AAV-mediated and pharmacological induction of Hsp70 expression stimulates survival of retinal ganglion cells following axonal injury.

We evaluated the effect of AAV2- and 17-AAG (17-N-allylamino-17-demethoxygeldanamycin)-mediated upregulation of Hsp70 expression on the survival of retinal ganglion cells (RGCs) injured by optic nerve crush (ONC). AAV2-Hsp70 expression in the retina was primarily observed in the ganglion cell layer. Approximately 75% of all transfected cells were RGCs. RGC survival in AAV2-Hsp70-injected animals was increased by an average of 110% 2 weeks after the axonal injury compared with the control. The increase in cell numbers was not even across the retinas with a maximum effect of approximately 306% observed in the inferior quadrant. 17-AAG-mediated induction of Hsp70 expression has been associated with cell protection in various models of neurodegenerative diseases. We show here that a single intravitreal injection of 17-AAG (0.2 ug ul(-1)) results in an increased survival of ONC-injured RGCs by approximately 49% compared with the vehicle-treated animals. Expression of Hsp70 in retinas of 17-AAG-treated animals was upregulated approximately by twofold compared with control animals. Our data support the idea that the upregulation of Hsp70 has a beneficial effect on the survival of injured RGCs, and the induction of this protein could be viewed as a potential neuroprotective strategy for optic neuropathies

Electrically-driven phase transition in magnetite nanostructures

Magnetite (Fe$_{3}$O$_{4}$), an archetypal transition metal oxide, has been used for thousands of years, from lodestones in primitive compasses[1] to a candidate material for magnetoelectronic devices.[2] In 1939 Verwey[3] found that bulk magnetite undergoes a transition at T$_{V}$ $\approx$ 120 K from a high temperature "bad metal" conducting phase to a low-temperature insulating phase. He suggested[4] that high temperature conduction is via the fluctuating and correlated valences of the octahedral iron atoms, and that the transition is the onset of charge ordering upon cooling. The Verwey transition mechanism and the question of charge ordering remain highly controversial.[5-11] Here we show that magnetite nanocrystals and single-crystal thin films exhibit an electrically driven phase transition below the Verwey temperature. The signature of this transition is the onset of sharp conductance switching in high electric fields, hysteretic in voltage. We demonstrate that this transition is not due to local heating, but instead is due to the breakdown of the correlated insulating state when driven out of equilibrium by electrical bias. We anticipate that further studies of this newly observed transition and its low-temperature conducting phase will shed light on how charge ordering and vibrational degrees of freedom determine the ground state of this important compound.Comment: 17 pages, 4 figure

Disentangling Cooper-pair formation above Tc from the pseudogap state in the cuprates

The discovery of the pseudogap in the cuprates created significant excitement amongst physicists as it was believed to be a signature of pairing, in some cases well above the room temperature. In this "pre-formed pairs" scenario, the formation of pairs without quantum phase rigidity occurs below T*. These pairs condense and develop phase coherence only below Tc. In contrast, several recent experiments reported that the pseudogap and superconducting states are characterized by two different energy scales, pointing to a scenario, where the two compete. However a number of transport, magnetic, thermodynamic and tunneling spectroscopy experiments consistently detect a signature of phase-fluctuating superconductivity above leaving open the question of whether the pseudogap is caused by pair formation or not. Here we report the discovery of a spectroscopic signature of pair formation and demonstrate that in a region of the phase diagram commonly referred to as the "pseudogap", two distinct states coexist: one that persists to an intermediate temperature Tpair and a second that extends up to T*. The first state is characterized by a doping independent scaling behavior and is due to pairing above Tc, but significantly below T*. The second state is the "proper" pseudogap - characterized by a "checker board" pattern in STM images, the absence of pair formation, and is likely linked to Mott physics of pristine CuO2 planes. Tpair has a universal value around 130-150K even for materials with very different Tc, likely setting limit on highest, attainable Tc in cuprates. The observed universal scaling behavior with respect to Tpair indicates a breakdown of the classical picture of phase fluctuations in the cuprates.Comment: 9 pages, 4 figure

The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1.

BACKGROUND AND OBJECTIVE: Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury. METHODS AND DESIGN: In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays. RESULTS: 2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes. CONCLUSIONS: In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury

A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome

Hydroxylated TiO2-induced high-density Ni clusters for breaking the activity-selectivity trade-off of CO2 hydrogenation

The reverse water gas shift reaction can be considered as a promising route to mitigate global warming by converting CO2 into syngas in a large scale, while it is still challenging for non-Cu-based catalysts to break the trade-off between activity and selectivity. Here, the relatively high loading of Ni species is highly dispersed on hydroxylated TiO2 through the strong Ni and -OH interactions, thereby inducing the formation of rich and stable Ni clusters (~1 nm) on anatase TiO2 during the reverse water gas shift reaction. This Ni cluster/TiO2 catalyst shows a simultaneous high CO2 conversion and high CO selectivity. Comprehensive characterizations and theoretical calculations demonstrate Ni cluster/TiO2 interfacial sites with strong CO2 activation capacity and weak CO adsorption are responsible for its unique catalytic performances. This work disentangles the activity-selectivity trade-off of the reverse water gas shift reaction, and emphasizes the importance of metal-OH interactions on surface

The muon system of the Daya Bay Reactor antineutrino experiment

postprin

Search for a Light Sterile Neutrino at Daya Bay

published_or_final_versio

Preferred response of the East Asian summer monsoon to local and non-local anthropogenic sulphur dioxide emissions

In this study, the atmospheric component of a state-of-the-art climate model (HadGEM2-ES) that includes earth system components such as interactive chemistry and eight species of tropospheric aerosols considering aerosol direct, indirect, and semi-direct effects, has been used to investigate the impacts of local and non-local emissions of anthropogenic sulphur dioxide on the East Asian summer monsoon (EASM). The study focuses on the fast responses (including land surface feedbacks, but without sea surface temperature feedbacks) to sudden changes in emissions from Asia and Europe. The initial responses, over days 1–40, to Asian and European emissions show large differences. The response to Asian emissions involves a direct impact on the sulphate burden over Asia, with immediate consequences for the shortwave energy budget through aerosol–radiation and aerosol–cloud interactions. These changes lead to cooling of East Asia and a weakening of the EASM. In contrast, European emissions have no significant impact on the sulphate burden over Asia, but they induce mid-tropospheric cooling and drying over the European sector. Subsequently, however, this cold and dry anomaly is advected into Asia, where it induces atmospheric and surface feedbacks over Asia and the Western North Pacific (WNP), which also weaken the EASM. In spite of very different perturbations to the local aerosol burden in response to Asian and European sulphur dioxide emissions, the large scale pattern of changes in land–sea thermal contrast, atmospheric circulation and local precipitation over East Asia from days 40 onward exhibits similar structures, indicating a preferred response, and suggesting that emissions from both regions likely contributed to the observed weakening of the EASM. Cooling and drying of the troposphere over Asia, together with warming and moistening over the WNP, reduces the land–sea thermal contrast between the Asian continent and surrounding oceans. This leads to high sea level pressure (SLP) anomalies over Asia and low SLP anomalies over the WNP, associated with a weakened EASM. In response to emissions from both regions warming and moistening over the WNP plays an important role and determines the time scale of the response

Effects of ranolazine on astrocytes and neurons in primary culture

Ranolazine (Rn) is an antianginal agent used for the treatment of chronic angina pectoris when angina is not adequately controlled by other drugs. Rn also acts in the central nervous system and it has been proposed for the treatment of pain and epileptic disorders. Under the hypothesis that ranolazine could act as a neuroprotective drug, we studied its effects on astrocytes and neurons in primary culture. We incubated rat astrocytes and neurons in primary cultures for 24 hours with Rn (10−7, 10−6 and 10−5 M). Cell viability and proliferation were measured using trypan blue exclusion assay, MTT conversion assay and LDH release assay. Apoptosis was determined by Caspase 3 activity assay. The effects of Rn on proinflammatory mediators IL-β and TNF-α was determined by ELISA technique, and protein expression levels of Smac/Diablo, PPAR-γ, Mn-SOD and Cu/Zn-SOD by western blot technique. In cultured astrocytes, Rn significantly increased cell viability and proliferation at any concentration tested, and decreased LDH leakage, Smac/Diablo expression and Caspase 3 activity indicating less cell death. Rn also increased anti-inflammatory PPAR-γ protein expression and reduced pro-inflammatory proteins IL-1 β and TNFα levels. Furthermore, antioxidant proteins Cu/Zn-SOD and Mn-SOD significantly increased after Rn addition in cultured astrocytes. Conversely, Rn did not exert any effect on cultured neurons. In conclusion, Rn could act as a neuroprotective drug in the central nervous system by promoting astrocyte viability, preventing necrosis and apoptosis, inhibiting inflammatory phenomena and inducing anti-inflammatory and antioxidant agents