Genome-wide transcriptome profiling reveals molecular response pathways of Trichoderma harzianum in response to salt stress.

Trichoderma harzianum exhibits a strong biological control effect on many important plant pathogens, such as Fusarium oxysporum, Botrytis cinerea, and Meloidogyne. However, its biocontrol effectiveness is weakened or reduced under salt stress. The aim of this study was to investigate the molecular response of T. harzianum to salt stress at the whole-genome level. Here, we present a 44.47 Mb near-complete genome assembly of the T. harzianum qt40003 strain for the first time, which was assembled de novo with 7.59 Gb Nanopore sequencing long reads (~170-fold) and 5.2 Gb Illumina short reads (~116-fold). The assembled qt40003 genome contains 12 contigs, with a contig N50 of 4.81 Mb, in which four of the 12 contigs were entirely reconstructed in a single chromosome from telomere to telomere. The qt40003 genome contains 4.27 Mb of repeat sequences and 12,238 protein-coding genes with a BUSCO completeness of 97.5%, indicating the high accuracy and completeness of our gene annotations. Genome-wide transcriptomic analysis was used to investigate gene expression changes related to salt stress in qt40003 at 0, 2% (T2), and 4% (T4) sodium chloride concentrations. A total of 2,937 and 3,527 differentially expressed genes (DEGs) were obtained under T2 and T4 conditions, respectively. GO enrichment analysis showed that the T2-treatment DEGs were highly enriched in detoxification (p < 0.001), while the T4 DEGs were mainly enriched in cell components, mostly in cellular detoxification, cell surface, and cell wall. KEGG metabolic pathway analysis showed that 91 and 173 DEGs were significantly enriched in the T2 and T4 treatments, respectively (p < 0.01), mainly in the glutathione metabolism pathway. We further experimentally analyzed the differentially expressed glutathione transferase genes in the glutathione metabolic pathway, most of which were downregulated (13/15). In addition, we screened 13 genes related to active oxygen clearance, including six upregulated and seven downregulated genes, alongside five fungal hydrophobic proteins, of which two genes were highly expressed. Our study provides high-quality genome information for the use of T. harzianum for biological control and offers significant insights into the molecular responses of T. harzianum under salt-stress conditions.

Structural Study of the Thermoelectric Work Units Encapsulated with Cement Paste for Building Energy Harvesting.

Cement-based material encapsulation is a method of encapsulating electronic devices in highly thermally conductive cement-based materials to improve the heat dissipation performance of electronic components. In the field of construction, a thermoelectric generator (TEG) encapsulated with cement-based materials used in the building envelope has significant potential for waste heat energy recovery. The purpose of this study was to investigate the effect of cement-based materials integrated with aluminum heatsinks on the heat dissipation of the TEG composite structure. In this work, three types of thermoelectric work units encapsulated with cement paste were proposed. Moreover, we explored the effect of encapsulated structure, heat dissipation area, the height of thermoelectric single leg, and heat input temperature on maintaining the temperature difference between the two sides of the thermoelectric single leg with COMSOL Multiphysics. The numerical simulation results showed that under the conditions of a heat source temperature of 313.15 K and ambient temperature of 298.15 K, the temperature difference between the two sides of the internal thermoelectric single leg of Type-III can maintain a stable temperature difference of 7.77 K, which is 32.14% higher than that of Type-I and Type-II (5.88 K), and increased by 26.82% in the actual experiment. This work provides a reference for the selection and application of TEG composite structures of cement-based materials combined with aluminum heatsinks.

Expression of mitochondrial transcription factor A in granulosa cells: implications for oocyte maturation and in vitro fertilization outcomes.

OBJECTIVE: In vitro fertilization-embryo transfer (IVF-ET) is a widely used treatment for infertility, with oocyte maturation and quality having a significant impact on oocyte fertilization, embryo development, and fetal growth. Mitochondrial transcription factor A (TFAM) is essential for maintaining the mitochondrial oxidative respiratory chain and supplying energy for oocyte development, fertilization, and embryonic development. In this study, we aimed to examine TFAM expression in women undergoing IVF-ET and assess its impact on the IVF outcomes. METHODS: We recruited 85 women who underwent IVF-ET treatment for infertility. On the date of egg collection, granulosa cells were extracted from the clear follicular fluid of the first mature egg using ultrasound-guided needle aspiration. The collected granulosa cells served three purposes: (1) detecting TFAM gene expression in granulosa cells via immunocytochemistry, (2) determining TFAM mRNA expression using reverse transcription-PCR (RT-PCR), and (3) measuring TFAM protein expression through western blotting. RESULT: Based on the results, we found that TFAM was localized and expressed in the cytoplasm of granulosa cells, whereas no expression was detected in the nucleus. Granulosa cells exhibited a linear correlation between TFAM mRNA and TFAM protein expression. The study participants were divided into three groups using the ternary method based on relative TFAM mRNA expression thresholds of 33% and 76%: the low-expression group (n = 30), the moderate-expression group (n = 27), and the high-expression group (n = 28). When compared to the other two groups, the moderate expression group exhibited a significantly higher egg utilization rate, 2 pronucleus rate, fertilization rate, and clinical pregnancy rate (P < 0.05). CONCLUSION: TFAM was detected in the cytoplasm of human ovarian granulosa cells. Women with moderate TFAM expression demonstrate enhanced outcomes in IVF.

Fondaparinux Results in Similar Pregnancy Outcomes with Lower Adverse Reaction Rates Compared to Low Molecular Weight Heparin in Chinese Recurrent Miscarriage Women.

Fondaparinux inhibits thrombin generation by inactivating factor Xa, which has the potential to treat recurrent miscarriage (RM). However, more clinical evidence is required to support its application in Chinese women with RM. This research aimed to compare the live birth rate, gestational weeks at delivery, birth weight, Apgar score of newborns, and adverse reaction rates between fondaparinux and low molecular weight heparin (LMWH) in Chinese women with RM. Totally, 132 women with RM treated with fondaparinux or LMWH were included in this retrospective study. According to the corresponding treatment, women with RM were divided into the fondaparinux cohort (N = 45) and LMWH cohort (N = 87). The live birth rate was 68.9% in the fondaparinux cohort and 56.3% in the LMWH cohort, which was not different between the two cohorts (P = 0.161). Multivariable logistics regression analysis suggested that only previous miscarriage times (≥ 4 times vs. < 4 times) were independently related to a lower possibility of live birth in women with RM (odds ratio = 0.431, P = 0.036). It was also observed that gestational weeks at delivery (38.1 ± 1.4 vs. 37.7 ± 1.7 weeks) (P = 0.258), birth weight (2,923.7 ± 355.0 vs. 2,807.8 ± 334.0 g) (P = 0.144), and Apgar score of newborns (9.8 ± 0.5 vs. 9.6 ± 0.8) (P = 0.175) were not different between the fondaparinux cohort and LMWH cohort. Inspiringly, the total adverse reaction rate was reduced in the fondaparinux cohort vs. the LMWH cohort (20.0% vs. 37.9%) (P = 0.036). Fondaparinux results in similar pregnancy outcomes with lower adverse reaction rates compared to LMWH in Chinese women with RM.

Hypomethylation of the ENPP3 promoter region contributes to the occurrence and development of ovarian endometriosis via the AKT/mTOR/4EBP1 signaling pathway.

Growing evidence indicates that aberrant methylation is pivotal in the development and progression of endometriosis (EMs). This study explores the relationship between abnormal methylation of the ENPP3 promoter and the pathogenesis of ovarian EMs, focusing on its regulatory effect on ENPP3 expression. We analyzed the methylation levels of ENPP3 in ectopic endometrial tissues from ovarian EMs patients and in normal endometrial tissues from women without EMs. The expression and distribution of ENPP3 were evaluated using RT-qPCR and immunohistochemistry. Transwell assays were conducted to examine the impact of ENPP3 overexpression on the migratory and invasive capabilities of endometrial stromal cells. Our results demonstrated significantly reduced methylation levels at the CpG sites of the ENPP3 promoter region in ectopic endometrial tissues compared to normal endometrial tissues. RT-qPCR findings revealed a marked increase in ENPP3 expression in ovarian EMs tissues relative to endometrial tissues from patients without EMs, and this upregulation was negatively correlated with the methylation levels of the ENPP3 promoter region. Immunohistochemical analyses confirmed elevated ENPP3 expression in the glandular epithelial cells and stroma of ovarian EMs tissues. Furthermore, in vitro experiments showed that overexpressed ENPP3 notably intensified the invasion and migration of endometrial stromal cells. Transcriptome sequencing and functional analyses indicated that the increased ENPP3 expression activated the AKT/mTOR/4EBP1 signaling pathway. In summary, the study suggests that hypomethylation in the ENPP3 promoter region may contribute to the initiation and advancement of ovarian EMs by activating the AKT/mTOR/4EBP1 pathway, supporting the theory that EMs might be an epigenetically regulated disorder.

A systematic analysis of marine lysogens and proviruses.

Viruses are ubiquitous in the oceans, exhibiting high abundance and diversity. Here, we systematically analyze existing genomic sequences of marine prokaryotes to compile a Marine Prokaryotic Genome Dataset (MPGD, consisting of over 12,000 bacterial and archaeal genomes) and a Marine Temperate Viral Genome Dataset (MTVGD). At least 40% of the MPGD genomes contain one or more proviral sequences, indicating that they are lysogens. The MTVGD includes over 12,900 viral contigs or putative proviruses, clustered into 10,897 viral genera. We show that lysogens and proviruses are abundant in marine ecosystems, particularly in the deep sea, and marine lysogens differ from non-lysogens in multiple genomic features and growth properties. We reveal several virus-host interaction networks of potential ecological relevance, and identify proviruses that appear to be able to infect (or to be transferred between) different bacterial classes and phyla. Auxiliary metabolic genes in the MTVGD are enriched in functions related to carbohydrate metabolism. Finally, we experimentally demonstrate the impact of a prophage on the transcriptome of a representative marine Shewanella bacterium. Our work contributes to a better understanding of the ecology of marine prokaryotes and their viruses.

Recent Advances in Properties and Applications of Carbon Fiber-Reinforced Smart Cement-Based Composites.

Under the strategies of low-carbon and environmental protection, promoting green technology innovation to achieve carbon neutrality in the construction field has become a universal goal. As the building material with the highest consumption, concrete has gradually begun to transform into a multi-functional and intelligent product. Therefore, the research on carbon fiber-reinforced cement-based composites (CFRCs) is of relative interest. It mainly uses carbon fibers (CFs) with high elasticity, strength, and conductivity to disperse evenly into the concrete as a functional filler, to achieve the intelligent integration of concrete structures and function innovatively. Furthermore, the electrical conductivity of CFRC is not only related to the content of CFs and environmental factors but also largely depends on the uniform dispersion and the interfacial bonding strength of CFs in cement paste. This work systematically presents a review of the current research status of the enhancement and modification mechanism of CFRC and the evaluation methods of CF dispersion. Moreover, it further discusses the improvement effects of different strengthening mechanisms on the mechanical properties, durability, and smart properties (thermoelectric effect, electrothermal effect, strain-sensitive effect) of CFRC, as well as the application feasibility of CFRC in structural real-time health monitoring, thermal energy harvesting, intelligent deformation adjustment, and other fields. Furthermore, this paper summarizes the problems and challenges faced in the efficient and large-scale applications of CFRCs in civil engineering structures, and accordingly promotes some proposals for future research.

Unexplored diversity and ecological functions of transposable phages.

Phages are prevalent in diverse environments and play major ecological roles attributed to their tremendous diversity and abundance. Among these viruses, transposable phages (TBPs) are exceptional in terms of their unique lifestyle, especially their replicative transposition. Although several TBPs have been isolated and the life cycle of the representative phage Mu has been extensively studied, the diversity distribution and ecological functions of TBPs on the global scale remain unknown. Here, by mining TBPs from enormous microbial genomes and viromes, we established a TBP genome dataset (TBPGD), that expands the number of accessible TBP genomes 384-fold. TBPs are prevalent in diverse biomes and show great genetic diversity. Based on taxonomic evaluations, we propose the categorization of TBPs into four viral groups, including 11 candidate subfamilies. TBPs infect multiple bacterial phyla, and seem to infect a wider range of hosts than non-TBPs. Diverse auxiliary metabolic genes (AMGs) are identified in the TBP genomes, and genes related to glycoside hydrolases and pyrimidine deoxyribonucleotide biosynthesis are highly enriched. Finally, the influences of TBPs on their hosts are experimentally examined by using the marine bacterium Shewanella psychrophila WP2 and its infecting transposable phage SP2. Collectively, our findings greatly expand the genetic diversity of TBPs, and comprehensively reveal their potential influences in various ecosystems.

Effect of tumor-stromal fibroblasts on the biological behavior of salivary gland pleomorphic adenoma cells in vitro.

OBJECTIVES: This study aims to investigate the effects of tumor-stromal fibroblasts (TSFs) on the proliferation, invasion, and migration of salivary gland pleomorphic adenoma (SPA) cells in vitro. METHODS: Salivary gland pleomorphic adenoma cells (SPACs), TSFs, and peri-tumorous normal fibroblasts (NFs) were obtained by tissue primary culture and identified by immunocytochemical staining. The conditioned medium was obtained from TSF and NF in logarithmic phase. SPACs were cultured by conditioned medium and treated by TSF (group TSF-SPAC) and NF (group NF-SPAC). SPACs were used as the control group. The proliferation, invasion, and migration of the three groups of cells were detected by MTT, transwell, and scratch assays, respectively. The expression of vascular endothelial growth factor (VEGF) in the three groups was tested by enzyme linked immunosorbent assay (ELISA). RESULTS: Immunocytochemical staining showed positive vimentin expression in NF and TSF. Results also indicated the weak positive expression of α-smooth muscle actin (SMA) and fibroblast activation protein (FAP) in TSFs and the negative expression of α-SMA and FAP in NFs. MTT assay showed that cell proliferation in the TSF-SPAC group was significantly different from that in the NF-SPAC and SPAC groups (P<0.05). Cell proliferation was not different between the NF-SPAC and SPAC groups (P>0.05). Transwell and scratch assays showed no difference in cell invasion and migration among the groups (P>0.05). ELISA showed that no significant difference in VEGF expression among the three groups (P>0.05). CONCLUSIONS: TSFs may be involved in SPA biological behavior by promoting the proliferation of SPACs but has no effect on the invasion and migration of SPACs in vitro. Hence, TSF may be a new therapeutic target in SPA treatment.

Comprehensive analysis of the WRKY gene family in Cucumis metuliferus and their expression profile in response to an early stage of root knot nematode infection.

Root-knot nematode (RKN) is a major factor that limits the growth and productivity of important Cucumis crops, such as cucumber and melon, which lack RKN-resistance genes in their genome. Cucumis metuliferus is a wild Cucumis species that displays a high degree of RKN-resistance. WRKY transcription factors were involved in plant response to biotic stresses. However, little is known on the function of WRKY genes in response to RKN infection in Cucumis crops. In this study, Cucumis metuliferus 60 WRKY genes (CmWRKY) were identified in the C. metuliferus genome, and their conserved domains were classified into three main groups based on multiple sequence alignment and phylogenetic analysis. Synteny analysis indicated that the WRKY genes were highly conserved in Cucumis crops. Transcriptome data from of C. metuliferus roots inoculated with RKN revealed that 16 CmWRKY genes showed differential expression, of which 13 genes were upregulated and three genes were downregulated, indicating that these CmWRKY genes are important to C. metuliferus response to RKN infection. Two differentially expression CmWRKY genes (CmWRKY10 and CmWRKY28) were selected for further functional analysis. Both CmWRKY genes were localized in nucleus, indicating they may play roles in transcriptional regulation. This study provides a foundation for further research on the function of CmWRKY genes in RKN stress resistance and elucidation of the regulatory mechanism.

The Genome of Fusarium oxysporum f. sp. phaseoli Provides Insight into the Evolution of Genomes and Effectors of Fusarium oxysporum Species.

Fusarium oxysporum f. sp. phaseoli, the causal agent of cowpea fusarium wilt, is a serious threat to cowpea production in China. In this study, a sample of cowpea fusarium wilt was identified as Fusarium oxysporum f. sp. phaseoli using the methods of morphological characters and molecular detection. We further reported the first genome assembly for Fusarium oxysporum f. sp. phaseoli, with 53.7 Mb genome sequence comprising 14,694 genes. Comparative genomic analysis among five Fusarium oxysporum genomes showed that four accessory chromosomes in the five Fusarium oxysporum display similar characteristics, with low sequence similarity (55.35%, vs. overall average of 81.76%), low gene density (2.18 genes/10 kb vs. 3.02 genes/Mb) and highly transposable element density (TEs) (15.01/100 kb vs. 4.89/100 kb), indicating that variable accessory chromosomes are the main source of Fusarium oxysporum evolution. We identified a total of 100 Fusarium oxysporum f. sp. phaseoli-specific effectors in the genome and found 13 specific effector genes located in large insertion or deletion regions, suggesting that insertion or deletion events can cause the emergence of species-specific effectors in Fusarium oxysporum. Our genome assembly of Fusarium oxysporum f. sp. phaseoli provides a valuable resource for the study of cowpea fusarium wilt, and the comparative genomic study of Fusarium oxysporum could contribute to the knowledge of genome and effector-associated pathogenicity evolution in Fusarium oxysporum study.

Bilirubin inhibits the anticancer activity of sorafenib by blocking MCL-1 degradation in hepatocellular carcinoma cells.

OBJECTIVE: Sorafenib is a first-line drug for advanced hepatocellular carcinoma (HCC). Unfortunately, most patients with HCC do not respond to sorafenib, mainly because of the frequent development of drug resistance. Bilirubin is an end metabolite of heme catabolism and an indicator of liver function, but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear. In the current study, we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC. METHODS: A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC. Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin, and cell proliferation, apoptosis, and signaling pathways were assayed. The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts. RESULTS: Serum levels of bilirubin (including total, direct, and indirect bilirubin) negatively correlated with the overall survival of patients with HCC treated with sorafenib (P < 0.05). Both in vitro and in vivo analyses demonstrated that bilirubin significantly abrogated sorafenib-mediated proliferation inhibition and apoptosis induction in HCC cells (P < 0.05). Mechanically, bilirubin inhibited sorafenib-induced activation of GSK-3ß and subsequent downstream MCL-1 degradation. CONCLUSIONS: Our study provides experimental evidence of the antagonistic effect of bilirubin toward sorafenib-mediated anticancer activity in HCC, and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatmen.

Resveratrol improves ovarian function in aged rat by inhibiting oxidative stress and activating the Sirt1.

Oxidative stress is a leading driver of ovarian aging. Silent mating-type information regulation 2 homolog-1 (Sirt1) plays an role in ovarian function. Resveratrol has numerous effects, including anti-oxidant and Sirt1 activator. The aim of the study was to investigate the effect of resveratrol on aging-induced ovarian change in rats. The female Sprague Dawley rats were randomly divided into three groups: young control (Con), Aged+Res (20 mg/kg/day resveratrol for 45 days), and Aged. Anti-Müllerian hormone (AMH) was detected by ELISA assay. Malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were detected by conventional method. The ovarian structure and follicles were observed by hematoxylin staining, the caspase-3 and Sirt1 were detected by immunohistochemistry and Western blotting. The AMH in the Aged+Res group was elevated, compared to that in Aged group (p < 0.05). The MDA was decreased and GSH-Px and SOD were increased in the Aged+Res group (p < 0.05). The primordial and primary follicles were increased in the Aged+Res group (p < 0.05). The Sirt1 was increased and caspase-3 was decreased in the Aged+Res group (p < 0.05). These results indicate that resveratrol can delay ovarian aging, probably by reducing oxidative damage and increasing Sirt1.

Induction of Heme Oxygenase-1 Modifies the Systemic Immunity and Reduces Atherosclerotic Lesion Development in ApoE Deficient Mice.

Heme oxygenase-1 (HO-1) has been reported to protect against oxidation and inflammation in atherosclerosis. It remains unclear how the immune system participates in the cytoprotective function of HO-1 in the context of atherosclerosis. In this study, we attempted to investigate the potential effect of a HO-1 inducer, hemin, and a HO-1 inhibitor, Tin-protoporphyrin IX (SnPP), on the progression of atherosclerosis in ApoE deficient mice. Using mass cytometry, 15 immune cell populations and 29 T cell sub-clusters in spleen and peripheral blood were thoroughly analyzed after hemin or SnPP treatment. SnPP elevated risk factors of atherosclerosis, whereas hemin reduced them. In-depth analysis showed that hemin significantly modified the immune system in both spleen and peripheral blood. Hemin increased dendritic (DC) and myeloid-derived suppressor cells (MDSCs), but decreased natural killer (NK) cells. An opposite effect was observed with SnPP treatment in terms of NK cells. NK cells and MDSCs were positively and negatively correlated with total cholesterol and low-density lipoprotein, respectively. Moreover, the T cell profiles were significantly reshaped by hemin, whereas only minor changes were observed with SnPP. Several hemin-modulated T cell clusters associated with atherosclerosis were also identified. In summary, we have unraveled an important regulatory role for HO-1 pathway in immune cell regulation and atherosclerosis. Our finding suggests that modulating HO-1 signaling represents a potential therapeutic strategy against atherosclerosis.

Hypermethylation of the GRHL2 promoter region is associated with ovarian endometriosis.

Abnormal gene expression caused by epigenetic changes, including DNA methylation, is associated with the development and progression of endometriosis. Grainyhead-like 2 gene (GRHL2), a suppressor of epithelial-mesenchymal transition, has been suggested to be associated with the occurrence, progression and poor survival of a variety of cancers. Although endometriosis is a benign disease, it has the biological behaviour of migration and invasion as malignant tumor. This study aims to determine whether the abnormal expression of the GRHL2 caused by aberrant methylation of its promoter is associated with the pathogenesis of ovarian endometriosis. Our results demonstrated that GRHL2 promoter region was significantly hypermethylated in the ectopic endometrium of patients with ovarian endometriosis compared with the normal endometrium of control patients. In contrast, the levels of GRHL2 mRNA and protein were significantly lower in the ectopic endometrium than in the control endometrium. Correlation analysis showed the methylation levels of GRHL2 were significantly negatively correlated with the mRNA expression of GRHL2. Moreover, the in vitro results suggested that the knockdown of GRHL2 could significantly increase the invasion and migration ability of EECs and may promote ZEB1 and vimentin expression while decreasing the expression of E-cadherin in EECs. Taken together, these results suggest that the low expression of GRHL2 caused by hypermethylation of the GRHL2 promoter is associated with ovarian endometriosis. The knockdown of GRHL2 may be involved in the occurrence of endometriosis by increasing EEC migration and invasion. This study provides more evidence for the hypothesis that endometriosis may be an epigenetic regulatory disorder.

Bilirubin ameliorates murine atherosclerosis through inhibiting cholesterol synthesis and reshaping the immune system.

Atherosclerosis is a chronic inflammatory disease caused mainly by lipid accumulation and excessive inflammatory immune response. Although the lipid-lowering and cardioprotective properties of bilirubin, as well as the negative relationship between bilirubin and atherosclerosis, were well documented, it is not yet clear whether bilirubin can attenuate atherosclerosis in vivo. In this study, we investigated the role of bilirubin in improving atherosclerosis. We found that mildly elevated bilirubin significantly reduced the risk factors of atherosclerosis, such as plasma glucose, total cholesterol, and low-density lipoprotein cholesterol, and the formation of atherosclerotic plaques, liver total cholesterol, and cholesterol ester concentration in apolipoprotein E-deficient (ApoE-/-) mice fed a western-type (high fat) diet. It was further found that bilirubin could promote the degradation of 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), a rate-limiting enzyme for endogenous cholesterol synthesis. Using mass cytometry-based high dimensional single cell analysis, we observed a decrease of natural killer cells and an increase of dendritic cells and myeloid-derived suppressor cells, which all are closely associated with atherosclerosis risk factors and contribute to the improvement of atherosclerosis, in ApoE-/- mice treated with bilirubin. By in-depth analysis, modulation of multiple spleen or peripheral blood T cell clusters exhibiting either positive or negative correlations with total cholesterol or low-density lipoprotein cholesterol was detected after bilirubin treatment. In this study, we demonstrate that bilirubin serves as a negative regulator of atherosclerosis and reduces atherosclerosis by inhibiting cholesterol synthesis and modulating the immune system.

Pharmacological characterization of a novel metal-based proteasome inhibitor Na-AuPT for cancer treatment.

The ubiquitin-proteasome system (UPS) is essential for maintaining cell homeostasis by orchestrating the protein degradation, but is impaired in various diseases, including cancers. Several proteasome inhibitors, such as bortezomib, are currently used in cancer treatment, but associated toxicity limits their widespread application. Recently metal complex-based drugs have attracted great attention in tumor therapy; however, their application is hindered by low water-solubility and poor absorbency. Herein, we synthesized a new type of gold (I) complex named Na-AuPT, and further characterized its anticancer activity. Na-AuPT is highly water-soluble (6 mg/mL), and it was able to potently inhibit growth of a panel of 11 cancer cell lines (A549, SMMC7721, H460, HepG2, BEL7402, LNCap, PC3, MGC-803, SGC-7901, U266, and K562). In A549 and SMMC7721 cells, Na-AuPT (in a range of 2.5-20 µM) inhibited the UPS function in a dose-dependent fashion by targeting and inhibiting both 20 S proteasomal proteolytic peptidases and 19 S proteasomal deubiquitinases. Furthermore, Na-AuPT induced caspase-dependent apoptosis in A549 and SMMC7721 cells, which was prevented by the metal chelator EDTA. Administration of Na-AuPT (40 mg · kg-1 · d-1, ip) in nude mice bearing A549 or SMMC7721 xenografts significantly inhibited the tumor growth in vivo, accompanied by increased levels of total ubiquitinated proteins, cleaved caspase 3 and Bax protein in tumor tissue. Moreover, Na-AuPT induced cell death of primary mononuclear cells from 5 patients with acute myeloid leukemia ex vivo with an average IC50 value of 2.46 µM. We conclude that Na-AuPT is a novel metal-based proteasome inhibitor that may hold great potential for cancer therapy.

The origin and impeded dissemination of the DNA phosphorothioation system in prokaryotes.

Phosphorothioate (PT) modification by the dnd gene cluster is the first identified DNA backbone modification and constitute an epigenetic system with multiple functions, including antioxidant ability, restriction modification, and virus resistance. Despite these advantages for hosting dnd systems, they are surprisingly distributed sporadically among contemporary prokaryotic genomes. To address this ecological paradox, we systematically investigate the occurrence and phylogeny of dnd systems, and they are suggested to have originated in ancient Cyanobacteria after the Great Oxygenation Event. Interestingly, the occurrence of dnd systems and prophages is significantly negatively correlated. Further, we experimentally confirm that PT modification activates the filamentous phage SW1 by altering the binding affinity of repressor and the transcription level of its encoding gene. Competition assays, concurrent epigenomic and transcriptomic sequencing subsequently show that PT modification affects the expression of a variety of metabolic genes, which reduces the competitive fitness of the marine bacterium Shewanella piezotolerans WP3. Our findings strongly suggest that a series of negative effects on microorganisms caused by dnd systems limit horizontal gene transfer, thus leading to their sporadic distribution. Overall, our study reveals putative evolutionary scenario of the dnd system and provides novel insights into the physiological and ecological influences of PT modification.

Diversity and distribution of viruses inhabiting the deepest ocean on Earth.

As the most abundant biological entities on the planet, viruses significantly influence the overall functioning of marine ecosystems. The abundance, distribution, and biodiversity of viral communities in the upper ocean have been relatively well studied, but our understanding of viruses in the hadal biosphere remains poor. Here, we established the oceanic trench viral genome dataset (OTVGD) by analysing 19 microbial metagenomes derived from seawater and sediment samples of the Mariana, Yap, and Kermadec Trenches. The trench viral communities harbored remarkably high novelty, and they were predicted to infect ecologically important microbial clades, including Thaumarchaeota and Oleibacter. Significant inter-trench and intra-trench exchange of viral communities was proposed. Moreover, viral communities in different habitats (seawater/sediment and depth-stratified ocean zones) exhibited distinct niche-dependent distribution patterns and genomic properties. Notably, microbes and viruses in the hadopelagic seawater seemed to preferably adopt lysogenic lifestyles compared to those in the upper ocean. Furthermore, niche-specific auxiliary metabolic genes were identified in the hadal viral genomes, and a novel viral D-amino acid oxidase was functionally and phylogenetically characterized, suggesting the contribution of these genes in the utilization of refractory organic matter. Together, these findings highlight the genomic novelty, dynamic movement, and environment-driven diversification of viral communities in oceanic trenches, and suggest that viruses may influence the hadal ecosystem by reprogramming the metabolism of their hosts and modulating the community of keystone microbes.