Flexible Usage and Interconnectivity of Diverse Cell Death Pathways Protect against Intracellular Infection.

Programmed cell death contributes to host defense against pathogens. To investigate the relative importance of pyroptosis, necroptosis, and apoptosis during Salmonella infection, we infected mice and macrophages deficient for diverse combinations of caspases-1, -11, -12, and -8 and receptor interacting serine/threonine kinase 3 (RIPK3). Loss of pyroptosis, caspase-8-driven apoptosis, or necroptosis had minor impact on Salmonella control. However, combined deficiency of these cell death pathways caused loss of bacterial control in mice and their macrophages, demonstrating that host defense can employ varying components of several cell death pathways to limit intracellular infections. This flexible use of distinct cell death pathways involved extensive cross-talk between initiators and effectors of pyroptosis and apoptosis, where initiator caspases-1 and -8 also functioned as executioners when all known effectors of cell death were absent. These findings uncover a highly coordinated and flexible cell death system with in-built fail-safe processes that protect the host from intracellular infections.

Vaccine-induced inflammation and inflammatory monocytes promote CD4+ T cell-dependent immunity against murine salmonellosis.

Prior infection can generate protective immunity against subsequent infection, although the efficacy of such immunity can vary considerably. Live-attenuated vaccines (LAVs) are one of the most effective methods for mimicking this natural process, and analysis of their efficacy has proven instrumental in the identification of protective immune mechanisms. Here, we address the question of what makes a LAV efficacious by characterising immune responses to a LAV, termed TAS2010, which is highly protective (80-90%) against lethal murine salmonellosis, in comparison with a moderately protective (40-50%) LAV, BRD509. Mice vaccinated with TAS2010 developed immunity systemically and were protected against gut-associated virulent infection in a CD4+ T cell-dependent manner. TAS2010-vaccinated mice showed increased activation of Th1 responses compared with their BRD509-vaccinated counterparts, leading to increased Th1 memory populations in both lymphoid and non-lymphoid organs. The optimal development of Th1-driven immunity was closely correlated with the activation of CD11b+Ly6GnegLy6Chi inflammatory monocytes (IMs), the activation of which can be modulated proportionally by bacterial load in vivo. Upon vaccination with the LAV, IMs expressed T cell chemoattractant CXCL9 that attracted CD4+ T cells to the foci of infection, where IMs also served as a potent source of antigen presentation and Th1-promoting cytokine IL-12. The expression of MHC-II in IMs was rapidly upregulated following vaccination and then maintained at an elevated level in immune mice, suggesting IMs may have a role in sustained antigen stimulation. Our findings present a longitudinal analysis of CD4+ T cell development post-vaccination with an intracellular bacterial LAV, and highlight the benefit of inflammation in the development of Th1 immunity. Future studies focusing on the induction of IMs may reveal key strategies for improving vaccine-induced T cell immunity.

Sulforaphane impaired immune checkpoint blockade therapy through activating ΔNP63α/PD-L1 axis in gastric cancer.

Sulforaphane (SFN) exerts anticancer effect on various cancers including gastric cancer. However, the regulatory effect of SFN on programmed death-ligand 1 (PD-L1) and checkpoint blockade therapy in gastric cancer have not been elucidated. Here we demonstrated that SFN suppressed gastric cancer cell growth both in vitro and in vivo study. SFN upregulated PD-L1 expression through activating ΔNP63α in gastric cancer cells. Further, we found that SFN impaired the anticancer effect of anti-PD-L1 monoclonal antibody (α-PD-L1 mab) on gastric cancer cells. These results uncover a novel PD-L1 regulatory mechanism and the double-edged role of SFN in gastric cancer intervention.

Phytochemicals in regulating PD-1/PD-L1 and immune checkpoint blockade therapy.

Clinical treatment and preclinical studies have highlighted the role of immune checkpoint blockade in cancer treatment. Research has been devoted to developing immune checkpoint inhibitors in combination with other drugs to achieve better efficacy or reduce adverse effects. Phytochemicals sourced from vegetables and fruits have demonstrated antiproliferative, proapoptotic, anti-migratory, and antiangiogenic effects against several cancers. Phytochemicals also modulate the tumor microenvironment such as T cells, regulatory T cells, and cytokines. Recently, several phytochemicals have been reported to modulate immune checkpoint proteins in in vivo or in vitro models. Phytochemicals decreased programmed cell death ligand-1 expression and synergized programmed cell death receptor 1 (PD-1) monoclonal antibody to suppress tumor growth. Combined administration of phytochemicals and PD-1 monoclonal antibody enhanced the tumor growth inhibition as well as CD4+ /CD8+ T-cell infiltration. In this review, we discuss immune checkpoint molecules as potential therapeutic targets of cancers. We further assess the impact of phytochemicals including carotenoids, polyphenols, saponins, and organosulfur compounds on cancer PD-1/programmed cell death ligand-1 immune checkpoint molecules and document their combination effects with immune checkpoint inhibitors on various malignancies.

Nanolaminate-based antireflection coatings for enhanced scratch and tribological performance.

Developing durable antireflection (AR) coatings with sapphire-like hardness and high transparency faces a significant challenge. Conventionally, achieving these requirements involves depositing thick, high-hardness nitride films. Here, we proposed an alternative approach that combines nanolaminate materials with optical design, overcoming the brittleness of thick nitride films. We selected Ta2O5/Si3N4 nanolaminates with similar refractive indices, improving tribological and optical performance through a unique optomechanical method. Our proposed AR coating exhibited a low reflectance of 0.8% (420-780 nm) and remarkable hardness of 22.8 GPa, and demonstrated the ability to withstand abrasion from steel wool up to 3,000 times on a glass substrate. This work successfully achieves a balance between hardness and toughness, opening new avenues for the development of highly durable coatings.

General-purpose mid-infrared micro-spectrometer based on hierarchical residual CNN and data augmentation.

Taking advantage of broad response range and snap-shot operation mode, reconstructive spectrometers based on integrated frequency-modulation microstructure and computational techniques attract lots of attention. The key problems in reconstruction are sparse samplings related with the limited detectors and generalization ability due to data-driving principle. Here, we demonstrate abstractly a mid-infrared micro-spectrometer covering 2.5-5 µm, which utilizes a grating-integrated lead selenide detector array for sampling and a hierarchal residual convolutional neural network (HRCNN) for reconstructions. Leveraging data augmentation and the powerful feature extraction ability of HRCNN, a spectral resolution of 15 nm is realized. Over one hundred chemicals, including untrained chemicals species tested with an average reconstruction error of ∼1E-4, exhibit the excellent reliability of the micro-spectrometer. The demonstration of the micro-spectrometer promotes the development of the reconstructed strategy.

Wide-angle broadband antireflection coatings with nano-taper hydrated alumina film.

Wide-angle and broadband antireflection (AR) coating is of the essence in modern optical systems in many fields, which has a great influence on the stray light and imaging quality. A simple and convenient manufacturing method is proposed to address this issue based on a composite coating combining the nano-tapered Al2O3•xH2O (AH) structure and high-low index thin film stack. The optical properties of nano-tapered AH structure at various thickness are first studied and modeled in optics by several homogeneous sub-layers with the graded equivalent index. The designed composite AR coatings are manufactured by vacuum deposition and wet etching subsequently in the hot deionized water. Compared to the common dielectric multilayer antireflection stack, the composite coating presents excellent AR performance. The measured average reflectance values of the double-side coated BK7 glass are as low as 0.40%, 0.41%, 0.56% and 3.13% in 400-1100nm band at angles of incidence (AOI) of 6°, 20°, 40°, and 60°, respectively, while the measured average transmittance at normal incidence increases up to 99.3%. Finally, the process reproductivity, environmental reliability test including long term storage, high temperature annealing and 85°C-85% relative humidity storage of the composite coatings are evaluated. The proposed AR scheme provides a low-cost, efficient, wide-angle and broadband AR coating for kinds of large-curvature components and complex surfaces in fields of consumer electronics, automotive, security, etc.

Outdoor Personal Thermal Management with Simultaneous Electricity Generation.

Outdoor personal thermal comfort is of substantial significance to ameliorate the health conditions of pedestrian and outdoor laborer. However, the uncontrollable sunlight, substantial radiative loss, and intense temperature fluctuations in the outdoor environment present majestic challenges to outdoor personal thermal management. Here, we report an eco-friendly passive nanostructured textile which harvests energy from the sun and the outer space for optional localized heating and cooling. Compared to conventional heating/cooling textiles like black/white cotton, its heating/cooling mode enables a skin simulator temperature increase/decrease of 8.1 °C/6 °C, respectively, under sunlight exposure. Meanwhile, the temperature gradient created between the textile and human skin allows a continuous electricity generation with thermoelectric modules. Owing to the exceptional outdoor thermoregulation ability, this Janus textile is promising to help maintain a comfortable microclimate for individuals in outdoor environment and provide a platform for pervasive power generation.

Broadband absorption coating for large-curvature surfaces by atomic layer deposition.

For many applications, large curvature surfaces or complicated 3D structures are required to absorb light that falls on them to reduce stray light or energy collection. A novel, to the best of our knowledge, strategy with a metal-dielectric film stack by the atomic layer deposition technique is put forward to achieve broadband absorption coating covering both sides of a quartz tube completely. Absorptive metallic material of titanium-aluminum-carbon composite and dielectric material of aluminum oxide (Al2O3) is employed to realize high absorption (>99%) for the 400-780 nm band with the configuration of a six-layer metal-dielectric film stack. Good angle insensitivity up to 50° for P- and S-polarizations is demonstrated experimentally with the proposed structure on a glass slab. The average absorption of the coated quartz tube reaches as high as 99% for all curving areas on the inner and outer sides, while the nonuniformity is confined to 1.5% for the axial and circumferential directions. This presented approach has enormous potential in the fields of optical detection, optical imaging, optical sensing, and energy management.

Effective, angle-independent radiative cooler based on one-dimensional photonic crystal.

A simple and low-cost radiative cooler based on one-dimensional photonic crystal is proposed in this work, which has an average emissivity of 96% within the atmospheric transparency window (8-13µm). The ultra-broadband emissivity property is realized by constructing the strongly overlapped optical resonances with a tandem structure composed of two lossy materials while an additional lossless material is adopted as the top layer to reduce the Fresnel reflection of the whole structure. The maximum cooling power density of the fabricated radiative cooler can reach 113.0W/m2 at night. When integrated with an excellent solar reflector that can reflect 97% incident solar power, it theoretically has the maximum cooling power of 83.0 W/m2 in the case of solar irradiance up to 1000 W/m2 at noon.

Highly efficient omnidirectional structural color tuning method based on dielectric-metal-dielectric structure.

A novel and convenient scheme is proposed to achieve angle insensitive color filtering across a large color gamut by simply altering the thickness of the dielectric layer of a dielectric-metal-dielectric grating structure. The plasmonic filter presents a great feature of angle resolved spectrum response up to 60° and is independent of the azimuthal angle and the polarization state as well so as to construct an omnidirectional filter for practical applications. The color tuning feature of the proposed filter with varied dielectric thickness is attributed to the modulation of the condition for the localized surface plasmon resonance, which bears responsibility for the omnidirectional property of this plasmonic filter. This color-tuning method with a single mold size required can have wide applications in fields of display, colorful decoration, printing, and so forth.

Trapping of naive lymphocytes triggers rapid growth and remodeling of the fibroblast network in reactive murine lymph nodes.

Adaptive immunity is initiated in T-cell zones of secondary lymphoid organs. These zones are organized in a rigid 3D network of fibroblastic reticular cells (FRCs) that are a rich cytokine source. In response to lymph-borne antigens, draining lymph nodes (LNs) expand several folds in size, but the fate and role of the FRC network during immune response is not fully understood. Here we show that T-cell responses are accompanied by the rapid activation and growth of FRCs, leading to an expanded but similarly organized network of T-zone FRCs that maintains its vital function for lymphocyte trafficking and survival. In addition, new FRC-rich environments were observed in the expanded medullary cords. FRCs are activated within hours after the onset of inflammation in the periphery. Surprisingly, FRC expansion depends mainly on trapping of naïve lymphocytes that is induced by both migratory and resident dendritic cells. Inflammatory signals are not required as homeostatic T-cell proliferation was sufficient to trigger FRC expansion. Activated lymphocytes are also dispensable for this process, but can enhance the later growth phase. Thus, this study documents the surprising plasticity as well as the complex regulation of FRC networks allowing the rapid LN hyperplasia that is critical for mounting efficient adaptive immunity.

Design and simulation of omnidirectional reflective color filters based on metal-dielectric-metal structure.

We propose omnidirectional reflective color filters based on metal-dielectric-metal subwavelength grating structure. By particle swarm optimization, the structural parameters of three color filters (yellow, magenta, cyan) are obtained. The optimized filters can present the same perceived specular color at unpolarized illumination for a broad range of incident angles. The reflectance curves at different incident angles keep almost invariable and the color difference is less than 6 in CIEDE2000 formula up to 45°. Angle-insensitive properties including the incident angular tolerance, azimuthal angular tolerance and the polarization effect are investigated thoroughly to construct a real omnidirectional color filter. Through the analysis of the magnetic field, the physical origin is verified that the total absorption band at specific wavelength results from the localized surface plasmon resonance responsible for the angle insensitive spectral filtering.

Removal of syndecan-1 promotes TRAIL-induced apoptosis in myeloma cells.

Syndecan is the major transmembrane proteoglycan in cells. Of the four syndecans, syndecan-1 is the dominant form expressed in multiple myeloma and is an indicator of poor prognosis. In the current study, we observed that early TRAIL-induced apoptotic processes were accompanied by cleavage of syndecan-1 intracellular region, and explored the possibility whether removal of syndecan-1 promotes apoptotic processes. We found that syndecan-1 knockdown by specific small interfering RNA in multiple myeloma enhanced TRAIL-induced apoptosis, even though the expression of TRAIL receptors and several apoptosis-associated molecules was unaffected. The enhanced TRAIL-mediated apoptosis in syndecan-1-deficient cells was not due to a decrease in surface heparan sulfate or a reduction in TRAIL receptor endocytosis. The increase in TRAIL-induced cell death was accompanied by an elevated caspase-8 activation and an enhanced formation of death-inducing signaling complexes, which could be attributed to an increased expression of TRAIL receptor O-glycosylation enzyme in syndecan-1-deficient cells. We also found that in H9 lymphoma and Jurkat cells, knockdown of the predominant syndecan member also led to an increase in Fas ligand-induced apoptosis. Our results demonstrate that syndecan plays a negative role in death receptor-mediated cell death, suggesting potential application of syndecan downregulation in the treatment of myeloma in combination with TRAIL.

Color-tuning method by filling porous alumina membrane using atomic layer deposition based on metal-dielectric-metal structure.

A novel and convenient color-tuning method by filling the porous alumina membrane (PAM) based on metal-dielectric-metal structure is proposed. The pore sizes of PAM as well as the thickness of TiO2 films, deposited by atomic layer deposition, causes various reflection colors due to multilayer interference effects. Overlapping films on top and within the PAM structure can be observed with a scanning electron microscope and will be used to show the change of the effective refractive index of the PAM composite layer. The color-tuning method resulting in changing the dynamics of the PAM layer can be widely applied in fields such as micro-optics, microstructures, nanomaterials, and micro/nanotechnology.

Design of reflective color filters with high angular tolerance by particle swarm optimization method.

We propose three color filters (red, green, blue) based on a two-dimensional (2D) grating, which maintain the same perceived specular colors for a broad range of incident angles with the average polarization. Particle swarm optimization (PSO) method is employed to design these filters for the first time to our knowledge. Two merit functions involving the reflectance curves and color difference in CIEDE2000 formula are respectively constructed to adjust the structural parameters during the optimization procedure. Three primary color filters located at 637nm, 530nm and 446nm with high saturation are obtained with the peak reflectance of 89%, 83%, 66%. The reflectance curves at different incident angles are coincident and the color difference is less than 8 for the incident angle up to 45°. The electric field distribution of the structure is finally studied to analyze the optical property.

Isothiocyanates attenuate immune checkpoint blockage therapy in gastric cancer via induction of PD-L1 expression.

The PD-1/PD-L1 immune checkpoint blockade therapy has shown revolutionary efficacy in the treatment of multiple cancers including gastric cancer. Isothiocyanates play important roles in cancer cell suppression and immunomodulation. However, the effects of isothiocyanates on immune checkpoint inhibitors are poorly understood in gastric cancer. The influence of three major isothiocyanates (sulforaphane, phenylethyl isothiocyanate, and benzhydryl isothiocyanate) on gastric cancer cell growth and PD-L1 expression was investigated. Syngeneic mouse models were administered by isothiocyanates and anti-PD-L1 monoclonal antibody, and the anti-tumor effects were assessed. The expression of PD-L1, proportion of lymphocytes and serum cytokine levels were detected to explore the underlying mechanisms. We found that PD-L1 expression was significantly induced by isothiocyanates which was associated with TAp63α up-regulation. We further revealed that TAp63α promoted PD-L1 through transcriptional activation. Combination treatment of isothiocyanates and anti-PD-L1 therapy weakened the sensitivity of gastric cancer cells to anti-PD-L1 drug. Moreover, in vivo studies illustrated that the interference effects of isothiocyanates on anti-PD-L1 antibody were related to PD-L1 expression and decreased infiltrating T lymphocytes in tumor bearing mouse hosts. Our findings provide novel insights as isothiocyanates could interfere with the successful application of immunotherapy in gastric cancer.

Liraglutide modulates adhesion molecules and enhances cell properties in three-dimensional cultures of olfactory ensheathing cells.

Cell transplantation using olfactory ensheathing cells (OECs) is a promising approach for nerve repair but there are numerous limitations with their delivery method. Three-dimensional (3D) cell culture systems potentially offer a powerful approach for cell production and delivery options. To further optimise the use of OECs, strategies to promote cell viability and maintain cell behaviours in 3D cultures become important. We previously demonstrated an anti-diabetic drug, liraglutide, could modulate OEC migration and re-model extracellular matrix in two-dimensional (2D) cultures. In the present study, we further investigated its beneficial effects in our 3D culture system using primary OECs. OECs treated with liraglutide at 100 nM showed improved cell viability and had modulated expression of N-cadherin and ß1-integrin (two important cell adhesion molecules). When formed into 3D spheroids, the pre-treated OECs generated spheroids with an increased volume and a decreased cell density compared to control spheroids. OECs that subsequently migrated out of the liraglutide pre-treated spheroids had higher capacity for migration with increased duration and length, which was attributed to a reduction in the pauses during the migration. Moreover, OECs that migrated out from liraglutide spheroids had a more bipolar morphology consistent with higher migratory capacity. In summary, liraglutide improved the viability of OECs, modulated cell adhesion molecules, and resulted in stable 3D cell constructs which conferred enhanced migratory capacity on the OECs. Overall, liraglutide may potentially improve the therapeutic use of OECs for neural repair by enhancing the generation of stable 3D constructs and increasing the migratory behaviour of OECs.

A booster regime of liposome-delivered live-attenuated CHIKV vaccine RNA genome protects against chikungunya virus disease in mice.

Mosquito-transmitted chikungunya virus (CHIKV) is the causal pathogen of CHIKV disease and is responsible for global epidemics of arthritic disease. CHIKV infection can lead to severe chronic and debilitating arthralgia, significantly impacting patient mobility and quality of life. Our previous studies have shown a live-attenuated CHIKV vaccine candidate, CHIKV-NoLS, to be effective in protecting against CHIKV disease in mice vaccinated with one dose. Further studies have demonstrated the value of a liposome RNA delivery system to deliver the RNA genome of CHIKV-NoLS directly in vivo, promoting de novo production of live-attenuated vaccine particles in vaccinated hosts. This system, designed to bypass live-attenuated vaccine production bottlenecks, uses CAF01 liposomes. However, one dose of CHIKV-NoLS CAF01 failed to provide systemic protection against CHIKV challenge in mice, with low levels of CHIKV-specific antibodies. Here we describe CHIKV-NoLS CAF01 booster vaccination regimes designed to increase vaccine efficacy. C57BL/6 mice were vaccinated with three doses of CHIKV-NoLS CAF01 either intramuscularly or subcutaneously. CHIKV-NoLS CAF01 vaccinated mice developed a systemic immune response against CHIKV that shared similarity to vaccination with CHIKV-NoLS, including high levels of CHIKV-specific neutralising antibodies in subcutaneously inoculated mice. CHIKV-NoLS CAF01 vaccinated mice were protected against disease signs and musculoskeletal inflammation when challenged with CHIKV. Mice given one dose of live-attenuated CHIKV-NoLS developed a long lasting protective immune response for up to 71 days. A clinically relevant CHIKV-NoLS CAF01 booster regime can overcome the challenges faced by our previous one dose strategy and provide systemic protection against CHIKV disease.

Color-preserving passive radiative cooling for an actively temperature-regulated enclosure.

Active temperature control devices are widely used for the thermal management of enclosures, including vehicles and buildings. Passive radiative cooling has been extensively studied; however, its integration with existing actively temperature regulated and decorative enclosures has slipped out of the research at status quo. Here, we present a photonic-engineered dual-side thermal management strategy for reducing the active power consumption of the existing temperature-regulated enclosure without sacrificing its aesthetics. By coating the exterior and interior of the enclosure roof with two visible-transparent films with distinctive wavelength-selectivity, simultaneous control over the energy exchange among the enclosure with the hot sun, the cold outer space, the atmosphere, and the active cooler can be implemented. A power-saving of up to 63% for active coolers of the enclosure is experimentally demonstrated by measuring the heat flux compared to the ordinary enclosure when the set temperature is around 26°C. This photonic-engineered dual-side thermal management strategy offers facile integration with the existing enclosures and represents a new paradigm toward carbon neutrality.