Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β

Extracellular plaques of amyloid-β and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer's disease. Plaques comprise amyloid-β fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of Alzheimer's disease. Despite the importance of plaques to Alzheimer's disease, oligomers are considered to be the principal toxic forms of amyloid-β. Interestingly, many adverse responses to amyloid-β, such as cytotoxicity, microtubule loss, impaired memory and learning, and neuritic degeneration, are greatly amplified by tau expression. Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-β are strongly associated with Alzheimer's disease, are more toxic than amyloid-β, residues 1-42 (Aβ(1-42)) and Aβ(1-40), and have been proposed as initiators of Alzheimer's disease pathogenesis. Here we report a mechanism by which pE-Aβ may trigger Alzheimer's disease. Aβ(3(pE)-42) co-oligomerizes with excess Aβ(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Aβ(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% Aβ(3(pE)-42) plus 95% Aβ(1-42) (5% pE-Aβ) seed new cytotoxic LNOs through multiple serial dilutions into Aβ(1-42) monomers in the absence of additional Aβ(3(pE)-42). LNOs isolated from human Alzheimer's disease brain contained Aβ(3(pE)-42), and enhanced Aβ(3(pE)-42) formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. We conclude that Aβ(3(pE)-42) confers tau-dependent neuronal death and causes template-induced misfolding of Aβ(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Aβ(3(pE)-42) acts similarly at a primary step in Alzheimer's disease pathogenesis.     

Effect of niobium alloying level on the oxidation behavior of titanium aluminides at 850°C

This work addresses the alloying of titanium aluminides used in aircraft engine applications and automobiles. The oxidation resistance behavior of two titanium aluminides of α₂ + γ(Ti₃Al + TiAl) and orthorhombic Ti₂NbAl, recognized as candidates for high-temperature applications, was investigated by exposure of the alloys for 100 h in air. Thus, oxidation resistance was expressed as the mass gain rate, whereas surface aspects were analyzed using scanning electron microscopy in conjunction with energy-dispersive X-ray spectroscopy, and the type of oxidation products was analyzed by X-ray diffraction and Raman spectroscopy. The orthorhombic Ti₂NbAl alloy was embrittled, and pores and microcracks were formed as a result of oxygen diffusion through the external oxide layer formed during thermal oxidation for 100 h.     

Bottom-up effects of plant diversity on multitrophic interactions in a biodiversity experiment

Biodiversity is rapidly declining, and this may negatively affect ecosystem processes, including economically important ecosystem services. Previous studies have shown that biodiversity has positive effects on organisms and processes across trophic levels. However, only a few studies have so far incorporated an explicit food-web perspective. In an eight-year biodiversity experiment, we studied an unprecedented range of above- and below-ground organisms and multitrophic interactions. A multitrophic data set originating from a single long-term experiment allows mechanistic insights that would not be gained from meta-analysis of different experiments. Here we show that plant diversity effects dampen with increasing trophic level and degree of omnivory. This was true both for abundance and species richness of organisms. Furthermore, we present comprehensive above-ground/below-ground biodiversity food webs. Both above ground and below ground, herbivores responded more strongly to changes in plant diversity than did carnivores or omnivores. Density and richness of carnivorous taxa was independent of vegetation structure. Below-ground responses to plant diversity were consistently weaker than above-ground responses. Responses to increasing plant diversity were generally positive, but were negative for biological invasion, pathogen infestation and hyperparasitism. Our results suggest that plant diversity has strong bottom-up effects on multitrophic interaction networks, with particularly strong effects on lower trophic levels. Effects on higher trophic levels are indirectly mediated through bottom-up trophic cascades.     

Mechanical properties of a Gum-type Ti-Nb-Zr-Fe-O alloy

A new Gum-type alloy (Ti-Nb-Zr-Fe-O) in which Fe is used instead of Ta was subjected to a particular thermomechanical processing scheme to assess whether its mechanical characteristics (fine β-grains with high strength and low modulus) render it suitable as a biomedical implant material. After a homogenization treatment followed by cold-rolling with 50% reduction, the specimens were subjected to one of three different recrystallization treatments at 1073, 1173, and 1273 K. The structural and mechanical properties of all of the treated specimens were analyzed. The mechanical characterization included tensile tests, microhardness determinations, and fractography by scanning electron microscopy. The possible deformation mechanisms were discussed using the Bo-Md diagram. By correlating all of the experimental results, we concluded that the most promising processing variant corresponds to recrystallization at 1073 K, which can provide suitable mechanical characteristics for this type of alloys:high yield and ultimate tensile strengths (1038 and 1083 MPa, respectively), a low modulus of elasticity (62 GPa), and fine crystalline grain size (approximately 50 μm).     

Judgement aggregation in scientific collaborations: The case for waiving expertise

The fragmentation of academic disciplines forces individuals to specialise. In doing so, they become experts over their narrow area of research. However, ambitious scientific projects, such as the search for gravitational waves, require them to come together and collaborate across disciplinary borders. How should scientists with expertise in different disciplines treat each others’ expert claims? An intuitive answer is that the collaboration should defer to the opinions of experts. In this paper we show that under certain seemingly innocuous assumptions, this intuitive answer gives rise to an impossibility result when it comes to aggregating the beliefs of experts to deliver the beliefs of a collaboration as a whole. We then argue that when experts’ beliefs come into conflict, they should waive their expert status.     

Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures

Sensory acuity and motor dexterity deteriorate when human limbs cool down, but pain perception persists and cold-induced pain can become excruciating. Evolutionary pressure to enforce protective behaviour requires that damage-sensing neurons (nociceptors) continue to function at low temperatures. Here we show that this goal is achieved by endowing superficial endings of slowly conducting nociceptive fibres with the tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Na(v)1.8 (ref. 2). This channel is essential for sustained excitability of nociceptors when the skin is cooled. We show that cooling excitable membranes progressively enhances the voltage-dependent slow inactivation of tetrodotoxin-sensitive VGSCs. In contrast, the inactivation properties of Na(v)1.8 are entirely cold-resistant. Moreover, low temperatures decrease the activation threshold of the sodium currents and increase the membrane resistance, augmenting the voltage change caused by any membrane current. Thus, in the cold, Na(v)1.8 remains available as the sole electrical impulse generator in nociceptors that transmits nociceptive information to the central nervous system. Consistent with this concept is the observation that Na(v)1.8-null mutant mice show negligible responses to noxious cold and mechanical stimulation at low temperatures. Our data present strong evidence for a specialized role of Na(v)1.8 in nociceptors as the critical molecule for the perception of cold pain and pain in the cold.