SUMO modification of cell surface Kv2.1 potassium channels regulates the activity of rat hippocampal neurons

Voltage-gated Kv2.1 potassium channels are important in the brain for determining activity-dependent excitability. Small ubiquitin-like modifier proteins (SUMOs) regulate function through reversible, enzyme-mediated conjugation to target lysine(s). Here, sumoylation of Kv2.1 in hippocampal neurons is shown to regulate firing by shifting the half-maximal activation voltage (V1/2) of channels up to 35 mV. Native SUMO and Kv2.1 are shown to interact within and outside channel clusters at the neuronal surface. Studies of single, heterologously expressed Kv2.1 channels show that only K470 is sumoylated. The channels have four subunits, but no more than two non-adjacent subunits carry SUMO concurrently. SUMO on one site shifts V1/2 by 15 mV, whereas sumoylation of two sites produces a full response. Thus, the SUMO pathway regulates neuronal excitability via Kv2.1 in a direct and graded manner

Comparison of the greenhouse gas emissions of a high-rise residential building assessed with different national LCA approaches – IEA EBC Annex 72

Introduction: The international research project IEA EBC Annex 72 investigates the life cycle related environmental impacts caused by buildings. The project aims inter alia to harmonise LCA approaches on buildings. Methods: To identify major commonalities and discrepancies among national LCA approaches, reference buildings were defined to present and compare the national approaches. A residential high-rise building located in Tianjin, China, was selected as one of the reference buildings. The main construction elements are reinforced concrete shear walls, beams and floor slabs. The building has an energy reference area of 4566 m2 and an operational heating energy demand of 250 MJ/m2a. An expert team provided information on the quantities of building materials and elements required for the construction, established a BIM model and quantified the operational energy demand. Results: The greenhouse gas emissions and environmental impacts of the building were quantified using 17 country-specific national assessment methods and LCA databases. Comparisons of the results are shown on the level of building elements as well as the complete life cycle of the building. Conclusions: The results of these assessments show that the main differences lie in the LCA background data used, the scope of the assessment and the reference study period applied. Despite the variability in the greenhouse gas emissions determined with the 17 national methods, the individual results are relevant in the respective national context of the method, data, tool and benchmark used. It is important that environmental benchmarks correspond to the particular LCA approach and database of a country in which the benchmark is applied. Furthermore, the results imply to include building technologies as their contribution to the overall environmental impacts is not negligible. Grant support: The authors thank the IEA for its organizational support and the funding organizations in the participating countries for their financial support.IEA -International Energy Agency(undefined

RSV604, a Novel Inhibitor of Respiratory Syncytial Virus Replication

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections worldwide, yet no effective vaccine or antiviral treatment is available. Here we report the discovery and initial development of RSV604, a novel benzodiazepine with submicromolar anti-RSV activity. It proved to be equipotent against all clinical isolates tested of both the A and B subtypes of the virus. The compound has a low rate of in vitro resistance development. Sequencing revealed that the resistant virus had mutations within the nucleocapsid protein. This is a novel mechanism of action for anti-RSV compounds. In a three-dimensional human airway epithelial cell model, RSV604 was able to pass from the basolateral side of the epithelium effectively to inhibit virus replication after mucosal inoculation. RSV604, which is currently in phase II clinical trials, represents the first in a new class of RSV inhibitors and may have significant potential for the effective treatment of RSV disease

Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes

Resting memory CD4+ T-cells harboring latent HIV proviruses represent a critical barrier to viral eradication. Histone deacetylase inhibitors (HDACis), such as suberanilohydroxamic acid (SAHA), romidepsin, and panobinostat have been shown to induce HIV expression in these resting cells. Recently, it has been demonstrated that the low levels of viral gene expression induced by a candidate HDACi may be insufficient to cause the death of infected cells by viral cytopathic effects, necessitating their elimination by immune effectors, such as cytotoxic T-lymphocytes (CTL). Here, we study the impact of three HDACis in clinical development on T-cell effector functions. We report two modes of HDACi-induced functional impairment: i) the rapid suppression of cytokine production from viable T-cells induced by all three HDACis ii) the selective death of activated T-cells occurring at later time-points following transient exposures to romidepsin or, to a lesser extent, panobinostat. As a net result of these factors, HDACis impaired CTL-mediated IFN-γ production, as well as the elimination of HIV-infected or peptide-pulsed target cells, both in liquid culture and in collagen matrices. Romidepsin exerted greater inhibition of antiviral function than SAHA or panobinostat over the dose ranges tested. These data suggest that treatment with HDACis to mobilize the latent reservoir could have unintended negative impacts on the effector functions of CTL. This could influence the effectiveness of HDACi-based eradication strategies, by impairing elimination of infected cells, and is a critical consideration for trials where therapeutic interruptions are being contemplated, given the importance of CTL in containing rebound viremia

The Physics of the B Factories

This work is on the Physics of the B Factories. Part A of this book contains a brief description of the SLAC and KEK B Factories as well as their detectors, BaBar and Belle, and data taking related issues. Part B discusses tools and methods used by the experiments in order to obtain results. The results themselves can be found in Part C

Comparison of the environmental assessment of an identical office building with national methods

The IEA EBC Annex 72 focuses on the assessment of the primary energy demand, greenhouse gas emissions and environmental impacts of buildings during production, construction, use (including repair and replacement) and end of life (dismantling), i.e. during the entire life cycle of buildings. In one of its activities, reference buildings (size, materialisation, operational energy demand, etc.) were defined on which the existing national assessment methods are applied using national (if available) databases and (national/regional) approaches. The ?be2226? office building in Lustenau, Austria was selected as one of the reference buildings. TU Graz established a BIM model and quantified the amount of building elements as well as construction materials required and the operational energy demand. The building assessment was carried out using the same material and energy demand but applying the LCA approach used in the different countries represented by the participating Annex experts. The results of these assessments are compared in view of identifying major discrepancies. Preliminary findings show that the greenhouse gas emissions per kg of building material differ up to a factor of two and more. Major differences in the building assessments are observed in the transports to the construction site (imports) and the construction activities as well as in the greenhouse gas emissions of the operational energy demand (electricity). The experts document their practical difficulties and how they overcame them. The results of this activity are used to better target harmonisation efforts.IEA -International Association for the Evaluation of Educational Achievement(Slovenia