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Photothermal therapy (PTT) was reported to induce synergistic immunogenic cell death (ICD) which may convert tumor cells into "therapeutic vaccines". However, this is often insufficient to prevent tumor recurrence, in part because of the immunosuppressive microenvironment in tumors. Therefore, remodeling tumor microenvironment is of great importance to enhance the therapeutic efficacy of PTT. We herein fabricated a versatile nano-photosensitizer by assembling quercetin and Ferrum ion (QFN). The released quercetin from QFN could reduce programmed death ligand 1 (PD-L1) in tumor cells by inhibiting the phosphorylation of JAK2 and STAT3, and reshape extracellular matrix (ECM) by down-regulating α-SMA

As endogenous courier vesicles, exosomes play crucial roles in macromolecule transmission and intercellular communication. Therefore, exosomes have drawn increasing attention as biomimetic drug-delivery vehicles over the past few years. However, few studies have investigated the encapsulation of peptide/protein drugs into exosomes for oral administration. Additionally, the mechanisms underlying their biomimetic properties as oral delivery vehicles remain unknown. Herein, insulin-loaded milk-derived exosomes (EXO@INS) were fabricated and the

Photodeposition is widely adopted for implanting metal/metal oxide cocatalysts on semiconductors. However, it is prerequisite that the photon energy should be sufficient to excite the host semiconductor. Here, we report a lower-energy irradiation powered deposition strategy for implanting CrOx cocatalyst on TiO2. Excitingly, CrOx-400 implanted under visible-light irradiation significantly promotes the CH4 evolution rate on TiO2 to 8.4 µmol g-1h−1 with selectivity of 98% from photocatalytic CO2 reduction, which is 15 times of that on CrOx-200 implanted under UV–visible-light irradiation. Moreover, CrOx-400 is identified to be composed of higher valence Cr species compared to CrOx-200. This valence states regulation of Cr species is indicated to provide more active sites for CO2 adsorption/activation and to modulate the reaction mechanism from single Cr site to Cr-Cr dual sites, thus endowing the superior CH4 production. This work demonstrates an alternative strategy for constructing efficient metal oxides cocatalysts on wide bandgap semiconductor.

Tumor metastasis is responsible for most mortality in cancer patients, and remains a challenge in clinical cancer treatment. Platelets can be recruited and activated by tumor cells, then adhere to circulating tumor cells (CTCs) and assist tumor cells extravasate in distant organs. Therefore, nanoparticles specially hitchhiking on activated platelets are considered to have excellent targeting ability for primary tumor, CTCs and metastasis in distant organs. However, the activated tumor-homing platelets will release transforming growth factor-β (TGF-β), which promotes tumor metastasis and forms immunosuppressive microenvironment. Therefore, a multitalent strategy is needed to balance the accurate tumor tracking and alleviate the immunosuppressive signals. In this study, a fucoidan-functionalized micelle (FD/DOX) was constructed, which could efficiently adhere to activated platelets through P-selectin. Compared with the micelle without P-selectin targeting effect, FD/DOX had increased distribution in both tumor tissue and metastasis niche, and exhibited excellent anti-tumor and anti-metastasis efficacy on 4T1 spontaneous metastasis model. In addition, due to the contribution of fucoidan, FD/DOX treatment was confirmed to inhibit the expression of TGF-β, thereby stimulating anti-tumor immune response and reversing the immunosuppressive microenvironment. The fucoidan-functionalized activated platelets-hitchhiking micelle was promising for the metastatic cancer treatment., Graphical abstract Fucoidan-functionalized micelles (FD/DOX) specially hitchhiked on activated platelets to track tumor cells, and inhibited TGF-β to reverse the immunosuppressive microenvironment, thus showing excellent anti-tumor and anti-metastasis efficacy.Image 1

The trade-off between the electrochemical performance and mechanical strength is still a challenge for Ti3C2Tx free-standing electrode. Herein, a facile approach was proposed to fabricate a Microfibrillated cellulose@Ti3C2Tx (MFC@Ti3C2Tx) self-assembled microgel film by means of hydrogen bonding linkage. Benefiting from the rich hydroxyl groups on the MFC, the Ti3C2Tx nanosheets coated on the MFC in a time scale of minutes (within 1 min) instead of hours. The ultralong 1D frame of MFC effectively mitigated the re-aggregation of Ti3C2Tx nanosheet. The fluffy MFC@Ti3C2Tx film structure and the constructed 1D/2D conducting Ti3C2Tx pathways in horizontal and vertical directions endowed the fast ion transport of the electrolytes and the improved accessibility to the Ti3C2Tx surface. As a result, the freestanding MFC@Ti3C2Tx microgel film delivered a high specific capacitance of 451F/g. And the rate performance was increased to 71% from the 64% of that of pristine Ti3C2Tx film. Furthermore, the tensile strength of MFC@Ti3C2Tx film was also promoted to 46.3 MPa, 3 folds of that of the pristine Ti3C2Tx film, due to the high strength of MFC and the hydrogen bonding effect.

Current clinical agents for autoimmunity disorders treatment often cause substantial adverse effects and safety concerns, owing to non-specific immune modulation. Due to the prominent contribution of effector T cells in pathogenesis of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), and preferential location of co-stimulatory receptor-ligand pair OX40-OX40L at the inflamed sites, selectively targeting autoaggressive T cells by blockade OX40-OX40L, might represent an alternative strategy. Herein, we developed a new strategy to antagonize OX40-OX40L interaction by engineering a cell membrane derived nanovesicles (NVs) expressing OX40 receptors (OX40 NVs), and explored their potential for autoimmune disorders therapy. OX40 NVs showed specific binding capability to inflamed HUVECs in vitro, it also possessed distinct arthritic-targeting capacity in RA inflamed joints, and preferential accumulation in IBD inflamed colon. OX40 NVs efficiently suppressed the progression of both RA and IBD diseases through reducing CD4+OX40+ T cells population, and proinflammatory cytokines (i.e., TNF-α and IL-1β), while reinforcing Tregs immune-suppressive effect, with superior therapeutic efficacy than anti-OX40L. Additionally, dexamethasone (DEX) loading can further enhance the potential of OX40 NVs for RA treatment. Owing to their preferential localization to inflamed sites, and potent immune-suppression ability, targeting OX40-OX40L blockade by OX40 NVs for autoimmune therapy is highly promising.

Currently, ischemic stroke is the leading cause of disability and death worldwide, and the performance of corresponding drugs is often unsatisfactory owing to the complex pathological processes and the impediment of the blood-brain barrier (BBB). Here, we employed various tertiary amino groups, including different linear, cyclic, and bimolecular drug structures, to modify 3-n-butylphthalide (NBP), a natural product used for ischemic stroke treatment, which has poor bioavailability, to generate a series of six prodrugs. These prodrugs showed significantly improved solubility and cellular uptake, which were primarily driven by putative pyrilamine cationic transporters. They also displayed more efficient brain delivery in vivo, reaching as high as 21.5-fold brain accumulation increase compared with NBP, leading to much higher bioavailability and stronger therapeutic effects. The toxicity of these molecules is also lower or similar to that of unmodified NBP. We showed that the tertiary amino group-modified NBP prodrugs are effective and safe for treating ischemic stroke with significantly enhanced druggability; hence, they have potential for further clinical development.

Sustained release vaccine carriers can facilitate an increased interaction time between the antigen and immune system to strengthen immune responses, but their promotion on adaptive immune responses, especially cellular immunity, are still unfavorable. Herein, we report a sustained antigen delivery vector, which carries abundant antigens, a nucleic acid adjuvant and pathogen-associated molecular patterns to simulate a natural pathogen to reinforce immune responses. Specifically, murine colorectal cancer cells MC38 lysate and Toll-like receptor 9 agonist CpG are loaded into yeast derived β-glucan particles (GPs). After vaccination, these particles can form a vaccine depot that continuously release the antigen similar to the traditional aluminum hydroxide gel, but recruit more immune cells and induce more cytokine secretion at the injection site. Stronger antibody responses, Th1 and Th17 biased cellular immunity and immune memory are achieved compared with aluminum hydroxide gel. More importantly, treatment with these particles significantly suppress tumor growth in a therapeutic tumor model. This work shed light on the efficacy of combining sustained antigen release with pathogen-mimicking manner in vaccine design.

Background Lobectomy with systematic lymph node dissection (SND) remains the standard procedure for resectable non–small-cell lung cancer (NSCLC), whereas lobe-specific lymph node dissection (LSND) was reported to have more advantages in perioperative recovery and complication reduction in treating early-stage diseases. Survival outcomes after LSND remains controversial compared with SND. Patients and Methods From 2014 to 2017, data of 546 patients with clinical stage IA solid-dominant NSCLC and who underwent curative lobectomies with LSND (n = 100) or SND (n = 446) at our institution were collected. Propensity score matching was conducted to eliminate the biases. Five-year disease-free survival and overall survival were compared between the groups. Perioperative parameters and postoperative complications were also analyzed. Results Lobectomies with LSND or SND were performed in 100 patients and 446 patients, respectively. After matching, there were 100 patients in each group and no significant differences in 5-year overall survival (P = .473) and disease-free survival (P = .789) were found between the groups. Recurrence patterns were also similar (P = .733). Perioperative parameters were similar, whereas the incidence of postoperative complications in the SND group was found to be significantly higher than that in the LSND group (P = .003). Conclusions Our study demonstrated that LSND has similar efficiency to SND in terms of survival, recurrence, lymph node dissection, and perioperative recovery of patients with clinical stage IA solid-dominant NSCLC, as well as significant advantages in reducing postoperative complications. Therefore, curative lobectomies with LSND may be more suitable and practical for clinical stage IA solid-dominant patients with NSCLC.

Immunotherapy has exhibited great potential in cancer treatment. However, for immunosuppressive tumors such as pancreatic cancer, immunotherapy is far from satisfactory. PI3K-γ and colony stimulating factor-1/colony stimulating factor-1 receptor (CSF-1/CSF-1R) pathways are involved in the infiltration and polarization of immunosuppressive cells including M2 tumor associated macrophages (M2 TAMs), causing a suppressive tumor immune microenvironment (TIME) in pancreatic cancer. Herein, a M2 TAM targeting nanomicelle was developed to co-deliver PI3K-γ inhibitor NVP-BEZ 235 and CSF-1R-siRNA for specific TAMs reprogramming and antitumor immune responses activation. M2 TAM targeting peptide M2pep was modified on a mixed micelle, which was potent to co-encapsulate BEZ 235 and CSF-1R siRNA. The formulated nanomicelle increased M2 TAM targeting efficiency both in vitro and in vivo. Compared with single pathway blockade, dual blockade of PI3k-γ and CSF-1R demonstrated enhanced TAM remodeling effects by reducing M2 TAM level and elevating M1 TAM level, and also suppressed tumor infiltration of myeloid-derived suppressor cells (MDSCs). Consequently, the M2 TAM targeting reprogramming system activated antitumor immune responses and achieved enhanced anti-pancreatic tumor effects via PI3K-γ blockade and downregulation of CSF-1R. The M2pep modified nanomicelle provides a promising method for co-delivery of siRNA and small molecule inhibitor to M2 TAM. Dual inhibition of both PI3K-γ and CSF-1R can remodel TIME and activate antitumor immune responses synergistically, providing an alternative approach for pancreatic cancer treatment.

Non-viral gene delivery systems have proven to be a promising approach in the treatment of brain metastatic cancers but facing delivery difficulties. Due to the existence of blood-brain barrier, non-viral gene carriers must pass through brain capillary endothelial cells to accumulate at the brain tumor sites. However, during this process, most of them trap into brain capillary endothelial cells and fail to penetrate to the brain tumor sites. Autophagy is involved in dynamic disposition of both intracellular and extracellular components, which theoretically affects intracellular fate of non-viral gene carriers during BBB penetration. In the present study, R6dGR peptide-modified PEGylated polyethyleneimine that carry therapeutic gene encoding human tumor necrosis factor-related apoptosis-inducing ligand (PPR/pTRAIL) are established as model non-viral gene delivery system and applied in breast cancer brain metastasis therapy. Autophagy-mediated lysosome degradation pathway is found to be involved in the degradation of PPR/pTRAIL in brain capillary endothelial cells and prevents them from BBB penetration. Pre-inhibiting BBB autophagy level by wortmannin loaded liposomes (Wtmn-Lip) can increase brain accumulation of non-viral gene carrier PPR without damaging BBB tight junctions. Besides, Wtmn-Lip synergistically induces apoptosis with TRAIL via different signaling pathways. Herein, pre-treatment of Wtmn-Lip might solve delivery difficulties of non-viral gene carriers in the treatment of brain metastatic cancers.

Oxidative-stress defense system stands for the vulnerability of tumor cells because of the stronger oxidative stress existing in tumor sites. TRPA-1 has been found to be overexpressed in various tumors, related to the tumor proliferation and metastasis, and promote reactive oxygen species (ROS) and chemotherapy tolerance through Ca2+-dependent anti-apoptotic pathway in recent studies, which provides a new anti-tumor approach to target oxidative-stress defense system. However, there are few studies on the mechanisms of TRPA-1 inhibition increasing the effectiveness of chemotherapy and inhibiting tumor metastasis. Here, in order to deliver drugs to the deep tumor where is full of stronger oxidative stress, a dual receptors-targeting and size-switchable “cluster bomb” co-loading doxorubicine (DOX) and TRPA-1 inhibitor AP-18 (DA-tMN) was designed. DSPE-PEG2000 micelles (M, ~10 nm) were connected to the master core of hyaluronic acid nanogels (N, ~100 nm) to realize HAase-responsive size-switchable and acquired targeting characteristics. Besides, tumor homing peptide tLyP-1 (t) was modified on the surface of micelles to further increase tumor accumulation. Our study showed that tLyP-1 modification enhanced tumor-targeting delivery of tLyP-1-modified micelles @ nanogels (tMN) in vitro and in vivo. Then, HAase responsive nanogel core realized the deep penetration of tMN in 4 T1 3D tumor spheres models and 4 T1 tumor-bearing mice models. In vitro anti-tumor and anti-metastasis mechanism studies indicated that AP-18 increased the sensitivity of tumor cells to DOX by inhibiting Ca2+ influx and AKT phosphorylation caused by DOX. Compared with DOX-loaded tLyP-1-modified micelles @ nanogels (D-tMN), DA-tMN had the enhanced anti-tumor and anti-metastasis effect in vitro and vivo. Furthermore, the further anti-metastasis mechanism studies showed that TRPA-1 inhibition downregulate the expression of N-cadherin and vimentin and upregulate the expression of E-cadherin, which suggested that metastases inhibition caused by TRPA-1 inhibition may be related to the inhibition of epithelial-mesenchymal transition (EMT) process.

We investigated the role of the STING1-CXCR3 axis using database data and verified it in a mouse model bearing Lewis lung carcinoma (LLC) cells exposed to hydrogen peroxide (H

Pancreatic ductal adenocarcinoma (PDA) is a highly fatal disease with 5-year survival of ∼8.5%. Nanoplatforms such as nab-paclitaxel and nanoliposomal irinotecan demonstrate superiority and utility in treating different progressions of PDA by prolonging the median overall survival by only a few months. Due to the dense surrounding stroma and the high autophagy in pancreatic cancer, integrin ɑvβ3 targeting, acid environmental sensitive, TR peptide-modified liposomal platforms loaded with combined autophagy inhibiting hydroxychloroquine (HCQ), and cytotoxic paclitaxel (PTX) were designed (TR-PTX/HCQ-Lip) to accomplish the aim of synergistically killing tumor cells while inhibiting stroma fibrosis. The results showed that TR peptide-modified liposomes (TR-Lip) have superior targeting and penetrating effects both in vitro and in vivo. TR-PTX/HCQ-Lip efficiently inhibited autophagy in pancreatic cells and surrounding cancer-associated fibroblasts. The synergistic anti-fibrosis roles were also confirmed both in vitro and in vivo, all of which contributes to the enhanced curative effects of TR-PTX/HCQ-Lip in both heterogenetic and orthotopic pancreatic cancer models. STATEMENT OF SIGNIFICANCE: Autophagy plays a significant role in pancreatic ductal adenocarcinoma, especially in activating cancer associated fibroblasts which is also related to collagen generation that promotes the formation of dense stroma, which hinder the cytotoxic drugs to target and kill cancer cells. In this study, we designed integrin ɑvβ3 targeting, acid environmental sensitive liposomal platforms to co-loaded paclitaxel and the autophagy inhibitor hydroxychloroquine. The results showed that the muti-functional liposomes can target to the pancreatic tumor and efficiently kill tumor cells and inhibit stroma fibrosis, thus improve the therapeutic effect in orthotopic pancreatic cancer models.

The development of well-ordered TiO2 nanotubes arrays (TNTAs) as a binder-free electrode in supercapacitors was hindered by their poor conductivity and low capacitance. Herein, the hierarchical structure of TNTAs/C/MnO2 (TNTCM) electrode was built via three-step process — typical anodization, carbon deposition and electrodeposition method. TiO2 nanotube arrays obtained from anodization provide a high surface area substrate for binder-free electrode, followed by carbon nanoparticles which could act as an electronic transfer medium penetrated into TNTAs using gas thermal penetration, the TNTAs/C electrode became high conductivity, then the two-dimension birnessite-type MnO2 nanoflakes were in situ growth onto TNTAs/C composites through scalable and easy electrodeposition method could storage energy by faradaic reaction. The resultant TNTCM hybrid composites manifest a remarkable specific areal capacitance of 492 mF/cm2, 207 times than that of TNTAs/C electrode, the value is comparable or much higher than those of previously reported TiO2 nanotubes-based electrode for supercapacitor. The synthesized TNTCM electrode exhibit a high energy density of 465 mWh/m2 at power density of 2.5 W/m2. In addition, the excellent energy storage performance is well maintained with a capacitance retention of 98% during 3000 charge–discharge cycles, indicating its promising application in energy storage and conversion fields.

This paper investigates the tracking control problem of a class of multi-input multi-output (MIMO) nonlinear systems under asymmetric full-state constraints. By integrating a nonlinear transformed function (NTF) with the upper bound estimation technique, we develop a robust adaptive dynamic surface control (DSC) method that exhibits several attractive features: 1) both symmetric and asymmetric state constraints are directly addressed without the need for converting the state constraints into new constraints on tracking errors (as used in the Barrier Lyapunov Function (BLF) in most existing works). Such control scheme (with its structure unchanged) is also applicable to the systems free from state constraints; 2) the undesirable feasibility conditions on virtual control laws commonly involved in most existing works are completely eliminated; and 3) the utilization of NTF-based DSC and upper bound estimation technique not only avoids the explosion of complexity problem in traditional backstepping design, but also allows a structurally simple and computationally inexpensive control scheme to be developed, in which only one single parameter updating is needed, significantly reducing the design complexity and online computation. The effectiveness of the proposed scheme is verified via simulation.

The hypoxic tumor microenvironment of pancreatic cancer contributes to the progression and metastasis of tumor cells. Downregulation of hypoxia-inducible factor-1α (HIF-1α) with CRISPR/Cas9 is a promising approach to modulate tumor microenvironment and inhibit tumor metastasis. However, the in vivo delivery of CRISPR/Cas9 system remains a challenge. In the present manuscript, a tumor targeted lipid-based CRISPR/Cas9 delivery system was developed to suppress HIF-1α. Plasmids encoding Cas9 and HIF-1α-targeting sgRNA were successfully constructed and coencapsulated in R8-dGR peptide modified cationic liposome with PTX. R8-dGR-Lip exhibited enhanced BxPC-3 cell targeting and deep penetration into tumor spheroids. R8-dGR-Lip/PTX/pHIF-1α successfully downregulated HIF-1α and its downstream molecules VEGF and MMP-9, leading to enhanced antimetastatic effects. Besides, the blockade of HIF-1α also promoted the cytotoxicity of PTX on BxPC-3 cell lines. Compared with pegylated liposomes, R8-dGR-Lip enhanced the distribution in tumor tissues. The targeted delivery of CRISPR/Cas9-HIF-1α system and PTX significantly inhibited tumor growth. More importantly, inhibition of HIF-1α suppressed the metastasis of pancreatic cancer and prolonged survival time. Since CRISPR/Cas 9-HIF-1α hardly affected HIF-1α expression in normal hepatic cells, the designed R8-dGR-Lip/PTX/pHIF-1α did not induce severe toxicity in vivo. This strategy broadened the in vivo application of CRISPR/Cas9 system. Downregulation of HIF-1α may be a feasible approach for antimetastatic therapy.

The zero valence iron (ZVI) Fenton-like catalyst has two main defects: one defect is that the surface passivation impairs the reusability of catalysts, and the other defect is the deactivation under neutral working pH. To overcome these problems, we synthesized a dendrite-like ZVI@Fe3O4 composite modified with carbon quantum dots (CQDs) and oxygen vacancies (OVs) by electrodeposition and solvothermal treatments. The results showed that the CQDs (approximately 5 nm) with polar C-groups on the surface of the composites were derived from the carbonization of glucose during thermal treatment, and the OVs (atomic scale) at the junction of Fe3O4 and the CQDs were induced by the reduction of the CQDs. The synthesized composite possessed excellent catalytic activity and reusability. Under the condition of 6 mmol/L H2O2, the synthesized composite catalyst with the dose of 0.10 g/L completely removed 35 ppm phenol within 10 min at pH 4.0 and within 60 min at neutral pH. Furthermore, the catalytic mechanism was proposed. The reducing effect of CQDs accelerated the Fe3+/ Fe2+ cycle, and the surface polar C-groups promoted the adsorption of phenol molecules; the OVs induced the formation of acidic micro regions and facilitated the dissociation of the O O bonds in H2O2 into OH, extending the application range of pH from ~4.0 to the neutral condition during the Fenton-like process.

Autophagy plays a key role in the stress response of tumor cells, which contributes to cancer cell survival and resistance to chemotherapy by degrading cytoplasmic proteins to provide energy and clear the hazardous substances. Therefore, combined treatment of chemotherapeutics and autophagy inhibitors is thought to obtain a desirable antitumor effect. Nanoparticles (NPs) show potential in tumor-targeting drug delivery because of the enhanced permeability and retention (EPR) effect. However, NPs with fixed particle size cannot achieve optimal delivery effect. Herein, a strategy based on Cu (I)-catalyzed click chemistry-triggered aggregation of azide/alkyne-modified micelles was developed for the co-delivery of the chemotherapeutic drug doxorubicin (Dox) and the autophagy inhibitor wortmannin (Wtmn). In vitro experiments showed that the size of micelles increased in a time-dependent manner, which enhanced micelle accumulation in both B16F10 and 4 T1 cells. The fluorescence resonance energy transfer (FRET) experiment and biodistribution study further demonstrated that the aggregation of micelles through click cycloaddition significantly improved the accumulation of drug-loading micelles at the tumor region. Furthermore, the decreased amount of autophagosomes observed by transmission electron microscopy (TEM), the declined expression of LC3-II, and the increased level of p62 by western blotting and immunohistochemistry (IHC) confirmed the obvious inhibition of autophagy induced by Dox/Wtmn co-loaded size-adjustable micelles, which had a synergistic effect in cancer suppression. In addition, the co-loaded size-adjustable micelles showed outstanding cytotoxicity and antitumor effect. Therefore, this strategy effectively suppressed melanoma and breast cancer in mice. Statement of Significance The therapeutic effects of chemotherapy can be limited by autophagy; hence, combined use of autophagy inhibitors with chemotherapeutics achieves desirable anticancer efficacy. In the present study, we designed size-adjustable micelles by modifying the click reaction substrate azide group and the alkyne group on the surface of micelles, and subsequently, the autophagy inhibitor wortmannin and the chemotherapeutic drug doxorubicin were co-loaded. The micelles could aggregate by click reaction at the tumor site when the catalysts were intratumorally injected. The results showed that the size-adjustable micelles achieved efficient drug delivery, penetration, and retention in tumors; through the combined effect of wortmannin-mediated autophagy inhibition and doxorubicin-mediated cytotoxicity, this strategy exerted significant anticancer effect in melanoma and breast cancer treatment.

In the prevalence of COVID-19, infection symptoms are different in children and adults. In this study to investigate the differences in the upper respiratory tract microbiome profile between healthy children and adults and to explore which microbiome protect them from COVID-19.Thirty healthy children and 24 healthy adults were enrolled between October 2020 and January 2021. Nasal and throat swabs were obtained at enrollment, and DNA was extracted. We performed 16S rDNA sequencing to compare the alpha and beta diversity of the nasal and throat microbiomes between children and adults and assessed potential microbiome biomarkers.In the nasal microbiome, there were significant differences between healthy children and adults, and Moraxella occupied the largest proportion in healthy children. Notably, there was no significant difference between healthy children and adults in the throat microbiome, and it was predominated by Firmicutes. In the function analysis, compared with adults, there was increased enrichment in pathways related to amino acid metabolism and lipid metabolism, in children.In the upper respiratory tract microbiome profiles, Moraxella may be involved in protecting children from COVID-19 infections and may be involved the amino acid metabolism and lipid metabolism.

Electrocatalytic nitrate reduction reaction (NO

Intratumoral environment as a hypoxic, non-inflamed "cold" state is difficult for many agents to accumulate and activate the immune system. Intrinsically, facultative anaerobic Salmonella VNP20009 target the tumor hypoxic areas, invade into tumor cells and exhibit an immune effect. Here we engineer the bacteria by decorating their surface with newly synthesized heptamethine cyanine dyes NHS-N782 and JQ-1 derivatives to obtain the biohybrid agent N-V-J, leading to the deep tumor targeted photothermal therapy and magnified immunotherapy. Due to the mitochondrial targeting capacity of NHS-N782, N-V-J becomes susceptive to the temperature rise when reaching tumors. This synergistic strategy promotes the systemic immunity by creating an inflamed "hot" tumor state from three different dimensions, which include the inherent immunogenicity of bacteria, the near-infrared laser triggered tumor antigens and the downregulation of PD-L1 expression. All these approaches result in effective and long-lasting T cell immune responses to prevent local and distant tumors for extended time. Leveraging the attenuated bacteria to transport dual drugs to the tumor tissues for self-synthetic vaccines provides a novel paradigm to enhance the bacteria-mediated cancer immunotherapy.

Postsurgical recurrence of breast cancer is closely related to the inflammatory tumor microenvironment evoked by surgical wounds. Toll-like receptor 4 (TLR4) signaling contributes to NF-κB activation thus secreting various inflammatory cytokines. Herein, we developed an in situ photo-crosslinked hydrogel (D/T gel) concurrently loaded with doxorubicin (DOX) and a TLR4 antagonist, resatorvid (TAK-242). Its therapeutic effect against breast cancer postsurgical relapse was accomplished through remodeling the proinflammatory tumor microenvironment. The obtained gel network exhibited excellent biodegradability and biocompatibility, which motivated dermal wound healing in the full thickness wound model in mice. Despite the initial burst release of DOX, D/T gels exhibited extended-release of both DOX and TAK-242 for up to 21 days in vitro . TAK-242 was demonstrated to inhibit the lipopolysaccharide-induced NF- κ B activation and downregulate TLR4 levels in both RAW264.7 and 4T1 cells. In a 4T1-Luc tumor postsurgical recurrence model, D/T gel significantly suppressed recurrent tumor growth by elevating the concentrations of DOX and TAK-242 at the tumor sites and remodeling the TLR4 activation-induced proinflammatory microenvironment. Overall, the D/T gel platform technology is proven to deliver therapeutics directly to the surgical wound bed, attenuating the dual inflammatory responses induced by DOX and surgical wounding thus greatly potentiating its efficacy in preventing postsurgical tumor recurrence.

Electrocatalytic dehalogenation provides a promising strategy to degrade refractory tribromoacetic acid (TBAA) pollutant into nontoxic acetic acid (AA) and bromide ions. Herein, a novel atomic nickel anchored nitrogenated carbon (Ni1-N-C) featured of Ni-Ni dual-atom catalysts (DACs) was first reported for the electrochemical debromination of TBAA. At the potential of −0.86 V vs. SCE, nearly 100% of TBAA (10 mg/L) was reduced to AA by Ni1-N-C within 3 h with a high selectivity (88%), surpassing Pd nanoparticles (NPs), Ni NPs and Ag NPs. Moreover, Ni1-N-C exhibited outstanding cycling performance during the long-term test. It is found that TBAA debromination followed a stepwise pathway via a direct mechanism and accorded with a pseudo-first-order kinetics. Density functional theory calculations reveal that Ni-Ni DACs was responsible for the efficient and selective debromination of TBAA to AA owing to the optimized adsorption and desorption for reaction intermediates as compared to Ni single-atom catalysts (Ni-N3 and Ni-N4). This work presents new perspectives to rationally design novel and efficient atomic catalysts for the electrochemical dehalogenation.

Extracts of a set of the Permian Lucaogou shales collected from the southern Junggar Basin in NW China were examined for their molecular compositions and compound-specific isotopic signatures. The distribution of n-alkanes, isoprenoids, steranes, hopanes (C27 to C34) and appearance of 25-norhopanes (C26 to C33) were found to vary between samples, indicating that different degrees of biodegradation occurred in the shale strata. The non-biodegraded sample showed a complete composition of n-alkanes and isoprenoids including pristane (Pr) and phytane (Ph). Moderately biodegraded shales were characterized by near-absence of n-alkanes, but Pr and Ph still showed noticeable contents; 25-norhopanes were not detected. Heavily biodegraded shale had imperceptible content of n-alkanes, isoprenoids and steranes, but a series of abundant 25-norhopanes appeared. Compound-specific isotopic data show negative δ13C values (−44.4‰ to −55.6‰) for the regular hopanes having the same carbon number in all the examined shales, indicating a substantial contribution of methanotrophs to the sediments. Moreover, the 25-norhopanes had consistent δ13C values to the corresponding regular hopanes, which are proposed to be their parent molecules. The distributional and isotopic signatures indicate the 25-norhopanes in the heavily biodegraded Permian Lucaogou shales were genetically formed during in situ biodegradation of the extractable bitumen when the strata were uplifted from depth and may have been linked to the incursion of meteoric water.

A compact laser-based absorption sensor system associated with a 152-m path length absorption cell for simultaneous second harmonic (2f) detection of atmospheric nitrous oxide (N2O), methane (CH4), and water vapor (H2O) is presented. An 8 μm external cavity quantum cascade laser (EC-QCL) was used as an excitation source to simultaneously target three neighboring absorption lines, N2O at 1255.424 cm−1, CH4 at 1255.000 cm−1, and H2O at 1254.732 cm−1. Minimum detection limits (1σ) of 0.9 ppb for N2O, 4.8 ppb for CH4 and 31 ppm for H2O were achieved with a 1-s integration time at an optimum pressure of 50 Torr. Both laboratory and atmospheric environmental mixing ratios of these three gases associated with basic meteorological parameters were recorded and the corresponding emission sources were analyzed. In particular, the N2O emission was studied during extended time periods including rainy intervals.

Cancer associated fibroblasts (CAFs) which shape the tumor microenvironment (TME) and the presence of blood brain barrier (BBB) remain great challenges in targeting breast cancer and its brain metastasis. Herein, we reported a strategy using PTX-loaded liposome co-modified with acid-cleavable folic acid (FA) and BBB transmigrating cell penetrating peptide dNP2 peptide (cFd-Lip/PTX) for enhanced delivery to orthotopic breast cancer and its brain metastasis. Compared with single ligand or non-cleavable Fd modified liposomes, cFd-Lip exhibited synergistic TME targeting and BBB transmigration. Moreover, upon arrival at the TME, the acid-cleavable cFd-Lip/PTX showed sensitive cleavage of FA, which reduced the hindrance effect and maximized the function of both FA and dNP2 peptide. Consequently, efficient targeting of folate receptor (FR)-positive tumor cells and FR-negative CAFs was achieved, leading to enhanced anti-tumor activity. This strategy provides a feasible approach to the cascade targeting of TME and BBB transmigration in orthotopic and metastatic cancer treatment.

Traditional chemotherapy against breast cancer usually accompanied with metastasis. Thus, it is significant to enhance anti-tumor and anti-metastasis efficacy simultaneously. The extracellular environment of most tumors is acidic with pH 6.5–6.9, which play an important role in driving promotion of tumor metastasis. Herein, we developed an intratumoral injectable phospholipids-based phase separation gel (PPSG) co-loaded with 5-fluotouracil (5FU) and magnesium oxide (MgO), termed as 5FU + MgO-PPSG. It was prepared by simple mixing, and showed in the appearance of a clear and yellow solution with good fluidity. After intratumoral injection, PPSG system achieved phase transition and sustained released alkaline substance to neutralize acidic microenvironment in tumor site. Both in vitro and in vivo research showed a strong anti-tumor and anti-metastasis efficacy. 4T1-bearing mice after administration with 5FU + MgO-PPSG was achieved significantly prolonged survival time, compared with other groups. In conclusion, the novel 5FU + MgO-PPSG system might have a great potential to improve treatment method against breast metastasis.

In this paper, we report on a novel enhancement-mode AlGaN/GaN gates-separating groove heterostructure field-effect transistor (GSG HFET), in which a block barrier exists between the double gates as realized by dry etching. The current transport dominated by thermionic emission or thermionic field emission results in a high drain current density. The threshold voltage modulation mechanism of AlGaN/GaN GSG HFET is investigated. Due to the increasing of block barrier height and width, the threshold voltage shifts obviously towards to the positive direction with increasing the gate length or gate-to-gate distance ( L gg ). By optimizing the device structure, a threshold voltage of 1.8 V and a comparable drain current density of 550 mA/mm are obtained at L gg = 180 nm, while the values of 2.5 V and 370 mA/mm are obtained at L gg = 280 nm. Moreover, it's noteworthy that the threshold voltage is less sensitive to recess depth and etching time. The devices show high-uniformity threshold voltage within etching time range from 8 to 9 min.

Using off-axis integrated cavity output spectroscopy, named OA-ICOS, the absorption spectrum of CO2 at 4.32 μm is recorded by using a quantum cascade laser (QCL). The concentration of the three isotopologues 16O12C16O, 16O13C16O and 16O12C18O is detected simultaneously. The isotope abundance ratio of 13C and 18O in CO2 gas can be obtained, which is most useful for ecological research. Since the ambient temperature has a serious influence on the output wavelength of the laser, even small temperature variations seriously affect the stability and sensitivity of the system. In this paper, a wavelength locking technique for QCL is proposed. The output of a digital potentiometer integrated in the laser current driver control is modified by software, resulting in a correction of the driving current of the laser and thus of its wavelength. This method strongly reduces the influence of external factors on the wavelength drift of lasers and thus substantially improves the stability and performance of OA-ICOS as is demonstrated with long-time measurements on CO2 in laboratory air.

Parkinson's disease (PD) remains one of the most common neurodegenerative movement disorders with limited treatment options available. A dopamine derivative N-3,4-bis(pivaloyloxy)-dopamine (BPD) previously developed in our group has demonstrated superior therapeutic outcome compared to levodopa in a PD mice model. To further improve the therapeutic performance of BPD, a brain targeted drug delivery system was designed using a 29 amino-acid peptide (RVG29) derived from rabies virus glycoprotein as the targeting ligand. RVG29 functionalized liposomes (RVG29-lip) showed significantly higher uptake efficiency in murine brain endothelial cells and dopaminergic cells, and high penetration efficiency across the blood brain barrier (BBB) in vitro. In vivo and ex vivo distribution studies demonstrated RVG29-lip selectively distributed to the brain, striatum and substantia nigra. Furthermore, BPD loaded RVG29-lip (BPD-RVG29-lip) exhibited improved therapeutic efficacy in a PD mouse model, while causing no obvious systemic toxicity after intravenous administration. Thus, BPD-RVG29-lip represents a highly promising approach for the brain targeted treatment of PD.

To achieve tumor-selective drug delivery, various nanocarriers have been explored using either passive or active targeting strategies. Despite the great number of studies published annually in the field, only nanocarriers using approved excipients reach the clinical stage. In our study, two classic nanoscale formulations, nanoemulsion (NE) and liposome (Lipo) were selected for the encapsulation of lycobetaine (LBT). To improve the lipid solubility of LBT, oleic acid (OA) was used to complex (LBT-OA) with lycobetaine (LBT). Besides, PEGylated lecithin was used to enhance the circulation time. The release behaviors of LBT from non-PEGylated and PEGylated NE and Lipo were compared. PEGylated LBT-OA loaded Lipo (LBT-OA-PEG-Lipo) exhibited a sustained release rate pattern, and in vivo pharmacokinetic profiles showed the extended circulation compared nanoemlusions. Besides, LBT-OA-PEG-Lipo showed an enhanced anti-tumor effect in the mice xenograft lung carcinoma model. Moreover, a multi-target peptide nRGD was co-administered as a therapeutic adjuvant with LBT-OA loaded formulations, which demonstrated improved tumor penetration and enhanced extravasation of formulations. Also, co-administration of nRGD significantly improved the in vivo antitumor efficacy of different formulations, likely due to the depletion of tumor-associated macrophages (TAMs). Thus, LBT-OA-PEG-Lipo+nRGD may represent a promising strategy for cancer chemotherapy against lung carcinoma.

Several welding methods are used in the manufacturing of the CFETR vacuum vessel. These welding methods will inevitably lead to the problems of welding residual stress and welding distortion. Relieving welding residual stress is one of the important works in CFETR vacuum vessel welding and vibration stress relief (VSR) is one of the methods to relief the residual stress in the welding of the CFETR vacuum vessel. In this paper, the vacuum vessel PS3 segment is selected as the research object, and the VSR technology such as excitation point and support regions, excitation force and excitation frequency can be obtained through software simulation combined with the actual situation, which provides technical guidance for improving the effect of residual stress relieving.

The change of stable isotope ratio of carbon dioxide (δ13CO2) in respiratory gases of patients before and after taking medicine can be used to judge whether Helicobacter pylori exists in patients’ intestines and stomach. The 4.3 μm band of blackbody radiation source and infrared dual path structure are selected for measurement, the incoherent broadband cavity enhanced absorption spectroscopy (IBBCEAS) technology was used to change the structure of the light path on one side of 13CO2 to make sure that the absorption intensity of 13CO2 and 12CO2 was in the same order of magnitude. The influence of different types of optical cavity, coating method of lens and reflectivity of mirror on effective optical path were compared in this article and the effective optical path length was the largest when the semi-stable cavity with 90% reflectivity and Ge coating material was used. The standard deviation of the measurement results was 0.191‰, which met the requirements of the precision and accuracy of the measurement index in medical detection. The system had the advantages of high precision, small volume, and accurate measurement results, which is of great significance for medical auxiliary detection.