Crosstalk between autophagy and inflammasomes in ricin-induced inflammatory injury.

Ricin (ricin toxin, RT) has the potential to cause damage to multiple organs and systems. Currently, there are no existing antidotes, vaccinations, or effective therapies to prevent or treat RT intoxication. Apart from halting protein synthesis, RT also induces oxidative stress, inflammation and autophagy. To explore the mechanisms of RT-induced inflammatory injury and specific targets of prevention and treatment for RT poisoning, we characterized the role of cross-talk between autophagy and NLRP3 inflammasome in RT-induced damage and elucidated the underlying mechanisms. We showed that RT-induced inflammation was attributed to activation of the TLR4/MyD88/NLRP3 signaling and ROS production, evidenced by increased ASC speck formation and attenuated TXNIP/TRX-1 interaction, as well as pre-treatment with MCC950, MyD88 knockdown and NAC significantly reduced IL-1ß, IL-6 and TNF-α mRNA expression. In addition, autophagy is also enhanced in RT-triggered MLE-12 cells. RT elevated the levels of ATG5, p62 and Beclin1 protein, provoked the accumulation of LC3 puncta detected by immunofluorescence staining. Treatment with rapamycin (Rapa) reversed the RT-caused TLR4/MyD88/NLRP3 signaling activation, ASC specks formation as well as the levels of IL-1ß, IL-6 and TNF-α mRNA. In conclusion, RT promoted NLRP3 inflammasome activation and autophgay. Inflammation induced by RT was attenuated by autophagy activation, which suppressed the NLRP3 inflammasome. These findings suggest Rapa as a potential therapeutic drug for the treatment of RT-induced inflammation-related diseases.

Advances in structural-guided modifications of siRNA.

To date, the US Food and Drug Administration (FDA) has approved six small interfering RNA (siRNA) drugs: patisiran, givosiran, lumasiran, inclisiran, vutrisiran, and nedosiran, serving as compelling evidence of the promising potential of RNA interference (RNAi) therapeutics. The successful implementation of siRNA therapeutics is improved through a combination of various chemical modifications and diverse delivery approaches. The utilization of chemically modified siRNA at specific sites on either the sense strand (SS) or antisense strand (AS) has the potential to enhance resistance to ribozyme degradation, improve stability and specificity, and prolong the efficacy of drugs. Herein, we provide comprehensive analyses concerning the correlation between chemical modifications and structure-guided siRNA design. Various modifications, such as 2'-modifications, 2',4'-dual modifications, non-canonical sugar modifications, and phosphonate mimics, are crucial for the activity of siRNA. We also emphasize the essential strategies for enhancing overhang stability, improving RISC loading efficacy and strand selection, reducing off-target effects, and discussing the future of targeted delivery.

Telecom-wavelength conversion in a high optical depth cold atomic system.

We experimentally investigate the frequency down-conversion through the four-wave mixing (FWM) process in a cold 85Rb atomic ensemble, with a diamond-level configuration. An atomic cloud with a high optical depth (OD) of 190 is prepared to achieve a high efficiency frequency conversion. Here, we convert a signal pulse field (795 nm) attenuated to a single-photon level, into a telecom light at 1529.3 nm within near C-band range and the frequency-conversion efficiency can reach up to 32%. We find that the OD is an essential factor affecting conversion efficiency and the efficiency may exceed 32% with an improvement in the OD. Moreover, we note the signal-to-noise ratio of the detected telecom field is higher than 10 while the mean signal count is larger than 0.2. Our work may be combined with quantum memories based on cold 85Rb ensemble at 795 nm and serve for long-distance quantum networks.

Highly Efficient Storage of 25-Dimensional Photonic Qudit in a Cold-Atom-Based Quantum Memory.

Building an efficient quantum memory in high-dimensional Hilbert spaces is one of the fundamental requirements for establishing high-dimensional quantum repeaters, where it offers many advantages over two-dimensional quantum systems, such as a larger information capacity and enhanced noise resilience. To date, it remains a challenge to develop an efficient high-dimensional quantum memory. Here, we experimentally realize a quantum memory that is operational in Hilbert spaces of up to 25 dimensions with a storage efficiency of close to 60% and a fidelity of 84.2±0.6%. The proposed approach exploits the spatial-mode-independent interaction between atoms and photons which are encoded in transverse-size-invariant vortex modes. In particular, our memory features uniform storage efficiency and low crosstalk disturbance for 25 individual spatial modes of photons, thus allowing the storing of qudit states programmed from 25 eigenstates within the high-dimensional Hilbert spaces. These results have great prospects for the implementation of long-distance high-dimensional quantum networks and quantum information processing.

Design and synthesis of novel GluN2A NMDAR positive allosteric modulators via scaffold hopping strategy as anti-stroke therapeutic agents.

NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo . Activation of NR2A-containing NMDA receptors promotes neuronal survival and exerts a neuroprotective action, whereas over activating GluN2B-containing receptor results in excitotoxicity, increasing neuronal apoptosis. Our previous study has identified Npam 43 as a NMDAR positive allosteric modulators. However, the cis-trans isomerization impedes the development of Npam 43 as potential neuroprotective agents. To discover more potent and selective GluN2A NMDAR positive allosteric modulators, 38 derivatives were synthesized and evaluated their neuroprotective effect on glutamate-exposed PC-12 cells. The allosteric activities of compounds were evaluated using calcium imaging approaches. Among them, compound 5c exhibit GluN1/2A selectivity over GluN1/2B and show neuroprotective activity in vitro and in vivo. This study reported a series of GluN1/2A positive allosteric modulators as neuroprotective agents, and provided a potential opportunity to discover new drugs for stroke treatment.

Long-Lived Memory for Orbital Angular Momentum Quantum States.

Quantum memories that are capable of storing multiple spatial modes offer advantages in speed and robustness when incorporated into quantum networks. When it comes to spatial degrees of freedom, orbital angular momentum (OAM) modes have received widespread attention since they enable encoding with inherent infinite number of dimensions. Although the faithful storage of OAM qubits or qutrits has been realized in previous works, the achieved lifetimes are still on the order of a few microseconds as limited by the spatially dependent decoherence. We here demonstrate a long-lived quantum memory for OAM qutrits by suppressing the decoherence in the transverse and longitude direction simultaneously; the achieved fidelity beats the quantum-classical criteria after a storage time of 400 µs, which is 2 orders of magnitude longer than earlier works. The present work is promising for establishing high-dimensional quantum networks.

A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects.

N-methyl-D-aspartate receptor (NMDAR) antagonists have been found to be effective to inhibit morphine dependence. However, the discovery of the selective antagonist for NMDAR GluN2B with low side-effects still remains challenging. In the present study, we report a selective NMDAR GluN2B antagonist con-T[M8Q](a conantokin-T variant) that potently inhibits the naloxone-induced jumping and conditioned place preference of morphine-dependent mice at nmol/kg level, 100-fold higher than ifenprodil, a classical NMDAR NR2B antagonist. Con-T[M8Q] displays no significant impacts on coordinated locomotion function, spontaneous locomotor activity, and spatial memory mice motor function at the dose used. Further molecular mechanism experiments demonstrate that con-T[M8Q] effectively inhibited the transcription and expression levels of signaling molecules related to NMDAR NR2B subunit in hippocampus, including NR2B, p-NR2B, CaMKII-α, CaMKII-ß, CaMKIV, pERK, and c-fos. The high efficacy and low side effects of con-T[M8Q] make it a good lead compound for the treatment of opiate dependence and for the reduction of morphine usage.

Entangled qutrits generated in four-wave mixing without post-selection.

High-dimensional entangled states and quantum repeaters are important elements in efficient long-range quantum communications. The high-dimensional property associated with the orbital angular momentum (OAM) of each photon improves the bandwidth of the quantum communication network. However, the generation of high-dimensional entangled states by the concentration method reduces the brightness of the entangled light source, making extensions to these higher dimensions difficult. To overcome this difficulty, we propose to generate entangled qutrits in the OAM space by loading the pump light with OAM. Compared with the concentration method, our experimental results show that the rate of generation of photon pairs improves significantly with an observed 5.5-fold increase. The increased generation rate provides the system with the ability to resist the noise and improve the fidelity of the state. The S value of the Clauser-Horne-Shimony-Holt inequality increases from 2.48 ± 0.07 to 2.69 ± 0.04 under the same background noise, and the fidelity of the reconstructed density matrix improves from 57.8 ± 0.14% to 70 ± 0.17%. These achievements exhibit the enormous advantages of high-dimensional entanglement generation.

Experimental realization of optical storage of vector beams of light in warm atomic vapor.

Vector beams have drawn considerable interest recently because of their unique properties in the transverse plane. Here we experimentally realize optical storage of a vector beam of light in a warm cell. The vector beam is tailored using a Sagnac interferometer containing an internal vortex phase plate, and the light pulse is stored in warm rubidium vapor. The preservation of both the spatial structure and the phase information is verified after retrieval. The implementation of vector beam storage in a room-temperature memory has potential for use in the fabrication of versatile vortex-based quantum networks.

TAT-Modified ω-Conotoxin MVIIA for Crossing the Blood-Brain Barrier.

As the first in a new class of non-opioid drugs, ω-Conotoxin MVIIA was approved for the management of severe chronic pains in patients who are unresponsive to opioid therapy. Unfortunately, clinical application of MVIIA is severely limited due to its poor ability to penetrate the blood-brain barrier (BBB), reaching the central nervous system (CNS). In the present study, we have attempted to increase MVIIA's ability to cross the BBB via a fusion protein strategy. Our results showed that when the TAT-transducing domain was fused to the MVIIA C-terminal with a linker of varied numbers of glycine, the MVIIA-TAT fusion peptide exhibited remarkable ability to cross the bio-membranes. Most importantly, both intravenous and intranasal administrations of MVIIA-TAT in vivo showed therapeutic efficacy of analgesia. Compared to the analgesic effects of intracerebral administration of the nascent MVIIA, these systemic administrations of MVIIA-TAT require higher doses, but have much prolonged effects. Taken together, our results showed that TAT conjugation of MVIIA not only enables its peripheral administration, but also maintains its analgesic efficiency with a prolonged effective time window. Intranasal administration also rendered the MVIIA-TAT advantages of easy applications with potentially reduced side effects. Our results may present an alternative strategy to improve the CNS accessibility for neural active peptides.

Design, Synthesis, and Biological Evaluation of Axitinib Derivatives.

Axitinib is an approved kinase inhibitor for the therapy of advanced metastatic renal cell carcinoma (RCC). It prevents angiogenesis, cellular adhesion, and induces apoptosis of cancer cells. Here, nine axitinib derivatives were designed by replacing the C=C moiety with the N=N group, and the substituted benzene or pyrrole analogs were considered to replace the pyridine ring. Biological activity results showed that most of nascent derivatives exhibited favorable VEGFR-2 kinase inhibitory activities, and TM6, 7, 9, and 11 behaved more potent anti-proliferative activities than axitinib. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.

Near-Infrared Photoswitching of Azobenzenes under Physiological Conditions.

Biological tissue exhibits an absorbance minimum in the near-infrared between 700 and 900 nm that permits deep penetration of light. Molecules that undergo photoisomerization in this bio-optical window are highly desirable as core structures for the development of photopharmaceuticals and as components of chemical-biological tools. We report the systematic design, synthesis, and testing of an azobenzene derivative tailored to undergo single-photon photoswitching with near-infrared light under physiological conditions. A fused dioxane ring and a methoxy substituent were used to place oxygen atoms in all four ortho positions, as well as two meta positions, relative to the azobenzene N═N double bond. This substitution pattern, together with a para pyrrolidine group, raises the pKa of the molecule so that it is protonated at physiological pH and absorbs at wavelengths >700 nm. This azobenzene derivative, termed DOM-azo, is stable for months in neutral aqueous solutions, undergoes trans-to-cis photoswitching with 720 nm light, and thermally reverts to the stable trans isomer with a half-life near 1 s.

Two-color hyper-entangled photon pairs generation in a cold 85Rb atomic ensemble.

Hyper-entangled photon pairs are very promising in the quantum information field for enhancing the channel capacity in communication and improving compatibility for networks. Here we report on the experimental generation of a hyper-entangled photon pair at a wavelength of 795 nm and 1475 nm via the spontaneous four-wave mixing process in a cold 85Rb atomic ensemble. The photons in each pair generated are entangled in both the time-frequency and polarization degrees of freedom. Such hyper-entangled photon pairs with special wavelength have potential applications in high-dimensional quantum communication and quantum physics.

Experimental realization of narrowband four-photon Greenberger-Horne-Zeilinger state in a single cold atomic ensemble.

Multi-photon entangled states not only play a crucial role in research on quantum physics but also have many applications in quantum information fields such as quantum computation, quantum communication, and quantum metrology. To fully exploit the multi-photon entangled states, it is important to establish the interaction between entangled photons and matter, which requires that photons have narrow bandwidth. Here, we report on the experimental generation of a narrowband four-photon Greenberger-Horne-Zeilinger state with a fidelity of 64.9% through multiplexing two spontaneous four-wave mixings in a cold Rb85 atomic ensemble. The full bandwidth of the generated GHZ state is about 19.5 MHz. Thus, the generated photons can effectively match the atoms, which are very suitable for building a quantum computation and quantum communication network based on atomic ensembles.

Controlling N2O formation during regeneration of NOx storage and reduction catalysts: from impact of platinum-group metal type to rational utilization.

Herein, we report an effective strategy for minimization of N2O emissions based on elucidating the impact of the type of platinum-group metals (PGMs = Pt, Pd, or Rh) on by-product formation during regeneration of PGM-BaO/Al2O3 catalysts. The significant differences in N2O or NH3 formation were thoroughly investigated from the perspective of an in situ reaction. Kinetic analysis of NO reduction by CO shows different turnover frequency and apparent activation energy values over these catalysts. The results reveal that the apparent kinetics is dependent on the type of platinum-group metal chosen. In situ DRIFTS data indicate that the unique adsorption behaviors of reactants via which they access each PGM essentially determine their individual reaction kinetics. The preferential adsorption of NO or CO molecules on the PGM surface controls the dominant intermediate (NOad/Nad, COad, or NCOad) species, which is a major factor responsible for various yields of N2O and NH3 during the rich period. Finally, a feasible strategy has been proposed via optimizing catalyst formulation to effectively control the N2O emissions.

Red-Shifting Azobenzene Photoswitches for in Vivo Use.

Recently, there has been a great deal of interest in using the photoisomerization of azobenzene compounds to control specific biological targets in vivo. These azo compounds can be used as research tools or, in principle, could act as optically controlled drugs. Such "photopharmaceuticals" offer the prospect of targeted drug action and an unprecedented degree of temporal control. A key feature of azo compounds designed to photoswitch in vivo is the wavelength of light required to cause the photoisomerization. To pass through tissue such as the human hand, wavelengths in the red, far-red, or ideally near infrared region are required. This Account describes our attempts to produce such azo compounds. Introducing electron-donating or push/pull substituents at the para positions delocalizes the azobenzene chromophore and leads to long wavelength absorption but usually also lowers the thermal barrier to interconversion of the isomers. Fast thermal relaxation means it is difficult to produce a large steady state fraction of the cis isomer. Thus, specifically activating or inhibiting a biological process with the cis isomer would require an impractically bright light source. We have found that introducing substituents at all four ortho positions leads to azo compounds with a number of unusual properties that are useful for in vivo photoswitching. When the para substituents are amide groups, these tetra-ortho substituted azo compounds show unusually slow thermal relaxation rates and enhanced separation of n-π* transitions of cis and trans isomers compared to analogues without ortho substituents. When para positions are substituted with amino groups, ortho methoxy groups greatly stabilize the azonium form of the compounds, in which the azo group is protonated. Azonium ions absorb strongly in the red region of the spectrum and can reach into the near-IR. These azonium ions can exhibit robust cis-trans isomerization in aqueous solutions at neutral pH. By varying the nature of ortho substituents, together with the number and nature of meta and para substituents, long wavelength switching, stability to photobleaching, stability to hydrolysis, and stability to reduction by thiols can all be crafted into a photoswitch. Some of these newly developed photoswitches can be used in whole blood and show promise for effective use in vivo. It is hoped they can be combined with appropriate bioactive targets to realize the potential of photopharmacology.

Orbital Angular Momentum-Entanglement Frequency Transducer.

Entanglement is a vital resource for realizing many tasks such as teleportation, secure key distribution, metrology, and quantum computations. To effectively build entanglement between different quantum systems and share information between them, a frequency transducer to convert between quantum states of different wavelengths while retaining its quantum features is indispensable. Information encoded in the photon's orbital angular momentum (OAM) degrees of freedom is preferred in harnessing the information-carrying capacity of a single photon because of its unlimited dimensions. A quantum transducer, which operates at wavelengths from 1558.3 to 525 nm for OAM qubits, OAM-polarization hybrid-entangled states, and OAM-entangled states, is reported for the first time. Nonclassical properties and entanglements are demonstrated following the conversion process by performing quantum tomography, interference, and Bell inequality measurements. Our results demonstrate the capability to create an entanglement link between different quantum systems operating in a photon's OAM degrees of freedom, which will be of great importance in building a high-capacity OAM quantum network.

Novel diamine-scaffold based N-acetylgalactosamine (GalNAc)-siRNA conjugate: synthesis and in vivo activities.

GalNAc-conjugated siRNA has shown remarkable potential in liver-targeted delivery in recent years. In general, tetrahydroxymethylmethane or other branching clusters constitute the basis of GalNAc's structure, which yields trivalent or tetravalent ligands. A novel diamine-scaffold GalNAc conjugate was synthesized and evaluated for its efficiency in siRNA administration. It exhibits comparable siRNA delivery effectiveness to a GalNAc NAG37 phase II clinical drug candidate targeting ANGPTL3. In addition, it exhibits more powerful silencing activity when connected to the 3'-end of the sense strand with an additional PS-linkage instead of a PO linkage between the ligand and the oligomer compared to a GalNAc L96 standard targeting TTR. Taken together, the incorporation of a diamine-scaffold into the GalNAc conjugate structure has potential in the field of gene therapy.

Discovery of novel positive allosteric modulators targeting GluN1/2A NMDARs as anti-stroke therapeutic agents.

Excitotoxicity due to excessive activation of NMDARs is one of the main mechanisms of neuronal death during ischemic stroke. Previous studies have suggested that activation of either synaptic or extrasynaptic GluN2B-containing NMDARs results in neuronal damage, whereas activation of GluN2A-containing NMDARs promotes neuronal survival against ischemic insults. This study applied a systematic in silico, in vitro, and in vivo approach to the discovery of novel and potential GluN1/2A NMDAR positive allosteric modulators (PAMs). Ten compounds were obtained and identified as potential GluN1/2A PAMs by structure-based virtual screening and calcium imaging. The neuroprotective activity of the candidate compounds was demonstrated in vitro. Subsequently, compound 15 (aegeline) was tested further in the model of transient middle cerebral artery occlusion (tMCAO) in vivo, which significantly decreased cerebral infarction. The mechanism by which aegeline exerts its effect on allosteric modulation was revealed using molecular dynamics simulations. Finally, we found that the neuroprotective effect of aegeline was significantly correlated with the enhanced phosphorylation of cAMP response element-binding protein (CREB). Our study discovered the neuroprotective effect of aegeline as a novel PAM targeting GluN1/2A NMDAR, which provides a potential opportunity for the development of therapeutic agents for ischemic stroke.

Wighteone, a prenylated flavonoid from licorice, inhibits growth of SW480 colorectal cancer cells by allosteric inhibition of Akt.

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice is a frequently used herbal medicine worldwide, and is used to treat cough, hepatitis, cancer and influenza in clinical practice of traditional Chinese medicine. Modern pharmacological studies indicate that prenylated flavonoids play an important role in the anti-tumor activity of licorice, especially the tumors in stomach, lung, colon and liver. Wighteone is one of the main prenylated flavonoids in licorice, and its possible effect and target against colorectal cancer have not been investigated. AIM OF THE STUDY: This study aimed to investigate the anti-colorectal cancer effect and underlying mechanism of wighteone. MATERIALS AND METHODS: SW480 human colorectal cancer cells were used to evaluate the in vitro anti-colorectal cancer activity and Akt regulation effect of wighteone by flow cytometry, phosphoproteomic and Western blot analysis. Surface plasmon resonance (SPR) assay, molecular docking and dynamics simulation, and kinase activity assay were used to investigate the direct interaction between wighteone and Akt. A nude mouse xenograft model with SW480 cells was used to verify the in vivo anti-colorectal cancer activity of wighteone. RESULTS: Wighteone inhibited phosphorylation of Akt and its downstream kinases in SW480 cells, which led to a reduction in cell viability. Wighteone had direct interaction with both PH and kinase domains of Akt, which locked Akt in a "closed" conformation with allosteric inhibition, and Gln79, Tyr272, Arg273 and Lys297 played the most critical role due to their hydrogen bond and hydrophobic interactions with wighteone. Based on Akt overexpression or activation in SW480 cells, further mechanistic studies suggested that wighteone-induced Akt inhibition led to cycle arrest, apoptosis and autophagic death of SW480 cells. Moreover, wighteone exerted in vivo anti-colorectal cancer effect and Akt inhibition activity in the nude mouse xenograft model. CONCLUSION: Wighteone could inhibit growth of SW480 cells through allosteric inhibition of Akt, which led to cell cycle arrest, apoptosis and autophagic death. The results contributed to understanding of the anti-tumor mechanism of licorice, and also provided a rationale to design novel Akt allosteric inhibitors for the treatment of colorectal cancer.