The T cell co-stimulatory molecule OX40 and its cognate ligand OX40L have attracted broad research interest as a therapeutic target in T cell-mediated diseases. Accumulating preclinical evidence ...highlights the therapeutic efficacy of both agonist and blockade of the OX40–OX40L interaction. Despite this progress, many questions about the immuno-modulator roles of OX40 on T cell function remain unanswered. In this review we summarize the impact of the OX40–OX40L interaction on T cell subsets, including Th1, Th2, Th9, Th17, Th22, Treg, Tfh, and CD8+ T cells, to gain a comprehensive understanding of anti-OX40 mAb-based therapies. The potential therapeutic application of the OX40–OX40L interaction in autoimmunity diseases and cancer immunotherapy are further discussed; OX40–OX40L blockade may ameliorate autoantigen-specific T cell responses and reduce immune activity in autoimmunity diseases. We also explore the rationale of targeting OX40–OX40L interactions in cancer immunotherapy. Ligation of OX40 with targeted agonist anti-OX40 mAbs conveys activating signals to T cells. When combined with other therapeutic treatments, such as anti-PD-1 or anti-CTLA-4 blockade, cytokines, chemotherapy, or radiotherapy, the anti-tumor activity of agonist anti-OX40 treatment will be further enhanced. These data collectively suggest great potential for OX40-mediated therapies.
This review discusses the biology of OX40 and OX40L and summarizes the impact of the OX40–OX40L interaction on T cell subsets to provide a comprehensive understanding of anti-OX40 mAbs-based therapy. The potential therapeutic application of OX40–OX40L interaction in autoimmunity diseases and cancer immunotherapy are also discussed. Display omitted
•Stepwise pyrolysis of the eustigmatophyte Nannochloropsis oculata carried out.•Range of biomarkers and lipid and protein degradation products identified.•n-Alkane/n-alkene pairs, n-alkan-2-ones and ...C29–C33 mid-chain ketones identified.•Core of the algaenan is built from interlinked C32 1,17-alkyl diols.•Stepwise pyrolysis can be used for rapid screening for novel biomarkers in algae.
Dried biomass of the eustigmatophyte Nannochloropsis oculata was subjected to stepwise pyrolysis at 50°C intervals from 310 to 610°C to test the potential of the technique for investigating the algaenan structure of N. oculata and for determining a broad suite of biochemical constituents. Pyrolysis at 310°C yielded mainly free lipids such as phytol, cholesterol, C32 alkyl diols, hexadecanamide and large amounts of phytol-derived alkenes from thermal desorption. Indole generated from protein degradation first appeared at 360°C, indicating the onset of biopolymer breakdown. The pyrolyzate of 410°C showed a simpler composition, dominated by 2-methyl-1H-indole and indole, and accompanied by low amounts of phenol and hexadecanamide. At 460°C, algaenan breakdown was evident from the detection of C15–C19n-alkan-2-ones with a strong predominance of C17, and of C29–C33 mid-chain ketones composed of a remarkable predominance of the symmetrical ketone C31n-alkan-16-one. Small amounts of the mono-unsaturated C31:1 mid-chain ketone and n-alkene/n-alkane doublets were also present. The chromatograms suggest that the algaenan structure of N. oculata is composed of repeating, interlinked C32n-alkan-1,17-diols, whereas the free plus bound lipids were dominated by the C32n-alkan-1,15-diol. The pyrolyzate at 510°C was dominated by a bimodal distribution of C8–C32n-alkene/n-alkane doublets showing a maximum at n-C14:1 and n-C26, with lesser amounts of ketones. Such a wide chain length distribution implies that other aliphatic lipids, perhaps derived from the long chain n-alkenols, might also be involved in the algaenan structure. Major constituents of the 560°C pyrolyzate were aromatic compounds, including toluene, phenol and indole, but absolute abundances were low. It is notable that high molecular weight compounds such as the n-alkene/n-alkane doublets were no longer detected at 560°C. The results show that stepwise pyrolysis provides simpler chromatograms than a single pyrolysis of a whole sample at 610°C and so can be a useful tool for identifying algaenan structures and/or related compounds in ancient sediments and modern microalgae.
•n-Alkan-2-ones were identified in the polar fraction of an Australian torbanite.•These had enriched δ13C values similar to those of lipids from Botryococcus.•An unusually strong predominance of ...even-chain C24, C26 and C28 was noted.•C24, C26 and C28 ketones had more enriched δ13C values, suggestive of a second source.
n-Alkan-2-ones (methyl ketones) ranging from C14 to C31, were recovered from the polar fraction of an extract of a torbanite from the Sydney Basin, Australia. There was a very slight even-over-odd predominance between C20 and C24n-alkan-2-ones, together with remarkably high contents of the C24, C26 and C28 homologues. A range of C16 to C28 macrocyclic alkanes, as well as their corresponding methylated counterparts (C19–C24), was also detected in the saturate fraction obtained after molecular sieve treatments. Due to the relatively high contents of the n-alkan-2-ones and macrocyclic alkanes, we were able to carry out GC–irMS analysis to determine the δ13C values of specific compounds. The even-numbered n-alkan-2-ones from C24 to C28 were significantly 13C-enriched, compared to the other n-alkan-2-ones, which had similar isotopic values to the macrocyclic alkanes. The majority of the n-alkan-2-ones detected here probably had the same algal source as the macrocyclic alkanes, which is likely to be lipids and algaenan of the green microalga Botryococcus braunii. However, the distribution and 13C enrichment of C24, C26 and C28n-alkan-2-ones indicates that an additional source must be present.
The chemical coupling interaction has been explored extensively to boost heterogeneous catalysis, but the insight into how chemical coupling interaction works on CO2 electroreduction remains unclear. ...Herein we demonstrate how the chemical coupling interaction between porous In2O3 nanobelts and reduced graphene oxide (rGO) could substantially improve the electrocatalytic activity toward CO2 electroreduction. Such an In2O3–rGO hybrid catalyst showed 1.4-fold and 3.6-fold enhancements in Faradaic efficiency and specific current density for the formation of formate at −1.2 V versus reversible hydrogen electrode relative to the catalyst prepared by physically loading of In2O3 nanobelts onto rGO, respectively. The density functional theory calculations and electrochemical analysis together revealed that the chemical coupling interaction boosted CO2 electroreduction activity by improving electrical conductivity and stabilizing key intermediate HCOO–*. The present work not only deepens an understanding of chemical coupling effect but also provides an effective lever to optimize the catalytic performance toward CO2 electroreduction.
Mixed lineage kinase domain-like protein （Mlkl） was recently found to interact with receptor interacting protein 3 （Rip3） and to be essential for tumor necrosis factor （TNF）-induced programmed ...necrosis （necroptosis） in cultured cell lines. We have generated Mlkl-deficient mice by transcription activator-like effector nucleases （TALENs）-mediated gene disruption and found Mlkl to be dispensable for normal mouse development as well as immune cell develop- ment. Mlkl-deficient mouse embryonic fibroblasts （MEFs） and macrophages both showed resistance to necrotic but not apoptotic stimuli. Mlkl-deficient MEFs and macrophages were indistinguishable from wild-type cells in their abil- ity to activate NF-KB, ERK, JNK, and p38 in response to TNF and lipopolysaccharides （LPS）, respectively. Consis- tently, Mlkl-deficient macrophages and mice exhibited normal interleukin-lp （IL-1β）, IL-6, and TNF production after LPS treatment. Mlkl deficiency protects mice from cerulean-induced acute pancreatitis, a necrosis-related disease, but has no effect on polymicrobial septic shock-induced animal death. Our results provide genetic evidence for the role of Mlkl in necroptosis.
Single-atom catalysts (SACs) exhibit intriguing catalytic performance owing to their maximized atom utilizations and unique electronic structures. However, the reported strategies for synthesizing ...SACs generally have special requirements for either the anchored metals or the supports. Herein, we report a universal approach of electrochemical deposition that is applicable to a wide range of metals and supports for the fabrication of SACs. The depositions were conducted on both cathode and anode, where the different redox reactions endowed the SACs with distinct electronic states. The SACs from cathodic deposition exhibited high activities towards hydrogen evolution reaction, while those from anodic deposition were highly active towards oxygen evolution reaction. When cathodically- and anodically-deposited Ir single atoms on Co
Fe
Se
@Ni foam were integrated into a two-electrode cell for overall water splitting, a voltage of 1.39 V was required at 10 mA cm
in alkaline electrolyte.
This paper studies the cooperative control problem of multiple humanoid robots handling a common payload in the presence of position and velocity constraints, unmeasurable velocity, as well as ...nonparametric uncertainties. By using a state observer to estimate the unmeasured velocity, a neuroadaptive output-feedback control scheme is developed, which by blending an error transformation with barrier Lyapunov function ensures that the full-state tracking error converges to a prescribed compact set around origin within a given finite time at a preassignable convergence rate. Furthermore, it is shown that all the signals in the closed-loop system are ultimately semiglobally uniformly bounded. Simulation results are verified to show the effectiveness and benefits of the proposed scheme.
Oral administration of protein drugs is greatly impeded by the lack of drug carriers that can efficiently overcome the absorption barriers of mucosa tissue, which consists of not only epithelium but ...also a blanket of mucus gel. We herein report a novel self-assembled nanoparticle (NP) platform for oral delivery of insulin by facilitating the efficient permeation through both of these two barriers. The NP possesses a core composed of insulin and trimethyl chitosan (TMC), and a dissociable “mucus-inert” hydrophilic coating of N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA) derivative. The NPs exhibited free Brownian motion and excellent permeability in mucus, which enabled the access of the NP core to the epithelial cell surface underneath the mucus. Moreover, investigation of NP behavior showed that the pHPMA molecules started to dissociate as the NP permeates through mucus, and the TMC NP core was then exposed to facilitate transepithelial transport via paracellular pathway. The pHPMA coating significantly improved transepithelial transport of TMC-based NP and their ability to open tight junctions between the mucus-secreting epithelial cells. Moreover, in diabetic rats, pHPMA coated NPs generated a prominent hypoglycemic response following oral administration, and exhibited a relative bioavailability 2.8-fold higher than that of uncoated TMC-based NPs. Our study provided the evidence of using pHPMA as “mucus-inert” agent to enhance mucus permeation of TMC-based NPs, and validated a novel strategy to overcome the multiple absorption barriers using NP platform with dissociable hydrophilic coating and TMC-based core possessing tight junction-opening ability.
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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.
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•It’s the first time to design a brain targeted drug delivery system using dopamine derivative BPD for the treatment of PD;•The application of a brain targeted drug delivery system has improved the therapeutic performance of BPD;•The findings provide novel insights into the solutions to the druggability of small molecule drugs.•For the first time, RVG29 was used as a dual-targeting ligand for the treatment of PD.
Nanoparticles (NPs) have demonstrated great potential for the oral delivery of protein drugs that have very limited oral bioavailability. Orally administered NPs could be absorbed by the epithelial ...tissue only if they successfully permeate through the mucus that covers the epithelium. However, efficient epithelial absorption and mucus permeation require very different surface properties of a nanocarrier. We herein report self-assembled NPs for efficient oral delivery of insulin by facilitating both of these two processes. The NPs possess a nanocomplex core composed of insulin and cell penetrating peptide (CPP), and a dissociable hydrophilic coating of N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA) derivatives. After systematic screening using mucus-secreting epithelial cells, NPs exhibit excellent permeation in mucus due to the “mucus-inert” pHPMA coating, as well as high epithelial absorption mediated by CPP. The investigation of NP behavior shows that the pHPMA molecules gradually dissociate from the NP surface as it permeates through mucus, and the CPP-rich core is revealed in time for subsequent transepithelial transport through the secretory endoplasmic reticulum/Golgi pathway and endocytic recycling pathway. The NPs exhibit 20-fold higher absorption than free insulin on mucus-secreting epithelium cells, and orally administered NPs generate a prominent hypoglycemic response and an increase of the serum insulin concentration in diabetic rats. Our study provides the evidence of using pHPMA as dissociable “mucus-inert” agent to enhance mucus permeation of NPs, and validates a strategy to overcome the multiple absorption barriers using NP platform with dissociable hydrophilic coating and drug-loaded CPP-rich core.
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