C-Jun N-terminal kinase 2 promotes liver injury via the mitochondrial permeability transition after hemorrhage and resuscitation

Hemorrhagic shock leads to hepatic hypoperfusion and activation of mitogen-activated stress kinases (MAPK) like c-Jun N-terminal kinase (JNK) 1 and 2. Our aim was to determine whether mitochondrial dysfunction leading to hepatic necrosis and apoptosis after hemorrhage/resuscitation (H/R) was dependent on JNK2. Under pentobarbital anesthesia, wildtype (WT) and JNK2 deficient (KO) mice were hemorrhaged to 30 mm Hg for 3 h and then resuscitated with shed blood plus half the volume of lactated Ringer's solution. Serum alanine aminotransferase (ALT), necrosis, apoptosis and oxidative stress were assessed 6 h after resuscitation. Mitochondrial polarization was assessed by intravital microscopy. After H/R, ALT in WT-mice increased from 130 U/L to 4800 U/L. In KO-mice, ALT after H/R was blunted to 1800 U/l (P < 0.05). Necrosis, caspase-3 activity and ROS were all substantially decreased in KO compared to WT mice after H/R. After sham operation, intravital microscopy revealed punctate mitochondrial staining by rhodamine 123 (Rh123), indicating normal mitochondrial polarization. At 4 h after H/R, Rh123 staining became dim and diffuse in 58% of hepatocytes, indicating depolarization and onset of the mitochondrial permeability transition (MPT). By contrast, KO mice displayed less depolarization after H/R (23%, P < 0.05). In conclusion, JNK2 contributes to MPT-mediated liver injury after H/R

Probing intrinsic transport properties of single metal nanowires: Direct-write contact formation using a focused ion beam

The transport characteristics of 70-nm-diameter platinum nanowires (NWs), fabricated using a pore-templated electrodeposition process and individually contacted using a focused ion beam (FIB) method, are reported. This approach yields nanowire devices with low contact resistances (similar to400 Omega) and linear current-voltage characteristics for current densities up to 65 kA/cm(2). The intrinsic nanowire resistivity (33+/-5 muOmega cm) indicates significant contributions from surface- and grain-boundary scattering mechanisms. Fits to the temperature dependence of the intrinsic NW resistance confirm that grain-boundary scattering dominates surface scattering (by more than a factor of 2) at all temperatures. Our results demonstrate that FIB presents a rapid and flexible method for the formation of low-resistance ohmic contacts to individual metal nanowires, allowing intrinsic nanowire transport properties to be probed

Rhabdovirus-based vaccine platforms against henipaviruses.

UNLABELLED: The emerging zoonotic pathogens Hendra virus (HeV) and Nipah virus (NiV) are in the genus Henipavirus in the family Paramyxoviridae. HeV and NiV infections can be highly fatal to humans and livestock. The goal of this study was to develop candidate vaccines against henipaviruses utilizing two well-established rhabdoviral vaccine vector platforms, recombinant rabies virus (RABV) and recombinant vesicular stomatitis virus (VSV), expressing either the codon-optimized or the wild-type (wt) HeV glycoprotein (G) gene. The RABV vector expressing the codon-optimized HeV G showed a 2- to 3-fold increase in incorporation compared to the RABV vector expressing wt HeV G. There was no significant difference in HeV G incorporation in the VSV vectors expressing either wt or codon-optimized HeV G. Mice inoculated intranasally with any of these live recombinant viruses showed no signs of disease, including weight loss, indicating that HeV G expression and incorporation did not increase the neurotropism of the vaccine vectors. To test the immunogenicity of the vaccine candidates, we immunized mice intramuscularly with either one dose of the live vaccines or 3 doses of 10 μg chemically inactivated viral particles. Increased codon-optimized HeV G incorporation into RABV virions resulted in higher antibody titers against HeV G compared to inactivated RABV virions expressing wt HeV G. The live VSV vectors induced more HeV G-specific antibodies as well as higher levels of HeV neutralizing antibodies than the RABV vectors. In the case of killed particles, HeV neutralizing serum titers were very similar between the two platforms. These results indicated that killed RABV with codon-optimized HeV G should be the vector of choice as a dual vaccine in areas where rabies is endemic. IMPORTANCE: Scientists have been tracking two new viruses carried by the Pteropid fruit bats: Hendra virus (HeV) and Nipah virus (NiV). Both viruses can be fatal to humans and also pose a serious risk to domestic animals. A recent escalation in the frequency of outbreaks has increased the need for a vaccine that prevents HeV and NiV infections. In this study, we performed an extensive comparison of live and killed particles of two recombinant rhabdoviral vectors, rabies virus and vesicular stomatitis virus (VSV), expressing wild-type or codon-optimized HeV glycoprotein, with the goal of developing a candidate vaccine against HeV. Based on our data from the presented mouse immunogenicity studies, we conclude that a killed RABV vaccine would be highly effective against HeV infections and would make an excellent vaccine candidate in areas where both RABV and henipaviruses pose a threat to human health

Longitudinal study of the effect of a 5-year exercise intervention on structural brain complexity in older adults. A Generation 100 substudy

Physical inactivity has been identified as an important risk factor for dementia. High levels of cardiorespiratory fitness (CRF) have been shown to reduce the risk of dementia. However, the mechanism by which exercise affects brain health is still debated. Fractal dimension (FD) is an index that quantifies the structural complexity of the brain. The purpose of this study was to investigate the effects of a 5-year exercise intervention on the structural complexity of the brain, measured through the FD, in a subset of 105 healthy older adults participating in the randomized controlled trial Generation 100 Study. The subjects were randomized into control, moderate intensity continuous training, and high intensity interval training groups. Both brain MRI and CRF were acquired at baseline and at 1-, 3- and 5-years follow-ups. Cortical thickness and volume data were extracted with FreeSurfer, and FD of the cortical lobes, cerebral and cerebellar gray and white matter were computed. CRF was measured as peak oxygen uptake (VO2peak) using ergospirometry during graded maximal exercise testing. Linear mixed models were used to investigate exercise group differences and possible CRF effects on the brain's structural complexity. Associations between change over time in CRF and FD were performed if there was a significant association between CRF and FD. There were no effects of group membership on the structural complexity. However, we found a positive association between CRF and the cerebral gray matter FD (p &lt; 0.001) and the temporal lobe gray matter FD (p &lt; 0.001). This effect was not present for cortical thickness, suggesting that FD is a more sensitive index of structural changes. The change over time in CRF was associated with the change in temporal lobe gray matter FD from baseline to 5-year follow-up (p &lt; 0.05). No association of the change was found between CRF and cerebral gray matter FD. These results demonstrated that entering old age with high and preserved CRF levels protected against loss of structural complexity in areas sensitive to aging and age-related pathology

Polyphenols of Camellia sinenesis decrease mortality, hepatic injury and generation of cytokines and reactive oxygen and nitrogen species after hemorrhage/resuscitation in rats

Background: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced during hemorrhagic shock and resuscitation (H/R), which may contribute to multiple organ failure. The AIM of this study was to test the hypothesis that green tea (Camellia sinenesis) extract containing 85% polyphenols decreases injury after H/R in rats by scavenging ROS and RNS. Method: S: Female Sprague Dawley rats were given 100 mg polyphenol extract/kg body weight or vehicle 2 h prior to hemorrhagic shock. H/R was induced by two protocols: 1) withdrawal of blood to a mean arterial pressure of 40 mm Hg followed by further withdrawals to decrease blood pressure progressively to 28 mm Hg over 1 h (severe), and 2) withdrawal of blood to a sustained hypotension of 40 mm Hg for 1 h (moderate). Rats were then resuscitated over 1 h with 60% of the shed blood volume plus twice the shed blood volume of lactated Ringer's solution. Serum samples were collected at 10 min and 2 h after resuscitation. At 2 or 18 h, livers were harvested for cytokine and 3-nitrotyrosine quantification, immunohistochemical detection of 4-hydroxynonenol (4-HNE) and inducible nitric oxide synthase (iNOS) protein expression. Results: After severe H/R, 18-h survival increased from 20% after vehicle to 70% after polyphenols (p<0.05). After moderate H/R, survival was greater (80%) and not different between vehicle and polyphenols. In moderate H/R, serum alanine aminotransferase (ALT) increased at 10 min and 2 h postresuscitation to 345 and 545 IU/L, respectively. Polyphenol treatment blunted this increase to 153 and 252 IU/L at 10 min and 2 h (p<0.01). Polyphenols also blunted increases in liver homogenates of TNFalpha (7.0 pg/mg with vehicle vs. 4.9 pg/mg with polyphenols, p<0.05), IL-1beta (0.80 vs. 0.37 pg/mg, p<0.05), IL-6 (6.9 vs. 5.1 pg/mg, p<0.05) and nitrotyrosine (1.9 pg/mg vs. 0.6 pg/mg, p<0.05) measured 18 h after H/R. Hepatic 4-HNE immunostaining indicative of lipid peroxidation also decreased from 4.8% after vehicle to 1.5% after polyphenols (p<0.05). By contrast, polyphenols did not block increased iNOS expression at 2 h after H/R. CONCLUSION: Polyphenols decrease ROS/RNS formation and are beneficial after hemorrhagic shock and resuscitation

Resting state alpha oscillatory activity is a valid and reliable marker of schizotypy

Schizophrenia is among the most debilitating neuropsychiatric disorders. However, clear neurophysiological markers that would identify at-risk individuals represent still an unknown. The aim of this study was to investigate possible alterations in the resting alpha oscillatory activity in normal population high on schizotypy trait, a physiological condition known to be severely altered in patients with schizophrenia. Direct comparison of resting-state EEG oscillatory activity between Low and High Schizotypy Group (LSG and HSG) has revealed a clear right hemisphere alteration in alpha activity of the HSG. Specifically, HSG shows a significant slowing down of right hemisphere posterior alpha frequency and an altered distribution of its amplitude, with a tendency towards a reduction in the right hemisphere in comparison to LSG. Furthermore, altered and reduced connectivity in the right fronto-parietal network within the alpha range was found in the HSG. Crucially, a trained pattern classifier based on these indices of alpha activity was able to successfully differentiate HSG from LSG on tested participants further confirming the specific importance of right hemispheric alpha activity and intrahemispheric functional connectivity. By combining alpha activity and connectivity measures with a machine learning predictive model optimized in a nested stratified cross-validation loop, current research offers a promising clinical tool able to identify individuals at-risk of developing psychosis (i.e., high schizotypy individuals)

A collaborative platform for integrating and optimising Computational Fluid Dynamics analysis requests

A Virtual Integration Platform (VIP) is described which provides support for the integration of Computer-Aided Design (CAD) and Computational Fluid Dynamics (CFD) analysis tools into an environment that supports the use of these tools in a distributed collaborative manner. The VIP has evolved through previous EU research conducted within the VRShips-ROPAX 2000 (VRShips) project and the current version discussed here was developed predominantly within the VIRTUE project but also within the SAFEDOR project. The VIP is described with respect to the support it provides to designers and analysts in coordinating and optimising CFD analysis requests. Two case studies are provided that illustrate the application of the VIP within HSVA: the use of a panel code for the evaluation of geometry variations in order to improve propeller efficiency; and, the use of a dedicated maritime RANS code (FreSCo) to improve the wake distribution for the VIRTUE tanker. A discussion is included detailing the background, application and results from the use of the VIP within these two case studies as well as how the platform was of benefit during the development and a consideration of how it can benefit HSVA in the future

Charge transport in a CoPt3 nanocrystal microwire

The electrical characteristics of single CoPt3 nanocrystal microwires formed by magnetic field-directed growth from colloidal solutions are presented. The wires comprise disordered assemblies of discrete nanocrystals, separated from each other by protective organic ligand shells. Electrical data indicate that the activated charge transport properties of the wires are determined by the nanocrystal charging energy, governed by the size and capacitance of the individual nanocrystals. Focused ion beam-assisted deposition of Pt metal at the wire-electrode junctions is employed to optimize the wire-electrode contacts, whilst maintaining the nanocrystal-dominated transport characteristics of these one-dimensional nanocrystal structures. (C) 2004 American Institute of Physics. (DOI:10.1063/1.1830684