bluuebunny/crossref_metadata_2025 huggingface dataset:
HyGain: High-performance, Energy-efficient Hybrid Gain Cell-based Cache Hierarchy
Authors: Singh Sarabjeet , Surana Neelam , Prasad Kailash , Jain Pranjali , Mekie Joycee , Awasthi Manu
Published: November 2022

In this article, we propose a “full-stack” solution to designing high-apacity and low-latency on-chip cache hierarchies by starting at the circuit level of the hardware design stack. We propose a novel half V

DD

precharge 2T Gain Cell (GC) design for the cache hierarchy. The GC has several desirable characteristics, including ~50% higher storage density and ~50% lower dynamic energy as compared to the traditional 6T SRAM, even after accounting for peripheral circuit overheads. We also demonstrate data retention time of 350 us (~17.5× of eDRAM) at 28 nm technology with V

DD

= 0.9V and temperature = 27°C that, combined with optimizations like staggered refresh, makes it an ideal candidate to architect all levels of on-chip caches. We show that compared to 6T SRAM, for a given area budget, GC-based caches, on average, provide 30% and 36% increase in IPC for single- and multi-programmed workloads, respectively, on contemporary workloads, including SPEC CPU 2017. We also observe dynamic energy savings of 42% and 34% for single- and multi-programmed workloads, respectively. Finally, in a quest to utilize the best of all worlds, we combine GC with STT-RAM to create hybrid hierarchies. We show that a hybrid hierarchy with GC caches at L1 and L2 and an LLC split between GC and STT-RAM is able to provide a 46% benefit in energy-delay product (EDP) as compared to an all-SRAM design, and 13% as compared to an all-GC cache hierarchy, averaged across multi-programmed workloads.
Physics of Human Crowds
Authors: Corbetta Alessandro , Toschi Federico
Published: November 2022

Understanding the behavior of human crowds is a key step toward a safer society and more livable cities. Despite the individual variability and will of single individuals, human crowds, from dilute to dense, invariably display a remarkable set of universal features and statistically reproducible behaviors. Here, we review ideas and recent progress in employing the language and tools from physics to develop a deeper understanding about the dynamics of pedestrians.
An Experimental Study of Humidity Distribution Dynamics in a Segmented PEM Fuel Cell
Authors: Schmitt Tobias , Bligny Rémi , Maranzana Gaël , Dillet Jerome , Sauter Ulrich
Published: November 2022

A novel approach for local and transient in operando measurements of humidification along the channel of a segmented Proton exchange membrane fuel cell (PEMFC) is presented. Based on the impedances at fixed frequencies and temperature, equivalent relative humidity data is acquired and compared between steady state and transient experiments. Based on our results we can show that the classic

1

kHz

resistance in combination with a proper parametrization is a good choice for monitoring the ionomer humidification. A fast acquisition rate offers high resolution insights into the spatio-temporal dynamics of a PEMFC. Our method reveals that the current density and humidity distribution responses to changes in stoichiometry and total current is highly inhomogeneous along the channel. Based on this compressive data, we were able to establish a qualitative model that explains and predicts local dynamic phenomena occurring along the channel during local drainage or humidification.
Mechanical Failure of Cu Current Collector Films Affecting Li Plating/Stripping Cycles at Cu/LiPON Interfaces
Authors: Motoyama Munekazu , Ejiri Makoto , Nakajima Hironori , Iriyama Yasutoshi
Published: November 2022

Herein an electro-chemo-mechanical theory, which states that mechanical work to deform a Cu current collector (CC) film influences the nucleation overpotential (η
nc) for Li nucleation at the Cu CC film/lithium phosphorus oxynitride (LiPON) electrolyte interface, is examined. The finite element method (FEM) simulated the mechanical pressure that the CC film exerted on the Li nuclei at the Cu/LiPON interface, and the results agreed with the trends in our previous study. In situ scanning electron microscopy (SEM) observations for cycling of Li plating/stripping showed that Li repeatedly nucleated and grew at positions where the CC film was locally fractured, and η
nc decreased with repeated Li plating/stripping because the mechanical pressure to the Li nuclei was no longer applied at locations where the CC film was fractured. On the other hand, for thicker CC films that did not crack, η
nc exhibited nearly consistent values in the Li plating/stripping cycles. Consequently, the experimental results in this study supported our nucleation theory for a metal/solid-state-electrolyte interfacial system.
High-resolution analysis of the cytosolic Ca2+ events in β cell collectives in situ
Authors: Postić Sandra , Sarikas Srdjan , Pfabe Johannes , Pohorec Viljem , Križančić Bombek Lidija , Sluga Nastja , Skelin Klemen Maša , Dolenšek Jurij , Korošak Dean , Stožer Andraž , Evans-Molina Carmella , Johnson James D. , Slak Rupnik Marjan
Published: November 2022

Physiological glucose or ryanodine stimulation of β cell collectives generates a large number of [Ca2+]c events, which can be rapidly assessed with our newly developed automatic image segmentation and [Ca2+]c event identification pipeline. The event durations segregate into three reproducible modes produced by a progressive temporal summation. Using pharmacological tools, we show that activation of ryanodine intracellular Ca2+ receptors is both sufficient and necessary for glucose-dependent [Ca2+]c oscillations in β cell collectives.
Ketone monoester ingestion increases postexercise serum erythropoietin concentrations in healthy men
Authors: Evans Eric , Walhin Jean-Philippe , Hengist Aaron , Betts James A. , Dearlove David J. , Gonzalez Javier T.
Published: November 2022

To our knowledge, this study was the first to assess the effects of ketone monoester ingestion on erythropoietin concentrations after exercise. We demonstrated that ingestion of a ketone monoester postexercise increased serum erythropoietin concentrations and reduced serum glucose concentrations in healthy men. These data reveal the possibility for ketone monoesters to alter hemoglobin mass.
Sensorimotor integration and motor learning during a novel visuomotor tracing task in young adults with attention-deficit/hyperactivity disorder
Authors: McCracken Heather S. , Murphy Bernadette , Ambalavanar Ushani , Zabihhosseinian Mahboobeh , Yielder Paul C.
Published: November 2022

Alterations to somatosensory-evoked potentials (SEPs) were present in young adults with attention-deficit/hyperactivity disorder (ADHD), when compared with neurotypical controls. The N18 and N30 SEP peak had differential changes between groups, suggesting alterations to olivary-cerebellar-M1 processing and SMI in those with ADHD when acquiring a novel visuomotor tracing task. This suggests that short-latency SEPs may be a useful biomarker in the assessment of differential responses to motor acquisition in those with ADHD.
Disruptions in network plasticity precede deficits in memory following inhibition of retinoid signaling
Authors: Wingrove Joel , de Hoog Eric , Spencer Gaynor E.
Published: November 2022

We provide novel evidence for how conditioning-induced changes in a CPG network are disrupted when retinoid signaling is inhibited. Inhibition of retinoic acid signaling prevents long-term memory formation following operant conditioning, but has no effect on learning. Simultaneous electrophysiological and behavioral analyses indicate network changes immediately following learning, but these changes are prevented with inhibition of retinoid signaling, before any overt changes in behavior. These data suggest sites for retinoid actions during memory formation.
The human motor cortex contributes to gravity compensation to maintain posture and during reaching
Authors: Hardesty Russell L. , Ellaway Peter H. , Gritsenko Valeriya
Published: November 2022

Animal studies suggest that the corticospinal tract and its collaterals are crucial for producing postural adjustments that accompany movement in limbs other than the moving limb. Here we provide evidence for a similar control schema for both arm posture maintenance and gravity compensation during movement of the same limb. The observed interplay between the postural and movement control signals within the corticospinal tract may help explain the underlying neural motor deficits after stroke.
Development of a Technique for Classifying Photovoltaic Panels Using Sentinel-1 and Machine Learning
Authors: Lee Seong-Hyeok , Yoon Dong-Hyeon , Lee Seung-kuk , Oh Kwan-Young , Lee Moung-Jin
Published: November 2022

With the increasing interest in effective renewable alternative energy sources resulting from the Paris Agreement on Climate Change in 2015, photovoltaic (PV) power generation is attracting attention as a practical measure. In this study, we develop procedures for efficiently monitoring PV panels in a large area and increasing their classification accuracy to enable efficient management of PV panels, an important component of renewable energy generation. To accomplish this, first, the persistent scatterer characteristics (e.g., polarization, imaging module, and topography) of PV panels in SAR images were utilized. Then, we developed a technique for classifying panels over a certain size using the polarization and pulse-scattering characteristics of Sentinel-1. Next, by stacking Sentinel-1 ground range Doppler (GRD) images and comparing them with the surroundings of the same area, the morphological features of PV panels were derived and built as learning data for machine learning. Then, a more precise classification of PV panels was performed by applying these learning data in AI algorithms. When SAR-based AI training data for the same PV panels were used in the YOLOv3 and YOLOv5 algorithms, both algorithms showed high accuracy of over 90%, but there were differences in precision and recall. These findings will enable more efficient monitoring of PV panels, the use of which is expected to increase in the future. In addition, they can serve as a proactive response tool to address environmental problems such as PV panel waste and panels washed away during natural disasters.
Resource Allocation for D2D Communication in Multiservice Cellular Network
Authors: Xie Gang , Chen Haidan
Published: November 2022

Allowing different services with different requirements to coexist is a hot topic for future communication. In order to meet the different communication requirements of users, this paper proposes a cellular communication system based on filtered orthogonal frequency division multiplexing (filtered-OFDM) supporting device-to-device (D2D) communication. Further, in order to improve the system performance, we study the user resource allocation problem in the system and propose a dynamic iterative resource allocation algorithm based on Hungarian algorithm (DRABH). The algorithm allocates resource blocks for D2D user pairs and all cellular users in the cell under the constraint of the lowest threshold of signal to interference plus noise ratio (SINR), and cellular users have high priority. Under the condition of ensuring that all cellular users can communicate, resource blocks are allocated to as many D2D user pairs as possible to maximize the number of user links in the network. Simulation results show that considering the interference introduced by filtered-OFDM and D2D communication, the proposed resource allocation scheme can significantly improve the number of user links.
Mechanism and Active Components of Qingre Lidan Tablets Alleviate Intrahepatic Cholestasis by Activating the Farnesoid X Receptor
Authors: Xia Yafei , Yan Shixin , Chang Yang , Yin Jiaoyang , Li Hongyu , Yan Shu
Published: November 2022

Background. Qingre Lidan tablets (QLTs) are a compound preparation of Chinese medicine that have long been used clinically to treat poor bile circulation caused by the inflammation and obstruction of the gallbladder and bile duct and to relieve jaundice and other symptoms. However, its material basis and mechanism are still unclear. The purpose of this study was to investigate the mechanism and active components of QLTs for treating intrahepatic cholestasis (IHC) in rat models. Methods. In vivo experiments verified the effect of QLTs on alpha-naphthyl isothiocyanate (ANIT)-induced IHC models in rats. The mRNA and protein expression levels of farnesoid X receptor (FXR), bile salt export pump (BSEP), and multidrug-associated protein 2 (MRP2) in the rat liver were detected. UPLC/Q-TOF-MS was used to separate and identify the monomers in QLTs, and a dual-luciferase reporter assay was used to select effective the monomers that stimulate FXR. Among the selected monomers, baicalein was used as a representative to verify the effect on rat IHC models. Results. QLTs and baicalein significantly reduced the serum biochemical indicators reflecting the changes in liver function among IHC rats and remitted the ANIT-induced liver histopathological changes. The expression levels of FXR, BSEP, and MRP2 in the liver were significantly increased after QLT treatment in a dose-dependent manner. Moreover, six types of active components that activate FXR were selected in QLTs, namely baicalein, wogonin, baicalein II, emodin, dibutyl phthalate, and diisooctyl phthalate. Conclusions. QLTs and the active component, baicalein, can alleviate IHC in model rats.
Estimation of Harvested RF Energy Based on Survey of Ambient RF Power for Optimized Rectifier Design
Authors: Arpanutud Kirote , Tontisirin Sitt , Chudpooti Nonchanutt , Chalermwisutkul Suramate
Published: November 2022

This paper presents estimation of harvested RF energy by means of measurement survey and rectifier circuit simulation. The survey was done in an indoor environment in Bangkok, Thailand using a low-cost in-house developed measurement system. From the survey, channel power distribution of a signal with 950 MHz center frequency and 20 MHz bandwidth was created. The maximum time averaged channel power is -7.6 dBm whereas the mean value with maximum signal statistic is -11.1 dBm. A single stage rectifier is simulated with 5 different nominal values of RF input power which is used to optimize the rectifier for maximum RF-to-DC power conversion efficiency. The rectifier composes a Schottky diode, a matching network and a simple load consisting of a resistor and a storage capacitor. Parameters of the simplified LC matching network have been varied to match the rectifier’s input impedance to 50 Ω for various nominal values of the RF input power. In addition, the load resistance was varied according to the nominal RF input power for an optimal power conversion efficiency of the rectifier. The rectifier delivers the highest harvested RF energy with a nominal RF input power of -9 dBm which is a value between the maximum and the mean values from the survey. The DC energy converted from ambient RF energy by the rectifier can be estimated. With this information, it can be assessed what type of applications based on available RF energy can be applied for the test area. This rectifier optimization strategy can be applied to any kind of RF signal since it is based on actual measurement results. Moreover, the proposed rectifier can be designed for reconfigurability regarding nominal RF input power at the location of interest by varying the matching network parameters and the load resistance. In practical applications, the reconfigurable rectifier can maintain a high level of power conversion efficiency over a wide range of RF input power. This can be done by optimizing the rectifier’s input matching network and the load resistance for the highest possible power harvested from the environment where the rectifier is located.
Screening of Biomarkers and Quality Control of Shaoyao Gancao Decoction Using UPLC-MS/MS Combined with Network Pharmacology and Molecular Docking Technology
Authors: Ma Yongben , Wu Lingfang , Niu Liying
Published: November 2022

Shaoyao Gancao Decoction (SGD) is a classic prescription of traditional Chinese medicine (TCM), which is composed of Paeoniae Radix Alba and Glycyrrhizae Radix et Rhizoma, and has the clinical effect of anti-liver injury, but its active ingredients are unclear. In this study, the joint application of phytochemical compositional analysis, network pharmacology, and molecular docking technology was utilized to screen the active components of SGD against liver injury. Firstly, a total of 110 compounds were identified by UPLC-Q-TOF-MS/MS, including 54 flavonoids, 23 triterpenoids, 10 monoterpenoids, 6 coumarins, and 17 other compounds. Secondly, based on the above plant chemical compositions, network pharmacology was used to search for the active components of SGD against liver injury, and 19 components were considered to be the active components, including 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose, ferulic acid, coniferyl ferulate, benzoyl paeoniflorin, hesperidin, liquiritin, liquiritigenin, glycyrrhizic acid, caffeic acid, rutin, chlorogenic acid, gallic acid, methyl gallate, isoliquiritin apioside, albiflorin, neochlorogenic acid, isoliquiritin, narirutin, and naringenin. Thirdly, molecular docking was used to verify the efficacy of the compounds and showed that the compounds bound well to key targets. Furthermore, the 19 components were detected in the rat serum, which also demonstrated that they could be biomarkers. Because it is generally believed that the ingredients that can be absorbed into the blood may be active ingredients. In the end, we determined the contents of 19 key components in 10 different batches of SGD. The method has satisfactory linearity, stability, accuracy, repeatability, and recovery. This study clarified the active components, key targets, and pathways of SGD against liver injury and provided a new idea for the selection of quality control indicators in traditional Chinese medicine.
Potential Plasma Metabolic Biomarkers of Tourette Syndrome Discovery Based on Integrated Non-Targeted and Targeted Metabolomics Screening
Authors: Xi Leying , Zhou Fuqiong , Ji Wenxiu , Zhu Weina , Ruan Jie , Zhang Yajie , Hu Xueling , Long Hongyan
Published: November 2022

Objective. Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by abnormal movements, phonations, and tics, but an accurate TS diagnosis remains challenging and indeed depends on its description of clinical symptoms. Our study was conducted to discover and verify some metabolite biomarkers based on nontargeted and targeted metabolomics. Methods. We conducted untargeted ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) for preliminary screening of potential biomarkers on 30 TS patients and 10 healthy controls and then performed validation experiments based on targeted ultrahigh-performance liquid chromatography triple quadrupole-MS (UHPLC/MS/MS) on 35 TS patients and 14 healthy controls. Results. 1775 differentially expressed metabolites were identified by partial least squares discriminant analysis (PLS-DA), fold-change analysis, T-test, and hierarchical clustering analysis (adjusted

p

value <0.05 and |logFC| > 1). TS plasma samples were found to be differentiated from healthy samples in our approach. Furthermore, aspartate and asparagine metabolism pathways were considered to be a significant enrichment pathway in TS progression based on metabolite pathway enrichment analysis. For the 8 metabolites involved in this pathway that we detected, we then performed validation experiments based on targeted UHPLC/MS/MS. The t-test, Mann–Whitney U test, and receiver operating characteristic (ROC) curve analysis were used to determine potential biomarkers. Ultimately, L-arginine and L-pipecolic acid were validated as significantly differentiated metabolites (

p
<
0.05

), with an AUC of 70.0% and 80.3%, respectively. Conclusion. L-pipecolic acid was defined as a potential biomarker for TS diagnosis by the combined application of nontargeted and targeted metabolomic analysis.
A New United Proportional Navigation Guidance for Impact Angle Constraint without Measurement Distance between Vehicle and Target
Authors: Yang Hao , Wu Hangjin , Bai Xibin , Zhang Shifeng
Published: November 2022

This paper proposed a united proportional navigation guidance (UPNG) method to alleviate the guidance command saltation with an impact angle constraint under the condition of no real-time distance between the vehicle and the target (line-of-sight (LOS) distance). Firstly, based on the biased proportional navigation guidance (BPNG), a smooth-biased proportional navigation guidance (SBPNG) method was proposed, whose bias term was designed as a trigonometric function. In SBPNG method, due to the continuous smooth change of the bias term, the guidance command would not saltus anymore, and the impact angle was controlled by the bias integral component. Secondly, biased on SBPNG method, the united proportional navigation guidance (UPNG) method combining SBPNG and variable coefficient proportional navigation guidance (VCPNG) was established. In UPNG method, because there was no LOS distance, the guidance coefficient was designed as a function of the difference between the expected impact angle and the estimated impact angle, so the closed-loop control of impact angle was realized. Finally, a lot of simulation experiments on different guidance laws were carried out without real-time LOS distance. The results verify that the UPNG method proposed in this paper solves the problem of guidance command saltation effectively and has better robustness in impact angle control.
The Effect of Pomegranate Juice and Sumac Consumption in the Treatment of Outpatients with COVID-19
Authors: Forouzanfar Fatemeh , Ahmadpoor Mohammadreza , Farahi Mostafa Moshirian , Hadianfar Ali , Sahebkar Amirhossein , Esmaily Habibollah , Nematy Mohsen , Rakhshandeh Hassan
Published: November 2022

Introduction. COVID-19, an epidemic of coronavirus infection, has become a major global threat. The coronavirus mainly targets the human respiratory system, followed by cytokine storm, and altered immune responses associated with disease progression and adverse outcomes. Sumac and pomegranate juice are rich in bioactive compounds, which potentially have antiviral activities. This study is aimed at investigating the effect of a diet based on the use of sumac and pomegranate juice on the treatment of outpatients with COVID-19. Methods. In this study, 182 outpatients with COVID-19 were randomly divided into two groups receiving a diet containing pomegranate juice and sumac along with standard treatment and the control group (group 2) receiving standard treatment. Results. Consumption of a diet containing pomegranate juice and sumac in outpatients with COVID-19, who were receiving standard-of-care treatment, led to a significant decrease in fever, chills, cough, weakness, smell and taste disorders, shortness of breath, diarrhea, nausea and vomiting, and abdominal pain compared with outpatients with COVID-19 who received only standard treatment. Conclusion. Clinical trials of outpatients have limitations such as patients’ resilience to post-COVID-19 follow-up. However, the use of pomegranate juice and sumac can be efficacious in reducing COVID-19 symptoms. This trial is registered with IRCT20190406043175N3.
Comparison of the Flow Fields between Nozzles with Full-Open and Open-Close Valves at Transonic Velocity
Authors: Li Zijie , Wang Hao
Published: November 2022

At transonic velocity, ejector nozzles require third auxiliary intake valves to increase air intake, resulting in good thrust performance. However, different intake structures will inevitably lead to different internal flow-field structures and thrust performances. To evaluate the differences between nozzles with full-open valve and open-close valve at transonic velocity, we established two numerical simulation models to analyze the flow-field structure and thrust performance in the ejector nozzle. The results show that at the transonic flight state (

Ma
=
1.2

), the mainstream of the two models always maintains an overexpansion state, and the primary flow fields are highly similar. However, the secondary and the third auxiliary flow fields are significantly different. Notably, in the nozzle with open-close valve, a lateral flow occurs near the wall of the nozzle tail, resulting in several vortexes. Contrarily, in the nozzle with full-open valve, there is almost no lateral flow or vortex. Further, we found that the secondary flow tends to roll up toward the third auxiliary valve instead of directly flowing into the nozzle. Thus, the thrust coefficients of the two nozzles differ.
Exploring the Antiovarian Cancer Mechanisms of Salvia Miltiorrhiza Bunge by Network Pharmacological Analysis and Molecular Docking
Authors: Xu Xiao , Zhang Zhiwei , Liu Likun , Che Cheng , Li Weiling
Published: November 2022

Background. Ovarian cancer was one of the gynecological malignant tumors. Salvia miltiorrhiza Bunge (SMB) was a kind of herbal medicine with an antitumor effect. However, the inhibitory effect of SMB on ovarian cancer and its potential mechanism were still unclear. Objective. The antitumor effect of SMB on ovarian cancer was studied by network pharmacology and molecular docking techniques, and its possible molecular mechanisms were analyzed. Method. The active ingredients of SMB and the target data of ovarian cancer were obtained from the Traditional Chinese Medicines for Systems Pharmacology Database (TCMSP) and the GeneCards database. The relationship between active ingredients of SMB and ovarian cancer targets was analyzed by String database, David 6.8 online database, and Cytoscape 3.7.2 software, and then potential pathways were screened out. In addition, molecular docking technology was used to verify further the binding effect of antiovarian cancer pathway targets with active ingredients of SMB. Finally, survival analysis was performed for all potential targets. Results. We analyzed 71 SMB–ovarian cancer common targets, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the PI3K-Akt signaling pathway might be an essential pathway for SMB to inhibit ovarian cancer. Luteolin, Tanshinone IIA, and Cryptotanshinone in SMB might play an important role. HSP90AA1, CDK2, and PIK3CG might be potential targets of SMB in inhibiting ovarian cancer. Conclusion. Through network pharmacology and molecular docking analysis, we found that SMB might partially inhibit ovarian cancer by the PI3K-Akt signaling pathway. We believe that SMB might be a potential therapeutic agent for ovarian cancer patients.
A Note on n‐Divisible Positive Definite Functions
Authors: Norvidas Saulius
Published: November 2022

Let PD(ℝ) be the family of continuous positive definite functions on ℝ. For an integer n > 1, a f ∈ PD(ℝ) is called n‐divisible if there is g ∈ PD(ℝ) such that gn = f. Some properties of infinite‐divisible and n‐divisible functions may differ in essence. Indeed, if f is infinite‐divisible, then for each integer n > 1, there is an unique g such that gn = f, but there is a n‐divisible f such that the factor g in gn = f is generally not unique. In this paper, we discuss about how rich can be the class {g ∈ PD(ℝ): gn = f} for n‐divisible f ∈ PD(ℝ) and obtain precise estimate for the cardinality of this class.
Single-Cell Analysis in Lung Adenocarcinoma Implicates RNA Editing in Cancer Innate Immunity and Patient Prognosis
Authors: Chan Tracey W. , Dodson Jack P. , Arbet Jaron , Boutros Paul C. , Xiao Xinshu
Published: November 2022

RNA editing modifies single nucleotides of RNAs, regulating primary protein structure and protein abundance. In recent years, the diversity of proteins and complexity of gene regulation associated with RNA editing dysregulation has been increasingly appreciated in oncology. Large-scale shifts in editing have been observed in bulk tumors across various cancer types. However, RNA editing in single cells and individual cell types within tumors has not been explored. By profiling editing in single cells from lung adenocarcinoma biopsies, we found that the increased editing trend of bulk lung tumors was unique to cancer cells. Elevated editing levels were observed in cancer cells resistant to targeted therapy, and editing sites associated with drug response were enriched. Consistent with the regulation of antiviral pathways by RNA editing, higher editing levels in cancer cells were associated with reduced antitumor innate immune response, especially levels of natural killer cell infiltration. In addition, the level of RNA editing in cancer cells was positively associated with somatic point mutation burden. This observation motivated the definition of a new metric, RNA editing load, reflecting the amount of RNA mutations created by RNA editing. Importantly, in lung cancer, RNA editing load was a stronger predictor of patient survival than DNA mutations. This study provides the first single cell dissection of editing in cancer and highlights the significance of RNA editing load in cancer prognosis.

Significance:

RNA editing analysis in single lung adenocarcinoma cells uncovers RNA mutations that correlate with tumor mutation burden and cancer innate immunity and reveals the amount of RNA mutations that strongly predicts patient survival.

See related commentary by Luo and Liang, p. 351
Elucidating the Genetic Landscape of Oral Leukoplakia to Predict Malignant Transformation
Authors: Wils Leon J. , Poell Jos B. , Brink Arjen , Evren Ilkay , Brouns Elisabeth R. , de Visscher Jan G.A.M. , Bloemena Elisabeth , Brakenhoff Ruud H.
Published: November 2022

Purpose:

Oral leukoplakia is the most common oral potentially malignant disorder with an annual malignant transformation rate of 1% to 5%. Consequently, oral leukoplakia patients have a 30% to 50% lifetime risk to develop oral squamous cell carcinoma. Although risk factors for malignant transformation of oral leukoplakia have been investigated, no definitive risk stratification model has been proposed. Next-generation sequencing can elucidate the genetic landscape of oral leukoplakia, which may be used to predict the risk for malignant transformation.

Experimental Design:

We investigated a retrospective cohort of 89 oral leukoplakia patients, and analyzed their oral leukoplakia lesions for the presence of genomic copy-number alterations and mutations in genes associated with oral squamous cell carcinoma.

Results:

In 25 of 89 (28%) patients, oral squamous cell carcinoma developed during follow-up. Seventy-nine of 89 (89%) oral leukoplakias harbored at least one genetic event. Copy-number alterations were present in 61 of 89 (69%) oral leukoplakias, most commonly gains of chromosome regions 8q24 (46%) and 20p11 (20%) and loss of 13q12 (19%). Mutations were present in 59 of 89 (66%) oral leukoplakias, most commonly in TP53 (28%), FAT1 (20%), and NOTCH1 (13%). Genetic data were combined with the presence of dysplasia to generate a prediction model, identifying three groups with a distinct risk for malignant transformation.

Conclusions:

We provide an extensive description of genetic alterations in oral leukoplakia and its relation to malignant transformation. On the basis of our data we provide a model for the prediction of malignant transformation of oral leukoplakia using dysplasia and genetic markers.
Congenital Hyperinsulinism: An Historical Perspective
Authors: Thornton Paul S. , Stanley Charles A. , De Leon Diva D.
Published: November 2022

Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in neonates, infants, and children. Since the first case descriptions in the 1950s, the field has advanced significantly. It was the development of the insulin radioimmunoassay by Yalow and Berson a decade later that made it possible to demonstrate that this form of persistent hypoglycemia was caused by insulin, and a few years later, Drash described the successful treatment of children with hyperinsulinism with the antihypertensive diazoxide, which until today remains the only approved treatment for hyperinsulinism. In the mid 1970s, Baker and Stanley described that hyperinsulinism can be recognized by inappropriate responses of metabolic fuels and hormones during the course of a provocative fasting challenge. Later, advances in molecular genetics led to the discovery of the different genetic subtypes of hyperinsulinism. One of the most impactful discoveries in the field was the recognition of the focal form of hyperinsulinism and the development of 18F-DOPA PET for the localization of focal lesions before surgery which has resulted in the possibility of cure for children with focal disease. However, treatment options for children with nonfocal diazoxide-unresponsive hyperinsulinism have continued to be limited. New drug development programs for hyperinsulinism promise to change this in the next few years. Unfortunately, despite all these advances, children with hyperinsulinism around the world continue to experience neurological sequelae at high rates, highlighting the importance of early diagnosis and effective treatment.
Clinical Pharmacist Intervention Reduces Potentially Inappropriate Prescriptions in a Geriatric Perioperative Care Unit Dedicated to Hip Fracture
Authors: Léguillon Romain , Varin Rémi , Pressat-Laffouilhère Thibaut , Chenailler Catherine , Chassagne Philippe , Roca Frédéric
Published: November 2022

Introduction: Clinical pharmacist (CP) intervention improves drug prescription by identifying potentially inappropriate prescriptions (PIPs). Geriatric perioperative care units (UPOGs) provide enhanced care for patients with hip fracture, including drug prescription. However, it is not known whether adding a CP intervention in a UPOG decreases the number of PIPs. This study aimed to evaluate the effect of a CP intervention, combining an implicit and an explicit method, on the number of PIPs in a UPOG. Methods: This single centre before-after-control-impact study recruited patients aged over 75 years admitted to a UPOG for a hip fracture. The “control group” (“before period”) received usual care including two medication reconciliations, one at admission and one at discharge. The “intervention group” (“after period”) received usual care and a CP intervention including two medication reconciliations, a medication review with two tools, STOPP/START and Medication Appropriateness Index, and a meeting between a CP and geriatricians. PIPs were assessed in both groups by STOPP/START and Medication Appropriateness Index and compared from hospital admission to discharge. Results: A total of 209 patients were included, 150 in the control group and 59 in the intervention group (mean age: 87.2 ± 5.9 years). The number of PIPs decreased in both groups from hospital admission to discharge (p < 0.001). The number of PIPs, potentially inappropriate medications, and potential prescribing omissions decreased more in the intervention group than in the control group (adjusted intervention effect: −2.46 (95% CI: −2.63; −2.24); −1.13 (95% CI: −1.27; −0.98); and −1.35 (95% CI: −1.52; −1.18), respectively, p < 0.001 for all). Discussion/Conclusion: A CP intervention with an explicit and implicit method improved prescriptions in a UPOG. Further randomized studies are necessary to evaluate the effect of a CP intervention on adverse drug events, health costs, and mortality.
Personality Disorder in Adolescent Patients with Anorexia Nervosa
Authors: Laczkovics Clarissa , Czernin Klara , Carlitscheck Jessica , Zeiler Michael , Schlund Pauline , Wunram Heidrun Lioba , Lehmkuhl Gerd , Krischer Maya
Published: November 2022

Objective: Anorexia nervosa (AN) is a highly debilitating disease which frequently results in chronification and often originates in adolescence. Personality traits have been associated with the onset and maintenance of AN; moreover, study results indicated a worse treatment outcome in patients with AN and comorbid personality disorder (PD). However, research on PD in adolescent AN is scarce. Methods: The sample consists of 73 female adolescent patients with AN. We investigated comorbid PD and AN symptom severity performing the International Personality Disorder Examination (IPDE) and the Eating Disorder Inventory 2 (EDI-2). Results: Almost a third (27.4%) of all participants were diagnosed with comorbid PD. They had significantly higher EDI-2 total scores reflecting overall stronger symptom severity, as well as significantly higher scores in the subscales “ineffectiveness,” “interpersonal distrust,” “interoceptive awareness,” “asceticism,” “impulse regulation,” and “social insecurity.” Conclusion: PD is an important and frequent comorbid condition in adolescent AN and should be addressed in diagnostic and treatment planning. Early diagnosis of comorbidity could have an impact on choosing specialized treatment for adolescents with AN and PD in order to enhance the outcome.
11-Oxygenated Androgen Metabolite Concentrations Are Affected by Pubertal Progression and Obesity
Authors: Breslow Emily , Taylor Anya , Chan Christine L. , Severn Cameron , Pyle Laura , Torchen Laura , Sisk Ryan , Legro Richard , Turcu Adina F. , Auchus Richard J. , Dunaif Andrea , Kelsey Megan Moriarty , Cree-Green Melanie
Published: November 2022

Introduction: 11-oxygenated C19 steroids (11-oxyandrogens) have been shown to rise during adrenarche and remain higher throughout adulthood than in early childhood. The patterns of circulating 11-oxyandrogens throughout normal puberty have not yet been described. Methods: We conducted a secondary analysis of healthy youth participants, both males and females, enrolled in six prior endocrine studies (N = 249). Participants were classified according to Tanner stage and body mass index (BMI). Concentrations of three adrenal-specific 11-oxygenated androgens, 11β-hydroxyandrostenedione (11OHA4), 11β-hydroxytestosterone (11OHT), and 11-ketotestosterone (11KT), were measured in fasting serum samples. Results: 11OHA4 and 11OHT increased modestly between early and late puberty in youth with normal weight (p < 0.05), whereas increases in 11KT did not reach statistical significance (p < 0.06). 11KT levels differed between sexes throughout puberty (p < 0.01), and changes in 11-oxyandrogens were small compared to the marked increases for estradiol in girls or testosterone in boys. The trajectories of 11KT and 11OHA4 changes throughout puberty differed by BMI category (p < 0.05). Conclusion: Beyond adrenarche, 11-oxyandrogens continue to rise during pubertal development. The differences in 11KT trajectories in males and females are small compared to changes in testosterone for males and estradiol for females during puberty. Obesity appears to influence the trajectories of 11-oxyandrogens during puberty.
Abstract 102: Autophagy Is Differentially Regulated In Leukocyte And Nonleukocyte Foam Cells During Atherosclerosis
Authors: Robichaud Sabrina , Rasheed Adil , Pietrangelo Antonietta , Kim Anne , Boucher Dominique , Emerton Chrissy , Vijithakumar Viyashini , Gharibeh Lara , Fairman Garrett , Mak Esther , Nguyen My-anh , Geoffrion Michele , Wirka Robert , Rayner Katey J , Ouimet Mireille I
Published: November 2022

Atherosclerosis is characterized by a build-up of foam cells in the arterial wall, resulting from excess cholesterol uptake and accumulation of cytosolic lipid droplets (LDs). Autophagy has been shown to be atheroprotective in part by promoting the catabolism of LDs which liberates free cholesterol for efflux out of foam cells to cholesterol acceptors (ApoA-I or HDL) for removal from the body. Apart from macrophages (MΦ), vascular smooth muscle cells (VSMCs) comprise 50-70% of foam cells in the plaques. Unlike MΦ, the capacity of VSMC foam cells to metabolize cholesterol via autophagy is unknown. Here, w
e performed a comparative analysis of the autophagic capacity and cholesterol efflux of arterial foam cell subtypes of the atherosclerotic plaque
.

Atherosclerosis was induced in hypercholesterolemic autophagy reporter mice (GFP-LC3 mice receiving PCSK9-AAV and fed a Western diet). Autophagic flux in aortic digests was assessed by quantifying GFP-LC3 fluorescence after
ex vivo
treatment with the autophagy inhibitor Bafilomycin A1 or vehicle. MΦ foam cells displayed functional autophagy as shown by an accumulation of GFP-LC3 upon autophagy inhibition. In contrast, VSMC foam cells did not similarly accumulate GFP-LC3 upon bafilomycin treatment, suggesting dysfunction autophagy in these cells. Additionally, immunostaining of late-stage aortic roots showed MΦ, but not VSMC, foam cells induction of the active autophagy marker pATG16L1. Cell culture studies of lipid loaded MΦ and VSMC corroborated this inability for VSMCs to initiate autophagy
in vivo
.

In vitro
, MΦ foam cells effluxed cholesterol to ApoA-I (14%) and HDL (50%), whereas VSMC foam cells minimally effluxed cholesterol to HDL (7%) but not apoA-I. However, unlike MΦ foam cells, VSMC efflux was pharmacologically induced by treatment with metformin.

Our data therefore demonstrates a lack of functional autophagy in VSMC, as compared to MΦ foam cells, which impairs their ability to perform cholesterol efflux. This autophagy defect in VSMC foam cells can be increased by autophagy activation using metformin, highlighting both the importance of understanding cholesterol metabolism in all foam cell populations and a new avenue to treat atherosclerosis.
Abstract 103: Cycling Of Plasma Cholesterol Increases The Rate Of Atherosclerosis Progression And Alters The Chromatin Landscape Of Bone Marrow Monocytes
Authors: Scolaro Bianca , Weinstock Ada , Kireccibasi Ozlem , Brown Emily , Fisher Edward
Published: November 2022

Background:
Coronary artery disease (CAD) is the leading cause of death worldwide. Although statins decrease CAD risk by lowering LDL cholesterol (LDL-C), only half of statin users adhere to treatment. Of those who discontinue, 75% resume statin therapy at a later time. Thus, many undergo recurring cycles of lower to higher LDL-C. High variability in LDL-C is an independent predictor of CVD events, but the direct effects of plasma cholesterol cycles on atherosclerosis plaque progression, or regression, remain unknown.

Methods:
Ldlr-/-
mice were fed a high fat/cholesterol-western diet (WD) for 16 weeks to develop advanced plaques (Baseline; BL). A first round of cholesterol lowering was attained with ApoB anti-sense oligonucleotide injections. Some animals were harvested after 4 weeks of cholesterol lowering (Regression; Reg) while the remaining continued on WD for 4 more weeks after stopping ASO injections, so that cholesterol levels were again increased (Cycled progression; CyP). Another round of cholesterol lowering followed for 4 weeks (Cycled regression; CyR). Mice that had continuous high levels of cholesterol were used as controls (progression; P).

Results:
Animals subjected to high cholesterol cycles (CyP) showed increased rates of macrophage (CD68+cell) accumulation in atherosclerotic plaques. This increase was two times greater than commonly seen when plasma cholesterol remained elevated. Plaques in CyP also showed a proinflammatory phenotype and increased monocyte recruitment. Despite this, a subsequent round of cholesterol lowering (CyR) effectively regressed plaques. ATAC-seq analysis of bone marrow (BM) monocytes showed distinct landscapes of chromatin accessibility between the groups, particularly with CyP showing a seemingly paradoxical and strong pattern of closed chromatin at inflammatory genes, such as
IL-6, TLR-4
, and
Ifnar2
, though plaque macrophages were more inflammatory.

Conclusion:
Cholesterol cycling aggravates atherosclerosis when high levels are regained vs. when they are sustained. Interestingly, plaque macrophages and BM monocytes may be differentially affected by cholesterol cycles. These results may be particularly relevant to patients with intermittent adherence to statins and higher risk for CVD.
Abstract 106: Ribosomal Protein Rpl17 Controls Endothelial Cell Translation: A Key Mediator Of Intima Growth And Vascular Disease
Authors: Chowdhury Sayantani , Wines-Samuelson Mary , Berk Bradford C
Published: November 2022

Background:
Carotid intima-media thickening (IMT) is a significant risk factor for cardiovascular disease (CVD). Using genetic analysis of the partial carotid ligation (PCL) model of disturbed flow induced IMT, we identified a strong association between decreased expression of the large ribosomal subunit protein 17 (RpL17) and increased IMT. RpL17 is located at the exit tunnel of the ribosome, making it critical for processing of newly translated proteins. To define the mechanism by which RpL17 inhibits IMT, we generated EC-restricted (Cdh5-Cre) conditional RpL17 heterozygous mice (EC-RpL17).

Results:
1) PCL of EC-RpL17 increased IMT vs wild type (Control) littermates. 2) EM analysis revealed decreases in total ribosome number and polysomes in EC-RpL17, consistent with decreased global translation. 3) RNA-seq showed major changes in two pathways: Eukaryotic Initiation Factor 2 (eIF2α) that promotes adaptive translational responses to stress, and oxidative phosphorylation (OXPHOS), the electron transport metabolic pathway that produces ATP. 4) Profiling of mRNAs bound to polysomes in RpL17-EC revealed increased translational efficiency (TE) of selective redox regulators, pro-inflammatory mediators, matrix metalloproteases, and endothelial to mesenchymal transition (endMT) factors; consistent with processes that promote IMT. 5) Increased levels of RNA binding proteins (RBPs) in EC-RpL17, such as QKI, HuR, and hn-RNP, correlated with enhanced stability of specific mRNAs and their TE. 6) Increased TE of glycolytic enzymes and the lactate transporter was consistent with increased EC glycolysis and OXPHOS dysfunction. 7) Increased glycolysis correlated with greater cell proliferation, suggesting RpL17 is a growth suppressor.

Conclusion:
These data define a new mechanism for control of EC function via selective changes in mRNA stability and ribosome profile and number that decreased OXPHOS and global protein translation, leading to EC-proliferation and endMT, which enhanced IMT in the PCL model of disturbed flow.