Profound Dependence Research Articles

Assessment of the sustainability of online food delivery from the perspective of CO2 emissions and transport intensity: A case study in Jakarta

This study examines the impact of online food delivery on CO2 emissions and transport intensity in Jakarta, Indonesia, by integrating data from both delivery drivers and customers. A total of 235 delivery instances were analyzed to discern typical distances and patterns inherent in these services. Additionally, insights into the demand side were obtained through customer surveys, yielding 203 valid responses, that included waiting times, costs, and behaviors related to alternative meal acquisition methods. CO2 emissions generated by delivery processes were estimated, utilizing travel distances recorded by drivers. The traffic impact was assessed by calculating the road occupancy of motorcycles used for deliveries. Furthermore, the assessment of CO2 emissions and transport intensity considered hypothetical emission scenarios without such delivery services based on customer indications of their alternative means of meal acquisition. This analysis revealed that frequent short journeys by delivery motorcycles significantly contribute to urban traffic congestion and CO2 emissions, highlighting the environmental and traffic pressures resulting from the rise of food delivery services. Results from the customer survey revealed a profound dependence on these services, indicating that their availability prompts a significant number of additional trips, thereby exacerbating these impacts. The findings suggest recommendations for mitigating these adverse effects, including promoting the use of electric motorcycles for deliveries and managing demand by reassessing delivery fees to reflect the actual environmental costs.

Exploring Rhodospirillum rubrum response to high doses of carbon monoxide under light and dark conditions

Environmental concerns about residues and the traditional disposal methods are driving the search for more environmentally conscious processes, such as pyrolysis and gasification. Their main final product is synthesis gas (syngas) composed of CO, CO2, H2, and methane. Syngas can be converted into various products using CO-tolerant microorganisms. Among them, Rhodospirillum rubrum is highlighted for its biotechnological potential. However, the extent to which high doses of CO affect its physiology is still opaque. For this reason, we have studied R. rubrum behavior under high levels of this gas (up to 2.5 bar), revealing a profound dependence on the presence or absence of light. In darkness, the key variable affected was the lag phase, where the highest levels of CO retarded growth to more than 20 days. Under light, R. rubrum ability to convert CO into CO2 and H2 depended on the presence of an additional carbon source, such as acetate. In those conditions where CO was completely exhausted, CO2 fixation was unblocked, leading to a diauxic growth. To enhance R. rubrum tolerance to CO in darkness, a UV-accelerated adaptive laboratory evolution (UVa-ALE) trial was conducted to isolate clones with shorter lag phases, resulting in the isolation of clones 1.4-2B and 1.7-2A. The adaptation of 1.4-2B was mainly based on mutated enzymes with a metabolic function, while 1.7-3A was mostly affected at regulatory genes, including the anti-repressor PpaA/AerR. Despite these mutations having slight effects on biomass and pigment levels, they successfully provoked a significant reduction in the lag phase (−50%).Keypoints• CO affects principally R. rubrum lag phase (darkness) and growth rate (light)• CO is converted to CO2/H2during acetate uptake and inhibits CO2fixation (light)• UVa-ALE clones showed a 50% reduction in the lag phase (darkness)Graphical

Ultra-slow ammonia flame speeds — A microgravity study on radiation

Ammonia/air flames burn slowly and are consequently affected by buoyancy-, radiation-, and stretch-related uncertainties more than many conventional hydrocarbon fuels. In this work, unique buoyancy-free ammonia/air flame speed data were acquired and analyzed, specifically considering the impact of radiation. First, outwardly propagating ammonia/air flames near the propagation limits were accurately measured under microgravity using two simultaneous techniques. Flame radius evolution was captured by a high-speed Schlieren arrangement (optical method) in a near-isobaric regime. Accompanying, pressure rise was measured and subsequently used for flame speed extraction during near-isentropic gas compression. A profound nonlinear dependence of flame propagation speed on stretch was captured over the optical results in the observable range of the current setup, which illustrates the limitations of the optical method in comparison to the pressure-rise method. Radiation-corrected optical and pressure-rise results have shown good agreement along multiple isentropes, thereby cross-validating applied methodologies and highlighting very good consistency of the acquired data. Pressure-rise data analysis has shown sensitivity in the assessment of kinetic mechanisms to the radiation effect. In the absence of appropriate radiation correction for flame speed data, misinterpretations may arise regarding the accuracy of kinetic models, introducing challenges in the development of accurate kinetic models. The performance of the chemical kinetic models was quantified in a wide range of unburned gas temperatures (< 500K) and pressures (< 9.3bar) against distinctive experimental flame speed data with and without radiation correction acquired under microgravity indicating good performance of the Han et al. (2019) model.

PAX3-FOXO1 uses its activation domain to recruit CBP/P300 and shape RNA Pol2 cluster distribution

Activation of oncogenic gene expression from long-range enhancers is initiated by the assembly of DNA-binding transcription factors (TF), leading to recruitment of co-activators such as CBP/p300 to modify the local genomic context and facilitate RNA-Polymerase 2 (Pol2) binding. Yet, most TF-to-coactivator recruitment relationships remain unmapped. Here, studying the oncogenic fusion TF PAX3-FOXO1 (P3F) from alveolar rhabdomyosarcoma (aRMS), we show that a single cysteine in the activation domain (AD) of P3F is important for a small alpha helical coil that recruits CBP/p300 to chromatin. P3F driven transcription requires both this single cysteine and CBP/p300. Mutants of the cysteine reduce aRMS cell proliferation and induce cellular differentiation. Furthermore, we discover a profound dependence on CBP/p300 for clustering of Pol2 loops that connect P3F to its target genes. In the absence of CBP/p300, Pol2 long range enhancer loops collapse, Pol2 accumulates in CpG islands and fails to exit the gene body. These results reveal a potential novel axis for therapeutic interference with P3F in aRMS and clarify the molecular relationship of P3F and CBP/p300 in sustaining active Pol2 clusters essential for oncogenic transcription.

Large eddy simulation-bivariate sectional model for non-spherical TiO2 nanoparticle synthesis in flame

Numerical simulation of nanoparticle synthesis in flame necessitates a high level of fidelity for turbulent flame, as well as delivers more detail insight into the evolution of structure and size distribution of particles undergoing various dynamic events. In the present work, a new simulation approach coupling large-eddy simulation (LES) and bivariate sectional model is proposed to explore the synthesis of nanoparticles in turbulent flame. More specifically, the nonlinear LES-partially stirred reactor model (NLES-PaSR) is utilized to simulate the turbulent flame, wherein the gradient-type structural subgrid-scale (SGS) model for turbulent flow and partially stirred reactor (PaSR) model for turbulent combustion are considered. In addition, the volume-based bivariate sectional model is thoroughly coupled with the LES model for the first time to describe the spatiotemporally resolved formation and growth of nanoparticles using particle number concentration and surface area concentration as two sets of variables. Compared directly with the LES-monodisperse (LES-Mono) and LES-univariate sectional (LES-UniSe) models, the LES-bivariate sectional (LES-BiSe) model has significant advantages in its ability to analyze and predict the size, morphology, as well as polydispersed particle size distribution (PSD) evolution of nanoparticles at a moderate computational cost simultaneously. In the LES framework, the proposed model successfully simulates the spatiotemporally resolved formation and growth of non-spherical TiO2 nanoparticle in turbulent diffusion burner. The predicted results derived from the LES-BiSe model are in good agreement with the experimental measurements. Also, the aggregate and primary particle size distribution shows highly temporal fluctuation, which mainly results from the continuous variations of particle path induced by the unsteady turbulent combustion. Furthermore, the present work demonstrates the profound dependence of particle morphological on both spatiotemporal evolution and their intrinsic size distribution. In particular, the large aggregates in the higher sections are commonly found as irregular structure with fractal-like dimensions.

Illegal Crossings of the Soviet-Finnish Border by Children and Youngsters in the 1920s

The study of behavioral practices of children in borderlands intersects two pivotal historical-anthropological research domains: childhood history and border studies. This article delves into unattended border crossings by children in the Karelian region of the Russian-Finnish borderlands during the 1920s. We present the results from an analysis of the two source sets housed in the Republic of Karelia National Archives. These sources comprise formal documents: questionnaire forms completed by teenagers upon their return from Finland and records from interrogations conducted by children’s social security bodies and national security agencies. We identified the factors and circumstances surrounding the illegal movements of underage citizens across the Russian-Finnish borderlands. Our findings reveal that the majority of these young border trespassers were ethnic Karelian teenage boys from borderland villages. The reasons and motivations for crossing the border from Russia to Finland, and subsequently returning home, evolved over time. While personal survival was the primary motivation during the civil war, in more peaceful times, the prevalent drive to go to Finland was economic – to earn money to improve living conditions for both the individual and their parents, reflecting a family survival strategy. We also detail how authorities addressed these transgressions. We conclude that the behavioral practices of these children, in violating national borders, depict them as autonomous actors on one side, yet also highlight their profound dependence on the immediate environment, shaped by its unique political, social, and geographical nuances, on the other.

DIGITALIZATION OF HIGHER EDUCATION

For an extended period, the higher education community has been diligently endeavoring to implement technologically advanced and more efficacious methodologies. The aim is to enhance effectiveness and cultivate a generation of graduates equipped to navigate the evolving labor market dynamics and adapt to the influences of globalization. The outbreak of the Covid-19 pandemic significantly catalyzed the adoption of digital education, often referred to as "E-Learning," as a predominant mode of instruction across a majority of countries. This shift was necessitated by the imperative to adhere to social distancing measures and prevent the potential collapse of the educational infrastructure. In the wake of this transformative paradigm, educational institutions were compelled to engineer inventive management approaches to effectively traverse this altered landscape, marking the dawn of a new era. This era is characterized by a profound dependence on advanced technology and unfettered information accessibility as pivotal factors for sustaining and optimizing performance.This paper aims to explain the basic ideas behind managing higher education while exploring the existing research that supports these ideas. By breaking down the various aspects and tools involved, the goal is to shed light on the complex nature of managing higher education. This exploration eventually leads to an examination of how the digitalization of education impacts different functional areas of education management. Through this in-depth analysis, a clear connection emerges between the need for digitalization and the necessity to update management systems. This connection is crucial for not only achieving but also sustaining effective operation in this new era that combines technology and education.

An indirect method for measurement of rock dynamic tensile strength and fracture energy using blasting experiments

Many parameters in numerical simulation can be directly measured through experiments, yet specific parameters pose challenges for experimental testing. The quantification of dynamic tensile strength and fracture energy in rocks constitutes an indispensable requirement for accurately predicting crack initiation location and propagation velocity. It is imperative to acknowledge that these two parameters exhibit a profound dependence on the strain rate imposed on the rocks. Hence, it is essential to establish a reliable strategy for accurately measuring these parameters. In this paper, a novel blasting experimental measuring system was used to determine crucial dynamic fracture parameters. A single internal crack circular disc (SICCD) configuration was proposed and applied in the sandstone specimens testing. A series of numerical models were developed using a tensile crack softening failure criterion. The mechanical behavior and fracture mechanism of the rock under blasting were analyzed numerically. The relationships between dynamic tensile strength, fracture energy, crack initiation time, and propagation velocity have been thoroughly assessed. Through the utilization of statistical methods and the rapid drawing method, the dynamic tensile strength and fracture energy of rocks can be predicted with high precision by integrating experimental and numerical methods specifically designed. The combined approach enables a comprehensive understanding of the dynamic behavior of rock under extreme loading conditions. Furthermore, the validity of the predicted dynamic tensile strength can be rigorously verified through meticulous testing and evaluation procedures.

Control of the Electroporation Efficiency of Nanosecond Pulses by Swinging the Electric Field Vector Direction.

Reversing the pulse polarity, i.e., changing the electric field direction by 180°, inhibits electroporation and electrostimulation by nanosecond electric pulses (nsEPs). This feature, known as "bipolar cancellation," enables selective remote targeting with nsEPs and reduces the neuromuscular side effects of ablation therapies. We analyzed the biophysical mechanisms and measured how cancellation weakens and is replaced by facilitation when nsEPs are applied from different directions at angles from 0 to 180°. Monolayers of endothelial cells were electroporated by a train of five pulses (600 ns) or five paired pulses (600 + 600 ns) applied at 1 Hz or 833 kHz. Reversing the electric field in the pairs (180° direction change) caused 2-fold (1 Hz) or 20-fold (833 kHz) weaker electroporation than the train of single nsEPs. Reducing the angle between pulse directions in the pairs weakened cancellation and replaced it with facilitation at angles <160° (1 Hz) and <130° (833 kHz). Facilitation plateaued at about three-fold stronger electroporation compared to single pulses at 90-100° angle for both nsEP frequencies. The profound dependence of the efficiency on the angle enables novel protocols for highly selective focal electroporation at one electrode in a three-electrode array while avoiding effects at the other electrodes. Nanosecond-resolution imaging of cell membrane potential was used to link the selectivity to charging kinetics by co- and counter-directional nsEPs.

Theory of the collective behavior of two-dimensional periodic ensembles of dipole-coupled magnetic nanoparticles

The magnetic behavior of two-dimensional (2D) periodic ensembles of dipole-coupled nanoparticles (NPs) is investigated theoretically by considering all possible structural organizations in 2D Bravais lattices, namely, square, triangular, rectangular, rhombic, and oblique lattices. The different interaction-energy landscapes (ELs) are characterized by determining the local minima that define the stable and metastable magnetic configurations as well as the transition states connecting them. The topology of the resulting ergodic ensemble of stationary states is analyzed from both local and energy perspectives by calculating the corresponding kinetic networks and disconnectivity graphs. For all lattices, the magnetic orders of the ground-state and low-lying metastable configurations are identified, including the elementary relaxation processes between them. A remarkable profound dependence of the collective magnetic behavior on the structural arrangement of the NPs is revealed. Square and triangular nanostructures are extremely good structure seekers, showing starlike kinetic networks and disconnectivity graphs with palm-tree form. Their continuously degenerate ground states are throughout-reaching hubs connected to nearly all excited magnetic configurations over a single first-order saddle point. Rhombic ensembles have double-funnel ELs in which the time-inversion-related ground states play the role of hubs with exceedingly high connectivity densities. These systems need to undergo very few elementary transitions with small downward energy barriers to relax from any configuration towards one of the ground states. However, the energy barriers between the two funnels are quite large and, furthermore, they increase as the number of particles in the unit cell is increased. Therefore, ergodicity breaking is expected in the thermodynamic limit. Finally, the rectangular and oblique lattices show contrasting ground-state orders, the former consists of an antiferromagnetic alternation of head-to-tail chains of spins while the latter is ferromagnetic. Nevertheless, the ELs of these nanostructures are qualitatively very similar. In both cases, all excited magnetic configurations consist of independent flipping of the chains of spins that are formed along the direction of the shorter Bravais vector. The whole energy spectrum of metastable magnetic configurations can thus be mapped to a one-dimensional Ising model. As a result, the kinetic network of stationary points is latticelike and the disconnectivity graphs have a willow-tree form. In conclusion, the collective magnetic behaviors of nanostructures having different point-group symmetries are contrasted and related by varying the parameters of the lattices that interpolate between them.

Abstract 3726: Histone acetylation axis in the control of RNA Pol2 clusters

Abstract Core regulatory transcription factors (CR TFs) orchestrate the placement of super enhancers (SEs) to activate transcription of cell-identity specifying gene networks and are critical in promoting cancer. We defined the core regulatory circuitry of fusion positive rhabdomyosarcoma (FP-RMS, a cancer of childhood) in primary tumors and cell lines, which includes PAX3-FOXO1 (P3F), MYOD1, SOX8, MYCN and others. To find chemical probes able to selectively inhibit CR TF transcription, we screened the Structural Genomics Consortium epigenetic probe set by RNA-seq. We found that chemical probes along the acetylation-axis, and not the methylation-axis, are able to cause selective disruption of CR TF transcription. Inhibitors of HDACs (acetylation erasers), BRD4 (acetylation readers) and CBP/p300 (acetylation writers) were all able to selectively halt CR TF transcription. For HDACs, this raised a conundrum: why would too much histone acetylation, an active chromatin mark, stop transcription at CR TFs? ChIP-seq showed that CR TFs build SEs that have the largest quantities of histone acetylation and the enzymes that write acetylation (i.e., p300), yet paradoxically also harbor the highest amounts of the opposing histone deacetylases (HDACs). To investigate the architectural effects of disabling HDACs and causing hyper acetylation, we developed Absolute Quantification of Architecture (AQuA) HiChIP, revealing erosion of native SE contacts at CR TFs, and extensive aberrant contacts. This did not cause an elongation defect, but rather removed RNA Pol2 from core regulatory genetic elements and eliminated RNA-Pol2 phase condensates in 20 minutes. We further dissected the contribution of HDAC isoforms using a set of HDAC selective inhibitors, finding HDAC1/2/3 are co-essential to CR transcription. Using HAT inhibitors/degraders, we discovered a profound dependence on CBP/p300 for clustering of Pol2 loops that connect P3F to its target genes. In the absence of CBP/p300, Pol2 long range enhancer loops collapse, Pol2 accumulates in CpG islands and fails to exit the gene body. These results reveal a potential novel axis for therapeutic interference with P3F in FP-RMS and clarify the molecular relationship of P3F and CBP/p300 in sustaining active Pol2 clusters essential for oncogenic transcription. Overall, our data reveals a SE-specific need for balancing histone acetylation states to maintain SE architecture, Pol2 clustering in 3D, and CR TF transcription. Citation Format: Berkley E. Gryder, Diana Chin, Hyunmin Kim, Issra Osman. Histone acetylation axis in the control of RNA Pol2 clusters. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3726.

Light Soaking Induced Halide Doping of Evaporated Spiro‐OMeTAD in Perovskite Solar Cells

AbstractIdentification and investigation of light soaking effect (LSE) as well as the associated physical mechanisms are crucial for achieving reliable power output and high stability of solar cells. Here, a profound LSE dependence on doping status of organic hole transport materials (HTMs) in perovskite solar cells is demonstrated. A tenfold efficiency enhancement is realized in the devices based on evaporated undoped HTMs caused by LSE. This light‐soaking behavior is attributed to the increased film conductivity, enhanced built‐in potential at perovskite/HTM interface, reduced interfacial charge accumulation, and suppressed nonradiative recombination in devices. Besides, chemical and structural analysis reveal that halide ions migration and subsequent photodoping of organic HTMs enables significant improvement of the film conductivity and hole mobility. Moreover, the HTM mobilities are proven to determine the LSE strength and kinetics, causing significant variation in photostability of devices.

Tailoring Charge Separation at Meticulously Engineered Conjugated Polymer/Perovskite Quantum Dot Interface for Photocatalyzing Atom Transfer Radical Polymerization.

In stark contrast to conventional organic ligand-capped counterparts, the ability to create stable metal halide perovskite nanocrystals strongly tethered with conjugated polymers (CPs) represents an important endeavor toward tailoring charge carrier dynamics at their interface that critically underpins applications of this unique class of all semiconducting, organic-inorganic nanomaterials for optoelectronics. This, however, has yet to be largely explored. Herein, we report, for the first time, the unraveling of efficient charge separation at judiciously designed CP/perovskite quantum dot (QD) interface for photoinduced atom transfer radical polymerization (p-ATRP). Such scrutiny is rendered by in situ crafting an array of monodisperse, highly stable, CP-ligated perovskite QDs with precisely controlled dimensions of each constituent via capitalizing on unimolecular, amphiphilic starlike block copolymers as nanoreactors. The intimate and permanent surface tethering of CPs imparts remarkable thermal, photo, and polar solvent stabilities of CP-ligated perovskite QDs. More importantly, they manifest efficient interfacial charge separation with a profound dependence on the length of ligated CPs and the size of perovskite QDs. The outstanding structural stabilities and charge separation characteristic enable CP-ligated perovskite QDs as robust photocatalysts for p-ATRP of a wide selection of monomers with stable and controllable reaction kinetics, also depending crucially on the length of CPs and the size of perovskite QDs. In principle, an exciting variety of CP-ligated, uniform perovskite QDs with virtually unlimited material choice of both markedly improved stabilities and tunable electronic band alignments can be readily accessed by exploiting the amphiphilic starlike block copolymer nanoreactor strategy for use in photodetectors, sensors, and LEDs, among other areas.

Shear-induced mixing of granular materials featuring broad granule size distributions.

Granular flows during a shear-induced mixing process are studied using discrete element methods. The aim is to understand the underlying elementary mechanisms of transition from unmixed to mixed phases for a granular material featuring a broad distribution of particles, which we investigate systematically by varying the strain rate and system size. Here the strain rate varies over four orders of magnitude and the system size varies from ten thousand to more than a million granules. A strain rate-dependent transition from quasistatic to purely inertial flow is observed. At the macroscopic scale, the contact stresses drop due to the formation of shear-induced instabilities that serves as an onset of granular flows and initiates mixing between the granules. The stress-drop displays a profound system size dependence. At the granular scale, mixing dynamics are correlated with the formation of shear bands, which result in significantly different timescales of mixing, especially for those regions that are close to the system walls and the bulk. Overall, our results reveal that although the transient dynamics display a generic behavior, these have a significant finite-size effect. In contrast, macroscopic behaviors at steady states have negligible system size dependence.

Set and Setting in the Santo Daime.

Set and setting is a fundamental concept in the field of psychedelic drug research, which points to the profound dependence of psychedelic effects on psychological, social, and cultural factors. Santo Daime is a Brazilian religion that makes elaborate use of ordering principles, techniques, and symbology to shape and direct the effects of the hallucinogenic brew ayahuasca. This paper systematically explores the tapestry of, inter alia, symbolic, social, cultural, psychological, aesthetic and musical elements that participate in the shaping of the psychedelic experience in the context of the Santo Daime ayahuasca religion. The methodically rich under the hood description of the mechanics of entheogenic initiation within the Santo Daime tradition provides a template for future studies of the role of context in psychedelic experimentation.

Flow-Induced Acoustic Resonance of Finned Cylinders With Varying Fin Heights

Abstract The flow-excited acoustic resonance phenomenon, which is instigated by periodic flow perturbation, leads to the generation of acute sound pressure. In this work, we investigated the characteristics of the flow-excited acoustic resonance for circular finned cylinders with different fin heights. The fin height is expressed as a normalized form considering the ratio of the fin diameter to the root cylinder diameter. The experiments are performed with finned cylinders having a range of diameter ratios between 1.5&amp;lt;Df/Dr&amp;lt;2.5. The diameter ratios are varied by changing the root diameter and fin diameter separately as well as simultaneously while keeping the fin pitch and the fin thickness constant. The results show that the excitation of acoustic resonance has profound dependence on the diameter ratio. Increasing the diameter ratios of the finned cylinder results in strong acoustic resonance excitation. The lock-in width and the onset of the acoustic resonance excitation also depend on the diameter ratio of the cylinders. Moreover, the results show that using an effective diameter based on the geometrical flow blockage does not take into account the changes occurring in the source of resonance excitation due to the addition of fins.

On the three-dimensional flow development around circular finned cylinders

The three-dimensional flow development around the circular finned cylinders is investigated numerically. Three finned cylinders with constant fin pitch (p), fin thickness (t), and effective diameter (Deff) and a range of diameter ratios (Df/Dr) within 1.25 ≤ Df/Dr ≤ 2.5 are considered in this study. One bare cylinder with a diameter equivalent to the effective diameter of the finned cylinders is also considered. The numerical simulations are performed using the large eddy simulation turbulence model for a free-stream velocity corresponding to the Reynolds number Re = 3900, defined based on the effective diameter (Deff). This study provides novel insights into the flow physics in the channel between the fins and its effect on the three-dimensional flow development. The results accentuate that the three-dimensional flow development around the finned cylinders fundamentally differs from that of the bare cylinder. In particular, the flow separation topology at the surface of the finned cylinders differs significantly from that of the bare cylinder due to flow entrainment between the fins. The distinct flow separation leads to the formation of streamwise edge vortices, which induces downwash flow in the near wake of the finned cylinders. The combined effect of the entrainment between the fins and downwash flow affects the vortex formation length and mean pressure distribution around the cylinder. As a result, the structural loading on the surface of the finned cylinders is distinctively different from that of the bare cylinder with profound dependence on the fin parameters.

Abstract 1910: Resistance to anti-HER2 therapy in HER2+ breast cancer is mediated by genomic alterations that switch pathway dependence from PI3K/AKT to RAS/MAPK

Abstract Although HER2 overexpression activates both PI3K-AKT and RAS-MAPK signaling, HER2+ breast tumors are primarily driven by PI3K-AKT. Thus, tumor resistance to HER2-targeted agents has been thought to emerge via downstream reactivation of PI3K signaling. We performed genomic profiling on 272 HER2-amplified breast tumors to identify genetic alterations associated with de novo or acquired resistance to anti-HER2 therapies. Surprisingly, we identified enrichment of mutations in RAS-MAPK pathway members, including NF1, ERBB2, and KRAS, in patients who had received prior HER2-targeted therapies, raising the possibility that activation of this pathway contributes to therapy resistance. To determine the impact of RAS-MAPK activation on response to anti-HER2 therapy in HER2+ breast cancer, we generated isogenic HER2+ breast cancer cell line and patient derived xenograft models harboring MAPK pathway alterations enriched in patients. Depletion of NF1 expression in HER2+ breast cancer cell lines using shRNA or CRISPR/Cas9 indeed promoted resistance to the HER2 inhibitors (HER2i) lapatinib and neratinib in vitro, as measured by increased proliferation and markers of cell cycle progression compared to parental lines. Unexpectedly, resistant models exhibited diminished dependence on AKT (MK2206 IC50 increase from 200 nM to 4500 nM) and were sensitized to MEK/ERK inhibition (trametinib IC50 decrease from 740 nM to 13 nM and SCH772984 from 2900 nM to 250 nM). To establish the basis for this change in pathway dependence, we examined the cell cycle profile of the cell line models upon drug treatment. Both cell cycle analysis by DNA content and immunoblot analysis revealed that NF1 null cells arrested in G1 upon MEK inhibition (but not upon AKT inhibition). Given the known regulation of CDK4/6 and CDK2 kinases by the RAS-MAPK pathway, we used both shRNA knockdown and small molecular inhibitors to define the G1 CDK responsible and found CDK2 to be required for resistance to HER2i and MEK sensitivity. Further, in vitro kinase assays using a recombinant RB substrate showed CDK2 activity to be MEK dependent in resistant cells and not in parental. We observed similar phenomena in isogenic HER2+ models in which we introduced mutant BRAF, KRAS, and ERBB2, and found each of these mutations also promoted HER2i resistance and MAPK/CDK2 dependence. Finally, using lentiviral CRISPR/Cas9, we knocked out NF1 in a HER2+ patient derived xenograft model and again found that this alteration promoted profound MEK dependence in vivo. Overall, these data suggest that MAPK-activating mutations constitute an important potential mode of acquired resistance to HER2-targeted therapies and demonstrate the potential utility of MEK/ERK targeted therapies for a subset of anti-HER2 therapy resistant HER2+ breast cancers. Citation Format: Alison E. Smith, Sarat Chandarlapaty. Resistance to anti-HER2 therapy in HER2+ breast cancer is mediated by genomic alterations that switch pathway dependence from PI3K/AKT to RAS/MAPK [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1910.

Coleridge: Sublimity or Beauty?

ABSTRACTThis article argues that the sublime, as formulated by Samuel Taylor Coleridge, has been systematically misunderstood. It demonstrates that texts principally concerned with the beautiful have been interpreted as if they were principally, or indeed exclusively, focused on the sublime. It also contests the apparent scholarly consensus that Coleridge’s notions of sublimity and beauty are irreconcilable. This critique focuses on Christopher Stokes’s Coleridge, Language and the Sublime, the only book-length study of Coleridge’s sublime, and, to a lesser degree, the analyses of Elinor Shaffer. My argument includes a demonstration of the Platonic, rather than the Kantian, character of Coleridge’s aesthetics. In proposing an alternative reading of Coleridge’s sublime, this article demonstrates that it can only be properly understood in terms of its profound dependence on the beautiful.

Preparing individuals with spinal cord injury for extreme storms in the era of climate change

Preparing individuals with spinal cord injury for extreme storms in the era of climate change