Structural Basis for Allosteric Control of the SERCA-Phospholamban Membrane Complex by Ca2+ and Phosphorylation

Phospholamban (PLN) is a mini-membrane protein that directly controls the cardiac Ca2+-transport response to β-adrenergic stimulation, thus modulating cardiac output during the fight-or-flight response. In the sarcoplasmic reticulum membrane, PLN binds to the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), keeping this enzyme's function within a narrow physiological window. PLN phosphorylation by cAMP-dependent protein kinase A or increase in Ca2+ concentration reverses the inhibitory effects through an unknown mechanism. Using oriented-sample solid-state NMR spectroscopy and replica-averaged NMR-restrained structural refinement, we reveal that phosphorylation of PLN’s cytoplasmic regulatory domain signals the disruption of several inhibitory contacts at the transmembrane binding interface of the SERCA-PLN complex that are propagated to the enzyme’s active site, augmenting Ca2+ transport. Our findings address long-standing questions about SERCA regulation, epitomizing a signal transduction mechanism operated by posttranslationally-modified bitopic membrane proteins.

Incredible utility: The lost causes and causal debris of psychological science

The tacit assumption that individuals differ quantitatively, not qualitatively, with respect to thepsychological structures, processes, and causal factors underlying their overt functioning does aremarkable amount of heavy lifting in social and behavioral sciences research. Remarkable in thesense that it serves as the load-bearing support beam for a scaffolding of corollary assumptions onwhich variable-oriented, sample-based individual differences research strategies and statisticalmodeling approaches to theoretical-causal inferences depend for their logic, coherence,justification, and presumed heuristic value. Psychological homogeneity and its corollaryassumptions are also wrong. They are contradicted by the evidence of our own senses,inconsistent with the basic tenets of virtually all psychological theories, and invalidated by asubstantial body of uncontested scientific knowledge about the unique design plasticity of thehuman brain and its extraordinary capacities for progressive use-dependent and experience-basedstructural modifications and elaborations across individual lifespans. This modifiability translatesinherited dispositions and unique experiences of individuals into qualitative differences in theirpsychological structures and processes. As a consequence of these qualitative differences, thestimulus properties, causal valences and impact potentials of events and experiences also varyqualitatively across individuals. Thus, cross-aggregate inter-individual correlations that areroutinely interpreted as indicators of a presumed unitary psychological causal structure are insteadfar more likely to reflect the causal debris field of multiple heterogeneous causal structures, thenumber and nature of which lie beyond the reach of sample-based methods predicated on thehomogeneity assumption.

UNCERTAINTY ANALYSIS TO C5G7-TD BENCHMARK BASED ON THE COST METHOD

A method of Covariance-Oriented Sample Transformation (COST) has been proposed in our previous work to provide the converged uncertainty analysis results with a minimal sample size. The transient calculation of nuclear reactor is a key part of the reactor-physics simulation, so the accuracy and confidence of the neutron kinetics results have attracted much attention. In this paper, the Uncertainty Quantification (UQ) function of the high fidelity neutronics code NECP-X has been developed based on our home-developed uncertainty analysis code UNICORN, building a platform for the UQ of the transient calculation. Furthermore, the well-known space-time heterogeneous neutron kinetics benchmark C5G7 and its uncertainty propagation from the nuclear data to the interested key parameters of the core have been investigated. To address the problem of “the curse of dimensionality” caused by the large number of input parameters, the COST method has been applied to generate multivariate normal-distribution samples in uncertainty analysis. As a result, the law of the assembly/pin normalized power and their uncertainty with respect to time after introducing an instantaneous perturbation has been obtained. From the numerical results, it can be observed that the maximum relative uncertainties for the assembly normalized power can up to be about 1.65% and the value for the pin-wise power distributions can be about 2.71%.

Structural Basis for Allosteric Control of the SERCA-Phospholamban Membrane Complex by Ca2+ and cAMP-dependent Phosphorylation

Phospholamban (PLN) is a mini-membrane protein that directly controls the cardiac Ca2+-transport response to β-adrenergic stimulation, thus modulating cardiac output during the fight- or-flight response. In the sarcoplasmic reticulum membrane, PLN binds to the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), keeping this enzyme’s function within a narrow physiological window. PLN phosphorylation by cAMP-dependent protein kinase A or increase in Ca2+ concentration reverses the inhibitory effects through an unknown mechanism. Using oriented-sample solid-state NMR spectroscopy and replica-averaged NMR-restrained structural refinement, we reveal that phosphorylation of PLN’s cytoplasmic regulatory domain signals the disruption of several inhibitory contacts at the transmembrane binding interface of the SERCA-PLN complex that are propagated to the enzyme’s active site, augmenting Ca2+ transport. Our findings address long-standing questions about SERCA regulation, epitomizing a signal transduction mechanism operated by posttranslationally-modified bitopic membrane proteins.

RPM-Oriented Query Rewriting Framework for E-commerce Keyword-Based Sponsored Search (Student Abstract)

Sponsored search optimizes revenue and relevance, which is estimated by Revenue Per Mille (RPM). Existing sponsored search models are all based on traditional statistical models, which have poor RPM performance when queries follow a heavy-tailed distribution. Here, we propose an RPMoriented Query Rewriting Framework (RQRF) which outputs related bid keywords that can yield high RPM. RQRF embeds both queries and bid keywords to vectors in the same implicit space, converting the rewriting probability between each query and keyword to the distance between the two vectors. For label construction, we propose an RPM-oriented sample construction method, labeling keywords based on whether or not they can lead to high RPM. Extensive experiments are conducted to evaluate performance of RQRF. In a one month large-scale real-world traffic of e-commerce sponsored search system, the proposed model significantly outperforms traditional baseline.

A Theoretical Assessment of the Structure Determination of Multi-Span Membrane Proteins by Oriented Sample Solid-State NMR Spectroscopy

Oriented sample solid-state NMR (OS-ssNMR) spectroscopy allows the direct determination of the structure and topology of membrane proteins reconstituted into aligned lipid bilayers. Although OS-ssNMR theoretically has no upper size limit, its application to multi-span membrane proteins has not been established because most studies have been restricted to single- or dual-span proteins and peptides. Here, we present a critical assessment of the application of this method to multi-span membrane proteins. We used molecular dynamics simulations to back-calculate [15N-1H] separated local field (SLF) spectra from a G protein-coupled receptor (GPCR) and show that fully resolved spectra can be obtained theoretically for a multi-span membrane protein with currently achievable resonance linewidths.