Laser direct overall water splitting for H2 and H2O2 production.

Hydrogen (H2) and hydrogen peroxide (H2O2) play crucial roles as energy carriers and raw materials for industrial production. However, the current techniques for H2 and H2O2 production rely on complex catalysts and involve multiple intermediate steps. In this study, we present a straightforward, environmentally friendly, and highly efficient laser-induced conversion method for overall water splitting to simultaneously generate H2 and H2O2 at ambient conditions without any catalysts. The laser direct overall water splitting approach achieves an impressive light-to-hydrogen energy conversion efficiency of 2.1%, with H2 production rates of 2.2 mmol/h and H2O2 production rates of 65 µM/h in a limited reaction area (1 mm2) within a short real reaction time (0.36 ms/h). Furthermore, we elucidate the underlying physics and chemistry behind the laser-induced water splitting to produce H2 and H2O2. The laser-induced cavitation bubbles create an optimal microenvironment for water-splitting reactions because of the transient high temperatures (104 K) surpassing the chemical barrier required. Additionally, their rapid cooling rate (1010 K/s) hinders reverse reactions and facilitates H2O2 retention. Finally, upon bubble collapse, H2 is released while H2O2 remains dissolved in the water. Moreover, a preliminary amplification experiment demonstrates the potential industrial applications of this laser chemistry. These findings highlight that laser-based production of H2 and H2O2 from water holds promise as a straightforward, environmentally friendly, and efficient approach on an industrial scale beyond conventional chemical catalysis.

Efficient and Rapid Hydrogen Extraction from Ammonia-Water via Laser Under Ambient Conditions without Catalyst.

As a good carrier of hydrogen, ammonia-water has been employed to extract hydrogen in many ways. Here, we demonstrate a simple, green, ultrafast, and highly efficient method for hydrogen extraction from ammonia-water by laser bubbling in liquids (LBL) at room temperature and ambient pressure without catalyst. A maximum apparent yield of 33.7 mmol/h and a real yield of 93.6 mol/h were realized in a small operating space, which were far higher than the yields of most hydrogen evolution reactions from ammonia-water under ambient conditions. We also established that laser-induced cavitation bubbles generated a transient high temperature, which enabled a very suitable environment for hydrogen extraction from ammonia-water. The laser used here can serve as a demonstration of potentially solar-pumped catalyst-free hydrogen extraction and other chemical synthesis. We anticipate that the LBL technique will open unprecedented opportunities to produce chemicals.

Catalyst-Free Activation and Fixation of Nitrogen by Laser-Induced Conversion.

Ultrafast N2 fixation reactions are quite challenging. Currently used methods for N2 fixation are limited, and strong dinitrogen bonds usually need to be activated via extreme temperature or pressure or by the use of an energy-consuming process with sophisticated catalysts. Herein, we report a novel laser-based chemical method for N2 fixation under ambient conditions without catalysts, this method is called laser bubbling in liquids (LBL), and it directly activates N2 in water (H2O) and efficiently converts N2 into valuable NH3 (max: 4.2 mmol h-1) and NO3- (0.17 mmol h-1). Remarkably, the highest yields of NH3 and NO3- are 4 orders of magnitude greater than the best values for electrocatalysis reported to date. Notably, we further validate the experimental mechanism by using optical emission spectroscopy to detect the production of intermediate plasma and by employing isotope tracing. We also establish that an extremely high-temperature environment far from thermodynamic equilibrium inside a laser-induced bubble and the kinetic process of rapid quenching of bubbles is crucial for N2 activation and fixation to generate NH3 and NOx via LBL. Based on these results, it is shown that LBL is a simple, safe, efficient, green, and sustainable technology that enables the rapid conversion of the renewable feedstocks H2O and N2 to NH3 and NO3-, facilitating new prospects for chemical N2 fixation.

Nuclear receptor RXRα binds the precursor of miR-103 to inhibit its maturation.

BACKGROUND: The maturation of microRNAs (miRNAs) successively undergoes Drosha, Dicer, and Argonaute -mediated processing, however, the intricate regulations of the individual miRNA maturation are largely unknown. Retinoid x receptor alpha (RXRα) belongs to nuclear receptors that regulate gene transcription by binding to DNA elements, however, whether RXRα binds to miRNAs to exert physiological functions is not known. RESULTS: In this work, we found that RXRα directly binds to the precursor of miR-103 (pre-miR-103a-2) via its DNA-binding domain with a preferred binding sequence of AGGUCA. The binding of RXRα inhibits the processing of miR-103 maturation from pre-miR-103a-2. Mechanistically, RXRα prevents the nuclear export of pre-miR-103a-2 for further processing by inhibiting the association of exportin-5 with pre-miR-103a-2. Pathophysiologically, the negative effect of RXRα on miR-103 maturation correlates to the positive effects of RXRα on the expression of Dicer, a target of miR-103, and on the inhibition of breast cancer. CONCLUSIONS: Our findings unravel an unexpected role of transcription factor RXRα in specific miRNA maturation at post-transcriptional level through pre-miRNA binding, and present a mechanistic insight regarding RXRα role in breast cancer progression.

Non-Covalently Stapled H+ /Cl- Ion Channels Activatable by Visible Light for Targeted Anticancer Therapy.

The development of stimuli-responsive artificial H+ /Cl- ion channels, capable of specifically disturbing the intracellular ion homeostasis of cancer cells, presents an intriguing opportunity for achieving high selectivity in cancer therapy. Herein, we describe a novel family of non-covalently stapled self-assembled artificial channels activatable by biocompatible visible light at 442 nm, which enables the co-transport of H+ /Cl- across the membrane with H+ /Cl- transport selectivity of 6.0. Upon photoirradiation of the caged C4F-L for 10 min, 90 % of ion transport efficiency can be restored, giving rise to a 10.5-fold enhancement in cytotoxicity against human colorectal cancer cells (IC50 =8.5 µM). The mechanism underlying cancer cell death mediated by the H+ /Cl- channels involves the activation of the caspase 9 apoptosis pathway as well as the scarcely reported disruption of the autophagic processes. In the absence of photoirradiation, C4F-L exhibits minimal toxicity towards normal intestine cells, even at a concentration of 200 µM.

Exosomes from adipose-derived mesenchymal stem cells improve liver fibrosis by regulating the miR-20a-5p/TGFBR2 axis to affect the p38 MAPK/NF-κB pathway.

OBJECTIVE: Human adipose-derived mesenchymal stem cell exosomes (ADSC-Exos) are active constituents for treating liver fibrosis. This paper attempted to preliminarily explain the functional mechanism of ADSC-Exos in liver fibrosis through the p38 MAPK/NF-κB pathway. METHODS: The cell models of hepatic fibrosis were established by inducing LX-2 cells with TGF-ß1. Mouse models of liver fibrosis were established by treating mice with CCl4. The in vivo and in vitro models of liver fibrosis were treated with ADSC-Exos. ADSCs were identified by flow cytometry/Alizarin red/oil red O/alcian blue staining. ADSC-Exos were identified by transmission electron microscopy, nanoparticle tracking analysis, and Western blot. LX-2 cell proliferation/viability were evaluated by MTT/BrdU assays. Exosomes were tracked in vivo and body weight changes in mice were monitored. Hepatic pathological changes were observed by HE/Masson staining. α-SMA/collagen I levels in liver tissues were assessed by immunohistochemistry. HA/PIIINP concentrations were measured using the magnetic particle chemiluminescence method. Liver function was assessed using an automatic analyzer. miR-20a-5p level was measured by RT-qPCR. The mRNA levels of fibrosis markers were determined by RT-qPCR, and their protein levels and levels of MAPK/NF-κB pathway-related proteins, as well as TGFBR2 protein level were measured by Western blot. The P65 nuclear expression in mouse liver tissues was quantified by immunofluorescence. RESULTS: ADSC-Exos suppressed TGF-ß1-induced LX-2 cell proliferation and fibrosis and reduced mRNA and protein levels of fibrosis markers in vitro. ADSC-Exos ameliorated liver fibrosis by inhibiting the p38 MAPK/NF-κB pathway activation. ADSC-Exos inhibited activation of the p38 MAPK/NF-κB pathway via regulating the miR-20a-5p/TGFBR2 axis. The in vivo experiment asserted that ADSC-Exos were mainly distributed in the liver, and ADSC-Exos relieved liver fibrosis in mice, which was evidenced by alleviating decreased body weight, reducing collagen and enhancing liver function, and repressed the activation of the p38 MAPK/NF-κB pathway via the miR-20a-5p/TGFBR2 axis. CONCLUSION: ADSC-Exos attenuated liver fibrosis by suppressing the activation of the p38 MAPK/NF-κB pathway via the miR-20a-5p/TGFBR2 axis.

Dihydrotrichodimerol Purified from the Marine Fungus Acremonium citrinum Prevents NAFLD by Targeting PPARα.

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is closely linked to the imbalance of lipid and glucose metabolism, in which peroxisome proliferator-activated receptors (PPARs) play essential roles. The clinical trials have shown the beneficial effects of the PPARs' ligands on NAFLD. In this study, we screen the extracts from the marine fungus Acremonium citrinum and identify the natural compounds dihydrotrichodimerol (L1A) and trichodimerol (L1B) as the ligands of PPARs, of which L1A is a dual PPARα/γ agonist, whereas L1B is a selective PPARγ agonist. L1A but not L1B significantly prevents hepatic lipid accumulation in an oleic acid-induced NAFLD cell model as well as in a high-fat-diet-induced NAFLD mouse model. Moreover, L1A potently inhibits hepatic steatosis in a PPARα-dependent manner in another NAFLD mouse model constructed by using a choline-deficient and amino acid-defined diet. Mechanistically, L1A transcriptionally up-regulates the expression of SIRT1 in a PPARα-dependent manner, followed by the activation of AMPK and inactivation of ACC, resulting in the inhibition of lipid anabolism and the increase of lipid catabolism. Taken together, our study reveals a dual ligand of PPARα/γ with a distinct structure and therapeutic effect on NAFLD, providing a potential drug candidate bridging the currently urgent need for the management of NAFLD.

Strong Metal-Support Interaction Boosts Activity, Selectivity, and Stability in Electrosynthesis of H2O2.

Noble metals have an irreplaceable role in catalyzing electrochemical reactions. However, large overpotential and poor long-term stability still prohibit their usage in many reactions (e.g., oxygen evolution/reduction). With regard to the low natural abundance, the improvement of their overall electrocatalytic performance (activity, selectivity, and stability) was urgently necessary. Herein, strong metal-support interaction (SMSI) was modulated through an unprecedented time-dependent mechanical milling method on Pd-loaded oxygenated TiC electrocatalysts. The encapsulation of Pd surfaces with reduced TiO2-x overlayers is precisely controlled by the mechanical milling time. This encapsulation induced a valence band restructuring and lowered the d-band center of surface Pd atoms. For hydrogen peroxide electrosynthesis through the two-electron oxygen reduction reaction (ORR), these electronic and geometric modifications resulted in optimal adsorption energies of reaction intermediates. Thus, SMSI phenomena not only enhanced electrocatalytic activity and selectivity but also created an encapsulating oxide overlayer that protected the Pd species, increasing its long-term stability. This SMSI induced by mechanical milling was also extended to other noble metal systems, showing great promise for the large-scale production of highly stable and tunable electrocatalysts.

Merbromin is a mixed-type inhibitor of 3-chyomotrypsin like protease of SARS-CoV-2.

3-chyomotrypsin like protease (3CLpro) has been considered as a promising target for developing anti-SARS-CoV-2 drugs. Herein, about 6000 compounds were analyzed by high-throughput screening using enzyme activity model, and Merbromin, an antibacterial agent, was identified as a potent inhibitor of 3CLpro. Merbromin strongly inhibited the proteolytic activity of 3CLpro but not the other three proteases Proteinase K, Trypsin and Papain. Michaelis-Menten kinetic analysis showed that Merbromin was a mixed-type inhibitor of 3CLpro, due to its ability of increasing the KM and decreasing the Kcat of 3CLpro. The binding assays and molecular docking suggested that 3CLpro possessed two binding sites for Merbromin. Consistently, Merbromin showed a weak binding to the other three proteases. Together, these findings demonstrated that Merbromin is a selective inhibitor of 3CLpro and provided a scaffold to design effective inhibitors of SARS-CoV-2.

Design, synthesis and biological evaluation of acyl hydrazones-based derivatives as RXRα-targeted anti-mitotic agents.

RXRα, a unique and important nuclear receptor, plays a vital role in various biological and pathological pathways, including growth, differentiation, and apoptosis. We recently reported a transcription-independent function of RXRα in cancer cells in which RXRα is phosphorylated by Cdk1 at the onset of mitosis, resulting in its translocation to the centrosome, where the phosphorylated RXRα (p-RXRα) interacts with polo-like kinase 1 (PLK1) to promote centrosome maturation and mitotic progression. Significantly, we also identified that a small molecule XS-060 binds to RXRα and selectively inhibits the p-RXRα/PLK1 interaction to induce mitotic arrest and catastrophe in cancer cells. Here, we report our design, synthesis, and biological evaluation of a series of XS-060 analogs as RXRα-targeted anti-mitotic agents. Our results identified B10 as an improved anti-mitotic agent. B10 bound to RXRα (Kd = 3.04 ± 0.58 µM) and inhibited the growth of cervical cancer cells (HeLa, IC50 = 1.46 ± 0.10 µM) and hepatoma cells (HepG2, IC50 = 3.89 ± 0.45 µM and SK-hep-1, IC50 = 5.74 ± 0.50 µM) with low cytotoxicity to nonmalignant cells(LO2, IC50 > 50 µM). Furthermore, our mechanistic studies confirmed that B10 acted as an anticancer agent by inhibiting the p-RXRα/PLK1 pathway. These results provide a basis for further investigation and optimization of RXRα-targeted anti-mitotic molecules for cancer therapy.

SAR study of oxidative DIMs analogs targeting the Nur77-mediated apoptotic pathway of cancer cells.

Nur77, an orphan nuclear receptor, is implicated in regulating diverse cellular biological processes including apoptosis and inflammation. We previously identified BI1071 (DIM-C-pPhCF3+MeSO3-), an oxidized methanesulfonate salt of (4-CF3-Ph-C-DIM), was a direct ligand of Nur77, which could activate the Nur77-Bcl-2 apoptotic pathway. To obtain more effective compounds targeting the Nur77-mediated apoptotic pathway, we designed and synthesized a series of BI1071 analogs by introducing various substituent groups in the indolyl-rings of BI1071. Structure-activity relationship study identified A11, B5 and B15 as improved analogs with stronger binding affinity to Nur77 and enhanced apoptotic activity compared to BI1071. Nur77-binding studies demonstrated that A11, B5 and B15 bind to Nur77 with a Kd of 34 nM, 19 nM and 16 nM, respectively. Furthermore, mechanism studies showed that A11, B5 and B15 induced apoptosis through utilizing the Nur77-Bcl-2 pathway.

Experimental Research on Vibration-Damping Effect of Combined Shear Hinge Prefabricated Steel Spring Floating Slab Track.

OBJECTIVE: The cast-in-place steel spring floating slab track (SSFST) is difficult to maintain and repair, while the mechanical strength of the end of the traditional prefabricated SSFST is poor. In order to overcome the above shortcomings, a shear-hinge-combined prefabricated SSFST was developed, and an indoor test was carried out to analyze its vibration-damping effect. METHODS: A combined shear hinge SSFST connection model with two length sizes was established. The dynamic response amplitude and frequency response characteristics of the foundation (ground) under different isolator installations and fatigue loads were studied, and the vibration-damping performance of two sizes of combined shear hinge SSFST was evaluated. RESULTS: The vibration-damping effect of the steel spring vibration isolator mainly acts in the middle and low-frequency bands of 16-400 Hz, and the vibration near 10 Hz will be aggravated after the vibration isolator is installed. The vibration index and variation law of the two sizes of SSFST are similar, and the vibration response of 4.8 m SSFST is slightly less than 3.6 m SSFST. There is almost no change in each index when the load is 5 million times, and there is a certain range of change when the load is 10 million times, but the overall change is small. CONCLUSIONS: The combined shear hinge prefabricated SSFST can have an excellent isolation effect on vibration and can still maintain good vibration-damping ability within 10 million fatigue loads (about 5 years); 4.8 m SSFST should be laid in straight sections with higher train speeds, while 3.6 m SSFST should be applied in curved sections to ensure smooth lines.

Engineering Support and Distribution of Palladium and Tin on MXene with Modulation of the d-Band Center for CO-resilient Methanol Oxidation.

The efficiency of direct methanol fuel cell (DMFC) is largely determined by the activity and durability of methanol oxidation reaction (MOR) catalysts. Herein, we present a CO-resilient MOR catalyst of palladium-tin nano-alloy anchored on Se-doped MXene (PdSn0.5 /Se-Ti3 C2 ) via a progressive one-step electrochemical deposition strategy. MOR mass activity resulting from Pd/Se-Ti3 C2 catalyst (1046.2 mA mg-1 ) is over 2-fold larger than that of Pd/Ti3 C2 , suggesting that the introduction of Se atoms on MXene might accelerate the reaction kinetics. PdSn0.5 /Se-Ti3 C2 with Se-doping progress of MXene and the cooperated Pd-Sn sites has a superior MOR mass activity (4762.8 mA mg-1 ), outperforming many other reported Pd-based catalysts. Both experimental results and theoretical calculation reveal that boosted electron interaction of metal crystals with Se-doped MXene and optimized distribution of Pd-Sn sites can modulate the d band center, reduce adsorption energies of CO* at Pd site and enhance OH* generation at Sn site, resulting in highly efficient removal of CO intermediates by reaction with neighboring OH species on adjacent Sn sites.

Tgfb3 and Mmp13 regulated the initiation of liver fibrosis progression as dynamic network biomarkers.

Liver fibrogenesis is a complex scar-forming process in the liver. We suggested that the liver first responded to chronic injuries with gradual changes, then reached the critical state and ultimately resulted in cirrhosis rapidly. This study aimed to identify the tipping point and key molecules driving liver fibrosis progression. Mice model of liver fibrosis was induced by thioacetamide (TAA), and liver tissues were collected at different time-points post-TAA administration. By dynamic network biomarker (DNB) analysis on the time series of liver transcriptomes, the week 9 post-TAA treatment (pathologically relevant to bridging fibrosis) was identified as the tipping point just before the significant fibrosis transition, with 153 DNB genes as key driving factors. The DNB genes were functionally enriched in fibrosis-associated pathways, in particular, in the top-ranked DNB genes, Tgfb3 negatively regulated Mmp13 in the interaction path and they formed a bistable switching system from a dynamical perspective. In the in vitro study, Tgfb3 promoted fibrogenic genes and down-regulate Mmp13 gene transcription in an immortalized mouse HSC line JS1 and a human HSC line LX-2. The presence of a tipping point during liver fibrogenesis driven by DNB genes marks not only the initiation of significant fibrogenesis but also the repression of the scar resolution.

3-Cl-AHPC inhibits pro-HGF maturation by inducing matriptase/HAI-1 complex formation.

Matriptase is an epithelia-specific membrane-anchored serine protease, and its dysregulation is highly related to the progression of a variety of cancers. Hepatocyte growth factor activator inhibitor-1 (HAI-1) inhibits matriptase activity through forming complex with activated matriptase. The balance of matriptase activation and matriptase/HAI-1 complex formation determines the intensity and duration of matriptase activity. 3-Cl-AHPC, 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid, is an adamantly substituted retinoid-related molecule and a ligand of retinoic acid receptor γ (RARγ). 3-Cl-AHPC is of strong anti-cancer effect but with elusive mechanisms. In our current study, we show that 3-Cl-AHPC time- and dose- dependently induces matriptase/HAI-1 complex formation, leading to the suppression of activated matriptase in cancer cells and tissues. Furthermore, 3-Cl-AHPC promotes matriptase shedding but without increasing the activity of shed matriptase. Moreover, 3-Cl-AHPC inhibits matriptase-mediated cleavage of pro-HGF through matriptase/HAI-1 complex induction, resulting in the suppression of pro-HGF-stimulated signalling and cell scattering. Although 3-Cl-AHPC binds to RARγ, its induction of matriptase/HAI-1 complex is not RARγ dependent. Together, our data demonstrates that 3-Cl-AHPC down-regulates matriptase activity through induction of matriptase/HAI-1 complex formation in a RARγ-independent manner, providing a mechanism of 3-Cl-AHPC anti-cancer activity and a new strategy to inhibit abnormal matriptase activity via matriptase/HAI-1 complex induction using small molecules.

Breaking Long-Range Order in Iridium Oxide by Alkali Ion for Efficient Water Oxidation.

Oxygen electrochemistry plays a critical role in clean energy technologies such as fuel cells and electrolyzers, but the oxygen evolution reaction (OER) severely restricts the efficiency of these devices due to its slow kinetics. Here, we show that via incorporation of lithium ion into iridium oxide, the thus obtained amorphous iridium oxide (Li-IrO x) demonstrates outstanding water oxidation activity with an OER current density of 10 mA/cm2 at 270 mV overpotential for 10 h of continuous operation in acidic electrolyte. DFT calculations show that lithium incorporation into iridium oxide is able to lower the activation barrier for OER. X-ray absorption characterizations indicate that both amorphous Li-IrO x and rutile IrO2 own similar [IrO6] octahedron units but have different [IrO6] octahedron connection modes. Oxidation of iridium to higher oxidation states along with shrinkage in the Ir-O bond was observed by in situ X-ray absorption spectroscopy on amorphous Li-IrO x, but not on rutile IrO2 under OER operando conditions. The much more "flexible" disordered [IrO6] octahedrons with higher oxidation states in amorphous Li-IrO x as compared to the periodically interconnected "rigid" [IrO6] octahedrons in crystalline IrO2 are able to act as more electrophilic centers and thus effectively promote the fast turnover of water oxidation.

Retinoid X Receptor Alpha Nitro-ligand Z-10 and Its Optimized Derivative Z-36 Reduce ß-Amyloid Plaques in Alzheimer's Disease Mouse Model.

Bexarotene, an agonist of retinoid X receptor alpha (RXRα), has been shown to increase the expression of apoE, ABCA1, and ABCG1 by activating RXR/LXR and RXR/PPAR heterodimers, resulting in amyloid ß (Aß)-protein clearance in the brain of an Alzheimer's disease (AD) mouse model and reversal of mouse cognitive deficits. Nitrostyrene derivative Z-10 is the first identified nitro-ligand of RXRα. We hypothesized that Z-10 and its derivatives have the similar effect as bexarotene. A series of Z-10 derivatives were synthesized by introducing methoxyl, hydroxyl, and methoxy groups in 2- or 4-position of naphthalene ring, respectively. Our reporter gene assays showed that the derivatives with substituted groups of methyl and methoxyl in position 2 were more potent to activate Gal4-DBD/RXRα-LBD and RXRα homodimer as well as RXRα heterodimers than the corresponding 4-substituted derivatives. The derivatives with hydroxyl substitution in either 2- or 4-position failed to activate RXRα. Consistently, the derivatives with stronger potency of RXRα activation had higher RXRα binding affinity. Z-10 and its 2-ethyoxyl substituted derivative Z-36 reduced Aß plaques in both hippocampus and cortex of AD mouse model significantly, of which Z-36 had stronger efficacy. This may due to the stronger ability of Z-36 than Z-10 in activating RXR/LXR and RXR/PPAR heterodimers and inducing ABCA1 and ABCG1 expressions. Thus, the 2- rather than 4-position was the better site for Z-10 modification as to RXRα transactivation, and Z-36 is an optimized derivative of Z-10 as to reducing Aß plaques in AD mouse model.

Lifetime super-resolution optical fluctuation imaging.

In this paper, we propose a promising super-resolution imaging scheme in fluorescence lifetime domain (lifetime super-resolution optical fluctuation imaging, ltSOFI). ltSOFI has the potential to obtain super-resolution images by taking advantage of fluorescence lifetime blinking under wide-field lifetime detection. The proof-of-concept for ltSOFI was demonstrated through numerical simulation of high-order cumulant analysis on fluorescence lifetime blinking emitters. As a tentative experimental demonstration, we obtained super-resolution lifetime imaging from time-lapse FLIM recording of HeLa cells expressing a cAMP sensor using ltSOFI method. ltSOFI is expected to initiate a new dimension in the lifetime domain for blinking-based super-resolution microscopy. LAY DESCRIPTION: We report on a promising super-resolution imaging scheme in fluorescence lifetime domain (lifetime super-resolution optical fluctuation imaging, ltSOFI). ltSOFI has the potential to obtain super-resolution images by taking advantage of fluorescence lifetime blinking under wide-field lifetime detection. Past advances in super-resolution fluorescence microscopy primarily rely on the spatiotemporal modulation of the fluorescence intensity. Although the applications of the Q-dot blinking have been discussed in the literature, most of the discussions have focused on the blinking of fluorescence intensity. Few studies have shown the possibility of super-resolution imaging through fluorescence lifetime fluctuations. In this paper, we proposed the ltSOFI scheme that explored the possibility of super-resolution reconstruction from the blinking of fluorescence lifetime. The proof-of-concept for ltSOFI was demonstrated through numerical simulation of high-order cumulant analysis on fluorescence lifetime blinking emitters. As a tentative experimental demonstration, we obtained super-resolution lifetime imaging from time-lapse FLIM recording of HeLa cells expressing a cAMP sensor using ltSOFI method. The ltSOFI method is expected to initiate a new dimension in the lifetime domain for blinking-based super-resolution microscopy. Moreover, the existing fluorescence lifetime imaging microscopy and super-resolution nanoscopy can benefit from the implementation of ltSOFI to significantly improve the imaging spatial resolution of fluorescence lifetime images. In addition, the proof-of-concept demonstration achieved by the numerical simulation and tentative experiment will provide a new perspective for obtaining fluorescence lifetime images with much finer details.

Discovery of atorvastatin as a tetramer stabilizer of nuclear receptor RXRα through structure-based virtual screening.

Retinoid X receptor alpha (RXRα), a central member of the nuclear receptor superfamily and a key regulator of many signal transduction pathways, has been an attractive drug target. We previously discovered that an N-terminally truncated form of RXRα can be induced by specific ligands to form homotetramers, which, as a result of conformational selection, forms the basis for inhibiting the nongenomic activation of RXRα. Here, we report the identification and characterization of atorvastatin as a new RXRα tetramer stabilizer by using structure-based virtual screening and demonstrate that virtual library screening can be used to aid in identifying RXRα ligands that can induce its tetramerization. In this study, docking was applied to screen the FDA-approved small molecule drugs in the DrugBank 4.0 collection. Two compounds were selected and purchased for testing. We showed that the selected atorvastatin could bind to RXRα to promote RXRα-LBD tetramerization. We also showed that atorvastatin possessed RXRα-dependent apoptotic effects. In addition, we used a chemical approach to aid in the studies of the binding mode of atorvastatin.

Theoretical and experimental investigation of broadband dispersion tailoring of high-order mode in the hybrid microsphere cavity.

The large normal dispersion of the fundamental mode (TEn=1 mode) in the whispering gallery modes (WGM) microsphere is detrimental to the visible comb generation. Herein, we demonstrate that this fundamental limitation can be removed by considering the high-order radial modes (TEn=2 mode) of the hybrid microsphere cavity (HMC). The studied HMC consists of a high-refractive-index coating (TiO2 or HfO2) and silica microsphere. The simulated electric field energy distribution and measured Q value in our experiment show that optical confinement of the coating effectively excites the TEn=2 mode and reduces the free spectral range (FSR) and modal dispersion. In addition, the observed redshift of WGM and decreased trend of FSR are in accordance with simulations. The zero-dispersion wavelength can be linearly shifted to a shorter wavelength or even into the visible region with the reduction of coating thickness or refractive index and larger microcavity, which advances the visible comb generation.