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The immunologically “cold” microenvironment of triple negative breast cancer results in resistance to current immunotherapy. Here, we reveal the immunoadjuvant property of gas therapy with cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation to augment aggregation-induced emission (AIE)-active luminogen (AIEgen)-based photoimmunotherapy. A virus-mimicking hollow mesoporous tetrasulfide-doped organosilica is developed for co-encapsulation of AIEgen and manganese carbonyl to fabricate gas nanoadjuvant. As tetra-sulfide bonds are responsive to intratumoral glutathione, the gas nanoadjuvant achieves tumor-specific drug release, promotes photodynamic therapy, and produces hydrogen sulfide (H 2 S). Upon near-infrared laser irradiation, the AIEgen-mediated phototherapy triggers the burst of carbon monoxide (CO)/Mn 2+ . Both H 2 S and CO can destroy mitochondrial integrity to induce leakage of mitochondrial DNA into the cytoplasm, serving as gas immunoadjuvants to activate cGAS-STING pathway. Meanwhile, Mn 2+ can sensitize cGAS to augment STING-mediated type I interferon production. Consequently, the gas nanoadjuvant potentiates photoimmunotherapy of poorly immunogenic breast tumors in female mice. Gas-based therapy is an emerging therapeutic option for cancer treatment. Here the authors design a virus-mimicking hollow mesoporous tetrasulfide-doped organosilica for co-encapsulation of an aggregation-induced emission (AIE)-active luminogen and manganese carbonyl to fabricate a STING activating gas nano-adjuvant for photo-immunotherapy, promoting anti-tumor immune response in preclinical models.

Electrochemical nitrate reduction to ammonia offers an attractive solution to environmental sustainability and clean energy production but suffers from the sluggish *NO hydrogenation with the spin–state transitions. Herein, we report that the manipulation of oxygen vacancies can contrive spin−polarized Fe 1 −Ti pairs on monolithic titanium electrode that exhibits an attractive NH 3 yield rate of 272,000 μg h −1 mg Fe −1 and a high NH 3 Faradic efficiency of 95.2% at −0.4 V vs. RHE, far superior to the counterpart with spin−depressed Fe 1 −Ti pairs (51000 μg h –1 mg Fe –1 ) and the mostly reported electrocatalysts. The unpaired spin electrons of Fe and Ti atoms can effectively interact with the key intermediates, facilitating the *NO hydrogenation. Coupling a flow−through electrolyzer with a membrane-based NH 3 recovery unit, the simultaneous nitrate reduction and NH 3 recovery was realized. This work offers a pioneering strategy for manipulating spin polarization of electrocatalysts within pair sites for nitrate wastewater treatment. Electrochemical nitrate reduction to ammonia offers an attractive solution to environmental sustainability and clean energy production. Here, the authors construct spin−polarized Fe 1 −Ti pairs via manipulating oxygen vacancies on monolithic titanium electrode for highly efficient nitrate to ammonia conversion.

In nature, coenzyme-independent oxidases have evolved in selective catalysis using isolated substrate-binding pockets. Single-atom nanozymes (SAzymes), an emerging type of non-protein artificial enzymes, are promising to simulate enzyme active centers, but owing to the lack of recognition sites, realizing substrate specificity is a formidable task. Here we report a metal-ligand dual-site SAzyme (Ni-DAB) that exhibited selectivity in uric acid (UA) oxidation. Ni-DAB mimics the dual-site catalytic mechanism of urate oxidase, in which the Ni metal center and the C atom in the ligand serve as the specific UA and O 2 binding sites, respectively, characterized by synchrotron soft X-ray absorption spectroscopy, in situ near ambient pressure X-ray photoelectron spectroscopy, and isotope labeling. The theoretical calculations reveal the high catalytic specificity is derived from not only the delicate interaction between UA and the Ni center but also the complementary oxygen reduction at the beta C site in the ligand. As a potential application, a Ni-DAB-based biofuel cell using human urine is constructed. This work unlocks an approach of enzyme-like isolated dual sites in boosting the selectivity of non-protein artificial enzymes. Single-atom nanozymes are a type of non-protein artificial enzymes and promising for mimicking enzyme active centers, but lack recognition sites to confer substrate specificity. Here, the authors report on a metal-ligand dual-site single-atom nanozyme (Ni-DAB) that mimics the dual-site catalytic mechanism of urate oxidase and has high selectivity in uric acid (UA) oxidation.

Chromite is one of the earliest crystallized minerals from mafic melts and has been used as an important \"petrogenetic indicator.\" Its composition may be modified by interaction with intercumulate melt and adjacent minerals. Thus, chromite in mafic-ultramafic rocks contains clues to the geochemical affinity, evolution, and mantle source of its parent magmas. The Devonian Xiarihamu intrusion, located in the East Kunlun Orogenic Belt in the northern Tibet Plateau, China, hosts a very large disseminated Ni-Co sulfide deposit. This study focuses on geochemistry of the chromite enclosed in olivine of ultramafic rocks of the intrusion. Enrichments in Mg and Al in the rim of the chromite indicate only minor effects of alteration on the compositions of the chromite. The chromites enclosed in the olivines with forsterite percentage (Fo) lower than 87 are characterized by large variations in major and trace elements, such as large ranges of Cr·100/(Cr+Al) (Cr#=15-47), Mg·100/(Mg+Fe2+) (Mg#=41-65), and Al2O3 (=26-53 wt%) as well as 380-3100 ppm V, 70-380 ppm Ga, and 1100-16300 ppm Zn. The chromites display positive correlations between Cr/(Cr+Al) and Ti, Mn, V, Ga, and Sc, inconsistent with fractional crystallization but indicative of an interaction between the chromites, intercumulate melts and hosting minerals. In contrast, chromites hosted in olivine with Fo>87 in harzburgite have small variations in Cr# (ranging from 37 to 41), Mg# (48 to 51), and Al2O3 (30 to 35 wt%) as well as restricted variation in trace elements, indicating relatively weak interaction with trapped liquid and adjacent phases; these compositions are close to those of the most primitive, earliest crystallized chromites. The most primitive chromite has similarities with chromite in mid-ocean ridge basalt (MORB) in TiO2 and Al2O3 contents (0.19-0.32 and 27.9-36.3 wt%, respectively) and depletion of Sc and enrichment of Ga and Zn relative to MORB chromite. The geochemistry of the chromite indicates a partial melting of the asthenospheric mantle that was modified by melts derived from the subduction slab at garnet-stable pressures.

Emerging immune therapy, such as with the anti-programmed cell death-1 (anti-PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 (Pd1-/-) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, Pd1-/- mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in Pd1-/- mice. Consistently, these beneficial effects in Pd1-/- mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti-PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.

Cytokine therapy, involving interleukin-15 (IL-15), is a promising strategy for cancer immunotherapy. However, clinical application has been limited due to severe toxicity and the relatively low immune response rate, caused by wide distribution of cytokine receptors, systemic immune activation and short half-life of IL-15. Here we show that a biomimetic nanovaccine, developed to co-deliver IL-15 and an antigen/major histocompatibility complex (MHC) selectively targets IL-15 to antigen-specific cytotoxic T lymphocytes (CTL), thereby reducing off-target toxicity. The biomimetic nanovaccine is composed of cytomembrane vesicles, derived from genetically engineered dendritic cells (DC), onto which IL-15/IL-15 receptor α (IL-15Rα), tumor-associated antigenic (TAA) peptide/MHC-I, and relevant costimulatory molecules are simultaneously anchored. We demonstrate that, in contrast to conventional IL-15 therapy, the biomimetic nanovaccine with multivalent IL-15 self-transpresentation (biNV-IL-15) prolonged blood circulation of the cytokine with an 8.2-fold longer half-life than free IL-15 and improved the therapeutic window. This dual targeting strategy allows for spatiotemporal manipulation of therapeutic T cells, elicits broad spectrum antigen-specific T cell responses, and promotes cures in multiple syngeneic tumor models with minimal systemic side effects. Cancer immune therapy utilizing interleukin 15 (Il-15) is hampered by the short half-life and systemic toxic effects of the cytokine. Here authors introduce a biomimetic nanovaccine, in which Il-15 and tumor-associated antigenic peptide/MHC-I complexes are co-anchored to cell membrane vesicles of dendritic cell origin, which elicits antigen-specific T cell response leading to superior anti-tumour effect in syngeneic mouse tumour models.

The growing maturity of nanofabrication has ushered massive sophisticated optical structures available on a photonic chip. The integration of subwavelength-structured metasurfaces and metamaterials on the canonical building block of optical waveguides is gradually reshaping the landscape of photonic integrated circuits, giving rise to numerous meta-waveguides with unprecedented strength in controlling guided electromagnetic waves. Here, we review recent advances in meta-structured waveguides that synergize various functional subwavelength photonic architectures with diverse waveguide platforms, such as dielectric or plasmonic waveguides and optical fibers. Foundational results and representative applications are comprehensively summarized. Brief physical models with explicit design tutorials, either physical intuition-based design methods or computer algorithms-based inverse designs, are cataloged as well. We highlight how meta-optics can infuse new degrees of freedom to waveguide-based devices and systems, by enhancing light-matter interaction strength to drastically boost device performance, or offering a versatile designer media for manipulating light in nanoscale to enable novel functionalities. We further discuss current challenges and outline emerging opportunities of this vibrant field for various applications in photonic integrated circuits, biomedical sensing, artificial intelligence and beyond.Recent years have witnessed substantial potential in allying meta-optics with diverse waveguide platforms to enable exotic manipulation of guided light signals. This review cataloged recent advances on meta-waveguides for photonic integration.

Diabetes mellitus, or hyperglycemia, is an independent risk factor for cognitive impairment. Here we systematically analyzed whether glycemic control could improve cognitive impairment in patients with diabetes mellitus (DM), hyperglycemia, or insulin resistance. Three databases (PubMed, EMBASE, and Cochrane Library) and ClinicalTrials.gov were searched for randomized controlled trials analyzing the relationship between glycemic control and cognitive function assessments, published from database inception to June 2022. Patients in experimental groups were treated with antidiabetic drugs, while control groups were treated with a placebo or alternative antidiabetic drugs. Data analysis was conducted using RevMan 5.3 and StataSE-64, and standardized mean difference (SMD) and 95% confidence intervals (CIs) were calculated. Thirteen studies comprising 19,314 participants were included. Analysis revealed that glycemic control significantly attenuated the degree of decline in cognitive function assessment scores (SMD  =  0.15; 95% CI 0.05, 0.26;  <  0.00001), and funnel plots confirmed no publication bias. Seven studies used Mini-Mental State Examination as the primary cognitive function assessment, showing that glycemic control significantly delayed the degree of decline in cognitive function assessment scores (SMD  =  0.18; 95% CI 0.03, 0.34;  =  0.02). Similar results were seen in two studies using the Montreal Cognitive Assessment scale, but without significant difference (SMD  =  0.05; 95% CI-0.10, 0.21;  =  0.51). One study using Auditory Word Learning Test (AVLT) showed that glycemic control significantly delayed the decline in cognitive function assessment scores (SMD  =  0.52; 95% CI 0.11,0.93;  =  0.01), and another used Wechsler Memory Scale Revised, showing similar results (SMD  =  1.45; 95% CI 0.86, 2.04;  <  0.00001). Likewise, a study that used Modified Mini-Mental State scale showed that glycemic control significantly delayed the decline in cognitive function assessment scores (SMD  =  -0.10; 95% CI-0.16, -0.03;  =  0.005). Lastly, one study used AVLT subtests to show that glycemic control delayed the decline in cognitive function assessment scores, although not statistically significant (SMD  =  0.09; 95% CI-0.53, 0.71;   =  0.78). Glycemic control through antidiabetic treatment correlates with the improvement of cognitive impairment in patients with DM, hyperglycemia or insulin resistance. However, further studies are needed to validate the results of this study. PROSPERO, identifier CRD42022342260.

Patients with advanced stage cancers frequently suffer from severe pain as a result of bone metastasis and bone destruction, for which there is no efficacious treatment. Here, using multiple mouse models of bone cancer, we report that agonists of the immune regulator STING (stimulator of interferon genes) confer remarkable protection against cancer pain, bone destruction, and local tumor burden. Repeated systemic administration of STING agonists robustly attenuates bone cancer-induced pain and improves locomotor function. Interestingly, STING agonists produce acute pain relief through direct neuronal modulation. Additionally, STING agonists protect against local bone destruction and reduce local tumor burden through modulation of osteoclast and immune cell function in the tumor microenvironment, providing long-term cancer pain relief. Finally, these in vivo effects are dependent on host-intrinsic STING and IFN-I signaling. Overall, STING activation provides unique advantages in controlling bone cancer pain through distinct and synergistic actions on nociceptors, immune cells, and osteoclasts. There is an unmet clinical need to develop therapies to alleviate metastatic bone pain, frequently observed in patients with advanced cancers. Here, using mouse models of bone cancer pain, the authors show that STING agonists not only suppress bone cancer tumor burden, but also attenuate bone pain and reduce cancer-induced bone destruction.

Histone phosphorylation is a ubiquitous post-translational modification that allows eukaryotic cells to rapidly respond to environmental stimuli. Despite correlative evidence linking histone phosphorylation to changes in gene expression, establishing the causal role of this key epigenomic modification at diverse loci within native chromatin has been hampered by a lack of technologies enabling robust, locus-specific deposition of endogenous histone phosphorylation. To address this technological gap, here we build a programmable chromatin kinase, called dCas9-dMSK1, by directly fusing nuclease-null CRISPR/Cas9 to a hyperactive, truncated variant of the human MSK1 histone kinase. Targeting dCas9-dMSK1 to human promoters results in increased target histone phosphorylation and gene activation and demonstrates that hyperphosphorylation of histone H3 serine 28 (H3S28ph) in particular plays a causal role in the transactivation of human promoters. In addition, we uncover mediators of resistance to the BRAF V600E inhibitor PLX-4720 in human melanoma cells using genome-scale screening with dCas9-dMSK1. Collectively, our findings enable a facile way to reshape human chromatin using CRISPR/Cas9-based epigenome editing and further define the causal link between histone phosphorylation and human gene activation. Histone phosphorylation is a ubiquitous post-translational modification. Here the authors present a programmable chromatin kinase, dCas9-dMSK1, that enables controlled histone phosphorylation and specific gene activation.