The Possibilist Transactional Interpretation and Relativity

A recent ontological variant of Cramer's Transactional Interpretation, called "Possibilist Transactional Interpretation" or PTI, is extended to the relativistic domain. The present interpretation clarifies the concept of 'absorption,' which plays a crucial role in TI (and in PTI). In particular, in the relativistic domain, coupling amplitudes between fields are interpreted as amplitudes for the generation of confirmation waves (CW) by a potential absorber in response to offer waves (OW), whereas in the nonrelativistic context CW are taken as generated with certainty. It is pointed out that solving the measurement problem requires venturing into the relativistic domain in which emissions and absorptions take place; nonrelativistic quantum mechanics only applies to quanta considered as 'already in existence' (i.e., 'free quanta'), and therefore cannot fully account for the phenomenon of measurement, in which quanta are tied to sources and sinks.Comment: Final version with some minor corrections as published in Foundations of Physics. This paper has significant overlap with Chapter 6 of my book on the Transactional Interpretation, forthcoming from Cambridge University Press: http://www.cambridge.org/us/knowledge/isbn/item6860644/?site_locale=en_US (Additional preview material is available at rekastner.wordpress.com) Comments welcom

Macronutrient intake and prevalence of markers of metabolic syndrome in white UK adult males in the National Diet and Nutrition Survey Rolling Programme 2008–2014

The amount of carbohydrates recommended for consumption by current dietary guidelines has been challenged in relation to their suitability to prevent or manage cardiometabolic (CM) diseases with suggestions that they should be decreased and replaced by protein or fat( 1 , 2 ). Others have argued that a more personalised approach is required( 3 ). Aim of this investigation was to assess the potential impact of lower versus higher consumption of dietary macronutrients and prevalence of CM risk markers in a representative sample of the UK male white population. Unweighted data from 642 white adult males aged 19 and over in the National Diet and Nutrition Survey Rolling Programme( 4 ) (NDNS RP) 2008–2014 with or without metabolic syndrome (MetS)( 5 ) were analysed for associations of dietary macronutrient intake as percentage food energy (%FE) with CM risk markers. Logistic regression analysis (adjusted for age group and smoking status) was used to compare the odds ratios [OR] of prevalence of individual markers of MetS between the lowest and highest quartiles of dietary macronutrient intake as %FE (⩽44 vs. ≥52 for carbohydrates; ⩽31 vs. ≥39 for fats; ⩽15. vs. ≥19 for protein). There was a significant (p < 0·05) reduction in likelihood of MetS (OR, .55; 95 % confidence interval [CI], .34 to .84), and elevated waist circumference (OR, .50; 95 % CI, .30 to .83) and glucose levels (OR, .51; 95 % CI, .30 to .87) for those in the highest quartile of carbohydrate %FE intake compared to the lowest quartile, whereas those in the highest quartile of protein %FE intake had a significantly (p < 0·05) increased risk of presenting with the same markers of MetS (OR, 1·75; 95 % CI, 1·05 to 2·93; OR, 2·12; 95 % CI, 1·24 to 3·63; and OR, 2·15; 95 % CI, 1·25 to 3·70 respectively). Those with the highest compared to the lowest total dietary fat intake also presented with elevated CM risk markers, albeit these findings were not significant. *Metabolic Syndrome (MetS) definition: 3 out of 5 of the following: triglycerides (TRIG) ≥1·7 mmol/L; High-density lipoprotein cholesterol (HDL-C) ⩽1·03 mmol/L for males; Waist circumference (WC) ≥94 cm for white males; Glucose (GLUC) ≥5·6 mmol/L; Blood pressure (BP) ≥130 mmHg systolic or ≥85 mmHg diastolic respectively; CHO%FE – total carbohydrates percentage food energy; FAT%FE – total fats food energy; PROT%FE– total protein food energy; OR – odds ratio (adjusted for age group and smoking status), 1st vs. 4th quartile of intake; CI – confidence interval; a p < 0·05 Further investigations need to confirm whether the quality of the macronutrients consumed and overall diet quality( 6 ) has had an impact on these results. In the context of a personalised approach to nutrition future cohort studies should also provide data that allow for examining inter-individual variations in responses to dietary macronutrients, especially carbohydrates, to achieve optimum CM health for a larger proportion of the population

The association between dietary macronutrient intake and fibrogen growth factor 21 in a sample of White UK adults with elevated cardiometabolic risk markers

Increased levels of Fibrogen growth factor 21 (FGF21) is an emerging risk marker for cardiometabolic (CM) disease(1). Little detail is known about the impact of the human diet on FGF21 levels. The aim of this investigation was to assess potential associations between mean daily dietary macronutrient intake and FGF21 levels in a sample of 10 healthy normal-weight and overweight Caucasian adults aged 32–60 (80 % male) at increased CM risk(2). This pilot study received ethical approval from Liverpool John Moores University Research Ethics Committee (16/ELS/029) and was registered with ClinicalTrials.gov (Ref. NCT03257085). Participants were randomly allocated to one of two groups and asked to either consume 50 % energy from CHO for a duration of 8 weeks. Blood plasma samples were col- lected at baseline (BL), interim point (IP) and endpoint (EP) after a 12-hour overnight fast, immediately processed and frozen at −80°C. Thawed plasma samples were analysed via Quantikine® enzyme-linked immunosorbent assay (ELISA) (R&D Systems) for FGF21 levels. Two-way mixed ANOVA and Pearson’s partial correlation adjusted for estimated weekly moderate and vigorous activity was undertaken using IBM SPSS 24®. There were no effects for diet between groups or over time (data not shown). Significant correlations between macronutrient intakes and FGF21 levels were found for both groups at IP, but not at BL or EP. Moderate and significant positive correlations were found in the overall group for intake (g/d) for glucose (rpartial = ·699, p = ·04) and fructose (rpartial = ·686, p = ·04) and strong and significant positive correlations for non-milk extrinsic sugars (rpartial = ·742, p = ·02). Strong and significant positive correlations were also found in the LC group for glucose intake (g/d) (rpartial = ·980, p = ·02) and fructose (rpartial = ·967, p = ·03) and for protein (rpartial =·998, p=·002) after adjusting for physical activity. Mean carbohydrate intake (g/d) was 160·0 (s.d. 124·5) overall and 44·2 (s.d. 14·9) in the LC group at IP. Mean protein intake (g/d) was 113·2 (21·4) 130·0 (s.d. 15·9) overall and in the LC group at IP. Mean FGF21 levels were 179·9 pg/mL (s.d. 144·9) in the overall group and 94.4 pg/ML (s.d. 48.6) in the LC group at IP. %TE Intake (g/d) PROT FAT CHO GLU FRU NMES PROT FAT rrrrrrrrrrr −·214 ·623 ·635 −·326 −·491 ·448 ·699* ·686* ·742* −·606 −·496 ·143 ·637 ·937 ·427 −·059 ·722 ·980* ·967* ·919 ·998** −·080 Total kcal CHO NMES T LC CHO-Total carbohydrates, FAT-Total fat, FRU-Fructose, GLUC-Glucose, LC-low-carbohydrate, high-fat group, NMES-non-milk extrinsic sugars, PROT-protein, T – total, %TE – percentage total energy, *p < ·05 **p < ·005. In conclusion, low-carbohydrate diets provide the opportunity to assess responses to even small amounts of CHO, which are likely to be replaced in part by proteins. Despite low overall intakes of fructose and glucose in the LC group, strong and positive correlations with FGF21 levels were observed. The lower levels of FGF21 in the LC compared to the overall group are in line with findings that FGF21 levels are elevated with high-carbohydrate, low-protein diets with dietary fats having only minor impact(3). However, the majority of studies have still been undertaken using rodent models. The impact of dietary macronutrients on FGF21 levels as novel CMR marker in humans and the mechanism behind this relationship warrant further investigation. 1. Lakhani I, Gong M, Wong W et al. (2018) Metabolism 2018 Feb 1. pii: S0026-0495(18)30023-4. [Epub ahead of print]. 2. Jebb S, Lovegrove J, Griffin B et al. (2010) Am J Clin Nutr 92, 748–58. 3. Solon-Biet S, Cogger V, Pulpitel T et al. (2016) Cell Metab 24, 555–565

Dietary carbohydrate intake, visceral adipose tissue and associated markers of cardiometabolic risk

Risk of cardiometabolic (CM) disease is characterised by elevated visceral adipose tissue (VAT) and a number of associated biomar- kers(1). Some dietary carbohydrates (CHO) have been found to contribute to VAT accumulation(2). Little is known about the impact of following a low-carbohydrate diet versus a high-carbohydrate diet on VAT, adiponectin (ADPN), leptin (LEPT) and leptin:adipo- nectin ratio (LAR). The aim of this investigation was to assess the impact of dietary carbohydrates (CHO) on VAT and emerging CM risk markers in a sample of 10 healthy normal-weight and overweight Caucasian adults aged 32–60 (80 % male) at increased CM risk(3). This pilot study received ethical approval from Liverpool John Moores University Research Ethics Committee (16/ELS/ 029) and was registered with ClinicalTrials.gov (Ref. NCT03257085). Participants were randomly allocated to one of two groups and asked to either consume 50 % energy from CHO (high-carb (HC)) for a duration of 8 weeks. VAT was ana- lysed via bioelectrical impedance (SECA mBCA 515). Blood plasma samples were collected at baseline (BL), interim point (IP) and endpoint (EP) after a 12-hour overnight fast, immediately processed and frozen at -80°C. Thawed plasma samples were analysed via immunoassay technology (Randox Evidence InvestigatorTM Metabolic Syndrome Arrays I and II) for ADPN and LEPT levels. Statistical analysis was undertaken using IBM SPSS 24®. Parametric data was analysed via two-way mixed ANOVA; non-parametric data was analysed via Mann-Whitney U test and Friedman test. Average daily carbohydrate intake in the LC group was 44·2 g at IP and 48·9 g at EP. There were no significant differences between groups at any time point for ADPN, LEPT, LAR or VAT and no significant inter- actions for time or group*time for ADPN, LEPT or LAR. However, in the LC group VAT decreased significantly between baseline and endpoint by 15 % (p = ·015) Over the course of the intervention ADPN and LEPT decreased non- significantly (by 4 % and 70 % respectively) in the LC group, whilst increasing non-significantly in the HC group (9 % and 65 % respectively). LAR increased in the HC group throughout the study, whilst LAR in the LC group decreased albeit not significantly. VAT (litre) ADPN (ng/mL) LEPT (ng/mL) LAR BL IP EP Median Median Median M SD M SD M SD BL IP EP BL IP EP BL IP EP LC 4·1a 1·2 3·8 1·3 3·5a 1·2 8·9 8·6 8·5 3·96 1·64 1·20 0·45 0·19 0·14 HC 2·7 0·1 1·6 0·3 2·5 0·1 11·3 13·4 12·3 0·97 1·1 1·60 0·07 0·07 0·46 ADPN = adiponectin, BL = baseline, EP = endpoint, HC = high-carbohydrate, moderate fat diet, IP = interim point, LAR = leptin:adiponectin ratio, LEPT = leptin, LC = low-carbohydrate, high-fat diet, VAT = visceral adipose tissue, ap = ·015. NB: interquartile ranges not provided for median values due to missing data. Higher LAR has been found to be a marker of increased CM risk(4). In conclusion, while the significant reduction in VAT in the LC group corresponds with the reduction of LAR further evidence is required to corroborate these findings. Previous evidence for LC is supportive for improved CM health from various biomarkers(5); LAR should be considered as a useful endocrine addition for future LC studies. 1. Krasimira A, Mozaffarian D & Pischon T (2018) Clin Chem 64, 142–153. 2. Rüttgers D, Fischer K, Koch M et al. (2015) Br J Nutr 114, 1929–1940. 3. Jebb S, Lovegrove J, Griffin B et al. (2010) Am J Clin Nutr 92, 748–58. 4. López-Jaramillo P, Gómez-Arbeláez D, López-López J et al. (2014) Horm Mol Biol Clin Investig 18, 37–45. 5. Bazzano L, Hi T, Reynolds K et al. (2014) Ann Intern Med 161, 309–318

Structural characterization suggests models for monomeric and dimeric forms of full-length ezrin

Ezrin is a member of the ERM (ezrin–radixin–moesin) family of proteins that have been conserved through metazoan evolution. These proteins have dormant and active forms, where the latter links the actin cytoskeleton to membranes. ERM proteins have three domains: an N-terminal FERM [band Four-point-one (4.1) ERM] domain comprising three subdomains (F1, F2, and F3); a helical domain; and a C-terminal actin-binding domain. In the dormant form, FERM and C-terminal domains form a stable complex. We have determined crystal structures of the active FERM domain and the dormant FERM:C-terminal domain complex of human ezrin. We observe a bistable array of phenylalanine residues in the core of subdomain F3 that is mobile in the active form and locked in the dormant form. As subdomain F3 is pivotal in binding membrane proteins and phospholipids, these transitions may facilitate activation and signaling. Full-length ezrin forms stable monomers and dimers. We used small-angle X-ray scattering to determine the solution structures of these species. As expected, the monomer shows a globular domain with a protruding helical coiled coil. The dimer shows an elongated dumbbell structure that is twice as long as the monomer. By aligning ERM sequences spanning metazoan evolution, we show that the central helical region is conserved, preserving the heptad repeat. Using this, we have built a dimer model where each monomer forms half of an elongated antiparallel coiled coil with domain-swapped FERM:C-terminal domain complexes at each end. The model suggests that ERM dimers may bind to actin in a parallel fashion

In vitro neuroprotective activities of two distinct probiotic consortia

Neurodegeneration has been linked to changes in the gut microbiota and this study compares the neuroprotective capability of two bacterial consortia, known as Lab4 and Lab4b, using the established SH-SY5Y neuronal cell model. Firstly, varying total antioxidant capacities (TAC) were identified in the intact cells from each consortia and their secreted metabolites, referred to as conditioned media (CM). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Crystal Violet (CV) assays of cell viability revealed that Lab4 CM and Lab4b CM could induce similar levels of proliferation in SH-SY5Y cells and, despite divergent TAC, possessed a comparable ability to protect undifferentiated and retinoic acid-differentiated cells from the cytotoxic actions of rotenone and undifferentiated cells from the cytotoxic actions of 1-methyl-4-phenylpyridinium iodide (MPP+). Lab4 CM and Lab4b CM also had the ability to attenuate rotenone-induced apoptosis and necrosis with Lab4b inducing the greater effect. Both consortia showed an analogous ability to attenuate intracellular reactive oxygen species accumulation in SH-SY5Y cells although the differential upregulation of genes encoding glutathione reductase and superoxide dismutase by Lab4 CM and Lab4b CM, respectively, implicates the involvement of consortia-specific antioxidative mechanisms of action. This study implicates Lab4 and Lab4b as potential neuroprotective agents and justifies their inclusion in further in vivo studies

Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue during Exercise

SummaryAcylcarnitine metabolites have gained attention as biomarkers of nutrient stress, but their physiological relevance and metabolic purpose remain poorly understood. Short-chain carnitine conjugates, including acetylcarnitine, derive from their corresponding acyl-CoA precursors via the action of carnitine acetyltransferase (CrAT), a bidirectional mitochondrial matrix enzyme. We show here that contractile activity reverses acetylcarnitine flux in muscle, from net production and efflux at rest to net uptake and consumption during exercise. Disruption of this switch in mice with muscle-specific CrAT deficiency resulted in acetyl-CoA deficit, perturbed energy charge, and diminished exercise tolerance, whereas acetylcarnitine supplementation produced opposite outcomes in a CrAT-dependent manner. Likewise, in exercise-trained compared to untrained humans, post-exercise phosphocreatine recovery rates were positively associated with CrAT activity and coincided with dramatic shifts in muscle acetylcarnitine dynamics. These findings show acetylcarnitine serves as a critical acetyl buffer for working muscles and provide insight into potential therapeutic strategies for combatting exercise intolerance

Life path analysis: scaling indicates priming effects of social and habitat factors on dispersal distances

1. Movements of many animals along a life-path can be separated into repetitive ones within home ranges and transitions between home ranges. We sought relationships of social and environmental factors with initiation and distance of transition movements in 114 buzzards Buteo buteo that were marked as nestlings with long-life radio tags. 2. Ex-natal dispersal movements of 51 buzzards in autumn were longer than for 30 later in their first year and than 35 extra-natal movements between home ranges after leaving nest areas. In the second and third springs, distances moved from winter focal points by birds that paired were the same or less than for unpaired birds. No post-nuptial movement exceeded 2 km. 3. Initiation of early ex-natal dispersal was enhanced by presence of many sibs, but also by lack of worm-rich loam soils. Distances travelled were greatest for birds from small broods and with relatively little short grass-feeding habitat near the nest. Later movements were generally enhanced by the absence of loam soils and short grassland, especially with abundance of other buzzards and probable poor feeding habitats (heathland, long grass). 4. Buzzards tended to persist in their first autumn where arable land was abundant, but subsequently showed a strong tendency to move from this habitat. 5. Factors that acted most strongly in ½-km buffers round nests, or round subsequent focal points, usually promoted movement compared with factors acting at a larger scale. Strong relationships between movement distances and environmental characteristics in ½-km buffers, especially during early ex-natal dispersal, suggested that buzzards became primed by these factors to travel far. 6. Movements were also farthest for buzzards that had already moved far from their natal nests, perhaps reflecting genetic predisposition, long-term priming or poor habitat beyond the study area

The Mathematical Universe

I explore physics implications of the External Reality Hypothesis (ERH) that there exists an external physical reality completely independent of us humans. I argue that with a sufficiently broad definition of mathematics, it implies the Mathematical Universe Hypothesis (MUH) that our physical world is an abstract mathematical structure. I discuss various implications of the ERH and MUH, ranging from standard physics topics like symmetries, irreducible representations, units, free parameters, randomness and initial conditions to broader issues like consciousness, parallel universes and Godel incompleteness. I hypothesize that only computable and decidable (in Godel's sense) structures exist, which alleviates the cosmological measure problem and help explain why our physical laws appear so simple. I also comment on the intimate relation between mathematical structures, computations, simulations and physical systems.Comment: Replaced to match accepted Found. Phys. version, 31 pages, 5 figs; more details at http://space.mit.edu/home/tegmark/toe.htm

Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans

Blood-borne factors regulate adult hippocampal neurogenesis and cognition in mammals. We report that elevating circulating unacylated-ghrelin (UAG), using both pharmacological and genetic methods, reduced hippocampal neurogenesis and plasticity in mice. Spatial memory impairments observed in ghrelin-O-acyl transferase-null (GOAT/) mice that lack acyl-ghrelin (AG) but have high levels of UAG were rescued by acyl-ghrelin. Acyl-ghrelin-mediated neurogenesis in vitro was dependent on non-cell-autonomous BDNF signaling that was inhibited by UAG. These findings suggest that post-translational acylation of ghrelin is important to neurogenesis and memory in mice. To determine relevance in humans, we analyzed circulating AG:UAG in Parkinson disease (PD) patients diagnosed with dementia (PDD), cognitively intact PD patients, and controls. Notably, plasma AG:UAG was only reduced in PDD. Hippocampal ghrelin-receptor expression remained unchanged; however, GOAT+ cell number was reduced in PDD. We identify UAG as a regulator of hippocampal-dependent plasticity and spatial memory and AG:UAG as a putative circulating diagnostic biomarker of dementia