Toll-like receptor 4 (TLR4) contributes to cerebral ischemia/reperfusion (I/R) injury and is a potential target for the treatment of ischemic stroke. This experiment is to evaluate the effect of an exogenous TLR4 antagonist, TAK-242, against acute cerebral I/R injury. A mouse model of cerebral I/R was induced by transient middle cerebral artery occlusion. TAK-242 (3 mg/kg body weight) was injected intraperitoneally 1 hour after ischemia. Our results showed that the concentration of TAK-242 in plasma increased to 52.0 ng/mL 3 hours after injection, was maintained at 54.1 ng/mL 8 hours after injection, and decreased to 22.6 ng/mL 24 hours after injection. The concentration of TAK-242 in brain tissue increased to 26.1 ng/mL in ischemic hemisphere and 14.2 ng/mL in nonischemic hemisphere 3 hours after injection, and was maintained at the similar levels 24 hours after injection. We found that TAK-242 significantly reduced cerebral infarction compared with vehicle control, improved neurologic function, inhibited the phosphorylation of downstream protein kinases in TLR4 signaling pathway, and downregulated the expression of inflammatory cytokines. We conclude that TAK-242 is able to cross blood-brain barrier, blocks TLR4 signaling, mediates the expression of inflammatory cytokines, and protects the brain from acute damage induced by I/R.

Progesterone (PROG) has been shown to protect the brain from traumatic injury and is now in Phase III clinical trials. Our work shows that PROG's beneficial effects can be reduced in vitamin D hormone (VDH) –deficient subjects. VDH can modulate neuronal apoptosis, trophic factors, inflammation, oxidative stress, excitotoxicity, and myelin and axon repair. We investigated whether VDH combined with PROG could improve behavioral outcomes more than PROG alone in VDH-sufficient rats given bilateral contusions of the medial frontal cortex. PROG and different doses of VDH (1 µg/kg, VDH1; 2.5 µg/kg, VDH2; 5 µg/kg, VDH3) were injected intraperitoneally 1 h post-injury. Eight additional doses of PROG were given subcutaneously over 8 days with tapering over the last two days. Neurobehavioral tests, necrotic cavity, neuronal death and activation of astrocytes were evaluated 21 days post-injury. We found that PROG and PROG+VDH preserve spatial memory processing. VDH1+PROG improved performance in acquisition more effectively than PROG alone, indicating that the low VDH dose is optimal for combination therapy. There were no significant differences in necrotic cavity size among the groups. The density of positive staining for reactive astrocytes (glial fibrillary acidic protein (GFAP)) increased and the cell bodies and processes of GFAP-positive cells were enlarged in the PROG+VDH1 group. Our data indicate that the combination of PROG and VDH is more effective than PROG alone in preserving spatial and reference memory, and that PROG plus low-dose VDH can activate GFAP reactions up to 21 days after injury. This effect may be one of the mechanisms underlying PROG's neuroprotective effects in combination with VDH.

A novel method based on laser induced breakdown spectroscopy(LIBS) combined with random forest regression(RFR) was proposed to quantitative analysis of multielement of fourteen steel samples. Normalized LIBS spectrum of steel in which characteristic line(Si, Mn, Cr, Ni and Cu) identified by NIST database was used as analysis spectrum. Then, two parameters of RFR were optimized by out-of-bag (OOB) error estimation. The performance of calibration model was investigated by different input variables(the whole spectral bands(220-800nm) and spectra feature bands(220-400nm), respectively). In order to validate the predictive ability of multielement calibration model in steels, we compared RFR with partial least-squares(PLS) and support vector machines(SVM) to predict the concentrations of multielement in steels. And, the three quantitative techniques are evaluated in terms of prediction accuracy and root mean square error(RMSE).Random forest is shown to correctly model nonlinear effects dues to self-absorption in the plasma and to provide the best results. It confirms that LIBS technique coupled with RFR has a good potential for the in situ rapid determination of multielement in steels and even metallurgy field.A novel method based on laser induced breakdown spectroscopy(LIBS) and random forest regression(RFR) was proposed to quantitative analyze of multi-elements in fourteen steel samples. Normalized LIBS spectra of steel in which characteristic line(Si, Mn, Cr, Ni and Cu) identified by NIST 10 database were used as analysis spectra. Then, two parameters of RFR were optimized by out-of-bag (OOB) error estimation. The performance of calibration model was investigated by different input variables(the whole spectral bands(220-800nm) and spectra feature bands(220-400nm), respectively). In order to validate the predictive ability of multi-elements calibration RFR model in steels, we compared RFR with partial least-squares(PLS) and support vector machines(SVM) by means of prediction accuracy 15 and root mean square error(RMSE). Thus, RFR model can eliminate the influence of nonlinear factors dues to self-absorption in the plasma and provide a better predictive result. It confirms that LIBS technique coupled with RFR has a good potential for the in situ rapid determination of multi-elements in steels and even metallurgy field.

Traumatic brain injury (TBI) initiates a cascade of numerous pathophysiological events that evolve over time. Despite the complexity of TBI, research aimed at therapy development has almost exclusively focused on single therapies, all of which have failed in multicenter clinical trials. Therefore, in February 2008 the National Institute of Neurological Disorders and Stroke, with support from the National Institute of Child Health and Development, the National Heart, Lung, and Blood Institute, and the Department of Veterans Affairs, convened a workshop to discuss the opportunities and challenges of testing combination therapies for TBI. Workshop participants included clinicians and scientists from a variety of disciplines, institutions, and agencies. The objectives of the workshop were to: (1) identify the most promising combinations of therapies for TBI; (2) identify challenges of testing combination therapies in clinical and pre-clinical studies; and (3) propose research methodologies and study designs to overcome these challenges. Several promising combination therapies were discussed, but no one combination was identified as being the most promising. Rather, the general recommendation was to combine agents with complementary targets and effects (e.g., mechanisms and time-points), rather than focusing on a single target with multiple agents. In addition, it was recommended that clinical management guidelines be carefully considered when designing pre-clinical studies for therapeutic development. To overcome the challenges of testing combination therapies it was recommended that statisticians and the U.S. Food and Drug Administration be included in early discussions of experimental design. Furthermore, it was agreed that an efficient and validated screening platform for candidate therapeutics, sensitive and clinically relevant biomarkers and outcome measures, and standardization and data sharing across centers would greatly facilitate the development of successful combination therapies for TBI. Overall there was great enthusiasm for working collaboratively to act on these recommendations.

Laser induced breakdown spectroscopy(LIBS) technique coupled with support vector machine(SVM) and partial least square(PLS) methods was proposed to perform quantitative and classification analysis of 20 slag samples. The characteristic line (Ca, Si, Al, Mg and Ti) of LIBS spectra for slag samples can be 10 identified based on NIST database. At first, quantitative analysis of the major components(Fe2O3, CaO, SiO2, Al2O3, MgO and TiO2) in slag samples was completed by SVM with the full spectra as input variable, and two parameters(kernel parameter of RBF-γ and σ 2 ) of SVM were optimized by grid search(GS) approach based on 5-fold cross-validation(CV). The performance of SVM calibration model was investigated by 5-fold CV, the prediction accuracy and root mean square error(RMSE) of SVM and 15 PLS were employed to validate the predictive ability of multivariate SVM calibration model in slag. SVM model can eliminate the influence of nonlinear factors due to self-absorption in the plasma and provide a better predictive result. And then, two type of slag samples(open-hearth furnace slag and high titanium slag) were identified and classified by partial least squares-discrimination analysis(PLS-DA) method with different input variables, sensitivity, specificity and accuracy were calculated to evaluate the classification 20 performance of PLS-DA model for slag samples. It has been confirms that LIBS technique coupled with SVM and PLS methods is promising approach to achieve the online analysis and process control of slag and even metallurgy field.

Progesterone (PROG) and vitamin D hormone (VDH) have both shown promise in treating traumatic brain injury (TBI). Both modulate apoptosis, inflammation, oxidative stress, and excitotoxicity. We investigated whether 21 days of VDH deficiency would alter cognitive behavior after TBI and whether combined PROG and VDH would improve behavioral and morphological outcomes more than either hormone alone in VDH-deficient middle-aged rats given bilateral contusions of the medial frontal cortex. PROG (16 mg/kg) and VDH (5 µg/kg) were injected intraperitoneally 1 hour post-injury. Eight additional doses of PROG were injected subcutaneously over 7 days post-injury. VDH deficiency itself did not significantly reduce baseline behavioral functions or aggravate impaired cognitive outcomes. Combination therapy showed moderate improvement in preserving spatial and reference memory but was not significantly better than PROG monotherapy. However, combination therapy significantly reduced neuronal loss and the proliferation of reactive astrocytes, and showed better efficacy compared to VDH or PROG alone in preventing MAP-2 degradation. VDH+PROG combination therapy may attenuate some of the potential long-term, subtle, pathophysiological consequences of brain injury in older subjects.

The feasibility of steel materials classification by support vector machines (SVMs), in combination with laser-induced breakdown spectroscopy (LIBS) technology, was investigated. Multi-classification methods based on SVM, the one-against-all and the one-against-one models, and a combination model, are applied to classify nine types of round steel. Due to the inhomogeneity of steel composition, the data obtained using the one-against-all and one-against-one models were ambiguous and difficult to discriminate; whereas, the combination model, was able to successfully distinguish most of the ambiguous data and control the computation cost within an acceptable range. The studies presented here demonstrate that LIBS-SVM is a useful technique for the identification and discrimination of steel materials, and would be very well-suited for process analysis in the steelmaking industry.

Objective Inflammation is an important component of the response to traumatic brain injury (TBI). Progesterone has been shown to inhibit neuroinflammation following (TBI), and may do so through Toll-like receptor (TLR) -mediated pathways. In vitro studies indicate that 1,25-dihydroxyvitamin D(3) (VDH) may also modulate the inflammatory response through the TLR4 pathway. We tested the hypothesis PROG and VDH would exert additive and synergistic neuroprotective effects compared with individual treatment by modulating TLR4/NF-κB-mediated inflammation pathways after TBI in rats. Research Design and Methods Bilateral medial frontal cortical impact injury was induced in young adult Sprague-Dawley rats. Progesterone (i.p., 16 mg/kg body weight) and VDH (1 ug/kg body weight) were injected separately or combined at 1 and 6 h after surgery. Rats were killed 24 h post-surgery and peri-contusional brain tissue harvested for immunostaining and protein measurement. Results TLR4, phosphorylation of NF-κB,. neuronal loss, and astrocyte activation were significantly reduced with combination treatment after TBI compared to each agent iven individually. Conclusions At 24h after TBI, combination therapy shows greater efficacy in reducing neuroinflammation compared to progesterone and VDH given separately, and does so by modulating the TLR4/NF-κB signaling pathway.