Sleep deprivation (SD) is increasingly common in modern society, which can lead to the dysregulation of inflammatory responses and cognitive impairment, but the mechanisms remain unclear. Emerging ...evidence suggests that gut microbiota plays a critical role in the pathogenesis and development of inflammatory and psychiatric diseases, possibly via gut microbiota-brain interactions and neuroinflammation. The present study investigated the impact of SD on gut microbiota composition and explored whether alterations of the gut microbiota play a causal role in chronic inflammatory states and cognitive impairment that are induced by SD. We found that SD-induced gut dysbiosis, inflammatory responses, and cognitive impairment in humans. Moreover, the absence of the gut microbiota suppressed inflammatory response and cognitive impairment induced by SD in germ-free (GF) mice. Transplantation of the "SD microbiota" into GF mice activated the Toll-like receptor 4/nuclear factor-κB signaling pathway and impaired cognitive function in the recipient mice. Mice that harbored "SD microbiota" also exhibited increases in neuroinflammation and microglial activity in the hippocampus and medial prefrontal cortex. These findings indicate that gut dysbiosis contributes to both peripheral and central inflammatory processes and cognitive deficits that are induced by SD, which may open avenues for potential interventions that can relieve the detrimental consequences of sleep loss.
Iron (Fe) is an essential micronutrient, and deficiency in available Fe is one of the most important limiting factors for plant growth. In some species including Medicago truncatula, Fe deficiency ...results in accumulation of riboflavin, a response associated with Fe acquisition. However, how the plant's Fe status is integrated to tune riboflavin biosynthesis and how riboflavin levels affect Fe acquisition and utilization remains largely unexplored. We report that protein kinase CIPK12 regulates ferric reduction by accumulation of riboflavin and its derivatives in roots of M. truncatula via physiological and molecular characterization of its mutants and over‐expressing materials. Mutations in CIPK12 enhance Fe accumulation and improve photosynthetic efficiency, whereas overexpression of CIPK12 shows the opposite phenotypes. The Calcineurin B‐like proteins CBL3 and CBL8 interact with CIPK12, which negatively regulates the expression of genes encoding key enzymes in the riboflavin biosynthesis pathway. CIPK12 negatively regulates Fe acquisition by suppressing accumulation of riboflavin and its derivatives in roots, which in turn influences ferric reduction activity by riboflavin‐dependent electron transport under Fe deficiency. Our findings uncover a new regulatory mechanism by which CIPK12 regulates riboflavin biosynthesis and Fe‐deficiency responses in plants.
Summary statement
In this study, we demonstrate that protein kinase CIPK12 negatively regulates iron acquisition by suppressing accumulation of riboflavin in roots, which influences ferric reduction activity under iron deficiency.
In the past decades, significant advances have been made on radical Smiles rearrangement. However, the eventually formed radical intermediates in these reactions are limited to the amidyl radical, ...except for the few examples initiated by a N-centered radical. Here, a novel and practical radical Smiles rearrangement triggered by photoredox-catalyzed regioselective ketyl–ynamide coupling is reported, which represents the first radical Smiles rearrangement of ynamides. This method enables facile access to a variety of valuable 2-benzhydrylindoles with broad substrate scope in generally good yields under mild reaction conditions. In addition, this chemistry can also be extended to the divergent synthesis of versatile 3-benzhydrylisoquinolines through a similar ketyl–ynamide coupling and radical Smiles rearrangement, followed by dehydrogenative oxidation. Moreover, such an ynamide Smiles rearrangement initiated by intermolecular photoredox catalysis via addition of external radical sources is also achieved. By control experiments, the reaction was shown to proceed via key ketyl radical and α-imino carbon radical intermediates.
Background and Aims
Hepatic ischemia‐reperfusion (I/R) injury, which mainly involves inflammatory responses and apoptosis, is a common cause of organ dysfunction in liver transplantation (LT). As a ...critical mediator of inflammation and apoptosis in various cell types, the role of tripartite motif‐containing (TRIM) 27 in hepatic I/R injury remains worthy of study.
Approach and Results
This study systemically evaluated the putative role of TRIM27/transforming growth factor β–activated kinase 1 (TAK1)/JNK (c‐Jun N‐terminal kinase)/p38 signaling in hepatic I/R injury. TRIM27 expression was significantly down‐regulated in liver tissue from LT patients, mice subjected to hepatic I/R surgery, and hepatocytes challenged by hypoxia/reoxygenation (H/R) treatment. Subsequently, using global Trim27 knockout mice (Trim27‐KO mice) and hepatocyte‐specific Trim27 transgenic mice (Trim27‐HTG mice), TRIM27 functions to ameliorate liver damage, reduce the inflammatory response, and prevent cell apoptosis. In parallel in vitro studies, activating TRIM27 also prevented H/R‐induced hepatocyte inflammation and apoptosis. Mechanistically, TRIM27 constitutively interacted with the critical components, TAK1 and TAK1 binding protein 2/3 (TAB2/3), and promoted the degradation of TAB2/3, leading to inactivation of TAK1 and the subsequent suppression of downstream JNK/p38 signaling.
Conclusions
TRIM27 is a key regulator of hepatic I/R injury by mediating the degradation of TAB2/3 and suppression of downstream TAK1‐JNK/p38 signaling. TRIM27 may be a promising approach to protect the liver against I/R‐mediated hepatocellular damage in transplant recipients.
Abstract
It is well known that most gamma-ray bursts (GRBs) are dominated by positive spectral lags, while a small fraction of GRBs show negative lags. However, Wei et al. first identified a ...well-defined transition from positive lags to negative lags in GRB 160625B, and then got robust limits on a possible violation of Lorentz invariance (LIV) based on the observation. Recently, such a transition has been found in three different emission episodes in GRB 190530A by Gunapati et al., which provides us a great opportunity to investigate whether the transition results from LIV-induced observed spectral lags. Our analysis shows that the LIV model cannot be compatible with the current observations, whereas, only the spectral evolution induced spectral lags could responsible for the transition. So, spectral evolution can also explain the positive to negative lag in GRB 190530A.
Hepatocellular carcinoma (HCC) is the most predominant primary malignancy in the liver. Genotoxic and genetic models have revealed that HCC cells are derived from hepatocytes, but where the critical ...region for tumor foci emergence is and how this transformation occurs are still unclear. Here, hyperpolyploidization of hepatocytes around the centrilobular (CL) region is demonstrated to be closely linked with the development of HCC cells after diethylnitrosamine treatment. We identify the CL region as a dominant lobule for accumulation of hyperpolyploid hepatocytes and preneoplastic tumor foci formation. We also demonstrate that upregulation of Aurkb plays a critical role in promoting hyperpolyploidization. Increase of AURKB phosphorylation is detected on the midbody during cytokinesis, causing abscission failure and hyperpolyploidization. Pharmacological inhibition of AURKB dramatically reduces nucleus size and tumor foci number surrounding the CL region in diethylnitrosamine-treated liver. Our work reveals an intimate molecular link between pathological hyperpolyploidy of CL hepatocytes and transformation into HCC cells.
Nutrient limitation and metal toxicity have been implicated in changes of grassland communities by nitrogen (N) deposition. Below‐ground processes, especially those at the soil–root interface, play ...important roles in determining variation in nutrient concentrations in plants. However, few studies have specifically focused on the roles of these processes in mineral‐element acquisition in grassland plants in response to N enrichment.
Here we investigated the contributions of below‐ground processes at the soil–root interface to the differential acquisition of phosphorus (P), calcium (Ca) and manganese (Mn) by forbs and grasses of a temperate steppe in response to N addition by combining field and glasshouse experiments.
Nitrogen addition increased the concentrations of both leaf P (P) and Mn (Mn) and decreased leaf Ca of forbs while it had little effects on leaf concentrations of these elements in grasses. Nitrogen addition led to a higher activity of acid phosphatase in the rhizosphere of forbs, and greater release of protons and carboxylates from forb roots than grass roots, contributing to the differential P, Ca and Mn in the leaves of forbs and grasses. Applying oxalate to soil to simulate the release of carboxylates by N enrichment enhanced P and Mn, and decreased Ca in the soil solution. However, addition of hydrogen‐ion increased P, Mn and Ca in the soil solution. Lime addition mitigated the N‐addition‐induced soil acidification while it did not abolish the stimulatory effect of short‐term N addition on leaf P and Mn of forbs. Therefore, we conclude that differences in the eco‐physiological processes at the soil–root interface account for changes in leaf P, Ca and Mn under short‐term N addition, and that soil acidification aggravates the responses of these elements, especially Ca and Mn, to long‐term N enrichment.
Synthesis. Our results highlight the contribution of below‐ground processes, especially those at the soil–root interface, to variation in plant element concentrations between dominant forbs and grasses in the temperate steppe. These findings greatly enhance our mechanistic understanding of the effects of N deposition on grassland communities.
We demonstrate that belowground processes at the soil‐root interface play important roles in determining differential acquisition of phosphorus, calcium and manganese by forb and grass species of a temperate steppe in response to N addition. These findings provide a new perspective for our mechanistic understanding of the effects of N deposition on grassland communities.
Control of plant viruses by cross‐protection is limited by the availability of effective protective strains. Incorporation of an NIa‐protease processing site in the extreme N‐terminal region of the ...helper component protease (HC‐Pro) of turnip mosaic virus (TuMV) resulted in a mutant virus TuHNDI that induced highly attenuated symptoms. Recombination analysis verified that two variations, F7I mutation and amino acid 7‐upstream‐deletion, in HC‐Pro co‐determined TuHNDI attenuation. TuHNDI provided complete protection to Nicotiana benthamiana and Brassica campestris subsp. chinensis plants against infection by the severe parental strain. Aphid transmission tests revealed that TuHNDI was not aphid‐transmissible. An RNA silencing suppression (RSS) assay by agroinfiltration suggested the RSS‐defective nature of the mutant HC‐Pro. In the context (amino acids 3–17) encompassing the two variations of HC‐Pro, we uncovered an FWKG−α‐helix 1 (αH1) element that influenced the functions of aphid transmission and RSS, whose motifs were located far downstream. We further demonstrated that HC‐Pro F7 was a critical residue on αH1 for HC‐Pro functions and that reinstating αH1 in the RSS‐defective HC‐Pro of TuHNDI restored the protein's RSS function. Yeast two‐hybrid and bimolecular fluorescence complementation assays indicated the FWKG−αH1 element as an integral part of the HC‐Pro self‐interaction domain. The possibility of regulation of the mechanistically independent functions of RSS and aphid transmission by the FWKG−αH1 element is discussed. Extension of TuMV HC‐Pro FWKG−αH1 variations to another potyvirus, zucchini yellow mosaic virus, also generated nonaphid‐transmissible cross‐protective mutant viruses. Hence, the modification of the FWKG−αH1 element can generate effective attenuated viruses for the control of potyviruses by cross‐protection.
The HC‐Pro extreme N‐terminal region FWKG−αH1 element, an integral part of the HC‐Pro self‐interaction domain, influences multiple functions of HC‐Pro: symptom expression, RNA silencing suppression, and aphid transmission.
Maintaining proper mitochondrial respiratory function is crucial for alleviating cardiac metabolic disorders during obesity, and mitophagy is critically involved in this process. Long non-coding RNA ...H19 (H19) is crucial for metabolic regulation, but its roles in cardiac disorders, mitochondrial respiratory function, and mitophagy during obesity are largely unknown. In this study, palmitic acid (PA)-treated H9c2 cell and Lep
mice were used to investigate cardiac metabolic disorders in vitro and in vivo, respectively. The effects of H19 on metabolic disorders, mitochondrial respiratory function, and mitophagy were investigated. Moreover, the regulatory mechanisms of PA, H19, mitophagy, and respiratory function were examined. The models tested displayed a reduction in H19 expression, respiratory function and mitochondrial number and volume, while the expression of mitophagy- and Pink1/Parkin signaling-related proteins was upregulated, as indicated using quantitative real-time PCR, Seahorse mitochondrial stress test analyzer, transmission electron microscopy, fluorescence indicators and western blotting. Forced expression of H19 helped to the recoveries of respiratory capacity and mitochondrial number while inhibited the levels of mitophagy- and Pink1/Parkin signaling-related proteins. Pink1 knockdown also attenuated PA-induced mitophagy and increased respiratory capacity. Mechanistically, RNA pull-down, mass spectrometry, and RNA-binding protein immunoprecipitation assays showed that H19 could hinder the binding of eukaryotic translation initiation factor 4A, isoform 2 (eIF4A2) with Pink1 mRNA, thus inhibiting the translation of Pink1 and attenuation of mitophagy. PA significantly increased the methylation levels of the H19 promoter region by upregulation Dnmt3b methylase levels, thereby inhibiting H19 transcription. Collectively, these findings suggest that DNA methylation-mediated the downregulation of H19 expression plays a crucial role in cardiomyocyte or H9c2 cells metabolic disorders and induces cardiac respiratory dysfunction by promoting mitophagy. H19 inhibits excessive mitophagy by limiting Pink1 mRNA translation, thus alleviating this cardiac defect that occurs during obesity.
A highly chemoselective reduction of phosphine oxides was demonstrated under transition‐metal‐free and alkaline reaction conditions. During the reaction, P=O bond was firstly electrophilically ...activated by an anhydride and subsequently reduced by the versatile and cheap NaH, which was strengthened by 15‐crown‐5. By this strategy, a variety of phosphine oxides including those bearing functional groups such as methyl, methoxyl, phenyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, nitrile, ester, alkenyl, alkynyl and heterocycles were transformed readily into the corresponding phosphines in good to high yields. This work represents an efficient method for reducing phosphine oxides forming phosphines.
A chemoselective reduction of phosphine oxides under transition‐metal‐free and alkaline conditions with the use of TFAA/NaH was developed. This reaction provides an efficient method for converting phosphine oxides into phosphines. It is deduced that P=O bond was firstly electrophilically activated by TFAA forming a phosphonium salt R3P(OOCCF3)2, and subsequently reduced by NaH, which was strengthened by 15‐crown‐5.
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