Equilibrium Properties of Temporally Asymmetric Hebbian Plasticity

A theory of temporally asymmetric Hebb (TAH) rules which depress or potentiate synapses depending upon whether the postsynaptic cell fires before or after the presynaptic one is presented. Using the Fokker-Planck formalism, we show that the equilibrium synaptic distribution induced by such rules is highly sensitive to the manner in which bounds on the allowed range of synaptic values are imposed. In a biologically plausible multiplicative model, we find that the synapses in asynchronous networks reach a distribution that is invariant to the firing rates of either the pre- or post-synaptic cells. When these cells are temporally correlated, the synaptic strength varies smoothly with the degree and phase of synchrony between the cells.Comment: 3 figures, minor corrections of equations and tex

Aquatic Foods to Nourish Nations

Despite contributing to healthy diets for billions of people, aquatic foods are often undervalued as a nutritional solution because their diversity is often reduced to the protein and energy value of a single food type (‘seafood’ or ‘fish’)1,2,3,4. Here we create a cohesive model that unites terrestrial foods with nearly 3,000 taxa of aquatic foods to understand the future impact of aquatic foods on human nutrition. We project two plausible futures to 2030: a baseline scenario with moderate growth in aquatic animal-source food (AASF) production, and a high-production scenario with a 15-million-tonne increased supply of AASFs over the business-as-usual scenario in 2030, driven largely by investment and innovation in aquaculture production. By comparing changes in AASF consumption between the scenarios, we elucidate geographic and demographic vulnerabilities and estimate health impacts from diet-related causes. Globally, we find that a high-production scenario will decrease AASF prices by 26% and increase their consumption, thereby reducing the consumption of red and processed meats that can lead to diet-related non-communicable diseases5,6 while also preventing approximately 166 million cases of inadequate micronutrient intake. This finding provides a broad evidentiary basis for policy makers and development stakeholders to capitalize on the potential of aquatic foods to reduce food and nutrition insecurity and tackle malnutrition in all its forms.Additional co-authors: Pierre Charlebois, Manuel Barange, Stefania Vannuccini, Ling Cao, Kristin M. Kleisner, Eric B. Rimm, Goodarz Danaei, Camille DeSisto, Heather Kelahan, Kathryn J. Fiorella, Edward H. Allison, Jessica Fanzo & Shakuntala H. Thilste

PRE-LOADED BETAINE IMPROVES THERMOREGULATION WHEN CYCLING IN THE HEAT

BACKGROUND: Heat-related illness compromises health and performance in endurance athletes during training and competition. Betaine (BET) is a nutrient that has been previously identified in animal models to act as an osmolyte and attenuates the effects of thermal stress. However, much of the prior research has only assessed the efficacy of preloading BET in passive heat models. Therefore, the purpose of this study is to examine the effects of preloaded BET in an active heat model. METHODS: Eight endurance-trained males (age 26.4 ± 6.8 years; VO2 Peak 55.5 ± 4.8 mL/kg/min) completed 60 min of cycling at 70% VO2 peak in a hot environment (33° C, 35% RH) after a 7-day supplement loading protocol (50 mg/kg, 2x daily) of placebo (PLA) or BET in a double blind, randomized, counterbalanced, crossover study. Core temperature and thermal sensation were measured at rest and every 10 minutes throughout the active heat protocol. Nude body weight was measured prior to- and immediately post-exercise to calculate sweat rate. No fluid ingestion was allowed during this time. Blood samples were collected at rest, 30 minutes, and immediately after exercise. Visual analog scales were administered before and immediately after exercise to quantify sensations of thirst. Bioelectrical impedance assessed fluid compartments before and after the respective supplementation weeks. RESULTS: Area under curve analysis identified BET as having a smaller overall increase in core body temperature compared to PLA (p = 0.012). Further analysis showed ending core temperature was significantly lower in BET (-0.023 ° C; p = 0.029) than PLA. BET also resulted in a significant increase in sweat rate (mean difference = 0.19 ± 0.20 L/hr; p = 0.02). Blood assessments revealed BET had lower hematocrit at the mid-exercise timepoint compared to PLA (BET: 48.3%; PLA: 50.8%; p = 0.02). Increases in total body water (TBW) and intracellular fluid (ICF) in the BET condition approached significance compared to PLA (TBW: +1.69 L, p = 0.055; ICF: +1.39L, p = 0.066). No significant differences were found between conditions in subjective measures of thermal sensation or thirst (p = 0.318; p = 0.862). CONCLUSION: BET supplementation may have the capacity to mitigate the rise in core body temperature and maintain plasma volume during exercise in an uncompensable heat stress environment, despite having no significant effect on subjective sensations of heat stress

Urinary metabolomic signature of esophageal cancer and Barrett’s esophagus

<p>Abstract</p> <p>Background</p> <p>Esophageal adenocarcinoma (EAC) often presents at a late, incurable stage, and mortality has increased substantially, due to an increase in incidence of EAC arising out of Barrett’s esophagus. When diagnosed early, however, the combination of surgery and adjuvant therapies is associated with high cure rates. Metabolomics provides a means for non- invasive screening of early tumor-associated perturbations in cellular metabolism.</p> <p>Methods</p> <p>Urine samples from patients with esophageal carcinoma (n = 44), Barrett’s esophagus (n = 31), and healthy controls (n = 75) were examined using ¹H-NMR spectroscopy. Targeted profiling of spectra using Chenomx software permitted quantification of 66 distinct metabolites. Unsupervised (principal component analysis) and supervised (orthogonal partial least-squares discriminant analysis OPLS-DA) multivariate pattern recognition techniques were applied to discriminate between samples using SIMCA-P⁺ software. Model specificity was also confirmed through comparison with a pancreatic cancer cohort (n = 32).</p> <p>Results</p> <p>Clear distinctions between esophageal cancer, Barrett’s esophagus and healthy controls were noted when OPLS-DA was applied. Model validity was confirmed using two established methods of internal validation, cross-validation and response permutation. Sensitivity and specificity of the multivariate OPLS-DA models were summarized using a receiver operating characteristic curve analysis and revealed excellent predictive power (area under the curve = 0.9810 and 0.9627 for esophageal cancer and Barrett’s esophagus, respectively). The metabolite expression profiles of esophageal cancer and pancreatic cancer were also clearly distinguishable with an area under the receiver operating characteristics curve (AUROC) = 0.8954.</p> <p>Conclusions</p> <p>Urinary metabolomics identified discrete metabolic signatures that clearly distinguished both Barrett’s esophagus and esophageal cancer from controls. The metabolite expression profile of esophageal cancer was also discrete from its precursor lesion, Barrett’s esophagus. The cancer-specific nature of this profile was confirmed through comparison with pancreatic cancer. These preliminary results suggest that urinary metabolomics may have a future potential role in non-invasive screening in these conditions.</p

Increased methylation variation in epigenetic domains across cancer types

Tumor heterogeneity is a major barrier to effective cancer diagnosis and treatment. We recently identified cancer-specific differentially DNA-methylated regions (cDMRs) in colon cancer, which also distinguish normal tissue types from each other, suggesting that these cDMRs might be generalized across cancer types. Here we show stochastic methylation variation of the same cDMRs, distinguishing cancer from normal, in colon, lung, breast, thyroid, and Wilms tumors, with intermediate variation in adenomas. Whole genome bisulfite sequencing shows these variable cDMRs are related to loss of sharply delimited methylation boundaries at CpG islands. Furthermore, we find hypomethylation of discrete blocks encompassing half the genome, with extreme gene expression variability. Genes associated with the cDMRs and large blocks are involved in mitosis and matrix remodeling, respectively. These data suggest a model for cancer involving loss of epigenetic stability of well-defined genomic domains that underlies increased methylation variability in cancer and could contribute to tumor heterogeneity

AMP-activated protein kinase pathway:a potential therapeutic target in cardiometabolic disease

AMPK (AMP-activated protein kinase) is a heterotrimetric enzyme that is expressed in many tissues, including the heart and vasculature, and plays a central role in the regulation of energy homoeostasis. It is activated in response to stresses that lead to an increase in the cellular AMP/ATP ratio caused either by inhibition of ATP production (i.e. anoxia or ischaemia) or by accelerating ATP consumption (i.e. muscle contraction or fasting). In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. There is increasing evidence that AMPK is implicated in the pathophysiology of cardiovascular and metabolic diseases. A principle mode of AMPK activation is phosphorylation by upstream kinases [e.g. LKB1 and CaMK (Ca2+/calmodulin-dependent protein kinase], which leads to direct effects on tissues and phosphorylation of various downstream kinases [e.g. eEF2 (eukaryotic elongation factor 2) kinase and p70 S6 kinase]. These upstream and downstream kinases of AMPK have fundamental roles in glucose metabolism, fatty acid oxidation, protein synthesis and tumour suppression; consequently, they have been implicated in cardiac ischaemia, arrhythmias and hypertrophy. Recent mechanistic studies have shown that AMPK has an important role in the mechanism of action of MF (metformin), TDZs (thiazolinediones) and statins. Increased understanding of the beneficial effects of AMPK activation provides the rationale for targeting AMPK in the development of new therapeutic strategies for cardiometabolic disease