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Endothelial dysfunction and inflammation are clinically significant risk factors for cardiovascular diseases in hypertension. Although immune cells play a role in hypertension, the impact of plasmacytoid dendritic cells in established renovascular hypertension-induced cardiovascular complications is not fully understood. We investigated plasmacytoid dendritic cells' contribution to arterial endothelial dysfunction and inflammation in renovascular hypertension.A two-kidney one-clip (2K1C) model for four weeks in both male and female mice was used to induce renovascular hypertension. We treated mice with or without anti-PDCA-1 antibodies for one week to deplete the plasmacytoid dendritic cells. Renovascular hypertension causes cardiac hypertrophy, lung edema, and microvascular endothelial dysfunction associated with inflammation induction in mice. Moreover, renovascular hypertension affects the profile of immune cells, including dendritic cells and macrophages, with variations between male and female mice. Interestingly, the depletion of plasmacytoid dendritic cells significantly reduces blood pressure, cardiac hypertrophy, lung edema, inflammation, and oxidative stress and improves microvascular endothelial function via the endoplasmic reticulum (ER) stress, autophagy, and mTOR-dependent mechanisms.Plasmacytoid dendritic cells significantly contribute to the development of cardiovascular complications in renovascular hypertension by modulating immune cells, inflammation, oxidative stress, and ER stress.

Polycrystalline diamond compact (PDC) cutters, the most widely used cutting tool in oil and gas drilling, often fail very quickly because of excessive wear and poor impact toughness in hard and complex formations. In this study, dense PDC samples doped with SiC whiskers (SiCw) were successfully synthesized under high pressure and high temperature (HPHT) conditions. The microstructures, elemental distributions, and phase compositions of the PDC samples were systematically investigated. The mechanical properties including the Vickers hardness, wear resistance, impact toughness and thermal stability, were tested. The introduction of SiCw reduced the Co content in the polycrystalline diamond layer. The testing results showed that the hardness of PDC doped with 0.5 wt% SiCw was 75.25 GPa, wear ratio was 145.6 × 104 and impact toughness reached 4020 J, which were 12.2%, 30.9%, and 142.2% higher than those of the control group (CG), respectively. The PDC-0.5 wt% SiCw had the lowest thermal expansion value, with a 57.5% reduction compared with the CG. In addition, the strengthening mechanism of SiCw was explored. SiCw partially replaced the weakening cobalt phase in the binder phase, thus improving the hardness, wear resistance, and thermal stability of the PDC. The introduction of SiCw inhibited the abnormal growth of WC at the interface of the cemented carbide substrate and changed the fracture mode from intergranular to transgranular, which were the main mechanisms responsible for the significant increase in the impact toughness of PDC.

Despite the increased severity of influenza A infection in pregnancy, knowledge about the expression of cell entry factors for influenza A virus (IAV) and the innate immune response in the nasal epithelium, the primary portal of viral entry, is limited. Here, we compared the expression of IAV cell entry factors and the status of the innate immune response in the nasal epithelium of pregnant vs. non-pregnant female rats. IAV cell entry factors — sialic acid [SA] α-2,3- and α-2,6-linked glycans for avian and human IAV, respectively — were detected and quantified with lectin-based immunoblotting and flow cytometry. Baseline frequencies of innate immune cell phenotypes in single cell suspensions of the nasal epithelium were studied with flow cytometry. Subsequently, the magnitude of interferon and cytokine responses was studied with ELISA and cytokine arrays after intranasal resiquimod, a Toll-like receptor 7/8 agonist that mimics IAV infection. We noted substantially increased expression of cell entry factors for both avian and human IAV in the nasal epithelium during pregnancy. Assessment of the innate immune state of the nasal epithelium during pregnancy revealed two previously unreported features: (i) increased presence of tissue-resident plasmacytoid dendritic cells, and (ii) markedly enhanced release of interferon-α but not of the other interferons or cytokines 2 h after intranasal resiquimod. Collectively, our findings challenge the conventional notion of pregnancy-induced immunosuppression as a cause for severe influenza A disease and suggest the need for focused studies on viral tropism during pregnancy to better understand the proximate cause for the observed immunopathology.

Recently, peptide-drug conjugate (PDC) has become the most promising conjugated drug for tumor therapy after antibody-drug conjugate due to stronger tumor penetration capacity and lower immunogenicity. CBP-1018 was a PDC with dual-ligand conjugated to MMAE via a cleavable linker (MC-Val-Cit-PABC) that can be lysed by cathepsins B. In this study, two specific LC-MS/MS methods were developed and validated for the determination of CBP-1018 and its metabolite MMAE in human plasma. To prevent the cleavable MC-Val-Cit-PABC linker from degradation, a protease inhibitor (cOmplete solution) was added to the pre-cooled vacuum tubes and the separated plasma samples. The assays involved the pretreatment of CBP-1018 by protein precipitation with H 2 O-ACN (1:9, v/v) and the extraction of MMAE by liquid-liquid extraction with ethyl acetate under alkaline condition to eliminate the interference of CBP-1018 on MMAE. The two analytes showed good linearities over the calibration ranges (R 2  ≥ 9980). Both accuracy and precision met the acceptance criteria. The validated methods were successfully applied to the phase I dose-escalation study of CBP-1018 injection in Chinese patients with solid tumors to evaluate the pharmacokinetic properties of CBP-1018 and MMAE. The results showed that CBP-1018 was eliminated immediately after injection and MMAE reached the maximum exposure at approximately 2 h after infusion. The maximum concentration of MMAE did not exceed 20.0 ng/mL, suggesting that the off-target toxicity of CBP-1018 injection was controllable., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Summary: Background: Type I IFN (IFN-I) is a family of cytokines involved in the pathogenesis of autoimmune and autoinflammatory diseases such as psoriasis. SIDT1 is an ER-resident protein expressed in the lymphoid lineage, and involved in anti-viral IFN-I responses in vivo, through an unclear mechanism. Herein we have dissected the role of SIDT1 in the natural IFN-producing cells, the plasmacytoid dendritic cells (pDC). Methods: The function of SIDT1 in pDC was determined by silencing its expression in human primary pDC and GEN2.2 cell line. SIDT1 role in vivo was assessed using the imiquimod-induced psoriasis model in the SIDT1-deficient mice (sidt1−/−). Findings: Silencing of SIDT1 in GEN2.2 led to a blockade of the IFN-I response after stimulation of TLR7 and TLR9, without affecting the pro-inflammatory responses or upregulation of maturation markers. We found that SIDT1 migrates from the ER to the endosomal and lysosomal compartments together with TLR9 after CpG stimulation, participating in the access of the TLR9-CpG complex to lysosome-related vesicles, and therefore mediating the activation of TBK1 and the nuclear migration of IRF7, but not of NF-κB. sidt1−/− mice showed a significant decrease in severity parameters of the imiquimod-induced acute psoriasis-like model, associated with a decrease in the production of IFN-I and IFN-dependent chemokines. Interpretation: Our findings indicate that SIDT1 is at the cross-road between the IFN-I and the proinflammatory pathways and constitutes a promising drug target for psoriasis and other diseases mediated by IFN-I responses. Funding: This work was supported by the Consejería de Salud y Familias de la Junta de Andalucía (PIER_S1149 and C2_S0050) and Instituto de Salud Carlos III (PI18/00082 and PI21/01151), partly supported by European FEDER funds, and prior funding to MEAR from the Alliance for Lupus Research and the Swedish Research Council.

Innate immune responses are important in the control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. We have previously found a lactic acid bacteria species, Lactococcus lactis strain Plasma (LC-Plasma), which possesses specific feature to activate plasmacytoid dendritic cells (pDCs) and thus may affect innate immune responses. Here, we investigated the impact of pDC activation by LC-Plasma on SARS-CoV-2 replication in vitro. Addition of the culture supernatant of pDCs stimulated with LC-Plasma resulted in suppression of SARS-CoV-2 replication in Vero and Calu-3 cells. We confirmed interferon-α (IFN-α) secretion in the supernatant of pDCs stimulated with LC-Plasma and induction of IFN-stimulated genes in cells treated with the pDC supernatant. Anti-IFN-α antibody impaired the suppression of SARS-CoV-2 replication by the supernatant of LC-Plasma-stimulated pDCs, suggesting that IFN-α plays an important role in the SARS-CoV-2 suppression. Our results indicate the potential of LC-Plasma to induce inhibitory responses against SARS-CoV-2 replication through pDC stimulation with IFN-α secretion., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Hiroshi Ishii, Kenta Jounai, Konomi Ohshio, Daisuke Fujiwara, and Tetsuro Matano have patent #PCT/JP2022/40242 pending to Licensee., (Copyright © 2023 Elsevier Inc. All rights reserved.)

After taking up pathogen-derived antigens, dendritic cells (DCs) leave peripheral organs and migrate into sentinel lymph nodes via afferent lymphatic vessels. During this process, they undergo maturation and produce proinflammatory cytokines, which leads to efficient antigen (Ag) presentation and activation of the innate and acquired immune systems. Recent evidence indicates that DC subsets cooperate to activate the innate immune system. It is becoming clear that the total DC population is composed of a network of DC subsets with distinct functions that are critical for sensing pathogens and orchestrating immune responses.

Toll-like receptors are sensing modulators of the innate immune system. One member of this protein family, Toll-like receptor (TLR)-9, is increasingly being investigated as therapeutic target for infectious diseases and cancer. Double-Stem Loop ImmunoModulator (dSLIM) is a new TLR-9 agonist in clinical development for patients with metastatic colorectal carcinoma. Compared with other TLR-9 ligands developed as immunomodulators, dSLIM comprises single- and double-stranded DNA, is covalently closed, and consists of natural nucleotide components only. All investigated biologic effects of dSLIM are strongly dependent on CG motifs, and the relevant cellular activation profile of dSLIM is distinct to that of other TLR-9 agonists. Here we describe the structure and biologic profile of dSLIM: in isolated human peripheral blood mononuclear cells (PBMCs), dSLIM induced a unique pattern of cytokine secretion, activated within the PBMC pool particular cell subpopulations, and exhibited specific cytotoxicity on target cells. Using cellular isolation and depletion setups, the mechanism of immunoactivation by dSLIM was deduced to be dependent on, but not restricted to, TLR-9-bearing plasmacytoid dendritic cells. The dSLIM-promoted cellular stimulation directs systemic activation of the immune response as revealed in cancer patients. The observed cellular activation cascades are discussed in the context of cancer therapy.

Plasmacytoid dendritic cells (pDC) are an important type I interferon producer that play an important role in the first line of host defence during viral infection. Abnormalities in pDC numbers and function have been associated with several health conditions. Quantifying pDC is important for understanding pDC related immune responses in viral infections and other diseases, however the current methods for quantifying pDC using flow cytometry have limited utility in large cohort studies involving multiple centres with limited access to flow cytometry. We reasoned that examining gene expression of the pDC marker C-type lectin domain family 4 member C (CLEC4C, also known as CD303 and BDCA2) in combination with pDC exclusive leukocyte immunoglobulin like receptor A4 (LILRA4, also known as CD85g and ILT7) might provide a more practical method that could be applied to multi-centre studies. Our results show a moderate correlation between pDC numbers measured by surface staining and CLEC4C gene expression in whole blood (rho = 0.39, P = .037, as well as a high correlation between CLEC4C gene expression in whole blood and peripheral blood mononuclear cells (rho = 0.79, P < .001). LILRA4 gene expression did not provide additional useful information. Our results indicate that measuring CLEC4C gene expression can provide an alternative method for quantifying pDC numbers in human samples., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Dendritic cells (DCs) are a unique class of immune cells that act as a bridge between innate and adaptive immunity. The discovery of DCs by Cohen and Steinman in 1973 laid the foundation for DC biology, and the advances in the field identified different versions of DCs with unique properties and functions. DCs originate from hematopoietic stem cells, and their differentiation is modulated by Flt3L. They are professional antigen-presenting cells that patrol the environmental interphase, sites of infection, or infiltrate pathological tissues looking for antigens that can be used to activate effector cells. DCs are critical for the initiation of the cellular and humoral immune response and protection from infectious diseases or tumors. DCs can take up antigens using specialized surface receptors such as endocytosis receptors, phagocytosis receptors, and C type lectin receptors. Moreover, DCs are equipped with an array of extracellular and intracellular pattern recognition receptors for sensing different danger signals. Upon sensing the danger signals, DCs get activated, upregulate costimulatory molecules, produce various cytokines and chemokines, take up antigen and process it and migrate to lymph nodes where they present antigens to both CD8 and CD4 T cells. DCs are classified into different subsets based on an integrated approach considering their surface phenotype, expression of unique and conserved molecules, ontogeny, and functions. They can be broadly classified as conventional DCs consisting of two subsets (DC1 and DC2), plasmacytoid DCs, inflammatory DCs, and Langerhans cells., (© 2019 Elsevier Inc. All rights reserved.)

Metabolism is essential to all living organisms that provide cells with energy, regulators, building blocks, enzyme cofactors and signaling molecules, and is in tune with nutritional conditions and the function of cells to make the appropriate developmental decisions or maintain homeostasis. As a fundamental biological process, metabolism state affects the production of multiple metabolites and the activation of various enzymes that participate in regulating gene expression, cell apoptosis, cancer progression and immunoreactions. Previous studies generally focus on the function played by the metabolic enzymes in the cytoplasm and mitochondrion. In this review, we conclude the role of them in the nucleus and their implications for cancer progression, immunity and metastasis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: We investigated interictal EEG activity in patients with childhood absence seizures with the aim of detecting markers of network defects generating "idiopathic" hyperexcitability in this form of epilepsy., Methods: We included 11 drug-naïve patients with childhood absence epilepsy (CAE), and 11 age matched controls (CTRL). We analyzed interictal EEG using partial directed coherence (PDC), a connectivity estimator in frequency domain based on autoregressive multivariate (MVAR) modeling giving the advantage of indicating the direction and strength of the interactions between multiple variables., Results: Our results revealed the presence of an abnormal cortico-cortical network occurring in the interictal condition in CAE and involving a large span of frequencies, with prominence in the alpha band; the most evident finding was a highly significant increase of out-going connectivity involving frontal and central cortical areas in CAE patients compared to CTRL subjects., Conclusions: Our observation indicates that, in interictal conditions, a distorted network characterizes CAE, and a hyperconnected network is already detectable under resting conditions in the delta, theta and alpha bands., Significance: The increased interictal EEG connectivity demonstrated here provides support for a persistent abnormal relationship between the thalamus and a hyperexcitable cortex outside the ictal phase., (Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

In this paper, a robust H∞ fuzzy output feedback controller is designed for a class of affine nonlinear systems with disturbance via Takagi-Sugeno (T-S) fuzzy bilinear model. The parallel distributed compensation (PDC) technique is utilized to design a fuzzy controller. The stability conditions of the overall closed loop T-S fuzzy bilinear model are formulated in terms of Lyapunov function via linear matrix inequality (LMI). The control law is robustified by H∞ sense to attenuate external disturbance. Moreover, the desired controller gains can be obtained by solving a set of LMI. A continuous stirred tank reactor (CSTR), which is a benchmark problem in nonlinear process control, is discussed in detail to verify the effectiveness of the proposed approach with a comparative study., (Copyright © 2014 ISA. Published by Elsevier Ltd. All rights reserved.)

Patients with asthma and chronic obstructive pulmonary disease (COPD) are susceptible to exacerbations, often caused by microbial pathogens. We hypothesised that intracellular Toll-like receptor (TLR) function in blood mononuclear cells (PBMCs) from these subjects would be impaired and that this impairment is related to exacerbation frequency. PBMCs stimulated with a TLR-9 agonist (but not TLR-3 or 7/8) produced significantly less IFN-α in asthma (26 [3-696]pg/ml) compared to control (943 [164-1651]) and COPD (597 [127-1186]) subjects (p = 0.0019) but this was not related to the number of exacerbations per year in asthma or COPD. In COPD, IFN-α levels were related to KCO (% predicted) in COPD (r = -0.41, p = 0.01). IFN-α was derived from plasmacytoid dendritic cells (pDCs) and their frequency was lower in asthma compared to control subjects (control 0.48% [0.33-0.64] versus asthma 0.29% [0.13-0.34], p = 0.019) whereas pDC function per se was not significantly impaired between groups. The mechanism underlying reduced IFN-α production and the clinical consequences in severe asthma remains to be established., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Protein- and peptide-drug conjugates hold a promising stance in the delivery of therapeutic agents by providing distinct advantage of improving therapeutic potential of drugs. Recent advancements in the proteomics and recombinant DNA technology, by enabling identification of distinct structural features of proteins and making it feasible to introduce specific functionalities in protein/peptide structure, has made it possible to synthesize high quality protein- and peptide-drug conjugates though a wide variety of coupling techniques. Additionally, use of specialized linkers makes them unique in their in vivo therapeutic application by providing target tissue-specific release of drug. Several protein- and peptide-drug conjugates are currently under clinical trials warranting their huge market potential in near future. Increased understanding in this field will surely enable us to produce high quality protein- and peptide-drug conjugates which will serve therapeutic needs demanded from drug delivery systems in clinical settings., (© 2015 Elsevier Inc. All rights reserved.)

Neutrophils are central players in the innate immune system. They generate neutrophil extracellular traps (NETs), which protect against invading pathogens but are also associated with the development of autoimmune and/or inflammatory diseases and thrombosis. Here, we report that lactoferrin, one of the components of NETs, translocated from the cytoplasm to the plasma membrane and markedly suppressed NETs release. Furthermore, exogenous lactoferrin shrunk the chromatin fibers found in released NETs, without affecting the generation of oxygen radicals, but this failed after chemical removal of the positive charge of lactoferrin, suggesting that charge-charge interactions between lactoferrin and NETs were required for this function. In a model of immune complex-induced NET formation in vivo, intravenous lactoferrin injection markedly reduced the extent of NET formation. These observations suggest that lactoferrin serves as an intrinsic inhibitor of NETs release into the circulation. Thus, lactoferrin may represent a therapeutic lead for controlling NETs release in autoimmune and/or inflammatory diseases.

For the first time, several multivariate calibration (MVC) models including partial least squares-1 (PLS-1), continuum power regression (CPR), multiple linear regression-successive projections algorithm (MLR-SPA), robust continuum regression (RCR), partial robust M-regression (PRM), polynomial-PLS (PLY-PLS), spline-PLS (SPL-PLS), radial basis function-PLS (RBF-PLS), least squares-support vector machines (LS-SVM), wavelet transform-artificial neural network (WT-ANN), discrete wavelet transform-ANN (DWT-ANN), and back propagation-ANN (BP-ANN) have been constructed on the basis of non-bilinear first order square wave voltammetric (SWV) data for the simultaneous determination of ascorbic acid (AA), uric acid (UA), dopamine (DP) and nitrite (NT) at a glassy carbon electrode (GCE) to identify which technique offers the best predictions. The compositions of the calibration mixtures were selected according to a simplex lattice design (SLD) and validated with an external set of analytes' mixtures. An asymmetric least squares splines regression (AsLSSR) algorithm was applied for correcting the baselines. A correlation optimized warping (COW) algorithm was used to data alignment and lack of bilinearity was tackled by potential shift correction. The effects of several pre-processing techniques such as genetic algorithm (GA), orthogonal signal correction (OSC), mean centering (MC), robust median centering (RMC), wavelet denoising (WD), and Savitsky-Golay smoothing (SGS) on the predictive ability of the mentioned MVC models were examined. The best preprocessing technique was found for each model. According to the results obtained, the RBF-PLS was recommended to simultaneously assay the concentrations of AA, UA, DP and NT in human serum samples., (© 2013 Elsevier B.V. All rights reserved.)

Objective: Recent evidence mainly based on hemodynamic measures suggests that the impairment of functional connections between different brain areas may help to clarify the neuronal dysfunction occurring in patients with disorders of consciousness (DOC). The aim of this study was to evaluate effective EEG connectivity in a cohort of 18 patients in a chronic vegetative state (VS) observed years after the occurrence of hypoxic (eight) and traumatic or hemorrhagic brain insult., Methods: we analysed the EEG signals recorded under resting conditions using a frequency domain linear index of connectivity (partial directed coherence: PDC) estimated from a multivariate autoregressive model. The results were compared with those obtained in ten healthy controls., Results: Our findings indicated significant connectivity changes in EEG activities in delta and alpha bands. The VS patients showed a significant and widespread decrease in delta band connectivity, whereas the alpha activity was hyper-connected in the central and posterior cortical regions., Conclusion: These changes suggest the occurrence of severe circuitry derangements probably due to the loose control of the subcortical connections. The alpha hyper-synchronisation may be due to simplified networks mainly involving the short-range connections between intrinsically oscillatory cortical neurons that generate aberrant EEG alpha sources. This increased connectivity may be interpreted as a reduction in information capacity, implying an increasing prevalence of stereotypic activity patterns., Significance: Our observations suggest a remarkable rearrangement of connectivity in patients with long-standing VS. We hypothesize that in persistent VS, after a first period characterized by a breakdown of cortical connectivity, neurodegenerative processes, largely independent from the type of initial insult, lead to cortex de-afferentation and to a severe reduction of possible cortical activity patterns and states., (Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Paramyxoviruses represent a remarkably diverse family of enveloped nonsegmented negative-strand RNA viruses, some of which are the most ubiquitous disease-causing viruses of humans and animals. This review focuses on paramyxovirus activation of innate immune pathways, the mechanisms by which these RNA viruses counteract these pathways, and the innate response to paramyxovirus infection of dendritic cells (DC). Paramyxoviruses are potent activators of extracellular complement pathways, a first line of defense that viruses must face during natural infections. We discuss mechanisms by which these viruses activate and combat complement to delay neutralization. Once cells are infected, virus replication drives type I interferon (IFN) synthesis that has the potential to induce a large number of antiviral genes. Here we describe four approaches by which paramyxoviruses limit IFN induction: by limiting synthesis of IFN-inducing aberrant viral RNAs, through targeted inhibition of RNA sensors, by providing viral decoy substrates for cellular kinase complexes, and through direct blocking of the IFN promoter. In addition, paramyxoviruses have evolved diverse mechanisms to disrupt IFN signaling pathways. We describe three general mechanisms, including targeted proteolysis of signaling factors, sequestering cellular factors, and upregulation of cellular inhibitors. DC are exceptional cells with the capacity to generate adaptive immunity through the coupling of innate immune signals and T cell activation. We discuss the importance of innate responses in DC following paramyxovirus infection and their consequences for the ability to mount and maintain antiviral T cells., (© 2013.)

SAMHD1 [sterile alpha motif and histidine-aspartic domain (HD) containing protein 1] is the most recent addition to a unique group of host restriction factors that limit retroviral replication at distinct stages of the viral life cycle. SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase that degrades the intracellular pool of deoxynucleoside triphosphates available during early reverse transcription. SAMHD1 activity is blocked by the Vpx accessory function present in human immunodeficiency virus type 2 and SIVsm. Mutations in SAMHD1 are associated with the autoimmune disorder Aicardi-Goutières syndrome, thus emphasizing its role in regulation of the immune response. SAMHD1 antiretroviral activity is modulated by post-translational modifications, cell-cycle-dependent functions and cytokine-mediated changes. Innate receptors that sense retroviral DNA intermediates are the focus of intense study, and recent studies have established a link among SAMHD1 restriction, innate sensing of DNA and protective immune responses. Cell-cycle-dependent regulation of SAMHD1 by phosphorylation and the increasingly broad range of viruses inhibited by SAMHD1 further emphasize the importance of these mechanisms of host restriction. This review highlights current knowledge regarding SAMHD1 regulation and its impact on innate immune signaling and retroviral restriction., (© 2013.)

Tetherin (BST-2, CD317) is an interferon-inducible cellular factor that inhibits the release of diverse enveloped viruses by tethering them to the cell surface. Its importance in antiviral immunity is underscored by the observation that various viruses have evolved antagonists against this restriction factor. Accumulating evidence suggests that this is not only due to its ability to inhibit virus release but that tetherin also acts as an innate immune sensor of viral infections that activates NF-κB to induce an inflammatory response. Furthermore, tetherin modulates immune activation through interactions with the immunoglobulin-like transcript 7 (ILT7, LILRA4). This surface receptor is specifically expressed on plasmacytoid dendritic cells, which are the main producers of type I interferons in response to viral infections. Here, we summarize some of our current knowledge about the role of tetherin as a viral immune sensor and discuss how the accessory HIV-1 (human immunodeficiency virus type 1) Vpu protein counteracts this effect., (© 2013.)

Selenium is an essential element for the normal cellular function of living organisms. However, selenium is toxic at concentrations of only three to five times higher than the essential concentration. The inorganic forms (mainly selenite and selenate) present in environmental water generally exhibit higher toxicity (up to 40 times) than organic forms. Therefore, the determination of low levels of different inorganic selenium species in water is an analytical challenge. Solid-phase extraction has been used as a separation and/or preconcentration technique prior to the determination of selenium species due to the need for accurate measurements for Se species in water at extremely low levels. The present paper provides a critical review of the published methods for inorganic selenium speciation in water samples using solid phase extraction as a preconcentration procedure. On the basis of more than 75 references, the different speciation strategies used for this task have been highlighted and classified. The solid-phase extraction sorbents and the performance and analytical characteristics of the developed methods for Se speciation are also discussed., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Glyoxylate is a peroxisomal intermediate of photorespiration, the recycling pathway for 2-phosphoglycolate (2-PG) produced by the oxygenase activity of Rubisco. Under hot and dry growth conditions, photorespiratory intermediates can accumulate and must be detoxified by alternative pathways, including plastidal reactions. Moreover, there is evidence that chloroplasts are capable of actively producing glyoxylate from glycolate. Further metabolic steps are unknown, but probably include a CO2 release step. Here, we report that CO2 production from glycolate and glyoxylate in isolated tobacco chloroplasts can be inhibited by pyruvate, but not related compounds. We isolated a protein fraction that was enriched for the chloroplast pyruvate dehydrogenase complex (PDC). The fraction contained a protein complex of several MDa in size that included all predicted subunits of the chloroplast PDC and a so far unidentified HSP93-V/ClpC1 heat shock protein. Glyoxylate competitively inhibited NADH formation from pyruvate in this fraction. The Km for pyruvate and the Ki for glyoxylate were 330 and 270 μM, respectively. Glyoxylate decarboxylation was also enriched in this fraction and could be in turn inhibited by pyruvate. Based on these data, we suggest that the chloroplast PDC might be part of a pathway for glycolate and/or glyoxylate oxidation in chloroplasts., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The phenotype and function of liver dendritic cells (LDCs) are poorly understood. This Snapshot summarizes our current knowledge on LDCs in the healthy and injured liver, and their role in fibrosis progression and reversal. It also draws attention to various pitfalls in the current experimental design and conclusions based on available data., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The heart rate is largely under control of the autonomic nervous system. The aim of the present study is to investigate the interactions between the brain and heart underlying volitional control of the heart and to explore the effectiveness of volition as a strategy to control the heart rate without biofeedback. Twenty seven healthy male subjects voluntarily participated in the study and were instructed to decrease and increase their heart beats according to rhythmic, computer generated sound either 10% faster or slower than the subjects' measured heart rate. Sympathetic and parasympathetic activities were estimated with the heart rate variability (HRV) obtained by power spectral analysis of RR intervals. Functional coupling patterns of cerebral cortex with the heart were determined by Partial directed coherence (PDC). In HR(slow) task; HR and sympathetic activity significantly decreased. However parasympathetic activity and power spectral density of EEG in low Alpha (8-10.5 Hz) band significantly increased. Moreover information flow from parietal area (P3 and P4) to RR interval significantly increased. During HR(quick) task; HR, sympathetic activity and power spectral density of EEG in low Beta (14-24 Hz) band significantly increased. Parasympathetic activity significantly decreased. Information flow from FT8, CZ and T8 electrodes to RR interval significantly increased. Our findings suggested that the heart beat can be controlled by volition and is related to some special areas in the cortex., (© 2013.)

Metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus are all linked to cardiovascular diseases such as cardiac hypertrophy and heart failure. Diabetic cardiomyopathy in particular, is characterized by structural and functional alterations in the heart muscle of people with diabetes that finally lead to heart failure, and which is not directly attributable to coronary artery disease or hypertension. Several mechanisms have been involved in the pathogenesis of diabetic cardiomyopathy, such as alterations in myocardial energy metabolism and calcium signaling. Metabolic disturbances during diabetic cardiomyopathy are characterized by increased lipid oxidation, intramyocardial triglyceride accumulation, and reduced glucose utilization. Overall changes result in enhanced oxidative stress, mitochondrial dysfunction and apoptosis of the cardiomyocytes. On the other hand, the progression of heart failure and cardiac hypertrophy usually entails a local rise in cytokines in cardiac cells and the activation of the proinflammatory transcription factor nuclear factor (NF)-κB. Interestingly, increasing evidences are arising in the recent years that point to a potential link between chronic low-grade inflammation in the heart and metabolic dysregulation. Therefore, in this review we summarize recent new insights into the crosstalk between inflammatory processes and metabolic dysregulation in the failing heart during diabetes, paying special attention to the role of NF-κB and peroxisome proliferator activated receptors (PPARs). In addition, we briefly describe the role of the AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1) and other pathways regulating cardiac energy metabolism, as well as their relationship with diabetic cardiomyopathy., (© 2013.)

The aim of this research was to study how the cell immobilization technique of forming foamed alginate gels influences the growth, vitality and metabolic activity of different yeasts. Two distinct strains were used, namely conventional yeast (exemplified by Saccharomyces cerevisiae) and a non-conventional strain (exemplified by Debaryomyces occidentalis). The encapsulation of the yeast cells was performed by the traditional process of droplet formation, but from a foamed alginate solution. The activities of two key enzymes, succinate dehydrogenase and pyruvate decarboxylase, together with the ATP content were measured in both the free and immobilized cells. This novel method of yeast cell entrapment had some notable effects. The number of living immobilized cells reached the level of 10(6)-10(7) per single bead, and was stable during the fermentation process. Reductions in both enzyme activity and ATP content were observed in all immobilized yeasts. However, S. cerevisiae showed higher levels of ATP and enzymatic activity than D. occidentalis. Fermentation trials with immobilized repitching cells showed that the tested yeasts adapted to the specific conditions. Nevertheless, the mechanical endurance of the carriers and the internal structure of the gel need to be improved to enable broad applications of alginate gels in industrial fermentation processes, especially with conventional yeasts. This is one of the few papers and patents that describe the technique of cell immobilization in foamed alginate and shows the fermentative capacities and activities of key enzymes in immobilized yeast cells., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background & Aims: Interferon-γ (IFN-γ), a cytokine produced by activated natural killer cells (NK) and T lymphocytes, is an important regulator of innate and adaptive immunity during hepatitis C virus (HCV) infection. However, the cellular sources and mechanisms of IFN-γ induction in HCV-infection are not fully understood., Methods: We cultured normal human peripheral blood mononuclear cells (PBMCs) with different populations of immune cells and JFH-1 HCV-infected HuH7.5 (JFH-1/HuH7.5) cells., Results: We found that PBMCs produced large amounts of IFN-γ after co-culture with JFH-1/HuH7.5 cells. Using intracellular cytokine staining, we confirmed that NK cells and NKT cells (to a lesser extent) were the major IFN-γ producers within PBMCs. Purified NK/NKT cells did not produce IFN-γ in response to JFH-1/HuH7.5 cells and depletion of accessory (HLA-DR(+)) cells prevented IFN-γ induction in PBMCs. Through selective cell depletion of dendritic cells or monocytes from PBMCs, we determined that plasmacytoid dendritic cells (pDCs) were indispensable for NK-IFN-γ induction and the presence of monocytes was needed for maximal NK-IFN-γ induction. We further revealed that NK-IFN-γ induction depended on pDC-derived IFN-α while other IFN-γ inducing cytokines, IL-12, and IL-18, played minimal roles. Close contact between JFH-1/HuH7.5 cells and NK cells was required for IFN-γ production and monocyte-derived IL-15 significantly augmented IFN-γ induction., Conclusions: We discovered a novel mechanism where NK cells interact with pDCs and monocytes, efficiently producing IFN-γ in response to HCV-infected cells. This indicates that co-operation between NK cells and accessory cells is critical for IFN-γ production and regulation of immunity during HCV infection., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

This paper investigates the mechanism of action of heavy ion radiation (HIR) on mouse testes. The testes of male mice subjected to whole body irradiation with carbon ion beam (0.5 and 4Gy) were analyzed at 7days after irradiation. A two-dimensional gel electrophoresis approach was employed to investigate the alteration of protein expression in the testes. Spot detection and matching were performed using the PDQuest 8.0 software. A difference of more than threefold in protein quantity (normalized spot volume) is the standard for detecting differentially expressed protein spots. A total of 11 differentially expressed proteins were found. Protein identification was performed using matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF-TOF). Nine specific proteins were identified by searching the protein sequence database of the National Center for Biotechnology Information. These proteins were found involved in molecular chaperones, metabolic enzymes, oxidative stress, sperm function, and spermatogenic cell proliferation. HIR decreased glutathione activity and increased malondialdehyde content in the testes. Given that Pin1 is related to the cell cycle and that proliferation is affected by spermatogenesis, we analyzed testicular histological changes and Pin1 protein expression through immunoblotting and immunofluorescence. Alterations of multiple pathways may be associated with HIR toxicity to the testes. Our findings are essential for studies on the development, biology, and pathology of mouse testes after HIR in space or radiotherapy., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)