A Semantic Compositional Network (SCN) is developed for image captioning, in which semantic concepts (i.e., tags) are detected from the image, and the probability of each tag is used to compose the parameters in a long short-term memory (LSTM) network. The SCN extends each weight matrix of the LSTM to an ensemble of tag-dependent weight matrices. The degree to which each member of the ensemble is used to generate an image caption is tied to the image-dependent probability of the corresponding tag. In addition to captioning images, we also extend the SCN to generate captions for video clips. We qualitatively analyze semantic composition in SCNs, and quantitatively evaluate the algorithm on three benchmark datasets: COCO, Flickr30k, and Youtube2Text. Experimental results show that the proposed method significantly outperforms prior state-of-the-art approaches, across multiple evaluation metrics.

We present a biophysically based kinetic model of the cardiac SERCA pump that consolidates a range of experimental data into a consistent and thermodynamically constrained framework. The SERCA model consists of a number of sub-states with partial reactions that are sensitive to Ca(2+) and pH, and to the metabolites MgATP, MgADP, and Pi. Optimization of model parameters to fit experimental data favors a fully cooperative Ca(2+)-binding mechanism and predicts a Ca(2+)/H(+) counter-transport stoichiometry of 2. Moreover, the order of binding of the partial reactions, particularly the binding of MgATP, proves to be a strong determinant of the ability of the model to fit the data. A thermodynamic investigation of the model indicates that the binding of MgATP has a large inhibitory effect on the maximal reverse rate of the pump. The model is suitable for integrating into whole-cell models of cardiac electrophysiology and Ca(2+) dynamics to simulate the effects on the cell of compromised metabolism arising in ischemia and hypoxia.

We present a metabolically regulated model of cardiac active force generation with which we investigate the effects of ischemia on maximum force production. Our model, based on a model of cross-bridge kinetics that was developed by others, reproduces many of the observed effects of MgATP, MgADP, Pi, and H(+) on force development while retaining the force/length/Ca(2+) properties of the original model. We introduce three new parameters to account for the competitive binding of H(+) to the Ca(2+) binding site on troponin C and the binding of MgADP within the cross-bridge cycle. These parameters, along with the Pi and H(+) regulatory steps within the cross-bridge cycle, were constrained using data from the literature and validated using a range of metabolic and sinusoidal length perturbation protocols. The placement of the MgADP binding step between two strongly-bound and force-generating states leads to the emergence of an unexpected effect on the force-MgADP curve, where the trend of the relationship (positive or negative) depends on the concentrations of the other metabolites and [H(+)]. The model is used to investigate the sensitivity of maximum force production to changes in metabolite concentrations during the development of ischemia.

We present an image caption system that addresses new challenges of automatically describing images in the wild. The challenges include high quality caption quality with respect to human judgments, out-of-domain data handling, and low latency required in many applications. Built on top of a state-of-the-art framework, we developed a deep vision model that detects a broad range of visual concepts, an entity recognition model that identifies celebrities and landmarks, and a confidence model for the caption output. Experimental results show that our caption engine outperforms previous state-of-the-art systems significantly on both in-domain dataset (i.e. MS COCO) and out-of-domain datasets.

Semantics-based model composition is an approach for generating complex biosimulation models from existing components that relies on capturing the biological meaning of model elements in a machine-readable fashion. This approach allows the user to work at the biological rather than computational level of abstraction and helps minimize the amount of manual effort required for model composition. To support this compositional approach, we have developed the SemGen software, and here report on SemGen’s semantics-based merging capabilities using real-world modeling use cases. We successfully reproduced a large, manually-encoded, multi-model merge: the “Pandit-Hinch-Niederer” (PHN) cardiomyocyte excitation-contraction model, previously developed using CellML. We describe our approach for annotating the three component models used in the PHN composition and for merging them at the biological level of abstraction within SemGen. We demonstrate that we were able to reproduce the original PHN model results in a semi-automated, semantics-based fashion and also rapidly generate a second, novel cardiomyocyte model composed using an alternative, independently-developed tension generation component. We discuss the time-saving features of our compositional approach in the context of these merging exercises, the limitations we encountered, and potential solutions for enhancing the approach.

Activation heat arises from two sources during the contraction of striated muscle. It reflects the metabolic expenditure associated with Ca pumping by the sarcoplasmic reticular Ca -ATPase and Ca translocation by the Na /Ca exchanger coupled to the Na ,K -ATPase. In cardiac preparations, investigators are constrained in estimating its magnitude by reducing muscle length to the point where macroscopic twitch force vanishes. But this experimental protocol has been criticised since, at zero force, the observed heat may be contaminated by residual crossbridge cycling activity. To eliminate this concern, the putative thermal contribution from crossbridge cycling activity must be abolished, at least at minimal muscle length. We achieved this using blebbistatin, a selective inhibitor of myosin II ATPase. Using a microcalorimeter, we measured the force production and heat output, as functions of muscle length, of isolated rat trabeculae from both ventricles contracting isometrically at 5 Hz and at 37°C. In the presence of blebbistatin (15 μmol l ), active force was zero but heat output remained constant, at all muscle lengths. Activation heat measured in the presence of blebbistatin was not different from that estimated from the intercept of the heat-stress relation in its absence. We thus reached two conclusions. First, activation heat is independent of muscle length. Second, residual crossbridge heat is negligible at zero active force; hence, the intercept of the cardiac heat-force relation provides an estimate of activation heat uncontaminated by crossbridge cycling. Both results resolve long-standing disputes in the literature.

When a muscle shortens against an afterload, the heat that it liberates is greater than that produced by the same muscle contracting isometrically at the same level of force. This excess heat is defined as 'shortening heat', and has been repeatedly demonstrated in skeletal muscle but not in cardiac muscle. Given the micro-structural similarities between these two muscle types, and since we imagine that shortening heat is the thermal accompaniment of cross-bridge cycling, we have re-examined this issue. Using our flow-through microcalorimeter, we measured force and heat generated by isolated rat trabeculae undergoing isometric contractions at different muscle lengths and work-loop (shortening) contractions at different afterloads. We simulated these experimental protocols using a thermodynamically constrained model of cross-bridge cycling and probed the mechanisms underpinning shortening heat. Predictions generated by the model were subsequently validated by a further set of experiments. Both our experimental and modelling results show convincing evidence for the existence of shortening heat in cardiac muscle. Its magnitude is inversely related to the afterload or, equivalently, directly related to the extent of shortening. Computational simulations reveal that the heat of shortening arises from the cycling of cross-bridges, and that the rate of ATP hydrolysis is more sensitive to change of muscle length than to change of afterload. Our results clarify a long-standing uncertainty in the field of cardiac muscle energetics.

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