bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B028: Overcoming resistance by driving melanoma cells into drug-susceptible states
Authors: Harmange Guillaume , Emert Ben , Schaff Dylan , Reyes-Hueros Raul , Shaffer Sydney 
Published: May 2022

Abstract
The goal of this study is to target pre-existing heterogeneity in gene expression to ultimately overcome resistance to targeted therapy in melanoma. Despite significant advances in the treatment of melanoma, many patients still fail to achieve durable responses to therapy due to the development of drug resistance. Our lab recently discovered that in drug-naive melanoma rare cells transiently enter distinct gene expression states that allows them to ultimately survive treatment with targeted therapy (we refer to these cells as “primed for drug resistance”). The goal of this work is to develop a strategy to overcome this form of resistance by driving cells out of states primed for resistance and into drug-susceptible states. To identify the pathways that regulate the transition to the primed state we combined single-cell RNA sequencing with DNA barcoding to extract the transcriptional profiles and lineage information of over 7,000 drug-naive melanoma cells. We found that cells in lineages that transitioned into states primed for drug resistance express high levels of genes associated with TGFβ and PI3K signaling compared to lineages that stayed in a drug-susceptible state. To test whether TGFβ can directly cause cells to enter the primed state, we treated cells with recombinant TGFβ which led to a significant increase in the number of primed cells. Intriguingly, we also found that treating with TGFB receptor inhibitor or PI3K inhibitor reduced the number of cells in the primed cell state. Further, we sequentially treated these cells first with either the TGFB or PI3K inhibitor followed by targeted therapy and ultimately reduced the number of resistant colonies, demonstrating the potential for this therapeutic paradigm. To better understand how targeting the TGFB and PI3K pathways shift the population dynamics, we used single-cell RNA-seq and cellular barcoding to track lineages following treatment with TGFB, TGFB inhibitor, and PI3K inhibitor. Our analysis reveals the population changes following each therapy and directly demonstrates that treating with PI3K inhibitor decreases the number of primed cells, shifting the population into a drug-susceptible expression state. Ultimately, this work defines two key pathways underlying the primed cell state in melanoma and presents a therapeutic paradigm to eliminate this form of therapy resistance.
Citation Format: Guillaume Harmange, Ben Emert, Dylan Schaff, Raul Reyes-Hueros, Sydney Shaffer. Overcoming resistance by driving melanoma cells into drug-susceptible states [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B028.
Abstract IA008: Charting normal and malignant differentiation topologies with single-cell multi-omics
Authors: Landau Dan 
Published: May 2022

Abstract
Somatic evolution is a novel emerging frontier in human biology, as cells within diverse normal and malignant tissues have been shown to diversify and undergo selection. We and others have shown that somatic evolution is driven by both genetic and non-genetic modes of inheritance (Cell, 2013; Cancer Cell, 2014; Nature, 2015; Nature Communications 2016 & 2019; Cell Systems, 2019). A key challenge is to integrate across these different layers of information at the level of the single cell – the atomic unit of the evolutionary process (Nature Reviews Genetics, 2020). To address this challenge, we have developed single-cell multi-omics technologies and analytical frameworks to link genetic, epigenetic and phenotypic information (Nature, 2019a & Nature, 2019b). We have applied these methods to chart how somatic mutations reshape the differentiation topographies of neoplastic and normal hematopoiesis (Nature, 2019a; Nature Genetics, 2020), as well as defined the epigenetic encoding, inheritance, and plasticity of malignant transcriptional cell states (Nature, 2019b; Nature Genetics, 2021).
Citation Format: Dan Landau. Charting normal and malignant differentiation topologies with single-cell multi-omics [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA008.
ATF4 Protects the Heart From Failure by Antagonizing Oxidative Stress
Authors: Wang Xiaoding , Zhang Guangyu , Dasgupta Subhajit , Niewold Erica L. , Li Chao , Li Qinfeng , Luo Xiang , Tan Lin , Ferdous Anwarul , Lorenzi Philip L. , Rothermel Beverly A. , Gillette Thomas G. , Adams Christopher M. , Scherer Philipp E. , Hill Joseph A. , Wang Zhao V. 
Published: May 2022

Background:
Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated.

Methods:
Pressure overload was triggered by transverse aortic constriction in mice. Transcriptomic and metabolomic regulations were evaluated by RNA-sequencing and metabolomics, respectively. Stable isotope tracer labeling experiments were conducted to determine metabolic flux in vitro. Neonatal rat ventricular myocytes and H9c2 cells were used to examine molecular mechanisms.

Results:
We show that production of cardiomyocyte NADPH, a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with fibrosis and cardiomyopathy. We report that the pentose phosphate pathway and mitochondrial serine/glycine/folate metabolic signaling, 2 NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced by transverse aortic constriction. We identify ATF4 (activating transcription factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these 2 pathways. Consistently, joint pathway analysis of transcriptomic and metabolomic data reveal that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in neonatal rat ventricular myocytes increases NADPH-producing enzymes‚ whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression augments metabolic flux within these 2 pathways. In vivo, cardiomyocyte-specific deletion of ATF4 exacerbates cardiomyopathy in the setting of transverse aortic constriction and accelerates heart failure development, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes.

Conclusions:
Our findings reveal that ATF4 plays a critical role in the heart under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.
A Biomarker‐Enhanced Model for Prediction of Acute Kidney Injury and Cardiovascular Risk Following Angiographic Procedures: CASABLANCA AKI Prediction Substudy
Authors: Mohebi Reza , van Kimmenade Roland , McCarthy Cian , Gaggin Hanna , Mehran Roxana , Dangas George , Januzzi James L. 
Published: May 2022

Background
The 2020 Acute Disease Quality Initiative Consensus provided recommendations on novel acute kidney injury biomarkers. In this study, we sought to assess the added value of novel kidney biomarkers to a clinical score in the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) study.

Methods and Results

We evaluated individuals undergoing coronary and/or peripheral angiography and added 4 candidate biomarkers for acute kidney injury (kidney injury molecule‐1, interleukin‐18, osteopontin, and cystatin C) to a previously described contrast‐associated acute kidney injury (CA‐AKI) risk score. Participants were categorized into integer score groups based on the risk assigned by the biomarker‐enhanced CA‐AKI model. Risk for incident cardiorenal outcomes during a median 3.7 years of follow‐up was assessed. Of 1114 participants studied, 55 (4.94%) developed CA‐AKI. In adjusted models, neither kidney injury molecule‐1 nor interleukin‐18 improved discrimination for CA‐AKI; addition of osteopontin and cystatin C to the CA‐AKI clinical model significantly increased the c‐statistic from 0.69 to 0.73 (
P
for change <0.001) and resulted in a Net Reclassification Index of 59.4. Considering those with the lowest CA‐AKI integer score as a reference, the intermediate, high‐risk, and very‐high‐risk groups were associated with adverse cardiorenal outcomes. The corresponding hazard ratios of the very‐high‐risk group were 3.39 (95% CI, 2.14–5.38) for nonprocedural acute kidney injury, 5.58 (95% CI, 3.23–9.63) for incident chronic kidney disease, 6.21 (95% CI, 3.67–10.47) for myocardial infarction, and 8.94 (95% CI, 4.83–16.53) for all‐cause mortality.

Conclusions
A biomarker‐enhanced risk model significantly improves the prediction of CA‐AKI beyond clinical variables alone and may stratify the risk of future cardiorenal outcomes.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00842868.
A Linear Superposition Model of Envelope and Frequency Following Responses May Help Identify Generators Based on Latency
Authors: Teichert Tobias , Gnanateja G. Nike , Sadagopan Srivatsun , Chandrasekaran Bharath 
Published: May 2022

Abstract
Envelope and frequency-following responses (FFRENV and FFRTFS) are scalp-recorded electrophysiological potentials that closely follow the periodicity of complex sounds such as speech. These signals have been established as important biomarkers in speech and learning disorders. However, despite important advances, it has remained challenging to map altered FFRENV and FFRTFS to altered processing in specific brain regions. Here we explore the utility of a deconvolution approach based on the assumption that FFRENV and FFRTFS reflect the linear superposition of responses that are triggered by the glottal pulse in each cycle of the fundamental frequency (F0 responses). We tested the deconvolution method by applying it to FFRENV and FFRTFS of rhesus monkeys to human speech and click trains with time-varying pitch patterns. Our analyses show that F0ENV responses could be measured with high signal-to-noise ratio and featured several spectro-temporally and topographically distinct components that likely reflect the activation of brainstem (&lt;5 ms; 200–1000 Hz), midbrain (5–15 ms; 100–250 Hz), and cortex (15–35 ms; ∼90 Hz). In contrast, F0TFS responses contained only one spectro-temporal component that likely reflected activity in the midbrain. In summary, our results support the notion that the latency of F0 components map meaningfully onto successive processing stages. This opens the possibility that pathologically altered FFRENV or FFRTFS may be linked to altered F0ENV or F0TFS and from there to specific processing stages and ultimately spatially targeted interventions.
Warding off Development: Local Control, Housing Supply, and NIMBYs
Authors: Mast Evan 
Published: May 2022

Abstract
Local control of land-use regulation creates a not-in-my-backyard (NIMBY) problem that can suppress housing construction, contributing to rising prices and potentially slowing economic growth. I study how increased local control affects housing production by exploiting a common electoral reform—changing from “at-large” to “ward” elections for town council. These reforms, which are not typically motivated by housing markets, shrink each representative’s constituency from the entire town to one ward. Results from a variety of difference-in-differences estimators show that this decentralization decreases housing units permitted by 20%, with similar effects on multi- and single-family permits. Effects are larger in whiter and higher-income towns.
Exporting, Abatement, and Firm-Level Emissions: Evidence from China’s Accession to the WTO
Authors: Rodrigue Joel , Sheng Dan , Tan Yong 
Published: May 2022

Abstract
This paper studies the joint impact of exporting and abatement on the environmental performance of Chinese manufacturers. For two common air pollutants (SO2 and industrial dust) we document that (a) exporters are significantly less emissions-intensive relative to their nonexporting counterparts and (b) this difference cannot be explained by differential rates of abatement alone. Employing variation in trade and environmental conditions across time and space, we quantify the impact of endogenous export and abatement decisions on firm-level emissions. We find that exporting reduces emissions by at least 36% across pollutants. We explore underlying determinants of export-driven reductions in emissions intensity.
Recommendations for Interinstitutional and Interdisciplinary Research Informed by a PIRE Graduate Student Cohort Perspective
Authors: Henny Lexi , Gaudet Lauriana C. , Lupo Kevin M. , Goods Kenya , Sanders Shadya , Zhang Yanda 
Published: May 2022

Abstract
The U.S.–Taiwan Partnership for International Research and Education (PIRE) “Building Extreme Weather Resiliency through Improved Weather and Climate Prediction and Emergency Response Strategies” was an NSF-funded grant between universities and institutions in the United States and Taiwan that intended to understand 1) weather forecast uncertainty during extreme precipitation events and 2) how emergency managers use such information to make decisions. In this reflective paper, graduate students from the project’s working groups, including climate, ensemble, microphysics, and decision science, share their experiences of being involved in this ambitious program. A notable strength of this PIRE was its opportunities for international collaboration and related cultural experiences; however, despite direct student involvement in PIRE, student experiences varied considerably (e.g., research experiences, cultural exposure). Recommendations for improvement are informed predominantly by U.S.-based graduate student experiences and are discussed with the intention of bolstering future interdisciplinary research for students and investigators. To this end, projects of this scale and scope could benefit from more frequent communication among leadership and research groups, as well as explicitly outlining and prioritizing interactions between groups to focus and strengthen collaboration toward the completion of interdisciplinary research goals.
ProbSevere LightningCast: A Deep-Learning Model for Satellite-Based Lightning Nowcasting
Authors: Cintineo John L. , Pavolonis Michael J. , Sieglaff Justin M. 
Published: May 2022

Abstract
Lightning strikes pose a hazard to human life and property, and can be difficult to forecast in a timely manner. In this study, a satellite-based machine learning model was developed to provide objective, short-term, location-specific probabilistic guidance for next-hour lightning activity. Using a convolutional neural network architecture designed for semantic segmentation, the model was trained using GOES-16 visible, shortwave infrared, and longwave infrared bands from the Advanced Baseline Imager (ABI). Next-hour GOES-16 Geostationary Lightning Mapper data were used as the truth or target data. The model, known as LightningCast, was trained over the GOES-16 ABI contiguous United States (CONUS) domain. However, the model is shown to generalize to GOES-16 full disk regions that are outside of the CONUS. LightningCast provides predictions for developing and advecting storms, regardless of solar illumination and meteorological conditions. LightningCast, which frequently provides 20 min or more of lead time to new lightning activity, learned salient features consistent with the scientific understanding of the relationships between lightning and satellite imagery interpretation. We also demonstrate that despite being trained on data from a single geostationary satellite domain (GOES-East), the model can be applied to other satellites (e.g., GOES-West) with comparable specifications and without substantial degradation in performance. LightningCast objectively transforms large volumes of satellite imagery into objective, actionable information. Potential application areas are also highlighted.

Significance Statement
The outcome of this research is a model that spatially forecasts lightning occurrence in a 0–60-min time window, using only images of clouds from the GOES-R Advanced Baseline Imager. This model has the potential to provide early alerts for developing and approaching hazardous conditions.
Lifetime medical costs attributable to sickle cell disease among nonelderly individuals with commercial insurance
Authors: Johnson Kate M. , Jiao Boshen , Ramsey Scott D. , Bender M. A. , Devine Beth , Basu Anirban 
Published: May 2022

AbstractSickle cell disease (SCD) is a severe monogenic disease associated with high morbidity, mortality, and a disproportionate burden on Black and Hispanic communities. Our objective was to estimate the total healthcare costs and out-of-pocket (OOP) costs attributable to SCD among commercially insured individuals over their nonelderly lifetimes (0 to 64 years of age). We constructed a retrospective cohort of individuals with diagnosed SCD using Truven Health Marketscan commercial claims data from 2007 through 2018, compared with matched control subjects from the Medical Expenditure Panel Survey. We estimated Kaplan-Meier sample average costs using previously reported survival curves for SCD and control subjects. Individuals with SCD (20 891) and control subjects (33 588) were included in our analysis. The SCD sample had a mean age of 25.7 (standard deviation, 17.4) years; 58.0% were female. Survival-adjusted costs of SCD peaked at age 13 to 24 years and declined at older ages. There was no significant difference in total medical costs or OOP costs between the sexes. SCD-attributable costs over 0 to 64 years of age were estimated to be $1.6 million (95% confidence interval [CI], $1.3M-$1.9M) and $1.7 million (95% CI, $1.4M-$2.1M) for females and males with SCD, respectively. The corresponding OOP estimates were $42 395 (95% CI, $34 756-$50 033) for females and $45 091 (95% CI, $36 491-$53 691) for males. These represent a 907% and 285% increase in total medical and OOP costs over control subjects, respectively. Although limited to the commercially insured population, these results indicate that the direct economic burden of SCD is substantial and peaks at younger ages, suggesting the need for curative and new medical therapies.
Radio communication-based method for analysis of train driving in an ERTMS signaling environment
Authors: Rosberg Tomas , Thorslund Birgitta 
Published: May 2022

Abstract
Background
ERTMS is an important project improving cross-border interoperability throughout Europe by a single rail signaling standard. One advantage following this development is a standardized radio signaling, which can be tracked by logging the data transfer using the ETCS protocol between Radio Block Center and train. This means that a broad spectrum of train driving can be analyzed in terms of for example driving behavior, signal planning and capacity in a new efficient way.

Methods
In this paper a radio-based protocol method to achieve this, is presented and applied for studying braking characteristics in terms of meeting point design. The aim was to design, apply and validate a radio-based train data collection method to enable cost-efficient and avoid time-consuming train data collections. To enable comparison between the results from the suggested radio-based method and traditional methods, a verification measurement was performed. Three different alternatives of speed calculation were validated. These were based on: Train Position Report speed; calculation of average speed based on reported train position; processed reported train position forming the average speed. The best alternative was then applied to examine deceleration towards different signal targets at single-track meeting points.

Results
The results from this study suggest that the ETCS Level 2 protocol is a feasible way to collect train dynamics data. The method is time saving when it comes to train driver behavior studies where several trains and drivers are needed to get significant results. Comparison with traditional GPS method suggest that the method is valid. Most promising is the alternative using processed train position.
Nanocluster-mediated photothermia improves eradication efficiency and antibiotic sensitivity of Helicobacter pylori
Authors: Meng Fansen , Tao Hongjin , Mi Yan , Yang Tianyu , Wang Xuanping , Go Yuyo , Lin Yunjuan , Wang Gangshi 
Published: May 2022

Abstract
Background
Helicobacter pylori (H. pylori) eradication plays a crucial role in gastric cancer prevention, but the antimicrobial resistance of H. pylori is obstructing this elimination process. In this study, we developed nanoclusters (NCs) from Zn0.3Fe2.7O4 nanoparticles using a poly(ethylene glycol)-b-poly(ε-caprolactone)-based nanocarrier as an innovative antibiotic-independent H. pylori management.

Results
The nanocluster showed minimal toxicity and maximal biocompatibility. With a low concentration (50 µg/mL) of NCs under a short time period (~ 2 min) of near-infrared (808 nm) irradiation, we kept the culture medium temperature to 41 °C for 20 min with continuous irradiation. The heated NCs exhibited efficient photothermal effects and resulted in an excellent inhibition of H. pylori growth, adhesion and ability to induce vacuolization in eukaryotic cells in in vitro investigation. Transmission electron microscopy showed a dramatic morphologic change after NCs photothermia on H. pylori, including cell wall and membrane rupture, as well as ribosome damage. Besides, levofloxacin and clarithromycin resistance was decreased after photothermal treatment in H. pylori NCTC 11637 and/or clinical strains, however metronidazole resistance was unchanged. We also discovered a significant decrease in the biofilm formation of H. pylori under the NCs-based photothermal application, while efflux pump function was unchanged.

Conclusions
Based on this novel NCs-based photothermal approach, we were able to demonstrate in vitro a significant inhibition of both H. pylori growth and molecular toxicity, and its improvement in antibiotic sensitivity alone with the eradication of H. pylori biofilms previously believed to be tolerant to conventional antibiotics.