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The plasma behavior in a parallel-plate dielectric barrier discharge (DBD) is simulated by a two-dimensional particle-in-cell/Monte Carlo collision model, comparing for the first time an unpacked (empty) DBD with a packed bed DBD, i.e., a DBD filled with dielectric spheres in the gas gap. The calculations are performed in air, at atmospheric pressure. The discharge is powered by a pulse with a voltage amplitude of −20 kV. When comparing the packed and unpacked DBD reactors with the same dielectric barriers, it is clear that the presence of the dielectric packing leads to a transition in discharge behavior from a combination of negative streamers and unlimited surface streamers on the bottom dielectric surface to a combination of predominant positive streamers and limited surface discharges on the dielectric surfaces of the beads and plates. Furthermore, in the packed bed DBD, the electric field is locally enhanced inside the dielectric material, near the contact points between the beads and the plates, and therefore also in the plasma between the packing beads and between a bead and the dielectric wall, leading to values of V m−1, which is much higher than the electric field in the empty DBD reactor, i.e., in the order of V m−1, thus resulting in stronger and faster development of the plasma, and also in a higher electron density. The locally enhanced electric field and the electron density in the case of a packed bed DBD are also examined and discussed for three different dielectric constants, i.e., (ZrO2), (Al2O3) and (SiO2). The enhanced electric field is stronger and the electron density is higher for a larger dielectric constant, because the dielectric material is more effectively polarized. These simulations are very important, because of the increasing interest in packed bed DBDs for environmental applications.

Reversibility of hepatic fibrosis is an intrinsic response to chronic injury, and with on-going damage, fibrosis can progress to its end-stage consequence, cirrhosis. Non-invasive and reliable biomarkers for early detection of liver fibrosis are needed. Based on the CCl 4 -induced liver fibrosis rat model, urinary and serum metabolic profiling performed by LC-QTOF-MS associated with histological progression were utilized to identify liver fibrosis-specific potential biomarkers for early prediction and to reveal significant fibrotic pathways and their dynamic changes in different stages of liver fibrosis. Finally, nine differential metabolites in urine and ten in serum were selected and identified involving the most relevant metabolic pathways. Perturbations of tryptophan, valine, leucine, isoleucine, and citrate (TCA) cycle metabolites, along with sphingolipid and glycerophospholipid metabolites, occurred from the onset of liver fibrosis. Furthermore, dysregulation of valine and bile acid biosynthesis metabolites occurred in the intermediate and advanced stages. More importantly, among these metabolites, urinary kynurenic acid, 5-hydroxyindoleacetyl glycine, 4-(2-amino-3-hydroxyphenyl)-2,4-dioxobutanoic acid and serum sphinganine, sphingomyelin, L-leucine, L-tryptophan, and LysoPC(17:0) changed at all time points and may serve as potential early biomarkers for the diagnosis of hepatic fibrosis and as therapeutic targets. Overall, this work evaluates the potential of these metabolites for the early detection of liver fibrosis.

Diabetes‐related depression (DD) is a major complication of diabetes mellitus. Our previous studies indicated that glutamate (Glu) and hippocampal neuron apoptosis are key signal and direct factor leading to diabetes‐related depression, respectively. However, the accurate pathogenesis remains to be unclear. We hypothesized that diabetes‐related depression might be associated with the mitophagy‐mediated hippocampal neuron apoptosis, triggered by aberrant Glu‐glutamate receptor2 (GluR2)‐Parkin pathway. To testify this hypothesis, here the rat model of DD in vivo and in vitro were both established so as to uncover the potential mechanism of DD based on mitophagy and apoptosis. We found that DD rats exhibit an elevated glutamate levels followed by monoamine neurotransmitter deficiency and depressive‐like behaviour, and DD modelling promoted autophagosome formation and caused mitochondrial impairment, eventually leading to hippocampal neuron apoptosis via aberrant Glu‐GluR2‐Parkin pathway. Further, in vitro study demonstrated that the simulated DD conditions resulted in an abnormal glutamate and monoamine neurotransmitter levels followed by autophagic flux increment, mitochondrial membrane potential reduction and mitochondrial reactive oxygen species and lactic dehydrogenase elevation. Interestingly, both GluR2 and mammalian target of rapamycin (mTOR) receptor blocker aggravated mitophagy‐induced hippocampal neuron apoptosis and abnormal expression of apoptotic protein. In contrast, both GluR2 and mTOR receptor agonist ameliorated those apoptosis in simulated DD conditions. Our findings revealed that mitophagy‐mediated hippocampal neuron apoptosis, triggered by aberrant Glu‐GluR2‐Parkin pathway, is responsible for depressive‐like behaviour and monoamine neurotransmitter deficiency in DD rats. This work provides promising molecular targets and strategy for the treatment of DD.

The Rab GTPase activating protein (RabGAP) AS160 translocates from the cytosol into the nucleus acting as a transcriptional co-activator of Signal Transducer and Activator of Transcription 3 (STAT3) to regulate proliferation of muscle satellite cells (MuSCs). How this AS160–STAT3 complex is regulated remains largely unclear yet. Here, we show that TBC1D1, a RabGAP related to AS160, forms a super-complex with AS160 and STAT3 to retain the AS160–STAT3 complex in the cytosol. Phosphorylation of TBC1D1-Thr 596 by protein kinase B dissociates TBC1D1 from AS160 thus releasing the cytosolic retention of the AS160–STAT3 complex. A non-phosphorylatable alanine substitution of Thr 596 inhibits MuSC proliferation and impairs repair of injured muscle. In contrast, TBC1D1 deficiency, but not its GAP-inactive mutation, promotes MuSC proliferation and muscle regeneration. Thus, TBC1D1 is a negative regulator of MuSC proliferation through cytosolic retention of the AS160–STAT3 complex and might be a valuable therapeutic target for muscle regeneration. MuSCs are vital for muscle renewal with unclear regulatory mechanisms. Here, the authors show that cytosolic TBC1D1 inhibits nuclear entry of the AS160-STAT3 complex and regulates MuSC proliferation. Deficiency of TBC1D1 improves muscle regeneration.

Fault slips and triggered rockbursts pose a significant threat to the safety of mining personnel and infrastructure in deep coal mines. Sudden and dynamic slip may occur along a pre-existing fault characterized by the presence of contact between two opposite faces. Such slips are capable of changing the balance of forces when mining activity is conducted in the area surrounding the fault at depth and are accompanied by energy release that has the potential to cause serious damage to roadways and working faces. The aim of the comprehensive investigation reported here was to elucidate the evolution of the stress field surrounding a fault due to mining activity in adjacent working faces, using Fast Lagrangian Analysis of Continua in 3 Dimensions (FLAC3D) numerical simulations, especially variations the high shear stress area. We then proposed the mining-induced fault slip mechanism. The evolution rule of sources during fault slip could be clearly explained using field microseism (MS) monitoring data, and the correlation between source parameters (e.g., static stress drop, peak particle velocity, and displacement) and fault slip was established. Correspondingly, the multi-parameter precursors of a rockburst induced by the fault slip were analyzed and summarized in detail. This work provides a number of reference points to be used for the warning and controlling of rockbursts triggered by fault slip in coal mines.

Over the past few decades, enantioselective phosphine organocatalysis has evolved rapidly into a highly efficient catalytic strategy for a range of useful reactions. However, as restricted by the traditional catalytic modes, some important reactions, such as asymmetric Strecker-type reactions, have thus far been out of reach of this strategy. Reported herein is an application of enantioselective phosphine organocatalysis for asymmetric Strecker-type reactions, enabled by a dual-reagent catalyst system in which the key organophosphorus zwitterion intermediate, generated in situ by mixing a chiral dipeptide-derived multifunctional organophosphine with methyl acrylate, is used as a highly efficient chiral Lewis base catalyst. The high efficiency of this catalytic system is demonstrated in the asymmetric cyanation of isatin-derived ketimines and azomethine aldimines as well as in the kinetic resolution of racemic 3-substituted azomethines. Mechanistic studies provide experimental evidence for the intermediacy of the putative zwitterion and its role as a catalytically active Lewis base. The Strecker reaction is a power method for the synthesis of cyano-substituted compounds. Here the authors report a dual-reagent system for asymmetric Strecker reactions, where an in situ formed organocatalyst/methyl acrylate zwitterionic adduct activates both the cyanide source and the electrophile.

Insulin is a potent inducer of mRNA transcription and translation, contributing to metabolic regulation. Insulin has also been suggested to regulate mRNA stability through the processing body (P-body) molecular machinery. However, whether and how insulin regulates mRNA stability via P-bodies is not clear. Here we show that the E3-ligase TRIM24 is a critical factor linking insulin signalling to P-bodies. Upon insulin stimulation, protein kinase B (PKB, also known as Akt) phosphorylates TRIM24 and stimulates its shuttling from the nucleus into the cytoplasm. TRIM24 interacts with several critical components of P-bodies in the cytoplasm, promoting their polyubiquitylation, which consequently stabilises Pparγ mRNA. Inactivation of TRIM24 E3-ligase activity or prevention of its phosphorylation via knockin mutations in mice promotes hepatic Pparγ degradation via P-bodies. Consequently, both knockin mutations alleviate hepatosteatosis in mice fed on a high-fat diet. Our results demonstrate the critical role of TRIM24 in linking insulin signalling to P-bodies and have therapeutic implications for the treatment of hepatosteatosis. Insulin promotes hepatic lipogenesis, though underlying regulation remains unclear. Here the authors show that insulin translocates TRIM24 from the nucleus into cytosolic P-bodies to stabilise hepatic Pparγ mRNA, and that inactivation of TRIM24 promotes Pparγ degradation and alleviates hepatosteatosis.

Pulmonary infections are among the most common and important infectious diseases due to their high morbidity and mortality, especially in older and immunocompromised individuals. However, due to the limitations in sensitivity and the long turn-around time (TAT) of conventional diagnostic methods, pathogen detection and identification methods for pulmonary infection with greater diagnostic efficiency are urgently needed. In recent years, unbiased metagenomic next generation sequencing (mNGS) has been widely used to detect different types of infectious pathogens, and is especially useful for the detection of rare and newly emergent pathogens, showing better diagnostic performance than traditional methods. There has been limited research exploring the application of mNGS for the diagnosis of pulmonary infections. In this study we evaluated the diagnostic efficiency and clinical impact of mNGS on pulmonary infections. A total of 100 respiratory samples were collected from patients diagnosed with pulmonary infection in Shanghai, China. Conventional methods, including culture and standard polymerase chain reaction (PCR) panel analysis for respiratory tract viruses, and mNGS were used for the pathogen detection in respiratory samples. The difference in the diagnostic yield between conventional methods and mNGS demonstrated that mNGS had higher sensitivity than traditional culture for the detection of pathogenic bacteria and fungi (95% vs 54%; p<0.001). Although mNGS had lower sensitivity than PCR for diagnosing viral infections, it identified 14 viral species that were not detected using conventional methods, including multiple subtypes of human herpesvirus. mNGS detected viruses with a genome coverage >95% and a sequencing depth >100× and provided reliable phylogenetic and epidemiological information. mNGS offered extra benefits, including a shorter TAT. As a complementary approach to conventional methods, mNGS could help improving the identification of respiratory infection agents. We recommend the timely use of mNGS when infection of mixed or rare pathogens is suspected, especially in immunocompromised individuals and or individuals with severe conditions that require urgent treatment.

Snakebite envenomation triggers a complex systemic inflammatory response; however, the immunological features underlying clinical severity remain incompletely characterized. The NLR reflects the balance between innate immune activation and adaptive immune suppression, yet its association with clinical severity in Gloydius brevicaudus envenomation has not been systematically evaluated. We performed a retrospective cohort study of 203 patients with confirmed G. brevicaudus envenomation. Clinical severity at presentation was assessed using a simplified bedside severity score based exclusively on clinical manifestations and dichotomized as mild or moderate-to-severe. Admission NLR was evaluated as a marker of inflammatory phenotype. Multivariable logistic regression models were constructed adjusting for demographic and bite-related factors. Dose-response relationships were explored using log-transformed NLR and quartile-based analyses with trend testing. Patients with moderate-to-severe envenomation exhibited significantly higher admission NLR values. After adjustment for baseline clinical characteristics, log-transformed NLR remained independently associated with inflammatory severity (adjusted odds ratio [OR] 1.98, 95% confidence interval [CI] 1.39-2.81). This association persisted after additional adjustment for infection status and leukocytosis. Quartile analyses demonstrated a clear dose-response relationship, with patients in the highest NLR quartile showing a nearly fourfold increased risk of moderate-to-severe envenomation compared with those in the lowest quartile (adjusted OR 3.94, 95% CI 1.69-9.17; P for trend < 0.001). Elevated admission NLR is strongly associated with inflammatory severity in G. brevicaudus envenomation and exhibits a robust dose-response relationship. These findings support NLR as a readily available marker reflecting envenomation-associated immune dysregulation and highlight the contribution of neutrophil-lymphocyte imbalance to severe inflammatory phenotypes following snakebite.

Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms. Striated muscle preferentially expressed protein kinase (SPEG) has two kinase-domains and is a critical cardiac regulator. Here we show that SPEG is phosphorylated on Ser 2461 /Ser 2462 /Thr 2463 by protein kinase B (PKB) in response to insulin. PKB-mediated phosphorylation of SPEG activates its second kinase-domain, which in turn phosphorylates sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) and accelerates calcium re-uptake into the SR. Cardiac-specific deletion of PKBα/β or a high fat diet inhibits insulin-induced phosphorylation of SPEG and SERCA2a, prolongs SR re-uptake of calcium, and impairs cardiac function. Mice bearing a Speg 3A mutation to prevent its phosphorylation by PKB display cardiac dysfunction. Importantly, the Speg 3A mutation impairs SERCA2a phosphorylation and calcium re-uptake into the SR. Collectively, these data demonstrate that insulin resistance impairs this PKB-SPEG-SERCA2a signal axis, which contributes to the development of diabetic cardiomyopathy. Molecular mechanisms linking myocardial insulin resistance to diabetic cardiomyopathy are incompletely understood. Here the authors show that myocardial insulin resistance impairs a PKB-SPEG-SERCA2a signaling axis, which contributes to the development of diabetic cardiomyopathy.