The pathological hallmark of Parkinson's disease (PD) is the formation of Lewy bodies containing aggregated alpha-synuclein (α-syn). Although PD is associated with these distinct histological ...changes, other pathological features such as microvascular alterations have been linked to neurodegeneration. These changes need to be investigated as they create a hostile brain microenvironment and may contribute to the development and progression of the disease. We use a human α-syn overexpression mouse model that recapitulates some of the pathological features of PD in terms of progressive aggregation of human α-syn, impaired striatal dopamine fiber density, and an age-dependent motor deficit consistent with an impaired dopamine release. We demonstrate for the first time in this model a compromised blood-brain barrier integrity and dynamic changes in vessel morphology from angiogenesis at earlier stages to vascular regression at later stages. The vascular alterations are accompanied by a pathological activation of pericytes already at an early stage without changing overall pericyte density. Our data support and further extend the occurrence of vascular pathology as an important pathophysiological aspect in PD. The model used provides a powerful tool to investigate disease-modifying factors in PD in a temporal sequence that might guide the development of new treatments.
As a potential treatment strategy for low immunogenic triple negative breast cancer (TNBC), photodynamic therapy (PDT) induced antitumor immunotherapy is greatly limited by the immunosuppressive ...tumor microenvironment (ITM), especially the M2 phenotype tumor-associated macrophages (TAMs). The balance of arginine metabolism plays an important role in TAMs polarization. Herein, a multifunctional nanoplatform (defined as HN-HFPA) was employed to burst the anti-tumor immunity of TNBC post PDT by reeducating TAMs through interfering the TAMs-associated arginine metabolism. The L-arginine (L-Arg) was loaded in the hollow cavity of HN-HFPA, which could not only generate nitric oxide (NO) for tumor therapy, but also serve as a substrate of arginine metabolism pathway. As an inhibitor of arginases-1 (Arg-1) of M2 TAMs, L-norvaline (L-Nor) was modified to the hyaluronic acid (HA), and coated in the surface of HFPA. After degradation of HA by hyaluronidase in tumor tissue and GSH-mediated disintegration, HN-HFPA depleted intracellular GSH, produced remarkable reactive oxygen species (ROS) under light irradiation and released L-Arg to generate NO, which induced tumor immunogenic cell death (ICD). Real-time ultrasound imaging of tumor was realized taking advantage of the gas feature of NO. The L-Nor suppressed the Arg-1 overexpressed in M2, which skewed the balance of arginine metabolism and reversed the ITM with increased ratios of M1 and CD8+ T cells, finally resulted in amplified antitumor immune response and apparent tumor metastasis inhibition. This study remodeled ITM to strengthen immune response post PDT, which provided a promising treatment strategy for TNBC.
The multifunctional nanodrugs (HN-HFPA) mediated high-efficient photodynamic immunotherapy by promoting photodynamic therapy elicited ICD and regulating arginine metabolism in tumor associated macrophages (TAMs) to remodel immunosuppressive tumor microenvironment (ITM), resulting in significant inhibition of primary and metastatic murine TNBCs in vivo. Display omitted
The metal-semiconductor heterojunction is imperative for the realization of electrically driven nanolasers for chip-level platforms. Progress in developing such nanolasers has hitherto rarely been ...realized, however, because of their complexity in heterojunction fabrication and the need to use noble metals that are incompatible with microelectronic manufacturing. Most plasmonic nanolasers lase either above a high threshold (10
-10
MW cm
) or at a cryogenic temperature, and lasing is possible only after they are removed from the substrate to avoid the large ohmic loss and the low modal reflectivity, making monolithic fabrication impossible. Here, for the first time, record-low-threshold, room-temperature ultraviolet (UV) lasing of plasmon-coupled core-shell nanowires that are directly grown on silicon is demonstrated. The naturally formed core-shell metal-semiconductor heterostructure of the nanowires leads to a 100-fold improvement in growth density over previous results. This unprecedentedly high nanowire density creates intense plasmonic resonance, which is outcoupled to the resonant Fabry-Pérot microcavity. By boosting the emission strength by a factor of 100, the hybrid photonic-plasmonic system successfully facilitates a record-low laser threshold of 12 kW cm
with a spontaneous emission coupling factor as high as ≈0.32 in the 340-360 nm range. Such architecture is simple and cost-competitive for future UV sources in silicon integration.
Incorporation of non‐equilibrium actions in the sequence of self‐assembly processes would be an effective means to establish bio‐like high functionality hierarchical assemblies. As a novel ...methodology beyond self‐assembly, nanoarchitectonics, which has as its aim the fabrication of functional materials systems from nanoscopic units through the methodological fusion of nanotechnology with other scientific disciplines including organic synthesis, supramolecular chemistry, microfabrication, and bio‐process, has been applied to this strategy. The application of non‐equilibrium factors to conventional self‐assembly processes is discussed on the basis of examples of directed assembly, Langmuir–Blodgett assembly, and layer‐by‐layer assembly. In particular, examples of the fabrication of hierarchical functional structures using bio‐active components such as proteins or by the combination of bio‐components and two‐dimensional nanomaterials, are described. Methodologies described in this review article highlight possible approaches using the nanoarchitectonics concept beyond self‐assembly for creation of bio‐like higher functionalities and hierarchical structural organization.
Simple self‐assembly methods cannot be used to attain high‐level organizations such as those found in biological systems. The introduction of non‐equilibrium processes and harmonization of multiple actions is required. As a novel methodology beyond self‐assembly, nanoarchitectonics, whose main conceptual aim is the formation of functional materials from nanoscopic units through the fusion of different scientific disciplines, has been proposed for the creation of bio‐like high functionality hierarchically organized structures.
Carbene insertion reactions initiated with diazo compounds have been widely used to develop unnatural enzymatic reactions. However, alternative functionalization of diazo compounds in enzymatic ...processes has been unexploited. Herein, we describe a photoenzymatic strategy for radical‐mediated stereoselective hydroalkylation with diazo compounds. This method generates carbon‐centered radicals through an ene reductase catalyzed photoinduced electron transfer process from diazo compounds, enabling the synthesis of γ‐stereogenic carbonyl compounds in good yields and stereoselectivities. This study further expands the possible reaction patterns in photo‐biocatalysis and offers a new approach to solving the selectivity challenges of radical‐mediated reactions.
A photoenzymatic strategy for radical‐mediated stereoselective hydroalkylation with diazo compounds has been developed. By this method, a series of γ‐chiral carbonyl compounds were synthesized in high yields and stereoselectivities.
The development of advanced catalysts for efficient electrochemical energy conversion technologies to alleviate the reliance on fossil fuels has attracted considerable interest in the last decades. ...Insight into the roles of reactive sites in nanomaterials is significant for understanding and implementing the design principles of nanocatalysts. Recently, the essential role of defects, including vacancies, reconstructed defects, and doped non-metal (or metal)-defect-based motifs, have been widely demonstrated to promote the diverse electrochemical processes (e.g., O2 or CO2 reduction reactions and H2 or O2 evolution reactions). Nevertheless, the in-depth exploration of the underlying defect electrocatalytic mechanism is still in its infancy. This review summarizes the state-of-the-art defect engineering strategies for designing highly efficient electrochemical nanocatalysts with special emphasis on the correlation between defect structures and electrocatalytic properties. Finally, some perspectives on the challenges and future research directions in this promising area are presented.
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Electrocatalytic energy conversion technologies have been widely considered a clean and sustainable way to alleviate the reliance on fossil fuels. The development of efficient and affordable electrocatalysts plays a key aspect in energy conversion processes by lowering the reaction kinetic barriers and thus boosting the efficiency and selectivity of diverse electrochemical reactions (e.g., oxygen and hydrogen evolution reactions and oxygen and carbon dioxide reduction reactions). Recently, defect engineering has emerged as a new strategy for tailoring the electronic structures and interface coordination; however, the role of “defect”-related sites in as-designed electrocatalysts has not yet been fully understood. In this review, we will shed light on the recent advances in tailoring nanomaterials from the aspects of constructing defect-based motifs as active sites for versatile electrochemical energy conversions as well as their underlying mechanism on structure-property correlations.
Recently, the essential role of defects, including vacancies, reconstructed defects, and doped non-metal/metal-defect-based motifs, has been widely demonstrated to promote the diverse electrochemical processes (e.g., O2/CO2 reduction reactions and H2/O2 evolution reactions). This review summarizes the state-of-the-art defect engineering strategies for designing highly efficient electrochemical nanocatalysts with special emphasis on the correlation between defect structures and electrocatalytic properties. Finally, some perspectives on the challenges and future research directions in this promising area are presented.
The cellular hallmarks of Parkinson’s disease (PD) are the loss of nigral dopaminergic neurons and the formation of α-synuclein-enriched Lewy bodies and Lewy neurites in the remaining neurons. Based ...on the topographic distribution of Lewy bodies established after autopsy of brains from PD patients, Braak and coworkers hypothesized that Lewy pathology primes in the enteric nervous system and spreads to the brain, suggesting an active retrograde transport of α-synuclein (the key protein component in Lewy bodies), via the vagal nerve. This hypothesis, however, has not been tested experimentally thus far. Here, we use a human PD brain lysate containing different forms of α-synuclein (monomeric, oligomeric and fibrillar), and recombinant α-synuclein in an in vivo animal model to test this hypothesis. We demonstrate that α-synuclein present in the human PD brain lysate and distinct recombinant α-synuclein forms are transported via the vagal nerve and reach the dorsal motor nucleus of the vagus in the brainstem in a time-dependent manner after injection into the intestinal wall. Using live cell imaging in a differentiated neuroblastoma cell line, we determine that both slow and fast components of axonal transport are involved in the transport of aggregated α-synuclein. In conclusion, we here provide the first experimental evidence that different α-synuclein forms can propagate from the gut to the brain, and that microtubule-associated transport is involved in the translocation of aggregated α-synuclein in neurons.
Li−CO2 batteries have received significant attention owing to their advantages of combining greenhouse gas utilization and energy storage. However, the high kinetic barrier between gaseous CO2 and ...the Li2CO3 product leads to a low operating voltage (<2.5 V) and poor energy efficiency. In addition, the reversibility of Li2CO3 has always been questioned owing to the introduction of more decomposition paths caused by its higher charging plateau. Here, a novel “trinity” Li−CO2 battery system was developed by synergizing CO2, soluble redox mediator (2,2,6,6‐tetramethylpiperidoxyl, as TEM RM), and reduced graphene oxide electrode to enable selective conversion of CO2 to Li2C2O4. The designed Li−CO2 battery exhibited an output plateau reaching up to 2.97 V, higher than the equilibrium potential of 2.80 V for Li2CO3, and an ultrahigh round‐trip efficiency of 97.1 %. The superior performance of Li−CO2 batteries is attributed to the TEM RM‐mediated preferential growth mechanism of Li2C2O4, which enhances the reaction kinetics and rechargeability. Such a unique design enables batteries to cope with sudden CO2‐deficient environments, which provides an avenue for the rationally design of CO2 conversion reactions and a feasible guide for next‐generation Li−CO2 batteries.
The “trinity” strategy provides a new perspective for the development of Li−CO2 batteries. The addition of a soluble mediator, TEM RM, was used to modulate the three‐phase interface and facilitate the conversion of CO2 to Li2C2O4. This strategy avoids a series of issues associated with the Li2CO3 product, contributing to excellent cycling performance for Li−CO2 battery.
Most N6-methyladenosine (m
A) associated regulatory proteins (i.e., m
A writer, eraser, and reader proteins) are involved in the pathogenesis of various cancers, mostly in m
A-dependent manners. As a ...component in the m
A 'writers', KIAA1429 is reported to be an RNA-binding protein and involved in the m
A modification, mRNA splicing and processing. Till now, the functions of KIAA1429 in tumorigenesis and related mechanism have not been reported. In the present study, we found KIAA1429 was highly expressed in breast cancer tissues, but frequently down-regulated in non-cancerous breast tissues. The overall survival of breast cancer patients with high-expression KIAA1429 was significantly shorter than those with low-expression KIAA1429. Then, we demonstrated that KIAA1429 was associated with breast cancer proliferation and metastasis in vivo and in vitro. The potential targeting genes of KIAA1429 in breast cancer were identified by RNA immunoprecipitation sequencing. One of these genes is cyclin-dependent kinase 1 (CDK1), which plays an oncogenic role in cancers. Furthermore, we confirmed that KIAA1429 played its oncogenic role in breast cancer by regulating CDK1 by an m
A-independent manner. 5'-fluorouracil was found to be very effective in reducing the expression of KIAA1429 and CDK1 in breast cancer. These findings indicated that KIAA1429 could promote breast cancer progression and was correlated with pathogenesis. It may represent a promising therapeutic strategy on breast cancer, especially in combination with CDK1 treatment.
Radiation‐induced lung injury (RILI) is the major complication of thoracic radiation therapy, and no effective treatment is available. This study explored the role of high‐mobility group box 1 ...(HMGB1) in acute RILI and the therapeutic effect of glycyrrhizin, an inhibitor of HMGB1, on RILI. C57BL/6 mice received a 20 Gy dose of X‐ray radiation to the whole thorax with or without administration of glycyrrhizin. Severe lung inflammation was present 12 weeks after irradiation, although only a mild change was noted at 2 weeks and could be alleviated by administration of glycyrrhizin. Glycyrrhizin decreased the plasma concentrations of HMGB1 and sRAGE as well as TNF‐α, IL‐1β and IL‐6 levels in the bronchoalveolar lavage fluid (BALF). The expression of RAGE was decreased while that of TLR4 was significantly increased at 12 weeks, but not 2 weeks, after irradiation in mouse lung tissue. In vitro, the expression of TLR4 increased in RAW 264.7 cells after conditioning with the supernatant from the irradiated MLE‐12 cells containing HMGB1 but showed no change when conditioned medium without HMGB1 was used. However, conditioned culture had no effect on RAGE expression in RAW 264.7 cells. Glycyrrhizin also inhibited the related downstream transcription factors of HMGB/TLR4, such as NF‐κB, JNK and ERK1/2, in lung tissue and RAW 264.7 cells when TLR4 was activated. In conclusion, the HMGB1/TLR4 pathway mediates RILI and can be mitigated by glycyrrhizin.
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