Fungal epidithiodiketopiperazines (ETPs) possess large structural diversity and complexity due to modifications of the cyclodipeptide skeleton. Elucidation of the biosynthetic pathway of ...pretrichodermamide A (1) in Trichoderma hypoxylon revealed a flexible catalytic machinery of multiple enzymes for generating ETP diversity. Seven tailoring enzymes encoded by the tda cluster are involved in 1 biosynthesis, that is, four P450s TdaB and TdaQ for 1,2‐oxazine formation, TdaI for C7′‐hydroxylation, and TdaG for C4, C5‐epoxidation, two methyltransferases TdaH for C6′‐ and TdaO for C7′‐O‐methylation, and a reductase TdaD for furan opening. Gene deletions led to the identification of 25 novel ETPs, including 20 shunt products, indicating the catalytic promiscuity of Tda enzymes. Particularly, TdaG and TdaD accept various substrates and catalyze regiospecific reactions at different stages of 1 biosynthesis. Our study not only uncovers a hidden library of ETP alkaloids, but also helps to understand the hidden chemical diversity of natural products by pathway manipulation.
The biosynthetic route of fungal epidithiodiketopiperazines (ETPs) was revealed by elucidating the biosynthesis of pretrichodermamide A. Diverse ETP derivatives, including 25 novel compounds, were characterized from tda gene deletion mutants, indicating divergent metabolic pathways of ETP intermediates and enzyme catalytic promiscuity.
Summary
Most marine copiotrophic bacteria can produce extracellular enzymes to degrade biopolymers into bio‐available smaller solutes, while oligotrophic bacteria usually cannot. Bacterial ...extracellular enzymes and enzymatic products can be a common resource that could be utilized by both copiotrophs and oligotrophs; when present, oligotrophs may outcompete the enzyme‐producing copiotrophs. However, copiotrophs and oligotrophs consistently coexist in the ocean. How they maintain coexistence has still not been experimentally studied. In this study, the interaction and coexistence of a copiotroph and an oligotroph, isolated from the same surface seawater sample and utilizing the same proteinaceous substrate, were experimentally investigated. The copiotroph could secrete extracellular proteases to degrade and then utilize the proteinaceous substrate. The oligotroph was unable to utilize the proteinaceous substrate by itself, but could grow by using the hydrolysate amino acids. The copiotroph outcompeted the oligotroph by adsorbing the amino acids quickly and having a higher growth rate in the rich medium. The oligotroph survived by adapting to low concentration of nutrients. The copiotroph and oligotroph were able to maintain long‐term (up to 142 days) coexistence in the laboratory. This study indicates that differences in the utilization of different concentrations of nutrients can drive the coexistence of marine copiotrophs and oligotrophs.
Abstract
The light-matter interaction between plasmonic nanocavity and exciton at the sub-diffraction limit is a central research field in nanophotonics. Here, we demonstrated the vertical ...distribution of the light-matter interactions at ~1 nm spatial resolution by coupling A excitons of MoS
2
and gap-mode plasmonic nanocavities. Moreover, we observed the significant photoluminescence (PL) enhancement factor reaching up to 2800 times, which is attributed to the Purcell effect and large local density of states in gap-mode plasmonic nanocavities. Meanwhile, the theoretical calculations are well reproduced and support the experimental results.
Air pollutant emissions from Chinese households Liu, Jun; Mauzerall, Denise L.; Chen, Qi ...
Proceedings of the National Academy of Sciences - PNAS,
07/2016, Volume:
113, Issue:
28
Journal Article
Peer reviewed
Open access
As part of the 12th Five-Year Plan, the Chinese government has developed air pollution prevention and control plans for key regions with a focus on the power, transport, and industrial sectors. Here, ...we investigate the contribution of residential emissions to regional air pollution in highly polluted eastern China during the heating season, and find that dramatic improvements in air quality would also result from reduction in residential emissions. We use the Weather Research and Forecasting model coupled with Chemistry to evaluate potential residential emission controls in Beijing and in the Beijing, Tianjin, and Hebei (BTH) region. In January and February 2010, relative to the base case, eliminating residential emissions in Beijing reduced daily average surface PM2.5 (particulate mater with aerodynamic diameter equal or smaller than 2.5 micrometer) concentrations by 14 ± 7 μg·m−3 (22 ± 6% of a baseline concentration of 67 ± 41 μg·m−3; mean ± SD). Eliminating residential emissions in the BTH region reduced concentrations by 28 ± 19 μg·m−3 (40 ± 9% of 67 ± 41 μg·m−3), 44 ± 27 μg·m−3 (43 ± 10% of 99 ± 54 μg·m−3), and 25 ± 14 μg·m−3 (35 ± 8% of 70 ± 35 μg·m−3) in Beijing, Tianjin, and Hebei provinces, respectively. Annually, elimination of residential sources in the BTH region reduced emissions of primary PM2.5 by 32%, compared with 5%, 6%, and 58% achieved by eliminating emissions from the transportation, power, and industry sectors, respectively. We also find air quality in Beijing would benefit substantially from reductions in residential emissions from regional controls in Tianjin and Hebei, indicating the value of policies at the regional level.
To compare radiofrequency ablation (RFA) with or without transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC).
A randomized controlled trial was ...conducted on 189 patients with HCC less than 7 cm at a single tertiary referral center between October 2006 and June 2009. Patients were randomly asssigned to receive TACE combined with RFA (TACE-RFA; n = 94) or RFA alone (n = 95). The primary end point was overall survival. The secondary end point was recurrence-free survival, and the tertiary end point was adverse effects.
At a follow-up of 7 to 62 months, 34 patients in the TACE-RFA group and 48 patients in the RFA group had died. Thirty-three patients and 52 patients had developed recurrence in the TACE-RFA group and RFA group, respectively. The 1-, 3-, and 4-year overall survivals for the TACE-RFA group and the RFA group were 92.6%, 66.6%, and 61.8% and 85.3%, 59%, and 45.0%, respectively. The corresponding recurrence-free survivals were 79.4%, 60.6%, and 54.8% and 66.7%, 44.2%, and 38.9%, respectively. Patients in the TACE-RFA group had better overall survival and recurrence-free survival than patients in the RFA group (hazard ratio, 0.525; 95% CI, 0.335 to 0.822; P = .002; hazard ratio, 0.575; 95% CI, 0.374 to 0.897; P = .009, respectively). There were no treatment-related deaths. On logistic regression analyses, treatment allocation, tumor size, and tumor number were significant prognostic factors for overall survival, whereas treatment allocation and tumor number were significant prognostic factors for recurrence-free survival.
TACE-RFA was superior to RFA alone in improving survival for patients with HCC less than 7 cm.
To understand the mechanism(s) of age‐dependent outcomes of hepatitis B virus (HBV) infection in humans, we previously established an age‐related HBV mouse model in which 6‐week‐old (N6W) C3H/HeN ...mice exhibited virus tolerance whereas 12‐week‐old (N12W) counterparts presented virus clearance. By investigating the hepatic myeloid cell dynamics in mice of these two ages, we aim to identify factors associated with HBV clearance. C3H/HeN mice were transfected with an HBV plasmid by hydrodynamic injection. Serum HBV markers were monitored weekly. Hepatic leucocyte populations and their cytokine/chemokine productions were examined at baseline, day 3 (D3), day 7 (D7), and day 14 after injection. C‐C chemokine receptor type 2 (CCR2) antagonist and clodronate (CLD) were respectively administered to N12W and N6W mice to study the roles of lymphocyte antigen 6 complex, locus C (Ly6C)+ monocytes and Kupffer cells (KCs) in viral clearance. N12W mice had a significantly higher number of TNF‐α–secreting Ly6C+ monocytes and fewer IL‐10–secreting KCs at D3 in the liver than their younger N6W counterparts after HBV transfection. In addition, the elevated number of interferon‐γ+TNF‐α+ CD8+ T cells at D7 was only seen in the older cohort. The enhanced Ly6C+ monocyte induction in N12W mice resulted from elevated C‐C motif chemokine ligand 2 (CCL2) secretion by hepatocytes. CCR2 antagonist administration hampered Ly6C+ monocyte recruitment and degree of KC reduction and delayed HBV clearance in N12W animals. Depletion of KCs by CLD liposomes enhanced Ly6C+ monocyte recruitment and accelerated HBV clearance in N6W mice. Conclusions: Ly6C+ monocytes and KCs may, respectively, represent the resistance and tolerance arms of host defenses. These two cell types play an essential role in determining HBV clearance/tolerance. Manipulation of these cells is a promising avenue for immunotherapy of HBV‐related liver diseases.
The aqueous reprocessing of spent nuclear fuel generates a considerable amount of plutonium alongside contaminated stainless steel, necessitating meticulous handling for safe decommission and ...long‐term management. The present work investigated the co‐immobilization of CeO2 (as an inactive surrogate for PuO2) with metallic Fe and Cr (representing a simplified stainless steel) within a zirconolite ceramic wasteform, nominally targeting Ca1−xCexZrTi2−2xFexCrxO7. After sintering at 1400°C under an air atmosphere, the zirconolite phase constituted 90.8–95.1 wt.% of the product across the solid solution range of 0.05 ≤ x ≤ 0.25, alongside perovskite and baddeleyite secondary phases in varying proportion; no evidence of the unincorporated CeO2 or metallic and oxidized Fe or Cr were identified. Above x = 0.30 CeO2 was detected inferring, the solubility limit was reached. A polytype transformation from zirconolite 2M to 3T was confirmed by X‐ray diffraction and selected area electron diffraction results, with the relative fraction of the 3T phase gradually increasing to 49.5 wt.% at x = 0.30. Deconvolution of X‐ray photoelectron spectroscopy data revealed the partial reduction of Ce4+–Ce3+, whereas Fe and Cr species maintained trivalent, in agreement with the targeted substitution scheme. Benefitting from the excellent chemical flexibility of zirconolite structured compounds, the co‐immobilization approach may be an effective disposal pathway for Pu‐containing wastes and contaminated stainless steel residues.
A diabetic foot ulcer (DFU) is one of the most devastating complications of diabetes. It has been reported that lncRNA GAS5 plays a vital role in wound healing in DFUs. However, the specific ...mechanism remains unclear. In this research, we aimed to investigate the role of GAS5 in wound healing in DFUs as well as the underlying mechanism. qPCR or western blotting was performed to measure the expression levels of GAS5, HIF1A, VEGF and TAF15. CCK-8 or EdU assays, flow cytometry, wound healing assays and tube formation assays were carried out to assess the proliferation, apoptosis, wound healing and in vitro angiogenesis of HUVECs, respectively. RNA pull-down and RIP assays were performed to verify the interaction between GAS5 and TAF15. ChIP and luciferase assays were conducted to verify the binding of TAF15 to the HIF1A promoter. In the DFU mouse model, H&E and Masson staining were used to determine epidermal and dermal thickness and collagen formation. GAS5 and HIF1A were downregulated in the skin tissues of DFU patients, and GAS5 overexpression promoted cell proliferation, wound healing and tubule formation in HG-treated HUVECs. In addition, GAS5 facilitated HIF1A expression by interacting with TAF15. Rescue assays demonstrated that the suppression of HIF1A/VEGF pathway activation partially reversed the functional roles of GAS5 in HUVECs. Furthermore, GAS5 accelerated wound healing by activating the HIF1A/VEGF pathway in mice with DFUs. GAS5 activates the HIF1A/VEGF pathway by binding to TAF15, resulting in accelerated wound healing in DFUs. Our findings may provide a theoretical basis for the clinical treatment of DFUs.
Long noncoding RNAs GAS5 activates the HIF1A/VEGF pathway by binding to TAF15 (a component of RNA polymerase II), resulting in accelerated wound healing in diabetic foot ulcers. These findings may provide a theoretical basis for clinical treatment.
Various infarct sizes induced by middle cerebral artery occlusion (MCAO) generate inconsistent outcomes for stroke preclinical study. Monitoring cerebral hemodynamics may help to verify the outcome ...of MCAO. The aim of this study was to investigate the changes in brain tissue optical properties by frequency-domain near-infrared spectroscopy (FD-NIRS), and establish the relationship between cerebral hemodynamics and infarct variation in MCAO model. The rats were undergone transient MCAO using intraluminal filament. The optical properties and hemodynamics were measured by placing the FD-NIRS probes on the scalp of the head before, during, and at various time-courses after MCAO. Bimodal infarction severities were observed after the same 90-min MCAO condition. Significant decreases in concentrations of oxygenated hemoglobin (HbO) and total hemoglobin (HbT), tissue oxygenation saturation (StO2), absorption coefficient (μa) at 830 nm, and reduced scattering coefficient (μs’) at both 690 and 830 nm were detected during the occlusion in the severe infarction but not the mild one. Of note, the significant increases in HbO, HbT, StO2, and μa at both 690 and 830 nm were found on day 3; and increases in μs’ at both 690 and 830 nm were found on day 2 and day 3 after MCAO, respectively. The interhemispheric correlation coefficient (IHCC) was computed from low-frequency hemodynamic oscillation of both hemispheres. Lower IHCCs standing for interhemispheric desynchronizations were found in both mild and severe infarction during occlusion, and only in severe infarction after reperfusion. Our finding supports that sequential FD-NIRS parameters may associated with the severity of the infarction in MCAO model, and the consequent pathologies such as vascular dysfunction and brain edema. Further study is required to validate the potential use of FD-NIRS as a monitor for MCAO verification.
Asunercept (company code APG101 Apogenix AG; company code CAN008 CANbridge Pharmaceuticals) is a novel glycosylated fusion protein that has shown promising effectiveness in glioblastoma. This Phase I ...study was initiated to evaluate the tolerability and safety of asunercept in combination with standard radiotherapy and temozolomide (RT/TMZ) in Asian patients with newly diagnosed glioblastoma. This was the Phase I portion of a Phase I/II open label, multicenter trial of asunercept plus standard RT/TMZ. Adults with newly-diagnosed glioblastoma received surgical resection followed by standard RT/TMZ plus asunercept 200 mg/week (Cohort 1) or 400 mg/week (Cohort 2) by 30-min IV infusion. The primary endpoint was the safety and tolerability of asunercept during concurrent asunercept and RT/TMZ; dose-limiting toxicities were observed for each dose. Secondary endpoints included pharmacokinetics (PK) and 6-month progression-free survival (PFS6). All patients (Cohort 1, n = 3; Cohort 2, n = 7) completed ≥ 7 weeks of asunercept treatment. No DLTs were experienced. Only one possibly treatment-related treatment emergent adverse event (TEAE), Grade 1 gingival swelling, was observed. No Grade > 3 TEAEs were reported and no TEAE led to treatment discontinuation. Systemic asunercept exposure increased proportionally with dose and showed low inter-patient variability. The PFS6 rate was 33.3% and 57.1% for patients in Cohort 1 and 2, respectively. Patients in Cohort 2 maintained a PFS rate of 57.1% at Month 12. Adding asunercept to standard RT/TMZ was safe and well tolerated in patients with newly-diagnosed glioblastoma and 400 mg/week resulted in encouraging efficacy.Trial registration NCT02853565, August 3, 2016.
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