The most prevalent pathological features of many neurodegenerative diseases are the aggregation of misfolded proteins and the loss of certain neuronal populations. Autophagy, as major intracellular ...machinery for degrading aggregated proteins and damaged organelles, has been reported to be involved in the occurrence of pathological changes in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. In this review, we summarize most recent research progress in this topic and provide a new perspective regarding autophagy regulation on the pathogenesis of neurodegenerative diseases. Finally, we discuss the signaling molecules in autophagy‐related pathways as therapeutic targets for the treatment of these diseases.
Nitric oxide (NO) has been known to preserve the level of chlorophyll (Chl) during leaf senescence. However, the mechanism by which NO regulates Chl breakdown remains unknown. Here we report that NO ...negatively regulates the activities of Chl catabolic enzymes during dark-induced leaf senescence. The transcriptional levels of the major enzyme genes involving Chl breakdown pathway except for RED CHL CATABOLITE REDUCTASE (RCCR) were dramatically up-regulated during dark-induced Chl degradation in the leaves of Arabidopsis NO-deficient mutant nos1/noa1 that exhibited an early-senescence phenotype. The activity of pheide a oxygenase (PAO) was higher in the dark-induced senescent leaves of nos1/noa1 compared with wild type. Furthermore, the knockout of PAO in nos1/noa1 background led to pheide a accumulation in the double mutant pao1 nos1/noa1, which retained the level of Chl during dark-induced leaf senescence. The accumulated pheide a in darkened leaves of pao1 nos1/noa1 was likely to inhibit the senescence-activated transcriptional levels of Chl catabolic genes as a feed-back inhibitory effect. We also found that NO deficiency led to decrease in the stability of photosynthetic complexes in thylakoid membranes. Importantly, the accumulation of pheide a caused by PAO mutations in combination with NO deficiency had a synergistic effect on the stability loss of thylakoid membrane complexes in the double mutant pao1 nos1/noa1 during dark-induced leaf senescence. Taken together, our findings have demonstrated that NO is a novel negative regulator of Chl catabolic pathway and positively functions in maintaining the stability of thylakoid membranes during leaf senescence.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alcoholic liver disease (ALD) is a global public health challenge due to the high incidence and lack of effective therapeutics. Evidence from animal studies and ALD patients has demonstrated that ...iron overload is a hallmark of ALD. Ethanol exposure can promote iron absorption by downregulating the hepcidin expression, which is probably mediated by inducing oxidative stress and promoting erythropoietin (EPO) production. In addition, ethanol may enhance iron uptake in hepatocytes by upregulating the expression of transferrin receptor (TfR). Iron overload in the liver can aggravate ethanol-elicited liver damage by potentiating oxidative stress via Fenton reaction, promoting activation of Kupffer cells (KCs) and hepatic stellate cells (HSCs), and inducing a recently discovered programmed iron-dependent cell death, ferroptosis. This article reviews the current knowledge of iron metabolism, regulators of iron homeostasis, the mechanism of ethanol-induced iron overload, detrimental effects of iron overload in the liver, and potential therapeutic targets.
The plant microbiota play a key role in plant productivity, nutrient uptake, resistance to stress and flowering. The flowering of moso bamboo has been a focus of study. The mechanism of flowering is ...related to nutrient uptake, temperature, hormone balance and regulation of key genes. However, the connection between microbiota of moso bamboo and its flowering is unknown. In this study, samples of rhizosphere soil, rhizomes, roots and leaves of flowering and nonflowering plants were collected, and 16S rRNA amplicon Illumina sequencing was utilized to separate the bacterial communities associated with different flowering stages of moso bamboo. We identified 5442 OTUs, and the number of rhizosphere soil OTUs was much higher than those of other samples. Principal component analysis (PCA) and hierarchical clustering (Bray Curtis dis) analysis revealed that the bacterial microorganisms related to rhizosphere soil and endophytic tissues of moso bamboo differed significantly from those in bulk soil and rhizobacterial and endosphere microbiomes. In addition, the PCA analyses of root and rhizosphere soil revealed different structures of microbial communities between bamboo that is flowering and not flowering. Through the analysis of core microorganisms, it was found that Flavobacterium, Bacillus and Stenotrophomonas played an important role in the absorption of N elements, which may affect the flowering time of moso bamboo. Our results delineate the complex host-microbe interactions of this plant. We also discuss the potential influence of bacterial microbiome in flowering, which can provide a basis for the development and utilization of moso bamboo.
In the clades of animals that diverged from the bony fish, a group of Mas-related G-protein-coupled receptors (MRGPRs) evolved that have an active role in itch and allergic signals
. As an MRGPR, ...MRGPRX2 is known to sense basic secretagogues (agents that promote secretion) and is involved in itch signals and eliciting pseudoallergic reactions
. MRGPRX2 has been targeted by drug development efforts to prevent the side effects induced by certain drugs or to treat allergic diseases. Here we report a set of cryo-electron microscopy structures of the MRGPRX2-G
trimer in complex with polycationic compound 48/80 or with inflammatory peptides. The structures of the MRGPRX2-G
complex exhibited shallow, solvent-exposed ligand-binding pockets. We identified key common structural features of MRGPRX2 and describe a consensus motif for peptidic allergens. Beneath the ligand-binding pocket, the unusual kink formation at transmembrane domain 6 (TM6) and the replacement of the general toggle switch from Trp
to Gly
(superscript annotations as per Ballesteros-Weinstein nomenclature) suggest a distinct activation process. We characterized the interfaces of MRGPRX2 and the G
trimer, and mapped the residues associated with key single-nucleotide polymorphisms on both the ligand and G-protein interfaces of MRGPRX2. Collectively, our results provide a structural basis for the sensing of cationic allergens by MRGPRX2, potentially facilitating the rational design of therapies to prevent unwanted pseudoallergic reactions.
Noninvasive prenatal testing (NIPT) using sequencing of fetal cellfree DNA from maternal plasma has enabled accurate prenatal diagnosis of aneuploidy and become increasingly accepted in clinical ...practice. We investigated whether NIPT using semiconductor sequencing platform (SSP) could reliably detect subchromosomal deletions/duplications in women carrying high-risk fetuses. We first showed that increasing concentration of abnormal DNA and sequencing depth improved detection. Subsequently, we analyzed plasma from 1,456 pregnant women to develop a method for estimating fetal DNA concentration based on the size distribution of DNA fragments. Finally, we collected plasma from 1,476 pregnant women with fetal structural abnormalities detected on ultrasound who also underwent an invasive diagnostic procedure. We used SSP of maternal plasma DNA to detect subchromosomal abnormalities and validated our results with array comparative genomic hybridization (aCGH). With 3.5 million reads, SSP detected 56 of 78 (71.8%) subchromosomal abnormalities detected by aCGH. With increased sequencing depth up to 10 million reads and restriction of the size of abnormalities to more than 1Mb, sensitivity improved to 69 of 73 (94.5%). Of 55 false-positive samples, 35 were caused by deletions/duplications present in maternal DNA, indicating the necessity of a validation test to exclude maternal karyotype abnormalities. This study shows that detection of fetal subchromosomal abnormalities is a viable extension of NIPT based on SSP. Although we focused on the application of cell-free DNA sequencing for NIPT, we believe that this method has broader applications for genetic diagnosis, such as analysis of circulating tumor DNA for detection of cancer.
•Rubber-modified recycled aggregate concrete with 3 different rubber contents was tested.•The best mix ratio of rubber content was provided.•Addition of recycled aggregate and rubber enhanced fatigue ...life of concrete.•Fatigue life equation of rubber-modified recycled aggregate concrete was presented.
Based on the performance requirements for airport pavement concrete, this study analyzes the mechanical properties, fatigue properties and damage characteristics of rubber-modified recycled aggregate concrete (RRAC) with waste rubber replacement rates of 10%, 20% and 30%. The test results for compressive strength, four-point flexural bending, elasticity modulus and fatigue life on RRAC showed that the compressive strength of recycled aggregate concrete (RAC) increased by 10.1% from that of normal concrete (NC) (rubber-free and recycled-aggregate-free concrete). The compressive strength, flexural strength and elasticity modulus of the RRAC decreased with the increase in rubber particle content. However, the peak deflection, peak strain and ultimate strain increased with the increase of rubber particle content with a certain range. When rubber particle content reached 20% of the sand, the ultimate strain of RRAC was 3.45times that of rubber-free RAC. Based on the Weibull theory, statistical analysis was performed on the test results, and double logarithm fatigue equations for RRAC under different failure probabilities were provided, which could be used to predict the ultimate fatigue strength of RRAC. An analysis of the damage characteristics showed that both recycled aggregate and rubber particle could enhance the concrete’s fatigue life. This enhancement was most significant when the rubber particle content reached 20%.
Combination of biological entities with functional nanostructure would produce the excellent systemic drug-delivery vehicles that possess the ability to cross the biological barriers. Herein, from a ...biomimetic point of view, erythrocyte membrane bioinspired optical nanocarrier is fabricated by integrating Red blood cell (RBC) membrane vesicle with near-infrared persistent luminescence nanophosphors (PLNPs). The triple-doped zinc gallogermanate nanostructures with super-long near-infrared persistent luminescence (ZGGO) are used as optical emission center, mesoporous silica coated on the PLNPs (ZGGO@mSiO2) is employed for drug delivery, and the RBC membrane vesicle is introduced for biomimetic functionalization to ensure the developed nanocarriers bypass macrophage uptake and systemic clearance. Owing to the coating of natural erythrocyte membrane along with membrane lipids and associated membrane proteins, the proposed bioinspired nanocarriers have exhibited cell-mimicking property. Retaining the applicability of PLNPs core that favored in vitro excitation, the developed RBC-ZGGO@mSiO2 biomimetic nanocarriers have demonstrated intense fluorescence, super-long persistent luminescence, monodispersed nanosize, red light renewability, and excellent biocompatibility. In vivo mice bioimaging and biodistribution study demonstrate the erythrocyte membrane bioinspired nanoprobe loaded with doxorubicin as ideal nanocarriers for long-circulating bioimaging, in situ real-time monitoring and drug delivery. We believe the PLNPs-based biomimetic nanocarriers offer a promising nano-platform for diagnostics and therapeutics application.
High-performance and low-cost bifunctional electrocatalysts play crucial roles in oxygen reduction and evolution reactions. Herein, a novel three-dimensional (3D) bifunctional electrocatalyst was ...prepared by embedding CoO nanoparticles into nitrogen and sulfur co-doped carbon nanofiber networks (denoted as CoO@N/S-CNF) through a facile approach. The carbon nanofiber networks were derived from a nanostructured biological material which provided abundant functional groups to nucleate and anchor nanoparticles while retaining its interconnected 3D porous structure. The composite possesses a high specific surface area and graphitization degree, which favors both mass transport and charge transfer for electrochemical reaction. The CoO@N/S-CNF not only exhibits highly efficient catalytic activity towards oxygen reduction reaction (ORR) in alkaline media with an onset potential of about 0.84 V, but also shows better stability and stronger resistance to methanol than Pt/C. Furthermore, it only needs an overpotential of 1.55 V to achieve a current density of 10 mA cm−2, suggesting that it is an efficient electrocatalyst for oxygen evolution reaction (OER). The ΔE value (oxygen electrode activity parameter) of CoO@N/S-CNF is calculated to be 0.828 V, which demonstrates that the composite could be a promising bifunctional electrocatalyst for both ORR and OER.
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The high speed of contaminants growth needs the burgeoning of new analytical techniques to keep up with the continuous demand for monitoring and legislation on food safety and environmental pollution ...control. Metal-organic frameworks (MOFs) are a kind of advanced crystal porous materials with controllable apertures, which are self-assembled by organic ligands and inorganic metal nodes. They have the merits of large specific surface areas, high porosity and the diversity of structures and functions. Latterly, the utilization of metal-organic frameworks has attracted much attention in environmental protection and the food industry. MOFs have exhibited great value as sensing materials for many targets. Among many sensing methods, fluorometric sensing is one of the widely studied methods in the detection of harmful substances in food and environmental samples. Fluorometric detection based on MOFs and its functional materials is currently one of the most key research subjects in the food and environmental fields. It has gradually become a hot research direction to construct the highly sensitive rapid sensors to detect harmful substances in the food matrix based on metal-organic frameworks. In this paper, we introduced the synthesis and detection application characteristics (absorption, fluorescence, etc.) of metal-organic frameworks. We summarized their applications in the MOFs-based fluorometric detection of harmful substances in food and water over the past few years. The harmful substances mainly include heavy metals, organic pollutants and other small molecules, etc. On this basis, the future development and possible application of the MOFs have prospected in this review paper.
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