The AAA plus chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system

Amyloid-like aggregates of the microtubule-associated protein Tau are associated with several neurodegenerative disorders including Alzheimer's disease. The existence of cellular machinery for the removal of such aggregates has remained unclear, as specialized disaggregase chaperones are thought to be absent inmammalian cells. Here we show in cell culture and in neurons that the hexameric ATPase valosin-containing protein (VCP) is recruited to ubiquitylated Tau fibrils, resulting in their efficient disaggregation. Aggregate clearance depends on the functional cooperation of VCP with heat shock 70 kDa protein (Hsp70) and the ubiquitin-proteasome machinery. While inhibition of VCP activity stabilizes large Tau aggregates, disaggregation by VCP generates seeding-active Tau species as byproduct. These findings identify VCP as a core component of the machinery for the removal of neurodegenerative disease aggregates and suggest that its activity can be associated with enhanced aggregate spreading in tauopathies

Understanding the mechanisms behind acute pain in dogs and cats

A basic understanding of the processes involved in nociception is a pre-requisite for successful management of acute pain. Peripheral and central sensitisation are key components contributing to pain in most cases, and a number of important concepts are now widely recognised as being crucial with regard to minimising their occurrence, and thereby improving the effectiveness of analgesia therapy. Although somewhat controversial in human medicine, pre-emptive analgesia - whereby analgesic agents are administered in advance of noxious stimulation - appears to be of importance in animals. Optimal pain relief is only likely to be achieved if a multimodal approach to analgesia is undertaken, utilising pharmaceutical agents acting at different points within the 'pain pathway'. In addition, preventive analgesia - wherein adequate pain relief is provided throughout the peri-operative period and well into recovery - is now considered one of the most significant areas in which acute pain management can be advanced

Central Arctic Ocean surface–atmosphere exchange of CO₂ and CH₄ constrained by direct measurements

The central Arctic Ocean (CAO) plays an important role in the global carbon cycle, but the current and future exchange of the climate-forcing trace gases methane (CH4) and carbon dioxide (CO2) between the CAO and the atmosphere is highly uncertain. In particular, there are very few observations of near-surface gas concentrations or direct air–sea CO2 flux estimates and no previously reported direct air–sea CH4 flux estimates from the CAO. Furthermore, the effect of sea ice on the exchange is not well understood. We present direct measurements of the air–sea flux of CH4 and CO2, as well as air–snow fluxes of CO2 in the summertime CAO north of 82.5∘ N from the Synoptic Arctic Survey (SAS) expedition carried out on the Swedish icebreaker Oden in 2021. Measurements of air–sea CH4 and CO2 flux were made using floating chambers deployed in leads accessed from sea ice and from the side of Oden, and air–snow fluxes were determined from chambers deployed on sea ice. Gas transfer velocities determined from fluxes and surface-water-dissolved gas concentrations exhibited a weaker wind speed dependence than existing parameterisations, with a median sea-ice lead gas transfer rate of 2.5 cm h−1 applicable over the observed 10 m wind speed range (1–11 m s−1). The average observed air–sea CO2 flux was −7.6 mmolm-2d-1, and the average air–snow CO2 flux was −1.1 mmolm-2d-1. Extrapolating these fluxes and the corresponding sea-ice concentrations gives an August and September flux for the CAO of −1.75 mmolm-2d-1, within the range of previous indirect estimates. The average observed air–sea CH4 flux of 3.5 µmolm-2d-1, accounting for sea-ice concentration, equates to an August and September CAO flux of 0.35 µmolm-2d-1, lower than previous estimates and implying that the CAO is a very small (≪ 1 %) contributor to the Arctic flux of CH4 to the atmosphere.</p