A novel function for MicroRNA-1: Regulation of Protein Quality Control

Ageing results in a progressive decline in all organ systems throughout the body. This is particularly evident in the musculature, where it can manifest as sarcopenia, the loss of muscle mass and strength. At the molecular level, ageing is often accompanied by a decline in muscle structure and function, as well as alterations in muscle proteostasis and metabolism. MicroRNAs (miRNAs) are small 22-26 nucleotide RNAs that bind with complementarity through their seed sequence to target mRNAs to downregulate gene expression. They can work as molecular switches or fine tune gene regulation through feedback, and typically have multiple targets, thereby coordinating cellular programs. As miRNAs could serve as therapeutic targets and are shown to be regulated with age, it would be of interest to investigate whether miRNAs can influence ageing parameters. Mir-1 is a muscle enriched microRNA highly conserved in evolution and is essential to mammalian muscle and heart function. However, elevated mir-1 levels are associated with muscle dysfunction and disease, suggesting a possible pleiotropic effect of mir-1 during the ageing process. Mir-1 mouse knockouts, however, are lethal and therefore difficult to study. By contrast, C. elegans mir-1 deletion mutants are viable, making it an ideal model organism to study the function of mir-1 in muscle ageing. In this work I focused on the potential role of mir-1 in regulating muscle function, proteostasis and organismal ageing. I found that mir-1 null mutations alleviate some of the known ageing-related symptoms: mir-1 null animals have increased motility, reduced aggregate formation under proteotoxic challenge, and show enhanced autophagy and lysosomal function. I subsequently identified lysosomal v-ATPase subunits and daf-16 as strong candidates for mediating the effect of mir-1 through proteomics- and bioinformatics-based screens. Follow-up experiments revealed that mir-1 downregulates VHA-13, a subunit of the lysosomal v-ATPase, in the muscle of C. elegans. It is likely that mir-1 directly suppresses vha- 13 mRNA translation through its binding to homologous sequences in the 3´UTR. Interestingly, I also identified mir-1-dependent effects outside of the muscle, such as increased lysosomal acidification in the gut of mir-1 mutants. This suggests potential non-tissue autonomous regulation by mir-1. In agreement with this observation I provided evidence that mir-1 is present in the circulation of Drosophila and possibly reaches target tissues. Elucidating, whether and how mir-1 could affect gene expression in tissues other than its site of expression could open up an interesting new field of research. In summary, this study reveals that muscle expressed mir-1 impacts organismal function, and implies both cell autonomous and non-autonomous control

Dissociation of behavioral and neural responses to provocation during reactive aggression in healthy adults with high versus low externalization

The externalizing spectrum describes a range of heterogeneous personality traits and behavioral patterns, primarily characterized by antisocial behavior, disinhibition, and substance (mis)use. In psychopathology, abnormalities in neural threat, reward responses and the impulse-control system may be responsible for these externalizing symptoms. Within the non-clinical range, mechanisms remain still unclear. In this fMRI-study, 61 healthy participants (31 men) from the higher versus lower range of the non-clinical variation in externalization (31 participants with high externalization) as assessed by the subscales disinhibition and meanness of the Triarchic-Psychopathy-Measure (TriPM) performed a monetary modified Taylor-Aggression-Paradigm (mTAP). This paradigm consisted of a mock competitive-reaction-time-task played against a fictional opponent with preprogrammed win- and lose-trials. In lose-trials, participants were provoked by subtraction of an amount of money between 0 and 90 cents. As a manipulation check, provocation induced a significant rise in behavioral aggression levels linked with an increased activation in the anterior cingulate cortex (ACC). High externalization predicted reduced ACC responses to provocation. However, high externalizing participants did not behave more aggressively than the low externalization group. Additionally, the high externalizing group showed a significantly lower positive affect while no group differences emerged for negative affect. In conclusion, high externalization in the non-clinical range was related to neural alterations in regions involved in affective decision-making as well as to changes in affect but did not lead to higher behavioral aggression levels in response to the mTAP. This is in line with previous findings suggesting that aberrations at multiple levels are essential for developing externalizing disorders

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

NFYB-1 regulates mitochondrial function and longevity via lysosomal prosaposin

Mitochondria are multidimensional organelles whose activities are essential to cellular vitality and organismal longevity, yet underlying regulatory mechanisms spanning these different levels of organization remain elusive(1-5). Here we show that Caenorhabditis elegans nuclear transcription factor Y, beta subunit (NFYB-1), a subunit of the NF-Y transcriptional complex(6-8), is a crucial regulator of mitochondrial function. Identified in RNA interference (RNAi) screens, NFYB-1 loss leads to perturbed mitochondrial gene expression, reduced oxygen consumption, mitochondrial fragmentation, disruption of mitochondrial stress pathways, decreased mitochondrial cardiolipin levels and abolition of organismal longevity triggered by mitochondrial impairment. Multi-omics analysis reveals that NFYB-1 is a potent repressor of lysosomal prosaposin, a regulator of glycosphingolipid metabolism. Limiting prosaposin expression unexpectedly restores cardiolipin production, mitochondrial function and longevity in the nfyb-1 background. Similarly, cardiolipin supplementation rescues nfyb-1 phenotypes. These findings suggest that the NFYB-1-prosaposin axis coordinates lysosomal to mitochondria signalling via lipid pools to enhance cellular mitochondrial function and organismal health

Validation of a monetary Taylor Aggression Paradigm: Associations with trait aggression and role of provocation sequence

The Taylor Aggression Paradigm (TAP) is widely used to measure reactive aggression in laboratory settings. While modified versions (mTAPs) with various stimulus characteristics (shocks, noise, pressure, heat) have already been established, a modified version with monetary stimuli has only been introduced very recently. In this experiment, 209 young healthy participants (104 males, 105 females) completed a mock Competitive Reaction Time Task (CRTT) with a fictional opponent with preprogrammed 40 win and 60 lose trials. In lose trials, participants were provoked by subtracting a low (0-20 euro cents), medium (30-60 cents) or high (70-90 cents) amount of money from their fictitious account. Provocation stimuli were either presented randomly or in a fixed sequence (experimental conditions). In contrast to a random sequence, the fixed sequence was generated by repeating trials from the same provocation category in series of three. Linear mixed models (LMMs) considering aggression trajectories revealed significant effects of provocation (low, medium, high) and trait aggression (K-FAF) on reactive aggression. Men showed significantly higher reactive aggression levels than women. In regard to provocation sequence, we found no significant difference in reactive aggression between the random vs. fixed stimulus sequences. The findings provide new evidence supporting the view that the monetary mTAP is able to induce as well as capture reactive aggression in the laboratory. Additionally, we found no advantage of a fixed sequence as the level of reactive aggression in a given trial appeared to be mainly predicted by the preceding provocation trial

Perioperative evolution of sodium levels in cirrhotic patients undergoing liver transplantation: an observational cohort and literature review

Hyponatremia is an important predictor of early death among cirrhotic patients in the orthotopic liver transplantation (OLT) waiting list. Evidence exists that prioritizing OLT waiting list according to the MELD score combined with plasma sodium concentration might prevent pre transplantation death. However, the evolution of plasma sodium concentrations during the perioperative period of OLT is not well known. We aimed to describe the evolution of perioperative sodium concentration during OLT and its relation to perioperative neurohormonal responses

Hexosamine Pathway Activation Improves Protein Homeostasis through the Integrated Stress Response

Activation of the hexosamine pathway (HP) through gain-of-function mutations in its rate-limiting enzyme glutamine fructose-6-phosphate amidotransferase (GFAT-1) ameliorates proteotoxicity and increases lifespan in Caenorhabditis elegans. Here, we investigate the role of the HP in mammalian protein quality control. In mouse neuronal cells, elevation of HP activity led to phosphorylation of both PERK and eIF2 alpha as well as downstream ATF4 activation, identifying the HP as a modulator of the integrated stress response (ISR). Increasing uridine 5'-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc) levels through GFAT1 gain-of-function mutations or supplementation with the precursor GlcNAc reduces aggregation of the polyglutamine (polyQ) protein Ataxin-3. Blocking PERK signaling or autophagy suppresses this effect. In C. elegans, overexpression of gfat-1 likewise activates the ISR. Consistently, co-overexpression of gfat-1 and proteotoxic polyQ peptides in muscles reveals a strong protective cell-autonomous role of the HP. Thus, the HP has a conserved role in improving protein quality control through modulation of the ISR