The immune response to RNA suppresses nucleic acid synthesis by limiting ribose 5-phosphate.

During infection viruses hijack host cell metabolism to promote their replication. Here, analysis of metabolite alterations in macrophages exposed to poly I:C recognises that the antiviral effector Protein Kinase RNA-activated (PKR) suppresses glucose breakdown within the pentose phosphate pathway (PPP). This pathway runs parallel to central glycolysis and is critical to producing NADPH and pentose precursors for nucleotides. Changes in metabolite levels between wild-type and PKR-ablated macrophages show that PKR controls the generation of ribose 5-phosphate, in a manner distinct from its established function in gene expression but dependent on its kinase activity. PKR phosphorylates and inhibits the Ribose 5-Phosphate Isomerase A (RPIA), thereby preventing interconversion of ribulose- to ribose 5-phosphate. This activity preserves redox control but decreases production of ribose 5-phosphate for nucleotide biosynthesis. Accordingly, the PKR-mediated immune response to RNA suppresses nucleic acid production. In line, pharmacological targeting of the PPP during infection decreases the replication of the Herpes simplex virus. These results identify an immune response-mediated control of host cell metabolism and suggest targeting the RPIA as a potential innovative antiviral treatment.

Fibroblast growth factor 21 alleviates diabetes-induced cognitive decline.

Diabetes mellitus (DM) causes damage to the central nervous system, resulting in cognitive impairment. Fibroblast growth factor 21 (FGF21) exhibits the potential to alleviate neurodegeneration. However, the therapeutic effect of intracerebroventricular (i.c.v) FGF21 infusion on diabetes-induced cognitive decline (DICD) and its potential mechanisms remain unclear. In this study, the impact of FGF21 on DICD was explored, and 1H nuclear magnetic resonance (NMR)-based metabolomics plus 13C NMR spectroscopy in combine with intravenous [1-13C]-glucose infusion were used to investigate the underlying metabolic mechanism. Results revealed that i.c.v FGF21 infusion effectively improved learning and memory performance of DICD mice; neuron loss and apoptosis in hippocampus and cortex were significantly blocked, suggesting a potential neuroprotective role of FGF21 in DICD. Metabolomics results revealed that FGF21 modulated DICD metabolic alterations related to glucose and neurotransmitter metabolism, which are characterized by distinct recovered enrichment of [3-13C]-lactate, [3-13C]-aspartate, [4-13C]-glutamine, [3-13C]-glutamine, [4-13C]-glutamate, and [4-13C]- γ-aminobutyric acid (GABA) from [1-13C]-glucose. Moreover, diabetes-induced neuron injury and metabolic dysfunctions might be mediated by PI3K/AKT/GSK-3ß signaling pathway inactivation in the hippocampus and cortex, which were activated by i.c.v injection of FGF21. These findings indicate that i.c.v FGF21 infusion exerts its neuroprotective effect on DICD by remodeling cerebral glucose and neurotransmitter metabolism by activating the PI3K/AKT/GSK-3ß signaling pathway.

Optimization of Clustering and Trajectory for Minimizing Age of Information in Unmanned Aerial Vehicle-Assisted Mobile Edge Computing Network.

With the development of the Internet of Things (IoT) technology, massive amounts of sensor data in applications such as fire monitoring need to be transmitted to edge servers for timely processing. However, there is an energy-hole phenomenon in transmitting data only through terrestrial multi-hop networks. In this study, we focus on the data collection task in an unmanned aerial vehicle (UAV)-assisted mobile edge computing (MEC) network, where a UAV is deployed as the mobile data collector for the ground sensor nodes (SNs) to ensure high information freshness. Meanwhile, the UAV is equipped with an edge server for data caching. We first establish a rigorous mathematical model in which the age of information (AoI) is used as a measure of information freshness, related to both the data collection time and the UAV's flight time. Then a mixed-integer non-convex optimization problem is formulated to minimize the peak AoI of the collected data. To solve the problem efficiently, we propose an iterative two-step algorithm named the AoI-minimized association and trajectory planning (AoI-MATP) algorithm. In each iteration, the optimal SN-collection point (CP) associations and CP locations for the parameter ε are first obtained by the affinity propagation clustering algorithm. The optimal UAV trajectory is found using an improved elite genetic algorithm. Simulation results show that based on the optimized ε, the AoI-MATP algorithm can achieve a balance between data collection time and flight time, reducing the peak AoI of the collected data.

Large-scale and stacked transfer of bilayers MoS2devices on a flexible polyimide substrate.

Two-dimensional transition metal dichalcogenides (TMDs), as flexible and stretchable materials, have attracted considerable attention in the field of novel flexible electronics due to their excellent mechanical, optical, and electronic properties. Among the various TMD materials, atomically thin MoS2has become the most widely used material due to its advantageous properties, such as its adjustable bandgap, excellent performance, and ease of preparation. In this work, we demonstrated the practicality of a stacked wafer-scale two-layer MoS2film obtained by transferring multiple single-layer films grown using chemical vapor deposition. The MoS2field-effect transistor cell had a top-gated device structure with a (PI) film as the substrate, which exhibited a high on/off ratio (108), large average mobility (∼8.56 cm2V-1s-1), and exceptional uniformity. Furthermore, a range of flexible integrated logic devices, including inverters, NOR gates, and NAND gates, were successfully implemented via traditional lithography. These results highlight the immense potential of TMD materials, particularly MoS2, in enabling advanced flexible electronic and optoelectronic devices, which pave the way for transformative applications in future-generation electronics.

Bidirectional longitudinal relationships between parents' marital satisfaction, parenting stress, and self-compassion in China.

Abundant research has shown that self-compassion robustly contributes to adults' psychological well-being. Meanwhile, a few studies have shown that self-compassion is rooted in early experiences with parents. However, it is unclear whether interactions with partners and children affect adults' self-compassion, and the role of their self-compassion in interactions with significant others. This study examined bidirectional longitudinal relationships between Chinese parents' marital satisfaction, parenting stress, and self-compassion following a three-wave longitudinal design. A sample of 322 Chinese father-mother dyads (father's Mage  = 35.84, SDage  = 5.76; mother's Mage  = 34.32, SDage  = 5.46) completed a set of questionnaires at three time points. The results showed that marital satisfaction positively predicted the fathers' and mothers' self-compassion, while parenting stress did not significantly predict the parents' self-compassion; In contrast, parents' self-compassion did not significantly predict marital satisfaction or parenting stress. Additionally, there was a bidirectional relationship between marital satisfaction and parenting stress in fathers and mothers. Finally, mothers' marital satisfaction positively mediated the relationship between parenting stress and self-compassion/next-stage parenting stress. This study revealed that adults' self-compassion can develop from caring and supportive relationships, including marital relationships. Highlighting key mechanisms of marital satisfaction, such as increasing self-compassion and reducing parenting stress, may contribute to the improvement of adults' mental health.

Longitudinal relationship between child maltreatment, bullying victimization, depression, and nonsuicidal self-injury among left-behind children in China: 2-year follow-up.

BACKGROUND: Left-behind childre (LBC) in China are deeply concerned by society because of their high risk of emotional and behavioral problems. Depression and nonsuicidal self-injury are the most harmful and worrying negative emotional and behavioral problems in LBC. Unfortunately, LBCs are in unfavorable environments for a long time and are prone to negative interpersonal interactions. Child maltreatment and bullying victimization, as the two most typical negative interpersonal interactions in family and school environments, maybe the key risk factors for depression and nonsuicidal self-injury among LBCs. However, we are less known of the longitudinal effects of child maltreatment and bullying victimization on LBC's depression and nonsuicidal self-injury and their underlying mechanisms. AIMS: This study used a two-year longitudinal design with three-time points to investigate the longitudinal effects of child maltreatment and bullying victimization on depression, nonsuicidal self-injury, and the mediating role of negative thoughts and self-compassion. MATERIALS & METHODS: A sample of 592 LBC (390 were males, Mage at time 1 = 9.56, SDage = 0.65; 202 were females, Mage at time 1 = 9.43, SDage = 0.63) completed a set of questionnaires at three-time points. This study used SPSS software (version 25.0) and MPLUS software (version 8.3) for all analyses. RESULTS: (1) Child maltreatment not only affects depression and nonsuicidal self-injury but also affects depression and nonsuicidal self-injury through negative thoughts. Child maltreatment affects depression through self-compassion and does not affect nonsuicidal self-injury. (2) Bullying victimization affects depression and nonsuicidal self-injury through negative thoughts and bullying victimization further affects depression through self-compassion but does not affect nonsuicidal self-injury. CONCLUSION: This study revealed the effects of negative interpersonal interactions (child maltreatment, bullying victimization) on LBC's adverse emotions and behaviors, and their underlying mechanisms, which helps to provide parents, schools, and psychoeducational workers with a new perspective on intervention.

[Metabolomic changes of neonatal sepsis: an exploratory clinical study]. / æ–°ç”Ÿå„¿è´¥è¡€ç—‡çš„ä»£è°¢ç»„å­¦æ”¹å˜ï¼šä¸€é¡¹æŽ¢ç´¢æ€§ä¸´åºŠç ”ç©¶.

OBJECTIVES: To study the metabolic mechanism of neonatal sepsis at different stages by analyzing the metabolic pathways involving the serum metabolites with significant differences in neonates with sepsis at different time points after admission. METHODS: A total of 20 neonates with sepsis who were hospitalized in the Department of Neonatology, Hunan Provincial People's Hospital, from January 1, 2019 to January 1, 2020 were enrolled as the sepsis group. Venous blood samples were collected on days 1, 4, and 7 after admission. Ten healthy neonates who underwent physical examination during the same period were enrolled as the control group. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used for the metabonomic analysis of serum samples to investigate the change in metabolomics in neonates with sepsis at different time points. RESULTS: On day 1 after admission, the differentially expressed serum metabolites between the sepsis and control groups were mainly involved in the biosynthesis of terpenoid skeleton. For the sepsis group, the differentially expressed serum metabolites between days 1 and 4 after admission were mainly involved in pyruvate metabolism, and those between days 4 and 7 after admission were mainly involved in the metabolism of cysteine and methionine. The differentially expressed serum metabolites between days 1 and 7 after admission were mainly involved in ascorbic acid metabolism. CONCLUSIONS: The metabolic mechanism of serum metabolites varies at different stages in neonates with sepsis and is mainly associated with terpenoid skeleton biosynthesis, pyruvate metabolism, cysteine/methionine metabolism, and ascorbic acid metabolism.

Regulation of actin dynamics by protein kinase R control of gelsolin enforces basal innate immune defense.

Primary resistance to pathogens is reliant on both basal and inducible immune defenses. To date, research has focused upon inducible innate immune responses. In contrast to resistance via cytokine induction, basal defense mechanisms are less evident. Here we showed that the antiviral protein kinase R (PKR) inhibited the key actin-modifying protein gelsolin to regulate actin dynamics and control cytoskeletal cellular functions under homeostatic conditions. Through this mechanism, PKR controlled fundamental innate immune, actin-dependent processes that included membrane ruffling and particle engulfment. Accordingly, PKR counteracted viral entry into the cell. These findings identify a layer of host resistance, showing that the regulation of actin-modifying proteins during the innate immune response bolsters first-line defense against intracellular pathogens and has a sustained effect on virus production. Moreover, these data provide proof of principle for a concept in which the cell cytoskeleton could be targeted to elicit broad antiviral protection.

Diminished stimulator of interferon genes production with cigarette smoke-exposure contributes to weakened anti-adenovirus vectors response and destruction of lung in chronic obstructive pulmonary disease model.

Cigarette smoke (CS) is the primary risk factor for chronic obstructive pulmonary disease (COPD) and dampens antiviral response, which increases viral infections and leads to COPD acute exacerbation (AECOPD). Adenovirus, a nonenveloped DNA virus, is linked with AECOPD, whose DNAs trigger innate immune response via interacting with pattern recognition receptors (PRRs). Stimulator of interferon genes (STING), as a cytosolic DNA sensor, participates in adenovirus-induced interferon ß (IFNß)-dependent antiviral response. STING is involved in various pulmonary diseases, but role of STING in pathogenesis of AECOPD is not well documented. In the present study, we explored relationship between STING and AECOPD induced by recombinant adenovirus vectors (rAdVs) and CS in wild type (WT) and STING-/- mice; and also characterized the inhibition of STING- IFNß pathway in pulmonary epithelium exposed to cigarette smoke extract (CSE). We found that CS or CSE exposure alone dramatically inhibited STING expression, but not significantly effected IFNß production. Moreover, CS or CSE-exposed significantly suppressed activation of STING-IFNß pathway induced by rAdVs and suppressed clearance of rAdVs DNA. Inflammation, fibrosis and emphysema of lung tissues were exaggerated when treated with CS plus rAdVs, which further deteriorate in absences of STING. In A549 cells with knockdown of STING, we also observed enhancing apoptosis related to emphysema, especially CSE and adenovirus vectors in combination. Therefore, STING may play a protective role in preventing the progress of COPD.

A Cataluminescence Sensor Based on NiO Nanoparticles for Sensitive Detection of Acetaldehyde.

Sensitive and selective detection of harmful gas is an important task in environmental monitoring. In this work, a gas sensor based on cataluminescence (CTL) for detection of acetaldehyde was designed by using nano-NiO as the sensing material. The sensor shows sensitive response to acetaldehyde at a relatively low working temperature of 200 °C. The linear range of CTL intensity versus acetaldehyde concentration is 0.02-2.5 mg/L, with a limit of detection of 0.006 mg/L at a signal-to-noise ratio of three. Mechanism study shows that electronically excited CO2 is the excited intermediate for CTL emission during the catalytic oxidation of acetaldehyde on the NiO surface. The proposed sensor has promising application in monitoring acetaldehyde in residential buildings and in the workplace.

A non-canonical function of Ezh2 preserves immune homeostasis.

Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone-H3 (H3K27me3) as part of the polycomb repressive complex 2 (PRC2) together with Suz12 and Eed. However, Ezh2 can also modify non-histone substrates, although it is unclear whether this mechanism has a role during development. Here, we present evidence for a chromatin-independent role of Ezh2 during T-cell development and immune homeostasis. T-cell-specific depletion of Ezh2 induces a pronounced expansion of natural killer T (NKT) cells, although Ezh2-deficient T cells maintain normal levels of H3K27me3. In contrast, removal of Suz12 or Eed destabilizes canonical PRC2 function and ablates NKT cell development completely. We further show that Ezh2 directly methylates the NKT cell lineage defining transcription factor PLZF, leading to its ubiquitination and subsequent degradation. Sustained PLZF expression in Ezh2-deficient mice is associated with the expansion of a subset of NKT cells that cause immune perturbation. Taken together, we have identified a chromatin-independent function of Ezh2 that impacts on the development of the immune system.

Genetic structure and variability of tobacco vein banding mosaic virus populations.

Tobacco vein banding mosaic virus (TVBMV) is of increasing importance in tobacco production. Knowledge of the genetic structure and variability of the virus population is vital for developing sustainable management. In this study, 24 new TVBMV isolates from Sichuan Province together with 46 previous isolates were studied based on their coat protein sequences. Two distinguishable clades were supported by phylogenetic analysis. The summary statistics PS, AI and MC showed a strong TVBMV-geography association between the isolates from Southwest China (SW) and Mainland China (MC). Further analysis indicated that the spatial genetic structure of TVBMV populations is likely to have been caused by natural selection. Phylogeographic analysis provided strong support for spatial diffusion pathways between the Southwest and Northwest tobacco-producing regions. The TVBMV CP gene was found to be under negative selection, and no significant positive selection of amino acids was detected in the SW group; however, the isolates of the MC group experienced significant positive selection pressure at the first and third amino acid sites of CP. This study suggests that natural selection and habitat heterogeneity are important evolutionary mechanisms affecting the genetic structure of the TVBMV population.

Specific Genes Identified in Pathotype 4 of the Clubroot Pathogen Plasmodiophora brassicae.

Clubroot is an important disease of cruciferous crops caused by Plasmodiophora brassicae, and pathotypes are classified based on the response of differential hosts. This study was conducted to identify genetic markers able to differentiate pathotypes. Differential expression of genes between pathotype 4 (P4) and pathotype 7 (P7) was assessed according to transcriptome data of molecular marker screening. Among the pathotypes (P2, P4, P5, P7, P9, P10, and P11) tested, six genes were exclusive to P4, dividing the isolates into three types: PBRA_003263 and PBRA_003268 were present in all P4 isolates, PBRA_000003/Novel512 were found in a type of P4 (P4-1), and Novel137/PBRA_005772 were found in another P4 type, P4-2. Amplicons for all six genes were produced for only one isolate, which we named P4-3. This study is the first to establish a molecular identification system for P4 the, predominant pathotype in China. The genes identified might serve as molecular markers for differentiation of P4 from other pathotypes and may also distinguish different types of P4.

BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs.

Inflammation is critical for host defense, but without appropriate control, it can cause chronic disease or even provoke fatal responses. Here we identify a mechanism that limits the inflammatory response. Probing the responses of macrophages to the key sensory Toll-like receptors, we identify that the Broad-complex, Tramtrack and Bric-a-brac/poxvirus and zinc finger (BTB/POZ), transcriptional regulator promyelocytic leukemia zinc finger (PLZF) limits the expression of inflammatory gene products. In accord with this finding, PLZF-deficient animals express higher levels of potent inflammatory cytokines and mount exaggerated inflammatory responses to infectious stimuli. Temporal quantitation of inflammatory gene transcripts shows increased gene induction in the absence of PLZF. Genome-wide analysis of histone modifications distinguish that PLZF establishes basal activity states of early response genes to maintain immune homeostasis and limit damaging inflammation. We show that PLZF stabilizes a corepressor complex that encompasses histone deacetylase activity to control chromatin. Together with our previous demonstration that PLZF promotes the antiviral response, these results suggest a strategy that could realize one of the major goals of immune therapy to retain immune resistance to pathogens while curbing damaging inflammation.

Robust Iterative Distributed Minimum Total MSE Algorithm for Secure Communications in the Internet of Things Using Relays.

In this article, we first investigate secure communications for a two-hop interference channel relay system with imperfect channel estimation in the wireless Internet of Things (IoT), where K source-destination pairs communicate simultaneously when an eavesdropper exists. We jointly conceive source, relay and destination matrices upon minimizing total mean-squared error (MSE) of all legitimate destinations while keeping the MSE at eavesdropper above a given threshold. We illuminate that the design of the source, relay and destination matrices is subject to both transmit power constraints and secrecy requirements. More specifically, we propose an efficient robust iterative distributed algorithm to simplify the process of the joint design for optimal source, relay and destination matrices. Furthermore, the convergence of the iterative distributed algorithm is described. Additionally, the performances of our proposed algorithm, such as its secrecy rate and MSE, are characterized in the form of simulation results. The simulation results reveal that the proposed algorithm is superior to the traditional approach. As a benefit, secure communications can be ensured by using the proposed algorithm for the multiple input multiple output (MIMO) interference relay IoT network in the presence of an eavesdropper.

The Smad3/Smad4/CDK9 complex promotes renal fibrosis in mice with unilateral ureteral obstruction.

Transforming growth factor-ß1 (TGF-ß1)/Smad signaling has a central role in the pathogenesis of renal fibrosis. Smad3 and Smad4 are pro-fibrotic, while Smad2 is anti-fibrotic. However, these Smads form heterogeneous complexes, the functions of which are poorly understood. Here we studied Smad complex function in renal fibrosis using the mouse model of unilateral ureteric obstruction. Mice heterozygous for Smad3/4 (Smad3/4+/-) exhibited substantial protection from renal fibrosis through day 7 of obstruction, whereas Smad2/3+/- and Smad2/4+/- mice showed only modest protection. Formation of Smad3/Smad4/CDK9 complexes was an early event following obstruction in wild-type mice, which involved nuclear phosphorylation of the linker regions of Smad3. Significantly, Smad3 or Smad4 deficiency decreased the formation of Smad4/CDK9 or Smad3/CDK9 complex, Smad3 linker phosphorylation, and fibrosis but at different degrees. In vitro, TGF-ß1 stimulation of collagen I promoter activity involved formation of Smad3/Smad4/CDK9 complexes, and overexpression of each component gave additive increases in collagen promoter activity. Co-administration of a CDK9 inhibitor and Smad3-specific inhibition achieved better protection from TGF-ß1-induced fibrotic response in vitro and renal interstitial fibrosis in vivo. Thus formation of Smad3/Smad4/CDK9 complex drives renal fibrosis during ureteral obstruction. Formation of this complex represents a novel target for antifibrotic therapies.

Comparative proteomic analysis using 2DE-LC-MS/MS reveals the mechanism of Fuzhuan brick tea extract against hepatic fat accumulation in rats with nonalcoholic fatty liver disease.

Fuzhuan brick tea has received increasing attention in recent years owing to its benefits for nonalcoholic fatty liver disease (NAFLD) and associated metabolic syndrome. For exploring the ameliorative mechanism, the liver proteomes from three groups of rats fed either a normal control diet (NCD), a high fat diet (HFD), or a HFD supplemented with high-dose Fuzhuan brick tea extract (FTE) (HFD + HFTE) were comprehensively compared by quantitative proteomics using 2DE-LC-MS/MS. This is the first study of the effects of tea aqueous extract on the liver proteome of rats suffering from metabolic syndrome. The results showed that 57 proteins displayed more than 1.5-fold differences in at least one of two comparisons of HFD versus NCD and HFD versus HFD + HFTE due to HFD feeding and FTE treatment, respectively. Of them, over 75% of proteins exhibited a similar tendency of expression in the two comparisons, meaning FTE was able to correct HFD effects on rat livers. By function analyses, an extensive list of proteins was involved in sugar and lipid metabolism. Compared with HFD-fed rats, the reduced lipogenesis and enhanced ß-oxidation, tricarboxylic acid cycle and respiratory chain in HFD + HFTE-fed rats, which mainly contributed to ameliorate hepatic fat accumulation and associated NAFLD. Additionally, some putative drug targets were also revealed such as COX2, PGAM1, ACACB, FAS, and ECHS1.

Interaction of smoothened with integrin-linked kinase in primary cilia mediates Hedgehog signalling.

Here we report that ILK localizes in the mouse primary cilium, a sensory organelle required for signalling by the Hedgehog (Hh) pathway. Genetic or pharmacological inhibition of ILK blocks ciliary accumulation of the Hh pathway effector smoothened (Smo) and suppresses the induction of Gli transcription factor mRNAs by SHh. Conditional deletion of ILK or Smo also inhibits SHh-driven activation of Gli2 in the embryonic mouse cerebellum. ILK regulation of Hh signalling probably requires the physical interaction of ILK and Smo in the cilium, and we also show selective cilia-associated interaction of ILK with ß-arrestin, a known mediator of Smo-dependent signalling.

Conformational rearrangements of RIG-I receptor on formation of a multiprotein:dsRNA assembly.

The retinoic acid inducible gene-I (RIG-I)-like family of receptors is positioned at the front line of our innate cellular defence system. RIG-I detects and binds to foreign duplex RNA in the cytoplasm of both immune and non-immune cells, and initiates the induction of type I interferons and pro-inflammatory cytokines. The mechanism of RIG-I activation by double-stranded RNA (dsRNA) involves a molecular rearrangement proposed to expose the N-terminal pair of caspase activation recruitment domains, enabling an interaction with interferon-beta promoter stimulator 1 (IPS-1) and thereby initiating downstream signalling. dsRNA is particularly stimulatory when longer than 20 bp, potentially through allowing binding of more than one RIG-I molecule. Here, we characterize full-length RIG-I and RIG-I subdomains combined with a stimulatory 29mer dsRNA using multi-angle light scattering and size-exclusion chromatography-coupled small-angle X-ray scattering, to build up a molecular model of RIG-I before and after the formation of a 2:1 protein:dsRNA assembly. We report the small-angle X-ray scattering-derived solution structure of the human apo-RIG-I and observe that on binding of RIG-I to dsRNA in a 2:1 ratio, the complex becomes highly extended and flexible. Hence, here we present the first model of the fully activated oligomeric RIG-I.