Predicting speech from a cortical hierarchy of event-based timescales

How do predictions in the brain incorporate the temporal unfolding of context in our natural environment? We here provide evidence for a neural coding scheme that sparsely updates contextual representations at the boundary of events. This yields a hierarchical, multilayered organization of predictive language comprehension. Training artificial neural networks to predict the next word in a story at five stacked time scales and then using model-based functional magnetic resonance imaging, we observe an event-based “surprisal hierarchy” evolving along a temporoparietal pathway. Along this hierarchy, surprisal at any given time scale gated bottom-up and top-down connectivity to neighboring time scales. In contrast, surprisal derived from continuously updated context influenced temporoparietal activity only at short time scales. Representing context in the form of increasingly coarse events constitutes a network architecture for making predictions that is both computationally efficient and contextually diverse

Cardiovascular consequences of metabolic syndrome

The metabolic syndrome (MetS) is defined as the concurrence of obesity-associated cardiovascular risk factors including abdominal obesity, impaired glucose tolerance, hypertriglyceridemia, decreased HDL cholesterol, and/or hypertension. Earlier conceptualizations of the MetS focused on insulin resistance as a core feature, and it is clearly coincident with the above list of features. Each component of the MetS is an independent risk factor for cardiovascular disease and the combination of these risk factors elevates rates and severity of cardiovascular disease, related to a spectrum of cardiovascular conditions including microvascular dysfunction, coronary atherosclerosis and calcification, cardiac dysfunction, myocardial infarction, and heart failure. While advances in understanding the etiology and consequences of this complex disorder have been made, the underlying pathophysiological mechanisms remain incompletely understood, and it is unclear how these concurrent risk factors conspire to produce the variety of obesity-associated adverse cardiovascular diseases. In this review, we highlight current knowledge regarding the pathophysiological consequences of obesity and the MetS on cardiovascular function and disease, including considerations of potential physiological and molecular mechanisms that may contribute to these adverse outcomes

Lean and Obese Coronary Perivascular Adipose Tissue Impairs Vasodilation via Differential Inhibition of Vascular Smooth Muscle K+ Channels

OBJECTIVE: The effects of coronary perivascular adipose tissue (PVAT) on vasomotor tone are influenced by an obese phenotype and are distinct from other adipose tissue depots. The purpose of this investigation was to examine the effects of lean and obese coronary PVAT on end-effector mechanisms of coronary vasodilation and to identify potential factors involved. APPROACH AND RESULTS: Hematoxylin and eosin staining revealed similarities in coronary perivascular adipocyte size between lean and obese Ossabaw swine. Isometric tension studies of isolated coronary arteries from Ossabaw swine revealed that factors derived from lean and obese coronary PVAT attenuated vasodilation to adenosine. Lean coronary PVAT inhibited K(Ca) and KV7, but not KATP channel-mediated dilation in lean arteries. In the absence of PVAT, vasodilation to K(Ca) and KV7 channel activation was impaired in obese arteries relative to lean arteries. Obese PVAT had no effect on K(Ca) or KV7 channel-mediated dilation in obese arteries. In contrast, obese PVAT inhibited KATP channel-mediated dilation in both lean and obese arteries. The differential effects of obese versus lean PVAT were not associated with changes in either coronary KV7 or K(ATP) channel expression. Incubation with calpastatin attenuated coronary vasodilation to adenosine in lean but not in obese arteries. CONCLUSIONS: These findings indicate that lean and obese coronary PVAT attenuates vasodilation via inhibitory effects on vascular smooth muscle K(+) channels and that alterations in specific factors such as calpastatin are capable of contributing to the initiation or progression of smooth muscle dysfunction in obesity

Leptin augments coronary vasoconstriction and smooth muscle proliferation via a Rho kinase dependent pathway

Leptin has been implicated as a key upstream mediator of pathways associated with coronary vascular dysfunction and disease. The purpose of this investigation was to test the hypothesis that leptin modifies the coronary artery proteome and promotes increases in coronary smooth muscle contraction and proliferation via influences on Rho kinase signaling. Global proteomic assessment of coronary arteries from lean swine cultured with obese concentrations of leptin (30 ng/mL) for 3 days revealed significant alterations in the coronary artery proteome (68 proteins) and identified an association between leptin treatment and calcium signaling/contraction (four proteins) and cellular growth and proliferation (35 proteins). Isometric tension studies demonstrated that both acute (30 min) and chronic (3 days, serum-free media) exposure to obese concentrations of leptin potentiated depolarization-induced contraction of coronary arteries. Inhibition of Rho kinase significantly reduced leptin-mediated increases in coronary artery contractions. The effects of leptin on the functional expression of Rho kinase were time-dependent, as acute treatment increased Rho kinase activity while chronic (3 day) exposure was associated with increases in Rho kinase protein abundance. Proliferation assays following chronic leptin administration (8 day, serum-containing media) demonstrated that leptin augmented coronary vascular smooth muscle proliferation and increased Rho kinase activity. Inhibition of Rho kinase significantly reduced these effects of leptin. Taken together, these findings demonstrate that leptin promotes increases in coronary vasoconstriction and smooth muscle proliferation and indicate that these phenotypic effects are associated with alterations in the coronary artery proteome and dynamic effects on the Rho kinase pathway

CARDIOVASCULAR AND HEMODYNAMIC EFFECTS OF GLUCAGON-LIKE PEPTIDE-1

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has been shown to have hemodynamic and cardioprotective capacity in addition to its better characterized glucoregulatory actions. Because of this, emerging research has focused on the ability of GLP-1 based therapies to drive myocardial substrate selection, enhance cardiac performance and regulate heart rate, blood pressure and vascular tone. These studies have produced consistent and reproducible results amongst numerous laboratories. However, there are obvious disparities in findings obtained in small animal models versus those of higher mammals. This species dependent discrepancy calls to question, the translational value of individual findings. Moreover, few studies of GLP-1 mediated cardiovascular action have been performed in the presence of a pre-existing comorbidities (e.g. obesity/diabetes) which limits interpretation of the effectiveness of incretin-based therapies in the setting of disease. This review addresses cardiovascular and hemodynamic potential of GLP-1 based therapies with attention to species specific effects as well as the interaction between therapies and disease

Regulation of myocardial oxygen delivery in response to graded reductions in hematocrit: Role of K+ channels

This study was designed to identify mechanisms responsible for coronary vasodilation in response to progressive decreases in hematocrit. Isovolemic hemodilution was produced in open-chest, anesthetized swine via concurrent removal of 500 ml of arterial blood and the addition of 500 ml of 37 °C saline or synthetic plasma expander (Hespan, 6% hetastarch in 0.9% sodium chloride). Progressive hemodilution with Hespan resulted in an increase in coronary flow from 0.39 ± 0.05 to 1.63 ± 0.16 ml/min/g (P < 0.001) as hematocrit was reduced from 32 ± 1 to 10 ± 1% (P < 0.001). Overall, coronary flow corresponded with the level of myocardial oxygen consumption, was dependent on arterial pressures ≥ ~ 60 mmHg, and occurred with little/no change in coronary venous PO2. Anemic coronary vasodilation was unaffected by the inhibition of nitric oxide synthase (l-NAME: 25 mg/kg iv; P = 0.92) or voltage-dependent K+ (K V) channels (4-aminopyridine: 0.3 mg/kg iv; P = 0.52). However, administration of the K ATP channel antagonist (glibenclamide: 3.6 mg/kg iv) resulted in an ~ 40% decrease in coronary blood flow (P < 0.001) as hematocrit was reduced to ~ 10%. These reductions in coronary blood flow corresponded with significant reductions in myocardial oxygen delivery at baseline and throughout isovolemic anemia (P < 0.001). These data indicate that vasodilator factors produced in response to isovolemic hemodilution converge on vascular smooth muscle glibenclamide-sensitive (K ATP) channels to maintain myocardial oxygen delivery and that this response is not dependent on endothelial-derived nitric oxide production or pathways that mediate dilation via K V channels

Contribution of hydrogen sulfide to the control of coronary blood flow

This study examined the mechanisms by which H2S modulates coronary microvascular resistance and myocardial perfusion at rest and in response to cardiac ischemia. Experiments were conducted in isolated coronary arteries and in open-chest anesthetized dogs. We found that the H2S substrate L-cysteine (1-10 mM) did not alter coronary tone of isolated arteries in vitro or coronary blood flow in vivo. In contrast, intracoronary (ic) H2S (0.1-3 mM) increased coronary flow from 0.49 ± 0.08 to 2.65 ± 0.13 ml/min/g (P□0.001). This increase in flow was unaffected by inhibition of Kv channels with 4-aminopyridine (P=0.127) but was attenuated (0.23 ± 0.02 to 1.13 ± 0.13 ml/min/g) by the KATP channel antagonist glibenclamide (P□0.001). Inhibition of NO synthesis (L-NAME) did not attenuate coronary responses to H2S. Immunohistochemistry revealed expression of cystathionine gamma-lyase (CSE), an endogenous H2S enzyme, in myocardium. Inhibition of CSE with β-cyano-L-alanine (10 µM) had no effect on baseline coronary flow or responses to a 15 sec coronary occlusion (P=0.82). These findings demonstrate that exogenous H2S induces potent, endothelial-independent dilation of the coronary microcirculation predominantly through the activation of KATP channels, however, our data do not support a functional role for endogenous H2S in the regulation of coronary microvascular resistance

Subcellular fractionation coupled to shotgun proteomics allows the identification of novel targets of the classical secretion pathway associated with increased productivity in recombinant CHO cells

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Perivascular adipose tissue and coronary vascular disease

Coronary perivascular adipose tissue is a naturally occurring adipose tissue depot that normally surrounds the major coronary arteries on the surface of the heart. Although originally thought to promote vascular health and integrity, there is a growing body of evidence to support that coronary perivascular adipose tissue displays a distinct phenotype relative to other adipose depots and is capable of producing local factors with the potential to augment coronary vascular tone, inflammation, and the initiation and progression of coronary artery disease. The purpose of the present review is to outline previous findings about the cardiovascular effects of coronary perivascular adipose tissue and the potential mechanisms by which adipose-derived factors may influence coronary vascular function and the progression of atherogenesis

Bioactivity of Cod and Chicken Protein Hydrolysates before and after in vitro Gastrointestinal Digestion

Bioactivity of cod (Gadus morhua) and chicken (Gallus domesticus) protein hydrolysates before and aft er in vitro gastrointestinal (GI) digestion was investigated using yeast Saccharomyces cerevisiae as a model organism. Both hydrolysates were exposed to in vitro GI digestion prior to cellular exposure to simulate digestion conditions in the human body and therefore investigate the role of modulations in the GI tract on the cell response. The eff ect of digested and undigested hydrolysates on intracellular oxidation, cellular metabolic energy and proteome level was investigated. No diff erence in the eff ect on intracellular oxidation activity was obtained between cod and chicken hydrolysates, while higher aff ect on intracellular oxidation was provided by digested hydrolysates, with relative values of intracellular oxidation of cod of (70.2±0.8) and chicken of (74.5±1.4) % than by undigested ones, where values of cod and chicken were (95.5±1.2) and (90.5±0.7) %, respectively. Neither species nor digestion had any eff ect on cellular metabolic energy. At proteome level, digested hydrolysates gave again signifi cantly stronger responses than undigested counterparts; cod peptides here also gave somewhat stronger response than chicken peptides. The knowledge of the action of food protein hydrolysates and their digests within live cells, also at proteome level, is important for further validation of their activity in higher eukaryotes to develop new functional food ingredients, such as in this case chicken and cod muscle-derived peptides