Metal chelation is generally considered as a promising antifungal approach but its specific mechanisms are unclear. Here, we identify 13 thiosemicarbazone derivatives that exert broad-spectrum ...antifungal activity with potency comparable or superior to that of fluconazole
by screening a small compound library comprising 89 thiosemicarbazone derivatives as iron chelators. Among the hits, 19ak exhibits minimal cytotoxicity and potent activity against either azole-sensitive or azole-resistant fungal pathogens. Mechanism investigations reveal that 19ak inhibits mitochondrial respiration mainly by retarding mitochondrial respiratory chain complex I activity through iron chelation, and further reduces mitochondrial membrane potential and ATP synthesis in Candida albicans. In addition, 19ak inhibits fungal ribosome biogenesis mainly by disrupting intracellular zinc homeostasis. 19ak also stimulates the activities of antioxidant enzymes and decreases reactive oxygen species formation in C. albicans, resulting in an increase in detrimental intracellular reductive stress. However, 19ak has minor effects on mammalian cells in depleting intracellular iron and zinc. Moreover, 19ak exhibits low capacity to induce drug resistance and
efficacy in a Galleria mellonella infection model. These findings uncover retarded fungal mitochondrial respiration and ribosome biogenesis as downstream effects of disruption of iron and zinc homeostasis in C. albicans and provide a basis for the thiosemicarbazone 19ak in antifungal application.
The increasing incidence of fungal infections and resistance to existing antifungals call for the development of broad-spectrum antifungals with novel mechanisms of action. In this study, we demonstrate that a thiosemicarbazone derivative 19ak selectively inhibits mitochondrial respiration mainly by retarding mitochondrial respiratory chain complex I activity through iron chelation and inhibits ribosome biogenesis mainly by disrupting intracellular zinc homeostasis in C. albicans. In addition, 19ak exhibits low capacity to induce fungal resistance, minimal cytotoxicity, and
antifungal efficacy. This study provides the basis of thiosemicarbazone derivative 19ak as a metal chelator for the treatment of fungal infections.
Histone lysine specific demethylase 1 (LSD1) has become a potential therapeutic target for the treatment of cancer. Discovery and develop novel and potent LSD1 inhibitors is a challenge, although ...several of them have already entered into clinical trials. Herein, for the first time, we reported the discovery of a series of 5-cyano-6-phenylpyrimidine derivatives as LSD1 inhibitors using flavin adenine dinucleotide (FAD) similarity-based designing strategy, of which compound 14q was finally identified to repress LSD1 with IC50 = 183 nmol/L. Docking analysis suggested that compound 14q fitted well into the FAD-binding pocket. Further mechanism studies showed that compound 14q may inhibit LSD1 activity competitively by occupying the FAD binding sites of LSD1 and inhibit cell migration and invasion by reversing epithelial to mesenchymal transition (EMT). Overall, these findings showed that compound 14q is a suitable candidate for further development of novel FAD similarity-based LSD1 inhibitors.
In this work, series II compounds (14a–w) were designed and synthesized based on the flavin adenine dinucleotide (FAD) similarity strategies. Further mechanism studies showed that compound 14q is an FAD competitive LSD1 inhibitor, which inhibits cell migration and invasion by reversing epithelial to mesenchymal transition (EMT). Display omitted
HIV-transmitted drug resistance (TDR) is found in antiretroviral therapy (ART)-naïve populations infected with HIV-1 with TDR mutations and is important for guiding future first- and second-line ART ...regimens. We investigated TDR and its effect on CD4 count in ART-naïve youths from the China-Myanmar border near the Golden Triangle to better understand TDR and effectively guide ART.
From 2009 to 2017, 10,832 HIV-1 infected individuals were newly reported along the Dehong border of China, 573 ART-naïve youths (16 ~ 25 y) were enrolled. CD4 counts were obtained from whole blood samples. HIV pol gene sequences were amplified from RNA extracted from plasma. The Stanford REGA program and jpHMM recombination prediction tool were used to determine genotypes. TDR mutations (TDRMs) were analyzed using the Stanford Calibrated Population Resistance tool.
The most common infection route was heterosexuals (70.51%), followed by people who inject drugs (PWID, 19.20%) and men who have sex with men (MSM) (8.90%). The distribution of HIV genotypes mainly included the unique recombinant form (URF) (44.08%), 38.68% were CRFs, 13.24% were subtype C and 4.04% were subtype B. The prevalence of TDR increased significantly from 2009 to 2017 (3.48 to 9.48%) in ART-naïve youths (4.00 to 13.16% in Burmese subjects, 3.33 to 5.93% in Chinese subjects), and the resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), and protease inhibitors (PIs) were 3.49, 2.62, and 0.52%, respectively. Most (94.40%, n = 34) of HIV-1-infected patients with TDRM had mutation that conferred resistance to a single drug class. The most common mutations Y181I/C and K103N, were found in 7 and 9 youths, respectively. The mean CD4 count was significantly lower among individuals with TDRMs (373/mm
vs. 496/mm
, p = 0.013).
The increase in the prevalence of HIV-1 TDR increase and a low CD4 count of patients with TDRMs in the China-Myanmar border suggests the need for considering drug resistance before initiating ART in HIV recombination hotspots.
Solid polymer electrolytes (SPEs) are highly promising for realizing high-capacity, low-cost, and safe Li metal batteries. However, the Li dendritic growth and side reactions between Li and SPEs also ...plague these systems. Herein, a fluorinated lithium salt coating (FC) with organic-inorganic gradient and soft–rigid feature is introduced on Li surface as an artificial protective layer by the in-situ reaction between Li metal and fluorinated carboxylic acid. The FC layer can improve the interface stability and wettability between Li and SPEs, assist the transport of Li ions, and guide Li nucleation, contributing to a dendrite-free Li deposition and long-lifespan Li metal batteries. The symmetric cell with FC-Li anodes exhibits a high areal capacity of 1 mAh cm−2 at 0.5 mA cm−2, and an ultra-long lifespan of 2000 h at a current density of 0.1 mA cm−2. Moreover, the full cell paired with the LiFePO4 cathode exhibits improved cycling stability, remaining 83.7% capacity after 500 cycles at 1 C. When matching with the S cathode, the FC layer can prevent the shuttle effect, contributing to stable and high-capacity Li–S battery. This work provided a promising way for the construction of stable all-solid-state lithium metal batteries with prolonged lifespan.
Fluorinated lithium salt coating (FC) with organic-inorganic gradient and soft–rigid feature improves the interface stability of Li anode/polymer electrolytes. FC layer can redistribute the Li ions and serve as nucleation sites, guiding homogeneous deposition. Display omitted
•Fluorinated lithium salt coating (FC) on Li metal anode with organic-inorganic gradient was obtained.•Organic layer close to the electrolyte improved the stability of FC-Li/PEO interface.•LiF-enriched layer close to the anode regulated Li nucleation and deposition.•All-solid-state cells with FC-Li anode exhibited a high capacity (1 mAh cm−2) and a long lifespan (2000 h).
In this work, few-layered MoS2 (FLM) nanosheet-reinforced Al matrix composites are developed through powder metallurgy and hot extrusion. The microstructure, mechanical properties, and strengthening ...mechanisms have been systematically investigated. It is found that Al12Mo and Al2S3 can be formed in-situ during the sintering process, resulting in the improvement of interfacial bonding between FLM and Al matrix. With 1.5 wt.% of FLM addition, an improved tensile strength of 234 MPa with a high elongation of 17% can be obtained. Moreover, the strengthening mechanisms are also demonstrated to be grain refinement, dislocation strengthening, and load transfer, and the calculation indicates that load transfer is the main contribution factor. This work will inspire more new designs of metal matrix composites with balanced strength and ductility.
Cadmium (Cd) is a highly toxic heavy metal that causes serious damage to plant and human health.
Roxb. has a large amount of aboveground biomass and a rapid growth rate, and it has been identified as ...a novel type of Cd hyperaccumulator that can be harnessed for phytoremediation. However, the molecular mechanisms underlying the response of
to Cd
stress remain largely unclear. In this study, the phenotype, biochemical, and physiological traits of
seeds and seedlings were analyzed under different concentrations of Cd
treatments. The results showed higher Cd
tolerance of
compared to common plants. Meanwhile, the Cd
content in shoots reached 449 mg/kg under 10 mg/L Cd
treatment, which was obviously higher than the threshold for Cd hyperaccumulators. To investigate the molecular mechanism underlying the adaptability of
to Cd stress, RNA-Seq was used to examine transcriptional responses of
to Cd stress. Transcriptome analysis found that 61 genes encoding TFs, 48 cell wall-related genes, 35 secondary metabolism-related genes, 133 membrane proteins and ion transporters, and 96 defense system-related genes were differentially expressed under Cd
stress, indicating that a series of genes were involved in Cd
stress, forming a complex signaling regulatory mechanism. These results provide new scientific evidence for elucidating the regulatory mechanisms of
response to Cd
stress and new clues for the molecular breeding of heavy metal phytoremediation.
Although sulfonic acid (SA)-based proton-exchange membranes (PEMs) dominate fuel cell applications at low temperature, while sulfonation on polymers would strongly decay the mechanical stability ...limit the applicable at elevated temperatures due to the strong dependence of proton conduction of SA on water. For the purpose of bifunctionally improving mechanical property and high-temperature performance, Nafion membrane, which is a commercial SA-based PEM, is composited with fabricated silica nanofibers with a three-dimensional network structure via electrospinning by considering the excellent water retention capacity of silica. The proton conductivity of the silica nanofiber-Nafion composite membrane at 110 °C is therefore almost doubled compared with that of a pristine Nafion membrane, while the mechanical stability of the composite Nafion membrane is enhanced by 44%. As a result, the fuel cell performance of the silica nanofiber-Nafion composite membrane measured at high temperature and low humidity is improved by 38%.
In this paper, a data-oriented model has been presented by nonlinear autoregressive exogenous model (NARX) neural network, which aims at predicting the mechanical behavior of a fuel cell stack for ...vehicle under the real-life operational conditions. A 300-hour vibration test with reproduction of SVP road spectrum was completed on a Multi-Axial Simulation Table. At the same time, data acquisition of drive displacement and acceleration response on stack was carried out in every 50 hours. All data collected were used to train and evaluate the model based on NARX. Result shows that the prediction model built is of good precision and consistent with the actual situation.
► This is the first report of using poplar processing residues for methane production. ► The residues weren’t good material for methane production without NaOH treatment. ► Enhancement of methane ...production can be achieved after alkaline treatment. ► The highest methane production was achieved at 35g/L with 5.0% alkaline dose.
Poplar processing residues were used for methane production by anaerobic digestion after alkaline treatment and methane production was measured. The highest methane production of 271.9L/kg volatile solid (VS) was obtained at conditions of 35g/L and 5.0% NaOH, which was 113.8% higher than non-alkaline treated samples, and 28.9% higher than that of corn straw, which is the conventional anaerobic digestion material in China. The maximal enhancement of 275.5% obtained at conditions of 50g/L and 7.0% NaOH. Degradation of cellulose, hemicellulose and lignin after treatment increased by 4.0–9.0%, 3.3–6.2%, and 11.1–20.5%, respectively, with NaOH dose ranged from 3.0% to 7.0%. Scanning electron microscopy (SEM), FTIR spectra and Crystallinity measurements showed that the lignocellulosic structures were disrupted by NaOH. The results indicate poplar processing residues might be an efficient substrate for methane production after alkaline treatment.
The clinical application of HIV fusion inhibitor, enfuvirtide (T20), was limited mainly because of its short half-life. Here we designed and synthesized two PEGylated C34 peptides, PEG2kC34 and ...PEG5kC34, with the PEG chain length of 2 and 5 kDa, respectively, and evaluated their anti-HIV-1 activity and mechanisms of action. We found that these two PEGylated peptides could bind to the HIV-1 peptide N36 to form high affinity complexes with high α-helicity. The peptides PEG2kC34 and PEG5kC34 effectively inhibited HIV-1 Env-mediated cell-cell fusion with an effective concentration for 50% inhibition (EC
) of about 36 nM. They also inhibited infection of the laboratory-adapted HIV-1 strain NL4-3 with EC
of about 4-5 nM, and against 47 HIV-1 clinical isolates circulating in China with mean EC
of PEG2kC34 and PEG5kC34 of about 26 nM and 32 nM, respectively. The plasma half-life (t
) of PEG2kC34 and PEG5kC34 was 2.6 h and 5.1 h, respectively, and the t
of PEGylated C34 was about 2.4-fold and 4.6-fold longer than C34 (~1.1 h), respectively. These findings suggest that PEGylated C34 with broad-spectrum anti-HIV-1 activity and prolonged half-life can be further developed as a peptide fusion inhibitor-based long-acting anti-HIV drug for clinical use to treat HIV-infected patients who have failed to respond to current anti-retrovirus drugs.
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