Summary
With the advent of rapid genotyping and next‐generation sequencing technologies, genome‐wide association study (GWAS) has become a routine strategy for decoding genotype–phenotype ...associations in many species. More than 1000 such studies over the last decade have revealed substantial genotype–phenotype associations in crops and provided unparalleled opportunities to probe functional genomics. Beyond the many ‘hits’ obtained, this review summarizes recent efforts to increase our understanding of the genetic architecture of complex traits by focusing on non‐main effects including epistasis, pleiotropy, and phenotypic plasticity. We also discuss how these achievements and the remaining gaps in our knowledge will guide future studies. Synthetic association is highlighted as leading to false causality, which is prevalent but largely underestimated. Furthermore, validation evidence is appealing for future GWAS, especially in the context of emerging genome‐editing technologies.
Significance Statement
This review summarizes the latest advances in generating an overall view of the genetic architecture associated with crop complex traits, and discusses how these updated insights will guide future studies. A multiple‐causal‐allele hypothesis was formulated to explain the increasingly common artifact/synthetic associations.
Highly efficient hydrogen evolution reaction (HER) electrocatalyst will determine the mass distributions of hydrogen‐powered clean technologies, while still faces grand challenges. In this work, a ...synergistic ligand modulation plus Co doping strategy is applied to 1T−MoS2 catalyst via CoMo‐metal‐organic frameworks precursors, boosting the HER catalytic activity and durability of 1T−MoS2. Confirmed by Cs corrected transmission electron microscope and X‐ray absorption spectroscopy, the polydentate 1,2‐bis(4‐pyridyl)ethane ligand can stably link with two‐dimensional 1T−MoS2 layers through cobalt sites to expand interlayer spacing of MoS2 (Co−1T−MoS2‐bpe), which promotes active site exposure, accelerates water dissociation, and optimizes the adsorption and desorption of H in alkaline HER processes. Theoretical calculations indicate the promotions in the electronic structure of 1T−MoS2 originate in the formation of three‐dimensional metal‐organic constructs by linking π‐conjugated ligand, which weakens the hybridization between Mo‐3d and S‐2p orbitals, and in turn makes S‐2p orbital more suitable for hybridization with H‐1s orbital. Therefore, Co−1T−MoS2‐bpe exhibits excellent stability and exceedingly low overpotential for alkaline HER (118 mV at 10 mA cm−2). In addition, integrated into an anion‐exchange membrane water electrolyzer, Co−1T−MoS2‐bpe is much superior to the Pt/C catalyst at the large current densities. This study provides a feasible ligand modulation strategy for designs of two‐dimensional catalysts.
A synergistic ligand modulation plus cobalt doping strategy is applied to modulate the orbital hybridization of 1T‐MoS2 catalyst via CoMo‐MOF precursors. The polydentate 1,2‐bis(4‐pyridyl)ethane (bpe) ligand can stably link with 1T‐MoS2 layers to achieve expanded interlayer spacing, which promotes the joint participation of highly efficient active sites in the basal plane and the interlayer in alkaline HER processes.
Photothermal therapy (PTT) has attracted tremendous attention due to its noninvasiveness and localized treatment advantages. However, heat shock proteins (HSPs) associated self‐preservation ...mechanisms bestow cancer cells thermoresistance to protect them from the damage of PTT. To minimize the thermoresistance of cancer cells and improve the efficacy of PTT, an integrated on‐demand nanoplatform composed of a photothermal conversion core (gold nanorod, GNR), a cargo of a HSPs inhibitor (triptolide, TPL), a mesoporous silica based nanoreservoir, and a photothermal and redox di‐responsive polymer shell is developed. The nanoplatform can be enriched in the tumor site, and internalized into cancer cells, releasing the encapsulated TPL under the trigger of intracellular elevated glutathione and near‐infrared laser irradiation. Ultimately, the liberated TPL could diminish thermoresistance of cancer cells by antagonizing the PTT induced heat shock response via multiple mechanisms to maximize the PTT effect for cancer treatment.
A triptolide nanoreservoir, which can be in situ activated by near‐infrared light (NIR) laser irradiation and intracellular high redox potential, is developed to overcome the thermoresistance of cancer cells. Thanks to the inhibited photothermal therapy (PTT) induced heat shock response, the photothermal therapy efficacy of the gold nanorod/mesoporous nanocomplex is greatly improved.
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Despite its prevalence in the management of peripheral tumors, compared to surgery and radiation therapy, chemotherapy is still a suboptimal intervention in fighting against brain ...cancer and cancer brain metastases. This discrepancy is mainly derived from the complicatedly physiological characteristic of intracranial tumors, including the presence of blood–brain barrier (BBB) and limited enhanced permeability and retention (EPR) effect attributed to blood–brain tumor barrier (BBTB), which largely lead to insufficient therapeutics penetrating to tumor lesions to produce pharmacological effects. Therefore, dependable methodologies that can boost the efficacy of chemotherapy for brain tumors are urgently needed. Recently, nanomedicines have shown great therapeutic potential in brain tumors by employing various transcellular strategies, paracellular strategies, and their hybrids, such as adsorptive-mediated transcytosis, receptor-mediated transcytosis, BBB disruption technology, and so on. It is compulsory to comprehensively summarize these practices to shed light on future directions in developing therapeutic regimens for brain tumors. In this review, the biological and pathological characteristics of brain tumors, including BBB and BBTB, are illustrated. After that, the emerging delivery strategies for brain tumor management are summarized into different classifications and supported with detailed examples. Finally, the potential challenges and prospects for developing and clinical application of brain tumor-oriented nanomedicine are discussed.
The biomimetic enzyme activity of cerium oxide nanoparticles (CeNPs) prefers ultrasmall particle size and bare surface. Unfortunately, those two features are not favorable for its in vivo application ...due to easy aggregation and fast renal filtration. To take advantage of the activity of CeNP for cancer therapy, a homologous targeted cerium oxide nanoparticle system, targeted CeNP (T‐CeNP), with the integration of a biodegradable dendritic mesoporous silica nanoparticle, superoxide dismutase and catalase mimicking CeNPs, and the camouflage coating of cancer cell membrane has been developed. Attributed to the homologous targeting effect of cancer cell membrane, nanoparticles with camouflage coating are retained in the tumor in an orthotopic breast cancer metastatic model. Subsequently, T‐CeNP effectively hinders cancer‐associated fibroblast transdifferentiation and reprograms it back to a normal fibroblast. Consequently, T‐CeNP coupled with doxorubicin reduces the size of primary tumors and prevents the post‐surgery lung metastasis and liver metastasis of breast cancer.
A homologous targeted cerium oxide nanoparticle system (T‐CeNP) is developed for remodeling the tumor microenvironment by inhibiting cancer‐associated fibroblast transdifferentiation and reprogramming them back to normal fibroblasts. T‐CeNP coupled with doxorubicin reduces the size of the primary tumor and prevents post‐surgery lung metastasis and liver metastasis of cancer in an orthotopic breast cancer model.
Abstract
Rationally constructing and manipulating the in situ formed catalytically active surface of catalysts remains a tremendous challenge for a highly efficient water electrolysis. Herein, an ...anion and cation co‐induced strategy is presented to modulate in situ catalyst dissolution‐redeposition and to achieve the directional reconstruction of Zn and S co‐doped Fe
2
O
3
and Fe
3
O
4
on iron foams (Zn,S‐Fe
2
O
3
‐Fe
3
O
4
/IF), for oxygen evolution reaction (OER). Benefiting from Zn, S co‐doping and the presence of Fe
3
O
4
, a directionally reconstructed surface is obtained. The Fe
2
O
3
in the Zn,S‐Fe
2
O
3
‐Fe
3
O
4
/IF is directionally reconstructed into FeOOH (Zn,S‐Fe
3
O
4
‐FeOOH/IF), in which the S leaching promotes the Fe dissolution and the Zn co‐deposition regulates the activity of the obtained FeOOH. Moreover, the presence of Fe
3
O
4
provides a stable site for FeOOH deposition, and thus causes more FeOOH active components to be formed. Directionally reconstructed Zn,S‐Fe
3
O
4
‐FeOOH/IF outperformes many state‐of‐the‐art OER catalysts and demonstrates a remarkable stability. The experimental and density functional theory (DFT) calculation results show that the introduction of Zn‐doped FeOOH with abundant oxygen vacancies through directional reconstruction has activated lattice O atoms, facilitating the OER process on the heterojunction surface following the lattice oxygen mechanism (LOM) pathway. This work makes a stride in co‐induced strategy modulating directional reconstruction.
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•Sulfur doping NiFe2O4 nanocones arrays on iron foam (S-NiFe2O4/IF) are obtained.•Low-valence Ni in tetrahedron sites are more actives sites than high-valence Fe atom.•S introduction ...optimizes the adsorption of OER intermediates on Ni sites.•S-NiFe2O4/IF achieves an industrial 500 mA cm−2 at overpotential of 310 mV for 100 h.•An AEM electrolyzer using S-NiFe2O4/IF delivers a 1 A cm−2 current density at 1.79 V.
The microstructure of active centers in bimetallic/multimetallic catalysts is under a long-time debate toward oxygen evolution reaction (OER). Here, sulfur doping NiFe2O4 nanocone arrays on iron foams (S-NiFe2O4/IF) is prepared via a scalable hydrothermal method. The favorable 3D nanocone arrays can offer large electrochemical surface area and allow for effective electrolyte access and O2 escape. Physical characterizations confirm low-valence Ni atoms in tetrahedron sites are more actives sites than high-valence Fe atoms in this S-doped bimetallic catalyst. Meanwhile, DFT calculations further verify the S introduction enhances the adsorption and dissociation of water, and optimizes the adsorption of OER intermediates on Ni sites. Therefore, the optimal S-NiFe2O4/IF achieves industrial-level 500 mA cm−2 at an overpotential of only 310 mV and maintains for 100 h in an alkaline medium. In addition, integrating S-NiFe2O4/IF into an anion-exchange membrane water electrolyzer can deliver a current density of 1.0 A cm−2 at 1.79 V.
Photodynamic therapy (PDT) of cancer is limited by tumor hypoxia. Platinum nanoparticles (nano‐Pt) as a catalase‐like nanoenzyme can enhance PDT through catalytic oxygen supply. However, the ...cytotoxic activity of nano‐Pt is not comprehensively considered in the existing methods to exert their multifunctional antitumor effects. Here, nano‐Pt are loaded into liposomes via reverse phase evaporation. The clinical photosensitizer verteporfin (VP) is loaded in the lipid bilayer to confer PDT activity. Murine macrophage cell membranes are hybridized into the liposomal membrane to confer biomimetic and targeting features. The resulting liposomal system, termed “nano‐Pt/VP@MLipo,” is investigated for chemophototherapy in vitro and in vivo in mouse tumor models. At the tumor site, oxygen produced by nano‐Pt catalyzation improves the VP‐mediated PDT, which in turn triggers the release of nano‐Pt via membrane permeabilization. The ultrasmall 3–5 nm nano‐Pt enables better penetration in tumors, which is also facilitated by the generated oxygen gas, for enhanced chemotherapy. Chemophototherapy with a single injection of nano‐Pt/VP@MLipo and light irradiation inhibits the growth of aggressive 4T1 tumors and their lung metastasis, and prolongs animal survival without overt toxicity.
The biomimetic liposomal nano‐Pt (nano‐Pt/VP@MLipo) targets the tumor sites, where oxygen produced by nano‐Pt catalyzation enhances the verteporfin (VP)‐mediated photodynamic therapy (PDT). PDT in turn permeabilizes the liposome membrane for efficient nano‐Pt release. These ultrasmall particles (3–5 nm) achieve penetration in deeper tumor tissue, which is also facilitated by the generated oxygen gas, for enhanced chemotherapy.
Tumor-associated macrophages (TAMs) play a critical role in the immunosuppressive solid tumor microenvironment, yet in situ engineering of TAMs for enhanced tumor immunotherapy remains a significant ...challenge in translational immune-oncology. Here, we report an innovative nanodrug-delivering-drug (STNSP@ELE) strategy that leverages two-dimensional (2D) stanene-based nanosheets (STNSP) and β-Elemene (ELE), a small-molecule anticancer drug, to overcome TAM-mediated immunosuppression and improve chemo-immunotherapy. Our results demonstrate that both STNSP and β-Elemene are capable of polarizing the tumor-supportive M2-like TAMs into tumor-suppressive M1-like phenotype, which acts with the ELE chemotherapeutic to booster anti-tumor responses. In vivo mouse studies demonstrate that STNSP@ELE treatment can reprogram the immunosuppressive TME by significantly increasing the intra-tumoral ratio of M1/M2-like TAMs, enhancing the population of CD4+ and CD8+ T lymphocytes and mature dendritic cells, and elevating the expression of immunostimulatory cytokines in B16F10 melanomas, thereby promoting a robust anti-tumor response. Our study not only demonstrates that the STNSP@ELE chemo-immunotherapeutic nanoplatform has immune-modulatory capabilities that can overcome TAM-mediated immunosuppression in solid tumors, but also highlights the promise of this nanodrug-delivering-drug strategy in developing other nano-immunotherapeutics and treating various types of immunosuppressive tumors.
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•Co(OH)(NO3) (CoNH) is adopted to instantaneously realize oriented atom substitution and vacancies generation.•The atom substitutional doping for S/Se/Mo/P into CoNH can be ...accomplished.•The electron arrangement, chemical environment, and adsorption ability are obtained.•This work provides fresh light on the accurate atom incorporation and vacancy engineering.
The accurate identification and manipulation for synergistic atom substitution and vacancy is significant and challenging for the overall water splitting (OWS) and theoretical analysis. Herein, a unique Co(OH)(NO3) (CoNH) material has been adopted to instantaneously realize oriented atom substitution and vacancies generation through fast impregnation. We found that in alkaline solution, the nitrate groups are prone to dissolve, thus forming nitrate vacancies that are the preferential sites for foreign atoms. Therefore, the controlled atom substitutional doping and vacancies can be simultaneously accomplished. As verification, after dipping in respective solution, S/Se/Mo/P was doped and nitrate deficiencies formed. The atom replacement and vacancy synergistically modulate the electron arrangement, chemical environment, and adsorption capability of host materials, thus boosting electrocatalytic OWS activity. In addition, the precise structure with definite lattice is propitious for the reveal of the structure–property connection. By theory calculation, the optimized electronic structure and adsorption ability of well-defined structures are also uncovered. This present work is expected to shed fresh light on accurate atom incorporation and vacancy engineering, thus achieving a deeper understanding of the structure-composition-property relationship.
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