Combined antiapoptotic and antioxidant approach to acute neuroprotection for stroke in hypertensive rats

We hypothesized that targeting key points in the ischemic cascade with combined neuroglobin (Ngb) overexpression and c-jun N-terminal kinase (JNK) inhibition (SP600125) would offer greater neuroprotection than single treatment after in vitro hypoxia/reoxygenation and in a randomized, blinded in vivo experimental stroke study using a clinically relevant rat strain. Male spontaneously hypertensive stroke-prone rats underwent transient middle cerebral artery occlusion (tMCAO) and were divided into the following groups: tMCAO; tMCAO+control GFP-expressing canine adenovirus-2, CAVGFP; tMCAO+Ngb-expressing CAV-2, CAVNgb; tMCAO+SP600125; tMCAO+CAVNgb+SP600125; or sham procedure. Rats were assessed till day 14 for neurologic outcome before infarct determination. In vitro, combined lentivirus-mediated Ngb overexpression+SP600125 significantly reduced oxidative stress and apoptosis compared with single treatment(s) after hypoxia/reoxygenation in B50 cells. In vivo, infarct volume was significantly reduced by CAVNgb, SP600125, and further by CAVNgb+SP600125. The number of Ngb-positive cells in the peri-infarct cortex and striatum was significantly increased 14 days after tMCAO in animals receiving CAVNgb. Neurologic outcome, measured using a 32-point neurologic score, significantly improved with CAVNgb+SP600125 compared with single treatments at 14 days after tMCAO. Combined Ngb overexpression with JNK inhibition reduced hypoxia/reoxygenation-induced oxidative stress and apoptosis in cultured neurons and reduced infarct and improved neurologic outcome more than single therapy after in vivo experimental stroke in hypertensive rats

Observational Constraints on Submillimeter Dust Opacity

Infrared extinction maps and submillimeter dust continuum maps are powerful probes of the density structure in the envelope of star-forming cores. We make a direct comparison between infrared and submillimeter dust continuum observations of the low-mass Class 0 core, B335, to constrain the ratio of submillimeter to infrared opacity (κ_(smm)/κ_(ir)) and the submillimeter opacity power-law index (κ ∝ λ–β). Using the average value of theoretical dust opacity models at 2.2 μm, we constrain the dust opacity at 850 and 450 μm. Using new dust continuum models based upon the broken power-law density structure derived from interferometric observations of B335 and the infall model derived from molecular line observations of B335, we find that the opacity ratios are ^κ_(850)_κ_(2.2) = (3.21 - 4.80)^(+0.44)_(-0.30) x 10^(-4) ^κ_(450)_κ(2.0) = (12.8-24.8)^(+2.4)_(-1.3) x 10^(-4) with a submillimeter opacity power-law index of β_(smm) = (2.18-2.58)^(+0.30)_(–0.30). The range of quoted values is determined from the uncertainty in the physical model for B335. For an average 2.2 μm opacity of 3800 ± 700 cm^2 g^(–1), we find a dust opacity at 850 and 450 μm of κ_(850) = (1.18-1.77)^9+0.36)_(–0.24) and κ_(450) = (4.72-9.13)^(+1.9)_(–0.98) cm^2 g^(–1) of dust. These opacities are from (0.65-0.97)κ^(OH5)_(850) of the widely used theoretical opacities of Ossenkopf and Henning for coagulated ice grains with thin mantles at 850 μm

The Bolocam Galactic Plane Survey. XI. Temperatures and Substructure of Galactic Clumps Based on 350 ?M Observations

We present 107 maps of continuum emission at 350 mu m from Galactic molecular clumps. Observed sources were mainly selected from the Bolocam Galactic Plane Survey (BGPS) catalog, with three additional maps covering star-forming regions in the outer Galaxy. The higher resolution of the SHARC-II images (8."5 beam) compared with the 1.1 mm images from BGPS (33"beam) allowed us to identify a large population of smaller substructures within the clumps. A catalog is presented for the 1386 sources extracted from the 350 mu m maps. The color temperature distribution of clumps based on the two wavelengths has a median of 13.3 K and mean of 16.3 +/- 0.4 K, assuming an opacity law index of 1.7. For the structures with good determination of color temperatures, the mean ratio of gas temperature, determined from NH3 observations, to dust color temperature is 0.88 and the median ratio is 0.76. About half the clumps have more than 2 substructures and 22 clumps have more than 10. The fraction of the mass in dense substructures seen at 350 mu m compared to the mass of their parental clump is similar to 0.19, and the surface densities of these substructures are, on average, 2.2 times those seen in the clumps identified at 1.1 mm. For a well-characterized sample, 88 structures (31%) exceed a surface density of 0.2 g cm(-2), and 18 (6%) exceed 1.0 g cm(-2), thresholds for massive star Formation suggested by theorists.National Science Foundation through NSF grant AST-0708403NRAONSF AST-9980846, AST-0206158, AST-1109116Fulbright FellowshipASI, AgenziaSpaziale Italiana I/038/080/0, I/029/12/0national funding agency: CSA (Canada)national funding agency: NAOC (China)national funding agency: CEA (France)national funding agency: ASI (Italy)national funding agency: MCINN (Spain)national funding agency: Stockholm Observatory (Sweden)national funding agency: STFC (UK)national funding agency: NASA (USA)national funding agency: CNES (France)national funding agency: CNRS (France)Astronom

The efficacy of allergen immunotherapy with cat dander in reducing symptoms in clinical practice.

Background. Allergy to cat dander is a common form of allergic disease. Allergen immunotherapy has been demonstrated to be effective in decreasing allergic symptoms. Objectives. To examine outcomes in allergic asthmatic patients on cat immunotherapy (CIT) compared to allergic asthmatics on traditional immunotherapy (IT) without cat sensitivity. Methods. A retrospective review identified allergic asthmatics on CIT for at least three years. An equal number of allergic asthmatics on IT were identified for comparison. Outcomes investigated include measurements of risk of asthma exacerbation. Results. Thirty-five patients were identified in each group. There were no differences in the CIT group versus the comparison group regarding total number of prednisone tapers (18 tapers versus 14 tapers, resp.), number of patients requiring prednisone tapers (10 patients versus 10 patients, resp.), total number of acute visits (29 visits versus 38 visits, resp.), and number of patients requiring acute visits (15 patients versus 21 patients, resp.). When stratified by concomitant ICS use, patients on CIT were less likely to require an acute visit (46% versus 78%, resp.). Conclusions. Allergic asthmatics with cat sensitivity on CIT with close dander exposure have similar risk of asthma exacerbation compared to allergic asthmatics without cat sensitivity on immunotherapy

Synthesis, electrochemistry and First Principles Calculation studies of layered Li-Ni-Ti-O compounds

New layered cathode materials, Li₀.₉Ni₀.₄₅Ti₀.₅₅O₂, were synthesized by means of ion-exchange from Na₀.₉Ni₀.₄₅Ti₀.₅₅O₂. The degree of cation disordering in the material depends critically on the synthesis conditions. Longer times and higher temperatures in the ion-exchange process induced more cation disordering. However, the partially disordered phase showed better capacity retention than the least disordered phase. First principles calculations indicated this could be attributed to the migration of Ti⁺⁴ into the Li layer during the electrochemical testing, which seems to depend sensitively on the Ni⁺² -Ti⁺⁴ configuration in the transition metal layer. The poor conductivity of this material could also be the reason for its low specific capacity according to the Density of States (DOS) obtained from first principles calculations indicating that only Ni participates in the electronic conductivity.Singapore-MIT Alliance (SMA

Progress toward curing HIV infection with hematopoietic cell transplantation.

HIV-1 infection afflicts more than 35 million people worldwide, according to 2014 estimates from the World Health Organization. For those individuals who have access to antiretroviral therapy, these drugs can effectively suppress, but not cure, HIV-1 infection. Indeed, the only documented case for an HIV/AIDS cure was a patient with HIV-1 and acute myeloid leukemia who received allogeneic hematopoietic cell transplantation (HCT) from a graft that carried the HIV-resistant CCR5-∆32/∆32 mutation. Other attempts to establish a cure for HIV/AIDS using HCT in patients with HIV-1 and malignancy have yielded mixed results, as encouraging evidence for virus eradication in a few cases has been offset by poor clinical outcomes due to the underlying cancer or other complications. Such clinical strategies have relied on HIV-resistant hematopoietic stem and progenitor cells that harbor the natural CCR5-∆32/∆32 mutation or that have been genetically modified for HIV-resistance. Nevertheless, HCT with HIV-resistant cord blood remains a promising option, particularly with inventories of CCR5-∆32/∆32 units or with genetically modified, human leukocyte antigen-matched cord blood

Anopheles stephensi p38 MAPK signaling regulates innate immunity and bioenergetics during Plasmodium falciparum infection.

BackgroundFruit flies and mammals protect themselves against infection by mounting immune and metabolic responses that must be balanced against the metabolic needs of the pathogens. In this context, p38 mitogen-activated protein kinase (MAPK)-dependent signaling is critical to regulating both innate immunity and metabolism during infection. Accordingly, we asked to what extent the Asian malaria mosquito Anopheles stephensi utilizes p38 MAPK signaling during infection with the human malaria parasite Plasmodium falciparum.MethodsA. stephensi p38 MAPK (AsP38 MAPK) was identified and patterns of signaling in vitro and in vivo (midgut) were analyzed using phospho-specific antibodies and small molecule inhibitors. Functional effects of AsP38 MAPK inhibition were assessed using P. falciparum infection, quantitative real-time PCR, assays for reactive oxygen species and survivorship under oxidative stress, proteomics, and biochemical analyses.ResultsThe genome of A. stephensi encodes a single p38 MAPK that is activated in the midgut in response to parasite infection. Inhibition of AsP38 MAPK signaling significantly reduced P. falciparum sporogonic development. This phenotype was associated with AsP38 MAPK regulation of mitochondrial physiology and stress responses in the midgut epithelium, a tissue critical for parasite development. Specifically, inhibition of AsP38 MAPK resulted in reduction in mosquito protein synthesis machinery, a shift in glucose metabolism, reduced mitochondrial metabolism, enhanced production of mitochondrial reactive oxygen species, induction of an array of anti-parasite effector genes, and decreased resistance to oxidative stress-mediated damage. Hence, P. falciparum-induced activation of AsP38 MAPK in the midgut facilitates parasite infection through a combination of reduced anti-parasite immune defenses and enhanced host protein synthesis and bioenergetics to minimize the impact of infection on the host and to maximize parasite survival, and ultimately, transmission.ConclusionsThese observations suggest that, as in mammals, innate immunity and mitochondrial responses are integrated in mosquitoes and that AsP38 MAPK-dependent signaling facilitates mosquito survival during parasite infection, a fact that may attest to the relatively longer evolutionary relationship of these parasites with their invertebrate compared to their vertebrate hosts. On a practical level, improved understanding of the balances and trade-offs between resistance and metabolism could be leveraged to generate fit, resistant mosquitoes for malaria control