GRW as an ontology of dispositions

The paper argues that the formulation of quantum mechanics proposed by Ghirardi, Rimini and Weber (GRW) is a serious candidate for being a fundamental physical theory and explores its ontological commitments from this perspective. In particular, we propose to conceive of spatial superpositions of non-massless microsystems as dispositions or powers, more precisely propensities, to generate spontaneous localizations. We set out five reasons for this view, namely that (1) it provides for a clear sense in which quantum systems in entangled states possess properties even in the absence of definite values; (2) it vindicates objective, single-case probabilities; (3) it yields a clear transition from quantum to classical properties; (4) it enables to draw a clear distinction between purely mathematical and physical structures, and (5) it grounds the arrow of time in the time-irreversible manifestation of the propensities to localize.     

Anandamide extends platelets survival through CB1-dependent Akt signaling

Platelets are stored at 22°C, since incubation at 37°C results in loss of viability. Nonetheless, in our body (37°C), platelets survive for 8–10 days. This discrepancy has been explained in terms of deprivation of viability factors or accumulation of apoptotic factors during storage. We report that the endocannabinoid anandamide (AEA) may be one of the agents allowing platelet survival. In fact, at 37°C, human platelets enhance the expression of pro-apoptotic proteins (caspases, Bax, Bak) and decrease the expression of Bcl-xL, thus changing the Bcl-xL/Bak ratio, a key platelet biological clock. AEA or its non-hydrolyzable analogue, methanandamide, extend platelet life span, without reversing the changes in Bcl-xL/Bak ratio induced by heat stress. Instead, AEA binding to type-1 cannabinoid receptor activates Akt, which regulates, through phosphorylation of Bad, the interactions among different Bcl-2 family members. These findings could have implications for platelet collection and, potentially, for their clinical use.     

The endocannabinoid system in rat gliosomes and its role in the modulation of glutamate release

The endocannabinoid system and endocannabinoid receptor-driven modulation of glutamate release were studied in rat brain cortex astroglial gliosomes. These preparations contained the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, as well their major biosynthetic (N-acyl-phosphatidylethanolamines-hydrolyzing-phospholipase D and diacylglycerol-lipase) and catabolic (fatty acid amide-hydrolase and monoacylglycerol-lipase) enzymes. Gliosomes expressed type-1 (CB1R), type-2 (CB2R) cannabinoid, and type-1 vanilloid (TRPV1) receptors, as ascertained by Western blotting and confocal microscopy. Methanandamide, a stable analogue of anandamide acting as CB1R, CB2R, and TRPV1 agonist, stimulated or inhibited the depolarization-evoked gliosomal [³H]d-aspartate release, at lower and higher concentrations, respectively. Experiments with ACEA (arachidonyl-2′-chloroethylamide), JWH133 ((6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]-pyran) and capsaicin, selective agonists at CB1R, CB2R and TRPV1, respectively, demonstrated that potentiation of [³H]d-aspartate release was due to CB1R while inhibition to CB2R and TRPV1 engagement. These findings were confirmed by using selective receptor antagonists. Furthermore, CB1R activation caused increase of intracellular IP3 and Ca²⁺ concentration, suggesting an involvement of phospholipase C.     

Regulation of autophagy in mammals and its interplay with apoptosis

A growing number of publications show that apoptosis induction is often associated with increased autophagy indicating the existence of an interplay between these two important cellular events. The simultaneous activation of both phenomena has been detected not only in experimental settings but also in vivo under physiological and pathological conditions. Despite these studies, the reciprocal influence of the two pathways in vivo has still not been completely understood. It is clear that autophagy and apoptosis are strictly interconnected, as highlighted by the finding that the two pathways share key molecular regulators. Many novel aspects of the crosstalk between apoptosis and autophagy have recently emerged showing how complex is this relationship and how critical is for the overall fate of the cell. In this mini-review we will focus on some key experiments trying to decipher as to whether autophagy contributes to apoptosis modulation in vivo.     

Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies

Although mutations in CYTB (cytochrome b) or BCS1L have been reported in isolated defects of mitochondrial respiratory chain complex III (cIII), most cIII-defective individuals remain genetically undefined. We identified a homozygous nonsense mutation in the gene encoding tetratricopeptide 19 (TTC19) in individuals from two families affected by progressive encephalopathy associated with profound cIII deficiency and accumulation of cIII-specific assembly intermediates. We later found a second homozygous nonsense mutation in a fourth affected individual. We demonstrated that TTC19 is embedded in the inner mitochondrial membrane as part of two high-molecular-weight complexes, one of which coincides with cIII. We then showed a physical interaction between TTC19 and cIII by coimmunoprecipitation. We also investigated a Drosophila melanogaster knockout model for TTC19 that showed low fertility, adult-onset locomotor impairment and bang sensitivity, associated with cIII deficiency. TTC19 is a putative cIII assembly factor whose disruption is associated with severe neurological abnormalities in humans and flies.     

Forecast Combinations in a DSGE‐VAR Lab

We explore the benefits of forecast combinations based on forecast‐encompassing tests compared to simple averages and to Bates–Granger combinations. We also consider a new combination algorithm that fuses test‐based and Bates–Granger weighting. For a realistic simulation design, we generate multivariate time series samples from a macroeconomic DSGE‐VAR (dynamic stochastic general equilibrium–vector autoregressive) model. Results generally support Bates–Granger over uniform weighting, whereas benefits of test‐based weights depend on the sample size and on the prediction horizon. In a corresponding application to real‐world data, simple averaging performs best. Uniform averages may be the weighting scheme that is most robust to empirically observed irregularities. Copyright © 2016 John Wiley & Sons, Ltd.     

Real ribozymes suggest a relaxed error threshold

The error threshold for replication, the critical copying fidelity below which the fittest genotype deterministically disappears, limits the length of the genome that can be maintained by selection. Primordial replication must have been error-prone, and so early replicators are thought to have been necessarily short. The error threshold also depends on the fitness landscape. In an RNA world, many neutral and compensatory mutations can raise the threshold, below which the functional phenotype, rather than a particular sequence, is still present. Here we show, on the basis of comparative analysis of two extensively mutagenized ribozymes, that with a copying fidelity of 0.999 per digit per replication the phenotypic error threshold rises well above 7,000 nucleotides, which permits the selective maintenance of a functionally rich riboorganism with a genome of more than 100 different genes, the size of a tRNA. This requires an order of magnitude of improvement in the accuracy of in vitro-generated polymerase ribozymes. Incidentally, this genome size coincides with that estimated for a minimal cell achieved by top-down analysis, omitting the genes dealing with translation.     

Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant

A SNP in the gene PTPN22 is associated with type 1 diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease and other autoimmune disorders. T cells from carriers of the predisposing allele produce less interleukin-2 upon TCR stimulation, and the encoded phosphatase has higher catalytic activity and is a more potent negative regulator of T lymphocyte activation. We conclude that the autoimmune-predisposing allele is a gain-of-function mutant.