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All sourcesNASA NTRSDOE OSTI
DOE OSTI2015

On the no-signaling approach to quantum nonlocality

The no-signaling approach to nonlocality deals with separable and inseparable multiparty correlations in the same set of probability states without conflicting causality. The set of half-spaces describing the polytope of no-signaling probability states that are admitted by the most general class of Bell scenarios is formulated in full detail. An algorithm for determining the skeleton that solves the no-signaling description is developed upon a new strategy that is partially pivoting and partially incremental. The algorithm is formulated rigorously and its implementation is shown to be effective to deal with the highly degenerate no-signaling descriptions. Several applications of the algorithm as a tool for the study of quantum nonlocality are mentioned. Applied to a large set of bipartite Bell scenarios, we found that the corresponding no-signaling polytopes have a striking high degeneracy that grows up exponentially with the size of the Bell scenario.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2017

Molecular basis for the substrate specificity of quorum signal synthases

In several Proteobacteria , LuxI-type enzymes catalyze the biosynthesis of acyl–homoserine lactones (AHL) signals using S -adenosyl– L -methionine and either cellular acyl carrier protein (ACP)-coupled fatty acids or CoA–aryl/acyl moieties as progenitors. Little is known about the molecular mechanism of signal biosynthesis, the basis for substrate specificity, or the rationale for donor specificity for any LuxI member. As such, here, we present several cocrystal structures of BjaI, a CoA-dependent LuxI homolog that represent views of enzyme complexes that exist along the reaction coordinate of signal synthesis. Complementary biophysical, structure–function, and kinetic analysis define the features that facilitate the unusual acyl conjugation with S -adenosylmethionine (SAM). We also identify the determinant that establishes specificity for the acyl donor and identify residues that are critical for acyl/aryl specificity. These results highlight how a prevalent scaffold has evolved to catalyze quorum signal synthesis and provide a framework for the design of small-molecule antagonists of quorum signaling.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Hedgehog–FGF signaling axis patterns anterior mesoderm during gastrulation

Significance Anterior–posterior axis patterning is a fascinating but poorly understood developmental process. Single-cell sequencing was utilized to interrogate patterning abnormalities in a mesoderm-specific Hedgehog (Hh) pathway mutant, which revealed selective anterior mesoderm defects. We found that Hh signaling was required for fibroblast growth factor (FGF) pathway activity in nascent mesoderm during gastrulation. Mouse genetics, cell biology, and genomic experiments indicate that FGF signaling acts downstream of Hh signaling in nascent mesoderm for anterior mesoderm morphogenesis. This work demonstrates the utility of applying single-cell technologies to resolve complex developmental phenotypes. Here, it revealed a role for Hh signaling from the node in organizing anterior mesoderm morphogenesis, independent of its role in left–right determination, by promoting FGF signaling in gastrulating mesoderm.

Guzzetta, Alexander↗
DOE OSTI2017

Outsourced probe data effectiveness on signalized arterials

This paper presents results of an I-95 Corridor Coalition sponsored project to assess the ability of outsourced vehicle probe data to provide accurate travel time on signalized roadways for the purposes of real-time operations as well as performance measures. The quality of outsourced probe data on freeways has led many departments of transportation to consider such data for arterial performance monitoring. From April 2013 through June of 2014, the University of Maryland Center for Advanced Transportation Technology gathered travel times from several arterial corridors within the mid-Atlantic region using Bluetooth traffic monitoring (BTM) equipment, and compared these travel times with the data reported to the I95 Vehicle Probe Project (VPP) from an outsourced probe data vendor. The analysis consisted of several methodologies: (1) a traditional analysis that used precision and bias speed metrics; (2) a slowdown analysis that quantified the percentage of significant traffic disruptions accurately captured in the VPP data; (3) a sampled distribution method that uses overlay methods to enhance and analyze recurring congestion patterns. (4) Last, the BTM and VPP data from each 24-hour period of data collection were reviewed by the research team to assess the extent to which VPP captured the nature of the traffic flow. Based on the analysis, probe data is recommended only on arterial roadways with signal densities (measured in signals per mile) up to one, and it should be tested and used with caution for signal densities between one and two, and is not recommended when signal density exceeds two.

33 ADVANCED PROPULSION SYSTEMS↗
DOE OSTI2014

The curious case of HD 41248. A pair of static signals buried behind red noise

Gaining a better understanding of the effects of stellar-induced radial velocity noise is critical for the future of exoplanet studies since the discovery of the lowest-mass planets using this method will require us to go below the intrinsic stellar noise limit. An interesting test case in this respect is that of the southern solar analog HD 41248. The radial velocity time series of this star has been proposed to contain either a pair of signals with periods of around 18 and 25 days, which could be due to a pair of resonant super-Earths, or a single and varying 25 day signal that could arise due to a complex interplay between differential rotation and modulated activity. In this work, we build up more evidence for the former scenario, showing that the signals are still clearly significant, even after more than 10 yr of observations, and they likely do not change in period, amplitude, or phase as a function of time, the hallmarks of static Doppler signals. We show that over the last two observing seasons, this star was more intrinsically active and the noise reddened, highlighting why better noise models are needed to find the lowest amplitude signals, in particular, models that consider noise correlations. This analysis shows that there is still sufficient evidence for the existence of two super-Earths on the edge of, or locked into, a 7:5 mean motion resonance orbiting HD 41248.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2015

The stacked thermal Sunyaev–Zel’Dovich signal of locally brightest galaxies in Planck full mission data: Evidence for galaxy feedback?

We use the Planck full mission temperature maps to examine the stacked thermal Sunyaev–Zel’dovich (tSZ) signal of 188,042 “locally brightest galaxies” (LBGs) selected from the Sloan Digital Sky Survey Data Release 7. Our LBG sample closely matches that of Planck Collaboration XI (PCXI), but our analysis differs in several ways. We work directly in terms of physically observable quantities, requiring minimal assumptions about the gas pressure profile. We explicitly model the dust emission from each LBG and simultaneously measure both the stacked tSZ and dust signals as a function of stellar mass M{sub ∗}. There is a small residual bias in stacked tSZ measurements; we measure this bias and subtract it from our results, finding that the effects are non-negligible at the lowest masses in the LBG sample. Finally, we compare our measurements with two pressure profile models, finding that the profile from Battaglia et al. provides a better fit to the results than the Arnaud et al. “universal pressure profile.” However, within the uncertainties, we find that the data are consistent with a self-similar scaling with mass—more precise measurements are needed to detect the relatively small deviations from self-similarity predicted by these models. Consistent with PCXI, we measure the stacked tSZ signal from LBGs with stellar masses down to log{sub 10}(M{sub ∗}/M{sub ⊙}) ∼ 11.1–11.3. For lower stellar masses, however, we do not see evidence for a stacked tSZ signal. We note that the stacked dust emission is comparable to, or larger than, the stacked tSZ signal for log{sub 10}(M{sub ∗}/M{sub ⊙})≲11.3. Future tSZ analyses with larger samples and lower noise levels should be able to probe deviations from self-similarity and thus provide constraints on models of feedback and the evolution of hot halo gas over cosmic time.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2022

Intramolecular carbon isotope signals reflect metabolite allocation in plants

Abstract Stable isotopes at natural abundance are key tools to study physiological processes occurring outside the temporal scope of manipulation and monitoring experiments. Whole-molecule carbon isotope ratios (13C/12C) enable assessments of plant carbon uptake yet conceal information about carbon allocation. Here, we identify an intramolecular 13C/12C signal at tree-ring glucose C-5 and C-6 and develop experimentally testable theories on its origin. More specifically, we assess the potential of processes within C3 metabolism for signal introduction based (inter alia) on constraints on signal propagation posed by metabolic networks. We propose that the intramolecular signal reports carbon allocation into major metabolic pathways in actively photosynthesizing leaf cells including the anaplerotic, shikimate, and non-mevalonate pathway. We support our theoretical framework by linking it to previously reported whole-molecule 13C/12C increases in cellulose of ozone-treated Betula pendula and a highly significant relationship between the intramolecular signal and tropospheric ozone concentration. Our theory postulates a pronounced preference for leaf cytosolic triose-phosphate isomerase to catalyse the forward reaction in vivo (dihydroxyacetone phosphate to glyceraldehyde 3-phosphate). In conclusion, intramolecular 13C/12C analysis resolves information about carbon uptake and allocation enabling more comprehensive assessments of carbon metabolism than whole-molecule 13C/12C analysis.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2021

Redshift-space distortions in simulations of the 21-cm signal from the cosmic dawn

ABSTRACT The 21-cm signal from the Cosmic Dawn (CD) is likely to contain large fluctuations, with the most extreme astrophysical models on the verge of being ruled out by observations from radio interferometers. It is therefore vital that we understand not only the astrophysical processes governing this signal, but also other inherent processes impacting the signal itself, and in particular line-of-sight effects. Using our suite of fully numerical radiative transfer simulations, we investigate the impact on the redshifted 21-cm from the CD from one of these processes, namely the redshift-space distortions (RSDs). When RSDs are added, the resulting boost to the power spectra makes the signal more or equally detectable for our models for all redshifts, further strengthening hopes that a power spectra measurement of the CD will be possible. RSDs lead to anisotropy in the signal at the beginning and end of the CD, but not while X-ray heating is underway. The inclusion of RSDs, however, decreases detectability of the non-Gaussianity of fluctuations from inhomogeneous X-ray heating as measured by the skewness and kurtosis. On the other hand, mock observations created from all our simulations that include telescope noise corresponding to 1000 h of observation with the Square Kilometre Array telescope show that we may be able to image the CD for all heating models considered and suggest RSDs dramatically boost fluctuations coming from the inhomogeneous Ly α background.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2023

Recombination smooths the time-signal disrupted by latency in within-host HIV phylogenies

Within-host HIV evolution involves several features that may disrupt standard phylogenetic reconstruction. One important feature is re-activation of latently integrated provirus, which has the potential to disrupt the temporal signal, leading to variation in the branch lengths and apparent evolutionary rates in a tree. Yet, real within-host HIV phylogenies tend to show clear, ladder-like trees structured by the time of sampling. Another important feature is recombination, which violates the fundamental assumption that evolutionary history can be represented by a single bifurcating tree. Thus, recombination complicates the within-host HIV dynamic by mixing genomes and creating evolutionary loop structures that cannot be represented in bifurcating trees. In this paper, we develop a coalescent-based simulator of within-host HIV evolution that includes latency, recombination, and effective population size dynamics that allows us to study the relationship between the true, complex genealogy of within-host HIV evolution, encoded as an Ancestral Recombination Graph (ARG), and the observed phylogenetic tree. To compare our ARG results to the familiar phylogeny format, we calculate the expected bifurcating tree after decomposing the ARG into all unique site trees, their combined distance matrix, and the overall corresponding bifurcating tree. While latency and recombination separately disrupt the phylogenetic signal, remarkably, we find that recombination recovers the temporal signal of within-host HIV evolution caused by latency by mixing fragments of old, latent genomes into the contemporary population. In effect, recombination averages over extant heterogeneity, whether it stems from mixed time-signals or population bottlenecks. Further, we establish that the signals of latency and recombination can be observed in phylogenetic trees despite being an incorrect representation of the true evolutionary history. Using an Approximate Bayesian Computation method, we develop a set of statistical probes to tune our simulation model to nine longitudinally-sampled within-host HIV phylogenies. Because ARGs are exceedingly difficult to infer from real HIV data, our simulation system allows investigating effects of latency, recombination, and population size bottlenecks by matching decomposed ARGs to real data as observed in standard phylogenies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Autocrine and paracrine interferon signalling as ‘ring vaccination’ and ‘contact tracing’ strategies to suppress virus infection in a host

The innate immune response, particularly the interferon response, represents a first line of defence against viral infections. The interferon molecules produced from infected cells act through autocrine and paracrine signalling to turn host cells into an antiviral state. Although the molecular mechanisms of IFN signalling have been well characterized, how the interferon response collectively contribute to the regulation of host cells to stop or suppress viral infection during early infection remain unclear. Here, we use mathematical models to delineate the roles of the autocrine and the paracrine signalling, and show that their impacts on viral spread are dependent on how infection proceeds. In particular, we found that when infection is well-mixed, the paracrine signalling is not as effective; by contrast, when infection spreads in a spatial manner, a likely scenario during initial infection in tissue, the paracrine signalling can impede the spread of infection by decreasing the number of susceptible cells close to the site of infection. Furthermore, we argue that the interferon response can be seen as a parallel to population-level epidemic prevention strategies such as ‘contact tracing’ or ‘ring vaccination’. Thus, our results here may have implications for the outbreak control at the population scale more broadly.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Correlating gravitational wave and gamma-ray signals from primordial black holes

Asteroid-mass primordial black holes (PBHs) can explain the observed dark matter abundance while being consistent with the current indirect detection constraints. These PBHs can produce gamma-ray signals from Hawking radiation that are within the sensitivity of future measurements by the AMEGO and e-ASTROGAM experiments. PBHs which give rise to such observable gamma-ray signals have a cosmic origin from large primordial curvature fluctuations. There must then be a companion, stochastic gravitational wave (GW) background produced by the same curvature fluctuations. We demonstrate that the resulting GW signals will be well within the sensitivity of future detectors such as LISA, DECIGO, BBO, and the Einstein Telescope. The multimessenger signal from the observed gamma-rays and GWs will allow a precise measurement of the primordial curvature perturbation that produces the PBH. Indeed, so we argue that the resulting correlation between the two types of observations can provide a smoking-gun signal of PBHs.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2025

Integrated Routing and Traffic Signal Control for CAVs via Reinforcement Learning Approach

Incorporating Connected and Automated Vehicles (CAVs) into urban traffic networks presents opportunities and challenges for traffic management systems. This paper aims to develop an integrated routing and traffic signal control system designed explicitly for CAVs, utilizing a Reinforcement Learning (RL) approach. The objective is to enhance traffic flow and improve overall transportation efficiency in the controlled areas. We propose an innovative framework that employs the Deep Reinforcement Learning (DRL) algorithm, especially the Deep Q-network (DQN), to dynamically adjust the number of vehicles in the routes and the duration of traffic signals. Our simulation results demonstrate that a DQN agent successfully optimizes the number of vehicles in the routes and traffic signal timings of traffic signal controllers, eventually reducing total travel time. The study illustrates the potential usage of RL-based systems in managing routing and traffic signals for CAVs, offering a promising opportunity for future urban traffic management strategies.

Park, Jiho [New York University]↗
DOE OSTI2026

Secure Wireless Communication Using Distributed Coherent Transmission and Spatial Signal Decomposition

We present a new approach to secure wireless communications using coherent distributed transmission of signals that are spatially decomposed between a two-element distributed antenna array. High-accuracy distributed coordination of microwave wireless systems supports the ability to transmit different parts of a signal from separate transmitters such that they combine coherently at a designated destination. In this article, we explore this concept using a two-element coherent distributed phased array where each of the two transmitters sends a separate component of a communication signal, where each symbol is decomposed into a sum of two pseudorandom signal vectors, the coherent summation of which yields the intended symbol. By directing the transmission to an intended receiver using distributed beamforming, the summation of the two vector components is largely confined to a spatial region at the destination receiver. We implement the technique in a $50−λ$ array operating at 3 GHz. We evaluate the symbol error rate (SER) in 2-D space through simulation and measurement, showing that the approach yields a spatially confined secure region where the information is recoverable (i.e., the received signal has low SER), and outside of which the information is unrecoverable (high SER). The proposed system is also compared against a traditional beamforming system where each node sends the same data. We validate experimentally that our approach achieves a low SER of 0.0082 at broadside and an SER above 0.25 at all other locations compared to a traditional beamforming approach that achieves a SER of 0 at all locations measured.

Engineering - Electronic and electrical engineerin↗
DOE OSTI2016

PREDICTIVE MODELING OF ACOUSTIC SIGNALS FROM THERMOACOUSTIC POWER SENSORS (TAPS)

Thermoacoustic Power Sensor (TAPS) technology offers the potential for self-powered, wireless measurement of nuclear reactor core operating conditions. TAPS are based on thermoacoustic engines, which harness thermal energy from fission reactions to generate acoustic waves by virtue of gas motion through a porous stack of thermally nonconductive material. TAPS can be placed in the core, where they generate acoustic waves whose frequency and amplitude are proportional to the local temperature and radiation flux, respectively. TAPS acoustic signals are not measured directly at the TAPS; rather, they propagate wirelessly from an individual TAPS through the reactor, and ultimately to a low-power receiver network on the vessel’s exterior. In order to rely on TAPS as primary instrumentation, reactor-specific models which account for geometric/acoustic complexities in the signal propagation environment must be used to predict the amplitude and frequency of TAPS signals at receiver locations. The reactor state may then be derived by comparing receiver signals to the reference levels established by predictive modeling. In this paper, we develop and experimentally benchmark a methodology for predictive modeling of the signals generated by a TAPS system, with the intent of subsequently extending these efforts to modeling of TAPS in a liquid sodium environmen

thermoacoustics, wireless in-core radiation detect↗
DOE OSTI2013

Reducing radiation dose to the female breast during CT coronary angiography: A simulation study comparing breast shielding, angular tube current modulation, reduced kV, and partial angle protocols using an unknown-location signal-detectability metric

Purpose: The authors compared the performance of five protocols intended to reduce dose to the breast during computed tomography (CT) coronary angiography scans using a model observer unknown-location signal-detectability metric.Methods: The authors simulated CT images of an anthropomorphic female thorax phantom for a 120 kV reference protocol and five “dose reduction” protocols intended to reduce dose to the breast: 120 kV partial angle (posteriorly centered), 120 kV tube-current modulated (TCM), 120 kV with shielded breasts, 80 kV, and 80 kV partial angle (posteriorly centered). Two image quality tasks were investigated: the detection and localization of 4-mm, 3.25 mg/ml and 1-mm, 6.0 mg/ml iodine contrast signals randomly located in the heart region. For each protocol, the authors plotted the signal detectability, as quantified by the area under the exponentially transformed free response characteristic curve estimator (A-caret{sub FE}), as well as noise and contrast-to-noise ratio (CNR) versus breast and lung dose. In addition, the authors quantified each protocol's dose performance as the percent difference in dose relative to the reference protocol achieved while maintaining equivalent A-caret{sub FE}.Results: For the 4-mm signal-size task, the 80 kV full scan and 80 kV partial angle protocols decreased dose to the breast (80.5% and 85.3%, respectively) and lung (80.5% and 76.7%, respectively) with A-caret{sub FE} = 0.96, but also resulted in an approximate three-fold increase in image noise. The 120 kV partial protocol reduced dose to the breast (17.6%) at the expense of increased lung dose (25.3%). The TCM algorithm decreased dose to the breast (6.0%) and lung (10.4%). Breast shielding increased breast dose (67.8%) and lung dose (103.4%). The 80 kV and 80 kV partial protocols demonstrated greater dose reductions for the 4-mm task than for the 1-mm task, and the shielded protocol showed a larger increase in dose for the 4-mm task than for the 1-mm task. In general, the CNR curves indicate a similar relative ranking of protocol performance as the corresponding A-caret{sub FE} curves, however, the CNR metric overestimated the performance of the shielded protocol for both tasks, leading to corresponding underestimates in the relative dose increases compared to those obtained when using the A-caret{sub FE} metric.Conclusions: The 80 kV and 80 kV partial angle protocols demonstrated the greatest reduction to breast and lung dose, however, the subsequent increase in image noise may be deemed clinically unacceptable. Tube output for these protocols can be adjusted to achieve a more desirable noise level with lesser breast dose savings. Breast shielding increased breast and lung dose when maintaining equivalent A-caret{sub FE}. The results demonstrated that comparisons of dose performance depend on both the image quality metric and the specific task, and that CNR may not be a reliable metric of signal detectability.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2013

A method to synchronize signals from multiple patient monitoring devices through a single input channel for inclusion in list-mode acquisitions

Purpose: This technical note documents a method that the authors developed for combining a signal to synchronize a patient-monitoring device with a second physiological signal for inclusion into list-mode acquisition. Our specific application requires synchronizing an external patient motion-tracking system with a medical imaging system by multiplexing the tracking input with the ECG input. The authors believe that their methodology can be adapted for use in a variety of medical imaging modalities including single photon emission computed tomography (SPECT) and positron emission tomography (PET). Methods: The authors insert a unique pulse sequence into a single physiological input channel. This sequence is then recorded in the list-mode acquisition along with the R-wave pulse used for ECG gating. The specific form of our pulse sequence allows for recognition of the time point being synchronized even when portions of the pulse sequence are lost due to collisions with R-wave pulses. This was achieved by altering our software used in binning the list-mode data to recognize even a portion of our pulse sequence. Limitations on heart rates at which our pulse sequence could be reliably detected were investigated by simulating the mixing of the two signals as a function of heart rate and time point during the cardiac cycle at which our pulse sequence is mixed with the cardiac signal. Results: The authors have successfully achieved accurate temporal synchronization of our motion-tracking system with acquisition of SPECT projections used in 17 recent clinical research cases. In our simulation analysis the authors determined that synchronization to enable compensation for body and respiratory motion could be achieved for heart rates up to 125 beats-per-minute (bpm). Conclusions: Synchronization of list-mode acquisition with external patient monitoring devices such as those employed in motion-tracking can reliably be achieved using a simple method that can be implemented using minimal external hardware and software modification through a single input channel, while still recording cardiac gating signals.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

WE-D-BRF-02: Acoustic Signal From the Bragg Peak for Range Verification in Proton Therapy

Purpose: Range verification in ion beam therapy relies to date on nuclear imaging techniques which require complex and costly detector systems. A different approach is the detection of thermoacoustic signals that are generated due to localized energy loss of ion beams. Aim of this work is to study the feasibility of determining the ion range with sub-mm accuracy by use of high frequency ultrasonic (US) transducers and to image the Bragg peak by tomography. Methods: A water phantom was irradiated by a pulsed 20 MeV proton beam with varying pulse intensity, length and repetition rate. The acoustic signal of single proton pulses was measured by different PZT-based US detectors (3.5 MHz and 10 MHz central frequencies). For tomography a 64 channel US detector array was used and moved along the ion track by a remotely controlled motor stage. Results: A clear signal of the Bragg peak was visible for an energy deposition as low as 10{sup 12} eV. The signal amplitude showed a linear increase with particle number per pulse and thus, dose. Range measurements were reproducible within +/− 20 micrometer and agreed well with Geant4 simulations. The tomographic reconstruction does not only allow to measure the ion range but also the beam spot size at the Bragg peak position. Conclusion: Range verification by acoustic means is a promising new technique for treatment modalities where the tumor can be localized by US imaging. Further improvement of sensitivity is required to account for higher attenuation of the US signal in tissue, as well as lower energy density in the Bragg peak in realistic treatment cases due to higher particle energy and larger spot sizes. Nevertheless, the acoustic range verification approach could offer the possibility of combining anatomical US imaging with Bragg Peak imaging in the near future. The work was funded by the DFG cluster of excellence Munich Centre for Advanced Photonics (MAP)

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Structural analysis of the PTEN:P-Rex2 signaling complex reveals how cancer-associated mutations coordinate to hyperactivate Rac1

The dual-specificity phosphatase PTEN functions as a tumor suppressor by hydrolyzing PI(3,4,5)P 3 to PI(4,5)P 2 to inhibit PI3K-AKT signaling and cellular proliferation. P-Rex2 is a guanine nucleotide exchange factor for Rho GTPases and can be activated by Gβγ subunits downstream of G protein–coupled receptor signaling and by PI(3,4,5)P 3 downstream of receptor tyrosine kinases. The PTEN:P-Rex2 complex is a commonly mutated signaling node in metastatic cancer. Assembly of the PTEN:P-Rex2 complex inhibits the activity of both proteins, and its dysregulation can drive PI3K-AKT signaling and cellular proliferation. Here, using cross-linking mass spectrometry and functional studies, we gained mechanistic insights into PTEN:P-Rex2 complex assembly and coinhibition. We found that PTEN was anchored to P-Rex2 by interactions between the PDZ-interacting motif in the PTEN C-terminal tail and the second PDZ domain of P-Rex2. This interaction bridged PTEN across the P-Rex2 surface, preventing PI(3,4,5)P 3 hydrolysis. Conversely, PTEN both allosterically promoted an autoinhibited conformation of P-Rex2 and blocked its binding to Gβγ. In addition, we observed that the PTEN-deactivating mutations and P-Rex2 truncations combined to drive Rac1 activation to a greater extent than did either single variant alone. These insights enabled us to propose a class of gain-of-function, cancer-associated mutations within the PTEN:P-Rex2 interface that uncouple PTEN from the inhibition of Rac1 signaling.

D’Andrea, Laura↗