an inverse trend with SGR. No significant differences were observed in condition factor, hepatosomatic index, viscerosomatic index, muscle moisture, crude protein and ash contents among dietary groups. Muscle lipid had the highest content in the 31.81 mg/kg group and was significantly higher (p < 0.05) than those in the 0.00, 3.96 and 8.07 mg/kg groups. The alanine aminotransferase, aspartate aminotransferase and malondialdehyde contents in the liver and serum of fish were significantly decreased with the increase in dietary riboflavin level up to 31.81 mg/kg, and then increased as dietary riboflavin level further increased. An inverse trend was observed for total superoxide dismutase and catalase activities. Serum total cholesterol and triglyceride levels were significantly decreased with the dietary of riboflavin levels up to 31.81 and 63.67 mg/kg, respectively. The cubic curve regression analysis based on SGR indicated that the optimum dietary riboflavin level was estimated to be 35.26 mg/kg for coho salmon post-smolts.

AHSA1 is a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma.

BACKGROUND: Currently, multiple myeloma (MM) is still an incurable plasma cell malignancy in urgent need of novel therapeutic targets and drugs. METHODS: Bufalin was known as a highly toxic but effective anti-cancer compound. We used Bufalin as a probe to screen its potential targets by proteome microarray, in which AHSA1 was the unique target of Bufalin. The effects of AHSA1 on cellular proliferation and drug resistance were determined by MTT, western blot, flow cytometry, immunohistochemistry staining and xenograft model in vivo. The potential mechanisms of Bufalin and KU-177 in AHSA1/HSP90 were verified by co-immunoprecipitation, mass spectrometry, site mutation and microscale thermophoresis assay. RESULTS: AHSA1 expression was increased in MM samples compared to normal controls, which was significantly associated with MM relapse and poor outcomes. Furthermore, AHSA1 promoted MM cell proliferation and proteasome inhibitor (PI) resistance in vitro and in vivo. Mechanism exploration indicated that AHSA1 acted as a co-chaperone of HSP90A to activate CDK6 and PSMD2, which were key regulators of MM proliferation and PI resistance respectively. Additionally, we identified AHSA1-K137 as the specific binding site of Bufalin on AHSA1, mutation of which decreased the interaction of AHSA1 with HSP90A and suppressed the function of AHSA1 on mediating CDK6 and PSMD2. Intriguingly, we discovered KU-177, an AHSA1 selective inhibitor, and found KU-177 targeting the same site as Bufalin. Bufalin and KU-177 treatments hampered the proliferation of flow MRD-positive cells in both primary MM and recurrent MM patient samples. Moreover, KU-177 abrogated the cellular proliferation and PI resistance induced by elevated AHSA1, and decreased the expression of CDK6 and PSMD2. CONCLUSIONS: We demonstrate that AHSA1 may serve as a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma.

NAT10 promotes cell proliferation by acetylating CEP170 mRNA to enhance translation efficiency in multiple myeloma.

Multiple myeloma (MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10 (NAT10) is the first reported regulator of mRNA acetylation that is activated in many cancers. However, the function of NAT10 in MM remains unclear. We found significant upregulation of NAT10 in MM patients compared to normal plasma cells, which was also highly correlated with MM poor outcome. Further enforced NAT10 expression promoted MM growth in vitro and in vivo, while knockdown of NAT10 reversed those effects. The correlation analysis of acetylated RNA immunoprecipitation sequencing (acRIP-seq) and ribosome profiling sequencing (Ribo-seq) combined with RIP-PCR tests identified centrosomal protein 170 (CEP170) as an important downstream target of NAT10. Interfering CEP170 expression in NAT10-OE cells attenuated the acceleration of cellular growth caused by elevated NAT10. Moreover, CEP170 overexpression promoted cellular proliferation and chromosomal instability (CIN) in MM. Intriguingly, remodelin, a selective NAT10 inhibitor, suppressed MM cellular growth, induced cellular apoptosis in vitro and prolonged the survival of 5TMM3VT mice in vivo. Collectively, our data indicate that NAT10 acetylates CEP1 70 mRNA to enhance CEP170 translation efficiency, which suggests that NAT10 may serve as a promising therapeutic target in MM.

catena-Poly[[trimethyl-tin(IV)]-µ-phenyl-seleninato-κO:O'].

In the title polymeric coordination compound, [Sn(CH(3))(3)(C(6)H(5)O(2)Se)](n), the Sn(IV) atom has a distorted trigonal-bipyramidal geometry, with two O atoms of two symmetry-related bridging phenyl-seleninate anions in axial positions and three methyl groups in equatorial positions. In the crystal, the complex exhibits a chain structure parallel to the b axis.