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Yong-Tai Zhang, Ji-Hui Zhao, Su-Juan Zhang, Yang-Zi Zhong, Zhi Wang, Ying Liu, Feng Shi, Nian-Ping FengSchool of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaObjective: The purpose of this study was to improve skin permeation of evodiamine and rutaecarpine for transdermal delivery with microemulsion as vehicle and investigate real-time cutaneous absorption of the drugs via in vivo microdialysis.Methods: Pseudoternary phase diagrams were constructed to evaluate microemulsion regions with various surfactants and cosurfactants. Nine formulations of oil in water microemulsions were selected as vehicles for assessing skin permeation of evodiamine and rutaecarpine in ex vivo transdermal experiments. With a microdialysis hollow fiber membrane implanted in the skin beneath the site of topical drug administration, dialysis sampling was maintained for 10 hours and the samples were detected directly by high performance liquid chromatography. Real-time concentrations of the drugs in rat skin were investigated and compared with those of conventional formulations, such as ointment and tincture. Furthermore, the drugs were applied to various regions of the skin using microemulsion as vehicle.Results: In ex vivo transdermal experiments, cutaneous fluxes of evodiamine and rutaecarpine microemulsions were 2.55-fold to 11.36-fold and 1.17-fold to 6.33-fold higher, respectively, than those of aqueous suspensions. Different drug loadings, microemulsion water content, and transdermal enhancers markedly influenced the permeation of evodiamine and rutaecarpine. In microemulsion application with in vivo microdialysis, the maximum concentration of the drugs (evodiamine: 18.23 ± 1.54 ng/mL; rutaecarpine: 16.04 ± 0.69 ng/mL) were the highest, and the area under the curve0–t of evodiamine and rutaecarpine was 1.52-fold and 2.27-fold higher than ointment and 3.06-fold and 4.23-fold higher than tincture, respectively. A greater amount of drugs penetrated through and was absorbed by rat abdominal skin than shoulder and chest, and a reservoir in the skin was found to supply drugs even after the microemulsion was withdrawn.Conclusion: Compared to conventional formulations, higher cutaneous fluxes of evodiamine and rutaecarpine were achieved with microemulsion. Based on this novel transdermal delivery, the transdermal route was effective for the administration of the two active alkaloids.Keywords: microemulsion, evodiamine, rutaecarpine, transdermal delivery, microdialysis

Bacterial infections and antibiotic resistance pose significant public health challenges globally. Natural products serve as valuable sources for discovering antimicrobial agents. Rhododendron simsii Planch, a folk medicine, is traditionally used to treat various inflammatory diseases. In this study, we investigated the antibacterial metabolites derived from R. simsii Planch. Rhodosimsiin A (1), bearing a 1,5- seco -1,6 and 3,6-epoxy grayanane diterpene skeleton, representing a novel 5/6/7/6/5 pentacyclic ring system, and 3 β ,16 α -dihydroxy-6 β -ethoxy-14 β -acetoxy-grayan-1(5)-ene-10-one (4), which represents the first example of the degradation of C-20 and carbonylation in C-10 diterpenoid, together with two new grayanane diterpenes (2-3), three new triterpenes (13-15), and known analogs (5-12, 16-30), were isolated from the leaves of R. simsii Planch by using the bioassay-guided method. Their structures were elucidated by comprehensive spectroscopic analyses, and absolute configurations were established by single-crystal X-ray diffraction and calculated ECD spectra. Compounds 14, 15, 18, 20, 27, 28, and 30 exhibited potent antibacterial activity with an MIC 50 of 1.4-24.3  μ g/mL against Staphylococcus aureus . The findings of this research indicate that secondary metabolites derived from R . simsii Planch are promising natural antimicrobial candidates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lai, Zhong, Liang, Chen, Liao, Li, Han, Cai and Wang.)

Two new paraherquamides (PHQs) namely aculeaquamides B and C (1 and 2), along with four known PHQs (3-6), were isolated from the co-culture of marine fungus Aspergillus aculeatinus WHUF0198 and mangrove-associated fungus Penicillium sp. DM27. Compound 1 represents the first PHQ derivative featuring an uncommon 7/6/5/5/6/5 hexacyclic system. The structures of the isolated compounds were elucidated based on exhaustive NMR spectroscopy measurement and HRESIMS data. The absolute configurations of new compounds were determined by TDDFT-ECD calculations. Compound 3 demonstrated suppression of AngII-induced cardiac hypertrophy while exhibiting relatively low cardiomyocyte toxicity., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cancer-associated fibroblasts (CAFs) assist in breast cancer (BRCA) invasion and immune resistance by overproduction of extracellular matrix (ECM). Herein, we develop FPC@S, a photodynamic immunomodulator that targets the ECM, to improve the photodynamic immunotherapy for fibrotic BRCA. FPC@S combines a tumor ECM-targeting peptide, a photosensitizer (protoporphyrin IX) and an antifibrotic drug (SIS3). After anchoring to the ECM, FPC@S causes ECM remodeling and BRCA cell death by generating reactive oxygen species (ROS) in situ . Interestingly, the ROS-mediated ECM remodeling can normalize the tumor blood vessel to improve hypoxia and in turn facilitate more ROS production. Besides, upon the acidic tumor microenvironment, FPC@S will release SIS3 for reprograming CAFs to reduce their activity but not kill them, thus inhibiting fibrosis while preventing BRCA metastasis. The natural physical barrier formed by the dense ECM is consequently eliminated in fibrotic BRCA, allowing the drugs and immune cells to penetrate deep into tumors and have better efficacy. Furthermore, FPC@S can stimulate the immune system and effectively suppress primary, distant and metastatic tumors by combining with immune checkpoint blockade therapy. This study provides different insights for the development of fibrotic tumor targeted delivery systems and exploration of synergistic immunotherapeutic mechanisms against aggressive BRCA.

Glioblastoma has been extensively studied due to its high mortality and short survival. The evolution mechanism of tumor-associated macrophages (TAMs) to Glioma-associated microglia and macrophages (GAMs) in the tumor microenvironment (TME) remains to be elucidated. The tumor cell-to-cell interaction patterns have not been well defined yet. The EF-Hand Domain Family Member D2 (EFHD2) has been reported to be differentially expressed as an immunomodulatory molecule in a variety of cancers. But large-scale clinical data from multiple ethnic communities have not been used to investigate the role of EFHD2 in glioma. RNA-seq data from 313 or 657 glioma patients from the Chinese Glioma Genome Atlas (CGGA) database and 603 glioma patients from the Cancer Genome Atlas (TCGA) database were analyzed retrospectively. Cell localization was performed using single-cell sequencing data from the CGGA database and the GSE131928 dataset. Mouse glioma cell lines and primary macrophages isolated from Efhd2 knockout mice were co-cultured to validate the immunomodulatory effects of EFHD2 on macrophages and the remodeling of TME of glioblastoma. EFHD2 is enriched in high-grade gliomas, isocitrate dehydrogenase wild-type, and 1p/19q non-co-deficient gliomas. It is a potential biomarker of glioma-proneuronal subtypes and an independent prognostic factor for overall survival in patients with malignant glioblastoma. EFHD2 regulates the monocyte-macrophage system function and positively correlates with immunosuppressive checkpoints. Further experimental data demonstrates that Efhd2 influences the polarization state of GAMs and inhibits the secretion of TGF-β1. In vitro experiments have revealed that macrophages lacking Efhd2 suppress the vitality of two glioma cell lines and decelerate the growth of glioma xenografts. In conclusion, EFHD2 promises to be a key target for TME-related immunotherapy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Eurycomanone (EN) is a diterpenoid compound isolated from the roots of Eurycoma longifolia ( E. longifolia ). Previous studies have confirmed that E. longifolia can enhance bone regeneration and bone strength. We previously isolated and identified ten quassinoids from E. longifolia , and the result displayed that five aqueous extracts have the effects on promotion of bone formation, among whom EN showed the strongest activity. However, the molecular mechanism of EN on bone formation was unknown, and we further investigated in this study., Methods: After the verification of purity of extracted EN, following experiments were conducted. Firstly, the pharmacologic action of EN on normal bone mineralization and the therapeutic effect of EN on Dex-induced bone loss using zebrafish larvae. The mineralization area and integral optical density (IOD) were evaluated using alizarin red staining. Then the vital signaling pathways of EN relevant to OP was identified through network pharmacology analysis. Eventually in vitro, the effect of EN on cell viability, osteogenesis activities were investigated in human bone marrow mesenchymal stem cells (hMSCs) and C3H10 cells, and the molecular mechanisms by which applying AKT inhibitor A-443654 in hMSCs., Results: In zebrafish larvae, the administration in medium of EN (0.2, 1, and 5 μM) dramatically enhanced the skull mineralization area and integral optical density (IOD), and increased mRNA expressions of osteoblast formation genes (ALP, RUNX2a, SP7, OCN). Meanwhile, exposure of EN remarkably alleviated the inhibition of bone formation induced by dexamethasone (Dex), prominently improved the mineralization, up-regulated osteoblast-specific genes and down-regulated osteoclast-related genes (CTSK, RANKL, NFATc1, TRAF6) in Dex-treated bone loss zebrafish larvae. Network pharmacology outcomes showed the MAPK and PI3K-AKT signaling pathways are closely associated with 10 hub genes (especially AKT1), and AKT/GSK-3β/β-catenin was selected as the candidate analysis pathway. In hMSCs and C3H10 cells, results showed that EN at appropriate concentrations of 0.008-5 μM effectively increased the cell proliferation. In addition, EN (0.04, 0.2, and 1 μM) significantly stimulated osteogenic differentiation and mineralization as well as significantly increased the protein phosphorylation of AKT and GSK-3β, and expression of β-catenin, evidencing by the results of ALP and ARS staining, qPCR and western blotting. Whereas opposite results were presented in hMSCs when treated with AKT inhibitor A-443654, which effectively inhibited the pro-osteogenesis effect induced by EN, suggesting EN represent powerful potential in promoting osteogenesis of hMSCs, which may be closely related to the AKT/GSK-3β/β-catenin signaling pathway., Conclusions: Altogether, our findings indicate that EN possesses remarkable effect on bone formation via activating AKT/GSK-3β/β-catenin signaling pathway in most tested concentrations., The Translational Potential of This Article: This study demonstrates EN is a new effective monomer in promoting bone formation, which may be a promising anabolic agent for osteoporosis (OP) treatment., Competing Interests: All authors disclosed no relevant relationship, and no potential conflict of interest was reported by the authors., (© 2023 Published by Elsevier B.V. on behalf of Chinese Speaking Orthopaedic Society.)

Membrane dynamics are important to the integrity and function of mitochondria. Defective mitochondrial fusion underlies the pathogenesis of multiple diseases. The ability to target fusion highlights the potential to fight life-threatening conditions. Here we report a small molecule agonist, S89, that specifically promotes mitochondrial fusion by targeting endogenous MFN1. S89 interacts directly with a loop region in the helix bundle 2 domain of MFN1 to stimulate GTP hydrolysis and vesicle fusion. GTP loading or competition by S89 dislodges the loop from the GTPase domain and unlocks the molecule. S89 restores mitochondrial and cellular defects caused by mitochondrial DNA mutations, oxidative stress inducer paraquat, ferroptosis inducer RSL3 or CMT2A-causing mutations by boosting endogenous MFN1. Strikingly, S89 effectively eliminates ischemia/reperfusion (I/R)-induced mitochondrial damage and protects mouse heart from I/R injury. These results reveal the priming mechanism for MFNs and provide a therapeutic strategy for mitochondrial diseases when additional mitochondrial fusion is beneficial., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Safe and effective strategies are urgently needed to fight against the life-threatening diseases of various cancers. However, traditional therapeutic modalities, such as radiotherapy, chemotherapy and surgery, exhibit suboptimal efficacy for malignant tumors owing to the serious side effects, drug resistance and even relapse. Phototherapies, including photodynamic therapy (PDT) and photothermal therapy (PTT), are emerging therapeutic strategies for localized tumor inhibition, which can produce a large amount of reactive oxygen species (ROS) or elevate the temperature to initiate cell death by non-invasive irradiation. In consideration of the poor bioavailability of phototherapy agents (PTAs), lots of drug delivery systems have been developed to enhance the tumor targeted delivery. Nevertheless, the carriers of drug delivery systems inevitably bring biosafety concerns on account of their metabolism, degradation, and accumulation. Of note, carrier-free nanomedicine attracts great attention for clinical translation with synergistic antitumor effect, which is characterized by high drug loading, simplified synthetic method and good biocompatibility. In this review, the latest advances of phototherapy with various carrier-free nanomedicines are summarized, which may provide a new paradigm for the future development of nanomedicine and tumor precision therapy., (© 2022 Wiley-VCH GmbH.)

Coronavirus disease (COVID-19) caused by SARS-COV-2 infection has been widely prevalent in many countries and has become a common challenge facing mankind. Traditional Chinese medicine (TCM) has played a prominent role in this pandemic, and especially TCM with the function of "heat-clearing and detoxifying" has shown an excellent role in anti-virus. Fufang Shuanghua oral liquid (FFSH) has been used to treat the corresponding symptoms of influenza such as fever, nasal congestion, runny nose, sore throat, and upper respiratory tract infections in clinic, which are typical symptoms of COVID-19. The content of chlorogenic acid, andrographolide and dehydrated andrographolide as the quality control components of FFSH is not less than 1.0 mg/mL, 60 μg/mL and 60 μg/mL respectively. In this study, UPLC-Q-TOF-MS/MS was employed to describe the chemical profile of FFSH. Virtual screening and fluorescence resonance energy transfer (FRET) were used to screen the effective components of FFSH acting on SARS-CoV-2 main protease (Mpro). As a result, 214 compounds in FFSH were identified or preliminarily characterized by UPLC-Q-TOF-MS/MS, and 61 active ingredients with potential inhibitory effects on Mpro were selected through receptor-based and ligand-based virtual screening. In particular, quercetin, forsythoside A, and linoleic acid showed a good inhibitory effect on Mpro in FRET evaluation with IC50 values of 26.15 μM, 22.26 μM and 47.09 μM respectively, and had a strong binding affinity with the receptor Mpro (6LU7) in molecular docking. CYS145 and HIS41 were the main amino acid residues affected by small molecules in the protein binding domain. In brief, we characterized, for the first time, 214 chemical components in FFSH, and three of them, including quercetin, forsythoside A and linoleic acid, were screened out to exert beneficial anti-COVID-19 effects through CYS145 and HIS41 sites, which may provide a new research strategy for TCM to develop new therapeutic drugs against COVID-19., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

In this work, we investigated the ameliorative effects of platycodin D (PD), a major active chemical ingredient isolated from the roots of Platycodon grandiflorum (PG), on high-fat diet (HFD)/streptozotocin (STZ)-induced type 2 diabetes (T2D) mice. PD treatment (2.5 and 5.0 mg kg -1 ) improved HFD-induced body weight gain. PD administration also decreased the fasting blood glucose (FBG) level and improved glucose and insulin tolerance levels. These data collectively showed that PD could maintain glucose homeostasis. In addition, the diabetic mice with PD treatment also showed fewer pathological changes in liver tissues and improved hepatic functional indexes with respect to the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and recovery of abnormal liver function caused by T2D. Except for these, PD decreased the decomposition of hepatic glycogen. The results from western blot analysis showed that PD treatment might regulate the hepatic gluconeogenesis pathway with the increased phosphorylation/expression of AMPK and decreased expressions of PCK1 and G6Pase. In the aspect of lipid metabolism, PD decreased the whole-body lipid levels, including total cholesterol (TC), triglycerides (TG), and high-density lipoprotein (HDL), and reduced the hepatic fat accumulation induced by T2D through the AMPK/ACC/CPT-1 fatty acid anabolism pathway. In addition, the results of molecular docking showed that PD may have a potential direct effect on AMPK and other key glycolipid metabolism proteins. To summarize, PD modulation of hepatic glycolipid metabolism abnormalities is promising for T2D therapy in the future.

Background: Drug resistance mutation (DRM)-associated virological failure has become a critical issue for ART and the elimination of HIV., Objectives: To investigate the distribution characteristics of DRMs of HIV CRF01_AE, CRF07_BC and CRF08_BC, the predominant subtypes in China., Methods: Patients receiving ART up to 31 August 2020 in Ganzhou in China were recruited. Full-length sequences of the HIV pol gene were amplified from patients with virological failure. DRMs and antiretroviral susceptibility were explored using the Stanford University HIV Drug Resistance Database HIVdb Program., Results: Overall, 279 of 2204 patients under ART were found to have virological failure. Nine HIV subtypes were identified among 211 sequences that were amplified successfully and CRF08_BC (37.0%), CRF01_AE (26.1%) and CRF07_BC (25.6%) were the most prevalent, with mutation frequencies of 44.9% (35/78), 52.7% (29/55) and 35.2% (19/54), respectively. The most common DRMs of these three subtypes were K103N and M184V, while the mutation frequencies of M41L, D67N, K70R, K101E, V106M, Y181C, K219E, H221Y and N348I were obviously different among subtypes. The resistance levels and frequencies for antiretroviral drugs for these three subtypes were similar and resistances to nevirapine, efavirenz, lamivudine and emtricitabine were the most frequently observed. Compared with CRF01_AE and CRF07_BC, CRF08_BC had higher proportions of DRMs for NRTIs and lower frequencies of resistance to NRTIs and NNRTIs., Conclusions: The distribution characteristics of DRMs of HIV CRF01_AE, CRF07_BC and CRF08_BC were inconsistent and should be considered when selecting antiretroviral strategies, developing new drugs and controlling HIV strains containing DRMs., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

α-Pinene, an important biologically active natural monoterpene, has been widely used in fragrances, medicines, and fine chemicals, especially, in high-density renewable fuels such as jet fuel. The development of an α-pinene production platform in a highly modifiable microbe from renewable substitute feedstocks could lead to a green, economical avenue, and sustainable biotechnological process for the biosynthesis of α-pinene. Here, we report engineering of an orthogonal biosynthetic pathway for efficient production of α-pinene in oleaginous yeast Yarrowia lipolytica that resulted in an α-pinene titer of 19.6 mg/L when using glucose as the sole carbon source, a significant 218-fold improvement than the initial titer. In addition, the potential of using waste cooking oil and lignocellulosic hydrolysate as carbon sources for α-pinene production from the engineered Y. lipolytica strains was analyzed. The results indicated that α-pinene titers of 33.8 and 36.1 mg/L were successfully obtained in waste cooking oil and lignocellulosic hydrolysate medium, thereby representing the highest titer reported to date in yeast. To our knowledge, this is also the first report related to microbial production of α-pinene from waste cooking oil and lignocellulosic hydrolysate.

Background: The incidence and prevalence of atrial fibrillation are increasing each year, and this condition is one of the most common clinical arrhythmias., Aim: To investigate the levels and significance of serum fibroblast growth factor 23 (FGF-23) and miR-208b in patients with atrial fibrillation and their relationship with prognosis., Methods: From May 2018 to October 2019, 240 patients with atrial fibrillation were selected as an observation group, including 134 with paroxysmal atrial fibrillation and 106 with persistent atrial fibrillation; 150 patients with healthy sinus rhythm were selected as a control group. The serum levels of FGF-23 and miR-208b in the two groups were measured. In the observation group, cardiac parameters were determined by echocardiography., Results: The serum levels of FGF-23 and miR-208b in the observation group were 210.20 ± 89.60 ng/mL and 5.30 ± 1.22 ng/mL, which were significantly higher than the corresponding values in the control group ( P < 0.05). In the observation group, the serum levels of FGF-23 and miR-208b in patients with persistent atrial fibrillation were 234.22 ± 70.05 ng/mL and 5.83 ± 1.00 ng/mL, which were significantly higher than the corresponding values in patients with paroxysmal atrial fibrillation ( P < 0.05). The left atrial dimension (LAD) of patients with persistent atrial fibrillation was 38.81 ± 5.11 mm, which was significantly higher than that of patients with paroxysmal atrial fibrillation ( P > 0.05). The serum levels of FGF-23 and miR-208b were positively correlated with the LAD ( r = 0.411 and 0.382, P < 0.05). In the observation group, the serum levels of FGF-23 and miR-208b in patients with a major cardiovascular event (MACE) were 243.30 ± 72.29 ng/mL and 6.12 ± 1.12 ng/mL, which were significantly higher than the corresponding values in patients without a MACE ( P < 0.05)., Conclusion: The serum levels of FGF-23 and miR-208b are increased in patients with atrial fibrillation and are related to the type of disease, cardiac parameters, and prognosis., Competing Interests: Conflict-of-interest statement: Dr. Lan J reports a grant from Dongguan Social Science and Technology Development Project (No. 2015108101025) during the conduct of the study. Other authors have no financial relationships to disclose., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Acetaminophen (APAP)-induced acute liver injury (ALI) is a health issue that has gradually attracted attention, and is often regarded as a model of drug-induced hepatotoxicity. The leaves of Lithocarpus polystachyus Rehd. (named as "sweet tea", ST) usually serve as tea drink and folk medicine for healthcare in the southwest part of China. In previous reports, it has been proven to protect various animal models, except for APAP-induced liver injury model. Therefore, this study initially explored the protective effect of ST leaf extract (STL-E) on hepatotoxicity induced by APAP in ICR mice. STL-E of 50 and 100 mg kg -1 were given to each group for 7 days. ALI was intraperitoneally induced by APAP treatment (i.p. 250 mg per kg body weight). Biochemical markers, levels of inflammatory factors, histopathological staining and western blotting were used to analyze the inflammation and apoptosis of liver tissues. Interestingly, the treatment with STL-E significantly attenuated APAP-induced liver injury ( p < 0.05). Moreover, STL-E partially mitigated APAP-induced liver injury by effectively activating the PI3K/Akt pathway and inhibiting the NF-κB pathway. In a word, STL-E protected liver against APAP-induced hepatotoxicity by inhibiting the PI3K/Akt-mediated apoptosis signal pathway and inhibiting the NF-κB-mediated signaling pathway., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

In this study, the Nordic Musculoskeletal Questionnaire (NMQ) was administered to a valid sample of 81 Taiwanese bakery workers to explore their discomfort or symptoms of work-related musculoskeletal disorders and identify the risk factors. Wrist postures were also examined during 3 typical dough operations (kneading, rolling, and rounding) by using an electrogoniometer. The prevalence of musculoskeletal discomfort in any part of the body in the past year among the respondents was 93.0%, with the highest prevalence of 66.3% and 51.8% in the hands/wrists (right and left), followed by the prevalence of 50.6% and 45.8% in the shoulders (right and left) and the lower back (48.2%), respectively. The results also revealed that during the 3 dough processing operations, the workers' wrist movements in specific operations were close to the recommended limits suggested in previous studies, especially the ulnar deviation and palm flexion of the right wrist during dough kneading and the radial deviation of the left wrist during dough rolling and rounding. The study findings can be used to explain why the bakers self-report a high proportion of wrist and shoulder disorders and can also serve as a reference for task rearrangement and redesign.

Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Mutations in MFN2 cause the neurodegenerative disease Charcot-Marie-Tooth type 2A (CMT2A). The molecular basis underlying the physiological and pathological relevance of MFN2 is unclear. Here, we present crystal structures of truncated human MFN2 in different nucleotide-loading states. Unlike other dynamin superfamily members including MFN1, MFN2 forms sustained dimers even after GTP hydrolysis via the GTPase domain (G) interface, which accounts for its high membrane-tethering efficiency. The biochemical discrepancy between human MFN2 and MFN1 largely derives from a primate-only single amino acid variance. MFN2 and MFN1 can form heterodimers via the G interface in a nucleotide-dependent manner. CMT2A-related mutations, mapping to different functional zones of MFN2, lead to changes in GTP hydrolysis and homo/hetero-association ability. Our study provides fundamental insight into how mitofusins mediate mitochondrial fusion and the ways their disruptions cause disease.

Recent intense effort has been devoted to exploring different manifestations of resonant excitations of strongly coupled plasmons and excitons, but so far such studies have been limited to situations where the Fano- or Rabi-type spectra are largely symmetric at zero detuning. Using a newly developed full quantum mechanical model, here we reveal the existence of a highly asymmetric spectroscopic regime for both the Rabi splitting and transparency dip. The asymmetric nature is inherently tied to the non-negligible exciton absorbance and is caused by substantial interference-induced energy repartitioning of the resonance peaks. This theoretical framework can be exploited to reveal the quantum behaviors of the two excitation entities with varying mutual coupling strengths in both linear and nonlinear regimes. We also use prototypical systems of rhodamine molecules strongly coupled with AuAg alloyed nanoparticles and well-devised control experiments to demonstrate the validity and tunability of the energy repartitioning and correlated electronic state occupations, as captured by the variations in the asymmetric spectroscopy and corresponding nonlinear absorption coefficient as a function of the Au:Ag ratio. The present study helps to substantially enrich our microscopic understanding of strongly coupled plasmon-exciton systems.

To explore the role of Brassinolide (BR) in improving the tolerance of Sigma Broad in foxtail millet (Setaria italica L.), effects of 0.1 mg/L of BR foliar application 24 h before 3.37 g/ha of Sigma Broad treatment at five-leaf stage of foxtail millet on growth parameters, antioxidant enzymes, malondialdehyde (MDA), chlorophyll, net photosynthetic rate (P N ), chlorophyll fluorescence and P 700 parameters were studied 7 and 15 d after herbicide treatment, respectively. Results showed that Sigma Broad significantly decreased plant height, activities of superoxide dismutase (SOD), chlorophyll content, P N , PS II effective quantum yield (Y (II)), PS II electron transport rate (ETR (II)), photochemical quantum yield of PSI(Y (I)) and PS I electron transport rate ETR (I), but significantly increased MDA. Compared to herbicide treatment, BR dramatically increased plant height, activities of SOD, Y (II), ETR (II), Y (I) and ETR (I). This study showed BR pretreatment could improve the tolerance of Sigma Broad in foxtail millet through improving the activity of antioxidant enzymes, keeping electron transport smooth, and enhancing actual photochemical efficiency of PS II and PSI.

Orexin, released from the hypothalamus, has been implicated in various basic non-somatic functions including feeding, the sleep-wakefulness cycle, emotion, and cognition. However, the role of orexin in somatic motor control is still little known. Here, using whole-cell patch clamp recording and immunostaining, we investigated the effect and the underlying receptor mechanism of orexin-A on neurons in the globus pallidus internus (GPi), a critical structure in the basal ganglia and an effective target for deep brain stimulation therapy. Our results showed that orexin-A induced direct postsynaptic excitation of GPi neurons in a concentration-dependent manner. The orexin-A-induced excitation was mediated via co-activation of both OX1 and OX2 receptors. Furthermore, the immunostaining results showed that OX1 and OX2 receptors were co-localized in the same GPi neurons. These results suggest that the central orexinergic system actively modulates the motor functions of the basal ganglia via direct innervation on GPi neurons and presumably participates in somatic-non-somatic integration.

Plasmon-mediated energy transfer is highly desirable in photo-electronic nanodevices, but the direct injection efficiency of "hot electrons" in plasmonic photo-detectors and plasmon-sensitized solar cells (plasmon-SSCs) is poor. On another front, Fano resonance induced by strong plasmon-exciton coupling provides an efficient channel of coherent energy transfer from metallic plasmons to molecular excitons, and organic dye molecules have a much better injection efficiency in exciton-SSCs than "hot electrons". Here, we investigate enhanced light-harvesting of chlorophyll-a molecules strongly coupled to Au nanostructured films via Fano resonance. The enhanced local field and plasmon resonance energy transfer are experimentally revealed by monitoring the ultrafast dynamical processes of the plexcitons and the photocurrent flows of the assembled plexciton-SSCs. By tuning the Fano factor and anti-resonance wavelengths, we find that the local field is largely enhanced and the efficiency of plexciton-SSCs consisting of ultrathin TiO2 films is significantly improved. Most strikingly, the output power of the plexciton-SSCs is much larger than the sum of those of the individual plasmon- and exciton-SSCs. Our observations provide a practical approach to monitor energy and electron transfer in plasmon-exciton hybrids at a strong coupling regime and also offer a new strategy to design photovoltaic nanodevices.

We examined the effects of the extract from leaves of Liquidambar formosana Hance on S180 cells and screened for antitumor active sites in the plant. Solvent extraction was conducted to prepare extracts from the leaves of L. formosana Hance and conduct preliminary separation, an MTT assay to determine the effect of leaf extract on the proliferation of S180 cells, and inverted microscopy to observe the effect of chloroform extract on the morphology of S180 cells. Double-staining (Annexin V/propidium iodide) with flow cytometry was conducted to determine the effect of the chloroform extract on S180 cell apoptosis. At some concentrations, the different extracts from the leaves of L. formosana Hance dose-dependently inhibited the proliferation of S180 cells. Among all extracts, the chloroform extract showed the strongest inhibitory effect on S180 cell proliferation. The IC50 values for the chloroform extract, ethyl acetate extract, n-butanol extract, and water layer were 0.238, 0.471, 0.844, and 0.411 mg/mL, respectively. We observed cell shrinkage, volume reduction, and varying sizes by inverted microscopy. Additionally, with increasing drug concentration, the number of cells decreased and debris increased. The cells showed typical apoptotic morphological changes. The chloroform extract induced the apoptosis of S180 cells in a dose-dependent manner. Different extracts from the leaves of L. formosana Hance inhibited the proliferation of S180 cells, and the chloroform extract was the main antitumor component. This extract from the leaves of L. formosana Hance inhibited the proliferation of S180 cells in part by inducing apoptosis.

We investigate tunable plasmon resonance and enhanced second harmonic generation (SHG) and up-converted fluorescence (UCF) of the hemispheric-like silver core/shell islands. The Ag, Ag/Ag2O, and Ag/Ag2O/Ag island films are prepared by using a sputtering technique. The SHG and UCF of the Ag/Ag2O/Ag core/shell islands near the percolating regime is enhanced 2.34 and 3.94 times compared to the sum of two individual counterparts of Ag/Ag2O core/shell and Ag shell islands. The ratio of SHG intensity induced by p- and s-polarization is 0.86 for the initial Ag islands and increase to 1.61 for the Ag/Ag2O/Ag core/shell samples. The tunable intensity ratio of SHG to UCF of the Ag islands treated by thermal and laser annealing processes is also observed. The physical mechanism of the enhanced SHG and UCF in the Ag/Ag2O/Ag core/shell islands is discussed. Our observations provide a new approach to fabricate plasmon-enhanced optical nonlinear nanodevices with tunable SHG and UCF.

Histone acetylation, which together with histone methylation regulates gene activity in response to stress, is an important epigenetic modification. There is an increasing research focus on histone acetylation in crops, but there is no information to date in peanut (Arachis hypogaea). We showed that osmotic stress and ABA affect the acetylation of histone H3 loci in peanut seedlings by immunoblotting experiments. Using RNA-seq data for peanut, we found a RPD3/HDA1-like superfamily histone deacetylase (HDAC), termed AhHDA1, whose gene is up-regulated by PEG-induced water limitation and ABA signaling. We isolated and characterized AhHDA1 from A. hypogaea, showing that AhHDA1 is very similar to an Arabidopsis HDAC (AtHDA6) and, in recombinant form, possesses HDAC activity. To understand whether and how osmotic stress and ABA mediate the peanut stress response by epigenetics, the expression of AhHDA1 and stress-responsive genes following treatment with PEG, ABA, and the specific HDAC inhibitor trichostatin A (TSA) were analyzed. AhHDA1 transcript levels were enhanced by all three treatments, as was expression of peanut transcription factor genes, indicating that AhHDA1 might be involved in the epigenetic regulation of stress resistance genes that comprise the responses to osmotic stress and ABA.

No data were available on the acute oral toxicity, short-term oral toxicity of vegetable carbon in animals. This study was designed to evaluate the safety of two commercially available dietary bamboo charcoal powders (BCP1 and BCP2). The size distribution of the two powders was determined by a Mastersizer 2000 laser particle size analyzer prior to the in vivo safety studies. For the acute toxicity study, a single dose of 11.24 g/kg body weight of BCP1 and BCP2 was given once orally to healthy Sprague-Dawley (SD) rats. Mortality and clinical symptoms were observed and recorded for the first 30 min after treatment, at 4 h post-administration, and then at least once daily for 14 days after administration. In the repeated dose 28-day oral toxicity study, BCP1 and BCP2 were administered orally at doses of 2.81, 5.62, and 11.24 g/kg body weight for 28 days to SD rats. Animals were sacrificed and organs and blood samples were analyzed. Results showed that both BCP1 and BCP2 were micro-sized and various in size. In the acute toxicity and the repeated dose 28-day oral toxicity studies, BCP caused neither mortality nor visible signs of toxicity in rats. No significant differences were found in the relative organ weights or in biochemical parameters in BCP treated groups compared to a control group. No treatment-related histological changes were observed in the organs of these animals. Based on these data, it is concluded that the median lethal dose (LD50) of BCP for both male and female rats is more than 11.24 g/kg body weight and the no-observed-adverse-effect level (NOAEL) is >11.24 g/kg body weight for 28 days.

Seeking plasmonic nanostructures with large field confinement and enhancement is significant for photonic and electronic nanodevices with high sensitivity, reproducibility, and tunability. Here, we report the synthesis of plasmonic arrays composed of two-segment dimer nanorods and coaxial cable nanorods with ∼1 nm gap insulated by a self-assembled Raman molecule monolayer. The gap-induced plasmon coupling generates an intense field in the gap region of the dimer junction and the cable interlayer. As a result, the longitudinal plasmon resonance of nanorod arrays with high tunability is obviously enhanced. Most interestingly, the field enhancement of dimer nanorod arrays can be tuned by the length ratio L1/L2 of the two segments, and the maximal enhancement appears at L1/L2 = 1. In that case, the two-photon luminescence (TPL) of dimer nanorod arrays and the Raman intensity in the dimer junction is enhanced by 27 and 30 times, respectively, under resonant excitation. In the same way, the Raman intensity in the gap region is enhanced 16 times for the coaxial cable nanorod arrays. The plasmonic nanorod arrays synthesized by the facile method, having tunable plasmon properties and large field enhancement, indicate an attractive pathway to the photonic nanodevices.

Objective: To establish the optimum submerged culture condition of Xylaria striata mycelium., Methods: One-factor-at-a-time method and orthogonal experiment design were applied and the dry weight of mycelium was tested for evaluation the biomass of the growth of Xylaria striata mycelium., Results: The results from one-factor-at-a-time experiments showed that maltose, glucose or corn powder could be used as the best carbon source and the optimum nitrogen source was soybean powder. The best ratio of carbon source to nitrogen source was 5:1. In addition, the higher dry weight of mycelium was found at pH 6 when 2 mycelial discs were inoculated and fermented for 7 days. Otherwise, the growth of mycelium was observed to be promoted significantly by addition with K,Mg,P and VB1. The consequence of orthogonal experiment showed that the optimum carbon source and nitrogen source were maltose 4% and soybean powder 0.8%, respectively,and the highest mycelium biomass could be obtained at pH 7 and 25 °C shaking for 13 days., Conclusion: A large amount of mycelium will be obtained under the optimum condition of liquid culture for Xylaria striata.

Colloidal semiconductor quantum dots have three-dimensional confined excitons with large optical oscillator strength and gain. The surface plasmons of metallic nanostructures offer an efficient tool to enhance exciton-exciton coupling and excitation energy transfer at appropriate geometric arrangement. Here, we report plasmon-mediated cooperative emissions of approximately one monolayer of ensemble CdSe/ZnS quantum dots coupled with silver nanorod complex cavities at room temperature. Power-dependent spectral shifting, narrowing, modulation, and amplification are demonstrated by adjusting longitudinal surface plasmon resonance of silver nanorods, reflectivity and phase shift of silver nanostructured film, and mode spacing of the complex cavity. The underlying physical mechanism of the nonlinear excitation energy transfer and nonlinear emissions are further investigated and discussed by using time-resolved photoluminescence and finite-difference time-domain numerical simulations. Our results suggest effective strategies to design active plasmonic complex cavities for cooperative emission nanodevices based on semiconductor quantum dots.

Heterotrinuclear Zn(2)Ln (Ln = Nd 2, Eu 3, Tb 4, Er 5, Yb 6) clusters [(Znq(2))(2)](mu-CH(3)COO){Ln(hfac)(2)} (q = 8-hydroxylquinolinate, hfac = hexafluoroacetylacetonate) have been synthesized. The Zn(2)Ln framework is ligated by two q ligands featuring mu-phenoxo and two q ligands featuring mu(3)-phenoxo coordination modes, and one mu-CH(3)COO(-) anions. Since the short intramolecular separations of Zn...Ln (ca. 3.354-3.373 A) allow energy transfer from Znq(2)-based sensitizers to the Ln(III) centres through two energy transfer pathways, the lanthanide luminescence is indeed "lighted up" by excitation of the Znq(2)-based chromopores. Photophysical measurements revealed that these Zn(2)Ln complexes exhibit the so-called "dual emission" originating from both Znq(2)-based luminophores and lanthanide emitters. By virtue of the dual luminescence with complementary colours, the Znq(2)-based cyan emission and Eu(III)-centred red luminescence are combined to generate a white-light emission in the Zn(2)Eu (3) complex.