Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke.

BACKGROUND AND PURPOSE: The role of autophagy in response to ischemic stroke has been confusing with reports that both enhancement and inhibition of autophagy decrease infarct size and improve post-stroke outcomes. We sought to clarify this by comparing pharmacologic modulation of autophagy in two clinically relevant murine models of stroke. METHODS: We used rapamycin to induce autophagy, and chloroquine to block completion of autophagy, by treating mice immediately after stroke and at 24 hours post-stroke in two different models; permanent Middle Cerebral Artery Ligation (MCAL), which does not allow for reperfusion of distal trunk of middle cerebral artery, and Embolic Clot Middle Cerebral Artery Occlusion (eMCAO) which allows for a slow reperfusion similar to that seen in most human stroke patients. Outcome measures at 48 hours post-stroke included infarct size analysis, behavioral assessment using Bederson neurological scoring, and survival. RESULTS: Chloroquine treatment reduced the lesion size by approximately 30% and was significant only in the eMCAO model, where it also improved the neurological score, but did not increase survival. Rapamycin reduced lesion size by 44% and 50% in the MCAL and eMCAO models, respectively. Rapamycin also improved the neurological score to a greater degree than chloroquine and improved survival. CONCLUSIONS: While both inhibition and enhancement of autophagy by pharmacological intervention decreased lesion size and improved neurological scores, the enhancement with rapamycin showed a greater degree of improvement in outcomes as well as in survival. The protective action seen with chloroquine may be in part due to off-target effects on apoptosis separate from blocking lysosomal activity in autophagy. We conclude pharmacologic induction of autophagy is more advantageous than its blockade in physiologically-relevant permanent and slow reperfusion stroke models.

Divergence of trends in US and UK aggregate exergy efficiencies 1960-2010.

National exergy efficiency analysis relates the quality of primary energy inputs to an economy with end useful work in sectoral energy uses such as transport, heat and electrical devices. This approach has been used by a range of authors to explore insights to macroscale energy systems and linkages with economic growth. However, these analyses use a variety of calculation methods with sometimes coarse assumptions, inhibiting comparisons. Therefore, building on previous studies, this paper first contributes toward a common useful work accounting framework, by developing more refined methodological techniques for electricity end use and transport exergy efficiencies. Second, to test this more consistent and granular approach, these advances are applied to the US and UK for 1960 to 2010. The results reveal divergent aggregate exergy efficiencies: US efficiency remains stable at around 11%, while UK efficiency rises from 9% to 15%. The US efficiency stagnation is due to "efficiency dilution", where structural shifts to lower efficiency consumption (e.g., air-conditioning) outweigh device-level efficiency gains. The results demonstrate this is an important area of research, with consequent implications for national energy efficiency policies.

Application of hybrid life cycle approaches to emerging energy technologies--the case of wind power in the UK.

Future energy technologies will be key for a successful reduction of man-made greenhouse gas emissions. With demand for electricity projected to increase significantly in the future, climate policy goals of limiting the effects of global atmospheric warming can only be achieved if power generation processes are profoundly decarbonized. Energy models, however, have ignored the fact that upstream emissions are associated with any energy technology. In this work we explore methodological options for hybrid life cycle assessment (hybrid LCA) to account for the indirect greenhouse gas (GHG) emissions of energy technologies using wind power generation in the UK as a case study. We develop and compare two different approaches using a multiregion input-output modeling framework - Input-Output-based Hybrid LCA and Integrated Hybrid LCA. The latter utilizes the full-sized Ecoinvent process database. We discuss significance and reliability of the results and suggest ways to improve the accuracy of the calculations. The comparison of hybrid LCA methodologies provides valuable insight into the availability and robustness of approaches for informing energy and environmental policy.

Bortezomib blocks the catabolic process of autophagy via a cathepsin-dependent mechanism, affects endoplasmic reticulum stress and induces caspase-dependent cell death in antiestrogen-sensitive and resistant ER+ breast cancer cells.

In recent studies, we and others showed that autophagy is critical to estrogen receptor positive (ER+) breast cancer cell survival and the development of antiestrogen resistance. Consequently, new approaches are warranted for targeting autophagy in breast cancer cells undergoing antiestrogen therapy. Because crosstalk has been demonstrated between the autophagy- and proteasome-mediated pathways of protein degradation, this study investigated how the proteasome inhibitor bortezomib affects autophagy and cell survival in antiestrogen-treated ER+ breast cancer cells. Bortezomib, at clinically achievable doses, induced a robust death response in ER+, antiestrogen-sensitive and antiestrogen-resistant breast cancer cells undergoing hormonal therapy. Cleavage of PARP and lamin A was detectable as a read-out of cell death, following bortezomib-induced mitochondrial dysfunction. Prior to induction of cell death, bortezomib-treated cells showed high levels of light chain 3 (LC3) and p62, two protein markers for autophagy. The accumulation of these proteins was due to bortezomib-mediated blockade of long-lived protein turnover during macroautophagy. This novel action of bortezomib was linked to its blockade of cathepsin-L activity, which is required for autolysosomal-mediated protein turnover in ER+ breast cancer cells. Further, bortezomib-treated breast cancer cells showed induction of the unfolded protein response, with upregulation of CH OP and GRP78. Bortezomib also induced high levels of the pro-apoptotic protein BNIP3. Knockdown of CH OP and/or BNIP3 expression via RNAi targeting significantly attenuated the death-promoting effects of bortezomib. Thus, bortezomib inhibits prosurvival autophagy, in addition to its known function in blocking the proteasome, and is cytotoxic to hormonally treated ER+ breast cancer cells. These findings indicate that combining a proteasome inhibitor like bortezomib with antiestrogen therapy may have therapeutic advantage in the management of early-stage breast cancer.