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Akt is usually considered to be a negative regulator of both autophagy and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling. In the present study, we found that SC66, a pyridine-based allosteric Akt inhibitor, suppressed basal and H2 O2 -induced autophagy concurrent with decreased phosphorylation and activity of AMPK. SC66 treatment led to the formation of a high molecular weight (HMW) form of SQSTM1/p62 (p62), which is an autophagic substrate and is essential for selective autophagy. Moreover, we observed that SC66 inhibited the binding of p62 and microtubule-associated protein light chain 3 (LC3). The immunoprecipitation results revealed the interaction between p62 and epidermal growth factor receptor (EGFR), and knockdown of EGFR reversed SC66-mediated autophagy inhibition without affecting the phosphorylation of acetyl-CoA carboxylase (ACC), a well-known substrate of AMPK. SC66 increased the interaction between EGFR and Beclin 1 and markedly decreased the association of EGFR with VPS34, a critical protein for autophagy induction. Collectively, the data presented here indicate that EGFR-p62 pathway plays a critical role in Akt-mediated positive regulation of autophagy. This article is protected by copyright. All rights reserved.

With technological advances in high-throughput sequencing, high resolution mass-spectrometry, and multi-omics data integrative tools and data repositories, the omics research in life sciences are evolving from single-omics strategy to multi-omics strategy. The research of system biology driven by multi-omics will bring a new paradigm in life sciences. This paper briefly summarizes the development of genomics, epigenomics, transcriptomics, proteomics and metabolomics, highlights the composition and function of multi-omics platforms as well as the applications of multi-omics technology, and prospects future applications of multi-omics in synthetic biology and biomedicine.

Oxytocin (OXT), a nine amino acid peptide produced in the hypothalamus and released by the posterior pituitary, has well-known actions in parturition, lactation, and social behavior1, and has become an intriguing therapeutic target for diseases like autism and schizophrenia2. Exogenous OXT has also been shown to promote weight loss, among other beneficial metabolic effects1,3, suggesting that its therapeutic potential may extend to diabetes and obesity1,4. It is unclear, however, whether endogenous OXT participates in metabolic homeostasis. Here we show that OXT is a critical regulator of adipose tissue lipolysis in both mice and humans. In addition, OXT serves to license the ability of β- adrenergic agonists to fully promote lipolysis. Most surprisingly, the relevant source of OXT in these metabolic actions is a previously unidentified subpopulation of tyrosine hydroxylase (TH)-positive sympathetic neurons. Our data reveal that OXT from the peripheral nervous system is an endogenous regulator of adipose and systemic metabolism.

Nitrogen and phosphorus pollution caused by land use seriously threatens the surface water ecosystem. However, the relationship between surface water quality and land use remains obscure in multiple spatiotemporal scales. The spatiotemporal variation characteristics of the eutrophication degree were discussed via the in situ investigation, and the effects of land use on water quality were quantitatively studied through correlation analysis and redundancy analysis in the Honghu Lake Basin, a typical active agriculturally disturbed basin. Results show that the water quality of the entire basin has suffered from serious nitrogen (with the total nitrogen ranging from 1.90 to 11.72 mg/L in the dry season and 1.07–9.24 mg/L in the rainy season) and phosphorus (with the total phosphorus ranging from 0.07 to 1.78 mg/L in the dry season and 0.02–0.56 mg/L in the rainy season) pollution. Seasonally, the nutrient concentration in dry the season are approximately 14–46% higher than those in the rainy season, and the nutrient concentration upstream is higher in spatial distribution. Correlation analysis indicates that forest and wetland were negatively correlated with nutrient concentrations, while cultivated land and residence community were positively correlated with nutrient concentrations. Redundancy analysis shows that the spatial variation of the water quality is best explained at a small scale (1000 m buffer) and in the rainy season (55%). Our study can provide a strategy for land use planning for water quality management and protection in a typical agriculturally disturbed basin, like the Honghu Lake basin.

Two potential non-ribosomal peptide synthetases (NRPSs) were identified in the genome of a guanophilic fungus Amphichorda guana by bioinformatics analysis and gene knockout experiments. Liquid chromatography coupled with mass spectrometry (LC-MS) guided isolation led to the discovery of a new cyclodepsipeptide isaridin H (1) and seven known analogs, desmethylisaridin E (2), isaridin E (3), isariin A (4), iso-isariin B (5), iso-isariin D (6), isariin E (7), and nodupetide (8). The absolute configuration of isaridin H (1) was achieved by Marfey's method. Isaridin H (1) showed significant antifungal activity against Botrytis cinerea and Alternaria solani.

Characterization of filamentous fungal regulatory elements remains challenging because of time-consuming transformation technologies and limited quantitative methods. Here we established a method for quantitative assessment of filamentous fungal promoters based on flow cytometry detection of the superfolder green fluorescent protein at single-cell resolution. Using this quantitative method, we acquired a library of 93 native promoter elements from Aspergillus nidulans in a high-throughput format. The strengths of identified promoters covered a 37-fold range by flow cytometry. P

Hybrid mechanisms combine the advantages of serial mechanisms and parallel mechanisms and have better stiffness and a larger workspace. In this paper, a novel workspace strongly coupled machining robot mechanism with a hybrid module is proposed. It is composed of a four-degrees-of-freedom (4DOF) R(3-RUHR)/UURP hybrid module and a 2-DOF (RRRP)R single-closed-loop serial rotation module, which has the advantages of small footprint, large workspace, high stiffness, and is ideal for machining robots applied to modular integrated manufacturing lines. However, due to the multi-closed loop between azimuth pitch rotations and hybrid module, the workspace is coupled, so that the mechanism has problems in building the forward and inverse position, kinematics, and dynamics analytical models, numerical solution calculation speed, and multi-solution. Based on the analysis of coupled characteristics of this mechanism, the concomitant motion neural network (NN) models of the 3-RUHR parallel mechanism and inverse position NN models of the (R(3-RUHR)/UURP)(RRRP)R hybrid robot are established using the Levenberg–Marquardt training algorithm with Bayesian regularization. Furthermore, the kinematics and dynamics models of the proposed hybrid robot are established using the equivalent screw method. And the correctness of position NN models, kinematics complete model, and dynamics complete model are verified through numerical examples, respectively. Finally, the prototype of this hybrid robot is further developed, and the coupled motion and multi-axis machining capability of the (R(3-RUHR)/UURP)(RRRP)R hybrid machining robot are verified by experiment. The hybrid mechanism and modeling method proposed in this paper can provide support for the application of machining robots with a small footprint, strongly coupled large workspace, and high stiffness.

LncRNAs are known to regulate a plethora of key events of cellular processes; however, little is known about the function of lncRNAs in autophagy. Here in the current study, we report lncRNA-IGFBP4 which has previously been known to regulate the proliferation and reprogramming of cancer cells, but its role in autophagy is not yet known. We found that serum starvation provokes autophagy-induced downregulation of lncRNA-IGFBP4 levels. Next, we determined that c-Myc can negatively regulate lncRNA-IGFBP4 in HeLa cells. Phenotypically, we found that upon depletion of lncRNA-IGFBP4, the HeLa cells undergo autophagy through ULK1/Beclin1 signaling. Furthermore, through TCGA data analysis, we found lncRNA-IGFB4 overexpressed in most cancers including cervical cancer. Based on these findings, we conclude that c-Myc maintains cellular homeostasis through negatively regulating lncRNA-IGFBP4 in cervical cancer cells.

Fungal natural products play a prominent role in the development of pharmaceuticalagents. Two new cyclic tetrapeptides (CTPs), westertide A (

Gliocladicillin C (3) is a cytotoxic epipolythiodioxopiperazine (ETP) isolated from the Ophiocordyceps-associated fungus Clonostachys rogersoniana. Although the disulfides/polysulfides in ETPs are believed to account for their cytotoxicity, and 11′-deoxyverticillin A was demonstrated to induce apoptosis and autophagy, how they mediate apoptosis and autophagy remained unknown. Here, we revealed that 3 activated caspase-dependent apoptosis and autophagy in human tumor cells, while the prepared disulfide-cleavage product failed to induce reactive oxygen species production and PARP cleavage, but further enhanced the autophagic flux compared to 3. Gliocladicillin C and its derivative also increased the phosphorylation of AMP-activated protein kinase and stimulated autophagy by affecting the glycolytic pathway. These results demonstrated that the disulfides played an essential role in inducing apoptosis, but not autophagy.

A genetic dereplication approach in combination with differential gene expression led to the discovery of three new sesquiterpenes, tricinoloniol acids (TRAs) A-C (1-3) and the known fusidilactone A (4) from T. hypoxylon. Comparative transcriptomic analysis and targeted deletion identified the biosynthetic route for TRAs. Our results demonstrate an alternative application of the genetic dereplication method for exploring the biosynthesis of cryptic secondary metabolites (SMs), which utilizes the coordinated expression of trichothecene (tri) and tra cluster genes.

A new p-terphenyl derivative aspergicandidusin A (1), a new cleistanthane diterpenoid 6-deoxyaspergiloid C (13), and 12 known compounds (2−12, and 14) were isolated from the mold Aspergillus candidus. The structures of the new compounds were elucidated by spectral analysis of NMR and MS data. The absolute configuration of C-1 in 13 was determined via the circular dichroism data of the [Rh2(OCOCF3)4] complex. Compounds 2−8 and 11 showed moderate inhibitory activity against K562 cell lines with the IC50 value in the range from 17.9 to 46.3 μM. Compound 13 exhibited moderate cytotoxicity against HepG2 cells with the IC50 value of 47.7 μM. Compounds 11 and 12 exhibited moderate activity against the growth of S. aureus with MIC value of 6.25 μM, respectively.

In the course of searching for cytotoxic metabolites from insects associated actinomyces, two new natural p-terphenyl glycosides, strepantibin D (1) and strepantibin E (2), along with terferol (3),...

Two new diterpenoids, hypoxyterpoids A (1) and B (2), and four new isocoumarin derivatives, hypoxymarins A–D (4–7), together, with seven known metabolites (3 and 8–13) were obtained from the crude extract of the mangrove-derived fungus Hypoxylon sp. The structures of the new compounds were elucidated on the basis of 1- and 2-dimensional (1D/2D) nuclear magnetic resonance (NMR) spectroscopic and mass spectrometric analysis. The absolute configurations of compounds 1, 2, 4, 5, and 7 were determined by comparison of experimental and calculated electronic circular dichroism (ECD) spectra, and the absolute configurations of C-4′ in 6 and C-9 in 7 were determined by [Rh2(OCOCF3)4]-induced ECD spectra. Compound 1 showed moderate α-glucosidase inhibitory activities with IC50 values of 741.5 ± 2.83 μM. Compounds 6 and 11 exhibited DPPH scavenging activities with IC50 values of 15.36 ± 0.24 and 3.69 ± 0.07 μM, respectively.

Both Raptor and Rictor are the key components in the complexes of mammalian target of rapamycin (mTOR), which play a vital role in mediating autophagy. Unlike mTOR, the regulatory role of either Raptor or Rictor in the regulation of autophagic process is relatively less explored. In present study, we found that rasfonin, which isolated from Talaromyces sp. 3656-A1 and was a fungal natural product, activated both caspase-dependent apoptosis and autophagy in ACHN, a renal carcinoma cell line. Knockdown of Raptor decreased both rasfonin-induced autophagic flux and PARP-1 cleavage, and in contrast, Rictor silencing increased apoptosis concomitantly enhancing rasfonin-induced autophagy. Unexpectedly, API-2, which was widely used as an inhibitor of Akt, promoted rasfonin-dependent autophagy in Raptor-depleted but not Rictor-deprived cells. Collectively, these results demonstrated that Raptor and Rictor could play a distinctly regulatory role in rasfonin-enhanced autophagy and apoptosis.

Nuclear-localized mitochondria were discovered over sixty years ago1; however, the function of these organelles in the initiation of nuclear formation and development remains unknown. Here, we showed that mitochondria fragmented into dense particles to initiate and develop a nucleus, and multiple nuclei were separately and simultaneously formed by fragmented mitochondria in a single cell. The combination of nuclei individually constructed by the mitochondrial assembly of dense particles for nuclear transition partitioned the cytoplasm to form an intranuclear inclusion (INC), whose formation was not related to herniation or invagination of the cytoplasm. During nuclear conversion of itself and neighbouring organelles, the mitochondrion was incorporated into the nucleus to become a nuclear mitochondrion. Knockdown of microtubule-associated protein light chain 3 (LC3), a key autophagic protein, increased free micronuclei by delaying nuclear fusion and enhancing the mitochondria-to-micronuclei transition.

Three new sesquiterpenoids, peniterpenoids A − C (1–3), together with six known metabolites (4–9) were isolated from an entomogenous fungus Penicillium janthinellum (LB1.20090001) collected from a wheat cyst nematode. The structures of the new compounds were elucidated based on NMR and HRESIMS spectroscopic analyses. The absolute configuration of the C-8 secondary alcohol of peniterpenoid B (2) was determined by [Rh2(OCOCF3)4]-induced ECD experiment. Subsequently, the antimicrobial and DPPH scavenging activities were determined. Compounds 6–8 exhibited moderate antibacterial activities against Staphylococcus aureus (CGMCC1.2465) with MIC values of 25.0, 50.0 and 12.5 μg/mL, respectively.

The function of nuclear-localized mitochondria remains unknown. We found that mitochondria assembled dense particles to fragment and disperse into the particles, which reassembled to initiate nuclear formation and development. Individually-formed nuclei in one single cell were joined together by mitochondrial fragmentation concurrently partitioning cytoplasm to form an intranuclear inclusion (INC), whose creation was not related to herniation or invagination of the cytoplasm. Along with the nuclear transition of a mitochondrion and its neighboring counterparts, the organelle included itself in the nucleus to become nuclear mitochondrion through peripherally assembling of dense particles. New medium reversed the nuclear formation of the organelles to recovery and re-establishment via the return of the particles, which consisted of dense microvesicles (MIVs).

Paenibacillus triticisoli BJ-18, a N2-fixing bacterium, is able to promote plant growth, but the secondary metabolites that may play a role in promoting plant growth have never been characterized. In this study, untargeted metabolomics profiling of P. triticisoli BJ-18 indicated the existence of 101 known compounds, including N2-acetyl ornithine, which is the precursor of siderophores, plant growth regulators such as trehalose 6-phosphate, betaine and trigonelline, and other bioactive molecules such as oxymatrine, diosmetin, luotonin A, (-)-caryophyllene oxide and tetrahydrocurcumin. In addition, six compounds were also isolated from P. triticisoli BJ-18 using a combination of silica gel chromatography, sephadex LH-20, octadecyl silane (ODS), and high-performance liquid chromatography (HPLC). The compound structures were further analyzed by Nuclear Magnetic Resonance (NMR), Mass Spectrometry (MS), and Electronic Circular Dichroism (ECD). The six compounds included three classical siderophore fusarinines identified as deshydroxylferritriacetylfusigen, desferritriacetylfusigen, and triacetylfusigen, and three indolic acids identified as paenibacillic acid A, 3-indoleacetic acid (IAA), and 3-indolepropionic acid (IPA). Both deshydroxylferritriacetylfusigen and paenibacillic acid A have new structures. Fusarinines, which normally occur in fungi, were isolated from bacterium for the first time in this study. Both siderophores (compounds 1 and 2) showed antimicrobial activity against Escherichia coli, Staphylococcus aureus and Bacillus subtilis, but did not show obvious inhibitory activity against yeast Candida albicans, whereas triacetylfusigen (compound 3) showed no antibiosis activity against these test microorganisms. Paenibacillic acid A, IAA, and IPA were shown to promote the growth of plant shoots and roots, and paenibacillic acid A also showed antimicrobial activity against S. aureus. Our study demonstrates that siderophores and indolic acids may play an important role in plant growth promotion by P. triticisoli BJ-18.

The H-bridge cascaded active power filter (APF) has broad application prospect in the harmonic procession of high voltage field. Due to differences between H bridges, the imbalance of DC side voltages affects not only compensation effect, but also the safe and stable operation of APF. By derivation of the power exchange model between APF and the power grid, the voltage balance among phases is achieved by the five-order zero-sequence voltage, and the global voltage balance is achieved by the fundamental positive-sequence active current. By appending an active voltage vector in the AC side of each H-bridge, the voltage balance is achieved within the single phase. This three-level equilibrium strategy controls each DC side voltage at the given value eventually. At the same time, the cascaded APF compensates harmonic and reactive current and reduces THD of the grid current. The feasibility of the method is verified by simulation and experimental results under low voltage conditions and provides the basis for application of the APF to a higher voltage level.

Hawk tea, prepared from the young leaves of Litsea coreana Levl. var. lanuginosa, is consumed as a tonic in China. Essential oils (EOs) from Hawk tea collected from six habitats in China were obtained by hydro distillation. Extraction yields ranged from 0.42% (g/g) in samples from Ningguo to 0.11% (g/g) in samples from Qingchuan. A total of 50 compounds in the six EO samples were identified by Gas Chromatography-Mass Spectrometer. The dominant compounds were citral (4.67–21.12%), caryophyllene (2.31–15.74%), dodecanal (2.10–15.38%), α-humulene (1.45–13.56%) and decanal (1.91–13.17%). Altitude may contribute the greatest effect on the chemical variation of the six EO samples. All the EO samples showed bioactivities. Among them, the EOs from the Pingshan sample showed the best ABTS radical scavenging activity (78.67 mg TEs /g) and better antimicrobial activities (MIC = 156.25–625 μg/mL) and had stronger DPPH radical scavenging activity (IC50 = 0.71 mg/mL) than BHT (IC50 = 0.76 mg/mL). The EOs from the Ningguo sample showed the highest reducing power (26.06 mg Fe2+/g) in a FRAP assay, the best inhibitory effect on α-glucosidase (1.71 mg/mL) and was the most cytotoxic (66.03–77.03 μg/mL) in an MTS assay. Therefore, the EOs from Hawk tea could be suitable for commercialization in the food, cosmetic or medical industries. Due to the activities of their EOs, plants growing in Pingshan and Ningguo are the optimal candidates.

Transition metal oxides (TMOs) generally suffer severe capacity degradation as the potential anode materials for lithium-ion batteries, since the large volume changes of TMO anodes during conversion reactions result in the collapse of electrode structures. Fabricating specific nanostructures of TMOs has been demonstrated as a successful approach to partially solve this issue. Besides the concern of capacity retention, our previous work has demonstrated that the specific capacities of TMOs can be improved by enhancing their degrees of crystallinity. Therefore, the TMO nanostructures with high degrees of crystallinity are highly desired to achieve both high specific capacity and good capacity retention. However, the high crystallinity and desired nanostructure are usually contradictory in nanofabrication since the thermal treatment will lead to the collapse of a nanostructure. To overcome the obstacle, herein, the polydopamine coating followed by a thermal treatment in nitrogen is first introduced as a confined crystallization strategy to enhance the degree of crystallinity and simultaneously maintain the nanostructure of ZnO microspheres. Electrochemical performance tests demonstrate that the appropriate coating thickness and heat treatment can enhance the specific capacity from 288.0 mAh g−1 of pristine ZnO to 527.0 mAh g−1 of carbon coated ZnO after 100 cycles. The present work provides a good opportunity to develop TMO anodes with high capacities and superior cycling performances by the polydopamine-derived carbon coating and confined crystallization.

The incorporation of organic fluorescent dyes into inorganic matrixes could greatly improve the luminous properties of organic dyes. In this study, we investigated the effect of three different types of layered mineral clays on the luminous properties of lucigenin (bis-N-methylacridinium nitrate, BNMA). Attempts were made to fit the isothermal data using Langmuir and Freundlich equations. The adsorption of BNMA onto montmorillonite and kaolinite were fitted well by Langmuir isotherm equation while that of BNMA onto rectorite was fitted by Freundlich equation. The results indicated that the adsorptive behavior, which was resulted from the different layer structures, had a direct impact on the luminous properties of the composites.

Trichoderma hypoxylon is a fungicolous species which produces rich secondary metabolites. However, no genetic transformation method is available for further studies. Here, we developed a marker-less transformation system based on the complementation of an uridine/uracil biosynthetic gene by protoplast transformation. An uridine/uracil auxotrophic mutant of Δthpyr4 was obtained by using a positive screening protocol with 5′-fluoroorotic acid as a selective reagent. To improve the homologous integration rates, the orthologues of ku70 and lig4 which play critical roles in non-homologous end-joining recombination were disrupted. The resulting thlig4 mutant showed remarkable transformation rates of 89 %, while no change was found in the thku70 deletion mutant compared with the WT strain. This suggests that thlig4 play a key role in the non-homologous recombination in this strain. Using this system, the biosynthetic gene cluster of trichothecene (tri) harzianum B was identified by deletion of the thtri5 in T. hypoxylon. Comparative genome analysis revealed that the trichothecene biosynthetic gene cluster in T. hypoxylon shared similar organizations with T. arundinaceum and T. brevicompactum, even though their encoded products are different in structures. Taken together, the highly efficient genetic system provides a convenient tool for studying the biosynthetic diversity and mining the novel natural product from the fungi.