The MDM2 and MDMX (also known as HDMX and MDM4) proteins are deregulated in many human cancers and exert their oncogenic activity predominantly by inhibiting the p53 tumour suppressor. However, the ...MDM proteins modulate and respond to many other signalling networks in which they are embedded. Recent mechanistic studies and animal models have demonstrated how functional interactions in these networks are crucial for maintaining normal tissue homeostasis, and for determining responses to oncogenic and therapeutic challenges. This Review highlights the progress made and pitfalls encountered as the field continues to search for MDM-targeted antitumour agents.
Alkaline water electrolyzers (AWEs) and anion‐exchange membrane fuel cells (AEMFCs) have received increasing attention for their natural compatibility with earth‐abundant materials and are regarded ...as the cutting‐edge of hydrogen energy techniques and the research focuses. However, the commercialization of these devices remains in the sluggish hydrogen electrode reactions due to the requirement of cooperative adsorption of both hydrogen species and hydroxyl species. The research on synergistic alkaline hydrogen oxidation/evolution reaction (HOR/HER) electrocatalysts is still in its infancy. This review summarizes the recent progress and strategies in constructing synergistic active sites for advancing alkaline HOR/HER electrocatalysts. The fundamentals of alkaline HOR/HER are first introduced with both theoretical and experimental verifications to rationalizing the necessity of constructing synergistic active sites. Then, this review systemically dissects the functionality of different active sites in recently reported innovative HOR/HER catalysts and introduces the synergistic effects. Finally, some perspectives on the challenges and opportunities for the future design and synthesis of the synergistic HOR and HER electrocatalysts are proposed, intending to promote the application of hydrogen‐based energy conversion systems.
In this review, the recent progress and strategies in constructing synergistic active sites for advancing alkaline hydrogen oxidation/evolution reaction electrocatalysts are systematically summarized, aiming at promoting the commercialization of hydrogen‐based energy conversion systems.
Flexible optoelectronic devices attract considerable attention due to their prominent role in creating novel wearable apparatus for bionics, robotics, health care, and so forth. Although bulk ...single-crystalline perovskite-based materials are well-recognized for the high photoelectric conversion efficiency than the polycrystalline ones, their stiff and brittle nature unfortunately prohibits their application for flexible devices. Here, we introduce ultrathin single-crystalline perovskite film as the active layer and demonstrate a high-performance flexible photodetector with prevailing bending reliability. With a much-reduced thickness of 20 nm, the photodetector made of this ultrathin film can achieve a significantly increased responsivity as 5600A/W, 2 orders of magnitude higher than that of recently reported flexible perovskite photodetectors. The demonstrated 0.2 MHz 3 dB bandwidth further paves the way for high-speed photodetection. Notably, all its optoelectronic characteristics resume after being bent over thousands of times. These results manifest the great potential of single-crystalline perovskite ultrathin films for developing wearable and flexible optoelectronic devices.
Phase change materials (PCMs), such as GeSbTe (GST) alloys and vanadium dioxide (VO2), play an important role in dynamically tunable optical metadevices. However, the PCMs usually require high ...thermal annealing temperatures above 700 K, but most flexible metadevices can only work below 500 K owing to the thermal instability of polymer substrates. This contradiction limits the integration of PCMs into flexible metadevices. Here, a mica sheet is chosen as the chemosynthetic support for VO2 and a smooth and uniformly flexible phase change material (FPCM) is realized. Such FPCMs can withstand high temperatures while remaining mechanically flexible. As an example, a metal‐FPCM‐metal infrared meta‐absorber with mechanical flexibility and electrical tunability is demonstrated. Based on the electrically‐tuned phase transition of FPCMs, the infrared absorption of the metadevice is continuously tuned from 20% to 90% as the applied current changes, and it remains quite stable at bending states. The metadevice is bent up to 1500 times, while no visible deterioration is detected. For the first time, the FPCM metastructures are significantly added to the flexible material family, and the FPCM‐based metadevices show various application prospects in electrically‐tunable conformal metadevices, dynamic flexible photodetectors, and active wearable devices.
In this work, a smooth and uniformly flexible phase change material (FPCM) is realized based on vanadium dioxide (VO2). As an example, a metal‐FPCM‐metal infrared meta‐absorber with mechanical flexibility and electrical tunability is demonstrated. It is expected that such FPCM‐based metadevices would show various application prospects in dynamic flexible photodetectors and active wearable devices.
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome that elevates the risk of hepatocellular carcinoma (HCC). Although alteration of lipid metabolism has ...been increasingly recognized as a hallmark of cancer cells, the deregulated metabolic modulation of HCC cells in the NAFLD progression remains obscure. Here, we discovers an endoplasmic reticulum-residential protein, Nogo-B, as a highly expressed metabolic modulator in both murine and human NAFLD-associated HCCs, which accelerates high-fat, high-carbohydrate diet-induced metabolic dysfunction and tumorigenicity. Mechanistically, CD36-mediated oxLDL uptake triggers CEBPβ expression to directly upregulate Nogo-B, which interacts with ATG5 to promote lipophagy leading to lysophosphatidic acid-enhanced YAP oncogenic activity. This CD36-Nogo-B-YAP pathway consequently reprograms oxLDL metabolism and induces carcinogenetic signaling for NAFLD-associated HCCs. Targeting the Nogo-B pathway may represent a therapeutic strategy for HCC arising from the metabolic syndrome.
The challenge to improve the clinical efficacy and enlarge the population that benefits from immune checkpoint inhibitors (ICIs) for non‐small‐cell lung cancer (NSCLC) is significant. Based on ...whole‐exosome sequencing analysis of biopsies from NSCLC patients before anti‐programmed cell death protein‐2 (PD‐1) treatment, we identified NLRP4 mutations in the responders with a longer progression‐free survival (PFS). Knockdown of NLRP4 in mouse Lewis lung cancer cell line enhanced interferon (IFN)‐α/β production through the cGAS‐STING‐IRF3/IRF7 axis and promoted the accumulation of intratumoral CD8+ T cells, leading to tumor growth retardation in vivo and a synergistic effect with anti‐PD‐ligand 1 therapy. This was consistent with clinical observations that more tumor‐infiltrating CD8+ T cells and elevated peripheral IFN‐α before receiving nivolumab treatment were associated with a longer PFS in NSCLC patients. Our study highlights the roles of tumor‐intrinsic NLRP4 in remodeling the immune contextures in the tumor microenvironment, making regional type I IFN beneficial for ICI treatment.
Our study addressed novel mechanisms for overcoming failures of immune checkpoint inhibitor (ICI) therapy for non‐small‐cell lung cancer (NSCLC) through endogenous regulation of NLRP4 on type I interferon. This is realized mostly through reshaping the tumor microenvironment to a “hot” tumor status, which is beneficial to the treatment of anti‐programmed cell death protein‐1. Furthermore, we provided new evidence on type I interferon (regulated by NLRP4 in our study) as a potential immune adjuvant to improve the efficacy of NSCLC patients ineffective to ICI treatment.
What kind of genetic variation contributes the most to adaptation is a fundamental question in evolutionary biology. By resequencing genomes of 80 individuals, we inferred the origin of genomic ...variants associated with a complex adaptive syndrome involving multiple quantitative traits, namely, adaptation between high and low altitudes, in the vinous-throated parrotbill (Sinosuthora webbiana) in Taiwan. By comparing these variants with those in the Asian mainland population, we revealed standing variation in 24 noncoding genomic regions to be the predominant genetic source of adaptation. Parrotbills at both high and low altitudes exhibited signatures of recent selection, suggesting that not only the front but also the trailing edges of postglacial expanding populations could be subjected to environmental stresses. This study verifies and quantifies the importance of standing variation in adaptation in a cohort of genes, illustrating that the evolutionary potential of a population depends significantly on its preexisting genetic diversity. These findings provide important context for understanding adaptation and conservation of species in the Anthropocene.
Constituting approximately 10% of flowering plant species, orchids (Orchidaceae) display unique flower morphologies, possess an extraordinary diversity in lifestyle, and have successfully colonized ...almost every habitat on Earth. Here we report the draft genome sequence of Apostasia shenzhenica, a representative of one of two genera that form a sister lineage to the rest of the Orchidaceae, providing a reference for inferring the genome content and structure of the most recent common ancestor of all extant orchids and improving our understanding of their origins and evolution. In addition, we present transcriptome data for representatives of Vanilloideae, Cypripedioideae and Orchidoideae, and novel third-generation genome data for two species of Epidendroideae, covering all five orchid subfamilies. A. shenzhenica shows clear evidence of a whole-genome duplication, which is shared by all orchids and occurred shortly before their divergence. Comparisons between A. shenzhenica and other orchids and angiosperms also permitted the reconstruction of an ancestral orchid gene toolkit. We identify new gene families, gene family expansions and contractions, and changes within MADS-box gene classes, which control a diverse suite of developmental processes, during orchid evolution. This study sheds new light on the genetic mechanisms underpinning key orchid innovations, including the development of the labellum and gynostemium, pollinia, and seeds without endosperm, as well as the evolution of epiphytism; reveals relationships between the Orchidaceae subfamilies; and helps clarify the evolutionary history of orchids within the angiosperms.
Abstract
Anion-exchange membrane fuel cells and Zn–air batteries based on non-Pt group metal catalysts typically suffer from sluggish cathodic oxygen reduction. Designing advanced catalyst ...architectures to improve the catalyst’s oxygen reduction activity and boosting the accessible site density by increasing metal loading and site utilization are potential ways to achieve high device performances. Herein, we report an interfacial assembly strategy to achieve binary single-atomic Fe/Co-N
x
with high mass loadings through constructing a nanocage structure and concentrating high-density accessible binary single-atomic Fe/Co–N
x
sites in a porous shell. The prepared FeCo-NCH features metal loading with a single-atomic distribution as high as 7.9 wt% and an accessible site density of around 7.6 × 10
19
sites g
−1
, surpassing most reported M–N
x
catalysts. In anion exchange membrane fuel cells and zinc–air batteries, the FeCo-NCH material delivers peak power densities of 569.0 or 414.5 mW cm
−2
, 3.4 or 2.8 times higher than control devices assembled with FeCo-NC. These results suggest that the present strategy for promoting catalytic site utilization offers new possibilities for exploring efficient low-cost electrocatalysts to boost the performance of various energy devices.
Background and Purpose
Acute lung injury (ALI) is a severe illness with a high rate of mortality. Maresin 1 (MaR1) was recently reported to regulate inflammatory responses. We used a LPS‐induced ALI ...model to determine whether MaR1 can mitigate lung injury.
Experimental Approach
Male BALB/c mice were injected, intratracheally, with either LPS (3 mg·kg−1) or normal saline (1.5 mL·kg−1). After this, normal saline, a low dose of MaR1 (0.1 ng per mouse) or a high dose of MaR1 (1 ng per mouse) was given i.v. Lung injury was evaluated by detecting arterial blood gas, pathohistological examination, pulmonary oedema, inflammatory cell infiltration, inflammatory cytokines in the bronchoalveolar lavage fluid and neutrophil–platelet interactions.
Key Results
The high dose of MaR1 significantly inhibited LPS‐induced ALI by restoring oxygenation, attenuating pulmonary oedema and mitigating pathohistological changes. A combination of elisa and immunohistochemistry showed that high‐dose MaR1 attenuated LPS‐induced increases in pro‐inflammatory cytokines (TNF‐α, IL‐1β and IL‐6), chemokines keratinocyte chemokine, monocyte chemoattractant protein‐5, macrophage inflammatory protein (MIP)‐1α and MIP‐1γ, pulmonary myeloperoxidase activity and neutrophil infiltration in the lung tissues. Consistent with these observations, flow cytometry and Western blotting indicated that MaR1 down‐regulated LPS‐induced neutrophil adhesions and suppressed the expression of intercellular adhesion molecule (ICAM)‐1, P‐selection and CD24.
Conclusions and Implications
High‐dose MaR1 mitigated LPS‐induced lung injury in mice by inhibiting neutrophil adhesions and decreasing the levels of pro‐inflammatory cytokines.
PDF
