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.

Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration.

Mutations in Sigma 1 receptor (SIGMAR1) have been previously identified in patients with amyotrophic lateral sclerosis and disruption of Sigmar1 in mouse leads to locomotor deficits. However, cellular mechanisms underlying motor phenotypes in human and mouse with disturbed SIGMAR1 function have not been described so far. Here we used a combination of in vivo and in vitro approaches to investigate the role of SIGMAR1 in motor neuron biology. Characterization of Sigmar1(-/-) mice revealed that affected animals display locomotor deficits associated with muscle weakness, axonal degeneration and motor neuron loss. Using primary motor neuron cultures, we observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by cell death. Disruption of SIGMAR1 function in motor neurons disturbed endoplasmic reticulum-mitochondria contacts, affected intracellular calcium signalling and was accompanied by activation of endoplasmic reticulum stress and defects in mitochondrial dynamics and transport. These defects were not observed in cultured sensory neurons, highlighting the exacerbated sensitivity of motor neurons to SIGMAR1 function. Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging and endoplasmic reticulum stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration. These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function and provide therapeutically relevant insight into motor neuronal diseases.

Quantifying the time for accurate EEG decoding of single value-based decisions.

BACKGROUND: Recent neuroimaging studies suggest that value-based decision-making may rely on mechanisms of evidence accumulation. However no studies have explicitly investigated the time when single decisions are taken based on such an accumulation process. NEW METHOD: Here, we outline a novel electroencephalography (EEG) decoding technique which is based on accumulating the probability of appearance of prototypical voltage topographies and can be used for predicting subjects' decisions. We use this approach for studying the time-course of single decisions, during a task where subjects were asked to compare reward vs. loss points for accepting or rejecting offers. RESULTS: We show that based on this new method, we can accurately decode decisions for the majority of the subjects. The typical time-period for accurate decoding was modulated by task difficulty on a trial-by-trial basis. Typical latencies of when decisions are made were detected at ∼500ms for 'easy' vs. ∼700ms for 'hard' decisions, well before subjects' response (∼340ms). Importantly, this decision time correlated with the drift rates of a diffusion model, evaluated independently at the behavioral level. COMPARISON WITH EXISTING METHOD(S): We compare the performance of our algorithm with logistic regression and support vector machine and show that we obtain significant results for a higher number of subjects than with these two approaches. We also carry out analyses at the average event-related potential level, for comparison with previous studies on decision-making. CONCLUSIONS: We present a novel approach for studying the timing of value-based decision-making, by accumulating patterns of topographic EEG activity at single-trial level.

Combined loss of the BH3-only proteins Bim and Bmf restores B-cell development and function in TACI-Ig transgenic mice.

Terminal differentiation of B cells depends on two interconnected survival pathways, elicited by the B-cell receptor (BCR) and the BAFF receptor (BAFF-R), respectively. Loss of either signaling pathway arrests B-cell development. Although BCR-dependent survival depends mainly on the activation of the v-AKT murine thymoma viral oncogene homolog 1 (AKT)/PI3-kinase network, BAFF/BAFF-R-mediated survival engages non-canonical NF-κB signaling as well as MAPK/extracellular-signal regulated kinase and AKT/PI3-kinase modules to allow proper B-cell development. Plasma cell survival, however, is independent of BAFF-R and regulated by APRIL that signals NF-κB activation via alternative receptors, that is, transmembrane activator and CAML interactor (TACI) or B-cell maturation (BCMA). All these complex signaling events are believed to secure survival by increased expression of anti-apoptotic B-cell lymphoma 2 (Bcl2) family proteins in developing and mature B cells. Curiously, how lack of BAFF- or APRIL-mediated signaling triggers B-cell apoptosis remains largely unexplored. Here, we show that two pro-apoptotic members of the 'Bcl2 homology domain 3-only' subgroup of the Bcl2 family, Bcl2 interacting mediator of cell death (Bim) and Bcl2 modifying factor (Bmf), mediate apoptosis in the context of TACI-Ig overexpression that effectively neutralizes BAFF as well as APRIL. Surprisingly, although Bcl2 overexpression triggers B-cell hyperplasia exceeding the one observed in Bim(-/-)Bmf(-/-) mice, Bcl2 transgenic B cells remain susceptible to the effects of TACI-Ig expression in vivo, leading to ameliorated pathology in Vav-Bcl2 transgenic mice. Together, our findings shed new light on the molecular machinery restricting B-cell survival during development, normal homeostasis and under pathological conditions. Our data further suggest that Bcl2 antagonists might improve the potency of BAFF/APRIL-depletion strategies in B-cell-driven pathologies.

Genomic Adaptations to the Loss of a Conserved Bacterial DNA Methyltransferase.

UNLABELLED: CcrM is an orphan DNA methyltransferase nearly universally conserved in a vast group of Alphaproteobacteria. In Caulobacter crescentus, it controls the expression of key genes involved in the regulation of the cell cycle and cell division. Here, we demonstrate, using an experimental evolution approach, that C. crescentus can significantly compensate, through easily accessible genetic changes like point mutations, the severe loss in fitness due to the absence of CcrM, quickly improving its growth rate and cell morphology in rich medium. By analyzing the compensatory mutations genome-wide in 12 clones sampled from independent ΔccrM populations evolved for ~300 generations, we demonstrated that each of the twelve clones carried at least one mutation that potentially stimulated ftsZ expression, suggesting that the low intracellular levels of FtsZ are the major burden of ΔccrM mutants. In addition, we demonstrate that the phosphoenolpyruvate-carbohydrate phosphotransfer system (PTS) actually modulates ftsZ and mipZ transcription, uncovering a previously unsuspected link between metabolic regulation and cell division in Alphaproteobacteria. We present evidence that point mutations found in genes encoding proteins of the PTS provide the strongest fitness advantage to ΔccrM cells cultivated in rich medium despite being disadvantageous in minimal medium. This environmental sign epistasis might prevent such mutations from getting fixed under changing natural conditions, adding a plausible explanation for the broad conservation of CcrM. IMPORTANCE: In bacteria, DNA methylation has a variety of functions, including the control of DNA replication and/or gene expression. The cell cycle-regulated DNA methyltransferase CcrM modulates the transcription of many genes and is critical for fitness in Caulobacter crescentus. Here, we used an original experimental evolution approach to determine which of its many targets make CcrM so important physiologically. We show that populations lacking CcrM evolve quickly, accumulating an excess of mutations affecting, directly or indirectly, the expression of the ftsZ cell division gene. This finding suggests that the most critical function of CcrM in C. crescentus is to promote cell division by enhancing FtsZ intracellular levels. During this work, we also discovered an unexpected link between metabolic regulation and cell division that might extend to other Alphaproteobacteria.

Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies.

Inherited peripheral neuropathies are a genetically heterogeneous group of disorders characterized by distal muscle weakness and sensory loss. Mutations in genes encoding aminoacyl-tRNA synthetases have been implicated in peripheral neuropathies, suggesting that these tRNA charging enzymes are uniquely important for the peripheral nerve. Recently, a mutation in histidyl-tRNA synthetase (HARS) was identified in a single patient with a late-onset, sensory-predominant peripheral neuropathy; however, the genetic evidence was lacking, making the significance of the finding unclear. Here, we present clinical, genetic, and functional data that implicate HARS mutations in inherited peripheral neuropathies. The associated phenotypic spectrum is broad and encompasses axonal and demyelinating motor and sensory neuropathies, including four young patients presenting with pure motor axonal neuropathy. Genome-wide linkage studies in combination with whole-exome and conventional sequencing revealed four distinct and previously unreported heterozygous HARS mutations segregating with autosomal dominant peripheral neuropathy in four unrelated families (p.Thr132Ile, p.Pro134His, p.Asp175Glu and p.Asp364Tyr). All mutations cause a loss of function in yeast complementation assays, and p.Asp364Tyr is dominantly neurotoxic in a Caenorhabditis elegans model. This study demonstrates the role of HARS mutations in peripheral neuropathy and expands the genetic and clinical spectrum of aminoacyl-tRNA synthetase-related human disease.

Fast oscillatory activity in the anterior cingulate cortex: dopaminergic modulation and effect of perineuronal net loss.

Dopamine release in the prefrontal cortex plays a critical role in cognitive function such as working memory, attention and planning. Dopamine exerts complex modulation on excitability of pyramidal neurons and interneurons, and regulates excitatory and inhibitory synaptic transmission. Because of the complexity of this modulation, it is difficult to fully comprehend the effect of dopamine on neuronal network activity. In this study, we investigated the effect of dopamine on local high-frequency oscillatory neuronal activity (in β band) in slices of the mouse anterior cingulate cortex (ACC). We found that dopamine enhanced the power of these oscillations induced by kainate and carbachol, but did not affect their peak frequency. Activation of D2R and in a lesser degree D1R increased the oscillation power, while activation of D4R had no effect. These high-frequency oscillations in the ACC relied on both phasic inhibitory and excitatory transmission and functional gap junctions. Thus, dopamine released in the ACC promotes high-frequency synchronized local cortical activity which is known to favor information transfer, fast selection and binding of distributed neuronal responses. Finally, the power of these oscillations was significantly enhanced after degradation of the perineuronal nets (PNNs) enwrapping most parvalbumin interneurons. This study provides new insights for a better understanding of the abnormal prefrontal gamma activity in schizophrenia (SZ) patients who display prefrontal anomalies of both the dopaminergic system and the PNNs.

Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes.

In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Navs is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Navs PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Navs in two different ways: via direct physical interference with Nav gating, or via the control of Nav trafficking. Both mechanisms have a profound impact on neuronal excitability. In this review we will discuss the role of Protein Kinase A, B, and C, Mitogen Activated Protein Kinases and Ca++/Calmodulin-dependent Kinase II in peripheral chronic pain syndromes. We will also discuss more recent findings that the ubiquitination of Nav1.7 by Nedd4-2 and the effect of methylglyoxal on Nav1.8 are also implicated in the development of experimental neuropathic pain. We will address the potential roles of other PTMs in chronic pain and highlight the need for further investigation of PTMs of Navs in order to develop new pharmacological tools to alleviate pain.

Animal modelling for inherited central vision loss.

Disease-causing variants of a large number of genes trigger inherited retinal degeneration leading to photoreceptor loss. Because cones are essential for daylight and central vision such as reading, mobility, and face recognition, this review focuses on a variety of animal models for cone diseases. The pertinence of using these models to reveal genotype/phenotype correlations and to evaluate new therapeutic strategies is discussed. Interestingly, several large animal models recapitulate human diseases and can serve as a strong base from which to study the biology of disease and to assess the scale-up of new therapies. Examples of innovative approaches will be presented such as lentiviral-based transgenesis in pigs and adeno-associated virus (AAV)-gene transfer into the monkey eye to investigate the neural circuitry plasticity of the visual system. The models reported herein permit the exploration of common mechanisms that exist between different species and the identification and highlighting of pathways that may be specific to primates, including humans.

Welfare loss with municipal amalgamations and the willingness-to-pay for the municipality name

Functional advantages and drawbacks are commonly mentioned to rationally justify or condemn municipality amalgamations. However, many consolidation projects are resisted by local governments or citizens on the grounds that amalgamation would dampen local identity. A municipality's name change is probably the most visible sign of the loss of community bond experienced by citizens at amalgamation time. This article aims to put a value on this loss by measuring citizen willingness to pay for their city name. This methodological approach innovates upon the literature on municipal amalgamation and place branding by exploiting the versatility of the so-called contingent valuation method (CVM). CVM confronts respondents, in a survey setting, with a hypothetical market in which a characteristic of interest is exchanged. Here the characteristic is the possibility to retain one's city name for an amalgamated jurisdiction. The article presents the estimates provided by a survey conducted in four Swiss cities.