NLRP3 Inflammasome Activation Mediates Hepatitis E Virus-Induced Neuroinflammation.

Hepatitis E virus (HEV) is a foodborne zoonotic pathogen that is supposed to be one of the most common causes of acute viral hepatitis. However, HEV infection has been recently associated with a wide spectrum of extrahepatic manifestations, particularly neurological disorders. Previous studies have shown that HEV is able to cross the blood-brain barrier (BBB) and induce inflammatory response of the central nervous system. However, the pathogenesis of HEV-induced neuroinflammation and tissue injury of the central nervous system have yet to be fully elucidated. In this study, activation of NLRP3 inflammasome following HEV infection were investigated. In a gerbil model infected by HEV, brain histopathological changes including gliosis, neuronophagia and neuron injury were observed and expression of NLRP3, caspase-1, IL-1ß and IL-18 were elevated. Brain microvascular endothelial cells (BMECs) are key components of the BBB that protects the brain from various challenges. Following HEV infection, virus-like particles range from 30 to 40 nm in diameter were observed in human BMECs (hBMECs). Enhanced expression levels of NLRP3 and subsequent ASC, caspase-1, IL-1ß and IL-18 were detected in infected cells. Treatment with MCC950 alleviated HEV infection induced activation of NLRP3 inflammasome, mitochondrial damage and VE-cadherin degradation. The findings provide new insights into HEV-associated neuroinflammation. Moreover, targeting NLRP3 inflammasome signalling is a promising therapeutic in HEV-induced neurological disorder.

Effect of oral administration of pregabalin on physiological and echocardiographic variables in healthy cats.

OBJECTIVES: The aim of this study was to evaluate the efficacy of a single dose of oral pregabalin (PGB) for sedation and its impact on physiological and echocardiographic variables in healthy cats. METHODS: This study was a randomised, blinded, crossover trial. Eight cats were randomly assigned to receive PGB or placebo, with a 1-week washout period between each administration. Cats in the treatment group received oral PGB at varying doses (low dose: 2.5 mg/kg, medium dose: 5 mg/kg, high dose: 10 mg/kg). Systolic blood pressure (SBP), pulse rate (PR), respiratory rate (RR) and sedation score were measured at intervals of 30 mins after administration. Echocardiography was performed 120 mins after administration. RESULTS: Oral administration of PGB 2.5 mg/kg and 5 mg/kg significantly increased sedation scores starting at 150 mins, while 10 mg/kg PGB showed a significant increase in sedation scores starting at 120 mins compared with placebo. PGB 5 mg/kg and 10 mg/kg resulted in a significant reduction in SBP compared with placebo, with minimal impact on PR and RR. In addition, PGB 10 mg/kg resulted in significant changes in the peak velocity of late diastolic transmitral flow (A) and the ratio of peak velocity of early diastolic transmitral flow and A; however, these changes were of marginal clinical significance. CONCLUSIONS AND RELEVANCE: A single dose of oral PGB could cause mild to moderate sedation. Hypotension was more prevalent in the PGB 5 mg/kg and 10 mg/kg groups among the majority of cats, but it was less frequently observed in the PGB 2.5 mg/kg group.

Cylindrical Vector Beam Holography without Preservation of OAM Modes.

Orbital angular momentum (OAM) multiplexed holograms have attracted a great deal of attention recently due to their physically unbounded set of orthogonal helical modes. However, preserving the OAM property in each pixel hinders fine sampling of the target image in principle and requires a fundamental filtering aperture array in the detector plane. Here, we demonstrate the concept of metasurface-based vectorial holography with cylindrical vector beams (CVBs), whose unlimited polarization orders and unique polarization distributions can be used to boost information storage capacity. Although CVBs are composed of OAM modes, the holographic images do not preserve the OAM modes in our design, enabling fine sampling of the target image in a quasi-continuous way like traditional computer-generated holograms. Moreover, the images can be directly observed by passing them through a polarizer without the need for a fundamental mode filter array. We anticipate that our method may pave the way for high-capacity holographic devices.

Tightly focusing metalens based on the high order Bessel function.

We propose a new, to the best of our knowledge, type of metalens of which the phase profile is extracted from the higher-order Bessel function. A light beam passing through this metalens would focus along the circular trajectory and produces a tightly focusing field. Utilizing phase binarization, we provide a method to design the geometric-phase dielectric metasurface both for phase and polarization modulations. We demonstrate two metalenses for circularly and radially polarized output beams at 633 nm, with the measured 0.737λ and 0.616λ focal spots, respectively. Theoretically, it can realize a super-diffraction-limit spot (0.38λ). This work can extend the way of realizing tightly focused optical devices.

Structure-Guided Design, Synthesis, and Antivirulence Assessment of Covalent Staphylococcus aureus Sortase A Inhibitors.

Sortase A (SrtA) is a membrane-associated cysteine transpeptidase required for bacterial virulence regulation and anchors surface proteins to cell wall, thereby assisting biofilm formation. SrtA is targeted in antivirulence treatments against Gram-positive bacterial infections. However, the development of potent small-molecule SrtA inhibitors is constrained owing to the limited understanding of the mode of action of inhibitors in the SrtA binding pocket. Herein, we designed and synthesized a novel class of covalent SrtA inhibitors based on the binding mode detailed in the X-ray crystal structure of the ML346/Streptococcus pyogenes SrtA complex. ML346 analog Y40 exhibited 2-fold increased inhibitory activity on Staphylococcus aureus SrtA and showed superior inhibitory effects on biofilm formation in vitro. Y40 protected Galleria mellonella larvae fromS. aureusinfections in vivo while minimally attenuating staphylococcal growth in vitro. Our study indicates that the covalent SrtA inhibitor Y40 is an antivirulence agent that is effective againstS. aureusinfections.

Vectorial holography for independent intensity and polarization control.

Metasurface-based vectorial holography can reconstruct images with different polarization states. However, the number of polarization channels in the holographic image is relatively small in traditional methods. Here, we propose and demonstrate a metasurface vectorial hologram which carries infinite polarization channels. It can independently control the holographic pattern and polarization distribution, which can be regarded as two independent storage dimensions. We use a supercell-based metasurface to independently control the complex amplitude of the left-handed circularly polarized and right-handed circularly polarized components of the transmitted light, which then superpose in the observation plane for the vectorial pattern generation. Different from most methods, our approach does not involve complex calculations, and it is suitable for far-field design. We anticipate that it may open avenues for future applications which require arbitrary intensity and polarization control.

Shexiang Baoxin Pill treats acute myocardial infarction by promoting angiogenesis via GDF15-TRPV4 signaling.

Angiogenesis has been considered a pivotal strategy for treating ischemic heart disease. One possible approach, the Shexiang Baoxin Pill (MUSKARDIA), has been noted to promote angiogenesis, but its underlying mechanism is still largely unknown. We aimed to determine the effects of MUSKARDIA on acute myocardial infarction (AMI), as well as the underlying mechanistic bases. AMI was induced in rats, using left anterior descending coronary arterial occlusion, and either 6 (low) or 12 (high-dose) mg/kg/day of MUSKARDIA was administered for 56 days. We found that MUSKARDIA improved cardiac function and counteracted against adverse remodeling among AMI rats, which most likely is due to it promoting angiogenesis. Transcriptome analysis by RNA-sequencing found that MUSKARDIA up-regulated cardiac pro-angiogenic genes, particularly growth differentiation factor 15 (GDF15), which was confirmed by RT-qPCR. This up-regulation was also correlated with elevated serum GDF15 levels. In vitro analyses with human umbilical vein endothelial cells found that increased GDF15, stimulated by MUSKARDIA, resulted in enhanced cell migration, proliferation, and tubular formation, all of which were reversed after GDF15 knockdown using a lentiviral vector. Gene Ontology, as well as Kyoto Genes and Genomes enrichment analyses identified calcium signaling pathway as a major contributor to these outcomes, which was verified by Western blot and Cal-590 AM loading showing that transient receptor potential cation channel subfamily V member 4 protein (TRPV4) and intracellular Ca2+ levels increased in accordance with MUSKARDIA-induced GDF15 up-regulation, and decreased with GDF15 knock-down. Therefore, MUSKARDIA may exert its cardioprotective effects via stimulating the GDF15/TRPV4/calcium signaling/angiogenesis axis.

Mathieu and Weber tightly autofocusing beams.

We theoretically investigate the propagation dynamics of vectorial Mathieu and Weber tightly autofocusing beams, which are constructed based on nonparaxial Weber and Mathieu accelerating beams, respectively. They can automatically focus along the paraboloid and ellipsoid, and the focal fields represent the tightly focusing properties resembling that generated with a high NA lens. We demonstrate the influence of the beam parameters on the spot size and energy proportion of longitudinal component of the focal fields. It reveals that Mathieu tightly autofocusing beam supports a more superior focusing performance, of which the longitudinal field component with superoscillatory feature could be enhanced by decreasing the order and selecting the suitable interfocal separation of the beam. These results are expected to provide new insights for the autofocusing beams and the tight focusing of the vector beams.

Assessment of the structure-activity relationship and antileukemic activity of diacylpyramide compounds as human ClpP agonists.

Human caseinolytic protease P (ClpP) is required for the regulatory hydrolysis of mitochondrial proteins. Allosteric ClpP agonists dysfunctionally activate mitochondrial ClpP in antileukemic therapies. We previously developed ZG111, a potent ClpP agonist derived from ICG-001, inhibits the proliferation of pancreatic ductal adenocarcinoma cell lines in vitro and in vivo by degrading respiratory chain complex proteins. Herein, we studied the structure-activity relationships of ICG-001 analogs as antileukemia agents. Compound ZG36 exhibited improved stabilization effects on the thermal stability of ClpP in acute myeloid leukemia (AML) cell lines compared with the stabilization effects of ZG111, indicating a direct binding between ZG36 and ClpP. Indeed, the resolved ZG36/ClpP structural complex reveals the mode of action of ZG36 during ClpP binding. Compound ZG36 nonselectively degrades respiratory chain complexes and decreases the mitochondrial DNA, eventually leading to the collapse of mitochondrial function and leukemic cell death. Finally, ZG36 treatment inhibited 3-D cell growth in vitro and suppressed the tumorigenesis of AML cells in xenografted mice models. Collectively, we developed a new class of human ClpP agonists that can be used as potential antileukemic therapies.

Phase-type diffractive micro-optics elements in sulfur-based polymeric glass by femtosecond laser direct writing.

Sulfur-based polymeric glasses are promising alternative low-cost IR materials due to their profoundly high IR transparency. In this Letter, femtosecond-laser-induced refractive index change (RIC) was investigated in one typical sulfur-based polymeric glass material, poly(S-r-DIB), for the first time, to the best of our knowledge. The RIC in the laser-engineered region was quantitively characterized, which laid a foundation for phase-type optical element design. By the integration of RIC traces, embedded phase-type micro-optics elements, including Fresnel zone plates, and a Dammann grating were fabricated in bulk poly(S-r-DIB) polymeric glass substrate via the femtosecond laser direct writing technique. The imaging and beam shaping performance were demoed in the near-infrared (NIR) region.

Phytochemicals, Biological Activities, Molecular Mechanisms, and Future Prospects of Plantago asiatica L.

Plantago asiatica L. has been used as a vegetable and nutritious food in Asia for thousands of years. According to recent phytochemical and pharmacological research, the active compositions of the plant contribute to various health benefits, such as antioxidant, anti-inflammatory, antibacterial, antiviral, and anticancer. This article reviews the 87 components of the plant and their structures, as well as their biological activities and molecular research progress, in detail. This review provides valuable reference material for further study, production, and application of P. asiatica, as well as its components in functional foods and therapeutic agents.

Spin-orbit coupling induced polarization transform in the autofocusing of ring Airy beams with hybrid polarizations.

Manipulating polarization is of significance for the application of light. Spin-orbit coupling provides a prominent pathway for manipulating the polarization of light field but generally requires tight focusing conditions or anisotropic media. In this paper, we construct ring Airy beams with hybrid polarizations and reveal the controllable polarization transforms in their autofocusing dynamics by manipulating concomitant spin-orbit coupling in free space. The numerical and experimental results show that the polarization transform is dependent on the azimuthal orders of amplitude and vortex phases of two spin constituents of ring Airy beams, that the focal spots present pure linear polarization whose orientation is determined by the initial phase when the vortex phase topological charge is equal to the amplitude angular factor, otherwise, the focal fields present cylindrical vector polarizations whose orders depend on the difference of amplitude angular orders and topological charges. Our work provides new insights for studying spin-orbit interactions and the depolarization of complex polarization.

Stokes meta-hologram toward optical cryptography.

Optical cryptography manifests itself a powerful platform for information security, which involves encrypting secret images into visual patterns. Recently, encryption schemes demonstrated on metasurface platform have revolutionized optical cryptography, as the versatile design concept allows for unrestrained creativity. Despite rapid progresses, most efforts focus on the functionalities of cryptography rather than addressing performance issues, such as deep security, information capacity, and reconstruction quality. Here, we develop an optical encryption scheme by integrating visual cryptography with metasurface-assisted pattern masking, referred to as Stokes meta-hologram. Based on spatially structured polarization pattern masking, Stokes meta-hologram allows multichannel vectorial encryption to mask multiple secret images into unrecognizable visual patterns, and retrieve them following Stokes vector analysis. Further, an asymmetric encryption scheme based on Stokes vector rotation transformation is proposed to settle the inherent problem of the need to share the key in symmetric encryption. Our results show that Stokes meta-hologram can achieve optical cryptography with effectively improved security, and thereby paves a promising pathway toward optical and quantum security, optical communications, and anticounterfeiting.

Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP.

The emergence of methicillin-resistant Staphylococcus aureus isolates highlights the urgent need to develop more antibiotics. ClpP is a highly conserved protease regulated by ATPases in bacteria and in mitochondria. Aberrant activation of  bacterial ClpP is an alternative method of discovering antibiotics, while it remains difficult to develop selective  Staphylococcus aureus ClpP activators that can avoid disturbing Homo sapiens ClpP functions. Here, we use a structure-based design to identify (R)- and (S)-ZG197 as highly selective Staphylococcus aureus ClpP activators. The key structural elements in Homo sapiens ClpP, particularly W146 and its joint action with the C-terminal motif, significantly contribute to the discrimination of the activators. Our selective activators display wide antibiotic properties towards an array of multidrug-resistant staphylococcal strains in vitro, and demonstrate promising antibiotic efficacy in zebrafish and murine skin infection models. Our findings indicate that the species-specific activators of Staphylococcus aureus ClpP are exciting therapeutic agents to treat staphylococcal infections.

Tightly autofocusing beams along the spherical surface.

We theoretically demonstrate different propagation trajectories of tightly autofocusing beams (TABs) along the spherical surface. The generalized expression of the TAB with spherical trajectory is given based on the nonparaxial accelerating Bessel beam. The effect of the spherical trajectory on the focusing performance of the TAB is analyzed. It reveals that the focal field with strong longitudinally polarized component and sub-diffraction-limit focal spot can be further enhanced by shortening the focal length of TAB. Theoretically, the minimum size of the focal spot can be close to 0.096λ2, and the proportion of longitudinal field can go up to 98.36%.

Flexible trajectory control of Bessel beams with pure phase modulation.

Spatial phase modulation has become an important method for the design of new self-accelerating light beams. Based on the transverse-longitudinal mapping of Bessel beam, we propose a method of pure phase modulation to directly convert a zero-order Bessel beam into a self-accelerating beam, of which the propagation trajectories can be flexibly predesigned. We experimentally demonstrate three typical types of curves that the modulated Bessel beam propagates along, and the parabolic, spiral, and teleporting self-accelarating beams are realized. The experimental results match the expected trajectory well. This method is simple to operate, and imposes fewer restrictions on the beam trajectory.

Controllable oscillated spin Hall effect of Bessel beam realized by liquid crystal Pancharatnam-Berry phase elements.

Pancharatnam-Berry (PB) phase has become an effective tool to realize the photonic spin Hall effect (PSHE) in recent years, due to its capacity of enhancing the spin-orbit interaction. Various forms of PSHEs have been proposed by tailoring the PB phase of light, however, the propagation trajectory control of the separated spin states has not been reported. In this paper, we realize the oscillated spin-dependent separation by using the well-designed PB phase optical elements based on the transverse-to-longitudinal mapping of Bessel beams. Two typical oscillated PSHEs, i.e., the spin states are circulated and reversed periodically, are experimentally demonstrated with two PB phase elements fabricated with liquid crystal. The displacements and periods of these oscillations can be controlled by changing the transverse vector of the input Bessel beam. The proposed method offers a new degree of freedom to manipulate the spin-dependent separation, and provides technical supports for the application in spin photonics.

Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma.

The mitochondrial caseinolytic protease P (ClpP) is a target candidate for treating leukemia; however, the effects of ClpP modulation on solid tumors have not been adequately explored. Here, we report a potent activator of ClpP with the therapeutic potential for pancreatic ductal adenocarcinoma (PDAC). We first validated that aberrant ClpP activation leads to growth arrest of PDAC cells and tumors. We then performed high-throughput screening and synthetic optimization, from which we identified ZG111, a potent activator of ClpP. ZG111 binds to ClpP and promotes the ClpP-mediated degradation of respiratory chain complexes. This degradation activates the JNK/c-Jun pathway, induces the endoplasmic reticulum stress response, and consequently causes the growth arrest of PDAC cells. ZG111 also produces inhibitory effects on tumor growth in cell line-derived and patient-derived xenograft mouse models. Altogether, our data demonstrate a promising therapeutic strategy for PDAC suppression through the chemical activation of ClpP.

Biocompatible Nanotomography of Tightly Focused Light.

Tightly focusing a spatially modulated laser beam lays the foundations for advanced optical techniques, such as a holographic optical tweezer and deterministic super-resolution imaging. Precisely mapping the subwavelength features of those highly confined fields is critical to improving the spatial resolution, especially in highly scattering biotissues. However, current techniques characterizing focal fields are mostly limited to conditions such as under a vacuum and on a glass surface. An optical probe with low cytotoxicity and resistance to autofluorescence is the key to achieving in vivo applications. Here, we use a newly emerging quantum reference beacon, the nitrogen-vacancy (NV) center in the nanodiamond, to characterize the focal field of the near-infrared (NIR) laser focus in Caenorhabditis elegans (C. elegans). This biocompatible background-free focal field mapping technique has the potential to optimize in vivo optical imaging and manipulation.

Poincaré sphere analogue for optical vortex knots.

We propose a Poincaré sphere (PS) analogue for optical vortex knots. The states on the PS analogue represent the light fields containing knotted vortex lines in three-dimensional space. The state changes on the latitude and longitude lines lead to the spatial rotation and scale change of the optical vortex knots, respectively. Furthermore, we experimentally generate and observe these PS analogue states. These results provide new insights for the evolution and control of singular beams, and can be further extended to polarization topology.