Search

Dramatic nuclear reorganization occurs during early development to convert terminally differentiated gametes to a totipotent zygote, which then gives rise to an embryo. Aberrant epigenome resetting severely impairs embryo development and even leads to lethality. How the epigenomes are inherited, reprogrammed, and reestablished in this critical developmental period has gradually been unveiled through the rapid development of technologies including ultrasensitive chromatin analysis methods. In this review, we summarize the latest findings on epigenetic reprogramming in gametogenesis and embryogenesis, and how it contributes to gamete maturation and parental-to-zygotic transition. Finally, we highlight the key questions that remain to be answered to fully understand chromatin regulation and nuclear reprogramming in early development.

AZD3759 is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) on the basis of gefitinib and has been proven to enter the central nervous system. Although the promising antitumor effects of AZD3759 on non-small cell lung cancer (NSCLC) have been demonstrated in clinical trials, the regulatory effects of this inhibitor on the antitumor efficacy of radiation (RA) are unclear. The present study aimed to compare the effects of AZD3759 and osimertinib on RA efficacy in NSCLC and explore the potential mechanism of action of AZD3759. We found that the survival in RA-treated NSCLC cells was significantly decreased by treatment with 500 nM AZD3759 and osimertinib at the RA dosage of 8 Gy. The apoptotic rate, cell cycle arrest, and DNA damage in RA-treated NSCLC cells and brain metastasis in RA-treated xenograft nude mice were significantly enhanced by the co-administration of AZD3759 and osimertinib, respectively. In addition, AZD3759 showed a significantly stronger efficacy than osimertinib did. Mechanistically, the receptor tyrosine kinase signaling antibody array revealed that Janus kinase-1 (JAK1) was specifically inhibited by AZD3759, but not by osimertinib. The effects of AZD3759 on RA efficacy in PC-9 cells and in a brain metastasis animal model were significantly abolished by the overexpression of JAK1. Collectively, our results suggested that AZD3759 promoted RA antitumor effects in NSCLC by synergistic blockade of EGFR and JAK1.

Bone infection has always been the focus of orthopedic research. Mesenchymal stem cells (MSCs) are the natural progenitors of osteoblasts, and the process of osteogenesis is triggered in response to different signals from the extracellular matrix. MSCs exert important functions including secretion and immune regulation and also play a key role in bone regeneration. The biological behavior of MSCs in acute and chronic inflammation, especially the transformation between acute inflammation and chronic inflammation, has aroused great interest among researchers. This paper reviews the recent literature and summarizes the behavior and biological characteristics of MSCs in acute and chronic inflammation to stimulate further research on MSCs and treatment of bone diseases.

Objective To investigate the potential effect of Lysimachia capillipes capilliposide (LCC) on the chemo sensitivity and the stemness of human ovarian cancer cells. Methods Cell Counting Kit-8 (CCK8) was used to measure the IC50 values. The apoptosis of cells was measured through flow cytometry. Evaluation of the stemness and differentiation markers was performed by the immunoblotting and the immunostaining assays. RNA-seq was performed through the Illumina HiSeq PE150 platform and differentially expressed genes (DEGs) were screened out through the bioinformation analysis. Overexpression or knockdown of Fos gene was achieved by shRNA transfection. Results Pre-exposure of A2780T cells with 10 μg/mL LCC sensitized them to paclitaxel, of which the IC50 value reduced from 8.644 μmol/L (95%CI: 7.315–10.082 μmol/L) to 2.5 μmol/L (95%CI: 2.233–2.7882 μmol/L). Exposure with LCC enhanced the paclitaxel-induced apoptosis and inhibited the colony formation of A2780T cells. LCC exposure reduced the expression of cancer stemness markers, ALDH1, Myd88 and CD44, while promoting that of terminal differentiation markers, NFATc1, Cathepsin K and MMP9. RNA-seq analysis revealed that the expressions of FOS and JUN were upregulated in LCC-treated A2780T cells. A2780T cells overexpressing Fos gene displayed increased paclitaxel-sensitivity and reduced cell stemness, and shared common phenotypes with LCC-treated A2780T cells. Conclusion These findings suggested that LCC promoted terminal differentiations of ovarian cancer cells and sensitized them to paclitaxel through activating the Fos/Jun pathway. LCC might become a novel therapy that targets at cancer stem cells and enhances the chemotherapeutic effect of ovarian cancer treatments.

Our findings revealed that the activity of Family_XIII_AD3011_group and Corynebacterium is strongly correlated with the beneficial regulation of physiological hormones and metabolic changes during pregnancy and lactation. These findings are key for guiding targeted microbial therapeutic approaches to modulate microbiomes in gestating and lactating mammals.

Spermatogonia are accountable for spermatogenesis and male fertility, but the underlying mechanisms involved in spermatogonia maintenance are not clear. B lymphoma Mo-MLV insertion region 1 (BMI1) is a key component of epigenetic silencers. BMI1 is essential for stem-cell maintenance. Here, we attempted to uncover the role of BMI1 in spermatogonia maintenance using a mouse spermatogonia cell line (GC-1) and Bmi1-knockout (KO) mouse model. We showed that BMI1 promoted the proliferation and inhibited apoptosis of GC-1 cells. Mechanistically, we present in vitro and in vivo evidence to show that BMI1 binds to the promoter region of the Protein tyrosine phosphatase receptor type M (PTPRM) gene, thereby driving chromatin remodeling and gene silencing. Knockdown of Ptprm expression significantly improved spermatogonia proliferation in BMI1-deficient GC-1 cells. Collectively, our data show, for the first time, an epigenetic mechanism involving in BMI1-mediated gene silencing in spermatogonia maintenance, and provide potential targets for the treatment of male infertility.

Aim: To explore the role and mechanism of long noncoding RNA AC245100.4 and NR4A3 in prostate cancer (PCa). Methods: RNA-sequencing analysis was used to detect the downstream genes of AC245100.4. A series of gain- and loss-of-function approaches were used to investigate the roles of AC245100.4 and NR4A3. RNA immunoprecipitation was performed to examine the interaction between AC245100.4 and STAT3. Results: AC245100.4 was significantly upregulated in PCa cells and tissues. Knockdown of AC21500.4 significantly inhibited the tumorigenesis of PCa cells. Mechanistically, AC245100.4 deregulated the transcription of NR4A3 via increasing p-STAT3, which acted as a transcriptional repressor of NR4A3. Conclusion: Knockdown of long noncoding RNA AC245100.4 inhibits the tumorigenesis of PCa cells via the STAT3/ NR4A3 axis.

In this study, effects of bioelectrochemical technique on methane emission and energy recovery, and related mechanism underlying microbial competition were investigated. The results showed that running MFC was beneficial in reducing CH4 emissions and promoting COD removal rates, regardless of whether the plant roots were located at the anode or the cathode. CH4 emission was significantly higher in open-circuit reactors (6.2 mg m-2 h-1) than in closed-circuit reactors (3.1 mg m-2 h-1). Plant roots at the cathode had the highest electricity generation and the lowest CH4 emissions. The highest power generation (0.49 V, 0.33 w m-3) and the lowest CH4 emissions (2.3 mg m-2 h-1) were observed in the reactors where Typha orientalis was planted with plant roots at the cathode. The role of plants in strengthening electron acceptor was greater than that of plant rhizodeposits in strengthening electron donors. Real-time quantitative PCR (q-PCR) and correlation analysis indicated that the mcrA genes and CH4 emissions were positively correlated (r = 0.98, p < 0.01), while no significant relationship between CH4 emissions and pmoA genes was observed. Illumina sequencing revealed that more abundant exoelectrogens and denitrifying bacteria were observed when plant roots were located in cathodes. Strictly acetotrophic archae (Methanosaetaceae) were likely the main electron donor competitors with exoelectrogens. The results showed that the location of both plant species and plant roots at the electrode played an important role in CH4 control and electricity generation. Therefore, it is necessary to strengthen plant configuration to reduce CH4 emissions, to promote sustainable development of wastewater treatment.

Background The increasing use of colistin causes a serious breach in our last line of defence against MDR Gram-negative pathogens. Our previous study showed that CpxR overexpression increases the susceptibility of acrB and cpxR double-deleted Salmonella enterica serovar Typhimurium to colistin. Objectives To identify the mechanism of CpxAR and efflux pumps that synergistically enhance the susceptibility of S. Typhimurium to colistin. Methods A series of cpxR- and tolC-deleted mutants and a cpxR-complemented strain from a multidrug-susceptible standard strain of S. Typhimurium (JS) were generated in our previous study. Herein, we investigated the susceptibility of these strains to colistin through the broth microdilution method, time–kill curves and survival assays. Growth curves were measured by OD600 in LB broth, tryptone-soy broth (TSB) and M9-glucose (0.2%) minimal media. Finally, molecular mechanisms underlying the mode of action were elucidated by transcriptomic analysis. Results We found that in contrast to JS (0.8 mg/L), the MIC of colistin for JSΔtolC::kan showed a 16-fold decrease (0.05 mg/L). Notably, JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR were associated with a 256-fold decrease (0.0031 mg/L) compared with JS. Growth curves identified that JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR displayed a markedly lower growth rate and poorer adaptability. In addition, time–kill curves and survival assays showed that JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR were more susceptible to colistin. Lastly, double deletion of cpxR and tolC enhanced oxidative damage through promoting oxidative phosphorylation, the tricarboxylic acid (TCA) cycle and trimethylamine N-oxide (TMAO) respiration. Conclusions Our findings revealed that double deletion of cpxR and tolC significantly increases the susceptibility of S. Typhimurium to colistin.

Background Foodborne illness caused by Vibrio parahaemolyticus (V. parahaemolyticus) is generally associated with the consumption of seafood. Fish and other seafood can be contaminated with V. parahaemolyticus, natural inhabitants of the marine, estuarine, and freshwater environment. In this study, the antibacterial activities of benzyl isothiocyanate (BITC) against V. parahaemolyticus were investigated by both transcriptomic analysis and morphological verification. Results Treatment with 1/8 minimum inhibitory concentration (1/8 MIC) BITC resulted in 234 upregulated genes and 273 downregulated genes. The results validated by quantitative real-time polymerase chain reaction (qRT-PCR) revealed that the relative expression levels of the six genes VP0820, VP0548, VP2233, VPA2362, fliA and fliG were only 31.0%, 31.1%, 55.8%, 57.0%, 75.3%, and 79.9% of the control group, respectively. Among them, genes VP2233, fliA and fliG are related to flagella and VP2362 can regulate a protein relevant to biofilm formation. Morphologically, we verified that the swimming diffusion diameter of V. parahaemolyticus was significantly reduced by 14.9% by bacterial swimming ability, and biofilm formation was significantly inhibited by treatment with 1/8 MIC BITC by crystal violet quantification assay. Conclusions These results indicated that 1/8 MIC BITC had antibacterial effect on V. parahaemolyticus by inhibiting virulence gene expression related to flagella and biofilm.

Gasterophilus spp. have been found to be widespread in reintroduced Przewalski's horses in the Kalamaili Nature Reserve (Northwest China). However, data on the annual variation in Gasterophilus infections are lacking. To analyze the epidemiological features and determine the cause of the annual variation in Gasterophilus infections, we treated 110 Przewalski's horses with ivermectin and collected Gasterophilus larvae from fecal samples each winter from 2007 to 2019. All 110 Przewalski's horses studied were found to be infected by Gasterophilus spp., and a total of 141 379 larvae were collected. Six species of Gasterophilus were identified with the following prevalence: G. pecorum (100%), G. nasalis (96.36%), G. nigricornis (94.55%), G. haemorrhoidalis (56.36%), G. intestinalis (59.09%), and G. inermis (3.64%). The mean infection intensity of Gasterophilus spp. larvae in Przewalski's horses was 1285 ± 653. G. pecorum (92.96% ± 6.71%) was the most abundant species. The intensity of Gasterophilus spp. (r = -0.561, P < 0.046) was significantly correlated with winter precipitation. Our findings confirmed that, in the Kalamaili Nature Reserve, gasterophilosis is a severe parasitic disease in Przewalski's horses. Winter precipitation at the beginning of the year can indirectly affect the intensity and composition of Gasterophilus spp. in Przewalski's horses at the end of the year. Therefore, the water-related ecological regulation should be carried out to help reduce the parasite infection of Przewalski's horses.

Soybean is an important crop worldwide, but its production is severely affected by salt stress. Understanding the regulatory mechanism of salt response is crucial for improving the salt tolerance of soybean. Here, we reveal a role for nuclear factor Y subunit GmNFYA in salt tolerance of soybean likely through the regulation of histone acetylation. GmNFYA is induced by salt stress. Overexpression of GmNFYA significantly enhances salt tolerance in stable transgenic soybean plants by inducing salt‐responsive genes. Analysis in soybean plants with transgenic hairy roots also supports the conclusion. GmNFYA interacts with GmFVE, which functions with putative histone deacetylase GmHDA13 in a complex for transcriptional repression possibly by reducing H3K9 acetylation at target loci. Under salt stress, GmNFYA likely accumulates and competes with GmHDA13 for interaction with GmFVE, leading to the derepression and maintenance of histone acetylation for activation of salt‐responsive genes and finally conferring salt tolerance in soybean plants. In addition, a haplotype I GmNFYA promoter is identified with the highest self‐activated promoter activity and may be selected during future breeding for salt‐tolerant cultivars. Our study uncovers the epigenetic regulatory mechanism of GmNFYA in salt‐stress response, and all the factors/elements identified may be potential targets for genetic manipulation of salt tolerance in soybean and other crops.

N6-Methyladenosine (m6A) is the most prevalent epigenetic RNA modification and is vital in regulating malignancies. The roles of m6A modifiers on noncoding RNAs have not been fully investigated in esophageal cancer. By screening all m6A modifiers, ALKBH5 was the most potent member related to patient outcomes and suppressing esophageal cancer malignancy in cell and animal models. It demethylated pri-miR-194-2 and inhibited miR-194-2 biogenesis through an m6A/DGCR8-dependent manner. RAI1, previously considered as a circadian clock transcriptional regulator, was the main target of miR-194-2. It enhanced transcription of Hippo pathway upstream genes by binding to their 3'UTR and suppressed YAP/TAZ nuclear translocation. The ALKBH5/miR-194-2/RAI1 axis was also validated in clinical samples. In addition, the increased malignancy by low ALKBH5 was abolished by the YAP inhibitor verteporfin. Our findings uncover a critical role of ALKBH5 in miRNAs biogenesis and provide novel insight for developing treatment strategies in esophageal cancer.

Y-chromosomal short tandem repeats (Y-STRs) are widely applied to evolutionary, genealogical, and kinship analyses of male linages in forensic studies, but these low to midrange mutated Y-STRs typically fail to separate related males from the same paternal lineage. Recently, rapidly mutating Y-STRs (RM Y-STRs) have been demonstrated to improve the differentiation of male relatives and individuals. The Microreader™ RM-Y ID System is a new RM Y-STR kit that is capable of simultaneously amplifying 17 RM Y-STRs. Herein, to verify the efficiency and accuracy of the Microreader™ RM-Y ID System, developmental validation was conducted, including PCR-based studies, sensitivity, stability, species specificity, mixture, stutter percentage, and precision studies. Full profiles could be obtained when the hematin concentration was 250 μM, humic acid concentration was 1500 ng/μl, and tannic acid concentration was 200 ng/μl. Full profiles of the mixture of males/males could be detected up to a ratio of 19:1, and full profiles of females/males could always be detected even at ratios up to 24,000:1. Moreover, the forensic characteristics of 250 DNA-confirmed father-son pairs were analysed. The results showed that these 17 RM Y-STRs had high power for forensic discrimination (HD = 1) in the Chinese Han population, and the mutation rates were in the range of 4 × 10−3 (95% CI 1.00 × 10−4 to 2.21 × 10−2, DYS464) to 8.8 × 10−2 (95% CI 5.60 × 10−2 to 1.30 × 10−1, DYF399S1), indicating that the kit was effective for RM Y-STR studies and absolute individualisation of interrelated male individuals.

Aims Using high-protein caragana as an unconventional feed supplement has promising application potential in livestock feeding programs and verifying its function is of great importance to guide efficient dietary management of livestock. Methods and results This study investigated the resulting changes in the growth, slaughter performance, serum physiological index, physical and chemical characteristics of meat, ruminal and intestine morphology, and gastrointestinal tract microbiota in sheep fed with caragana (CAR), corn straw (COR), and alfalfa (ALF) diets. The CAR group showed an increased abundance of Christensenellaceae R-7 group, Marvinbryantia, Ruminococcaceae NK4A214, Lachnospiraceae UCG-002, and Desulfuromonas in the rumen compared with ALF, and CAR group mainly enhanced starch and sucrose metabolism, fructose and mannose metabolism, photosynthesis, D-alanine metabolism in the rumen compared with ALF. Conclusions CAR diet positively changed the fatty acid profile of longissimus dorsi muscle and significantly altered the composition and function of the microbiota in the rumen, ileum, and cecum. Significance and impact of the study This study systematically demonstrated the feasibility of CAR as an alternative to ALF for animal fattening in a complete formula granulated feed, and provided a fundamental basis for further research and development of CAR as an unconventional feed source for ruminants.

Anthocyanin plays an important role in wine color and quality. The anthocyanin concentration in grapes depends on the variety and is influenced by environmental factors, such as temperature, sunlight, soil, and grapevine practice. In this study, the anthocyanin profiles of two varieties, namely Cabernet Sauvignon and Merlot, from five regions (11 plots) in Xinjiang were examined. The climatic parameters performed noticeable difference between northern and southern of Xinjiang region. Result showed that northern of Xinjiang possessed the relatively lower humidity and higher average temperature in comparison with southern area. In addition, the total anthocyanin profiles of Cabernet sauvignon, which in Changji, Wushitala, Heshuo respectively, were higher than of other plots. This result might be caused by which those have relatively higher altitude than in other plots. For merlot, the higher anthocyanin concentrations performed in southern of Xinjiang, which could be contributed to the lower average temperature and higher relative humidity. Comparing Cabernet sauvignon and Merlot, the latter was easily affected by environment factors, and the anthocyanin composition and concentration of Merlot showed significant differences in different regions.

Soybean (Glycine max) is one of the most important oilseed crops. However, the regulatory mechanism that governs the process of oil accumulation in soybean remains poorly understood. In this study, GmZF392, a tandem CCCH zinc finger (TZF) protein which was identified in our previous RNA-seq analysis of seed-preferred transcription factors, was found to function as a positive regulator of lipid production. GmZF392 promotes seed oil accumulation in both transgenic Arabidopsis and stable transgenic soybean plants by binding to a bipartite cis-element, containing TG- and TA-rich sequences, in promoter regions, activating the expression of genes in the lipid biosynthesis pathway. GmZF392 physically interacts with GmZF351, our previously identified transcriptional regulator of lipid biosynthesis, to synergistically promote downstream gene expression. Both GmZF392 and GmZF351 are further upregulated by GmNFYA, another transcription factor involved in lipid biosynthesis, directly (in the former case) and indirectly (in the latter case). Promoter sequence diversity analysis showed that the GmZF392 promoter may have been selected at the origin of the Glycine genus and further mildly selected during domestication from wild soybeans to cultivated soybeans. Our study reveals a regulatory module containing three transcription factors in the lipid biosynthesis pathway, and manipulation of the module may improve oil production in soybean and other oilseed crops.

Non-specific phospholipase C (NPC) is involved in plant growth, development and stress responses. To elucidate the mechanism by which NPCs mediate cellular functions, here we show that NPC4 is S-acylated at the C terminus and that acylation determines its plasma membrane (PM) association and function. The acylation of NPC4 was detected using NPC4 isolated from Arabidopsis and reconstituted in vitro. The C-terminal Cys-533 was identified as the S-acylation residue, and the mutation of Cys-533 to Ala-533 in NPC4 (NPC4C533A ) led to the loss of S-acylation and membrane association of NPC4. The knockout of NPC4 impeded the phosphate deficiency-induced decrease of the phosphosphingolipid glycosyl inositol phosphoryl ceramide (GIPC), but introducing NPC4C533A to npc4-1 failed to complement this defect, thereby supporting the hypothesis that the non-acylated NPC4C533A fails to hydrolyze GIPC during phosphate deprivation. Moreover, NPC4C533A failed to complement the primary root growth in npc4-1 under stress. In addition, NPC4 in Brassica napus was S-acylated and mutation of the S-acylating cysteine residue of BnaC01.NPC4 led to the loss of S-acylation and its membrane association. Together, our results reveal that S-acylation of NPC4 in the C terminus is conserved and required for its membrane association, phosphosphingolipid hydrolysis and function in plant stress responses.

Background: Although previous studies have found that melatonin can promote seed germination, the phytohormone regulation mechanism by which exogenous melatonin mediates salt tolerance during cotton seed germination is still largely unknown. We investigated the effect of melatonin on the germination traits and physiological parameters of GXM9 cotton seeds (Gossypium hirsutum L.) under three salt stress treatments (CK, germination of seeds pretreated with water alone; S, germination of seeds pretreated in 150 mM NaCl under salt stress; SM, germination of seeds pretreated in 20 µM melatonin under 150 mM NaCl solution) in the laboratory.Results: We found that salt stress (150 mM) inhibited cotton seed germination and endogenous melatonin accumulation, and pretreatment with 20 µM exogenous melatonin enhanced the cotton germination rate and hypocotyl length as well as the content of endogenous melatonin during seed germination. This suggests that exogenous melatonin promotes seed germination from a morphological perspective. The contents of starch, α-amylase (EC3.3.1.1), β-galactosidase (EC3.2.1.23), abscisic acid (ABA), and gibberellin (GA) were determined simultaneously. The results showed that the α-amylase and β-galactosidase contents in the cotton seeds decreased by 56.97% and 20.18%, respectively, under salt stress compared with the control, while the starch content increased by 11.53% compared with the control at day 7. The ABA content increased by 25.18% and GA content decreased by 27.99% under salt stress compared with the control at 24 h. When exogenous melatonin was applied to the cotton seeds, the content of α-amylase and β-galactosidase increased by 121.77% and 32.76%, respectively, whereas the starch contents decreased by 13.55% compared with the S treatment at day 7. Similarly, the ABA content increased by 12.20% and the GA content increased by 4.77% at 24 h. To elucidate the molecular mechanism by which melatonin promotes seed germination under salt stress, the effects of ABA- and GA-related genes on plant hormone signal transduction were analyzed by quantitative real-time PCR and RNA sequencing. The results indicated that melatonin regulated the expression of ABA and GA genes in the plant signal transduction pathway, induced embryo root development and seed germination, and alleviated dormancy. We found that the expression of the ABA signaling gene GhABF2 was up-regulated and GhDPBF2 was down-regulated, and the expression of GA signaling genes (e.g., GhGID1C and GhGID1B) was up-regulated by melatonin.Conclusions: We discovered that melatonin enhances salt tolerance in cotton seeds by regulating ABA and GA and by mediating the expression of hormone-related genes in plant hormone signal transduction. This should help us to explore the regulatory mechanisms of cotton resistance and provide a foundation for the cultivation of new varieties.

A bacterial strain ASLT-13 was successfully isolated from activated sludge and identified as Pseudomonas amygdali. Gas chromatograph-mass spectrometer (GC-MS) analysis indicated that strain ASLT-13...

Noorda blitealis (Lepidoptera: Pyraloidea: Crambidae) is a major defoliating pest of Moringa trees. Focusing on its mating and reproduction, here we sequenced and analyzed the transcriptome of its pheromone glands (PGs) with a combination of Illumina sequencing, bioinformatics and phylogenetics approaches, coupled with a genome-based analysis. Transcriptome sequencing led to the yields of approximately 162 million clean reads, which were assembled into 60,578 unigenes and 121,692 transcripts, respectively. From the transcriptome, totally 117 genes encoding eight pheromone biosynthesis enzymes and one pheromone degradation enzyme were identified, 90 of which had complete open reading frames. A comparative analysis between PGs and bodies (removing PGs) revealed a large number of differentially expressed genes, including 79 pheromone biosynthesis and degradation related genes. Of the identified genes, NbliDES12 belonging to the △11 desaturase group was likely to a strong candidate for the desaturation of sex pheromones in N. blitealis, as implied by phylogenetic analyses and expression profiles. Finally and most notably, through genome and transcriptome analyses we discovered, for the first time, a novel aldehyde oxidase 6 (AOX6) group of the superfamily Pyraloidea that have been slightly expanded by gene duplications. Moreover, each orthologous AOX group shared highly conserved gene structure. Together, this current study has characterized the genes associated with sex pheromone biosynthesis and degradation from the PG transcriptome of N. blitealis, and more importantly, identifies a novel AOX group of the Pyraloidea.

Lipoproteins in the outer membrane of Gram-negative bacteria are involved in various vital physiological activities, including multidrug resistance. Synthesized in the cytoplasm and matured in the inner membrane, lipoproteins must be transported to the outer membrane through the Lol pathway mediated by the ATP-binding cassette transporter LolCDE in the inner membrane via an unknown mechanism. Here, we report cryo-EM structures of Escherichia coli LolCDE in apo, lipoprotein-bound, LolA-bound, ADP-bound and AMP-PNP-bound states at a resolution of 3.2–3.8 A, covering the complete lipoprotein transport cycle. Mutagenesis and in vivo viability assays verify features of the structures and reveal functional residues and structural characteristics of LolCDE. The results provide insights into the mechanisms of sorting and transport of outer-membrane lipoproteins and may guide the development of novel therapies against multidrug-resistant Gram-negative bacteria. Cryo-EM structures of the E. coli ABC transporter LolCDE in different functional states reveal mechanism of lipoprotein transport to the outer membrane of Gram-negative bacteria.

Background The departure of the mature larvae of the horse stomach bot fly from the host indicates the beginning of a new infection period. Gasterophilus pecorum is the dominant bot fly species in the desert steppe of the Kalamaili Nature Reserve (KNR) of northwest China as a result of its particular biological characteristics. The population dynamics of G. pecorum were studied to elucidate the population development of this species in the arid desert steppe. Methods Larvae in the freshly excreted feces of tracked Przewalski’s horses (Equus przewalskii) were collected and recorded. The larval pupation experiments were carried out under natural conditions. Results There was a positive correlation between the survival rate and the number of larvae expelled (r = 0.630, p G. pecorum has only one generation per year, its occurrence peaked twice annually, i.e. the studied population has a bimodal distribution, which doubles parasitic pressure on the local host. This phenomenon is very rarely recorded in studies on insect life history, and especially in those on parasite epidemiology. Conclusion The period during which G. pecorum larvae are naturally expelled from the host exceeds 7 months in KNR, which indicates that there is potentially a long period during which hosts can become infected with this parasite. The phenomenon of two annual peaks of larvae expelled in feces is important as it provides one explanation for the high rate of equine myiasis in KNR. Graphical Abstract

Direct infusion (DI) has an extraordinary high-throughput advantage. Pseudo-targeted metabolomics (PTM) has been demonstrated integrating the merits of both nontargeted and targeted metabolomics. Herein, we attempted to implant DI into the PTM concept to configure a new strategy allowing shotgun PTM. First, a versatile MS/MSALL program was applied to acquire MS1 and MS2 spectra. Second, online energy-resolved MS (online ER-MS) was conducted to obtain breakdown graph as well as optimal collision energy (OCE) for each ion transition paired by precursor ion and the dominant product ion. Third, selected reaction monitoring (SRM) was responsible to output a quantitative dataset with a constant length. Moreover, breakdown graph also served as orthogonal structural evidence when matching MS2 spectra between DI-MS/MS and an in-house library to strengthen structural annotation confidence. To evaluate and illustrate the utility of the new strategy toward shotgun PTM of medicinal plants, in-depth chemome comparison was conducted within three Cistanche species, all of which are edible medicinal plants and playing essential roles for turning the deserts into the oases. A total of 185 variables participated in the quantitative measurement program. Each diagnostic ion pair was featured with an OCE. Significant species differences occurred, and echinacoside, acteoside, isoacteoside, 2'-acetyl-acteoside, tubuloside B, mannitol, sucrose, betaine, malate, as well as choline were found to be confirmative chemical markers offering primary contributions toward the species discrimination. After cross-validation with LC-MS/MS, DI-MS/MS fortified with the new strategy is an eligible tool for shotgun PTM, beyond Cistanche plants.

Irrational application of chemical fertilizers causes soil nutrient imbalance, reduced microbial diversity, soil diseases, and other soil quality problems and is one of the main sources of non-point pollution. The application of microbial inoculant (MI) can improve the soil environment and crop growth to reduce problems caused by irrational application of chemical fertilizers. Field experiments were carried out in high-phosphorus soils to study the effects of the addition of various MIs combined with chemical fertilizers on soil properties, wheat growth, and soil microbial composition and structure. The MIs consisted of one fungal agent: Trichoderma compound agent (TC) and five bacterial agents, namely soil remediation agent (SR), anti-repeat microbial agent (AM), microbial agent (MA), plant growth-promoting rhizobacteria (PG), and biological fertilizer agent (BF). The wheat yield increased by 15.2–33.4% with the addition of MIs, and PG with Bacillus subtilis as the core microorganism had the most obvious effect on increasing the production (p

The release of lysosomal hydrolase into the cytoplasm is accompanied by several systems of apoptosis signal transduction, and the imbalance between cell viability and apoptosis induces tumorigenesis. Tea polysaccharides (TPs) are the main bioactive components in green tea with hopeful anti-tumor efficacy, while their mechanism is still unclear. Here, TPs significantly promoted the death of colon cancer cell line CT26. RNA-seq results showed that the signal pathways up-regulated by TPs included lysosome pathways, apoptosis, the release of mitochondrial pigment c and programmed cell death. Among them, the results of AO-EB and annexin V-FITC/PI double staining indicated that TPs significantly up-regulated apoptosis. In addition, TPs significantly disrupted the function of lysosomes, which would cause mitochondrial damage. Intriguingly, TPs treatment increased the expression of Bak1, cleaved caspase-9 and cleaved caspase-3, but decreased the level of Bcl-2 and mitochondrial membrane potential, which indicated that TPs induced mitochondrial-mediated apoptosis. Moreover, TPs ameliorated the reduced lysosomal numbers by Baf A1 (lysosomal inhibitor). Therefore, our data indicated that TPs targeted lysosomes and induced apoptosis by a lysosomal-mitochondrial pathway mediated caspase cascade, thereby inhibiting the proliferation of CT26 cells. In short, the data would help the development of TPs as potential cancer drug therapeutics.

Glioma is an intracranial malignant tumor with high morbidity in China. Limited efficacy has been achieved in the treatment of glioma through the application of epidermal growth factor receptor (EGFR) inhibitors, which is reported to be related to the poor permeability of the brain–blood barrier (BBB) to EGFR inhibitors. AZD3759 and osimertinib are both BBB-penetrating EGFR inhibitors. The present study aimed to investigate the inhibitory effects of AZD3759 and osimertinib on glioma and compare their efficacy and the underlying mechanisms. C6 and U87 cells were incubated with different concentrations of AZD3759 (1, 2, and 4 μM) and 4 μM osimertinib, respectively. C6-LUC xenograft animals were administered different doses of AZD3759 (15, 30, and 60 mg/kg) and 60 mg/kg osimertinib. We found that proliferation was significantly suppressed and that apoptosis and cell cycle arrest were dramatically induced in both C6 and U87 cells by AZD3759 in a dose-dependent manner. Compared to AZD3759, osimertinib had inferior effects on proliferation, apoptosis, and cell cycle. In vivo experiments verified that the anti-tumor efficacy of AZD3759 against C6 xenograft tumors was dose dependent and superior to that of osimertinib. The inhibitory effects of AZD3759 on the Janus kinase (JAK)/STAT pathway were observed in both glioma cells and tumor tissues, which were more significant than those of osimertinib. In conclusion, AZD3759 may inhibit the progression of glioma via a synergistic blockade of the EGFR and JAK/STAT signaling pathways.

Motivation Tumor stratification has a wide range of biomedical and clinical applications, including diagnosis, prognosis and personalized treatment. However, cancer is always driven by the combination of mutated genes, which are highly heterogeneous across patients. Accurately subdividing the tumors into subtypes is challenging. Results We developed a network-embedding based stratification (NES) methodology to identify clinically relevant patient subtypes from large-scale patients’ somatic mutation profiles. The central hypothesis of NES is that two tumors would be classified into the same subtypes if their somatic mutated genes located in the similar network regions of the human interactome. We encoded the genes on the human protein–protein interactome with a network embedding approach and constructed the patients’ vectors by integrating the somatic mutation profiles of 7344 tumor exomes across 15 cancer types. We firstly adopted the lightGBM classification algorithm to train the patients’ vectors. The AUC value is around 0.89 in the prediction of the patient’s cancer type and around 0.78 in the prediction of the tumor stage within a specific cancer type. The high classification accuracy suggests that network embedding-based patients’ features are reliable for dividing the patients. We conclude that we can cluster patients with a specific cancer type into several subtypes by using an unsupervised clustering algorithm to learn the patients’ vectors. Among the 15 cancer types, the new patient clusters (subtypes) identified by the NES are significantly correlated with patient survival across 12 cancer types. In summary, this study offers a powerful network-based deep learning methodology for personalized cancer medicine. Availability and implementation Source code and data can be downloaded from https://github.com/ChengF-Lab/NES. Supplementary information Supplementary data are available at Bioinformatics online.

A bacterial strain that could effectively degrade DEHP was isolated from the activated sludge and identified as Bacillus sp. by DNA sequencing. The biochemical degradation pathway of DEHP was further analyzed by GC-MS, and the results showed that DEHP was first decomposed into phthalates (DBP). Diuretic sylycol (DEP) was then generated, and phthalates (PA) were generated by a continuous de-ehelateization reaction. Phthalic acid (PA) was oxidized, dehydrogenated, and decarboxylated into protocatechins. Protocatechins enter the TCA cycle through orthotopic ring opening. To enhance DEHP degradation, sodium alginate and calcium chloride were used as embedding and cross-linking materials, and the strain was immobilized. The immobilization conditions were optimized via an orthogonal experiment, and the results showed that the optimal immobilization conditions were SA mass fraction of 4%, CaCl2 mass fraction of 5%, ratio of bacteria to SA of 1:1, and the crosslinking time of 6 hours. The immobilized bacteria agent was further applied to MBR systems. The results showed that the removal rate of DEHP (5mg/L) in the system by immobilized bacteria was 91.9%, which is significantly higher than that of free bacteria. The 3, 4-dioxygenase gene and microbial community dynamics were analyzed by q-PCR and Illumina Miseq sequencing. The q-PCR results showed that the number of copies of 3, 4-dioxygenase gene in the immobilized system was significantly higher than that of free bacteria. Illumina Miseq sequencing results showed that Micromonospora, Rhodococcus, Bacteroides and Pseudomonas were the dominant generas in the MBR system. The analysis of bacterial community structure indicated that immobilization technology had a positive impact on the system stability. The results implied that this immobilized technique had potential applications in DEHP wastewater treatment.

Neoseiulus bicaudus (Wainstein) (Acari: Phytoseiidae) is a native predatory mite species in Xinjiang, China, and a biological control agent for some small pests, such as Tetranychus turkestani (Acari: Tetranychidae) and Thrips tabaci (Thysanoptera: Thripidae) in greenhouse. However, little is known whether N. bicaudus could be an effective natural enemy of Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae). A series of laboratory and greenhouse experiments were conducted to evaluate the efficiency of N. bicaudus on B. tabaci. The present data showed that each stage of N. bicaudus demonstrated type II functional response when fed on B. tabaci. The adult females showed the highest consumption rate and attack rate, and the shortest handling times were obtained when they preyed on eggs and 1st instar nymphs. The 1st instar of B. tabaci was preferred for the feeding of N. bicaudus adult females than eggs, followed by 2nd instar nymphs of B. tabaci. Under greenhouse conditions, this predator effectively suppressed the population growth of B. tabaci throughout the experimental period. Accordingly, N. bicaudus could be an efficient predator for B. tabaci.

A simple visual strategy was developed for the RNase H colorimetric measurement using DNAzyme-mediated signal amplification. When RNase H was presented, the RNA strand of the duplex formed by the G-rich DNA sequence (G-Rich) and its complementary RNA sequence (cp-RNA) was digested, releasing G-Rich to form HRP-mimicking DNAzymes of the G-quadruplex/hemin complexes in the presence of hemin. These DNAzymes catalyze the oxidation reaction of the substrate of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) to produce green-color products of ABTS

The SKU5 similar (SKS) genes encode a family of multi-copper-oxidase-like proteins with cupredoxin domains similar to those in laccase and ascorbate oxidase. Although SKS proteins are known to function in root growth and cotyledon vascular patterning in Arabidopsis, their role in plant reproductive processes is poorly understood. Here, we identified a seed mutant of maize (Zea mays), generated by ethyl methane sulfonate (EMS) mutagenesis, that we designated defective kernel-zk1 (dek-zk1). The mutant produced small, shriveled kernels with an aberrant basal endosperm transfer layer (BETL) and placento-chalazal (PC) layer and irregular starch granules. Map-based cloning revealed that Dek-zk1 encodes an SKU5 similar 13 (GenBank: ONM36900.1), so it was named ZmSKS13. ZmSKS13 comprises a paralogous pair with Zm00001d012524, but the transcript abundance of ZmSKS13 in developing kernels is 15 times higher than that of Zm00001d012524, resulting in dek-zk1 mutation conveying a distinct kernel phenotype. ZmSKS13 loss of function led to overaccumulation of reactive oxygen species (ROS) and severe DNA damage in the nucellus and BETL and PC layer cells, and exogenous antioxidants significantly alleviated the defects of the mutant kernels. Our results thus demonstrate that ZmSKS13 is a novel regulator that plays a crucial role in kernel development in maize through the modulation of ROS homeostasis.

Significance Although geneticists often emphasize diversity generated during sexual reproduction, genomic alterations that occur during vegetative growth are an important source of genetic diversity. In the current study, we have measured the rate and location of single-base mutations, large deletions/duplications, ploidy alterations, and mitotic recombination events in extensively subcultured diploid isolates of the yeast Saccharomyces cerevisiae. We were able to determine the relative frequency of these events and to predict the frequency of loss of heterozygosity of allelic markers resulting from mitotic recombination. This analysis is relevant to understanding of genomic evolution, as well as the mitotic recombination events in humans that predispose cells to form tumors., Genomic alterations including single-base mutations, deletions and duplications, translocations, mitotic recombination events, and chromosome aneuploidy generate genetic diversity. We examined the rates of all of these genetic changes in a diploid strain of Saccharomyces cerevisiae by whole-genome sequencing of many independent isolates (n = 93) subcloned about 100 times in unstressed growth conditions. The most common alterations were point mutations and small (

This study investigated the effects of blockade of IL-6 on bone loss induced by modeled microgravity (MG). Adult male mice were exposed to hind-limb suspension (HLS) and treated with IL-6-neutralizing antibody (IL-6 nAb) for 4 weeks. HLS in mice led to upregulation of IL-6 expression in both sera and femurs. IL-6 nAb treatment in HLS mice significantly alleviated bone loss, evidenced by increased bone mineral density of whole tibia, trabecular thickness and number, bone volume fraction of proximal tibiae, and ultimate load and stiffness of femoral diaphysis. IL-6 nAb treatment in HLS mice significantly enhanced levels of osteocalcin in sera and reduced levels of deoxypyridinoline. In MC3T3-E1 cells exposed to MG in vitro, IL-6 nAb treatment increased mRNA expression and activity of alkaline phosphatase, mRNA expression of osteopontin and runt-related transcription factor 2, and protein levels of osteoprotegerin and decreased protein levels of receptor activator of the NF-κB ligand. In RAW254.7 cells exposed to MG, IL-6 nAb treatment downregulated mRNA expression of cathepsin K and tartrate-resistant acid phosphatase (TRAP) and reduced numbers of TRAP-positive multinucleated osteoclasts. In conclusion, blockade of IL-6 alleviated the bone loss induced by MG.

Plant roots are sustained through meristem activity at the root tip. Two transcriptional pathways, one mediated by PLETHORAs (PLTs) and the other by SHORTROOT and SCARECROW, play major roles in root meristem development. The role of PLTs during root meristem development requires a concentration gradient, which is not only contributed by posttranslational regulation such as growth dilution and intercellular movement but also likely by a largely unknown fine-tuned transcriptional regulatory mechanism. We report here that Arabidopsis (Arabidopsis thaliana) JANUS positively regulates PLT1 expression in the root meristem by recruiting RNA polymerase II (Pol II) to PLT1 and by interacting with PLT1. JANUS-dependent recruitment of Pol II is inhibited through the competitive binding of JANUS by GRF-INTERACTING FACTOR1 (GIF1)/ANGUSTIFOLIA3, a transcriptional cofactor that negatively regulates PLT1 expression. Finally, GIF1 and JANUS, the antagonistic regulators of PLT1, both depend on Arabidopsis IMPORTIN β4 for their nuclear accumulation. The combination of an importin and its two antagonistic cargos in PLT1 transcription may have logistic benefits in fine-tuning the transcription of PLT1 in root meristem.

The quality control of Saussurea involucrata has been greatly improved by macroscopic and microscopic identification and chemical profiling described in Chinese Pharmacopoeia since 2005. However, these methods have their own limitations, e.g., their dependence on personal experience and expertise, and it is a huge challenge to identify closely related species that share similar or identical morphological characteristics and chemical profiles. A novel and generally accepted identification strategy is urgently needed as a complement to regulations for protecting the public health interests. In this work, a comprehensive chromatographic fingerprint method was developed and tested on 43 samples from four haplotypes of S. involucrata according to DNA barcoding. Three common patterns consisting of 20, 14, and 7 common peaks were generated by frequency filters of median, upper quartile, and 100%, respectively. Based on two formerly screened patterns, S. involucrata can be effectively identified from its five easily confused snow lotus species, including the most closely related plant (S. orgaadayi) in the orthogonal partial least-squares discriminant analysis (OPLS-DA) models. The model is supported by good R and Q coefficients. In addition, different haplotypes of S. involucrata can be discriminated in the OPLS-DA model using the 20 common peaks. Among them, peaks 9, 11, 16 (zaluzanin C), and 18 (dehydrocostus lactone) have been identified as fingerprint markers of S. involucrata via S-plots and VIP values (>1). Additionally, peaks 19 and 20 were identified as linolenic acid and linoleic acid with anti-inflammatory activity, and they were isolated from the herb for the first time. Collectively, the chromatographic fingerprint of S. involucrata can be an effective and integrated method for the identification of authentic herbs from adulterant species or related plants, and discrimination of its different haplotypes provides an objective and reliable tool for quality control.

The “macrotrabecular-massive” (MTM) pattern of hepatocellular carcinoma (HCC) has been suggested to represent a distinct HCC subtype and is associated with specific molecular features. Since the immune microenvironment is heterogenous in HCC, it is important to evaluate the immune microenvironment of this novel variant. CMTM6, a key regulator of PD-L1, is an important immunocheckpoint inhibitor. This study aimed to evaluate the prognostic effect of CMTM6/PD-L1 coexpression and its relationship with inflammatory cells in HCC. We analyzed 619 HCC patients and tumors were classified into MTM and non-MTM HCC subtypes. The expression levels of CMTM6 and PD-L1 in tumor and inflammatory cells were evaluated by immunohistochemistry. The density of inflammatory cells in the cancer cell nest was calculated. Tumoral PD-L1 expression and inflammatory cell density were higher in the MTM type than in the non-MTM type. CMTM6-high expression was significantly associated with shorter OS and DFS than CMTM6-low expression in the whole HCC patient population and the MTM HCC patient population. Moreover, MTM HCC patients with CMTM6/PD-L1 coexpression experienced a higher risk of HCC progression and death. In addition, CMTM6/PD-L1 coexpression was shown to be related to a high density of inflammatory cells. Notably, a new immune classification, based on CMTM6/PD-L1 coexpression and inflammatory cells, successfully stratified OS and DFS in MTM HCC. CMTM6/PD-L1 coexpression has an adverse effect on the prognosis of HCC patients, especially MTM HCC patients. Our study provides evidence for the combination of immune status assessment with anti-CMTM6 and anti-PD-L1 therapy in MTM HCC patients. Electronic supplementary material The online version of this article (10.1007/s00262-020-02691-9) contains supplementary material, which is available to authorized users.

Inactivating mutations in the liver kinase B1 (LKB1) tumor suppressor gene underlie Peutz-Jeghers syndrome (PJS) and occur frequently in various human cancers. We previously showed that LKB1 regulates centrosome duplication via PLK1. Here, we report that LKB1 further helps to maintain genomic stability through negative regulation of survivin, a member of the chromosomal passenger complex (CPC) that mediates CPC targeting to the centromere. We found that loss of LKB1 led to accumulation of misaligned and lagging chromosomes at metaphase and anaphase and increased the appearance of multi- and micro-nucleated cells. Ectopic LKB1 expression reduced these features and improved mitotic fidelity in LKB1-deficient cells. Through pharmacological and genetic manipulations, we showed that LKB1-mediated repression of survivin is independent of AMPK, but requires p53. Consistent with the key influence of LKB1 on survivin expression, immunohistochemical analysis indicated that survivin is highly expressed in intestinal polyps from a PJS patient. Lastly, we reaffirm a potential therapeutic avenue to treat LKB1-mutated tumors by demonstrating the increased sensitivity to survivin inhibitors of LKB1-deficient cells.

Aim: Mycobacterium tuberculosis in vitro biofilm is associated with the virulence and persistence capability. Our aim is to delineate factors involved in biofilms development. Materials & methods: We performed transposon mutants screen and found that mutation of MSMEG_3641, a homolog of M. tuberculosis Rv1836c, can change M. smegmatis colony morphology and biofilm. Results: MSMEG_3641 contains a vWA domain that is highly conserved among Mycobacteria. The phenotypes of MSMEG_3641 mutants include disrupted biofilm, weakened migration ability and changed colony morphology. All phenotypes might be contributed to the enhanced cell wall permeability and declined cell aggregation ability. Conclusion: To our knowledge, this is the first report concerning the mycobacteria Von Willebrand factor domain function, especially in colony morphology and biofilm development.

To study the variations in microorganisms and enzyme activity during sewage sludge composting, the dynamic changes in temperature, enzyme activity and microorganism composition were studied by co-composting municipal sludge and corn straw. The results show that the pile underwent mesophilic, thermophilic, and cooling phases and that the high-temperature duration (³ 50 °C) had reached 5 days, which meets harmlessness requirements. During the composting process, the protease, arylsulfatase (ARS) and cellulase content increased gradually; urease content first decreased and then increased rapidly; and peroxidase (POD) content first increased and then decreased. Ureibacillus, Bacillus, Pseudomonas, Flavobacterium and Sporosarcina were the dominant bacteria during sludge composting. Microorganisms played different roles at different stages of the composting. Ureibacillus and Bacillus were the dominant strains in the mesophilic and thermophilic phases, respectively, and Pseudomonas and Flavobacterium were the dominant strains in the cooling phase. Sporosarcina mainly played a role later in the thermophilic and cooling phases. The effect of different bacteria on enzyme activity varied; Pseudomonas played a clear role in promoting the production of urease while Bacillus had a clear inhibitory effect on the production of urease. Ureibacillus inhibited the production of ARS, POD, protease and cellulase. By studying the changes in microbial and enzymatic activities at different stages of sludge composting, it is possible to thoroughly explore the nature of the latter and provide a reference for optimizing composting processes.

The circadian rhythm plays a central role in immune function, and its disruption has been closely linked to the etiology of depression. However, the mechanisms underlying the association between depression and circadian rhythm remain unclear. We found that mice deficient of Per2, a central clock component of circadian output, were resilient to neuroinflammation-induced depressive behavior. After repeated central lipopolysaccharide (LPS) injections, MCP-1, MIP-1β, and RANTES increased in wild type (WT) but not in Per2-deficient mice. In addition, intracerebroventricular injection of RANTES resulted in depression-like behavior, and Met-RANTES, a CCR5 antagonist, could reverse depression-like behavior induced by LPS treatments. These results indicated that the Per2 gene contributes to depression via chemokines, especially RANTES. Furthermore, BMAL1 expression decreased in LPS-treated Per2-deficient mice and BMAL1 could bind to the promoter of Rantes, indicating clock gene can act as a regulator for neuroinflammation. In conclusion, Rantes, a clock-controlled gene (CCG), is involved in clock-immunological mechanisms underlying the effects of Per2 on neuroinflammation-induced depression-like behavior.

Yeast strains with low levels of the replicative DNA polymerases (alpha, delta, and epsilon) have high levels of chromosome deletions, duplications, and translocations. By examining the patterns of mutations induced in strains with low levels of DNA polymerase by the human protein APOBEC3B (a protein that deaminates cytosine in single-stranded DNA), we show dramatically elevated amounts of single-stranded DNA relative to a wild-type strain. During DNA replication, one strand (defined as the leading strand) is replicated processively by DNA polymerase epsilon and the other (the lagging strand) is replicated as short fragments initiated by DNA polymerase alpha and extended by DNA polymerase delta. In the low DNA polymerase alpha and delta strains, the APOBEC-induced mutations are concentrated on the lagging-strand template, whereas in the low DNA polymerase epsilon strain, mutations occur on the leading- and lagging-strand templates with similar frequencies. In addition, for most genes, the transcribed strand is mutagenized more frequently than the nontranscribed strand. Lastly, some of the APOBEC-induced clusters in strains with low levels of DNA polymerase alpha or delta are greater than 10 kb in length.

Hydroquinone (HQ), an active metabolite of benzene, plays an important role in the malignant hematopathy caused by benzene. Malignant transformation has been observed after 20 or 29 weeks of in vit...

As a substrate for function, large-scale brain structural networks are crucial for fundamental and systems-level understanding of primate brains. However, it is challenging to acquire a complete primate whole-brain structural connectome using track tracing techniques. Here, we acquired a weighted brain structural network across 91 cortical regions of a whole macaque brain hemisphere with a connectivity density of 59% by predicting missing links from the CoCoMac-based binary network with a low density of 26.3%. The prediction model combines three factors, including spatial proximity, topological similarity, and cytoarchitectural similarity—to predict missing links and assign connection weights. The model was tested on a recently obtained high connectivity density yet partial-coverage experimental weighted network connecting 91 sources to 29 target regions; the model showed a prediction sensitivity of 74.1% in the predicted network. This predicted macaque hemisphere-wide weighted network has module segregation closely matching functional domains. Interestingly, the areas that act as integrators linking the segregated modules are mainly distributed in the frontoparietal network and correspond to the regions with large wiring costs in the predicted weighted network. This predicted weighted network provides a high-density structural dataset for further exploration of relationships between structure, function, and metabolism in the primate brain.