Engineered Bacteria Labeled with Iridium(III) Photosensitizers for Enhanced Photodynamic Immunotherapy of Solid Tumors.

Despite metal-based photosensitizers showing great potential in photodynamic therapy for tumor treatment, the application of the photosensitizers is intrinsically limited by their poor cancer-targeting properties. Herein, we reported a metal-based photosensitizer-bacteria hybrid, Ir-HEcN, via covalent labeling of an iridium(III) photosensitizer to the surface of genetically engineered bacteria. Due to its intrinsic self-propelled motility and hypoxia tropism, Ir-HEcN selectively targets and penetrates deeply into tumor tissues. Importantly, Ir-HEcN is capable of inducing pyroptosis and immunogenic cell death of tumor cells under irradiation, thereby remarkably evoking anti-tumor innate and adaptive immune responses in vivo and leading to the regression of solid tumors via combinational photodynamic therapy and immunotherapy. To the best of our knowledge, Ir-HEcN is the first metal complex decorated bacteria for enhanced photodynamic immunotherapy.

A Nanobody-Bioorthogonal Catalyst Conjugate Triggers Spatially Confined Prodrug Activation for Combinational Chemo-immunotherapy.

Checkpoint inhibitors have been used with chemotherapy to improve antitumor efficacy. However, overcoming the immunosuppressive effect of chemotherapeutics remains a challenge. We report a nanobody-catalyst conjugate Ru-PD-L1 by fusing a ruthenium catalyst to an anti-PD-L1 nanobody. After administration of Ru-PD-L1 and a doxorubicin (DOX) prodrug, Ru-PD-L1 disrupts the PD-L1/PD-1 interaction and catalyzes the uncaging of the DOX prodrug. The spatially confined release of DOX reduces its systemic toxicity and leads to immunogenic cell death (ICD). The induced ICD triggers antitumor immune responses, which are further amplified by PD-L1 blockade to elicit synergistic chemo-immunotherapy, substantially increasing the number of tumor-infiltrating T-cells by 49.7% compared with the controls, thereby exhibiting high antitumor activity and low cytotoxicity in murine models. The combinational treatment could inhibit the growth of mice tumors by 67.7% compared to the control group. This combinational approach circumvents the negative immunogenic effects of chemotherapeutics and provides a potential chemo-immunotherapy strategy for human cancer treatment.

Whole-brain mapping of histaminergic projections in mouse brain.

Histamine is a conserved neuromodulator in mammalian brains and critically involved in many physiological functions. Understanding the precise structure of the histaminergic network is the cornerstone in elucidating its function. Herein, using histidine decarboxylase (HDC)-CreERT2 mice and genetic labeling strategies, we reconstructed a whole-brain three dimensional (3D) structure of histaminergic neurons and their outputs at 0.32 × 0.32 × 2 µm3 pixel resolution with a cutting-edge fluorescence microoptical sectioning tomography system. We quantified the fluorescence density of all brain areas and found that histaminergic fiber density varied significantly among brain regions. The density of histaminergic fiber was positively correlated with the amount of histamine release induced by optogenetic stimulation or physiological aversive stimulation. Lastly, we reconstructed a fine morphological structure of 60 histaminergic neurons via sparse labeling and uncovered the largely heterogeneous projection pattern of individual histaminergic neurons. Collectively, this study reveals an unprecedented whole-brain quantitative analysis of histaminergic projections at the mesoscopic level, providing a foundation for future functional histaminergic study.

The Diverse Network of Brain Histamine in Feeding: Dissect its Functions in a Circuit-specific Way.

Feeding is an intrinsic and important behavior regulated by complex molecular, cellular and circuit-level mechanisms, one of which is the brain histaminergic network. In the past decades, many studies have provided a foundation of knowledge about the relationship between feeding and histamine receptors, which are deemed to have therapeutic potential but are not successful in treating feeding- related diseases. Indeed, the histaminergic circuits underlying feeding are poorly understood and characterized. This review describes current knowledge of histamine in feeding at the receptor level. Further, we provide insight into putative histamine- involved feeding circuits based on the classic feeding circuits. Understanding the histaminergic network in a circuit-specific way may be therapeutically relevant for increasing the drug specificity and precise treatment in feeding-related diseases.

Aberration analysis of a projection-type CGH display with an expanded FOV based on the HOE screen.

This paper proposed a holographic optical element as a see-through screen for the computer-generated hologram projection system with 3D images. The proposed holographic screen consisted of a linear grating and a lens phase. The linear grating is used to redirect the information light and guide information into the observer's eye and achieve the see-through function. The lens phase is used to magnify the field of view of the holographic projection system. The aberration caused by the screen was analyzed in this paper and the aberration can be pre-corrected in the hologram calculation algorithm. Finally, the proposed system achieved 20.3 by 14.3 degrees field of view at 532 nm laser based on the spatial light modulator with 6.4 µm pixels.

Tunable focal waveguide-based see-through display with negative liquid crystal lens.

A see-through display based on a planar holographic waveguide with a tunable focal plane is presented. A negative liquid crystal lens is attached on the outcoupling location of the waveguide to manipulate the image distance. The continuous tunable range for the focal length is from negative infinity to -65 cm. The demonstrated prototype system provides 10.5° field-of-view (FOV) for the images not locating at infinity. The FOV for the images not locating at infinity is limited by the diameter of the liquid crystal lens. The lens function of the liquid crystal lens is polarization dependent. By controlling the polarization states of the real scene and the input information image, the liquid crystal lens keeps the see-through function for a real scene and simultaneously plays the role of a negative lens for the input information image. Compared to the see-through display system with a single focal plane, the presented system offers a more comfortable augmented reality (AR) experience.

Effect of product-based pedagogy on students' project management skills, learning achievement, creativity, and innovative thinking in a high-school artificial intelligence course.

The purpose of this study is to explore the effectiveness of product-based pedagogy (PBP) on students' creativity and innovative thinking in artificial intelligence (AI) education. A seven-step model (i.e., phenomenon, problem, plan, prototype, product, presentation, price) in accordance with PBP was proposed, in which the key function of the product as a linkage between creativity and innovation was emphasized. A total of 209 students from a major high school in South China were randomly assigned to a treatment group with PBP and a control group with direct instruction. Results indicated no significant difference was found in students' learning performance; however, students in the treatment group performed significantly better than the control group in terms of students' project management skills, creativity, and innovative thinking. This research validates the feasibility and effectiveness of the PBP and highlights its advantages for high-school AI education, which indicates a new direction for cultivating creative and innovative talents.

In Situ Prodrug Activation by an Affibody-Ruthenium Catalyst Hybrid for HER2-Targeted Chemotherapy.

Transition-metal catalysts exhibit great potential as therapeutic agents to inhibit tumor growth. However, the precise delivery and in situ catalysis are challenging in catalytic medicine. Herein, we report an anti-HER2 affibody-ruthenium catalyst hybrid, named Ru-HER2 for selective and effective killing of cancer cells. Ru-HER2 binds to the HER2 receptor on a tumor cell and in situ catalyzes the activation of gemcitabine prodrug, resulting in enhanced selectivity in suppression of tumor growth and reduction of side effects. Immunoblotting reveals that Ru-HER2 in combination with gemcitabine prodrug can not only induce DNA damage, but also effectively block the HER2 signaling pathway in cancer cells. Therefore, the HER2-targeted chemotherapy exhibits substantially high anticancer activity toward HER2-positive cancer cells in vitro and in vivo. In a word, we report the first affibody-ruthenium catalyst hybrid and reveal its potential for effective HER2-targeted cancer chemotherapy.

An H2R-dependent medial septum histaminergic circuit mediates feeding behavior.

Novel targets for treating feeding-related diseases are of great importance, and histamine has long been considered an anorexigenic agent. However, understanding its functions in feeding in a circuit-specific way is still limited. Here, we report a medial septum (MS)-projecting histaminergic circuit mediating feeding behavior. This MS-projecting histaminergic circuit is functionally inhibited during food consumption, and bidirectionally modulates feeding behavior via downstream H2, but not H1, receptors on MS glutamatergic neurons. Further, we observed a pathological decrease of histamine 2 receptors (H2Rs) expression in MS glutamatergic neurons in diet-induced obesity (DIO) mice. Genetically, down-regulation of H2Rs expression in MS glutamatergic neurons accelerates body-weight gain. Importantly, chronic activation of H2Rs in MS glutamatergic neurons (with its clinical agonist amthamine) significantly slowed down the body-weight gain in DIO mice, providing a possible clinical utility to treat obesity. Together, our results demonstrate that this MS-projecting histaminergic circuit is critically involved in feeding, and H2Rs in MS glutamatergic neurons is a promising target for treating body-weight problems.

Binocular dynamic holographic floating image display.

This paper proposes a binocular holographic floating display. The device consists of two phase-modulation spatial light modulators (SLM) and a dihedral corner reflector array (DCRA) element. The conjugate images of the SLMs generated by the DCRA become the system's exit pupils. Exit pupils that are larger than the pupils of human eyes are arranged to locate at the position of observer's eyes. Therefore, the dimension of the SLM will not limit the viewing angle, although the pixel pitch of the SLM still limits the maximum field of view. For the laser light source, the resolution of the images can achieve 3 arc minutes when the distance between images and DCRA is less than 20 cm. The full-color display function is also performed in the proposed device.

Astigmatism correction and quality optimization of computer-generated holograms for holographic waveguide displays.

In this manuscript, the astigmatism of the waveguide combiner with a pair of symmetry HOEs was analyzed. The light field can be predicted by the modified convolution formulation of Fresnel diffraction when the information of light passes through the astigmatism causing element. Then the astigmatism can be corrected. The theory was experimentally proved by the system with a phase-only SLM and a diffraction planar waveguide. Furthermore, the image quality of astigmatism corrected phase-type CGHs can be improved via the iteration process. Since the coherence of light source was employed, the temporal averaging method was utilized to avoid speckle noise.

A disinhibitory nigra-parafascicular pathway amplifies seizure in temporal lobe epilepsy.

The precise circuit of the substantia nigra pars reticulata (SNr) involved in temporal lobe epilepsy (TLE) is still unclear. Here we found that optogenetic or chemogenetic activation of SNr parvalbumin+ (PV) GABAergic neurons amplifies seizure activities in kindling- and kainic acid-induced TLE models, whereas selective inhibition of these neurons alleviates seizure activities. The severity of seizures is bidirectionally regulated by optogenetic manipulation of SNr PV fibers projecting to the parafascicular nucleus (PF). Electrophysiology combined with rabies virus-assisted circuit mapping shows that SNr PV neurons directly project to and functionally inhibit posterior PF GABAergic neurons. Activity of these neurons also regulates seizure activity. Collectively, our results reveal that a long-range SNr-PF disinhibitory circuit participates in regulating seizure in TLE and inactivation of this circuit can alleviate severity of epileptic seizures. These findings provide a better understanding of pathological changes from a circuit perspective and suggest a possibility to precisely control epilepsy.

Direct Septum-Hippocampus Cholinergic Circuit Attenuates Seizure Through Driving Somatostatin Inhibition.

BACKGROUND: Previous studies indicated the involvement of cholinergic neurons in seizure; however, the specific role of the medial septum (MS)-hippocampus cholinergic circuit in temporal lobe epilepsy (TLE) has not yet been completely elucidated. METHODS: In the current study, we used magnetic resonance imaging and diffusion tensor imaging to characterize the pathological change of the MS-hippocampus circuit in 42 patients with TLE compared with 22 healthy volunteers. Using optogenetics and chemogenetics, combined with in vivo or in vitro electrophysiology and retrograde rabies virus tracing, we revealed a direct MS-hippocampus cholinergic circuit that potently attenuates seizure through driving somatostatin inhibition in animal TLE models. RESULTS: We found that patients with TLE with hippocampal sclerosis showed a decrease of neuronal fiber connectivity of the MS-hippocampus compared with healthy people. In the mouse TLE model, MS cholinergic neurons ceased firing during hippocampal seizures. Optogenetic and chemogenetic activation of MS cholinergic neurons (but not glutamatergic or GABAergic [gamma-aminobutyric acidergic] neurons) significantly attenuated hippocampal seizures, while specific inhibition promoted hippocampal seizures. Electrophysiology combined with modified rabies virus tracing studies showed that direct (but not indirect) MS-hippocampal cholinergic projections mediated the antiseizure effect by preferentially targeting hippocampal GABAergic neurons. Furthermore, chemogenetic inhibition of hippocampal somatostatin-positive (rather than parvalbumin-positive) subtype of GABAergic neurons reversed the antiseizure effect of the MS-hippocampus cholinergic circuit, which was mimicked by activating somatostatin-positive neurons. CONCLUSIONS: These findings underscore the notable antiseizure role of the direct cholinergic MS-hippocampus circuit in TLE through driving the downstream somatostatin effector. This may provide a better understanding of the changes of the seizure circuit and the precise spatiotemporal control of epilepsy.

Astigmatism and deformation correction for a holographic head-mounted display with a wedge-shaped holographic waveguide.

In this study, a head-mounted display (HMD) system based on a wedge-shaped holographic waveguide that can present holographic virtual images with tunable distance is achieved. The compact computer-generated-hologram system using a spatial light modulator was employed to offer the dynamic image, where the probe beam for the hologram reconstruction is a convergent wave, and the DC term of the diffraction wave can be blocked by a barrier. The wedge-shaped holographic waveguide element was used as the combiner of the HMD system to generate a compact structure. A wedge with a polished surface was designed for in-coupling the image into the waveguide, and a reflection-type holographic optical element (HOE) was used for out-coupling the image from the waveguide. The astigmatism aberration and deformation of the diffraction images at various distances are analyzed and then are compensated. Finally, the virtual image can be obtained without aberration with experimental verification.

Dispersion Differences and Consistency of Artificial Periodic Structures.

Dispersion differences and consistency of artificial periodic structures, including phononic crystals, elastic metamaterials, as well as periodic structures composited of phononic crystals and elastic metamaterials, are investigated in this paper. By developing a K(ω) method, complex dispersion relations and group/phase velocity curves of both the single-mechanism periodic structures and the mixing-mechanism periodic structures are calculated at first, from which dispersion differences of artificial periodic structures are discussed. Then, based on a unified formulation, dispersion consistency of artificial periodic structures is investigated. Through a comprehensive comparison study, the correctness for the unified formulation is verified. Mathematical derivations of the unified formulation for different artificial periodic structures are presented. Furthermore, physical meanings of the unified formulation are discussed in the energy-state space.

Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells.

Sorafenib is a multikinase inhibitor used as a first-line treatment for advanced hepatocellular carcinoma (HCC), but it has shown modest to low response rates. The characteristic tumour hypoxia of advanced HCC maybe a major factor underlying hypoxia-mediated treatment failure. Thus, it is urgent to elucidate the mechanisms of hypoxia-mediated sorafenib resistance in HCC. In this study, we found that hypoxia induced the nuclear translocation of Yes associate-Protein (YAP) and the subsequent transactivation of target genes that promote cell survival and escape apoptosis, thereby leading to sorafenib resistance. Statins, the inhibitors of hydroxymethylglutaryl-CoA reductase, could ameliorate hypoxia-induced nuclear translocation of YAP and suppress mRNA levels of YAP target genes both in vivo and in vitro. Combined treatment of statins with sorafenib greatly rescued the loss of anti-proliferative effects of sorafenib under hypoxia and improved the inhibitory effects on HepG2 xenograft tumour growth, accompanied by enhanced apoptosis as evidenced by the increased sub-G1 population and PARP cleavage. The expression levels of YAP and its target genes were highly correlated with poor prognosis and predicted a high risk of HCC patients. These findings collectively suggest that statins utilization maybe a promising new strategy to counteract hypoxia-mediated resistance to sorafenib in HCC patients.

Schottky diode fabricated on a single crystalline diamond rod.

The fabrication process of Al/diamond Schottky diodes on single crystalline diamond rods (SCDRs) was demonstrated. SCDRs of submicron diameters were obtained by etching a polished polycrystalline diamond film in oxygen plasma. The as-scratched SCDR was confirmed to be single crystalline diamond by electron diffraction measurements showing the same fuzzy spot pattern at different parts of an SCDR. Each SCDR was extracted from a grain in the polycrystalline film where the grain size served as a limit of the length of an SCDR. Al/Ti and Al metals were deposited to form ohmic and Schottky contacts, respectively. A hydrogen plasma treatment is an essential step prior to the formation of an Al/diamond Schottky contact in order to improve the device performance. The submicron scale Al/diamond Schottky diode exhibits a very high current density of 1.4 × 10(4) A cm(-2) at a forward bias (V(F)) voltage of - 3 V.