RRM adjacent TARDBP mutations disrupt RNA binding and enhance TDP-43 proteinopathy.

Amyotrophic lateral sclerosis (ALS) presents with focal muscle weakness due to motor neuron degeneration that becomes generalized, leading to death from respiratory failure within 3-5 years from symptom onset. Despite the heterogeneity of aetiology, TDP-43 proteinopathy is a common pathological feature that is observed in >95% of ALS and tau-negative frontotemporal dementia (FTD) cases. TDP-43 is a DNA/RNA-binding protein that in ALS and FTD translocates from being predominantly nuclear to form detergent-resistant, hyperphosphorylated aggregates in the cytoplasm of affected neurons and glia. Mutations in TARDBP account for 1-4% of all ALS cases and almost all arise in the low complexity C-terminal domain that does not affect RNA binding and processing. Here we report an ALS/FTD kindred with a novel K181E TDP-43 mutation that is located in close proximity to the RRM1 domain. To offer predictive gene testing to at-risk family members, we undertook a series of functional studies to characterize the properties of the mutation. Spectroscopy studies of the K181E protein revealed no evidence of significant misfolding. Although it is unable to bind to or splice RNA, it forms abundant aggregates in transfected cells. We extended our study to include other ALS-linked mutations adjacent to the RRM domains that also disrupt RNA binding and greatly enhance TDP-43 aggregation, forming detergent-resistant and hyperphosphorylated inclusions. Lastly, we demonstrate that K181E binds to, and sequesters, wild-type TDP-43 within nuclear and cytoplasmic inclusions. Thus, we demonstrate that TDP-43 mutations that disrupt RNA binding greatly enhance aggregation and are likely to be pathogenic as they promote wild-type TDP-43 to mislocalize and aggregate acting in a dominant-negative manner. This study highlights the importance of RNA binding to maintain TDP-43 solubility and the role of TDP-43 aggregation in disease pathogenesis.

Nanofluid Development Using Silver Nanoparticles and Organic-Luminescent Molecules for Solar-Thermal and Hybrid Photovoltaic-Thermal Applications.

Exploiting solar energy using photo-thermal (PT) and/or hybridised photovoltaic/thermal (PVT) systems can represent a viable alternative to the growing demand for renewable energy. For large-scale implementation, such systems require thermal fluids able to enhance the combined conversion efficiency achievable by controlling the 'thermal' and 'electrical' components of the solar spectrum. Nanofluids are typically employed for these purposes and they should exhibit high heat-transfer capabilities and optical properties tuned towards the peak performance spectral window of the photovoltaic (PV) component. In this work, novel nanofluids, composed of highly luminescent organic molecules and Ag nanoparticles dispersed within a base fluid, were tested for PT and PVT applications. These nanofluids were designed to mimic the behaviour of luminescent down-shifting molecules while offering enhanced thermo-physical characteristics over the host base fluid. The nanofluids' conversion efficiency was evaluated under a standard AM1.5G weighted solar spectrum. The results revealed that the Ag nanoparticles' inclusion in the composite fluid has the potential to improve the total solar energy conversion. The nanoparticles' presence minimizes the losses in the electrical power component of the PVT systems as the thermal conversion increases. The enhanced performances recorded suggest that these nanofluids could represent suitable candidates for solar energy conversion applications.