Showing papers by "California Institute of Technology published in 2022"

Electrochemically driven cross-electrophile coupling of alkyl halides

Abstract: Recent research in medicinal chemistry has suggested that there is a correlation between an increase in the fraction of sp3 carbons-those bonded to four other atoms-in drug candidates and their improved success rate in clinical trials1. As such, the development of robust and selective methods for the construction of carbon(sp3)-carbon(sp3) bonds remains a critical problem in modern organic chemistry2. Owing to the broad availability of alkyl halides, their direct cross-coupling-commonly known as cross-electrophile coupling-provides a promising route towards this objective3-5. Such transformations circumvent the preparation of carbon nucleophiles used in traditional cross-coupling reactions, as well as stability and functional-group-tolerance issues that are usually associated with these reagents. However, achieving high selectivity in carbon(sp3)-carbon(sp3) cross-electrophile coupling remains a largely unmet challenge. Here we use electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution to forge a new carbon-carbon bond. This protocol enables efficient cross-electrophile coupling of a variety of functionalized and unactivated alkyl electrophiles in the absence of a transition metal catalyst, and shows improved chemoselectivity compared with existing methods.

Quantitative SARS-CoV-2 Viral-Load Curves in Paired Saliva Samples and Nasal Swabs Inform Appropriate Respiratory Sampling Site and Analytical Test Sensitivity Required for Earliest Viral Detection

Abstract: Early detection of SARS-CoV-2 infection is critical to reduce asymptomatic and presymptomatic transmission, curb the spread of variants, and maximize treatment efficacy. Low-analytical-sensitivity nasal-swab testing is commonly used for surveillance and symptomatic testing, but the ability of these tests to detect the earliest stages of infection has not been established. In this study, conducted between September 2020 and June 2021 in the greater Los Angeles County, California, area, initially SARS-CoV-2-negative household contacts of individuals diagnosed with COVID-19 prospectively self-collected paired anterior-nares nasal-swab and saliva samples twice daily for viral-load quantification by high-sensitivity reverse-transcription quantitative PCR (RT-qPCR) and digital-RT-PCR assays. We captured viral-load profiles from the incidence of infection for seven individuals and compared diagnostic sensitivities between respiratory sites. Among unvaccinated persons, testing saliva with a high-analytical-sensitivity assay detected infection up to 4.5 days before viral loads in nasal swabs reached concentrations detectable by low-analytical-sensitivity nasal-swab tests. For most participants, nasal swabs reached higher peak viral loads than saliva but were undetectable or at lower loads during the first few days of infection. High-analytical-sensitivity saliva testing was most reliable for earliest detection. Our study illustrates the value of acquiring early (within hours after a negative high-sensitivity test) viral-load profiles to guide the appropriate analytical sensitivity and respiratory site for detecting earliest infections. Such data are challenging to acquire but critical to designing optimal testing strategies with emerging variants in the current pandemic and to respond to future viral pandemics.

Safe Controller Synthesis With Tunable Input-to-State Safe Control Barrier Functions

Abstract: To bring complex systems into real world environments in a safe manner, they will have to be robust to uncertainties—both in the environment and the system. This letter investigates the safety of control systems under input disturbances, wherein the disturbances can capture uncertainties in the system. Safety, framed as forward invariance of sets in the state space, is ensured with the framework of control barrier functions (CBFs). Concretely, the definition of input-to-state safety (ISSf) is generalized to allow the synthesis of non-conservative, tunable controllers that are provably safe under varying disturbances. This is achieved by formulating the concept of tunable input-to-state safe control barrier functions (TISSf-CBFs), which guarantee safety for disturbances that vary with state and, therefore, provide less conservative means of accommodating uncertainty. The theoretical results are demonstrated with a simple control system with input disturbance and also applied to design a safe connected cruise controller for a heavy duty truck.

Quantum computational advantage via high-dimensional Gaussian boson sampling

Abstract: A programmable quantum computer based on fiber optics outperforms classical computers with a high level of confidence.

Au-activated N motifs in non-coherent cupric porphyrin metal organic frameworks for promoting and stabilizing ethylene production

Abstract: Direct implementation of metal-organic frameworks as the catalyst for CO2 electroreduction has been challenging due to issues such as poor conductivity, stability, and limited > 2e- products. In this study, Au nanoneedles are impregnated into a cupric porphyrin-based metal-organic framework by exploiting ligand carboxylates as the Au3+ -reducing agent, simultaneously cleaving the ligand-node linkage. Surprisingly, despite the lack of a coherent structure, the Au-inserted framework affords a superb ethylene selectivity up to 52.5% in Faradaic efficiency, ranking among the best for metal-organic frameworks reported in the literature. Through operando X-ray, infrared spectroscopies and density functional theory calculations, the enhanced ethylene selectivity is attributed to Au-activated nitrogen motifs in coordination with the Cu centers for C-C coupling at the metalloporphyrin sites. Furthermore, the Au-inserted catalyst demonstrates both improved structural and catalytic stability, ascribed to the altered charge conduction path that bypasses the incoherent framework. This study underlines the modulation of reticular metalloporphyrin structure by metal impregnation for steering the CO2 reduction reaction pathway.

Topological dissipation in a time-multiplexed photonic resonator network

Abstract: Topological phases feature robust edge states that are protected against the effects of defects and disorder. These phases have largely been studied in conservatively coupled systems, in which non-trivial topological invariants arise in the energy or frequency bands of a system. Here we show that, in dissipatively coupled systems, non-trivial topological invariants can emerge purely in a system’s dissipation. Using a highly scalable and easily reconfigurable time-multiplexed photonic resonator network, we experimentally demonstrate one- and two-dimensional lattices that host robust topological edge states with isolated dissipation rates, measure a dissipation spectrum that possesses a non-trivial topological invariant, and demonst rate topological protection of the network’s quality factor. The topologically non-trivial dissipation of our system exposes new opportunities to engineer dissipation in both classical and quantum systems. Moreover, our experimental platform’s straightforward scaling to higher dimensions and its ability to implement inhomogeneous, non-reciprocal and long range couplings may enable future work in the study of synthetic dimensions.

Synthetic multistability in mammalian cells

Abstract: In multicellular organisms, gene regulatory circuits generate thousands of molecularly distinct, mitotically heritable states through the property of multistability. Designing synthetic multistable circuits would provide insight into natural cell fate control circuit architectures and would allow engineering of multicellular programs that require interactions among distinct cell types. We created MultiFate, a naturally inspired, synthetic circuit that supports long-term, controllable, and expandable multistability in mammalian cells. MultiFate uses engineered zinc finger transcription factors that transcriptionally self-activate as homodimers and mutually inhibit one another through heterodimerization. Using a model-based design, we engineered MultiFate circuits that generate as many as seven states, each stable for at least 18 days. MultiFate permits controlled state switching and modulation of state stability through external inputs and can be expanded with additional transcription factors. These results provide a foundation for engineering multicellular behaviors in mammalian cells.

Risk-Averse Control via CVaR Barrier Functions: Application to Bipedal Robot Locomotion

Abstract: Enforcing safety in the presence of stochastic uncertainty is a challenging problem. Traditionally, researchers have proposed safety in the statistical mean as a safety measure for systems subject to stochastic uncertainty. However, ensuring safety in the statistical mean is only reasonable if system’s safe behavior in the large number of runs is of interest, which precludes the use of mean safety in practical scenarios. In this letter, we propose a risk sensitive notion of safety called conditional-value-at-risk (CVaR) safety. We introduce CVaR barrier functions as a tool to enforce CVaR-safety and propose conditions for their Boolean compositions. Given a legacy controller, we show that we can design a minimally interfering CVaR-safe controller via solving difference convex programs (DCPs). We elucidate the proposed method by applying it to a bipedal robot locomotion case study.

A learning-based multiscale method and its application to inelastic impact problems

Abstract: The macroscopic properties of materials that we observe and exploit in engineering application result from complex interactions between physics at multiple length and time scales: electronic, atomistic, defects, domains etc. Multiscale modeling seeks to understand these interactions by exploiting the inherent hierarchy where the behavior at a coarser scale regulates and averages the behavior at a finer scale. This requires the repeated solution of computationally expensive finer-scale models, and often a priori knowledge of those aspects of the finer-scale behavior that affect the coarser scale (order parameters, state variables, descriptors, etc.). We address this challenge in a two-scale setting where we learn the fine-scale behavior from off-line calculations and then use the learnt behavior directly in coarse scale calculations. The approach builds on the recent success of deep neural networks by combining their approximation power in high dimensions with ideas from model reduction. It results in a neural network approximation that has high fidelity, is computationally inexpensive, is independent of the need for a priori knowledge, and can be used directly in the coarse scale calculations. We demonstrate the approach on problems involving the impact of magnesium, a promising light-weight structural and protective material.

Nuclear spin-wave quantum register for a solid-state qubit

Abstract: Solid-state nuclear spins surrounding individual, optically addressable qubits1,2 are a crucial resource for quantum networks3–6, computation7–11 and simulation12. Although hosts with sparse nuclear spin baths are typically chosen to mitigate qubit decoherence13, developing coherent quantum systems in nuclear-spin-rich hosts enables exploration of a much broader range of materials for quantum information applications. The collective modes of these dense nuclear spin ensembles provide a natural basis for quantum storage14; however, using them as a resource for single-spin qubits has thus far remained elusive. Here, by using a highly coherent, optically addressed 171Yb3+ qubit doped into a nuclear-spin-rich yttrium orthovanadate crystal15, we develop a robust quantum control protocol to manipulate the multi-level nuclear spin states of neighbouring 51V5+ lattice ions. Via a dynamically engineered spin-exchange interaction, we polarize this nuclear spin ensemble, generate collective spin excitations, and subsequently use them to implement a quantum memory. We additionally demonstrate preparation and measurement of maximally entangled 171Yb–51V Bell states. Unlike conventional, disordered nuclear-spin-based quantum memories16–24, our platform is deterministic and reproducible, ensuring identical quantum registers for all 171Yb3+ qubits. Our approach provides a framework for utilizing the complex structure of dense nuclear spin baths, paving the way towards building large-scale quantum networks using single rare-earth ion qubits15,25–28. Via spin-exchange interactions with 51V5+ ions, an optically addressed 171Yb3+ qubit in a nuclear-spin-rich yttrium orthovanadate crystal is used to implement a reproducible nuclear-spin-based quantum memory, and entangled Yb–V Bell states are demonstrated.

Safety-Critical Kinematic Control of Robotic Systems

Abstract: Over the decades, kinematic controllers have proven to be practically useful for applications like set-point and trajectory tracking in robotic systems. To this end, we formulate a novel safety-critical paradigm by extending the methodology of control barrier functions (CBFs) to kinematic equations governing robotic systems. We demonstrate a purely kinematic implementation of a velocity-based CBF, and subsequently introduce a formulation that guarantees safety at the level of dynamics. This is achieved through a new form of CBFs that incorporate kinetic energy with the classical forms, thereby minimizing model dependence and conservativeness. The approach is then extended to underactuated systems. This method and the purely kinematic implementation are demonstrated in simulation on two robotic platforms: a 6-DOF robotic manipulator, and a cart-pole system.

Narrowband Searches for Continuous and Long-duration Transient Gravitational Waves from Known Pulsars in the LIGO-Virgo Third Observing Run

Abstract: Isolated neutron stars that are asymmetric with respect to their spin axis are possible sources of detectable continuous gravitational waves. This paper presents a fully-coherent search for such signals from eighteen pulsars in data from LIGO and Virgo's third observing run (O3). For known pulsars, efficient and sensitive matched-filter searches can be carried out if one assumes the gravitational radiation is phase-locked to the electromagnetic emission. In the search presented here, we relax this assumption and allow the frequency and frequency time-derivative of the gravitational waves to vary in a small range around those inferred from electromagnetic observations. We find no evidence for continuous gravitational waves, and set upper limits on the strain amplitude for each target. These limits are more constraining for seven of the targets than the spin-down limit defined by ascribing all rotational energy loss to gravitational radiation. In an additional search we look in O3 data for long-duration (hours-months) transient gravitational waves in the aftermath of pulsar glitches for six targets with a total of nine glitches. We report two marginal outliers from this search, but find no clear evidence for such emission either. The resulting duration-dependent strain upper limits do not surpass indirect energy constraints for any of these targets.

Searches for Gravitational Waves from Known Pulsars at Two Harmonics in the Second and Third LIGO-Virgo Observing Runs

Abstract: We present a targeted search for continuous gravitational waves (GWs) from 236 pulsars using data from the third observing run of LIGO and Virgo (O3) combined with data from the second observing run (O2). Searches were for emission from the $l=m=2$ mass quadrupole mode with a frequency at only twice the pulsar rotation frequency (single harmonic) and the $l=2, m=1,2$ modes with a frequency of both once and twice the rotation frequency (dual harmonic). No evidence of GWs was found so we present 95\% credible upper limits on the strain amplitudes $h_0$ for the single harmonic search along with limits on the pulsars' mass quadrupole moments $Q_{22}$ and ellipticities $\varepsilon$. Of the pulsars studied, 23 have strain amplitudes that are lower than the limits calculated from their electromagnetically measured spin-down rates. These pulsars include the millisecond pulsars J0437\textminus4715 and J0711\textminus6830 which have spin-down ratios of 0.87 and 0.57 respectively. For nine pulsars, their spin-down limits have been surpassed for the first time. For the Crab and Vela pulsars our limits are factors of $\sim 100$ and $\sim 20$ more constraining than their spin-down limits, respectively. For the dual harmonic searches, new limits are placed on the strain amplitudes $C_{21}$ and $C_{22}$. For 23 pulsars we also present limits on the emission amplitude assuming dipole radiation as predicted by Brans-Dicke theory.

The context-dependent, combinatorial logic of BMP signaling

Abstract: •Systematic pairwise analysis of BMP ligands reveals diverse combinatorial effects•Receptor expression profile (context) controls how ligands signal in combinations•Contextual equivalence groups classify ligands and explain previous observations•A model based on alternative ligand-receptor complex formation can explain data Cell-cell communication systems typically comprise families of ligand and receptor variants that function together in combinations. Pathway activation depends on the complex way in which ligands are presented extracellularly and receptors are expressed by the signal-receiving cell. To understand the combinatorial logic of such a system, we systematically measured pairwise bone morphogenetic protein (BMP) ligand interactions in cells with varying receptor expression. Ligands could be classified into equivalence groups based on their profile of positive and negative synergies with other ligands. These groups varied with receptor expression, explaining how ligands can functionally replace each other in one context but not another. Context-dependent combinatorial interactions could be explained by a biochemical model based on the competitive formation of alternative signaling complexes with distinct activities. Together, these results provide insights into the roles of BMP combinations in developmental and therapeutic contexts and establish a framework for analyzing other combinatorial, context-dependent signaling systems. Cell-cell communication systems typically comprise families of ligand and receptor variants that function together in combinations. Pathway activation depends on the complex way in which ligands are presented extracellularly and receptors are expressed by the signal-receiving cell. To understand the combinatorial logic of such a system, we systematically measured pairwise bone morphogenetic protein (BMP) ligand interactions in cells with varying receptor expression. Ligands could be classified into equivalence groups based on their profile of positive and negative synergies with other ligands. These groups varied with receptor expression, explaining how ligands can functionally replace each other in one context but not another. Context-dependent combinatorial interactions could be explained by a biochemical model based on the competitive formation of alternative signaling complexes with distinct activities. Together, these results provide insights into the roles of BMP combinations in developmental and therapeutic contexts and establish a framework for analyzing other combinatorial, context-dependent signaling systems. Cell-cell communication pathways such as Bone Morphogenetic Protein (BMP), Wnt, and Fibroblast Growth Factor (FGF) play pivotal roles in normal development, disease, therapeutics, and regenerative medicine (Nusse, 2005Nusse R. Wnt signaling in disease and in development.Cell Res. 2005; 15: 28-32https://doi.org/10.1038/sj.cr.7290260Crossref PubMed Scopus (777) Google Scholar; Ornitz and Itoh, 2015Ornitz D.M. Itoh N. The fibroblast growth factor signaling pathway.Wiley Interdiscip. Rev. Dev. Biol. 2015; 4: 215-266https://doi.org/10.1002/wdev.176Crossref PubMed Scopus (1010) Google Scholar; Salazar et al., 2016Salazar V.S. Gamer L.W. Rosen V. BMP signalling in skeletal development, disease and repair.Nat. Rev. Endocrinol. 2016; 12: 203-221https://doi.org/10.1038/nrendo.2016.12Crossref PubMed Scopus (396) Google Scholar). A striking feature of these pathways is their use of families of homologous ligand variants. Within each pathway, multiple ligands typically function together in combinations (Alok et al., 2017Alok A. Lei Z. Jagannathan N.S. Kaur S. Harmston N. Rozen S.G. Tucker-Kellogg L. Virshup D.M. Wnt proteins synergize to activate β-catenin signaling.J. Cell Sci. 2017; 130: 1532-1544https://doi.org/10.1242/jcs.198093Crossref PubMed Scopus (36) Google Scholar; Antebi et al., 2017Antebi Y.E. Linton J.M. Klumpe H. Bintu B. Gong M. Su C. McCardell R. Elowitz M.B. Combinatorial signal perception in the BMP pathway.Cell. 2017; 170: 1184-1196.e24https://doi.org/10.1016/j.cell.2017.08.015Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar; Kadam et al., 2012Kadam S. Ghosh S. Stathopoulos A. Synchronous and symmetric migration of Drosophila caudal visceral mesoderm cells requires dual input by two FGF ligands.Development. 2012; 139: 699-708https://doi.org/10.1242/dev.068791Crossref PubMed Scopus (33) Google Scholar). Further, the effect of any given ligand can vary dramatically with cell or tissue context (Chen et al., 2013Chen H. Brady Ridgway J. Sai T. Lai J. Warming S. Chen H. Roose-Girma M. Zhang G. Shou W. Yan M. Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development.Proc. Natl. Acad. Sci. USA. 2013; 110: 11887-11892https://doi.org/10.1073/pnas.1306074110Crossref PubMed Scopus (76) Google Scholar; Eubelen et al., 2018Eubelen M. Bostaille N. Cabochette P. Gauquier A. Tebabi P. Dumitru A.C. Koehler M. Gut P. Alsteens D. Stainier D.Y.R. et al.A molecular mechanism for Wnt ligand-specific signaling.Science. 2018; 361: eaat1178https://doi.org/10.1126/science.aat1178Crossref PubMed Scopus (88) Google Scholar; Fortin et al., 2005Fortin D. Rom E. Sun H. Yayon A. Bansal R. Distinct fibroblast growth factor (FGF)/FGF receptor signaling pairs initiate diverse cellular responses in the oligodendrocyte lineage.J. Neurosci. 2005; 25: 7470-7479https://doi.org/10.1523/JNEUROSCI.2120-05.2005Crossref PubMed Scopus (112) Google Scholar; Kadam et al., 2009Kadam S. McMahon A. Tzou P. Stathopoulos A. FGF ligands in Drosophila have distinct activities required to support cell migration and differentiation.Development. 2009; 136: 739-747https://doi.org/10.1242/dev.027904Crossref PubMed Scopus (64) Google Scholar; Verkaar and Zaman, 2010Verkaar F. Zaman G.J.R. A model for signaling specificity of Wnt/Frizzled combinations through co-receptor recruitment.FEBS Lett. 2010; 584: 3850-3854https://doi.org/10.1016/j.febslet.2010.08.030Crossref PubMed Scopus (25) Google Scholar). Despite the prevalence of these features and extensive information about the biochemical interactions and developmental roles of particular ligands, we lack a unified description of how ligands signal in combinations and across biological contexts. Understanding the principles of contextual combinatorial signaling could allow more predictive control of these pathways in natural and synthetic systems. A prime example of combinatorial and contextual ligand activity can be seen in the BMP pathway. This pathway comprises approximately ten major homodimeric ligand variants, as well as four type I and three type II receptors subunits (Figure 1A). Distinct combinations of these components regulate the development of diverse tissues, including skeleton, kidney, eye, and brain (Butler and Dodd, 2003Butler S.J. Dodd J. A role for BMP heterodimers in roof plate-mediated repulsion of commissural axons.Neuron. 2003; 38: 389-401https://doi.org/10.1016/S0896-6273(03)00254-XAbstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar; Godin et al., 1999Godin R.E. Robertson E.J. Dudley A.T. Role of BMP family members during kidney development.Int. J. Dev. Biol. 1999; 43: 405-411https://www.ncbi.nlm.nih.gov/pubmed/10535316PubMed Google Scholar; Huang et al., 2015Huang J. Liu Y. Filas B. Gunhaga L. Beebe D.C. Negative and positive auto-regulation of BMP expression in early eye development.Dev. Biol. 2015; 407: 256-264https://doi.org/10.1016/j.ydbio.2015.09.009Crossref PubMed Scopus (26) Google Scholar; Salazar et al., 2016Salazar V.S. Gamer L.W. Rosen V. BMP signalling in skeletal development, disease and repair.Nat. Rev. Endocrinol. 2016; 12: 203-221https://doi.org/10.1038/nrendo.2016.12Crossref PubMed Scopus (396) Google Scholar). Interestingly, a given pair of ligands can exhibit either redundant or distinct roles depending on context. For example, BMP9 can replace the essential role of BMP10 in proper vasculature formation but not in the developing heart (Chen et al., 2013Chen H. Brady Ridgway J. Sai T. Lai J. Warming S. Chen H. Roose-Girma M. Zhang G. Shou W. Yan M. Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development.Proc. Natl. Acad. Sci. USA. 2013; 110: 11887-11892https://doi.org/10.1073/pnas.1306074110Crossref PubMed Scopus (76) Google Scholar). Similarly, BMP4 can replace BMP7 in the developing kidney but not in the developing eye (Oxburgh et al., 2005Oxburgh L. Dudley A.T. Godin R.E. Koonce C.H. Islam A. Anderson D.C. Bikoff E.K. Robertson E.J. BMP4 substitutes for loss of BMP7 during kidney development.Dev. Biol. 2005; 286: 637-646https://doi.org/10.1016/j.ydbio.2005.08.024Crossref PubMed Scopus (56) Google Scholar). In addition to variation across tissue context, BMP ligands also have non-overlapping roles when signaling in combinations, as observed in the developing joint (Bandyopadhyay et al., 2006Bandyopadhyay A. Tsuji K. Cox K. Harfe B.D. Rosen V. Tabin C.J. Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis.PLoS Genet. 2006; 2: e216https://doi.org/10.1371/journal.pgen.0020216Crossref PubMed Scopus (460) Google Scholar). They can also combine with each other non-additively (Antebi et al., 2017Antebi Y.E. Linton J.M. Klumpe H. Bintu B. Gong M. Su C. McCardell R. Elowitz M.B. Combinatorial signal perception in the BMP pathway.Cell. 2017; 170: 1184-1196.e24https://doi.org/10.1016/j.cell.2017.08.015Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar; Klammert et al., 2015Klammert U. Mueller T.D. Hellmann T.V. Wuerzler K.K. Kotzsch A. Schliermann A. Schmitz W. Kuebler A.C. Sebald W. Nickel J. GDF-5 can act as a context-dependent BMP-2 antagonist.BMC Biol. 2015; 13: 77https://doi.org/10.1186/s12915-015-0183-8Crossref PubMed Scopus (31) Google Scholar; Piscione et al., 1997Piscione T.D. Yager T.D. Gupta I.R. Grinfeld B. Pei Y. Attisano L. Wrana J.L. Rosenblum N.D. BMP-2 and OP-1 exert direct and opposite effects on renal branching morphogenesis.Am. J. Physiol. 1997; 273: F961-F975https://doi.org/10.1152/ajprenal.1997.273.6.F961Crossref PubMed Google Scholar; Ying et al., 2001Ying Y. Qi X. Zhao G.Q. Induction of primordial germ cells from murine epiblasts by synergistic action of BMP4 and BMP8B signaling pathways.Proc. Natl. Acad. Sci. USA. 2001; 98: 7858-7862https://doi.org/10.1073/pnas.151242798Crossref PubMed Scopus (251) Google Scholar). As a result, it remains challenging to understand the roles of different BMP signaling components in a variety of skeletal, respiratory, and brain diseases (Cunha and Pietras, 2011Cunha S.I. Pietras K. ALK1 as an emerging target for antiangiogenic therapy of cancer.Blood. 2011; 117: 6999-7006https://doi.org/10.1182/blood-2011-01-330142Crossref PubMed Scopus (135) Google Scholar; Salazar et al., 2016Salazar V.S. Gamer L.W. Rosen V. BMP signalling in skeletal development, disease and repair.Nat. Rev. Endocrinol. 2016; 12: 203-221https://doi.org/10.1038/nrendo.2016.12Crossref PubMed Scopus (396) Google Scholar; Valer et al., 2019Valer J.A. Sánchez-de-Diego C. Pimenta-Lopes C. Rosa J.L. Ventura F. ACVR1 function in health and disease.Cells. 2019; 8: 1366https://doi.org/10.3390/cells8111366Crossref Scopus (22) Google Scholar) and to identify therapeutic BMPs for biomedical applications and cell fate control (Carragee et al., 2011Carragee E.J. Hurwitz E.L. Weiner B.K. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned.Spine J. 2011; 11: 471-491https://doi.org/10.1016/j.spinee.2011.04.023Abstract Full Text Full Text PDF PubMed Scopus (1038) Google Scholar; Cicciù et al., 2014Cicciù M. Herford A.S. Cicciù D. Tandon R. Maiorana C. Recombinant human bone morphogenetic protein-2 promote and stabilize hard and soft tissue healing for large mandibular new bone reconstruction defects.J. Craniofac. Surg. 2014; 25: 860-862https://doi.org/10.1097/SCS.0000000000000830Crossref PubMed Scopus (98) Google Scholar; Seeherman et al., 2019Seeherman H.J. Berasi S.P. Brown C.T. Martinez R.X. Juo Z.S. Jelinsky S. Cain M.J. Grode J. Tumelty K.E. Bohner M. et al.A BMP/activin A chimera is superior to native BMPs and induces bone repair in nonhuman primates when delivered in a composite matrix.Sci. Transl. Med. 2019; 11: eaar4953https://doi.org/10.1126/scitranslmed.aar4953Crossref PubMed Scopus (22) Google Scholar). The primary framework for functionally classifying BMP ligands is based on their receptor preferences. Ligand-receptor affinities govern the formation of signaling complexes, each of which contains a dimeric ligand bound to two type I and two type II receptor subunits (Figure 1A). These signaling complexes phosphorylate SMAD1/5/8 effector proteins (as well as non-canonical targets) to regulate downstream genes. Although ligands differ in the type I and type II receptors that they bind and signal through (David and Massagué, 2018David C.J. Massagué J. Contextual determinants of TGFβ action in development, immunity and cancer.Nat. Rev. Mol. Cell Biol. 2018; 19: 419-435https://doi.org/10.1038/s41580-018-0007-0Crossref PubMed Scopus (319) Google Scholar; Shimasaki et al., 2004Shimasaki S. Moore R.K. Otsuka F. Erickson G.F. The bone morphogenetic protein system in mammalian reproduction.Endocr. Rev. 2004; 25: 72-101https://doi.org/10.1210/er.2003-0007Crossref PubMed Scopus (555) Google Scholar), receptor preferences as currently understood cannot explain key functional differences between ligands. For instance, BMP9 and BMP10 exhibit similar preferences for some receptors (David et al., 2007David L. Mallet C. Mazerbourg S. Feige J.J. Bailly S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells.Blood. 2007; 109: 1953-1961https://ashpublications.org/blood/article-abstract/109/5/1953/23209Crossref PubMed Scopus (485) Google Scholar) but behave non-equivalently, as discussed above (Chen et al., 2013Chen H. Brady Ridgway J. Sai T. Lai J. Warming S. Chen H. Roose-Girma M. Zhang G. Shou W. Yan M. Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development.Proc. Natl. Acad. Sci. USA. 2013; 110: 11887-11892https://doi.org/10.1073/pnas.1306074110Crossref PubMed Scopus (76) Google Scholar). Moreover, BMP receptors are expressed in combinations (Figure 1B), compete with one another for binding to ligands, and generate complex functional responses to ligand combinations, all of which make it difficult to predict the distribution of signaling complexes and thereby the overall pathway activity, from qualitative affinity preferences alone (Antebi et al., 2017Antebi Y.E. Linton J.M. Klumpe H. Bintu B. Gong M. Su C. McCardell R. Elowitz M.B. Combinatorial signal perception in the BMP pathway.Cell. 2017; 170: 1184-1196.e24https://doi.org/10.1016/j.cell.2017.08.015Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). To address these issues, we sought to map the combinatorial effects of ligands and, more specifically, to identify groups of ligands that function equivalently, across different cell contexts. We define two ligands as equivalent (interchangeable) if they exhibit similar individual activation strengths and interactions with all other ligands. (Analogous to the convention for drug interactions, we will use the term “ligand interactions” to refer to non-additive responses to ligand combinations, without implying direct molecular interaction between the ligands.) To determine ligand equivalence in a given cell context, we can measure responses to BMP pairs and cluster ligands into “equivalence groups” based on the similarity of their pairwise interactions (Figure 1C). Repeating these measurements in different cell types can further reveal how equivalence groups vary between developmental contexts. Although previous work identified pairwise responses among a few BMPs, the full set of pairwise interactions is necessary to determine this equivalence structure. (Ligand equivalence groups, which are defined here, are distinct from equivalence groups in development, which describe groups of cells with the same fate potential [Greenwald and Rubin, 1992Greenwald I. Rubin G.M. Making a difference: the role of cell-cell interactions in establishing separate identities for equivalent cells.Cell. 1992; 68: 271-281https://doi.org/10.1016/0092-8674(92)90470-wAbstract Full Text PDF PubMed Google Scholar].) This approach was inspired by previous work showing that pairwise analysis of mutations can efficiently reveal the structure of gene modules and protein functions (Costanzo et al., 2016Costanzo M. VanderSluis B. Koch E.N. Baryshnikova A. Pons C. Tan G. Wang W. Usaj M. Hanchard J. Lee S.D. et al.A global genetic interaction network maps a wiring diagram of cellular function.Science. 2016; 353: aaf1420https://doi.org/10.1126/science.aaf1420Crossref PubMed Scopus (561) Google Scholar; Schwikowski et al., 2000Schwikowski B. Uetz P. Fields S. A network of protein–protein interactions in yeast.Nat. Biotechnol. 2000; 18: 1257-1261https://doi.org/10.1038/82360Crossref PubMed Scopus (1036) Google Scholar; Segrè et al., 2005Segrè D. Deluna A. Church G.M. Kishony R. Modular epistasis in yeast metabolism.Nat. Genet. 2005; 37: 77-83https://doi.org/10.1038/ng1489Crossref PubMed Scopus (461) Google Scholar) and that pairwise analysis of antibiotics can similarly classify them into groups with similar biochemical mechanisms of action (Yeh et al., 2006Yeh P. Tschumi A.I. Kishony R. Functional classification of drugs by properties of their pairwise interactions.Nat. Genet. 2006; 38: 489-494https://doi.org/10.1038/ng1755Crossref PubMed Scopus (261) Google Scholar). In these studies, clusters of genes or drugs are defined by patterns in phenotypic, pairwise responses and are shown to emerge from underlying features of the interacting components. Similarly, in the case of BMP signaling, we reasoned that equivalence groups could emerge from subtle or unknown differences in the biochemical properties of different ligands. Equivalence groups could thus empirically distill the functional consequences of unknown parameters, constrain mathematical models of underlying components and interactions, and provide a useful framework for classification and prediction. Here, we analyzed pairwise combinations of ten of the best-characterized BMP ligands across multiple receptor contexts. This analysis classifies the ten ligands into a smaller number of equivalence groups. Further, we show that these equivalence groups reorganize depending on the receptor expression profile of the signal-receiving cell, helping to explain context-dependent effects in development. Finally, to understand how the observed combinatorial ligand responses could emerge from underlying molecular features of the pathway, we fit the full data set to a simplified mathematical model of competitive ligand-receptor interactions. This analysis shows how contextual, combinatorial BMP responses can emerge from the interplay between the affinities that govern signaling complex formation and the specific phosphorylation activities of the resulting complexes. Together, these results reveal the combinatorial and contextual logic of BMP signaling and provide a framework for understanding other pathways that similarly integrate multi-ligand inputs with promiscuous protein-protein interactions. BMPs assemble heterotetramers of type I and type II receptors that phosphorylate SMAD1/5/8, which in turn translocates to the nucleus to bind DNA as part of larger transcriptional complexes (Alarcón et al., 2009Alarcón C. Zaromytidou A.-I. Xi Q. Gao S. Yu J. Fujisawa S. Barlas A. Miller A.N. Manova-Todorova K. Macias M.J. et al.Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways.Cell. 2009; 139: 757-769https://doi.org/10.1016/j.cell.2009.09.035Abstract Full Text Full Text PDF PubMed Scopus (534) Google Scholar; Chen et al., 1997Chen X. Weisberg E. Fridmacher V. Watanabe M. Naco G. Whitman M. Smad4 and FAST-1 in the assembly of activin-responsive factor.Nature. 1997; 389: 85-89https://doi.org/10.1038/38008Crossref PubMed Scopus (487) Google Scholar; Hata et al., 2000Hata A. Seoane J. Lagna G. Montalvo E. Hemmati-Brivanlou A. Massagué J. OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways.Cell. 2000; 100: 229-240https://doi.org/10.1016/s0092-8674(00)81561-5Abstract Full Text Full Text PDF PubMed Google Scholar; Ross and Hill, 2008Ross S. Hill C.S. How the Smads regulate transcription.Int. J. Biochem. Cell Biol. 2008; 40: 383-408https://doi.org/10.1016/j.biocel.2007.09.006Crossref PubMed Scopus (297) Google Scholar). Here, we quantify the effects of BMP combinations on the activation of this canonical SMAD1/5/8-dependent transcriptional response, which play pivotal roles across a wide range of developmental processes (Hegarty et al., 2013Hegarty S.V. O’Keeffe G.W. Sullivan A.M. BMP-Smad 1/5/8 signalling in the development of the nervous system.Prog. Neurobiol. 2013; 109: 28-41https://doi.org/10.1016/j.pneurobio.2013.07.002Crossref PubMed Scopus (98) Google Scholar; Lowery and de Caestecker, 2010Lowery J.W. de Caestecker M.P. BMP signaling in vascular development and disease.Cytokine Growth Factor Rev. 2010; 21: 287-298https://doi.org/10.1016/j.cytogfr.2010.06.001Crossref PubMed Scopus (107) Google Scholar; Salazar et al., 2016Salazar V.S. Gamer L.W. Rosen V. BMP signalling in skeletal development, disease and repair.Nat. Rev. Endocrinol. 2016; 12: 203-221https://doi.org/10.1038/nrendo.2016.12Crossref PubMed Scopus (396) Google Scholar). Non-canonical BMP responses (Blitz and Cho, 2009Blitz I.L. Cho K.W.Y. Finding partners: how BMPs select their targets.Dev. Dyn. 2009; 238: 1321-1331https://doi.org/10.1002/dvdy.21984Crossref PubMed Scopus (38) Google Scholar; Gunnell et al., 2010Gunnell L.M. Jonason J.H. Loiselle A.E. Kohn A. Schwarz E.M. Hilton M.J. O’Keefe R.J. TAK1 regulates cartilage and joint development via the MAPK and BMP signaling pathways.J. Bone Miner. Res. 2010; 25: 1784-1797https://doi.org/10.1002/jbmr.79Crossref PubMed Scopus (61) Google Scholar; Saxena et al., 2018Saxena M. Agnihotri N. Sen J. Perturbation of canonical and non-canonical BMP signaling affects migration, polarity and dendritogenesis of mouse cortical neurons.Development. 2018; 145 (dev147157)https://doi.org/10.1242/dev.147157Crossref PubMed Scopus (11) Google Scholar) and the parallel SMAD2/3-dependent TGF-β pathway (Holtzhausen et al., 2014Holtzhausen A. Golzio C. How T. Lee Y.H. Schiemann W.P. Katsanis N. Blobe G.C. Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development.FASEB J. 2014; 28: 1248-1267https://doi.org/10.1096/fj.13-239178Crossref PubMed Scopus (67) Google Scholar) could also exhibit combinatorial dependence on BMP ligands but are not investigated here. To read out SMAD1/5/8 transcriptional activity, we designed a fluorescent reporter containing a fusion histone 2B (H2B)-mCitrine protein controlled by a synthetic SMAD1/5/8-activated BMP responsive element (BRE) (Korchynskyi and ten Dijke, 2002Korchynskyi O. ten Dijke P. Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter.J. Biol. Chem. 2002; 277: 4883-4891https://doi.org/10.1074/jbc.M111023200Abstract Full Text Full Text PDF PubMed Scopus (686) Google Scholar); note that for simplicity, mCitrine levels are reported as yellow fluorescent protein (YFP) levels throughout the remainder of the text. The BRE is based on the wild-type Id1 promoter, which responds to BMP but not TGF-β, depends on the activity of receptors considered specific to BMP (ACVR1, BMPR1A, BMPR1B) but not those specific to TGF-β (ACVR1B, TGFβR1), and exhibits increased responsiveness following the overexpression of BMP-specific SMAD1 and SMAD5 (Korchynskyi and ten Dijke, 2002Korchynskyi O. ten Dijke P. Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter.J. Biol. Chem. 2002; 277: 4883-4891https://doi.org/10.1074/jbc.M111023200Abstract Full Text Full Text PDF PubMed Scopus (686) Google Scholar). BMP ligand addition produced similar fold increases in both YFP expression from the BRE promoter and phospho-SMAD1/5/8 20 min after ligand stimulation (Antebi et al., 2017Antebi Y.E. Linton J.M. Klumpe H. Bintu B. Gong M. Su C. McCardell R. Elowitz M.B. Combinatorial signal perception in the BMP pathway.Cell. 2017; 170: 1184-1196.e24https://doi.org/10.1016/j.cell.2017.08.015Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Thus, the BRE reporter captures SMAD1/5/8-dependent pathway activation and allows analysis of the cell context-dependent effects that arise downstream of SMAD activation but upstream of gene regulation effects, such as variations in chromatin state and expression of transcriptional co-factors (Massagué, 2012Massagué J. TGFβ signalling in context.Nat. Rev. Mol. Cell Biol. 2012; 13: 616-630https://doi.org/10.1038/nrm3434Crossref PubMed Scopus (1982) Google Scholar). As a base cell line, we selected NAMRU mouse mammary gland (NMuMG) epithelial cells (Figure S1A), which can respond to BMP signals without differentiating (Piek et al., 1999Piek E. Moustakas A. Kurisaki A. Heldin C.H. ten Dijke P. TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells.J. Cell Sci. 1999; 112: 4557-4568https://www.ncbi.nlm.nih.gov/pubmed/10574705Crossref PubMed Google Scholar), and express five of the seven BMP receptors: ACVR1, ACVR2A, ACVR2B, BMPR1A, and BMPR2 (Antebi et al., 2017Antebi Y.E. Linton J.M. Klumpe H. Bintu B. Gong M. Su C. McCardell R. Elowitz M.B. Combinatorial signal perception in the BMP pathway.Cell. 2017; 170: 1184-1196.e24https://doi.org/10.1016/j.cell.2017.08.015Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). NMuMG cells stably expressing the BRE reporter exhibited unimodal distributions of YFP fluorescence levels that responded in a dose-dependent manner to varying concentrations of BMP ligands (Figure S1B), allowing quantitative readout of pathway activity in response to ligands (Figure S1C). We identified ten homodimeric BMP ligands that play pivotal roles in development and activate SMAD1/5/8; these include Growth Differentiation Factors 5, 6, and 7 (GDF5, GDF6, and GDF7), which, despite the difference of naming convention, activate the same SMADs as the included BMPs (Hinck et al., 2016Hinck A.P. Mueller T.D. Springer T.A. Structural biology and evolution of the TGF-β family.Cold Spring Harbor Perspect. Biol. 2016; 8: a022103https://doi.org/10.1101/cshperspect.a022103Crossref PubMed Scopus (151) Google Scholar; Weiss and Attisano, 2013Weiss A. Attisano L. The TGFbeta superfamily signaling pathway.Wiley Interdiscip. Rev. Dev. Biol. 2013; 2: 47-63https://doi.org/10.1002/wdev.86Crossref PubMed Scopus (346) Google Scholar; Figure 1A). This core set omits BMP heterodimers, which have been shown to produce higher levels of pathway activation per unit mass than homodimers (Aono et al., 1995Aono A. Hazama M. Notoya K. Taketomi S. Yamasaki H. Tsukuda R. Sasaki S. Fujisawa Y. Potent ectopic bone-inducing activity of bone morphogenetic protein-4/7 heterodimer.Biochem. Biophys. Res. Commun. 1995; 210: 670-677https://doi.org/10.1006/bbrc.1995.1712Crossref PubMed Scopus (218) Google Scholar; Israel et al., 1996Israel D.I. Nove J. Kerns K.M. Kaufman R.J. Rosen V. Cox K.A. Wozney J.M. Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo.Growth Factors. 1996; 13: 291-300https://doi.org/10.3109/08977199609003229Crossref PubMed Scopus (287) Google Scholar; Miao et al., 2018Miao C. Qin D. Cao P. Lu P. Xia Y. Li M. Sun M. Zhang W. Yang F. Zhang Y. et al.BMP2/7 heterodimer enhances osteogenic differentiation of rat BMSCs via ERK signaling compared with respective homodimers.J. Cell. Biochem. 2018; https://doi.org/10.1002/jcb.28162Crossref Scopus (9) Google Scholar; Morimoto et al., 2015Morimoto T. Kaito T. Matsuo Y. Sugiura T. Kashii M. Makino T. Iwasaki M. Yoshikawa H. The bone morphogenetic protein-2/7 heterodimer is a stronger inducer of bone regeneration than the individual homodimers in a rat spinal fusion model.Spine J. 2015; 15: 1379-1390https://doi.org/10.1016/j.spinee.2015.02.034Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar; Sun et al., 2012Sun P. Wang J. Zheng Y. Fan Y. Gu Z. BMP2/7 heterodimer is a stronger inducer of bone regeneration in peri-implant bone defects model than BMP2 or BMP7 homodimer.Dent. Mater. J. 2012; 31: 239-248https://doi.org/10.4012/dmj.2011-191Crossref PubMed Scopus (43) Google Scholar; Suzuki et al., 1997Suzuki A. Kaneko E. Maeda J. Ueno N. Mesoderm induction by BMP-4 and -7 heterodimers.Biochem. Biophys. Res. Commun. 1997; 232: 153-156https://doi.org/10.1006/bbrc.1997.6219Crossref PubMed Scopus (127) Google Scholar; Valera et al., 2010Valera E. Isaacs M.J. Kawakami Y. Izpisúa Belmonte J.C. Choe S. BMP-2/6 heterodimer is more effective than BMP-2 or BMP-6 homodimers as inductor of differentiation of human embryonic stem cells.PLoS One. 2010; 5: e11167https://doi.org/10.1371/journal.pone.0011167Crossref PubMed Scopus (68) Google Scholar) and whose physiological relevance is increasingly recognized (Butler and Dodd, 2003Butler S.J. Dodd J. A role for BMP heterodimers in roof plate-mediated repulsion of commissural axons.Neuron. 2003; 38: 389-401https://doi.org/10.1016/S0896-6273(03)00254-XAbstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar; Tajer et al., 2021Tajer B. Dutko J.A. Litt

First predicted cosmic ray spectra, primary-to-secondary ratios, and ionization rates from MHD galaxy formation simulations

Abstract: ABSTRACT We present the first simulations evolving resolved spectra of cosmic rays (CRs) from MeV–TeV energies (including electrons, positrons, (anti)protons, and heavier nuclei), in live kinetic-magnetohydrodynamics galaxy simulations with star formation and feedback. We utilize new numerical methods including terms often neglected in historical models, comparing Milky Way analogues with phenomenological scattering coefficients ν to Solar-neighbourhood [Local interstellar medium (LISM)] observations (spectra, B/C, e+/e−, $\mathrm{\bar{p}}/\mathrm{p}$, 10Be/9Be, ionization, and γ-rays). We show it is possible to reproduce observations with simple single-power-law injection and scattering coefficients (scaling with rigidity R), similar to previous (non-dynamical) calculations. We also find: (1) The circumgalactic medium in realistic galaxies necessarily imposes an $\sim 10\,$ kpc CR scattering halo, influencing the required ν(R). (2) Increasing the normalization of ν(R) re-normalizes CR secondary spectra but also changes primary spectral slopes, owing to source distribution and loss effects. (3) Diffusive/turbulent reacceleration is unimportant and generally sub-dominant to gyroresonant/streaming losses, which are sub-dominant to adiabatic/convective terms dominated by $\sim 0.1-1\,$ kpc turbulent/fountain motions. (4) CR spectra vary considerably across galaxies; certain features can arise from local structure rather than transport physics. (5) Systematic variation in CR ionization rates between LISM and molecular clouds (or Galactic position) arises naturally without invoking alternative sources. (6) Abundances of CNO nuclei require most CR acceleration occurs around when reverse shocks form in SNe, not in OB wind bubbles or later Sedov–Taylor stages of SNe remnants.

Pembrolizumab versus chemotherapy for patients with esophageal squamous cell carcinoma enrolled in the randomized KEYNOTE-181 trial in Asia

Abstract: In the randomized phase III KEYNOTE-181 study, pembrolizumab prolonged overall survival (OS) compared with chemotherapy as second-line therapy in patients with advanced esophageal cancer and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥10. We report a post hoc subgroup analysis of patients with esophageal squamous cell carcinoma (ESCC) enrolled in KEYNOTE-181 in Asia, including patients from the KEYNOTE-181 China extension study.Three hundred and forty Asian patients with advanced/metastatic ESCC were enrolled in KEYNOTE-181, including the China cohort. Patients were randomly assigned 1 : 1 to receive pembrolizumab 200 mg every 3 weeks for ≤2 years or investigator's choice of paclitaxel, docetaxel, or irinotecan. OS, progression-free survival, response, and safety were analyzed without formal comparisons. OS was evaluated based on PD-L1 CPS expression level.In Asian patients with ESCC, median OS was 10.0 months with pembrolizumab and 6.5 months with chemotherapy [hazard ratio (HR), 0.63; 95% CI 0.50-0.80; nominal P < 0.0001]. Median progression-free survival was 2.3 months with pembrolizumab and 3.1 months with chemotherapy (HR, 0.79; 95% CI 0.63-0.99; nominal P = 0.020). Objective response rate was 17.1% with pembrolizumab and 7.1% with chemotherapy; median duration of response was 10.5 months and 7.7 months, respectively. In patients with PD-L1 CPS <1 tumors (pembrolizumab versus chemotherapy), the HR was 0.99 (95% CI 0.56-1.72); the HR (95% CI) for death was better for patients with PD-L1 CPS cut-offs >1 [CPS ≥1, 0.57 (0.44-0.75); CPS ≥5, 0.56 (0.41-0.76); CPS ≥10, 0.53 (0.37-0.75)]. Treatment-related adverse events were reported in 71.8% of patients in the pembrolizumab group and 89.8% in the chemotherapy group; grade 3-5 events were reported in 20.0% and 44.6%, respectively.Pembrolizumab monotherapy demonstrated promising efficacy in Asian patients with ESCC, with fewer treatment-related adverse events than chemotherapy. PD-L1 CPS ≥1 is an appropriate cut-off and a predictive marker of pembrolizumab efficacy in Asian patients with ESCC.

Multi-Rate Control Design Under Input Constraints via Fixed-Time Barrier Functions

Abstract: In this letter, we introduce the notion of periodic safety, which requires that the system trajectories periodically visit a subset of a forward-invariant safe set, and utilize it in a multi-rate framework where a high-level planner generates a reference trajectory that is tracked by a low-level controller under input constraints. We introduce the notion of fixed-time barrier functions which is leveraged by the proposed low-level controller in a quadratic programming framework. Then, we design a model predictive control policy for high-level planning with a bound on the rate of change for the reference trajectory to guarantee that periodic safety is achieved. We demonstrate the effectiveness of the proposed strategy on a simulation example, where the proposed fixed-time stabilizing low-level controller shows successful satisfaction of control objectives, whereas an exponentially stabilizing low-level controller fails.

STING agonist cGAMP enhances anti-tumor activity of CAR-NK cells against pancreatic cancer

Abstract: Activation of the stimulator of interferon gene (STING)-mediated innate immune response has been suggested as a promising therapeutic strategy for cancers. However, the effects of STING agonist on natural killer (NK) cell-mediated anti-tumor responses in pancreatic cancer remains unknown. Herein, we evaluated the effects of a classical STING agonist cyclic GMP-AMP (cGAMP) on NK cells in pancreatic cancer. We found that cGAMP could directly activate NK cells and enhance the sensitivity of pancreatic cancer cells to NK cell cytotoxicity, suggesting that cGAMP may become a potential adjuvant for NK cell therapy. In addition, combination of CAR-NK-92 cells targeting mesothelin and cGAMP displayed greater antitumor efficacy by inhibiting tumor growth and prolonging survival of the mouse model of pancreatic cancer. These results suggest that the combination of a STING agonist and NK cells may become a novel immunotherapy strategy for pancreatic cancer.

Transfer learning-based thermal error prediction and control with deep residual LSTM network

Abstract: The thermal error is a dominant factor that seriously hinders the high-accuracy machining of complex parts. The weak robustness and low predictive accuracy have always been barriers to the wide use of data-based models. To improve the robustness, the transfer learning-based error control method is proposed in this study. The error mechanism modeling is conducted to demonstrate the memory behavior of thermal errors, and the applicability of a long short-term memory network (LSTMN) for the error prediction is proven. Then an improved least mean square (ILMS) is proposed to filter the high-frequency noises and remove singular values. A pre-activated residual block is designed, and is embedded into the deep residual LSTMN (DRLSTMN). The differential spotted hyenas optimization algorithm (DSHOA) is proposed based on the chaos initialization strategy, differential mutation operator, and nonlinear control factor to optimize the hyper-parameters of DRLSTMN. Then the ILMS-DSHOA-DRLSTMN error prediction model is proposed for machine tool #1. The transfer learning model is established for machine tool #2 based on ILMS-DSHOA-DRLSTMN to enhance the robustness. The predictive abilities of the transfer learning models of ILMS-DSHOA-DRLSTMN, ILMS-DRLSTMN, ILMS-DSHOA-LSTMN, ILMS-back propagation network (ILMS-BP), ILMS-multiple linear regression analysis (ILMS-MLRA), ILMS-least squared support vector machine (ILMS-LSSVM), ILMS-CNNs-LSTM (ILMS-CL), and ILMS-deep calibration (ILMS-DC) are 98.37%, 97.95%, 97.60%, 94.51%, 95.41%, 96.02%, 96.43%, and 96.06%, respectively. Finally, the actual machining experiments were performed. When the thermal error is controlled with the transfer learning model, the fluctuation ranges for the geometric errors for D1 and D2 are [−4μm, 4μm] and [−3μm, 3μm], respectively.