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In patients with head and neck cancer (HNC), lymph node (N) metastases are associated with cancer aggressiveness and poor prognosis. Identifying meaningful gene modules and representative biomarkers relevant to the N stage helps predict prognosis and reveal mechanisms underlying tumor progression. The present study used a step‑wise approach for weighted gene co‑expression network analysis (WGCNA). Dataset GSE65858 was subjected to WGCNA. RNA sequencing data of HNC downloaded from the Cancer Genome Atlas (TCGA) and dataset GSE39366 were utilized to validate the results. Following data preprocessing, 4,295 genes were screened, and blue and black modules associated with the N stage of HNC were identified. A total of 16 genes [keratinocyte differentiation associated protein, suprabasin, cornifelin (CNFN), small proline rich protein 1B, desmoglein 1 (DSG1), chromosome 10 open reading frame 99, keratin 16 pseudogene 3, gap junction protein β2, dermokine, LY6/PLAUR domain containing 3, transmembrane protein 79, phospholipase A2 group IVE, transglutaminase 5, potassium two pore domain channel subfamily K member 6, involucrin, kallikrein related peptidase 8] that had a negative association with the N‑stage in the blue module, and two genes (structural maintenance of chromosomes 4 and mutS homolog 6) that had a positive association in the black module, were identified to be candidate hub genes. Following further validation in TCGA and dataset GSE65858, it was identified that CNFN and DSG1 were associated with the clinical stage of HNC. Survival analysis of CNFN and DSG1 was subsequently performed. Patients with increased expression of CNFN displayed better survival probability in dataset GSE65858 and TCGA. Therefore, CNFN was selected as the hub gene for further verification in the Gene Expression Profiling Interactive Analysis database. Finally, functional enrichment and gene set enrichment analyses were performed using datasets GSE65858 and GSE39366. Three gene sets, namely 'P53 pathway', 'estrogen response early' and 'estrogen response late', were enriched in the two datasets. In conclusion, CNFN, identified via the WGCNA algorithm, may contribute to the prediction of lymph node metastases and prognosis, probably by regulating the pathways associated with P53, and the early and late estrogen response.

Pulsed eddy current (PEC) testing was originally reported to sort out heat-treated bearing rings noncontactly and nondestructively in terms of hardness, which is expected to solve the difficulty of online classification and small parts inspection. The signals gathered from PEC system were processed by fast Fourier transform and principal component analysis (PCA) respectively. Then, random forest algorithm was used for smart classification. The results obtained with these processes were presented in this paper and the classification results were discussed. It was observed that the use of PCA produces more robust and better prediction performance on bearing rings classification.

Diacylglycerol acyltransferases (DGAT) catalyze the final committed step of de novo biosynthesis of triacylglycerol (TAG) in plant seeds. This study was to functionally characterize DGAT3 genes in Camelina sativa, an important oil crops accumulating high levels of unsaturated fatty acids (UFAs) in seeds. Three camelina DGAT3 genes (CsDGAT3-1, CsDGAT3-2 and CsDGAT3-3) were identified, and the encoded proteins were predicted to be cytosolic-soluble proteins present as a homodimer containing the 2Fe-2S domain. They had divergent expression patterns in various tissues, suggesting that they may function in tissue-specific manner with CsDGAT3-1 in roots, CsDGAT3-2 in flowers and young seedlings, and CsDGAT3-3 in developing seeds. Functional complementation assay in yeast demonstrated that CsDGAT3-3 restored TAG synthesis. TAG content and UFAs, particularly eicosenoic acid (EA, 20:1n-9) were largely increased by adding exogenous UFAs in the yeast medium. Further heterogeneously transient expression in N. benthamiana leaves and seed-specific expression in tobacco seeds indicated that CsDGAT3-3 significantly enhanced oil and UFA accumulation with much higher level of EA. Overall, CsDGAT3-3 exhibited a strong abilty catalyzing TAG synthesis and high substrate preference for UFAs, especially for 20:1n-9. The present data provide new insights for further understanding oil biosynthesis mechanism in camelina seeds, indicating that CsDGAT3-3 may have practical applications for increasing both oil yield and quality.

BACKGROUND Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) is highly lethal. In previous models of combined TBI + HS, we showed that early resuscitation with fresh frozen plasma (FFP) improves neurologic outcomes. Delivering FFP, however, in austere environments is difficult. Lyophilized plasma (LP) is a logistically superior alternative to FFP, but data are limited regarding its efficacy for treatment of TBI. We conducted this study to determine the safety and long-term outcomes of early treatment with LP in a large animal model of TBI + HS. METHODS Adult anesthetized swine underwent TBI and volume-controlled hemorrhage (40% blood volume) concurrently. After 2 hours of shock, animals were randomized (n = 5 per /group) to FFP or LP (1× shed blood) treatment. Serial blood gases were drawn, and thromboelastography was performed on citrated, kaolin-activated whole-blood samples. Five hours after treatment, packed red blood cells were administered, and animals recovered. A 32-point Neurologic Severity Score was assessed daily for 30 days (0 = normal, 32 = most severe injury). Cognitive functions were tested by training animals to retrieve food from color-coded boxes. Brain lesion size was measured on serial magnetic resonance imaging, and an autopsy was performed at 30 days. RESULTS The severity of shock and the degree of resuscitation were similar in both groups. Administration of FFP and LP was well tolerated with no differences in reversal of shock or thromboelastography parameters. Animals in both groups displayed the worst Neurologic Severity Score on postoperative Day 1 with rapid recovery and return to baseline within 7 days of injury. Lesion size on Day 3 in FFP-treated animals was 645 ± 85 versus 219 ± 20 mm 3 in LP-treated animals (p < 0.05). There were no differences in cognitive functions or delayed treatment-related complications. CONCLUSIONS Early treatment with LP in TBI + HS is safe and provides neuroprotection that is comparable to FFP.

Traumatic brain injury and hemorrhagic shock (TBI+HS) elicit a complex inflammatory response that contributes to secondary brain injury. There is currently no proven pharmacologic treatment for TBI+HS, but modulation of the epigenome has been shown to be a promising strategy. The aim of this study was to investigate whether valproic acid (VPA), a histone deacetylase inhibitor, modulates the expression of cerebral inflammatory gene profiles in a large animal model of TBI+HS. Ten Yorkshire swine were subjected to computer-controlled TBI+HS (40% blood volume). After 2 h of shock, animals were resuscitated with Hextend (HEX) or HEX+VPA (300 mg/kg, n = 5/group). Six hours after resuscitation, brains were harvested, RNA was isolated, and gene expression profiles were measured using a porcine microarray. Ingenuity Pathway Analysis® (IPA), gene ontology (GO), Parametric Gene Set Enrichment Analysis (PGSEA), and DAVID (Database for Annotation, Visualization, and Integrated Discovery) were used for pathway analysis. Key microarray findings were verified using real-time polymerase chain reaction (PCR). IPA analysis revealed that VPA significantly down-regulated the complement system (p

Background We have recently shown that inhibition of peptidylarginine deiminase (PAD) improves survival in a rodent model of lethal cecal ligation and puncture. The roles of PAD inhibitors in hemorrhagic shock (HS), however, are largely unknown. The goal of this study was to investigate the effects of YW3-56, a novel PAD inhibitor, on survival after severe HS. Methods Mouse macrophages were exposed to hypoxic conditions followed by reoxygenation in the presence or absence of YW3-56. Enzyme-linked immunosorbent assay (ELISA) was performed to measure levels of secreted tumor necrosis factor α and interleukin-6 in the culture medium. Cell viability was determined by methyl thiazolyl tetrazolium assay. In the survival experiment, anesthetized male Wistar–Kyoto rats ( n = 10/group) were subjected to 55% blood loss, and treated with or without YW3-56 (10 mg/kg, intraperitoneally). Survival was monitored for 12 h. In the nonsurvival experiment, morphologic changes of the lungs were examined. Levels of circulating cytokine-induced neutrophil chemoattractant 1 (CINC-1) and myeloperoxidase (MPO) in the lungs were measured by ELISA. Expression of lung intercellular adhesion molecules-1 (ICAM-1) was also determined by Western blotting. Results Hypoxia/reoxygenation (H/R) insult induced tumor necrosis factor α and interleukin-6 secretion from macrophages, which was significantly attenuated by YW3-56 treatment. YW3-56 treatment also increased cell viability when macrophages were exposed to H/R up to 6/15 h and improved survival rate from 20% to 60% in lethal HS rat model. Compared to the sham groups, pulmonary MPO activity and ICAM-1 expression in the HS group were significantly increased, and acute lung injury was associated with a higher degree of CINC-1 levels in serum. Intraperitoneal delivery of YW3-56 significantly reduced pulmonary MPO and ICAM-1 expression and attenuated acute lung injury. Conclusions Our results demonstrate for the first time that administration of YW3-56, a novel PAD inhibitor, can improve survival in a rat model of HS and in a cell culture model of H/R. The survival advantage is associated with an attenuation of local and systemic pro-inflammatory cytokines and the protection against acute lung injury after hemorrhage. Thus, PAD inhibition may represent a novel and promising therapeutic strategy for severe HS.

The objective of this study is to characterize effects of autophagy inhibition by 3-methyladenine on astaxanthin and fatty acid accumulation in Haematococcus pluvialis cultivated under high light condition. The present data show that 0.02 mM 3-methyladenine treatment effectively inhibited autophagosome formation but no impact on the cell growth and biomass of H. pluvialis, leading to a large increase in cellular reactive oxygen species (ROS), astaxanthin and fatty acid accumulation as well as palmitic acid enrichment under high light of 700 μmol·m−2·s−1. Furthermore, the key genes such as phytoene synthase (PSY), β-carotene ketolase (CRTO), and β-carotene hydroxylase (CRTR-b) in astaxanthin pathway are upregulated significantly whereas the expressions of the lipid-related genes biotin carboxylase (BC) and diacylglycerol acyltransferase (HpDGAT2D) just increased slightly in the 3-methyladenine-treated cells. Astaxanthin accumulation is not perfectly linear with fatty acid biosynthesis in H. pluvialis treated by 3-methyladenine under high light. Overall, autophagy might function importantly in astaxanthin and lipid enrichment in H. pluvialis under stress condition. The findings provide new insights to further investigation on the metabolic regulation in microalgae.

Osteogenesis imperfecta (OI) is a rare heritable disease with systemic connective tissue disorder. Most of the patients represent autosomal dominant form of OI, and are usually resulting from the mutations in type I collagen genes. However, the gene mutations reported previously only account for ∼70% of the OI cases. Here, in a Chinese OI family, we examined seven patients and nine normal individuals using the whole genome sequencing and molecular genetic analysis. The mutation of rs66612022 (COL1A2:p.Gly328Ser) related to glycine substitution was found in the seven patients. Moreover, we identified a novel missense mutation (HMMR:p.Glu2Gln). Interestingly, the individuals of this family with both the mutations were suffering from OI, while the others carried one or none of them are normal. The mutations of COL1A2 and HMMR and their combined effect on OI would further expand the genetic spectrum of OI.

A single-dose (150 mg/kg) of valproic acid (VPA) has been shown to decrease brain lesion size and improve neurologic recovery in preclinical models of traumatic brain injury (TBI). However, the longer-term (30 days) impact of single-dose VPA treatment after TBI has not been well evaluated.Yorkshire swine were subjected to TBI (cortical impact), hemorrhagic shock, and polytrauma. Animals remained in hypovolemic shock for 2 hours before resuscitation with normal saline (NS; volume = 3× hemorrhaged volume) or NS + VPA (150 mg/kg) (n = 5/cohort). Brain samples were harvested 30 days after injuries. The cerebral cortex adjacent to the site of cortical impact was evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry, and Western blot analysis. Neural apoptosis, inflammation, degeneration, plasticity, and signaling pathways were evaluated.For apoptosis, VPA treatment significantly decreased (p0.05) the number of TUNEL (+) cells and expression of cleaved-caspase 3. For inflammation and degeneration, expression of ionized calcium binding adaptor molecule-1, glial fibrillary acid protein, amyloid-β, and phosphorylated-Tau protein were significantly attenuated (p0.05) in the VPA-treated animals compared with the NS group. For, plasticity, VPA treatment also increased expression of brain-derived neurotrophic factor significantly (p0.05) compared with the NS group. For signaling pathways, nuclear factor-κB was decreased significantly (p0.05) and cytosolic IκBα expression was increased significantly (p0.05) in the VPA-treated animals compared with the NS group.Administration of a single dose of VPA (150 mg/kg) can decrease neural apoptosis, inflammation, and degenerative changes, and promote neural plasticity at 30 days after TBI. In addition, VPA acts, in part, via regulation of nuclear factor-κB and IκBα pathways.

Enhancing soybean (Glycine max) oil production is crucial to meet the market demand of vegetable oil. Diacylglycerol acyltransferase (DGAT) catalyzes the final acylation reaction of triacylglycerol (TAG) synthesis, acting as one of the rate-limiting enzymes for oil biosynthesis in plant seeds. Here, a cDNA clone VgDGAT1A encoding the DGAT1 protein was isolated from the high oil plant Vernonia galamensis. VgDGAT1A was specifically overexpressed in soybean seeds, and several high-generation transgenic lines (T7) were obtained by continuous selection. qPCR analysis showed that VgDGAT1A was highly expressed in the mid-development stage (30-45 DAF) of the transgenic seeds. Accordingly, the DGAT enzyme activity in the transgenic seeds was increased by 7.8 folds in comparison with the wild-type controls. Seed oil and starch contents were, respectively, increased by 5.1% (Dry weight) and reduced by 2%-3% in the transgenic soybeans. Importantly, protein content was not significantly different between transgenic and control seeds. Seed weight and germination rate of the transgenic lines exhibited no negative effect. Fatty acid profiling demonstrated that antioxidant oleic acid (C18:1Δ9) content in the transgenic seed oil was elevated by 8.2% compared to the control, and correspondingly, easily-oxidized linoleic acid (C18:2Δ9,12) and linolenic acid (C18:3Δ9,12,15) were decreased by 6% and 2% respectively. Taken together, seed-specific overexpression of an exogenous VgDGAT1A gene can break the negative linkage of oil and protein contents in soybean seeds, indicating that engineering of this highly-active DGAT enzyme is an effective strategy to improve oil yield and nutritional value in oilseeds.为提高大豆Glycine max 种子含油量和营养品质，文中以二酰甘油酰基转移酶1 (Diacylglycerol acyltransferase 1，DGAT1) 基因为遗传修饰靶标。将来自高油植物斑鸠菊Vernonia galamensis L.编码DGAT1 酶蛋白的cDNA 克隆VgDGAT1A 在大豆种子特异超表达。连续选择获得高代 (T7) VgDGAT1A 转基因大豆株系。转基因株系表型鉴定显示，在大豆种子发育中期 (30–45 DAF)，VgDGAT1A 高表达，相应地DGAT 酶活性是非转基因野生型和空载体转化对照的7.8 倍。转基因成熟种子含油量比对照提高了5.1%，淀粉含量比对照减少2%–3%，蛋白质含量与对照无显著差异。此外，转基因大豆种子百粒重 (14.5 g) 和种子萌发率 (95.6%) 与对照亦无明显差异。种子油脂脂肪酸成分分析显示，转基因大豆种子油中抗氧化的油酸 (C18:1Δ9) 含量比对照提高8.2%，相应地易氧化的亚油酸 (C18:2Δ9,12) 和亚麻酸 (C18:3Δ9,12,15) 分别减少6%和2%。这些数据表明，种子特异超表达外源VgDGAT1A 基因，打破了大豆种子含油量和蛋白质含量的负连锁，显著提高种子含油量且未导致蛋白含量降低。转基因大豆种子重量和萌发率亦未显负效应，而且种子油脂抗氧化性和营养品质得以改善。研究表明应用这一高酶活性VgDGAT1A 的基因工程是提高种子含油量和改善油脂品质的一条有效途径。.

Over-the-air (OTA) radiated testing for multi-input multi-output (MIMO) capable mobile terminals has been actively discussed in the standardization in recent years, where multiprobe anechoic chamber (MPAC) method has been selected. Setting up a multiprobe configuration is costly, so finding ways to limit the number of probes will make the implementation of the test system simpler and cheaper. In this paper, two probe subset selection algorithms for three dimensional (3D) MPAC and fading emulator are proposed, namely, decremental selection algorithm (DSA) and error threshold selection algorithm based on alternating search (SAAS), where the goal is to minimize the number of probe antennas while ensuring the accuracy of the target channel emulation. Simulation results show that a small number of probe sets are selected under the given error threshold by the two algorithms, which greatly saves the cost of setup configuration. The performance of SAAS generally outperform that of DSA, especially when there are fewer probes selected.

In this paper, we propose an indoor positioning model using the principle of Bayesian estimation. By analyzing the mobile features of the target and combining these features with state transition probability, we narrow down the belief region of the location distribution. To make our system model more intuitive, some basic concepts about the factor graph and the corresponding sum-product algorithm are introduced. Then, we map our system model onto the factor graph and make basic rules for message propagation. Based on the probability graphic model, mobile features enhanced sum-product algorithm is implemented to calculate the posterior probability of the target given range measurement observations. Simulation results show that the positioning precision of the proposed algorithm is higher than that of the existing algorithms at different speed levels, and the proposed algorithm also performs more robust in noisy indoor environment.

As location information becomes vitally important, positioning has been a highly desirable feature of 5G system which enables a huge amount of location-based applications and services. Millimeter wave (mmWave) is the promising technology for both offering better spectrum resource and positioning performance. A virtualized indoor office scenario with only one mmWave base station (BS) is considered in this paper. User equipment (UE) motion feature, mmWave line-of-sight (LoS) and first order reflection paths' AoA-ToA are fused for indoor positioning. Firstly, an improved least mean square (LMS) algorithm that combines motion message is proposed to refine the multi-path AoA estimation. Furthermore, a modified multi-path unscented Kalman filter (UKF) is proposed to track UE's position in the scenario. The information exchanges of the two stages not only consist of estimates(position, AoA) but also variance of position. Based on the simulation results, the proposed methods provide 2 times LoS-AoA estimation gains and centimeter 3D positioning accuracy respectively. Besides, this strategy is capable of positioning task with insufficient anchor nodes (AN).

Hemorrhage remains the leading cause of preventable deaths in trauma. Endovascular management of non-compressible torso hemorrhage has been at the forefront of trauma care in recent years. Since complete aortic occlusion presents serious concerns, the concept of partial aortic occlusion has gained a growing attention. Here, we present a large animal model of hemorrhagic shock to investigate the effects of a novel partial aortic balloon occlusion catheter and compare it with a catheter that works on the principles of complete aortic occlusion. Swine are anesthetized and instrumented in order to conduct controlled fixed-volume hemorrhage, and hemodynamic and physiological parameters are monitored. Following hemorrhage, aortic balloon occlusion catheters are inserted and inflated in the supraceliac aorta for 60 min, during which the animals receive whole-blood resuscitation as 20% of the total blood volume (TBV). Following balloon deflation, the animals are monitored in a critical care setting for 4 h, during which they receive fluid resuscitation and vasopressors as needed. The partial aortic balloon occlusion demonstrated improved distal mean arterial pressures (MAPs) during the balloon inflation, decreased markers of ischemia, and decreased fluid resuscitation and vasopressor use. As swine physiology and homeostatic responses following hemorrhage have been well-documented and are like those in humans, a swine hemorrhagic shock model can be used to test various treatment strategies. In addition to treating hemorrhage, aortic balloon occlusion catheters have become popular for their role in cardiac arrest, cardiac and vascular surgery, and other high-risk elective surgical procedures.

We have found earlier that Tubastatin A (TubA), a selective inhibitor of histone deacetylase 6 (HDAC6), improves survival in a mouse model of lethal cecal ligation and puncture (CLP)-induced sepsis. However, the underlying mechanisms have not been fully established. This study sought to test the hypothesis that TubA could affect both lung and splenic function. C57BL/6J mice were subjected to CLP, and randomized to receive either TubA (70 mg/kg) dissolved in dimethyl sulfoxide (DMSO), or DMSO alone, 1 hour following CLP. Sham animals acted as a control. Twenty-four hours later, lung tissue was harvested for pathological examination, and splenic tissue was harvested for bacterial colonization. In a parallel study, the spleen was collected 48 hours following CLP, and single cell suspension was prepared. Splenocytes then underwent flow cytometry to analyze the immune cell population. RAW264.7 macrophages were treated with lipopolysaccharide (LPS) with or without the presence of TubA (10 μΜ) at 37°C for 3h to assess the effect on macrophage phagocytosis. We found that acute lung injury secondary to lethal sepsis was attenuated by TubA. Treatment with TubA restored the percentage of B lymphocytes, and significantly increased percentages of innate immune cells and macrophages compared to the vehicle-treated CLP group. Moreover, TubA significantly decreased the bacterial load in spleen, and improved the phagocytic ability of RAW264.7 murine macrophages in vitro. Such findings may help to explain the beneficial effects of TubA treatment in a model of lethal sepsis, as previously reported.

Plant-specific GRAS transcription factors regulate various biological processes in plant growth, development and stress responses. However, this important gene family was not fully characterized in pepper (Capsicum annuumL.), an economically important vegetable crop. Here, a total of 50 CaGRAS members were identified in pepper genome and renamed by their respective chromosomal distribution. Genomic organization revealed that mostCaGRASgenes (84%) have no intron. Phylogenetic analysis divided pepper CaGRAS members into 10 subfamilies, with each having distinct conserved domains and functions. For the expansion of theGRASgenes in pepper, segmental duplication contributed more than tandem duplication did. Gene expression analysis in various tissues demonstrated that most ofCaGRASgenes exhibited a tissue- and development stage-specific expression pattern, uncovering their potential functions in pepper growth and development. Moreover, 21CaGRASgenes were differentially expressed under cold, drought, salt and gibberellin acid (GA) treatments, indicating that they may implicated in plant response to abiotic stress. Notably, GA responsivecis-elements were detected in the promoter regions of the majority ofCaGRASgenes, suggesting that CaGRAS may involve in signal cross-talking. The first comprehensive analysis of GRAS gene family in pepper genome by this study provide insights into understanding the GRAS-mediated regulation network, benefiting the genetic improvements in pepper and some other relative plants.

Machine-type communication (MTC) is endorsed in the fifth-generation (5G) networks to realize innovative IoT based applications, such as smart city and intelligent manufacturing. MTC devices with sensing and communication capabilities can monitor the surrounding environment and transmit the collected information back to Base Station (BS) for further data analysis. The dense deployment of sensing devices calls for a clustering structure to preprocess the redundant data to avoid traffic overload. Moreover, due to limited battery capacity, the energy cost remains a critical concern in such IoT systems. In this paper, we propose an energy-efficient clustering routing algorithm. Considering the non-uniform traffic distribution, we propose an uneven cluster formation scheme for load balancing and energy efficiency. Moreover, we propose a distributed cluster head (CH) rotation mechanism to balance energy consumption within each cluster. As for long distance transmission to BS, we design a dynamic multi-hop routing algorithm among CH nodes based on a proposed distance-and-energy-aware cost function to avoid the energy hole problem. Simulation results show that the performance of our proposed algorithm is competitive in terms of network lifetime, throughput and energy efficiency.

Frictional temperature rise (FTR) can cause sharp temperature increase in the contact area between wheel and rail, then affects the pulsed eddy current (PEC) signal. The paper proposes a novel method based on classical Hertz contact theory and the multi-field coupling finite element (FE) model to study the interaction between FTR and PEC signal. The results show that the transient temperature field caused by FTR can lead to the confusion of surface defect and interior defect using PEC testing.

Dynamic time division duplex (TDD) downlink/uplink (DL/UL) reconfiguration has been regarded as a promising technique to enhance the radio resource utilization. However, serious co-channel co-subframe DL-UL interference caused by the opposite transmission direction may weaken the system performance. In this paper, we propose a novel cluster-based enhanced interference mitigation and traffic adaption (eIMTA) scheme, which considers the number of times that the cluster configuration does not meet the transmission demand of the cell. In order to maximize the packet throughput and resource utilization, cells with severe DL-UL interferences and similar transmission demands will be clustered together in our proposed scheme. The balance between traffic adaption flexibility and interference mitigation is obtained. Furthermore, an optimized reconfiguration algorithm is developed to select the configuration that matches the transmission requirements of the cells in cluster best based on the buffered DL/UL traffic ratio. System level simulation results indicate that our cluster-based eIMTA scheme can achieve substantial gains in the cell average packet throughput and cell-edge UE packet throughput.

Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) is highly lethal. In a nonsurvival model of TBI + HS, addition of high-dose valproic acid (VPA) (300 mg/kg) to hetastarch reduced brain lesion size and associated swelling 6 hours after injury; whether this would have translated into better neurologic outcomes remains unknown. It is also unclear whether lower doses of VPA would be neuroprotective. We hypothesized that addition of low-dose VPA to normal saline (NS) resuscitation would result in improved long-term neurologic recovery and decreased brain lesion size.TBI was created in anesthetized swine (40-43 kg) by controlled cortical impact, and volume-controlled hemorrhage (40% volume) was induced concurrently. After 2 hours of shock, animals were randomized (n = 5 per group) to NS (3× shed blood) or NS + VPA (150 mg/kg). Six hours after resuscitation, packed red blood cells were transfused, and animals were recovered. Peripheral blood mononuclear cells were analyzed for acetylated histone-H3 at lysine-9. A Neurological Severity Score (NSS) was assessed daily for 30 days. Brain magnetic resonance imaging was performed on Days 3 and 10. Cognitive performance was assessed by training animals to retrieve food from color-coded boxes.There was a significant increase in histone acetylation in the NS + VPA-treated animals compared with NS treatment. The NS + VPA group demonstrated significantly decreased neurologic impairment and faster speed of recovery as well as smaller brain lesion size compared with the NS group. Although the final cognitive function scores were similar between the groups, the VPA-treated animals reached the goal significantly faster than the NS controls.In this long-term survival model of TBI + HS, addition of low-dose VPA to saline resuscitation resulted in attenuated neurologic impairment, faster neurologic recovery, smaller brain lesion size, and a quicker normalization of cognitive functions.

Background: Seven isoforms of histone deacetylase Class III have been reported - Sirtuin (SIRT) 1-7. We recently demonstrated that EX-527, an inhibitor of SIRT1, reduces mortality in a mouse model of lethal-cecal-ligation-and-puncture (CLP)-induced septic shock. Our present study was aimed at determining whether selective inhibition of SIRT2, with AGK2, would decrease animal death and attenuate the inflammatory response in a septic model. Methods: Experiment I: C57BL/6J mice were intraperitoneally given either AGK2 (82 mg/kg) in dimethyl sulfoxide (DMSO) or DMSO alone, and 2 h later subjected to CLP. Survival was monitored for 240 hours. Experiment II: mice treated the same way as Experiment I, were grouped into (i) DMSO vehicle, and (ii) AGK2, with sham mice (operating but without any treatment) serving as controls. Peritoneal fluid and peripheral blood were examined at 24 and 48 hours for cytokine production. Samples of blood at 48 h were also allocated to assess coagulability using Thrombelastography (TEG). Morphological changes of bone marrow were evaluated from long bones (femurs and tibias) with hematoxylin and eosin (H&E) staining. Bone marrow atrophy was quantified by a blinded pathologist. Experiment III: cytokines in supernatant of the cultured normal primary splenocytes were measured after the cells were stimulated by lipopolysaccharide and treated with or without AGK2 (10 μM) for 6 hours. Results: AGK2 significantly reduced mortality and decreased levels of cytokines in blood (TNF-α: 298.3±24.6 vs 26.8±2.8 pg/ml, p=0.0034; IL-6: 633.4±82.8 vs 232.6±133.0 pg/ml, p=0.0344) and peritoneal fluid (IL-6: 704.8±67.7 vs 391.4±98.5 pg/ml, p=0.033) compared to vehicle control. Also, AGK2 suppressed the TNF-α and IL-6 production in the cultured splenocytes (TNF-α: 68.1±6.4 vs 23.9±2.8 pg/ml, p=0.0009; IL-6: 73.1±4.2 vs 49.6±3.0 pg/ml; p=0.0051). The TEG data showed that the mice subjected to CLP displayed prolonged fibrin formation and fibrin cross-linkage time, slower clot formation, decreased platelet function, and clot rigidity. AGK2 treatment was associated with dramatic improvements in fibrin cross-linkage and clot formation times, without a significant impact on the clot initiation parameters or platelet function. Additionally, AGK2 significantly attenuated the bone marrow atrophy (58.3±6.5 vs 30.0±8.2%, p=0.0262). Conclusion: Selective inhibition of SIRT2 significantly improves survival, and attenuates sepsis-associated “cytokine storm”, coagulopathy, and bone marrow atrophy in a mouse model of lethal septic shock.

In this letter, we study the feasibility of interference neutralization (IN) for a two-user interference channel (IC) with a multi-input-multi-output (MIMO) instantaneous relay. With this channel model, Lee et al. show that instantaneous relaying is a promising approach to neutralize interference and increase the degrees of freedom (DoF). However, only the scenario where each node has the same number of antennas has been studied yet, for general antenna configuration at the relay, the maximum achievable DoF remains unknown. Assuming linear transceivers with an amplify-and-forward (AF) relay, we first present the necessary condition for generalized IN. Then, we derive the necessary and sufficient conditions for pure IN and coordinated IN. The derived sufficient conditions give rise to the minimum relay antenna configuration to support interference-free transmission. Our proof throws lights on how to use the relay resources to neutralize the interference efficiently.

Defect recognition plays an important role in the structure integrity and health monitor of in-service equipment. However, it is difficult to recognise deep-layer defect or small-size defect in conductive structure during pulsed eddy current (PEC) testing. Aiming at the issue, this article proposes a method based on Hilbert–Huang transform which consists of two modules: data processing and defect recognition. In the data processing module, the PEC response signal is decomposed into a few of intrinsic mode functions (IMFs) using ensemble empirical mode decomposition method. The IMFs whose variance contribution rates are bigger than 1% are chosen to reconstruct signal in order to remove noise. In the defect recognition module, the features based on specific frequency components of marginal spectrum (MS) of the reconstructed signals are extracted to discriminate those defects in surface and subsurface. Furthermore, the normalisation MS energy ratio is proposed to quantify defects which cannot be distinguishe...

Therapeutic hypothermia (hypo) and valproic acid (VPA, a histone deacetylase inhibitor) have independently been shown to be protective in models of trauma and hemorrhagic shock but require logistically challenging doses to be effective. Theoretically, combined treatment may further enhance effectiveness, allowing us to use lower doses of each modality. The aim of this study was to determine whether a combination of mild hypo and VPA treatments would offer better cytoprotection compared with that of individual treatments in a hemorrhage model.Male Sprague-Dawley rats were subjected to 40% volume-controlled hemorrhage, kept in shock for 30 min, and assigned to one of the following treatment groups: normothermia (36°C-37°C), hypo (30 ± 2°C), normothermia + VPA (300 mg/kg), and hypo + VPA (n = 5 per group). After 3 h of observation, the animals were sacrificed, liver tissue was harvested and subjected to whole cell lysis, and levels of key proteins in the prosurvival Akt pathway were measured using Western blot.Activation of the proapoptotic protein cleaved caspase-3 was significantly lower in the combined treatment group relative to normothermia (P0.05). Levels of the prosurvival Bcl-2 was significantly higher in the combined treatment group relative to sham, normothermia, and normothermia + VPA groups (P0.005). The downstream prosurvival protein phospho-GSK-3β was significantly higher in the sham, hypo, and combined treatment groups compared with that in normothermia groups with or without VPA (P0.05). Levels of the prosurvival β-catenin were significantly higher in the combined treatment group relative to normothermia (P0.01).This is the first in vivo study to demonstrate that combined treatment with VPA and hypo offers better cytoprotection than these treatments given independently.

Background Lipopolysaccharide (LPS) has a deleterious effect on several organs, including the liver, and eventually leads to endotoxic shock and death. LPS-induced hepatotoxicity is characterized by disturbed intracellular redox balance and excessive reactive oxygen species (ROS) accumulation, leading to liver injury. We have shown that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a murine model of LPS-induced shock, but the protective effect of SAHA against liver damage remains unknown. The goal of this study was to investigate the mechanism underlying SAHA action in murine livers. Method Male C57BL/6J mice (6–8 wk), weighing 20–25 g, were randomly divided into three groups: (A) a sham group was given isotonic sodium chloride solution (10 μL/g body weight, intraperitoneal, i.p.) with dimethyl sulfoxide (DMSO; 1 μL/g body weight, i.p.); (B) an LPS group was challenged with LPS (20 mg/kg, i.p.) dissolved in isotonic sodium chloride solution with DMSO; (C) and an LPS plus SAHA group was treated with SAHA (50 mg/kg, i.p.) dissolved in DMSO immediately after injection of LPS (20 mg/kg, i.p.). Mice were anesthetized, and their livers were harvested 6 or 24 h after injection to analyze whether SAHA affected production of ROS and activation of apoptotic proteins in the liver cells of challenged mice. Results SAHA counteracted LPS-induced production of ROS (thiobarbituric acid reactive substances and nitrite) and reversed an LPS-induced decrease in antioxidant enzyme, glutathione. SAHA also attenuated LPS-induced hepatic apoptosis. Moreover, SAHA inhibited activation of the redox-sensitive kinase, apoptosis signal-regulating kinase-1, and the mitogen-activated protein kinases, p38 and Jun N-terminal kinase. Conclusions Our data indicate, for the first time, that SAHA is capable of alleviating LPS-induced hepatotoxicity and suggest that a blockade of the upstream events required for apoptosis signal-regulating kinase-1 action may serve as a new therapeutic option in the treatment of LPS-induced inflammatory conditions.

The present research deals with the important issue of assessing surface water quality ranking by combining the use of two advanced multivariate statistical techniques: Kohonen's self-organizing maps (SOM) and the Hasse diagram technique (HDT). The object of the study is the Mudan River of Mudanjiang city region, China. Samples were collected on a regular monthly basis in 2007–2011 from all sampling sites along the river, involving six major water quality parameters. The grouping of water parameters and the clustering of sampling events by the use of SOM has helped in their pre-processing for application of the HDT. The HDT orders clusters according to the pre-clustered water sampling events. The water quality was ranked against norms established by the Ministry of Environmental Protection of the People's Republic of China in order to assess in detail the water quality of the whole river system. The resulting map of the spatial and temporal changes in the water quality at each sampling site was specifically described by ArcGIS.

Dynamic time-division duplexing (TDD) allows flexible resource allocation among different transmission directions to adapt to the traffic variation. However, strong cross-link interference (CLI), e.g. downlink (DL)-to-uplink (UL) and UL-to-DL interference, may lead to significant performance degradation. In this paper, a joint user scheduling and transceiver design based CLI suppression (CLIS) scheme is investigated in multi-cell multi-user massive multiple-input multiple-output (MIMO) dynamic TDD systems. To eliminate UL-to-DL interference, an algorithm is designed to avoid scheduling DL user equipments (UEs) which will be interfered by neighboring UL UEs. To suppress DL-to-UL interference, the DL-to-UL interference channel is divided into several interference sub-channels and a novel precoding and detection design strategy is provided to make the wanted signal channel orthogonal to these interference sub-channels. Finally, the simulation results show that the proposed scheme can effectively eliminate CLI so that the UL user rate is significant improved compared to conventional schemes.

The plant-specific WRINKLED1 (WRI1) is a member of the AP2/EREBP class of transcription factors that positively regulate oil biosynthesis in plant tissues. Limited information is available for the role of WRI1 in oil biosynthesis in castor bean (Ricinus connunis L.), an important industrial oil crop. Here, we report the identification of two alternatively spliced transcripts of RcWRI1, designated as RcWRI1-A and RcWRI1-B. The open reading frames of RcWRI1-A (1341 bp) and RcWRI1-B (1332 bp) differ by a stretch of 9 bp, such that the predicted RcWRI1-B lacks the three amino acid residues “VYL” that are present in RcWRI1-A. The RcWRI1-A transcript is present in flowers, leaves, pericarps and developing seeds, while the RcWRI1-B mRNA is only detectable in developing seeds. When the two isoforms were individually introduced into an Arabidopsis wri1-1 loss-of-function mutant, total fatty acid content was almost restored to the wild-type level, and the percentage of the wrinkled seeds was largely reduced in the transgenic lines relative to the wri1-1 mutant line. Transient expression of each RcWRI1 splice isoform in N. benthamiana leaves upregulated the expression of the WRI1 target genes, and consequently increased the oil content by 4.3–4.9 fold when compared with the controls, and RcWRI1-B appeared to be more active than RcWRI1-A. Both RcWRI1-A and RcWRI1-B can be used as a key transcriptional regulator to enhance fatty acid and oil biosynthesis in leafy biomass.

Energy efficiency is a critical issue for mobile target tracking in wireless sensor networks, which typically consist of small-sized battery-operated devices with limited processing capability. Clustering techniques are widely adopted for target tracking in large-scale sensor networks to reduce energy consumption and delay. In this paper, we propose an energy efficient target tracking algorithm, called triangular cluster-based target tracking (TCTT). However, clustering based target tracking suffers from the boundary problem caused by insufficient switch among clusters when the target moves close to the boundary. To overcome the boundary problem, we propose a cluster transforming mechanism to prevent loss of the target. To reduce the complexity of accurately locating the target position, we employ the gray model prediction algorithm with wavelet denoising. Through simulation results, we show that our proposed scheme achieves better energy efficiency compared with other typical target tracking algorithms.

The automatic recognition of hidden defects plays a key role in the structure integrity and healthy monitoring (SIHM) system. The article proposes a novel method that combines the Hilbert Huang transform (HHT) and hybrid support vector machine-particle swarm optimization (Hybrid SVM-PSO) model for recognizing hidden defects during using pulsed eddy current (PEC) testing. The proposed approach uses the HHT algorithm to extract feature from PEC response signal to indicate various defects, and the first step of HHT, ensemble empirical mode decomposition (EEMD) method, is improved in order to obtain accurate intrinsic mode function components (IMFs). The defects are recognized by the proposed Hybrid SVM-PSO model, which is composed of classification module and optimization module. The optimization module made up of PSO method is used to configure the key parameters of classification module realized by SVM. A set of experimental data collected from a self-made rail specimen is used to validate the proposed approach. The results show that the proposed method based on the HHT and hybrid SVM-PSO model is beneficial to improve the automatic recognition of hidden defects.

Hemorrhage is a common cause of death in the battlefield. Valproic acid (VPA) has been associated with improved outcomes in multiple models of trauma, when combined with isotonic fluid resuscitation. However, isotonic fluid administered in this setting is logistically impractical and may be associated with complications. In this study, we sought to evaluate the feasibility and immunologic impact of combining VPA treatment with low-volume hypertonic saline (HTS). In vivo: female Yorkshire swine were subjected to hemorrhage (40% total blood volume) and polytrauma (rib fracture and delayed liver injury). Animals were kept in shock for 30 minutes and resuscitated with (1) normal saline (NS, 3× hemorrhaged volume), (2) HTS (7.5% saline, 4 mL/kg), or (3) HTS + VPA (4 mg/kg; 150 mg/kg; n = 3/cohort). After 18 hours of observation, animals were euthanized and the lungs evaluated for acute injury and expression of myeloperoxidase (MPO) and caveolin-1 (Cav-1). In vitro: human umbilical vein endothelial cells (HUVECs) were exposed to anoxic conditions (5% CO2, 95% N2) for 16 hours in (1) normosmotic, (2) hyperosmotic (400 mOsm), or (3) hyperosmotic + VPA (4 mM) media. Immunohistochemistry and Western blots were performed to determine Cav-1 expression. Lungs from VPA-treated animals demonstrated decreased acute injury, MPO expression, and endothelial expression of Cav-1 when compared to lungs from animals resuscitated with NS or HTS alone. Similarly, HUVECs cultured in hyperosmotic media containing VPA demonstrated decreased expression of Cav-1. This study demonstrates that combined treatment with VPA and HTS is a viable strategy in hemorrhagic shock and polytrauma. Attenuation of lung injury following VPA treatment may be related to modulation of the inflammatory response.

Current biomarkers for sepsis are limited by their non-specificity, short half-life, and insensitive response to therapy. Recently, we have demonstrated that citrullinated histone H3(CitH3) is released into the blood from neutrophil extracellular traps(NETs) in response to severe infection, and CitH3 may be a potential biomarker for sepsis. In the present study, we found that NET components were released in mouse models of both lipopolysaccharide(LPS)-induced shock (LPSS) and hemorrhagic shock (HS). To further quantify CitH3 in the NETs, we established a CitH3 specific enzyme-linked immunosorbent assay. Circulating CitH3 was found to be elevated only in LPSS but not in HS. Importantly, blood CitH3 was detected 30 minutes after LPS insult, and remained elevated for 24 hours (period of the highest mortality). Treatment of endotoxic mice with YW3-56, a peptidylarginine deiminase-2/4 inhibitor, significantly diminished levels of CitH3 in the blood. Interleukin-1β did not respond to LPS early, and interleukin-1β and interleukin-6 fluctuated although they responded to treatment. Procalcitonin reacted to LPS insult late. Compared to CitH3, these biomarkers were non-specifically induced in LPSS and HS. Collectively, our results demonstrate that YW3-56 protects animals from LPSS, and CitH3 is a reliable biomarker due to its early appearance, specificity, duration, and response to therapeutic intervention.

We have recently demonstrated that inhibition of histone deacetylase (HDAC) Class I, II, and IV with nonspecific HDAC inhibitors improves survival in a mouse model of lethal cecal ligation and puncture (CLP). However, the consequence of HDAC Class III inhibition is unknown in this model. The aims of the present study were to explore the effect of EX-527, a selective Sirtuin 1 (SIRT1) inhibitor, on survival in the lethal model of CLP-sepsis and to assess the impact of the treatment on inflammatory cytokine production, coagulopathy, and bone marrow atrophy during severe sepsis.For Experiment I, C57BL/6J mice were subjected to CLP and, 1 hour later, intraperitoneally injected with either EX-527 dissolved in dimethyl sulfoxide (DMSO) or DMSO only. Survival was monitored for 10 days. For Experiment II, 1 hour after CLP animals were randomly treated with (1) DMSO vehicle and (2) EX-527. Peritoneal fluid and blood samples were collected for measurement of cytokines, and blood was also used to evaluate coagulation status using thrombelastography. In addition, long bones (femurs and tibias) were examined to determine morphologic changes in the marrow by hematoxylin and eosin staining. For Experiment III, normal primary splenocytes were cultured and treated with lipopolysaccharide in the presence or absence of EX-527 to assess cytokine production.EX-527 significantly improved survival (50% vs. 0% survival as compared to vehicle, p = 0.0007) and attenuated levels of cytokines tumor necrosis factor α and interleukin 6 in the blood and the peritoneal fluid compared with the vehicle control. It also decreased tumor necrosis factor α and interleukin 6 production by splenocytes in vitro. Selective inhibition of SIRT1 was associated with significant improvements in fibrin cross-linkage, platelet function, and clot rigidity but had no significant impact on the clot initiation parameters. Moreover, inhibition of SIRT1 was associated with a significant decrease in bone marrow atrophy.Selective inhibition of Class III HDAC SIRT1 significantly improves survival, attenuates cytokine levels and sepsis-associated coagulopathy, and decreases bone marrow atrophy in a lethal mouse septic model.

Background Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of trauma-related deaths. These insults disrupt coagulation and endothelial systems. This study investigated whether previously reported differences in lesion size and brain swelling during normal saline (NS), colloids (Hextend [HEX]), and fresh frozen plasma (FFP) resuscitation are associated with differential effects on coagulation and endothelial systems. Methods We subjected 15 Yorkshire swine to TBI and HS (40% blood volume), and kept in HS for 2 hours before resuscitation with NS, HEX, or FFP. Markers of endothelial activation (E-selectin, Intercellular adhesion molecule [ICAM]-1), coagulation activation (prothrombin fragment 1 + 2), and natural anticoagulation (activated protein C [aPC]) were determined in serum and brain whole cell lysates. Results Serum levels of aPC were greater in the NS group (203 ± 30 pg/mL) compared with HEX (77 ± 28 pg/mL; P = .02) and FFP (110 ± 28 pg/mL; P = .09), as was PF 1 + 2 in the brain when compared with FFP (PF 1 + 2, 89 ± 46 vs 37 ± 14 ng/mL; P = .035). Brain E-selectin was greater in the NS group compared with FFP (3.36 ± 0.02 vs 3.31 ± 0.01 ng/mL; P = .029). Circulating ICAM-1 levels were increased in the NS group (151 ± 9 ng/mL) compared with the HEX (100 ± 9 ng/mL; P Conclusion In this clinically realistic large animal model of TBI + HS, NS resuscitation was associated with an early activation of coagulation, natural anticoagulation, and endothelial systems, compared with HEX and FFP.

We have recently demonstrated that in a rodent model of lipopolysaccharide (LPS)-induced shock, an increase in circulating citrullinated histone H3 (Cit H3) is associated with lethality of sepsis, and treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor (HDACI), significantly improves survival. However, the role of Cit H3 in pathogenesis and therapeutics of sepsis are largely unknown. The present study was designed to test whether treatment with HDACI could inhibit cellular Cit H3 production, and inhibition of peptidylarginine deiminase (PAD, an enzyme producing Cit H3) with Cl-amidine (PAD inhibitor) or neutralization of blood Cit H3 with anti-Cit H3 antibody could improve survival in a clinically relevant mouse model of cecal ligation and puncture (CLP)-induced septic shock.Three experiments were carried out. In experiment I, HL-60 neutrophilic cells grown on a coverslip were treated with LPS (100 ng/mL) in the presence or absence of SAHA (5 μmol) for 3 hours, and subjected to immunostaining with anti-Cit H3 antibody to assess effect of SAHA on Cit H3 production under a fluorescence microscope. The ratio of Cit H3 positive cells was calculated as mean values ± SD (n = 3). In experiment II, male C57BL/6J mice were subjected to CLP, and 1 hour later randomly divided into 2 groups for intraperitoneal injection as follows: (1) Dimethyl sulfoxide (DMSO), (2) SAHA (50 mg/kg) in DMSO, and (3) Cl-amidine (80 mg/kg) in DMSO (n = 10/group). In experiment III, male C57BL/6J mice were divided into control and treatment groups, and subjected to CLP. Two hours later, immunoglobulin (Ig)G and Cit H3 antibody (20 mg/kg IV; n = 5/group) were injected into the control and treatment groups, respectively. Survival was monitored for ≤10 days.In experiment I, LPS induced Cit H3 production in the HL-60 cells, and SAHA treatment inhibited H3 citrullination significantly (P.05). In experiment II, all vehicle-injected mice died within 3 days with increased circulating Cit H3 levels, whereas treatment with HDACI or Cl-amidine notably improved long-term survival (P.01). In experiment III, administration of IgG did not improve survival, but a single treatment with Cit H3 specific antibody significantly improved survival (P.014).Inhibition of HDAC or PAD significantly suppresses Cit H3 production in vitro and improves survival in vivo. Neutralization of Cit H3 significantly improves survival in septic mice. Collectively, our findings indicate for the first time that Cit H3 could not only serve as a potential biomarker, but also a novel therapeutic target in sepsis.

Background An overproduction of corticosterone during severe sepsis results in increased apoptosis of immune cells, which may result in relative immunosuppression and an impaired ability to fight infections. We have previously demonstrated that administration of tubastatin A, a selective inhibitor of histone deacetylase-6 (HDAC6), improves survival in a lethal model of cecal ligation and puncture (CLP) in mice. The purpose of this study was to characterize the effects of this treatment on sepsis-induced stress responses and immune function. Methods C57BL/6J mice were subjected to CLP, and 1 hour later given an intraperitoneal injection of either tubastatin A dissolved in dimethyl sulfoxide (DMSO), or DMSO only. Blood samples were collected to measure the levels of circulating corticosterone and adrenocorticotropic hormone (ACTH). Thymus and long bones (femur and tibia) were subjected to hematoxylin and eosin staining, and immunohistochemistry was utilized to detect cleaved-caspase 3 in the splenic follicles as a measure of cellular apoptosis. Results All vehicle-treated CLP animals died within 3 days, and displayed increased corticosterone and decreased ACTH levels compared with the sham-operated group. These animals also developed atrophy of thymic cortex with a marked depletion of thymocytes. Tubastatin A treatment significantly attenuated the stress hormone abnormalities. Treated animals also had significantly lower percentages of thymic atrophy (95.0 ± 5.0 vs 42.5 ± 25.3; P = .0366), bone marrow depletion and atrophy (58.3 ± 6.5 vs 25.0 ± 14.4%; P = .0449), and cellular apoptosis in the splenic follicles (41.2 ± 3.7 vs 28.5 ± 4.3 per 40× field; P = .0354). Conclusion Selective inhibition of HDAC6 in this lethal septic model was associated with a significant blunting of the stress responses, with attenuated thymic and bone marrow atrophy, and decreased splenic apoptosis. Our findings identify a novel mechanism behind the survival advantage seen with tubastatin A treatment.

Background Sepsis has a profound impact on the inflammatory and hemostatic systems. In addition to systemic inflammation, it can produce disseminated intravascular coagulation, microvascular thrombosis, consumptive coagulopathy, and multiple organ failure. We have shown that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), improves survival in a lethal model of cecal ligation and puncture (CLP) in mice, but its effect on coagulation remains unknown. The goal of this study was to quantify the impact of SAHA treatment on coagulopathy in sepsis. Methods C57BL/6J mice were subjected to CLP, and 1 hour later given intraperitoneally either SAHA dissolved in dimethyl sulfoxide (DMSO) or DMSO only. Sham-operated animals were handled in similar manner without CLP. Blood samples were collected by cardiac puncture and evaluated using the TEG 5000 Thrombelastograph Hemostasis Analyzer System. Results Compared with the sham group, all animals in DMSO vehicle group died within 72 hours, and developed coagulopathy that manifested as prolonged initial fibrin formation and fibrin cross-linkage time, and decreased clot formation speed, platelet function, and clot rigidity. SAHA treatment significantly improved survival and was associated with improvement in fibrin cross-linkage and clot formation, as well as platelet function and clot rigidity, without a significant impact on the clot initiation parameters. Conclusion SAHA treatment enhances survival and attenuates sepsis-associated coagulopathy by improving fibrin cross-linkage, rate of clot formation, platelet function, and clot strength. HDACI may represent a novel therapeutic strategy for correcting sepsis-associated coagulopathy.

This paper consists of two parts. The first part addresses the joint modeling of both spatial and temporal elements to perform dynamic evaluation of groundwater quality. In this part, a grey prediction method was used to predict missing values and then, on the basis of an entropy-weighting method, to build a dynamic weight model which continually changes with time; finally, a fuzzy evaluation method was used to evaluate groundwater quality. MATLAB was used to integrate these mathematical models. The second part describes the construction of a dynamic simulation platform which integrated mathematical models, a property database, and a spatial database, with secondary developments in geographic information system (GIS) and cloud-based simulation technology. All calculation steps and simulation programs were carried out on the simulation platform. The results indicated the grade of groundwater quality between II and IV. Groundwater quality gradually rose in the first and fourth quarters, but continually decreased in the second and third quarters. The lowest groundwater-quality value for the entire year appeared in October. This result also illustrates that turning points in groundwater quality appear when groundwater levels increase or decrease along rivers.

Hemorrhagic shock (HS) can initiate an exaggerated systemic inflammatory response and multiple organ failure, especially if followed by a subsequent inflammatory insult ("second hit"). We have recently shown that histone deacetylase inhibitors can improve survival in rodent models of HS or septic shock, individually. In the present study, we examined whether valproic acid (VPA), a histone deacetylase inhibitor, could prolong survival in a rodent "two-hit" model: HS followed by septic shock from cecal ligation and puncture (CLP).Male Sprague-Dawley rats (250-300 g) were subjected to sublethal HS (40% blood loss) and then randomly divided into two groups (n = 7/group): VPA and control. The VPA group was treated intraperitoneally with VPA (300 mg/kg in normal saline [NS], volume = 750 μL/kg). The control group was injected with 750 μL/kg NS. After 24 h, all rats received CLP followed immediately by injection of the same dose of VPA (VPA group) or NS (vehicle group). Survival was monitored for 10 days. In a parallel study, serum and peritoneal irrigation fluid from VPA- or vehicle-treated rats were collected 3, 6, and 24 h after CLP, and enzyme-linked immunosorbent assay was performed to analyze myeloperoxidase activity and determine tumor necrosis factor α and interleukin 6 concentrations. Hematoxylin-eosin staining of lungs at 24-h time point was performed to investigate the grade of acute lung injury.Rats treated with VPA (300 mg/kg) showed significantly higher survival rates (85.7%) compared with the control (14.3%). Moreover, VPA significantly suppressed myeloperoxidase activity (marker of neutrophil-mediated oxidative damage) and inhibited levels of proinflammatory cytokine tumor necrosis factor α and interleukin 6 in the serum and peritoneal cavity. Meanwhile, the severity of acute lung injury was significantly reduced in VPA-treated animals.We have demonstrated that VPA treatment improves survival and attenuates inflammation in a rodent two-hit model.

Background Valproic acid (VPA) has been shown to improve survival in animal models of hemorrhagic shock at a dose of 300 mg/kg. Our aim was to identify the ideal dose through dose-escalation, split-dosing, and dose de-escalation regimens. Materials and methods Rats were subjected to sublethal 40% hemorrhage and treated with vehicle or VPA (dose of 300, 400, or 450 mg/kg) after 30 min of shock. Acetylated histones and activated proteins from the PI3K–Akt–GSK-3β survival pathway at different time points were quantified by Western blot analysis. In a similar model, a VPA dose of 200 mg/kg followed 2 h later by another dose of 100 mg/kg was administered. Finally, animals were subjected to a lethal 50% hemorrhage and VPA was administered in a dose de-escalation manner (starting at dose of 300 mg/kg) until a significant drop in percent survival was observed. Results Larger doses of VPA resulted in greater acetylation of histone 3 and increased activation of PI3K pathway proteins. Dose-dependent differences were significant in histone acetylation but not in the activation of the survival pathway proteins. Split-dose administration of VPA resulted in similar results to a single full dose. Survival was as follows: 87.5% with 300 and 250 mg/kg of VPA, 50% with 200 mg/kg of VPA, and 14% with vehicle-treated animals. Conclusions Although higher doses of VPA result in greater histone acetylation and activation of prosurvival protein signaling, doses as low as 250 mg/kg of VPA confer the same survival advantage in lethal hemorrhagic shock. Also, VPA can be given in a split-dose fashion without a reduction in its cytoprotective effectiveness.

Accurate and rapid recognition of defects is essential for structural integrity and health monitoring of in-service device using eddy current (EC) non-destructive testing. This paper introduces a novel model-free method that includes three main modules: a signal pre-processing module, a classifier module and an optimisation module. In the signal pre-processing module, a kind of two-stage differential structure is proposed to suppress the lift-off fluctuation that could contaminate the EC signal. In the classifier module, multi-class support vector machine (SVM) based on one-against-one strategy is utilised for its good accuracy. In the optimisation module, the optimal parameters of classifier are obtained by an improved particle swarm optimisation (IPSO) algorithm. The proposed IPSO technique can improve convergence performance of the primary PSO through the following strategies: nonlinear processing of inertia weight, introductions of the black hole and simulated annealing model with extremum disturbance...

Traumatic brain injury (TBI) and hemorrhagic shock (HS) are major causes of trauma-related deaths and are especially lethal as a combined insult. Previously, we showed that early administration of fresh frozen plasma (FFP) decreased the size of the brain lesion and associated swelling in a swine model of combined TBI+HS. We have also shown separately that addition of valproic acid (VPA) to the resuscitation protocol attenuates inflammatory markers in the brain as well as the degree of TBI. The current study was performed to determine whether a combined FFP+VPA treatment strategy would exert a synergistic effect.Yorkshire swine (42-50 kg) were instrumented to measure hemodynamic parameters, intracranial pressure, and brain tissue oxygenation. TBI was created through a 20-mm craniotomy using a computer-controlled cortical impactor: 15-mm cylindrical tip impactor at 4 m/s velocity, 100 ms dwell time, and 12-mm penetration depth. The TBI was synchronized with the initiation of volume-controlled hemorrhage (40 ± 5% of total blood volume). After a 2-hour period of shock, animals were randomized to 1 of 3 resuscitation groups (n = 5 per group): (1) 0.9% saline (NS); (2) FFP; and (3) FFP and VPA 300 mg/kg (FFP+VPA). The resuscitative volume for FFP was equivalent to the shed blood, whereas NS was 3 times this volume. VPA treatment was started 1 hour after hemorrhage. Animals were monitored for 6 hours post-resuscitation. At this time the brains were harvested, sectioned into 5-mm slices, and stained with 2,3,5-triphenyltetrazolium chloride to quantify the lesion size (mm(3)) and brain swelling (percent change compared with the uninjured side).The combined TBI+HS model resulted in a highly reproducible brain injury. Lesion size and brain swelling (mean value ± standard error of the mean) in the FFP+VPA group (1,459 ± 218 mm(3) and 13 ± 1%, respectively) were less than the NS group (3,285 ± 131 mm(3) [P.001] and 37 ± 2% [P.001], respectively), and the FFP alone group (2,160 ± 203 mm(3) [P.05] and 22 ± 1% [P.001], respectively).In a large animal model of TBI+HS, early treatment with a combination of FFP and VPA decreases the size of brain lesion and the associated swelling.

Production of innate and adaptive immune cells from hematopoietic stem cells, and maturation of T lymphocytes are effective immune responses to fight severe microbial infection. In sepsis, this emergency myelopoiesis is damaged, leading to failure of bacterial clearance, and excessive stress-induced steroids cause immature T-lymphocyte apoptosis in thymus. We recently found that Cl-amidine, a peptidylarginine deiminase (PAD) inhibitor, improves survival in a mouse model of cecal ligation and puncture (CLP)-induced septic shock. In the present study we investigated how Cl-amidine promotes survival, focusing on protective effects of Cl-amidine on immune response. We confirmed survival-improving effect of Cl-amidine and are the first to explore the role of Cl-amidine in immune response. CLP caused bone marrow (BM) and thymus atrophy, decreased innate immune cells in BM. CLP increased levels of cytokines (IL-1β, IL-6, and TNF-α) and bacteria load in blood/liver. In primary splenocyte culture, lipopolysaccharide increased TNF-α production. In contrast, Cl-amidine attenuated these CLP and lipopolysaccharide-induced alterations. Moreover, Cl-amidine increased circulating monocytes. Collectively, our results demonstrate Cl-amidine plays protective roles by significantly decreasing BM and thymus atrophy, restoring innate immune cells in BM, increasing blood monocytes and blood/liver bacteria clearance, and attenuating pro-inflammatory cytokine production in a murine model of lethal sepsis.

Link-16, an excellent tactical data link developed by US army, provides security and reliable tactical data for aeroamphibious platforms and it's communication terminal, Joint Tactical Information Distribution System (JTIDS), features Reed-Solomon (RS) codes for random error, interlaced codes to for burst error. In the past decades, a variety of new-style electromagnetic weapons are constantly emerging and military communication environment becomes more and more complex and inscrutability, the BER performance of original JTIDS will be difficult to adapt to modern warfare increasingly harsh channel environment. In this paper, we establish a new burst-error channel to simulate the attack of electromagnetic weapons and we find a sharp fall in jam-resistant performance of original JTIDS. Furthermore, a new JTIDS based on LDPC codes over GF(q) which are capacity-approaching codes is proposed for confronting the new channel model.

BACKGROUND High doses of the histone deacetylase inhibitor valproic acid (VPA, 150-400 mg/kg) improve outcomes in animal models of lethal insults. We are conducting a US Food and Drug Administration-approved Phase I, double-blind, placebo-controlled trial to evaluate the safety and tolerability of ascending doses of VPA in human volunteers. We hypothesized that VPA would induce significant changes in the proteome of healthy humans when given at doses lower than those used in prior animal studies. METHODS Peripheral blood mononuclear cells were obtained from three healthy subjects randomized to receive VPA (120 mg/kg over 1 hour) at baseline and at 4 and 8 hours following infusion. Detailed proteomic analysis was performed using 1D gel electrophoresis, liquid chromatography, and mass spectrometry. Proteins with differential expression were chosen for functional annotation and pathway analysis using Ingenuity Pathway Analysis (Qiagen GmbH, Hilden, Germany) and Panther Gene Ontology. RESULTS A total of 3,074 unique proteins were identified. The average number of proteins identified per sample was 1,716 ± 459. There were a total of 140 unique differentially expressed proteins (p < 0.05). There was a minor and inconsistent increase in histone and nonhistone protein acetylation. Functional annotation showed significant enrichment of apoptosis (p = 3.5E-43), cell death (p = 9.9E-72), proliferation of cells (p = 1.6E-40), dementia (p = 9.6E-40), amyloidosis (p = 6.3E-38), fatty acid metabolism (p = 4.6E-76), quantity of steroid (p = 4.2E-75), and cell movement (p = 1.9E-64). CONCLUSIONS Valproic acid induces significant changes to the proteome of healthy humans when given at a dose of 120 mg/kg. It alters the expression of key proteins and pathways, including those related to cell survival, without significant modification of protein acetylation. In the next part of the ongoing Phase I trial, we will study the effects of VPA on trauma patients in hemorrhagic shock. LEVEL OF EVIDENCE Therapeutic study, level V.