The approval of two chimeric antigen receptor-modified T cell types by the US Food and Drug Administration (FDA) for the treatment of hematologic malignancies is a milestone in immunotherapy; ...however, the application of CAR-T cells has been limited by antigen escape and on-target, off-tumor toxicities. Therefore, it may be a potentially effective strategy to select appropriate targets and to combine multi-antigen-targeted CAR-T cells with "OR", "AND" and "NOT" Boolean logic gates. We summarize the current limitations of CAR-T cells as well as the efficacy and safety of logic-gated CAR-T cells in antitumor therapy. This review will help to explore more optimized strategies to expand the CAR-T cell therapeutic window.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Holometabolous insects stop feeding at the final larval instar stage and then undergo metamorphosis; however, the mechanism is unclear. In the present study, using the serious lepidopteran ...agricultural pest Helicoverpa armigera as a model, we revealed that 20-hydroxyecdysone (20E) binds to the dopamine receptor (DopEcR), a G protein-coupled receptor, to stop larval feeding and promote pupation. DopEcR was expressed in various tissues and its level increased during metamorphic molting under 20E regulation. The 20E titer was low during larval feeding stages and high during wandering stages. By contrast, the dopamine (DA) titer was high during larval feeding stages and low during the wandering stages. Injection of 20E or blocking dopamine receptors using the inhibitor flupentixol decreased larval food consumption and body weight. Knockdown of DopEcR repressed larval feeding, growth, and pupation. 20E, via DopEcR, promoted apoptosis; and DA, via DopEcR, induced cell proliferation. 20E opposed DA function by repressing DA-induced cell proliferation and AKT phosphorylation. 20E, via DopEcR, induced gene expression and a rapid increase in intracellular calcium ions and cAMP. 20E induced the interaction of DopEcR with G proteins αs and αq. 20E, via DopEcR, induced protein phosphorylation and binding of the EcRB1-USP1 transcription complex to the ecdysone response element. DopEcR could bind 20E inside the cell membrane or after being isolated from the cell membrane. Mutation of DopEcR decreased 20E binding levels and related cellular responses. 20E competed with DA to bind to DopEcR. The results of the present study suggested that 20E, via binding to DopEcR, arrests larval feeding and promotes pupation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
For primordial perturbations, deviations from Gaussian statistics on the tail of the
probability distribution can be associated with non-perturbative effects of inflation. In this
paper, we ...present some particular examples in which the tail of the distribution becomes highly
non-Gaussian although the statistics remains almost Gaussian in the perturbative regime. We begin
with an extension of the ultra-slow-roll inflation that incorporates a transition process, where
the inflaton climbs up a tiny potential step at the end of the non-attractor stage before it
converges to the slow-roll attractor. Through this example, we identify the key role of the
off-attractor behaviour for the upward-step transition, and then extend the analysis to another
type of the transition with two slow-roll stages connected by a tiny step. We perform both the
perturbative and non-perturbative analyses of primordial fluctuations generated around the step in
detail, and show that the tiny but nontrivial transition may affect large perturbations in the
tail of the distribution, while the perturbative non-Gaussianity remains small. Our result
indicates that the non-Gaussian tails can have rich phenomenology which has been overlooked in
conventional analyses. We also study the implications of this non-Gaussian tail for the formation
of primordial black holes, and find that their mass fraction can be parametrically amplified by
several orders of magnitudes in comparison with the case of the Gaussian
distribution. Additionally, we also discuss a mechanism of primordial black holes formation for
this upward step inflation model by trapping the inflaton in the bottom of the step.
Endomorphins have shown great promise as pharmaceutics for the treatment of pain. We have previously confirmed that novel endomorphin analogues CEMR-1 and CEMR-2 behaved as potent μ agonists and ...displayed potent antinociceptive activities at the supraspinal and peripheral levels. The present study was undertaken to evaluate the antinociceptive properties of CEMR-1 and CEMR-2 following intrathecal (i.t.) administration. Furthermore, their antinociceptive tolerance and opioid-like side effects were also determined.
The spinal antinociceptive effects of CEMR-1 and CEMR-2 were determined in a series of pain models, including acute radiant heat paw withdrawal test, spared nerve injury-induced neuropathic pain, complete Freund's adjuvant-induced inflammatory pain, visceral pain and formalin pain. Antinociceptive tolerance was evaluated in radiant heat paw withdrawal test.
Spinal administration of CEMR-1 and CEMR-2 produced potent and prolonged antinociceptive effects in acute pain. CEMR-1 and CEMR-2 may produce their antinociception through distinct μ receptor subtypes. These two analogues also exhibited significant analgesic activities in neuropathic, inflammatory, visceral and formalin pain at the spinal level. It is noteworthy that CEMR-1 showed non-tolerance-forming analgesic properties, while CEMR-2 exhibited substantially reduced antinociceptive tolerance. Furthermore, both analogues displayed no or reduced side effects on conditioned place preference response, physical dependence, locomotor activity and gastrointestinal transit.
The present investigation demonstrated that CEMR-1 and CEMR-2 displayed potent and long-lasting antinociception with a favourable side effect profile at the spinal level. Therefore, CEMR-1 and CEMR-2 might serve as promising analgesic compounds with minimal opioid-like side effects.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Anaplastic lymphoma kinase (ALK) activation has been associated with many types of human cancer. Significant efforts have been devoted to the development of ALK inhibitors to antagonize the kinase ...activity of ALK. Four ALK inhibitors have been approved by the FDA to date for treating patients with ALK-positive non-small cell lung cancers (NSCLC). However, drug resistance has been observed in the majority of patients treated with these inhibitors. New therapeutic strategies (e.g., compounds with novel mechanisms of action) are needed to overcome the drug resistance issue. The emerging PROTAC (Proteolysis Targeting Chimera) technology has been successfully applied to selective degradation of multiple protein targets, but not ALK. Since ALK protein levels are not important for viability in mammals, ALK PROTACs could lead to novel therapeutics with minimal toxicity. Here we report the design, synthesis and biological evaluation of novel PROTACs (degraders) of ALK. MS4077 (5) and MS4078 (6) potently decreased cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells. The ALK protein degradation induced by compounds 5 and 6 was cereblon and proteasome dependent. In addition, compounds 5 and 6 potently inhibited proliferation of SU-DHL-1 cells. Furthermore, compound 6 displayed good plasma exposure in a mouse pharmacokinetic study, thus is suitable for in vivo efficacy studies. We also developed MS4748 (7) and MS4740 (8), very close analogs of 5 and 6 respectively, which are incapable to degrade the ALK fusion proteins, as negative controls. Compounds 5–8 are valuable chemical tools for investigating effects of ALK pharmacological degradation. Our study paved the way for developing the next generation of ALK PROTACs.
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•We discovered novel ALK PROTACs (MS4077 and MS4078) and their close analogs as negative controls.•MS4077 and MS4078 potently reduced cellular ALK protein levels in a cereblon and proteasome dependent manner.•MS4077 and MS4078 potently inhibited cellular ALK signaling.•MS4077 and MS4078 effectively inhibited cancer cell proliferation.•MS4078 displayed good plasma exposure in mice, thus is suitable for in vivo efficacy studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Supercapacitors known as typical electrochemical capacitors have been considered as one of the most promising candidates of energy storage systems owing to their advantages such as high-power ...density, long life span and lower production cost. The electrode materials play a crucial role on properties of supercapacitors. Hence, many researches have been focused on the development of novel electrode materials for high-performance supercapacitors. NiCo2O4 as supercapacitor electrode material has drawn more and more attentions in recent years due to its outstanding advantages, such as high theoretical capacity, low cost, natural abundance and easy of synthesis. However, the NiCo2O4 always suffer from severe capacity deterioration because of the low electrical conductivity and small surface area. Hence, it is necessary to systematically and comprehensively summarize the progress in understanding and modifying NiCo2O4-based materials from various aspects. In this review, the structure and synthesis method of NiCo2O4-based materials are discussed in detail. And then, the major goal of this review is to highlight new progress in using proposed strategies to improve the cycling stability and rate capacity of NiCo2O4-based materials, including synthesis, control of special morphologies and design of composite materials. Finally, an insight into the future research and development of NiCo2O4-based materials for supercapacitors is prospected.
Strategies in the synthesis of NiCo2O4-based materials are discussed. Progress in understanding and modifying NiCo2O4-based materials from various aspects is summarized. Key strategies for improving the cycling stability of NiCo2O4-based material are discussed. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Due to the strong constraint from the LUX experiment, the scalar portal dark matter cannot generally explain a gamma-ray excess in the galactic center by the annihilation of dark matter to bb¯. With ...the motivation of eliminating the tension, we add a scalar dark matter to the aligned two-Higgs-doublet model, and focus on a simplified scenario, which has two main characteristics: (i) The heavy CP-even Higgs is the discovered 125 GeV Higgs boson, which has the same couplings to the gauge bosons and fermions as the SM Higgs. (ii) Only the light CP-even Higgs mediates the dark matter interactions with SM particles, which have no couplings to WW and ZZ, but have the independent couplings to the up-type quarks, down-type quarks and charged leptons. We find that the tension between 〈σv〉SS→bb¯ and the constraint from LUX induced by the scalar portal dark matter can go away for the isospin-violating dark matter–nucleon coupling with −1.0<fn/fp<0.7, and the constraints from the Higgs search experiments and the relic density of Planck are also satisfied.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In humid temperate forests, the occurrence of frequent freeze–thaw cycles (FTC) is a main factor limiting tree growth, as xylem embolism induced by FTC poses a serious threat to the hydraulic ...integrity of trees. A high resilience to hydraulic dysfunction involves the enhancement of embolism resistance and/or extra non‐structural carbohydrate (NSC) inputs for restoration of an impaired hydraulic system. However, potentially negative implications of such NSC allocation on tree growth have not yet been explored.
At a temperate forest site of northeast China, we studied xylem hydraulics and NSC contents in relation to winter embolism resilience in 15 sympatric broadleaf tree species belonging to three genera with relatively high species richness, but having distinct strategies in maintaining hydraulic integrity over the winter, that is, Acer species that generate positive stem and root pressures contributing to winter embolism refilling, Betula species that only generate root pressure and Populus species that do not generate positive pressure.
Acer and Betula species had higher soluble sugar contents in the dormant season and indeed had higher hydraulic resilience to FTC‐induced embolism but slower stem growth. Populus species had higher NSC contents during the growing season and their faster stem growth was also consistent with higher hydraulic efficiency and leaf photosynthetic rate. The positive correlation between tree trunk radial growth rate and hydraulic conductivity suggests that xylem water transport efficiency can be a fundamental basis for tree productivity due to a significant hydraulic‐photosynthetic coordination. The negative correlation between soluble sugar concentration in the dormant season and stem growth rate indicates that metabolic carbon costs for enhancing hydraulic resilience may compromise tree growth during the growing season.
Comparisons among Acer, Betula and Populus and the correlation analyses based on phylogenetic independent contrasts strongly support the existence of a trade‐off between hydraulic resilience against FTC‐induced embolism and growth rate among sympatric tree species under humid temperate climate conditions. This trade‐off has likely contributed to the sorting of temperate tree species and genera to different niches along environmental gradients with respect to freezing stress and interspecific competition.
A free Plain Language Summary can be found within the Supporting Information of this article.
A free Plain Language Summary can be found within the Supporting Information of this article.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Ophiolites commonly sample the uppermost parts (15–20 km) of fossil oceanic lithosphere. However, in recent years, the documentation of diamonds, super‐reducing (e.g., SiC), and other “unusual” ...minerals from several ophiolitic peridotites and chromitites (e.g., Tibet and the Polar Urals) has caused debate concerning their origin (i.e., deep vs. shallower upper mantle). Here we report on symplectite‐bearing lherzolites from the Purang ophiolite in Tibet, which preserve the first compelling evidence of garnet‐facies protoliths. These lherzolites were previously formed and stabilized at a depth of ~85–100 km, which is much deeper than generally suggested and approaches the depth (~120 km) required for stabilizing the diamonds. Combining with other key observations, we suggest the Purang garnet‐bearing peridotites may represent mixtures of oceanic lithosphere domains with diverse origins; they were rapidly exhumed at a variety of mantle depths within a subduction channel associated with oceanic slab retreat.
Plain Language Summary
Ophiolites are remnants of fossil ocean basins that have been emplaced on land and usually sample the upper 15–20 km of oceanic lithosphere. However, the discovery of diamonds, super‐reducing, and other “unusual” minerals from several ophiolitic peridotites suggests that these peridotites might originate in the deep upper mantle (>300 km), challenging conventional models of ophiolite formation. In this study, we show that symplectite‐bearing lherzolites from the Purang diamond‐bearing ophiolite (Tibet) were originally garnet‐bearing peridotites, with a previous equilibration depth of ~85–100 km. Our results suggest that the Purang peridotites may represent mixtures of oceanic lithosphere domains with different nature and origins, which were exhumed and mixed within an oceanic subduction channel associated with slab retreat.
Key Points
Symplectite‐bearing lherzolites from a Tibetan diamond‐bearing ophiolite formed from garnet peridotite protoliths
These lherzolites were previously formed and stabilized at a depth of ~85‐100 km, much deeper than previously suggested
An oceanic subduction channel model is suggested for exhumation of some of the Tibetan diamond‐bearing peridotites
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Conspectus Immune checkpoint blockade (ICB) therapy elicits antitumor response by inhibiting immune suppressor components, including programmed cell death protein 1 and its ligand (PD-1/PD-L1) and ...cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Despite improved therapeutic efficacy, the clinical response rate is still unsatisfactory as revealed by the fact that only a minority of patients experience durable benefits. Additionally, “off-target” effects after systemic administration remain challenging for ICB treatment. To this end, the local and targeted delivery of ICB agents instead could be a potential solution to maximize the therapeutic outcomes while minimizing the side effects. In this Account, our recent studies directed at the development of different strategies for the local and targeted delivery of ICB agents are discussed. For example, transdermal microneedle patches loaded with anti-programmed death-1 antibody (aPD1) and anti-CTLA4 were developed to facilitate sustained release of ICB agents at the diseased sites. Triggered release could also be achieved by various stimuli within the tumor microenvironment, including low pH and abnormally expressed enzymes. Recently, the combination of an anti-programmed death-ligand 1 antibody (aPD-L1) loaded hollow-structured microneedle patch with cold atmospheric plasma (CAP) therapy was also reported. Microneedles provided microchannels to facilitate the transdermal transport of CAP and further induce immunogenic tumor cell death, which could be synergized by the local release of aPD-L1. In addition, in situ formed injectable or sprayable hydrogels were tailored to deliver immunomodulatory antibodies to the surgical bed to inhibit tumor recurrence after primary tumor resection. In paralell, inspired by the unique targeting ability of platelets toward the inflammatory sites, we engineered natural platelets decorated with aPD-L1 for targeted delivery after tumor resection to inhibit tumor recurrence. We further constructed a cell–cell combination delivery platform based on conjugates of platelets and hematopoietic stem cells (HSCs) for leukemia treatment. With the homing ability of HSCs to the bone marrow, the HSC–platelet–aPD1 assembly could effectively deliver aPD1 in an acute myeloid leukemia mouse model. Besides living cells, we also leveraged HEK293T-derived vesicles with PD1 receptors on their surfaces to disrupt the PD-1/PD-L1 immune inhibitory pathway. Moreover, the inner space of the vesicles allowed the packaging of an indoleamine 2,3-dioxygenase inhibitor, further reinforcing the therapeutic efficacy. A similar approach has also been demonstrated by genetically engineering platelets overexpressing PD1 receptor for postsurgical treatment. We hope the local and targeted ICB agent delivery methods introduced in this collection would further inspire the development of advanced drug delivery strategies to improve the efficiency of cancer treatment while alleviating side effects.
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IJS, KILJ, NUK, PNG, UL, UM
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