Enhanced pyroptosis induction with pore-forming gene delivery for osteosarcoma microenvironment reshaping.

Osteosarcoma is the most common malignant bone tumor without efficient management for improving 5-year event-free survival. Immunotherapy is also limited due to its highly immunosuppressive tumor microenvironment (TME). Pore-forming gasdermins (GSDMs)-mediated pyroptosis has gained increasing concern in reshaping TME, however, the expressions and relationships of GSDMs with osteosarcoma remain unclear. Herein, gasdermin E (GSDME) expression is found to be positively correlated with the prognosis and immune infiltration of osteosarcoma patients, and low GSDME expression was observed. A vector termed as LPAD contains abundant hydroxyl groups for hydrating layer formation was then prepared to deliver the GSDME gene to upregulate protein expression in osteosarcoma for efficient TME reshaping via enhanced pyroptosis induction. Atomistic molecular dynamics simulations analysis proved that the hydroxyl groups increased LPAD hydration abilities by enhancing coulombic interaction. The upregulated GSDME expression together with cleaved caspase-3 provided impressive pyroptosis induction. The pyroptosis further initiated proinflammatory cytokines release, increased immune cell infiltration, activated adaptive immune responses and create a favorable immunogenic hot TME. The study not only confirms the role of GSDME in the immune infiltration and prognosis of osteosarcoma, but also provides a promising strategy for the inhibition of osteosarcoma by pore-forming GSDME gene delivery induced enhanced pyroptosis to reshape the TME of osteosarcoma.

Microgel-based carriers enhance skeletal stem cell reprogramming towards immunomodulatory phenotype in osteoarthritic therapy.

Skeletal stem cells (SSC) have gained attentions as candidates for the treatment of osteoarthritis due to their osteochondrogenic capacity. However, the immunomodulatory properties of SSC, especially under delivery operations, have been largely ignored. In the study, we found that Pdpn+ and Grem1+ SSC subpopulations owned immunoregulatory potential, and the single-cell RNA sequencing (scRNA-seq) data suggested that the mechanical activation of microgel carriers on SSC induced the generation of Pdpn+Grem1+Ptgs2+ SSC subpopulation, which was potent at suppressing macrophage inflammation. The microgel carriers promoted the YAP nuclear translocation, and the activated YAP protein was necessary for the increased expression of Ptgs2 and PGE2 in microgels-delivered SSC, which further suppressed the expression of TNF-ɑ, IL-1ß and promoted the expression of IL-10 in macrophages. SSC delivered with microgels yielded better preventive effects on articular lesions and macrophage activation in osteoarthritic rats than SSC without microgels. Chemically blocking the YAP and Ptgs2 in microgels-delivered SSC partially abolished the enhanced protection on articular tissues and suppression on osteoarthritic macrophages. Moreover, microgel carriers significantly prolonged SSC retention time in vivo without increasing SSC implanting into osteoarthritic joints. Together, our study demonstrated that microgel carriers enhanced SSC reprogramming towards immunomodulatory phenotype to regulate macrophage phenotype transformation for effectively osteoarthritic therapy by promoting YAP protein translocation into nucleus. The study not only complement and perfect the immunological mechanisms of SSC-based therapy at the single-cell level, but also provide new insight for microgel carriers in stem cell-based therapy.

High power single-frequency 1112†nm laser by an insertable Nd:YAG/YAG bonded monolithic planar ring oscillator.

A high power single-frequency operation at 1112 nm with novel insertable monolithic planar ring oscillator based on a Nd:YAG/YAG bonded crystal is proposed. In a proof-of-principle experiment, a finely designed coating on the output surface is carried out to ensure single-wavelength oscillation at 1112 nm, together with a half-wave plate and a Tb3Ga5O12 crystal inserted in the open space of the bonded block to realize the unidirectional operation with power scalability. Consequently, the single-frequency laser delivers an output power of 3.9 W at 1112.3 nm with a slope efficiency of 58.6% and an optical-to-optical efficiency of 17.7%. The power fluctuation is measured to be within ± 0.26% over 20 min, and the laser linewidth is estimated to be 4.15 MHz (Δλ = 0.017 pm).

Zinc oxide nanoparticles inhibit osteosarcoma metastasis by downregulating ß-catenin via HIF-1α/BNIP3/LC3B-mediated mitophagy pathway.

Osteosarcoma (OS) therapy faces many challenges, especially the poor survival rate once metastasis occurs. Therefore, it is crucial to explore new OS treatment strategies that can efficiently inhibit OS metastasis. Bioactive nanoparticles such as zinc oxide nanoparticles (ZnO NPs) can efficiently inhibit OS growth, however, the effect and mechanisms of them on tumor metastasis are still not clear. In this study, we firstly prepared well-dispersed ZnO NPs and proved that ZnO NPs can inhibit OS metastasis-related malignant behaviors including migration, invasion, and epithelial-mesenchymal transition (EMT). RNA-Seqs found that differentially expressed genes (DEGs) in ZnO NP-treated OS cells were enriched in wingless/integrated (Wnt) and hypoxia-inducible factor-1 (HIF-1) signaling pathway. We further proved that Zn2+ released from ZnO NPs induced downregulation of ß-catenin expression via HIF-1α/BNIP3/LC3B-mediated mitophagy pathway. ZnO NPs combined with ICG-001, a ß-catenin inhibitor, showed a synergistic inhibitory effect on OS lung metastasis and a longer survival time. In addition, tissue microarray (TMA) of OS patients also detected much higher ß-catenin expression which indicated the role of ß-catenin in OS development. In summary, our current study not only proved that ZnO NPs can inhibit OS metastasis by degrading ß-catenin in HIF-1α/BNIP3/LC3B-mediated mitophagy pathway, but also provided a far-reaching potential of ZnO NPs in clinical OS treatment with metastasis.

Cognitive changes are associated with increased blood-brain barrier leakage in non-brain metastases lung cancer patients.

To explore the relationship between cognitive function and blood-brain barrier leakage in non-brain metastasis lung cancer and healthy controls. 75 lung cancers without brain metastasis and 29 healthy controls matched with age, sex, and education were evaluated by cognitive assessment, and the Patlak pharmacokinetic model was used to calculate the average leakage in each brain region according to the automated anatomical labeling atlas. After that, the relationships between cognitive and blood-brain barrier leakage were evaluated. Compared with healthy controls, the leakage of bilateral temporal gyrus and whole brain gyrus were higher in patients with lung cancers (P < 0.05), mainly in patients with advanced lung cancer (P < 0.05), but not in patients with early lung cancer (P > 0.05). The cognitive impairment of advanced lung cancers was mainly reflected in the damage of visuospatial/executive, and delayed recall. The left temporal gyrus with increased blood-brain barrier leakage showed negative correlations with delayed recall (r = -0.201, P = 0.042). An increase in blood-brain barrier leakage was found in non-brain metastases advanced lung cancers that corresponded to decreased delayed recall. With progression in lung cancer staging, blood-brain barrier shows higher leakage and may lead to brain metastases and lower cognitive development.

Blood-brain barrier and brain structural changes in lung cancer patients with non-brain metastases.

Purpose: To explore the relationship between blood-brain barrier (BBB) leakage and brain structure in non-brain metastasis lung cancer (LC) by magnetic resonance imaging (MRI) as well as to indicate the possibility of brain metastasis (BM) occurrence. Patients and methods: MRI were performed in 75 LC patients and 29 counterpart healthy peoples (HCs). We used the Patlak pharmacokinetic model to calculate the average leakage in each brain region according to the automated anatomical labeling (AAL) atlas. The thickness of the cortex and the volumes of subcortical structures were calculated using the FreeSurfer base on Destrieux atlas. We compared the thickness of the cerebral cortex, the volumes of subcortical structures, and the leakage rates of BBB, and evaluated the relationships between these parameters. Results: Compared with HCs, the leakage rates of seven brain regions were higher in patients with advanced LC (aLC). In contrast to patients with early LC (eLC), the cortical thickness of two regions was decreased in aLCs. The volumes of twelve regions were also reduced in aLCs. Brain regions with increased BBB penetration showed negative correlations with thinner cortices and reduced subcortical structure volumes (P<0.05, R=-0.2 to -0.50). BBB penetration was positively correlated with tumor size and with levels of the tumor marker CYFRA21-1 (P<0.05, R=0.2-0.70). Conclusion: We found an increase in BBB permeability in non-BM aLCs that corresponded to a thinner cortical thickness and smaller subcortical structure volumes. With progression in LC staging, BBB shows higher permeability and may be more likely to develop into BM.

Transcriptome-Wide Characterization of piRNAs during the Developmental Process of European Honey-Bee Larval Guts.

piRNAs play pivotal roles in maintaining genome stability, regulating gene expression, and modulating development and immunity. However, there are few piRNA-associated studies on honey-bees, and the regulatory role of piRNAs in the development of bee guts is largely unknown. Here, the differential expression pattern of piRNAs during the developmental process of the European honey-bee (Apis mellifera) larval guts was analyzed, followed by investigation of the regulatory network and the potential function of differentially expressed piRNAs (DEpiRNAs) in regulating gut development. A total of 843 piRNAs were identified in the larval guts of A. mellifera; among these, 764 piRNAs were shared by 4- (Am4 group), 5- (Am5 group), and 6-day-old (Am6 group) larval guts, while 11, 67, and one, respectively, were unique. The first base of piRNAs in each group had a cytosine (C) bias. Additionally, 61 up-regulated and 17 down-regulated piRNAs were identified in the "Am4 vs. Am5" comparison group, further targeting 9, 983 genes, which were involved in 50 GO terms and 142 pathways, while two up-regulated and five down-regulated piRNAs were detected in the "Am5 vs. Am6" comparison group, further targeting 1, 936 genes, which were engaged in 41 functional terms and 101 pathways. piR-ame-742536 and piR-ame-856650 in the "Am4 vs. Am5" comparison group as well as piR-ame-592661 and piR-ame-31653 in the "Am5 vs. Am6" comparison group were found to link to the highest number of targets. Further analysis indicated that targets of DEpiRNAs in these two comparison groups putatively regulate seven development-associated signaling pathways, seven immune-associated pathways, and three energy metabolism pathways. Moreover, the expression trends of five randomly selected DEpiRNAs were verified based on stem-loop RT-PCR and RT-qPCR. These results were suggestive of the overall alteration of piRNAs during the larval developmental process and demonstrated that DEpiRNAs potentially modulate development-, immune-, and energy metabolism-associated pathways by regulating the expression of corresponding genes via target binding, further affecting the development of A. mellifera larval guts. Our data offer a novel insight into the development of bee larval guts and lay a basis for clarifying the underlying mechanisms.

Sea urchin-like Bi2S3/curcumin heterojunction rapidly kills bacteria and promotes wound healing under near-infrared light.

Bacterial infection is an urgent public health problem. We design a novel photo-responsive hybrid material by growing small molecules of curcumin (Cur) in situ on a sea urchin-like Bi2S3 surface by a one-step hydrothermal reaction method, thus forming an organic-inorganic hybrid material with interfacial contact. The Bi2S3/Cur hybrid material has good antibacterial effect under 808 nm near-infrared (NIR) light irradiation. The antibacterial mechanism is that the electron redistribution at the interface of Bi2S3/Cur excited by 808 nm NIR light will cause a large number of electrons to gather on the side of Bi2S3, forming an internal electric field to drive the excited electrons from Bi2S3 to Cur, which accelerates the separation of photoexcited electron-hole pairs and enhances the production of reactive oxygen species (ROS). In conclusion, due to these synergistic effects of the photothermal properties of Bi2S3, the production of more ROS and the release of small molecules of Cur from traditional Chinese medicine in Bi2S3/Cur, the antibacterial efficacy against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) is 99.96% and 99.03%, respectively. In vivo experiments in animals show that Bi2S3/Cur can reduce the inflammatory response and promote wound healing. This paper presents a simple, rapid and safe strategy for the treatment of wound infections with near-infrared light.

ALD-induced TiO2/Ag nanofilm for rapid surface photodynamic ion sterilization.

The daily life of people in the intelligent age is inseparable from electronic device, and a number of bacteria on touch screens are increasingly threatening the health of users. Herein, a photocatalytic TiO2/Ag thin film was synthesized on a glass by atomic layer deposition and subsequent in situ reduction. Ultraviolet-visible (UV-Vis) spectra showed that this film can harvest the simulated solar light more efficiently than that of pristine TiO2. The antibacterial tests in vitro showed that the antibacterial efficiency of the TiO2/Ag film against S. aureus and E. coli was 98.2% and 98.6%, under visible light irradiation for 5 min. The underlying mechanism was that the in-situ reduction of Ag on the surface of TiO2 reduced the bandgap of TiO2 from 3.44 to 2.61 eV due to the formation of Schottky heterojunction at the interface between TiO2 and Ag. Thus, TiO2/Ag can generate more reactive oxygen species for bacterial inactivation on the surface of electronic screens. More importantly, the TiO2/Ag film had great biocompatibility with/without light irradiation. The platform not only provides a more convenient choice for the traditional antibacterial mode but also has limitless possibilities for application in the field of billions of touch screens.

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Shrubs are the major components of vegetation in arid and semi-arid areas, and play a pivotal role in maintaining ecosystem stability and function. The nurse effects of shrubs can help with the regeneration of native target plant species by alleviating the adverse influences that limit their growth and reproduction in degraded habitats. We summarized the main research results and application of shrub nurse effects in the last 20 years. We discussed several facilitation mechanisms of nurse shrubs, including microhabitat amelioration, fertile island formation, defense and resistance against herbivores, introduction of beneficial microorganism and propagule propagation or preservation, as well as changes in the patterns of interspecific competitive networks. Key factors affecting nurse effects were analyzed, including abiotic environments, biological disturbances, plant life history as well as growth and reproductive strategies. Prospects for future research were also considered from the aspects of improving theore-tical mechanisms of nurse effects by shrubs and building models involved in multiple plant species interaction affec-ted by multifactors.

Redox-Unlockable Nanoparticle-Based MST1 Delivery System to Attenuate Hepatic Steatosis via the AMPK/SREBP-1c Signaling Axis.

To date, few effective treatments have been licensed for nonalcoholic fatty liver disease (NAFLD), which a kind of chronic liver disease. Mammalian sterile 20-like kinase 1 (MST1) is reported to be involved in the development of NAFLD. Thus, we evaluated the suitability of a redox-unlockable polymeric nanoparticle Hep@PGEA vector to deliver MST1 or siMST1 (HCP/MST1 or HCP/siMST1) for NAFLD therapy. The Hep@PGEA vector can efficiently deliver the condensed functional nucleic acids MST1 or siMST1 into NAFLD-affected mouse liver to upregulate or downregulate MST1 expression. The HCP/MST1 complexes significantly improved liver insulin resistance sensitivity and reduced liver damage and lipid accumulation by the AMPK/SREBP-1c pathway without significant adverse events. Instead, HCP/siMST1 delivery exacerbates the NAFLD. The analysis of NAFLD patient samples further clarified the role of MST1 in the development of hepatic steatosis in patients with NAFLD. The MST1-based gene intervention is of considerable potential for clinical NAFLD therapy, and the Hep@PGEA vector provides a promising option for NAFLD gene therapy.

Psoralen alleviates radiation-induced bone injury by rescuing skeletal stem cell stemness through AKT-mediated upregulation of GSK-3ß and NRF2.

BACKGROUND: Repairing radiation-induced bone injuries remains a significant challenge in the clinic, and few effective medicines are currently available. Psoralen is a principal bioactive component of Cullen corylifolium (L.) Medik and has been reported to have antitumor, anti-inflammatory, and pro-osteogenesis activities. However, less information is available regarding the role of psoralen in the treatment of radiation-induced bone injury. In this study, we explored the modulatory effects of psoralen on skeletal stem cells and their protective effects on radiation-induced bone injuries. METHODS: The protective effects of psoralen on radiation-induced osteoporosis and irradiated bone defects were evaluated by microCT and pathological analysis. In addition, the cell proliferation, osteogenesis, and self-renewal of SSCs were explored. Further, the underlying mechanisms of the protective of psoralen were investigated by using RNA sequencing and functional gain and loss experiments in vitro and in vivo. Statistical significance was analyzed using Student's t test. The one-way ANOVA was used in multiple group data analysis. RESULTS: Here, we demonstrated that psoralen, a natural herbal extract, mitigated radiation-induced bone injury (irradiation-induced osteoporosis and irradiated bone defects) in mice partially by rescuing the stemness of irradiated skeletal stem cells. Mechanistically, psoralen restored the stemness of skeletal stem cells by alleviating the radiation-induced suppression of AKT/GSK-3ß and elevating NRF2 expression in skeletal stem cells. Furthermore, the expression of KEAP1 in skeletal stem cells did not significantly change in the presence of psoralen. Moreover, blockade of NRF2 in vivo partially abolished the promising effects of psoralen in a murine model of irradiation-induced osteoporosis and irradiated bone regeneration. CONCLUSIONS: In summary, our findings identified psoralen as a potential medicine to mitigate bone radiation injury. In addition, skeletal stem cells and AKT-GSK-3ß and NRF2 may thus represent therapeutic targets for treating radiation-induced bone injury.

QCW surface-pumped cryogenically cooled single-slab laser with 1 kW level at 946 nm.

We present a kilowatt-level quasi-continuous-wave (QCW) cryogenically cooled 946-nm slab laser oscillator for the first time, to the best of our knowledge. The laser system is based on a double-face-pumped large-size single-slab Nd:YAG design, delivering a record-high average power of 1.06 kW without additional amplification. This laser oscillator operates at repetition rate of 400 Hz with a pulse duration of 175 µs, resulting in a single pulse energy of 2.65 J. To the best of our knowledge, these results represent the highest output power and pulse energy for any all-solid-state 946-nm laser ever reported to date. Our scheme paves a new path for the development of the compact high-power solid-state 946-nm laser.

Preparation of polycation with hydroxyls for enhanced delivery of miRNA in osteosarcoma therapy.

Osteosarcoma, a malignant bone tumor that usually occurs in children and adolescents, has a high rate of death and disability, bringing great pains to society and families. Improving treatment approaches for osteosarcoma patients remains a constant and major goal for researchers and clinical groups due to the limited therapeutic efficiency and survival rate. MiRNAs have been reported to play a crucial role in osteosarcoma occurrence, progression, and metastasis, which provides a new insight for osteosarcoma therapy. In other words, the intervention of the involved miRNA may be a promising way for osteosarcoma. In this study, we developed ethanolamine (EA)-decorated poly(glycidyl methacrylate) (PGMA) polycations (termed as PGEAs) to deliver miR-223 for osteosarcoma inhibition. The introduced hydroxyl groups via EA modification in the PGEA vector can form a hydration shell, hinder protein adsorption, and help the PGEA-based delivery system escape from the in vivo clearance, which further benefits the accumulation of the delivery system in the tumor area. A series of in vitro anti-tumor assays illustrate that the PGEA-2 vector can efficiently deliver miR-223 into osteosarcoma cells for impressive anti-tumor effects via inhibiting malignant behavior of osteosarcoma cells, including proliferation, migration, and invasion. Osteosarcoma inhibition assays in vivo further confirmed the anti-tumor efficiency of PGEA-2/miR-223 complexes without inducing evident toxicity. This work will help develop miRNA for osteosarcoma therapy, and the proposed PGEA based delivery system also provides a promising and safe strategy for gene therapy of osteosarcoma.

1.53 W all-solid-state nanosecond pulsed mid-infrared laser at 6.45 µm.

A compact and robust all-solid-state mid-infrared (MIR) laser at 6.45 µm with high average output power and near-Gaussian beam quality is demonstrated. A maximum output power of 1.53 W with a pulse width of approximately 42 ns at 10 kHz is achieved using a ZnGeP2 (ZGP) optical parametric oscillator (OPO). This is the highest average power at 6.45 µm of any all-solid-state laser to the best of our knowledge. The average beam quality factor is measured to be M2 = 1.19. Moreover, high output power stability is confirmed, with a power fluctuation of less than 1.35% rms over 2 h, and the laser can run efficiently for more than 500 h in total. Using this 6.45 µm pulse as a radiation source, ablation of animal brain tissue is tested. Furthermore, the collateral damage effect is theoretically analyzed for the first time, to the best of our knowledge, and the results indicate that this MIR laser has excellent ablation ability, making it a potential replacement for free electron lasers.

Primary aberration optimization for double-plane symmetric beam shaping systems using a pair of curved reference surfaces.

The geometric aberration of centered refracting double-plane symmetric optical systems (DPSOS) is investigated. For DPSOS with different defocus values in the tangential plane and the sagittal plane (astigmatic wavefront), a pair of curved reference surfaces which vanishes the quadratic terms of the optical path difference (OPD) between a general ray and a reference ray are deduced. With the curved reference surfaces, the primary (fourth-order) wave aberration function for DPSOS is calculated and analyzed, which can be used for beam shaping designs with astigmatic input wavefront, such as slab lasers and semiconductor lasers. Further, the proposed curved reference surfaces can be applied to analyze the aberrations of general DPSOS.

Hypervalent iodine promoted the synthesis of cycloheptatrienes and cyclopropanes.

A new strategy is reported for intramolecular Buchner-type reactions using PIDA as a promotor. Traditionally, the Buchner reaction is achieved via Rh-carbenoids derived from RhII catalysts with diazo compounds. Herein, the first metal-free Buchner-type reaction to construct highly strained cycloheptatriene- and cyclopropane-fused lactams is presented. The advantage of these transformations is in their mild reaction conditions, simple operation, broad functional group compatibility and rapid synthetic protocol. In addition, scaled-up experiments and a series of follow-up synthetic procedures were performed to clarify the flexibility and practicability of this method. DFT calculations were carried out to clarify the mechanism.

Compact integrated aberration-compensating module for a 9 kW Nd:YAG slab laser based on an off-axis stable-unstable resonator.

An integrated aberration-compensating module (IACM), consisting mainly of an adjustable slab-aberration compensator, a one-dimensional Shack-Hartmann wavefront sensor, and a data processor, which meet the urgent requirements of correcting the specific wavefront aberrations of a slab laser based on an off-axis stable-unstable resonator, is designed and experimentally demonstrated. Benefits include compactness, robustness, simplicity, automation, and cost-effectiveness. The particular wavefront aberrations of the 9 kW level quasi-continuous-wave Nd:YAG slab laser, which have characteristics of asymmetry, large amplitude and gradient, high spatial frequency, and low temporal frequency, were measured and theoretically analyzed. In the experiment, the wavefront aberrations of the slab laser were corrected by the IACM. At the average output power of 9 kW, the diffraction-limited factor ß was improved from 20.3 times diffraction limit (DL) to 3.6 times DL. The peak-to-valley and root-mean-square values of aberrations were reduced from 9.6 to 0.85 µm and from 2.86 to 0.18 µm within five iterations of the IACM, respectively. Moreover, The IACM is capable of maintaining the compensating surface figure after power-off.

Direct Access to Bridged Polycyclic Skeletons by Merging Oxidative C-H Annulation and Cascade [4 + 2] Cycloaddition.

We report a step-economic strategy for the direct synthesis of bridged polycyclic skeletons by merging oxidative C-H annulation and cascade cycloaddition. In the protocol, spiro[cyclopentane-1,3'-indoline]-2,4-dien-2'-ones were first synthesized by oxidative C-H annulation of ethylideneoxindoles with alkynes. Subsequent cascade [4 + 2] cycloaddition with dienophiles gave the bridged bicyclo[2.2.1]quinolin-2(1H)-ones and enabled the one-pot construction of two quaternary carbon centers and three C-C bonds. Mechanistic investigations of the latter suggest a cascade ring-opening, 1,5-sigmatropic rearrangement, and [4 + 2] cycloaddition process.