Clearance of Alzheimer's Aβ Peptide The Many Roads to Perdition

AbstractThe amyloid hypothesis of Alzheimer's disease (AD) maintains that the accumulation of the amyloid β protein (Aβ) is a critical event in disease pathogenesis. A great deal of both academic and commercial research has focused on the mechanisms by which Aβ is generated. However, investigations into the mechanisms underlying Aβ clearance have blossomed over the last several years. This minireview will summarize pathways involved in the removal of cerebral Aβ, including enzymatic degradation and receptor-mediated efflux out of the brain

MAF1 is a chronic repressor of RNA polymerase III transcription in the mouse.

Maf1 <sup>-/-</sup> mice are lean, obesity-resistant and metabolically inefficient. Their increased energy expenditure is thought to be driven by a futile RNA cycle that reprograms metabolism to meet an increased demand for nucleotides stemming from the deregulation of RNA polymerase (pol) III transcription. Metabolic changes consistent with this model have been reported in both fasted and refed mice, however the impact of the fasting-refeeding-cycle on pol III function has not been examined. Here we show that changes in pol III occupancy in the liver of fasted versus refed wild-type mice are largely confined to low and intermediate occupancy genes; high occupancy genes are unchanged. However, in Maf1 <sup>-/-</sup> mice, pol III occupancy of the vast majority of active loci in liver and the levels of specific precursor tRNAs in this tissue and other organs are higher than wild-type in both fasted and refed conditions. Thus, MAF1 functions as a chronic repressor of active pol III loci and can modulate transcription under different conditions. Our findings support the futile RNA cycle hypothesis, elaborate the mechanism of pol III repression by MAF1 and demonstrate a modest effect of MAF1 on global translation via reduced mRNA levels and translation efficiencies for several ribosomal proteins

Let the river erode! Enabling lateral migration increases geomorphic unit diversity

River restoration practice frequently employs conservative designs that create and maintain prescribed, static morphology. Such approaches ignore an emerging understanding of resilient river systems that typically adjust their morphology in response to hydrologic, vegetative and sediment supply changes. As such, using increased dynamism as a restoration design objective will arguably yield more diverse and productive habitats, better managed expectations, and more self-sustaining outcomes. Here, we answer the following question: does restoring lateral migration in a channelised river that was once a wandering gravel-bed river, result in more diverse in-channel geomorphology? We acquired pre- and post-restoration topographic surveys on a segment of the Allt Lorgy, Scotland to quantify morphodynamics and systematically map geomorphic units, using Geomorphic Unit Tool (GUT) software. GUT implements topographic definitions to discriminate between a taxonomy of fluvial landforms that have been developed from an extension of the River Styles framework, using 3-tiered hierarchy: (1) differentiation based on stage or elevation relative to channel; (2) classification of form based on shape (mound, bowl, trough, saddle, plane, wall); and (3) mapping geomorphic units based on attributes (e.g., position and orientation). Results showed restoration increased geomorphic unit diversity, with the Shannon Diversity Index increasing from 1.40 pre-restoration (2012) to 2.04 (2014) and 2.05 (2016) after restoration. Channel widening, due to bank erosion, caused aerial coverage of in-channel geomorphic units to increase 23% after restoration and 6% further in the two-years following restoration. Once bank protection was removed, allowing bank erosion yieled a local supply of sediment to enable the formation and maintenance of lateral and point bars, riffles and diagonal bar complexes, and instream wood created structurally-forced pools and riffles. The methodology used systematically quantifies how geomorphic unit diversity increases when a river is given back its freedom space. The framework allows for testing restoration design hypotheses in post-project appraisal

Loss of the RNA polymerase III repressor MAF1 confers obesity resistance.

MAF1 is a global repressor of RNA polymerase III transcription that regulates the expression of highly abundant noncoding RNAs in response to nutrient availability and cellular stress. Thus, MAF1 function is thought to be important for metabolic economy. Here we show that a whole-body knockout of Maf1 in mice confers resistance to diet-induced obesity and nonalcoholic fatty liver disease by reducing food intake and increasing metabolic inefficiency. Energy expenditure in Maf1(-/-) mice is increased by several mechanisms. Precursor tRNA synthesis was increased in multiple tissues without significant effects on mature tRNA levels, implying increased turnover in a futile tRNA cycle. Elevated futile cycling of hepatic lipids was also observed. Metabolite profiling of the liver and skeletal muscle revealed elevated levels of many amino acids and spermidine, which links the induction of autophagy in Maf1(-/-) mice with their extended life span. The increase in spermidine was accompanied by reduced levels of nicotinamide N-methyltransferase, which promotes polyamine synthesis, enables nicotinamide salvage to regenerate NAD(+), and is associated with obesity resistance. Consistent with this, NAD(+) levels were increased in muscle. The importance of MAF1 for metabolic economy reveals the potential for MAF1 modulators to protect against obesity and its harmful consequences

Metabolic programming a lean phenotype by deregulation of RNA polymerase III.

As a master negative regulator of RNA polymerase (Pol) III, Maf1 modulates transcription in response to nutrients and stress to balance the production of highly abundant tRNAs, 5S rRNA, and other small noncoding RNAs with cell growth and maintenance. This regulation of Pol III transcription is important for energetic economy as mice lacking Maf1 are lean and resist weight gain on normal and high fat diets. The lean phenotype of Maf1 knockout (KO) mice is attributed in part to metabolic inefficiencies which increase the demand for cellular energy and elevate catabolic processes, including autophagy/lipophagy and lipolysis. A futile RNA cycle involving increased synthesis and turnover of Pol III transcripts has been proposed as an important driver of these changes. Here, using targeted metabolomics, we find changes in the liver of fed and fasted Maf1 KO mice consistent with the function of mammalian Maf1 as a chronic Pol III repressor. Differences in long-chain acylcarnitine levels suggest that energy demand is higher in the fed state of Maf1 KO mice versus the fasted state. Quantitative metabolite profiling supports increased activity in the TCA cycle, the pentose phosphate pathway, and the urea cycle and reveals changes in nucleotide levels and the creatine system. Metabolite profiling also confirms key predictions of the futile RNA cycle hypothesis by identifying changes in many metabolites involved in nucleotide synthesis and turnover. Thus, constitutively high levels of Pol III transcription in Maf1 KO mice reprogram central metabolic pathways and waste metabolic energy through a futile RNA cycle

SCS3 and YFT2 Link Transcription of Phospholipid Biosynthetic Genes to ER Stress and the UPR

10.1371/journal.pgen.1002890PLoS Genetics88e100289

Local magnetism and spin correlations in the geometrically frustrated cluster magnet LiZn2Mo3O8

LiZn2Mo3O8 has been proposed to contain S=½Mo3O13 magnetic clusters arranged on a triangular lattice with antiferromagnetic nearest-neighbor interactions. Here, microwave and terahertz electron spin resonance, Li7 nuclear magnetic resonance, and muon spin rotation spectroscopies are used to characterize the local magnetic properties of LiZn2Mo3O8. These results show the magnetism in LiZn2Mo3O8 arises from a single isotropic S=½electron per cluster and that there is no static long-range magnetic ordering down to T = 0.07 K. Further, there is evidence of gapless spin excitations with spin fluctuations slowing down as the temperature is lowered. These data indicate strong spin correlations, which, together with previous data, suggest a low-temperature resonating valence-bond state in LiZn2Mo3O8