The 70-kDa heat shock protein (HSP70) is known to protect the brain from injury through multiple mechanisms. We investigated the effect of pharmacological HSP70 induction in experimental traumatic brain injury (TBI). 3-month-old male C57/B6 mice were given 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) intraperitoneally (IP, 2 mg/kg) or intracerebroventricularly (ICV, 1 μg/kg) to determine whether HSP70 could be induced in the brain. Mice were subjected to TBI via cortical controlled impact, and were treated with 17-AAG (or vehicle) IP according to one of two treatment regimens: (1) 2 mg/kg at the time of injury, (2) a total of three doses (4 mg/kg) at 2 and 1d prior to TBI and again at the time of injury. Brains were assessed for HSP70 induction, hemorrhage volume at 3 d, and lesion size at 14 d post-injury. Immunohistochemistry showed that both IP and ICV administration of 17-AAG increased HSP70 expression primarily in microglia and in a few neurons by 24 h but not in astrocytes. 17-AAG induced HSP70 in injured brain tissue as early as 6 h, peaking at 48 h and largely subsiding by 72 h after IP injection. Both treatment groups showed decreased hemorrhage volume relative to untreated mice as well as improved neurobehavioral outcomes. These observations indicate that pharmacologic HSP70 induction may prove to be a promising treatment for TBI.

Stroke is a frequent cause of long-term disability and death worldwide. Ischemic stroke is more commonly encountered compared to hemorrhagic stroke, and leads to tissue death by ischemia due to occlusion of a cerebral artery. Inflammation is known to result as a result of ischemic injury, long thought to be involved in initiating the recovery and repair process. However, work over the past few decades indicates that aspects of this inflammatory response may in fact be detrimental to stroke outcome. Acutely, inflammation appears to have a detrimental effect, and anti-inflammatory treatments have been been studied as a potential therapeutic target. Chronically, reports suggest that post-ischemic inflammation is also essential for the tissue repairing and remodeling. The majority of the work in this area has centered around innate immune mechanisms, which will be the focus of this review. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. A better understanding of the roles of the different immune cells and their temporal profile of damage versus repair will help to clarify more effective modulation of inflammation post stroke.

As the resident immune cells of the central nervous system, microglia rapidly respond to brain insults, including stroke and traumatic brain injury. Microglial activation plays a major role in neuronal cell damage and death by releasing a variety of inflammatory and neurotoxic mediators. Their activation is an early response that may exacerbate brain injury and many other stressors, especially in the acute stages, but are also essential to brain recovery and repair. The full range of microglial activities is still not completely understood, but there is accumulating knowledge about their role following brain injury. We review recent progress related to the deleterious and beneficial effects of microglia in the setting of acute neurological insults and the current literature surrounding pharmacological interventions for intervention.

Inflammation is an important event in ischemic injury. These immune responses begin with the expression of pro-inflammatory genes modulating transcription factors, such as nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and signal transducers and activator of transcription-1 (STAT-1). The 70-kDa heat shock protein (Hsp70) can both induce and arrest inflammatory reactions and lead to improved neurological outcome in experimental brain injury and ischemia. Since Hsp70 are induced under heat stress, we investigated the link between Hsp70 neuroprotection and phosphorylation of inhibitor of κB (IκB), c-Jun N-terminal kinases (JNK) and p38 through co-immunoprecipitation and enzyme-linked immunosorbent assay (ELISA) assay. Transcription factors and pro-inflammatory genes were quantified by immunoblotting, electrophoretic-mobility shift assay and reverse transcription-polymerase chain reaction assays. The results showed that heat stress led to Hsp70 overexpression which rendered neuroprotection after ischemia-like injury. Overexpression Hsp70 also interrupts the phosphorylation of IκB, JNK and p38 and blunts DNA binding of their transcription factors (NF-κB, AP-1 and STAT-1), effectively downregulating the expression of pro-inflammatory genes in heat-pretreated astrocytes. Taken together, these results suggest that overexpression of Hsp70 may protect against brain ischemia via an anti-inflammatory mechanism by interrupting the phosphorylation of upstream of transcription factors.

Traumatic brain injury (TBI) causes disruption of the blood brain barrier (BBB) leading to hemorrhage which can complicate an already catastrophic illness. Matrix metalloproteinases (MMPs) involved in the breakdown of the extracellular matrix may lead to brain hemorrhage. We explore the contribution of the 70 kDa heat shock protein (Hsp70) to outcome and brain hemorrhage in a model of TBI. Male, wildtype (Wt), Hsp70 knockout (Ko) and transgenic (Tg) mice were subjected to TBI using controlled cortical impact (CCI). Motor function, brain hemorrhage and lesion size were assessed at 3, 7 and 14 days. Brains were evaluated for the effects of Hsp70 on MMPs.In Hsp70 Tg mice, CCI led to smaller brain lesions, decreased hemorrhage and reduced expression and activation of MMPs compared to Wt. CCI also significantly decreased right-biased swings and corner turns in the Hsp70 Tg mice. Conversely, Hsp70 Ko mice had significantly increased lesion size, worsened brain hemorrhage and increased expression and activation of MMPs with worsened behavioral outcomes compared to Wt. Hsp70 is protective in experimental TBI. To our knowledge, this is the direct demonstration of brain protection by Hsp70 in a TBI model. Our data demonstrate a new mechanism linking TBI-induced hemorrhage and neuronal injury to the suppression of MMPs by Hsp70, and support the development of Hsp70 enhancing strategies for the treatment of TBI. © 2013 Elsevier Inc.

Advanced Tokamak research in DIII-D seeks to develop a scientific basis for steady-state high-performance tokamak operation. Fully noninductive (fNI ≈ 100%) in-principle steady-state discharges have been maintained for several confinement times. These plasmas have weak negative central shear with qmin ≈ 1.5-2, βN ≈ 3.5, and large, well-aligned bootstrap current. The loop voltage is near zero across the entire profile. The remaining current is provided by neutral beam current drive (NBCD) and electron cyclotron current drive (ECCD). Similar plasmas are stationary with fNI ≈ 90-95% and duration up to 2 s, limited only by hardware. In other experiments, βN ≈ 4 is maintained for 2 s with internal transport barriers, exceeding previously achieved performance under similar conditions. This is allowed by broadened profiles and active magnetohydrodynamic instability control. Modifications now underway on DIII-D are expected to allow extension of these results to higher performance and longer duration. A new pumped divertor will allow density control in high triangularity double-null divertor configurations, facilitating access to similar in-principle steady-state regimes with βN > 4. Additional current drive capabilities, both off-axis ECCD and on-axis fast wave current drive (FWCD), will increase the magnitude, duration, and flexibility of externally driven current. © 2006 Elsevier B.V. All rights reserved.

A search for the dinucleon decay pp → K+ K+ has been performed using 91.6  kton·yr data from Super-Kamiokande-I. This decay provides a sensitive probe of the R-parity-violating parameter λ112''. A boosted decision tree analysis found no signal candidates in the data. The expected background was 0.28±0.19 atmospheric neutrino induced events and the estimated signal detection efficiency was 12.6%±3.2%. A lower limit of 1.7×10(32)  years has been placed on the partial lifetime of the decay O16 → C14K+ K+ at 90% C.L. A corresponding upper limit of 7.8×10(-9) has been placed on the parameter λ112''.

A search for neutron-antineutron (n-n¯) oscillation was undertaken in Super-Kamiokande using the 1489 live-day or 2.45×1034 neutron-year exposure data. This process violates both baryon and baryon minus lepton numbers by an absolute value of two units and is predicted by a large class of hypothetical models where the seesaw mechanism is incorporated to explain the observed tiny neutrino masses and the matter-antimatter asymmetry in the Universe. No evidence for n-n¯ oscillation was found; the lower limit of the lifetime for neutrons bound in O16, in an analysis that included all of the significant sources of experimental uncertainties, was determined to be 1.9×1032years at the 90% confidence level. The corresponding lower limit for the oscillation time of free neutrons was calculated to be 2.7×108s using a theoretical value of the nuclear suppression factor of 0.517×1023s-1 and its uncertainty.

A new event reconstruction algorithm based on a maximum likelihood method has been developed for Super-Kamiokande. Its improved kinematic and particle identification capabilities enable the analysis of atmospheric neutrino data in a detector volume 32% larger than previous analyses and increase the sensitivity to the neutrino mass hierarchy.Analysis of a 253.9 kton•year exposure of the Super-Kamiokande IV atmospheric neutrino data has yielded a weak preference for the normal hierarchy, disfavoring the inverted hierarchy at 74% assuming oscillations at the best fit of the analysis.

Neutral current (NC) interactions of atmospheric neutrinos on oxygen form one of the major backgrounds in the search for supernova relic neutrinos with water-based Cherenkov detectors. The NC channel is dominated by neutrino quasielastic (NCQE) scattering off nucleons inside O16 nuclei. In this paper we report the first measurement of NCQE cross section using atmospheric neutrinos at Super-Kamiokande (SK). The measurement used 2,778 live days of SK-IV data with a fiducial volume of 22.5 kiloton water. Within the visible energy window of 7.5-29.5 MeV, we observed 117 events compared to the expected 71.9 NCQE signal and 53.1 background events. Weighted by the atmospheric neutrino spectrum from 160 MeV to 10 GeV, the flux averaged NCQE cross section is measured to be (1.01±0.17(stat.)-0.30+0.78(sys.))×10-38 cm2.