Combined immunotherapy targeting the immune checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1), or CTLA-4 and the PD-1 ligand (PD-L1) ...exhibits superior anti-tumor responses compared with single-agent therapy. Here, we examined the molecular basis for this synergy. Using reconstitution assays with fluorescence readouts, we found that PD-L1 and the CTLA-4 ligand CD80 heterodimerize in cis but not trans. Quantitative biochemistry and cell biology assays revealed that PD-L1:CD80 cis-heterodimerization inhibited both PD-L1:PD-1 and CD80:CTLA-4 interactions through distinct mechanisms but preserved the ability of CD80 to activate the T cell co-stimulatory receptor CD28. Furthermore, PD-L1 expression on antigen-presenting cells (APCs) prevented CTLA-4-mediated trans-endocytosis of CD80. Atezolizumab (anti-PD-L1), but not anti-PD-1, reduced cell surface expression of CD80 on APCs, and this effect was negated by co-blockade of CTLA-4 with ipilimumab (anti-CTLA-4). Thus, PD-L1 exerts an immunostimulatory effect by repressing the CTLA-4 axis; this has implications to the synergy of anti-PD-L1 and anti-CTLA-4 combination therapy.
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•Cis-CD80 blocks PD-L1:PD-1 interaction and PD-1 signaling•Cis-PD-L1 inhibits CD80:CTLA-4 interaction by disrupting CD80 homodimers•Cis-PD-L1 protects CD80 from CTLA-4-mediated trans-endocytosis•Anti-PD-L1, but not anti-PD-1, depletes CD80 on APCs in a CTLA-4-dependent manner
Combined immunotherapy targeting the checkpoint receptors CTLA-4 and PD-1, or CTLA-4 and the PD-1 ligand (PD-L1) results in superior anti-tumor responses. Zhao et al. show that PD-L1 heterodimerizes with CD80, a shared ligand for CTLA-4 and CD28, to selectively weaken CD80:CTLA-4 interaction but not CD80:CD28 interaction. Thus, PD-L1 can repress the CTLA-4 axis; this has implications to the synergy observed in combination immunotherapies.
Palladium diselenide (PdSe2), a peculiar noble metal dichalcogenide, has emerged as a new two-dimensional material with high predicted carrier mobility and a widely tunable band gap for device ...applications. The inherent in-plane anisotropy endowed by the pentagonal structure further renders PdSe2 promising for novel electronic, photonic, and thermoelectric applications. However, the direct synthesis of few-layer PdSe2 is still challenging and rarely reported. Here, we demonstrate that few-layer, single-crystal PdSe2 flakes can be synthesized at a relatively low growth temperature (300 °C) on sapphire substrates using low-pressure chemical vapor deposition (CVD). The well-defined rectangular domain shape and precisely determined layer number of the CVD-grown PdSe2 enable us to investigate their layer-dependent and in-plane anisotropic properties. The experimentally determined layer-dependent band gap shrinkage combined with first-principle calculations suggest that the interlayer interaction is weaker in few-layer PdSe2 in comparison with that in bulk crystals. Field-effect transistors based on the CVD-grown PdSe2 also show performances comparable to those based on exfoliated samples. The low-temperature synthesis method reported here provides a feasible approach to fabricate high-quality few-layer PdSe2 for device applications.
Experimental and observational studies on seedling dynamics posit mechanisms that can influence forest diversity, structure and function. However, high mortality and slow growth of seedlings make it ...difficult to evaluate the importance of this life‐history filter to total tree life history. Quantifying the duration and transition of the seedling phase would help us understand this ‘black box’ in tree population biology.
We used a 16‐year dataset of comprehensive seedling‐to‐sapling demography from a subtropical rainforest to construct population models that capture temporal demographic fluctuations for eight major tree species. We used data‐driven demographic models and simulations to estimate the transition ratios from newly recruited seedlings to saplings of 2‐m height and the time taken to attain 2‐m height for a newly recruited seedling conditional on its survival.
Projections among species estimated that as few as 57 to more than 40,000 seedlings (with a median of 2,087) were required to make a single 2‐m high sapling. Furthermore, it would take 22–200 years (with a median of 47) for a newly recruited seedling to become a 2‐m high sapling. We found that temporal variation in demographic rates could greatly reduce the number of seedlings per established sapling, but not passage times (PTs). We also identified the importance of consistently fast growth rates for seedlings to escape the high mortality of early stages.
Synthesis. Our findings demonstrate that high mortality in the very early seedling stage severely limits the probability that a newly recruited seedling will transition to the sapling stage. Although the PTs vary, we found this to be true across species with a range of life‐history strategies. Only seedlings with consistently fast growth rates are expected to pass through this life‐history filter. Findings from seedling studies should consider how short‐term studies of seedling demography might capture the rare exceptional individuals and exceptional conditions that might define the dynamics of this seedling bottleneck.
摘要
許多小苗的動態監測與實驗研究均假定此階段的動態變化會影響森林的多樣性、結構與功能。然而，受限於小苗的高死亡率與低生長率，我們很難評估小苗階段的篩選對於樹木整體生活史動態的重要性。具體量化樹木個體在小苗階段的停留時間與轉換比例，可以幫助我們了解這個樹木族群動態中的「黑盒子」。
我們使用台灣福山亞熱帶雨林長達16年的小苗動態監測資料，來建構該森林中8種主要樹種的族群模式，此一模式可以忠實呈現樹木小苗生長率、死亡率隨時間變化之特性。我們透過此一族群模式進行數值模擬，估算樹木從剛萌發的新增苗成長到2 m高小樹之轉換比例，以及若小苗可以順利存活，其成長到2 m高所需的時間。
依據模式所推估的結果，有的樹種平均只需要57株新增苗就能有一株能長成2 m高的小樹，但也有樹種需要超過40,000株新增苗才能有一株小樹 (中位數為2,087株小苗)。而樹木個體在這個階段的停留時間，則介於22到200年 (中位數為47年)。當模式中納入小苗存活率與生長率之年間變化時，可以大幅地提高新增苗成長為小樹的成功率，但並不會影響在此階段的停留時間。我們也發現，樹木小苗持續性的快速生長是其能否突破小苗建立初期高死亡率的關鍵。
我們的研究顯示樹木小苗建立初期的高死亡率是新增苗能否成長為小樹的主要限制。儘管具有不同生活史策略的樹種從小苗成長為小樹時間有所差異，但其小苗同樣都受到這個限制的影響，只有能持續快速生長的小苗可以突破這層篩選。未來我們在詮釋小苗研究成果時，必須考慮小苗調查中能否涵蓋這些稀有但是能快速生長的個體，以及能讓小苗快速生長的條件，這兩者是決定樹木是否能突破「小苗瓶頸」的關鍵因子。
We used a demographic process model to quantify the seedling‐to‐sapling transition in a subtropical rainforest. Our results show that consistently fast growth is critical for tree seedlings to escape the high mortality of early stages, suggesting that the rare exceptional individuals (and exceptional conditions) might define the dynamics of this life‐history bottleneck.
Blue, green, and red electrophosphorescent polymer light‐emitting diodes have been fabricated on silver nanowire‐polymer composite electrode. The devices are 20%‐50% more efficient than control ...devices on ITO/glass and exhibit small efficiency roll‐off at high luminances. The blue PLEDs were repeatedly bent to 1.5 mm radius concave or convex with calculated strain in the emissive layer approximately 5% (tensile or compressive).
Immunotherapy with checkpoint inhibitors for liver cancer, while active in many clinical trials worldwide, may have uncertain outcomes due to the unique immunotolerant microenvironment of the liver. ...In previous experiments, we unexpectedly identified a robust liver tumor‐preventive effect of a synthetic double‐stranded RNA, polyinosinic‐polycytidylic acid (polyIC), in mice. Herein we further demonstrate that polyIC given at the precancer stage effectively prevented liver tumorigenesis by activating natural killer cells, macrophages, and some T‐cell subsets; no inhibitory effect was observed on tumor progression if injected after tumor initiation. Nevertheless, polyIC administration potently induced programmed death ligand 1 (PD‐L1) expression in liver sinusoid endothelial cells, which prompted us to test a combined treatment of polyIC and PD‐L1 antibody (Ab). Although injecting PD‐L1 Ab alone did not show any therapeutic effect, injection of polyIC sensitized the hepatic response to PD‐L1 blockade. Combination of polyIC and PD‐L1 Ab resulted in sustained accumulation of active cluster of differentiation 8 cytotoxic T cells and robust liver tumor suppression and conferred a survival advantage in mice. These preclinical data in animal models suggest that, despite the low efficacy of PD‐L1/PD‐1 blockade alone, careful design of mechanism‐based combinatorial immunotherapeutic protocols may shift the paradigm in liver cancer treatment by coordinating maximal activation of multiple innate and adaptive immune functions. Conclusion: We provide proof of principle for the development of an efficient prevention strategy of liver tumorigenesis and a powerful combination immunotherapy for primary liver cancer.
To overcome the limitations of memristors in neuromorphic computation, memcapacitors are gaining attention owing to their scalability, low power dissipation, and sneak‐path‐free nature. This study ...focuses on the progressive capacitive switching of a bilayered metal‐oxide WOx/ZrOx heterojunction memcapacitor. To gain a better understanding of the interfacial switching behavior, density functional theory simulations are used to analyze the defects and oxide formation energy of the heterostructure. The memcapacitive characteristics are studied using the capacitance–voltage curves under different voltage‐sweeping conditions and impedance analysis. The memcapacitive characteristics can be attributed to the trapping of carriers in the depletion region of the WOx/ZrOx heterojunction, which is modulated by the relocation of oxygen vacancies under the electric field. The device exhibits a wider dynamic range of capacitance values than other metal‐oxide memcapacitors reported, and demonstrates versatile synaptic functions, such as potentiation/depression behavior, paired‐pulse facilitation, experience‐dependent plasticity, and learning–relearning behavior. Furthermore, an accuracy of 99.01% is achieved in handwritten digit classification using the capacitive state as the weight through a computing‐in‐memory emulator. The results affirm the applicability of the WOx/ZrOx memcapacitor in future capacitive neural networks.
A bilayered oxide WOx/ZrOx heterojunction memcapacitor demonstrates a wide dynamic capacitance range and multiple synaptic functions. The density functional theory simulation along with the impedance analysis and voltage sweeping rate‐dependent capacitance measurement is used to characterize the interface and defect dynamics. 99.01% accuracy of dataset classification is conducted through multilayer perceptron and LeNet‐5 neural network using CIMulator platform.
Fueling the fire in the gut Lin, Chia-Hao; Lu, Li-Fan
The Journal of experimental medicine,
07/2022, Letnik:
219, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Gut dysbiosis has long been associated with the development of Crohn's disease and other gastrointestinal disorders. Otake-Kasamoto et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20211291) ...report that dysbiotic microbiota-derived bioactive lipids, lysophosphatidylserines, can promote pathological Th1 cell responses through inducing metabolic reprogramming and epigenetic changes.
Aim
This quasi‐experimental study aimed to explore effects of walking exercise on disease activity, sleep quality, and quality of life among individuals with systemic lupus erythematosus.
Methods
...After recruiting people with systemic lupus erythematosus from a hospital in Taiwan between October 2020 and June 2021, participants were free to opt to receive one walking exercise programme plus standard care for 3 months or to membership of a control group receiving routine care. Primary outcomes included Systemic Lupus Erythematosus Disease Activity Score, the Pittsburgh Sleep Quality Scale, and a quality‐of‐life scale for patients with systemic lupus erythematosus, namely, LupusQoL. These scales were administered first, at baseline and later, within 1 week following completion of the intervention. Between‐group effects were compared using generalized estimating equations with adjustment for baseline variables.
Results
The experimental and control groups each included 40 participants. Multivariate analysis indicated that adding the walking exercise programme into routine care elevated sleep quality and LupusQoL (the latter in the subscales of physical health, planning, and intimate relationships), except for disease activity.
Conclusion
Findings of this study supported the addition of walking exercise as part of routine care for people with systemic lupus erythematosus and may be a reference in the provision of adequate care for these patients.
Summary statements
What is already known about this topic?
Systemic lupus erythematosus is a lifelong autoimmune disease that affects any organs throughout the body, thus insidiously causing negative impacts on the affected patients.
Today, use of exercise programmes such as walking exercise has been studied as a remedy for many medical conditions, but its effectiveness in minimizing the symptoms of distress among people with systemic lupus erythematosus is unknown.
What this study adds?
Participants with systemic lupus erythematosus who opt to receive the walking exercise programme for 3 months in addition to routine care experience improved sleep quality and quality of life compared with those receiving routine care alone.
The implications of this paper:
In accordance with the belief that “an ounce of prevention is worth a pound of cure,” early implementation of an exercise programme should be considered in addition to routine care for patients with systemic lupus erythematosus.
Evidence from this research could provide empirically informed and robust data for healthcare policymakers and in turn might help to reduce the incidence of morbidity among patients with systemic lupus erythematosus.
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