End State Research Articles

Bioengineered Extracellular Vesicles Delivering siMDM2 Sensitize Oxaliplatin Therapy Efficacy in Colorectal Cancer.

Oxaliplatin (OXA) is the first-line drug for the treatment of colorectal cancer (CRC), and susceptibility to drug resistance affects patient prognosis. However, the exact underlying mechanisms remain unclear. Platinum-acquired resistance in CRC is a continuous transition process; though, current research has mainly focused on the end state of drug resistance, and the early events of drug resistance have been ignored. In this study, single-cell transcriptome sequencing is combined with a dynamic network biomarker (DNB), and found that the functional inhibition of the mitochondrial electron transport chain complex I occur early in the development of attained resistance to OXA in CRC cells, as evidenced by a decrease in the levels of subunit proteins, primarily NDUFB8. Specifically, the mouse double minute 2 homologue (MDM2) mediates the ubiquitination and degradation of NDUFB8, reducing intracellular reactive oxygen species (ROS) generation under chemotherapeutic stress, consequently contributing to drug resistance. Based on this, the study constructs engineered extracellular vesicles carrying siMDM2 by electroporation and validates the application of EV-siMDM2 to improve the efficacy of OXA-based chemotherapy by inhibiting the MDM2/NDUFB8/ROS signaling axis in patient-derived xenograft (PDX) and hepatic and pulmonary metastasis mouse models, thus providing new ideas and an experimental basis for the platinum-resistant treatment of CRC.

Data-Driven Clustering Analysis for Representative Electric Vehicle Charging Profile in South Korea.

As the penetration of electric vehicles (EVs) increases, an understanding of EV operation characteristics becomes crucial in various aspects, e.g., grid stability and battery degradation. This can be achieved through analyzing large amounts of EV operation data; however, the variability in EV data according to the user complicates unified data analysis and identification of representative patterns. In this research, a framework that captures EV charging characteristics in terms of charge-discharge area is proposed using actual field data. In order to illustrate EV operation characteristics in a unified format, an individual EV operation profile is modeled by the probability distribution of the charging start and end states of charge (SoCs).Then, hierarchical clustering analysis is employed to derive representative charging profiles. Using large amounts of real-world, vehicle-specific EV data in South Korea, the analysis results reveal that EV charging characteristics in terms of the battery charge-discharge area can be summarized into seven representative profiles.

Optical control of topological end states via soliton formation in a 1D lattice

Abstract Discrete spatial solitons are self-consistent solutions of the discrete nonlinear Schrödinger equation that maintain their shape during propagation. Here we show, using a pump-probe technique, that soliton formation can be used to optically induce and control a linear topological end state in the bulk of a Su–Schrieffer–Heeger lattice, using evanescently-coupled waveguide arrays. Specifically, we observe an abrupt nonlinearly-induced transition above a certain power threshold due to an inversion symmetry-breaking nonlinear bifurcation. Our results demonstrate all-optical active control of topological states.

On the Modelling of Asymptotic Wavefronts in Long Ducts with Chambers

A novel method of determining the possible shapes of pressure wavefronts in ducts after they have travelled sufficient distances to evolve to asymptotic states is introduced. Although it is possible in principle to achieve the same outcome by simulating complete flow histories from the time of the creation of the wavefronts, this can be impracticable. It is especially unsuitable to use such methods when extremely small grid lengths are needed to represent the final outcome adequately. The new method does not simulate the propagation phase at all. Instead, it explores what final end states are possible, but gives no information about the initiating disturbance or the wavefront evolution towards the assessed asymptotic state. Accordingly, the two methods do not overlap, but instead are complementary to each other. A typical case in which the new capability has high potential is described and used to illustrate the purpose and use of the methodology. However, the primary focus is on the presentation and assessment of the method, not on any particular phenomenon. It is shown that the required computational resources are far smaller than those needed for conventional unsteady flow simulations of propagating wavefronts. The potential numerical limitations of the method are highlighted and, with one exception, are shown to be either of no consequence or easily reduced to acceptable levels. Special attention is paid to the one exception because it cannot be proven to be unimportant and, indeed, it would be unsafe to use it in general analyses of wave propagation. However, strong evidence is presented of its acceptability for the study of asymptotic wavefronts.

Generating Protein Structures for Pathway Discovery Using Deep Learning.

Resolving the intricate details of biological phenomena at the molecular level is fundamentally limited by both length- and time scales that can be probed experimentally. Molecular dynamics (MD) simulations at various scales are powerful tools frequently employed to offer valuable biological insights beyond experimental resolution. However, while it is relatively simple to observe long-lived, stable configurations of, for example, proteins, at the required spatial resolution, simulating the more interesting rare transitions between such states often takes orders of magnitude longer than what is feasible even on the largest supercomputers available today. One common aspect of this challenge is pathway discovery, where the start and end states of a scientific phenomenon are known or can be approximated, but the mechanistic details in between are unknown. Here, we propose a representation-learning-based solution that uses interpolation and extrapolation in an abstract representation space to synthesize potential transition states, which are automatically validated using MD simulations. The new simulations of the synthesized transition states are subsequently incorporated into the representation learning, leading to an iterative framework for targeted path sampling. Our approach is demonstrated by recovering the transition of a RAS-RAF protein domain (CRD) from membrane-free to interacting with the membrane using coarse-grain MD simulations.

Conformal symmetries in Vaidya geometry and collapse

In this paper, we perform a comprehensive analysis of conformal symmetries in the generalized Vaidya spacetime and establish several new results. First, a proper conformal Killing vector is shown to exist in the radial direction and interestingly the generalized Vaidya spacetimes with this symmetry are shown to be the subclass of those, which are embeddable in five-dimensional Euclidean space. The general form of the mass function that enables the proper and planar conformal symmetry in the [Formula: see text]–[Formula: see text] plane is also determined. This treatment also includes earlier results. We also consider the gravitational collapse of these spacetimes with proper planar conformal symmetry in the context of cosmic censorship conjecture. We obtain an interesting and novel result that censorship is always obeyed for these spacetimes, and no locally naked central singularity forms as the end state of the continual collapse.

Unpacking the learning dynamics of a military task force in Afghanistan from a project-based organising perspective

ABSTRACT From a theoretical perspective of project-based organising, this study analyses how a deployed military task force heuristically learns. Empirically, learning within Task Force Uruzgan (TFU) in southern Afghanistan, is scrutinised. This contribution of the Netherlands armed forces to NATO’s International Security Assistance Force (ISAF) lasted for four years and saw successive rotations of task forces simultaneously fighting an insurgency and trying to stabilise a part of Afghanistan through reconstruction and development projects. Above all, the study has found that task ambiguity can make it challenging for a task force deployed to deal with varying contingencies at the same time. Two effects are noteworthy. First, learning can become compartmentalised, with different organisational elements following their own learning trajectories. Second, learning can also become short-term focused, responding to the most imminent and familiar threat. Combined, both learning impulses affect organisational coherence in meeting the overarching mission end state.

Landscape of epithelial cell subpopulations in the human esophageal squamous cell carcinoma microenvironment

AimsWe sought to reveal the landscape of epithelial cell subpopulations in the human esophageal squamous cell carcinoma microenvironment and investigate their parts on esophageal squamous carcinoma (ESCC) development. BackgroundEpithelial cells play an important role in the occurrence and development of ESCC through multiple mechanisms. While the landscape of epithelial cell subpopulations in ESCC, remains unclear. ObjectiveExploring the role of epithelial cell subpopulations in ESCC progression. MethodsSeurat R package was used for single-cell RNA sequencing (scRNA-seq) data filtering, dimensionality reduction, clustering and differentially expressed genes analysis. Cellmarker database was adopted for cell cluster annotation. Functional enrichment analysis was carried out by Gene Ontology (GO) analysis. InferCNV package was conducted for copy number variation (CNV) of epithelial cell subpopulations in all chromosomal regions. Pseudotime trajectory analysis was implemented for exploring differentiation trajectory of epithelial cells subgroups during the cancer progression. CellChat analysis was used for probing the interactions between epithelial cells and NK/T cells. cellular experiments were performed using Quantitative Real-Time Polymerase Chain Reaction (RT-qPCR), Wound-Healing Assay and transwell. Results11 major cell subpopulations were identified in ESCC and adjunct tissues. Further reclassification of epithelial cells uncovered 4 subpopulations. Enrichment analysis revealed that highly expressed genes in 4 epithelial cell subpopulations were related to cell proliferation, immune response and angiogenesis. CNV analysis found that UBD + epithelial cells and GAS2L3+ epithelial cells had a higher proportion of CNV. Cell differentiation trajectories disclosed that KRT6C+ and GSTA1+ epithelial cells were in an intermediate state of differentiation, while UBD+ and GAS2L3+ epithelial cells are in an end state of differentiation during ESCC progression. Finally, we found that four epithelial cell subpopulations all inhibited NK/T cells through NECTIN2-TIGIT and CLEC2B-KLRB1. Low ATF3 and DDIT3 mRNA expression inhibited ESCC cell migration and invasion. ConclusionHere, we obtained a through epithelial cell atlas of ESCC at single-cell resolution, explored the role of epithelial cell in ESCC progression, and unveiled immunosuppressive signals to NK/T cells in promoting ESCC. Our findings expand the comprehension of epithelial cells and offer a theoretical guidance for future anti-epithelial cell treatment of ESCC.

The (absence of the) presence-absence distinction in motivation science.

A focal stimulus (object, end state, outcome, event, experience, characteristic, possibility, etc.) may represent a presence, an occurrence, or something, or it may represent an absence, a nonoccurrence, or nothing. This presence-absence distinction has received extensive and explicit attention in cognitive psychology (it is the central figure), but it has received minimal and primarily implicit attention in motivation science (it is the ground, not the figure). Herein, we explicitly place the presence-absence distinction in the role of figure in a motivational account of behavior, and we do so in the context of the foundational approach-avoidance motivation distinction. We review pertinent literature in cognitive psychology and motivation science, and we provide a model integrating the approach-avoidance and the presence-absence distinctions, along with numerous examples, illustrations, and observations. We believe that attending to the presence-absence distinction in motivation science holds great promise for theory, research, and application, and we encourage researchers to attend to this distinction moving forward. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Topological boundary states in engineered quantum-dot molecules on the InAs(111)A surface: Odd numbers of quantum dots

Atom manipulation by scanning tunneling microscopy was used to construct quantum dots on the InAs(111)A surface. Each dot comprised six ionized indium adatoms. The positively charged adatoms create a confining potential acting on surface-state electrons, leading to the emergence of a bound state associated with the dot. By lining up the dots into N-dot chains with alternating tunnel coupling between them, quantum-dot molecules were constructed that revealed electronic boundary states as predicted by the Su-Schrieffer-Heeger (SSH) model of one-dimensional topological phases. Dot chains with odd N were constructed such that they host a single end or domain-wall state, allowing one to probe the localization of the boundary state on a given sublattice by scanning tunneling spectroscopy. We found probability density also on the forbidden sublattice together with an asymmetric energy spectrum of the chain-confined states. This deviation from the SSH model arises because the dots are charged and create a variation in on-site potential along the chain—which does not remove the boundary states but shifts their energy away from the midgap position. Our results demonstrate that topological boundary states can be created in quantum-dot arrays engineered with atomic-scale precision. Published by the American Physical Society 2024

Dynamics of dissipative gravitational collapse in the Morris–Thorne wormhole metric: One scenario - several outcomes

We consider the dynamical Morris–Thorne metric with radiating heat flow. By matching the interior Morris–Thorne metric with an exterior Vaidya metric we trace out the collapse solutions for the corresponding spherically symmetric inhomogeneous distribution of matter. The solutions obtained are broadly of four different types, giving different end state dynamics. Corresponding to three of the solutions we elaborate the collapsing dynamics of the Morris–Thorne type evolving wormhole. We show that for all those cases where collapse upto zero proper volume is obtained in finite time, the ensuing singularity is always a black hole type. However our solutions can also show other end states, like oscillating wormhole-black hole pair or infinite time contracting universe or a conformal past matter dominated universe. In all the cases we have worked out the background dynamics and physics of the solution. All our solutions are illustrated with appropriate graphical descriptions.

Mapping the Slow Stabilization of End States with Length along a Laterally Extended Graphene Nanoribbon.

With a lateral bisnaphtho-extended chemical structure, finite 7-13 carbon atom wide armchair graphene nanoribbons (7-13-aGNRs) were on-surface synthesized. For all lengths up to N = 7 monomer units, low-temperature ultrahigh vacuum scanning tunneling spectroscopy and spatial dI/dV maps were recorded at each captured tunneling resonance. The degeneracy of the two central electronic end states (ESs) occurs in a slowly decaying regime with N converging toward zero for N = 6 long 7-13-aGNR (12 bonded anthracenes), while it is N = 2 (4 bonded anthracenes) for seven carbon atoms wide armchair GNRs (7-aGNRs). The two end dI/dV conductance maxima of ESs are also shifted away from strictly two ends of the 7-13-aGNR compared to the 7-aGNR. Using the quantum topology graph filiation between finite length polyacetylene and 7-13-aGNRs wires, we show that this slow decay of 7-13-aGNR ESs is coming from the property of the topological Hückel band matrix that expels the ESs into its eigenvalue spectrum gaps to keep harmony in the core spectrum.

Risk of BSE transmission when fishmeal derived from fish fed bovine spray-dried red blood cells is included in calf milk replacers

The use of residual streams from agricultural production and food consumption containing animal proteins entails the risk of disease transmission as illustrated by the epidemics of bovine spongiform encephalopathy (BSE) and African swine fever. To combat this risk, the use of animal proteins in livestock feed was banned in the European Union, resulting in a drain of valuable proteins from the agricultural system. With an increasing call for a circular food system, the use of residual streams as a feed ingredient needs to be reconsidered with the associated disease risks being assessed and mitigated where needed. In this study, we assessed the BSE risk of bovine spray-dried red blood cells (SDRBC) as an ingredient of aquafeed. Fish fed with bovine SDRBC could indirectly result in exposure of ruminants to BSE infectivity because one of the exemptions of the feed ban is the use of fishmeal as an ingredient in calf milk replacers. A quantitative risk model was built to evaluate the BSE infectivity present in blood sourced from a slaughtered BSE-infected cow and the reduction of infectivity due to processing steps along the production chain. The end point of the model was the BSE infectivity, expressed in cattle oral ID50 (CoID50), reaching calves fed calf milk replacer containing fishmeal, and the corresponding probability that this will result in at least one new BSE infection.The expected BSE infectivity in blood from a BSE-infected cow at the clinical end state of infection is 0.75 CoID50 (median value). Infectivity in blood mainly results from cross-contamination with brain tissue during stunning at the slaughterhouse. The initial infectivity is reduced along the pathway from slaughtered cow to calf milk replacer, with the highest reduction achieved by clearance of infectivity by fish fed bovine SDRBC as an ingredient of aquafeed, although this parameter has high uncertainty. The final infectivity reaching calves via inclusion of fishmeal in calf milk replacer is estimated to be very low (median value: 1.1 × 10−5 CoID50). Assuming an exponential dose-response model, this corresponds with an expected probability that < 10 out of a million slaughtered BSE-infected cows will result in new BSE infections, which is far below the threshold value of 1 for the basic reproduction number (R0) to initiate a new epidemic. We thus conclude that it is very unlikely that the use of bovine SDRBC as ingredient of aquafeed will result in a new BSE epidemic in cattle. What-if analysis indicated that this conclusion is robust, despite high uncertainty for some input parameters.

Standardized Assessment of Gravity Settling Human Body Models for Virtual Testing.

The increased use of computational human models in evaluation of safety systems demands greater attention to selected methods in coupling the model to its seated environment. This study assessed the THUMS v4.0.1 in an upright driver posture and a reclined occupant posture. Each posture was gravity settled into an NCAC vehicle model to assess model quality and HBM to seat coupling. HBM to seat contact friction and seat stiffness were varied across a range of potential inputs to evaluate over a range of potential inputs. Gravity settling was also performed with and without constraints on the pelvis to move towards the target H-Point. These combinations resulted in 18 simulations per posture, run for 800 ms. In addition, 5 crash pulse simulations (51.5 km/h delta V) were run to assess the effect of settling time on driver kinematics. HBM mesh quality and HBM to seat coupling metrics were compared at kinetically identical time points during the simulation to an end state where kinetic energy was near zero. A gravity settling time of 350 ms was found to be optimal for the upright driver posture and 290 ms for the reclined occupant posture. This suggests that reclined passengers can be settled for less time than upright passengers, potentially due to the increased contact area. The pelvis constrained approach was recommended for the upright driver posture and was not recommended for the reclined occupant posture. The recommended times were sufficient to gravity settle both postures to match the quality metrics of the 800 ms gravity settled time. Driver kinematics were found to be vary with gravity settling time. Future work will include verifying that these recommendations hold for different HBMs and test modes.

Superradiance in the bulk protects quantum state evolution of rapidly rotating matter on the boundary

It has been argued that the rate at which the interior of an AdS black hole evolves is dual to the rate of evolution of the (quantum state of the) strongly coupled matter on the boundary which, according to holography, is dual to the black hole. However, we have shown elsewhere that it seems to be possible, by adjusting the specific angular momentum of an AdS5-Kerr black hole, to reduce this rate to (effectively) zero. We argue that this is unphysical, and that it is prevented by the intervention of a superradiant instability, which causes the black hole to shed angular momentum when the angular velocity exceeds a certain critical value. The precise way in which this works has recently been explained by the “grey galaxy” model of the end state, in which the angular momentum is transferred to a “galactic disc.” Thus, the black hole itself cannot sustain a specific angular momentum beyond a critical value: there is an effective upper bound. The holographic interpretation is that, beyond a certain limiting specific angular momentum, strongly coupled matter (corresponding to the black hole) will spontaneously shed angular momentum to some other, confined, form of matter (corresponding to the disc). This idea is supported by recent numerical work on ultra-vortical plasmas. Such an upper bound on specific angular momentum would prevent arbitrarily small rates of quantum state evolution on the boundary. We give a tentative discussion of the relevant observational data in the case of the vortical Quark-Gluon Plasma, and suggest a way in which such an upper bound might appear in future observations.

JWST COMPASS: A NIRSpec/G395H Transmission Spectrum of the Sub-Neptune TOI-836c

Planets between the sizes of Earth and Neptune are the most common in the Galaxy, bridging the gap between the terrestrial and giant planets in our solar system. Now that we are firmly in the era of JWST, we can begin to measure, in more detail, the atmospheres of these ubiquitous planets to better understand their evolutionary trajectories. The two planets in the TOI-836 system are ideal candidates for such a study, as they fall on either side of the radius valley, allowing for direct comparisons of the present-day atmospheres of planets that formed in the same environment but had different ultimate end states. We present results from the JWST NIRSpec G395H transit observation of the larger and outer of the planets in this system, TOI-836c (2.587 R ⊕, 9.6 M ⊕, T eq ∼ 665 K). While we measure average 30-pixel binned precisions of ∼24 ppm for NRS1 and ∼43 ppm for NRS2 per spectral bin, we do find residual correlated noise in the data, which we attempt to correct using the JWST Engineering Database. We find a featureless transmission spectrum for this sub-Neptune planet and are able to rule out atmospheric metallicities <175× solar in the absence of aerosols at ≲1 mbar. We leverage microphysical models to determine that aerosols at such low pressures are physically plausible. The results presented herein represent the first observation from the COMPASS (Compositions of Mini-Planet Atmospheres for Statistical Study) JWST program, which also includes TOI-836b and will ultimately compare the presence and compositions of atmospheres for 12 super-Earths/sub-Neptunes.

Quantum vortex stability in draining fluid flows

Quantum vortices with more than a single circulation quantum are usually unstable and decay into clusters of smaller vortices. One way to prevent the decay is to place the vortex at the center of a convergent (draining) fluid flow, which tends to force vortices together. It is found that while the primary splitting instability is suppressed in this way (and completely quenched for strong enough flows) a secondary instability can emerge in circular trapping geometries. This behavior is related to an instability of rotating black holes when superradiantly amplified waves are confined inside a reflective cavity. The end state of the secondary instability is dramatic, manifesting as a shock wave that propagates round the circular wall and nucleates many more vortices. Published by the American Physical Society 2024

Critical and near-critical relaxation of holographic superfluids

We investigate the relaxation of holographic superfluids after quenches, when the end state is either tuned to be exactly at the critical point, or very close to it. By solving the bulk equations of motion numerically, we demonstrate that in the former case the system exhibits a power law falloff, as well as an emergent discrete scale invariance. The latter case is in the regime dominated by critical slowing down, and we show that there is an intermediate time range before the onset of late-time exponential falloff, where the system behaves similarly to the critical point with its power law falloff. We further postulate a phenomenological Gross-Pitaevskii-like equation (corresponding to model F of Hohenberg and Halperin) that is able to make quantitative predictions for the behavior of the holographic superfluid after near-critical quenches into the superfluid and normal phase. Intriguingly, all parameters of our phenomenological equation, which describes the nonlinear time evolution, may be fixed with information from the static equilibrium solutions and linear response theory. Published by the American Physical Society 2024

Topologically Localized Vibronic Excitations in Second-Layer Graphene Nanoribbons.

It is of fundamental importance to characterize the intrinsic properties, like the topological end states, in the on-surface synthesized graphene nanoribbons (GNRs), but the strong electronic interaction with the metal substrate usually smears out their characteristic features. Here, we report our approach to investigate the vibronic excitations of the topological end states in self-decoupled second-layer GNRs, which are grown using an on-surface squeezing-induced spillover strategy. The vibronic progressions show highly spatially localized distributions at the second-layer GNR ends, which can be ascribed to the decoupling-extended lifetime of charging through resonant electron tunneling at the topological end states. In combination with theoretical calculations, we assign the vibronic progressions to specific vibrational modes that mediate the vibronic excitations. The spatial distribution of each resolved excitation shows evident characteristics beyond the conventional Franck-Condon picture. Our work by direct growth of second-layer GNRs provides an effective way to explore the interplay between the intrinsic electronic, vibrational, and topological properties.

Robust correlated magnetic moments in end-modified graphene nanoribbons

We conduct a theoretical examination of the electronic and magnetic characteristics of end-modified 7-atom wide armchair graphene nanoribbons (AGNRs). Our investigation is performed within the framework of a single-band Hubbard model, beyond a mean-field approximation. First, we carry out a comprehensive comparison of various approaches for accommodating di-hydrogenation configurations at the AGNR ends. We demonstrate that the application of an on-site potential to the modified carbon atom, coupled with the addition of an electron, replicates phenomena such as the experimentally observed reduction of the bulk-states (BS) gap. These results for the density of states (DOS) and electronic densities align closely with those obtained through a method explicitly designed to account for the orbital properties of hydrogen atoms. Furthermore, our study enables a clear differentiation between magnetic moments already described in a mean-field (MF) approach, which are spatially confined to the same sites as the topological end-states (ES), and correlation-induced magnetic moments, which exhibit localization along all edges of the AGNRs. Notably, we show the robustness of these correlation-induced magnetic moments relative to end modifications, within the scope of the method we employ.