Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Mediates Neuronal Aβ42 Uptake and Lysosomal Trafficking

Alzheimer's disease (AD) is characterized by the presence of early intraneuronal deposits of amyloid-beta 42 (Abeta42) that precede extracellular amyloid deposition in vulnerable brain regions. It has been hypothesized that endosomal/lysosomal dysfunction might be associated with the pathological accumulation of intracellular Abeta42 in the brain. Our previous findings suggest that the LDL receptor-related protein 1 (LRP1), a major receptor for apolipoprotein E, facilitates intraneuronal Abeta42 accumulation in mouse brain. However, direct evidence of neuronal endocytosis of Abeta42 through LRP1 is lacking.Here we show that LRP1 endocytic function is required for neuronal Abeta42 uptake. Overexpression of a functional LRP1 minireceptor, mLRP4, increases Abeta42 uptake and accumulation in neuronal lysosomes. Conversely, knockdown of LRP1 expression significantly decreases neuronal Abeta42 uptake. Disruptions of LRP1 endocytic function by either clathrin knockdown or by removal of its cytoplasmic tail decreased both uptake and accumulation of Abeta42 in neurons. Finally, we show that LRP1-mediated neuronal accumulation of Abeta42 is associated with increased cellular toxicity.These results demonstrate that LRP1 endocytic function plays an important role in the uptake and accumulation of Abeta42 in neuronal lysosomes. These findings emphasize the central function of LRP1 in neuronal Abeta metabolism

Indonesian Christian Young People Resisting the Dominant Discourses of Men as Desiring/Dangerous and Women as Non-sexual/Vulnerable

Contemporary feminist studies have demonstrated how the binary constitution of men as desiring/dangerous and women as non-sexual/vulnerable has enabled, normalised, and sustained intimate partner sexual violence against women. Such binary positioning has given rise to gendered religious and sexual subjectivities that severely constrain women’s sexual agency. However, only a few studies have explored the ways this binary might be contested in one’s becoming of a sexual subject, particularly the identification of alternative discourses one’s may draw upon to challenge the dominant one. Seeking to fill this gap, this chapter presents four vignettes of resistance which might rework this gendered positioning among young Indonesian Christians vis-à-vis intimate partner sexual violence. The analysis revealed that these young participants drew on various alternative discourses to which they have access – from feminist, religious, to same-sex sexuality – to give new meanings to men and women as sexual subjects and resist the normalisation of intimate partner sexual violence

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Carbon-cycle imbalances in the Sargasso Sea

The net exchange of carbon dioxide between the atmosphere and the ocean, and thus the nature of the oceanic carbon sink, is dominated by the seasonal dynamics of carbon cycling in the upper ocean. This cycle represents a balance between abiotic and biotic carbon transport into, and export out of, the ocean's upper layer. Here we report measurements of these processes made over five years in the Sargasso Sea off Bermuda, as part of the US Joint Global Ocean Flux Study (JGOFS). We find that the decrease in carbon stocks from the spring to the autumn in the upper 150 m of the ocean is three times larger than the measured sum of biotic and abiotic fluxes out of this layer. This discrepancy can be explained either by failure to account for horizontal advection of carbon or by inaccuracies in the fluxes of sinking particles as measured using sediment traps. Either the traps miss 80% of the sinking particles, or 70% of the carbon cycling is due to advection (or a combination of both processes is responsible). Sediment-trap measurements of the 234Th flux during this period suggest that most of the discrepancy may be due to inaccuracies in the trap methods, which would require a very general reassessment of existing ideas about particle export and remineralization of carbon in the oceans. If, on the other hand, advection is the main source of the discrepancy, the traditional one-dimensional (vertical) modelling of the oceanic carbon cycle cannot give a full account of carbon dynamics