bluuebunny/crossref_metadata_2025 huggingface dataset:
Analyzing the Risk Factors of COVID-19 in India Using Intuitionistic Fuzzy VIKOR Method Based on Entropy Weighting
Authors: Aicevarya Devi S
Published: June 2022

The virus that arises from Wuhan, popularly called as “coronavirus” has been spread all over the world in a short period. India has also taken preventive measures to control this threatening virus. In addition to precautions, it is necessary to analyze the risk factors of COVID-19 in overpopulated countries to reduce the impact of the virus. As India is the second-populated country, analyzing the risk factor of COVID-19 helps in categorizing the likely and non-likely people affect by the virus. The work manages the fuzziness through intuitionistic fuzzy sets combine with the VIKOR decision-making process to find the most influencing risk factors of COVID-19. The objective weights of the criteria are evaluated by entropy as it measures the randomness in discrete distribution. Moreover, sensitivity analysis is conducted to verify the robustness of the results of the proposed method.
A Decision-Making Problem for Selecting an optimal Antivirus Mask over COVID-19 Pandemic under Pythagorean Fuzzy Information Based on Hybrid TODIM - Inferior Ratio Method
Authors: Kumar Sunit , Kumar Satish
Published: June 2022

Yager was the first who developed the concept of Pythagorean fuzzy sets (PFSs) to tackle uncertainty and vagueness. PFSs is applicable when Intuitionistic fuzzy sets are not able to tackle the uncertainty in real life. In the present paper, based on the concept of Gini-Simpson Entropy, a Pythagorean fuzzy entropy measure is introduced under Pythagorean fuzzy environment. The maximality feature and monotonic behaviour of the developed information measure have been presented to satisfy some elegant mathematical properties which prepare the ground for applications in various disciplines. We extend the TODIM-Inferior ratio method for solving the (MCDM) multicriteria decision-making problems where the behaviour of experts, are taken into consideration. The proposed Pythagorean information measure has been established based on the different cases when weights are partially known. A real-life numerical example has been successfully illustrated to demonstrate the flexibility and efficacy of the developed method.
Bi-Quadratic Varying Deceleration Parameter to Study the Cosmological Model
Authors: Kumar R , Arora S
Published: June 2022

This paper investigates a cosmological model employing a four-degree function of cosmic time t in the f(R, T) gravity theory using an extended form of deceleration parameter. Under the constraints of flat, diagonal, and Bianchi type-1 metrics, we develop the exact solution of Einstein field equations (EFE). We research early time deceleration and accomplish the definite solution of EFE using an extended form of deceleration parameter, as well as the always super-exponential expansion behaviour of bi-quadratically variable deceleration parameter using a graph. We explore the model’s efficacy by examining the relationship between the deceleration parameter and red shift, which offers a valid result concerning the FRW metric’s consistent homogeneous structure in light of recent cosmological observations.
Green synthesis of carboxymethyl cellulose from agricultural waste its characterization
Authors: Singh R , Singh J , Sonika  , Singh H
Published: June 2022

In the present study, corncob (an agricultural waste) has been explored as a source of cellulose. Cellulose was extracted from corncob through removal of hemicellulose and lignin. The carboxymethyl cellulose (CMC) was then synthesized from extracted cellulose by alkalization and etherification with 30% NaOH and 120% monochloro acetic acid (MCA) in ethanol medium respectively. Characterization of prepared CMC was carried out by various techniques like Fourier Transform Infra-Red (FTIR) spectroscopy, X-Ray Diffraction (XRD) and Scanning Electron Microscpoe (SEM). Back titration method was used to determine the Degree of Substitution (DS). The synthesized CMC obtained has a large DS value of 2.27. The purity of CMC was high at 91.65% and showed a yield of 1.20g/g, intrinsic viscosity of 1.02, water holding capacity 3.81g/g and oil holding capacity 1.66g/g. Higher degree of substitution is achieved in this work. The synthesized product is effective suitable additive for food and various pharmaceuticals industries.
Analysis of growth in population through nonlinear stochastic process
Authors: Bhagirath Kirti
Published: June 2022

Probability density evolution of an insect population is discussed by taking non linear stochastic differential equations for the growth and also using the related Fokker-Plank equations for the probability densities which are time dependent. It can be seen that the variance behavior depends on initial conditions whereas the effect of initial conditions disappears rapidly in mean case. We can observe the difference in the response of mean and variance as the growth of insects proceeds. It is found that variance of the process may increase monotonically to a level above the steady state variance before getting back to steady state variance.
Sol-gel Derived (Pb0.65Sr0.35)(Zr0.5, Ti0.5)O3 Ferroelectric Thin Films: Structural and Electrical Properties
Authors: Bhasker V. , Sharma U. , Kumar G. , Thomas R.
Published: June 2022

The Pb(Zr0.5, Ti0.5)O3 (PZT) is one of the ferroelectric materials used in the non-volatile memories. However, PZT usually suffers from fatigue that degrades the polarization with metallic electrodes. The high stability associated with Sr-O bonding reduces oxygen vacancies which in turn lessens fatigue and hence Sr in introduced at Pb site. In the present study (Pb0.65Sr0.35)(Zr0.5, Ti0.5)O3 (PSZT) ferroelectric thin films were successfully prepared by sol-gel method. The structural and morphological properties of the thin film were studied by x-ray diffraction and atomic force microscopy, respectively. The crystallization of the film was completed at 600°C of annealing and the root mean square roughness of the 300 nm film was around 4.5 nm. When Pb in Pb(Zr0.5, Ti0.5)O3 was substituted with 35% Sr, the coercive field increased and the remnant polarization reduced as compared to pure PZT. The films were ferroelectric at room temperature with the phase transition temperature at ~375°K. The dielectric constant and the loss tangent at room temperature were 257 and 0.023, respectively at 100 kHz.
Numerical simulation of MASnI3/CuI heterojunction based perovskite solar cell
Authors: Sharma Amit K , Kaushik Deepak Kumar
Published: June 2022

The lead (Pb) free perovskite solar cells have gained much attention due to non-toxic nature. Owing to a smaller band gap of 1.3 eV, methylammonium tin iodide (III) (MASnI3) can be considered an alternate light absorber layer compare to the lead-based perovskites (MAPbClxI3-x). In this article, MASnI3based perovskite solar cell has been studied using a 1-D SCAPS simulator. The solar cell structure ITO/TiO2/MASnI3/CuI is simulated in superstrate configuration which achieves a photovoltaic efficiency less than 8 %. Photovoltaic efficiency of the solar cell is further improved to 17.93 % by optimizing thickness and total defect density of the absorber layer. Moreover, the role of defects at the interfaces: TiO2/MASnI3and MASnI3/CuI on the solar cell performance is also analyzed.
Quantity Based weights forecasting for TAIEX
Authors: Garov A K
Published: June 2022

Many models of the forecasting have been proposed on stock index. In this paper, the consideration of Taiwan Stock Exchange Capitalization Weights Stock Index (TAIEX) has been taken and founded forecasted index value. Here forecasting is done by using Quantity based fuzzy time series (QBFTS), Quantity based factor TAIEX and forecasting methods are QBFLR and QBFLRGs. The approach of Statistical weights assigned for different weights to various quantity based fuzzy logical relationships for considered quantity-based dataset of TAIEX. Hence got the comparative result better than the other models.
Data Mining Prediction Techniques in Health Care Sector
Authors: sharma Minakshi
Published: June 2022

Knowledge discovery in databases (KDD) is another name of Data mining. It is an interdisciplinary area which focuses on extraction of useful knowledge from data in every sector like health, education, business etc. Nowadays, as covid pandemic is affecting everyone and due to surge in coronavirus cases causing shortage of hospital beds, oxygen supplies, vaccine and turning away patients from hospitals, put creaky health infrastructure in spotlight. The plenty of data is available in the medical field of these conditions. Data mining approaches can be used to extract useful patterns from these types of data to follow the upcoming trends. This paper focuses on various data mining techniques which can be used in medical industries for the best outcome.
Fourier Series And Fourier Integral Equations And Their Applications In Elasticity
Authors: Awasthi A K , Rachna
Published: June 2022

The role of Fourier Series and Fourier Integral Equations in both theoretical and applied mathematics is extremely important. The aim of this paper is to introduce the reader to some of the most critical aspects of historical development of Fourier series and Fourier integrals theory and applications. The paper is based on the work of Sneddon, Srivastva et al. on solving Dual Fourier series, Triple Fourier series and Quadruple Fourier series Equations by using various methods. The different methods for solving Dual integral equations, Triple integral equations and Quadruple integral equations given by Parihar, Tranter et al. will also be mentioned. Finally, some recent applications of these equations to the mathematical theory of elasticity also stated.
Recent advances in the electrical and optical properties of Alq3 and Alq3 derivatives based OLEDS
Authors: Debsharma Mrinmoy , Pramanik Tanay , Daka Chisomo , Mukherjee Rupam
Published: June 2022

OLEDs (Organic light-emitting diodes) have become he most popular organic lighting-technology to fabricate full color, flexible, flat panel displays and various other lighting purposes in recent years. The greatest technical challenges so far in this area has been identified as finding new organic semiconducting electroluminescent materials with higher efficiency, longer durability and low operating voltage and long-term stability. Tris(8-hydroxyquino-linato) aluminium (Alq3) is one such promising material with an octahedral coordination che-lated aluminium (III) structure which has proved its versatile optical properties since long time. Alq3 is a typical electron transporting material used as electron transport layer (ETL)and also used as host material of emissive layer in organic light emitting diodes (OLEDs). In this review paper, our main focus is on recent advances in the optical and electrical properties of Alq3 and Alq3 derivatives-based OLEDs developed so far. On addition, we provide a comparison table of electroluminescence and photoluminescence performance and efficiency through EL spectra, PL spectra, Absorption spectra, Current-voltage plot data collected from different research groups all around the world.
Beyond the Carceral/Anti-carceral Binary: Considerations for Addressing Gender-based and Sexual Violence
Authors: Brockbank Maddie , Greene Saara
Published: June 2022

This article aims to contribute to the burgeoning scholarship on carceral and anti-carceral feminist approaches to addressing gender-based and sexual violence (GBSV). Specifically, this article attempts to draw out the contributions and tensions of carceral and anti-carceral approaches towards the elimination of GBSV within the context of feminist social work practices and policies. Engaging in a reflexive process that draws on our collective experience of social work education, practice, activism, and research, we argue that, rather than reinforcing the carceral/anti-carceral binary, a critical consideration of current tensions and debates in this area may provide a more productive way forward in addressing gender-based and sexual violence more broadly.
Identifying the Presence, Activity, and Status of Extraintestinal Manifestations of Inflammatory Bowel Disease Using Natural Language Processing of Clinical Notes
Authors: Stidham Ryan W , Yu Deahan , Zhao Xinyan , Bishu Shrinivas , Rice Michael , Bourque Charlie , Vydiswaran Vinod V G
Published: June 2022

Background

Extraintestinal manifestations (EIMs) occur commonly in inflammatory bowel disease (IBD), but population-level understanding of EIM behavior is difficult. We present a natural language processing (NLP) system designed to identify both the presence and status of EIMs using clinical notes from patients with IBD.

Methods

In a single-center retrospective study, clinical outpatient electronic documents were collected in patients with IBD. An NLP EIM detection pipeline was designed to determine general and specific symptomatic EIM activity status descriptions using Python 3.6. Accuracy, sensitivity, and specificity, and agreement using Cohen’s kappa coefficient were used to compare NLP-inferred EIM status to human documentation labels.

Results

The 1240 individuals identified as having at least 1 EIM consisted of 54.4% arthritis, 17.2% ocular, and 17.0% psoriasiform EIMs. Agreement between reviewers on EIM status was very good across all EIMs (κ = 0.74; 95% confidence interval [CI], 0.70-0.78). The automated NLP pipeline determining general EIM activity status had an accuracy, sensitivity, specificity, and agreement of 94.1%, 0.92, 0.95, and κ = 0.76 (95% CI, 0.74-0.79), respectively. Comparatively, prediction of EIM status using administrative codes had a poor sensitivity, specificity, and agreement with human reviewers of 0.32, 0.83, and κ = 0.26 (95% CI, 0.20-0.32), respectively.

Conclusions

NLP methods can both detect and infer the activity status of EIMs using the medical document an information source. Though source document variation and ambiguity present challenges, NLP offers exciting possibilities for population-based research and decision support in IBD.
The Kinematics and Functional Significance of Chemosensory Tongue-Flicking in Northern Water Snakes (Nerodia sipedon) on Land, in Water, and in between
Authors: Ryerson William G , Schwenk Kurt
Published: June 2022

Synopsis

As organisms transition between different environments, they must do more than simply move through that transition and those environments. Changes in the environment must be detected via the senses. The types of sensory information and the mechanisms of collecting that information may also change as an individual moves through different environments. We use tongue-flicking in northern water snakes, Nerodia sipedon, to examine the mechanics of sensory behavior as snakes move from terrestrial to aquatic habitats. A combination of high-speed video and mesocosm experiment revealed that water snakes will alter the mechanics of tongue-flicking in the context of their environment. Tongue-flicks on land are distinctive, with multiple oscillations, large protrusion distance, and high velocities. Comparatively, tongue-flicks under water are much shorter events, with reduced protrusion and fewer oscillations. At the surface of the water, in the presence of potential anuran prey, water snakes will tap the tips of the tongue on the surface of the water, without undergoing the full oscillations observed on land or underwater. We attribute the differences in the aerial and underwater tongue-flicks to trade-offs in the physical and chemical properties of the environment. The surface tapping behavior we observed is likely snakes altering their behavior to maximize the encounter and collection of frog-specific chemical cues, which are known to travel on the water's surface. Given the ecological transitions and distinctive biogeographical patterns rooted in water snake ecology, there are likely more examples of changing sensory mechanics to be discovered upon further investigation.
MyCap: a flexible and configurable platform for mobilizing the participant voice
Authors: Harris Paul A , Swafford Jonathan , Serdoz Emily S , Eidenmuller Jessica , Delacqua Giovanni , Jagtap Vaishali , Taylor Robert J , Gelbard Alexander , Cheng Alex C , Duda Stephany N
Published: June 2022

This paper provides a description of the MyCap data collection platform, utilization metrics, and vignettes associated with use from diverse research institutions. MyCap is a participant-facing mobile application for survey data collection and the automated administration of active tasks (activities performed by participants using mobile device sensors under semi-controlled conditions). Launched in 2018, MyCap is a no-code solution for research teams conducting longitudinal studies, integrates tightly with REDCap and is available at no cost to research teams at academic, nonprofit, or government organizations. MyCap has been deployed at multiple research institutions with application usage logged across 135 countries in 2021. Vignettes demonstrate that MyCap empowered research teams to explore and implement novel methods of information collection and use. MyCap’s integration with REDCap provides a comprehensive data collection ecosystem and is best suited for longitudinal studies with frequent requests for information from participants.
Quantification of methane emitted by ruminants: a review of methods
Authors: Tedeschi Luis Orlindo , Abdalla Adibe Luiz , Álvarez Clementina , Anuga Samuel Weniga , Arango Jacobo , Beauchemin Karen A , Becquet Philippe , Berndt Alexandre , Burns Robert , De Camillis Camillo , Chará Julián , Echazarreta Javier Martin , Hassouna Mélynda , Kenny David , Mathot Michael , Mauricio Rogerio M , McClelland Shelby C , Niu Mutian , Onyango Alice Anyango , Parajuli Ranjan , Pereira Luiz Gustavo Ribeiro , del Prado Agustin , Paz Tieri Maria , Uwizeye Aimable , Kebreab Ermias
Published: June 2022

The contribution of greenhouse gas (GHG) emissions from ruminant production systems varies between countries and between regions within individual countries. The appropriate quantification of GHG emissions, specifically methane (CH4), has raised questions about the correct reporting of GHG inventories and, perhaps more importantly, how best to mitigate CH4 emissions. This review documents existing methods and methodologies to measure and estimate CH4 emissions from ruminant animals and the manure produced therein over various scales and conditions. Measurements of CH4 have frequently been conducted in research settings using classical methodologies developed for bioenergetic purposes, such as gas exchange techniques (respiration chambers, headboxes). While very precise, these techniques are limited to research settings as they are expensive, labor-intensive, and applicable only to a few animals. Head-stalls, such as the GreenFeed system, have been used to measure expired CH4 for individual animals housed alone or in groups in confinement or grazing. This technique requires frequent animal visitation over the diurnal measurement period and an adequate number of collection days. The tracer gas technique can be used to measure CH4 from individual animals housed outdoors, as there is a need to ensure low background concentrations. Micrometeorological techniques (e.g., open-path lasers) can measure CH4 emissions over larger areas and many animals, but limitations exist, including the need to measure over more extended periods. Measurement of CH4 emissions from manure depends on the type of storage, animal housing, CH4 concentration inside and outside the boundaries of the area of interest, and ventilation rate, which is likely the variable that contributes the greatest to measurement uncertainty. For large-scale areas, aircraft, drones, and satellites have been used in association with the tracer flux method, inverse modeling, imagery, and LiDAR (Light Detection and Ranging), but research is lagging in validating these methods. Bottom-up approaches to estimating CH4 emissions rely on empirical or mechanistic modeling to quantify the contribution of individual sources (enteric and manure). In contrast, top-down approaches estimate the amount of CH4 in the atmosphere using spatial and temporal models to account for transportation from an emitter to an observation point. While these two estimation approaches rarely agree, they help identify knowledge gaps and research requirements in practice.
Application of resistivity sounding in Quaternary stratigraphic division in Yixing, Eastern China
Authors: Tian Shaobing , Zhang Ping , Shang Tongxiao , Chen Huogen , Li Yongxiang , Xu Shugang
Published: June 2022

Stratigraphic classification and correlation are fundamental for the study of regional geology, tectonic structures and paleogeographic evolution. Geological structures have undergone a dramatic change since the Quaternary. However, the division of the Quaternary stratigraphic boundary in southeastern China is debated. In this study, we used a direct current vertical electric sounding method to study the Quaternary strata in Yixing, Jiangsu, China. Using one-dimensional resistivity inversion and analyzing the regional geology and geological core data, the electrical features of the study area were evaluated. We found good agreement between the geological core data and lithological data, and we were able to identify two stratigraphic groups: the hilly sedimentary area in the southwest and the Tai Lake plain sedimentary area in the northeast. The latter can further subdivided into two parts. Division and classification of the Quaternary strata in the study area provide a basis for locating areas likely to have a high pore-confined water content (such as Gaoteng, Heqiao and Wanshi town), whereby useful information is provided for groundwater exploitation for emergency use.
Inhibiting Matrix Metalloproteinases Protects Evoked Electromyography Amplitudes and Muscle Tension in the Orbicularis Oris Muscle in a Rat Model of Facial Nerve Injury
Authors: Wu Shuang , Song Lijun , Yu Meirong , Gong Chao , Chen Lianhua
Published: June 2022

Facial nerve injury results in degradation of the neuromuscular junction (NMJ) and blocks neurotransmission between the pre- and postsynaptic structures, which are separated by a synaptic cleft. Matrix metalloproteinases (MMPs), enzymes that degrade and modify the extracellular matrix, play critical roles in regulating NMJ remodeling. We previously demonstrated that MMP1, MMP2, MMP3, MMP7, and MMP9 are overexpressed in facial nerve-innervated orbicularis oris muscle after facial nerve injury in a rat model. In the present study, the MMP inhibitor prinomastat was administered to rats after facial nerve injury. The MMP levels, agrin expression, and muscle-specific kinase (MuSK) phosphorylation were evaluated. Variations in evoked electromyography (EEMG) amplitude were also recorded. Compared with the control group, MMP expression in the orbicularis oris after facial nerve injury was significantly reduced in the prinomastat group. Inhibition of MMP expression maintained agrin expression and MuSK phosphorylation; the NMJ morphology was also protected after the injury. Moreover, prinomastat treatment sustained EEMG amplitude and muscle tension after the injury. These findings indicate that inhibiting MMPs can protect the function and morphology of the NMJ and demonstrate the need for protection of the NMJ at early stages after facial nerve injury.
Demographic and Glycemic Factors Linked With Diabetes Distress in Teens With Type 1 Diabetes
Authors: Inverso Hailey , LeStourgeon Lauren M , Parmar Angie , Bhangui Isha , Hughes Bailey , Straton Emma , Alford Madeleine , Streisand Randi , Jaser Sarah S
Published: June 2022

Objective

Diabetes distress (DD) is a negative emotional response related to the burdens of living with type 1 diabetes (T1D) and is linked with diabetes outcomes, such as hemoglobin A1c (A1c). Yet, less is known about how other glycemic indicators, average blood glucose and time in range, relate to DD, and which demographic characteristics are associated with higher DD.

Methods

In total, 369 teens (Mage 15.6 ± 1.4, 51% female, MT1D duration 6.7 ± 3.8 years) screened for DD using The Problem Areas in Diabetes—Teen Version to determine eligibility for an ongoing multi-site behavioral trial. The associations of DD, demographic factors, and glycemic indicators (A1c, average blood glucose, and time in range) were analyzed.

Results

Twenty-nine percent of teens (n = 95) scored above the clinical cutoff (≥44) for DD. Females scored significantly higher on average than males. Black/African American, non-Hispanic youth screened significantly higher compared to youth from other racial/ethnic groups. Higher DD scores were related to higher A1c and average blood glucose, and lower time in range. Logistic regression models revealed that females were significantly more likely to report clinically elevated DD than males, and teens with higher A1c were 1.3 times more likely to report DD. Age and diabetes duration were not significantly associated with clinically elevated DD scores.

Conclusions

Results demonstrated that DD is most prevalent in Black, non-Hispanic and female teens, and DD is associated with higher average blood glucose and lower time in range. Further investigation into these disparities is warranted to promote optimal health outcomes for teens with T1D.
Symptoms and Central Sensory Integration in People With Chronic mTBI: Clinical Implications
Authors: Martini Douglas N , Gera Geetanjali , Brumbach Barbara H , Campbell Kody R , Parrington Lucy , Chesnutt James , King Laurie A
Published: June 2022

Introduction

Balance deficits in people with chronic mild traumatic brain injury (mTBI; ≥3 months post-mTBI), thought to relate to central sensory integration deficits, are subtle and often difficult to detect. The purpose of this study was to determine the sensitivity of the instrumented modified clinical test of sensory integration for balance (mCTSIB) in identifying such balance deficits in people with symptomatic, chronic mTBI and to establish the associations between balance and mTBI symptom scores in the chronic mTBI group.

Methods

The Institutional Review Board approved these study methods. Forty-one people with chronic mTBI and balance complaints and 53 healthy controls performed the mCTSIB (eyes open/closed on firm/foam surfaces; EoFi, EcFi, EoFo, and EcFo) with a wearable sensor on their waist to quantify sway area (m2/s4). Sensory reweighting variables were calculated for the firm and foam stance conditions. A stopwatch provided the clinical outcome for the mCTSIB (time). Each participant completed the Neurobehavioral Symptom Inventory (NSI), which quantifies mTBI-related symptoms and provides a total score, as well as sub-scores on affective, cognitive, somatic, and vestibular domains.

Results

The mTBI group reported significantly higher symptom scores across each NSI sub-score (all Ps < .001). The mTBI group had a significantly larger sway area than the control group across all mCTSIB conditions and the mTBI group had significantly higher sensory reweighting scores compared to the control group on both the firm (P = .01) and foam (P = .04) surfaces. Within the mTBI group, the NSI vestibular score significantly related to the mCTSIB sway area EcFi (r = 0.38; P = .02), sway area EcFo (r = 0.43; P = .006), sensory reweighting firm (r = 0.33; P = .04), and sensory reweighting foam (r = 0.38; P = .02). The average sway area across the 4 mCTSIB conditions was significantly (area under the curve: 0.77; P < .001) better at differentiating groups than the mCTSIB clinical total score. The average sway area across the 4 mCTSIB conditions had a sensitivity of 73% and a specificity of 71%. The clinical mCTSIB outcome scores were not different between groups.

Conclusion

People with chronic mTBI appear to have central sensory integration deficits detectable by instrumented measures of postural assessment. These findings suggest that central sensory integration should be targeted in rehabilitation for people with chronic mTBI.
Stellar populations of the globular cluster NGC 5053 investigated using AstroSat-Ultra Violet Imaging Telescope
Authors: Nikitha K J , Vig S , Ghosh S K
Published: June 2022

Globular clusters (GCs), being old and densely packed, serve as ideal laboratories to test stellar evolution theories. Although there is enormous literature on GCs in optical bands, studies in the ultraviolet (UV) regime are sparse. In this work, we study the stellar populations of a metal-poor and a rather dispersed GC, NGC 5053, using the UV instrument of AstroSat, namely the Ultra Violet Imaging Telescope in three far-UV (F154W, F169M, F172M) and three near-UV (N219M, N245M, N263M) filters. Photometry was carried out on these images to construct a catalogue of UV stars, of which the cluster members were identified using Gaia EDR3 catalogue. UV and optical colour–magnitude diagrams (CMDs) help us locate known stellar populations such as blue horizontal branch stars, RR-Lyrae stars, red horizontal branch stars, blue straggler stars (BSSs), SX-Phe, red giant branch, and AGB stars. Based on their locations in the CMDs, we have identified eight new BSS candidates, six probable eBSSs, and an extreme horizontal branch candidate. Their nature has been confirmed by fitting their spectral energy distributions (SEDs) with stellar atmospheric models. We believe the BSS population of this cluster is likely to have a collisional origin based on our analyses of their radial distribution and SEDs. BaSTI-IAC isochrones were generated to characterize the cluster properties, and we find that the observed brightness and colours of cluster members are best fit with a model that is α-enhanced with Y =0.247, [Fe/H] = −1.9, and age =12.5 ± 2.0 Gyr.
Exploring the outskirts of the EAGLE disc galaxies
Authors: Varela-Lavin Silvio , Tissera Patricia B , Gómez Facundo A , Bignone Lucas A , Lagos Claudia del P
Published: June 2022

Observations show that the surface brightness of disc galaxies can be well-described by a single exponential (TI), up-bending (TIII), or down-bending (TII) profiles in the outskirts. Here we characterize the mass surface densities of simulated late-type galaxies from the eagle project according to their distribution of mono-age stellar populations, the star formation activity, and angular momentum content. We find a clear correlation between the inner scale lengths and the stellar spin parameter, λ, for all three disc types with λ > 0.35. The outer scale lengths of TII and TIII discs show a positive trend with λ, albeit weaker for the latter. TII discs prefer fast rotating galaxies. With regards to the stellar age distribution, negative and U-shape age profiles are the most common for all disc types. Positive age profiles are determined by a more significant contribution of young stars in the central regions, which decrease rapidly in the outer parts. TII discs prefer relative higher contributions of old stars compared to other mono-age populations across the discs whereas TIII discs become progressively more dominated by intermediate age (2–6 Gyr) stars for increasing radius. The change in slope of the age profiles is located after the break of the mass surface density. We find evidence of larger flaring for the old stellar populations in TIII systems compared to TI and TII, which could indicate the action of other processes. Overall, the relative distributions of mono-age stellar populations and the dependence of the star formation activity on radius are found to shape the different disc types and age profiles.
Rhenium(I) conjugates as tools for tracking cholesterol in cells
Authors: Lazniewska Joanna , Bader Christie , Hickey Shane M , Selemidis Stavros , O'Leary John , Simpson Peter V , Stagni Stefano , Plush Sally E , Massi Massimiliano , Brooks Doug
Published: June 2022

Cholesterol is vital to control membrane integrity and fluidity, but is also a precursor to produce steroid hormones, bile acids, and vitamin D. Consequently, altered cholesterol biology has been linked to many diseases, including metabolic syndromes and cancer. Defining the intracellular pools of cholesterol and its trafficking within cells is essential to understand both normal cell physiology and mechanisms of pathogenesis. We have synthesized a new cholesterol mimic (ReTEGCholestanol), comprising a luminescent rhenium metal complex and a cholestanol targeting unit, linked using a tetraethylene glycol (TEG) spacer. ReTEGCholestanol demonstrated favourable imaging properties and improved water solubility when compared to a cholesterol derivative, and structurally related probes lacking the TEG linker. A non-malignant and three malignant prostate cell lines were used to characterize the uptake and intracellular distribution of ReTEGCholestanol. The ReTEGCholestanol complex was effectively internalized and mainly localized to late endosomes/lysosomes in non-malignant PNT1a cells, while in prostate cancer cells it also accumulated in early endosomes and multivesicular bodies, suggesting disturbed cholesterol biology in the malignant cells. The ReTEGCholestanol is a novel imaging agent for visualizing endosomal uptake and trafficking, which may be used to define cholesterol related biology including membrane integration and altered lipid trafficking/processing.
Systematic evaluation of parameters in RNA bisulfite sequencing data generation and analysis
Authors: Johnson Zachary , Xu Xiguang , Pacholec Christina , Xie Hehuang
Published: June 2022

The presence of 5-methylcytosine (m5C) in RNA molecules has been known for decades and its importance in regulating RNA metabolism has gradually become appreciated. Despite recent advances made in the functional and mechanistic understanding of RNA m5C modifications, the detection and quantification of methylated RNA remains a challenge. In this study, we compared four library construction procedures for RNA bisulfite sequencing and implemented an analytical pipeline to assess the key parameters in the process of m5C calling. We found that RNA fragmentation after bisulfite conversion increased the yield significantly, and an additional high temperature treatment improved bisulfite conversion efficiency especially for sequence reads mapped to the mitochondrial transcriptome. Using Unique Molecular Identifiers (UMIs), we observed that PCR favors the amplification of unmethylated templates. The low sequencing quality of bisulfite-converted bases is a major contributor to the methylation artifacts. In addition, we found that mitochondrial transcripts are frequently resistant to bisulfite conversion and no p-m5C sites with high confidence could be identified on mitochondrial mRNAs. Taken together, this study reveals the various sources of artifacts in RNA bisulfite sequencing data and provides an improved experimental procedure together with analytical methodology.
ATRT-01. Reconstitution of cGAS/ STING pathway via epigenetic reprogramming leads to anti-viral inflammatory signaling in Atypical teratoid rhabdoid tumors (ATRTs)
Authors: Mangoli Avani , Hariharan Seetha , Ashley David , Fuller Rebecca , Bowie Michelle , Briley Aaron , Brown Michael , Hostettler Janell
Published: June 2022

BACKGROUND: Atypical teratoid rhabdoid tumors (ATRTs) are highly aggressive brain tumors that affect young children characterized by biallelic inactivation of the SMARCB1 gene. Though patients benefit from multimodal therapy, there is no improvement in overall survival which necessitates the exploration of alternative approaches. Innate-based immune and epigenetic therapies have shown benefits in several cancers. The role of innate immune signaling has not been investigated in ATRTs. Our previous data from several ATRT cell lines showed loss of expression of key innate signaling components, like cGAS and STING that are needed for sensing extracellular dsDNA. Additionally, ATRT cell lines do not respond to STING agonists, like cGAMP or ISD. RESULTS: Co-treatment of ATRT cell lines, BT-12 and BT-16 with two epigenetic modulators, panobinostat and decitabine, leads to re-expression of cGAS and STING in a time-dependent manner. Furthermore, treatment with decitabine alone leads to demethylation of several CpG sites on the STING promoter and increased expression of STING mRNA. Panobinostat and decitabine co-treatment reconstitute STING-mediated innate signaling, as measured by IRF-3 and STAT1 phosphorylation and production of ISG-15 and IFIT-1 after treatment with cGAMP, a STING agonist. Co-treatment with panobinostat and decitabine also induced expression of antiviral pro-inflammatory chemokines/cytokines in ATRT cell lines, including type III IFN, IL-6, IL-8, IL-28, and IL-29. CONCLUSION: Our data suggest that ATRT cell lines are unresponsive to innate agonists possibly due to the loss of expression of key innate immune components. However, the cGAS/STING pathway is reactivated by epigenetic drugs, specifically the combination of panobinostat and decitabine. This is further potentiated by treating with STING agonists like cGAMP. Combination treatment of ATRT cell lines with panobinostat and decitabine also induced antiviral inflammatory signaling. This response could be a potential treatment modality to inhibit tumor growth and/or mediate cancer immunotherapy in these aggressive tumors.
ATRT-17. A phase II study of continuous low dose panobinostat in paediatric patients with malignant rhabdoid tumours and atypical teratoid rhabdoid tumours.
Authors: Wood Paul , Desai Jayesh , Waldeck Kelly , Cain Jason , Gottardo Nicholas , Strong Robyn , Kinross Kathryn , Carr Michelle , Jones Janelle , Wong Lily , Ziegler David , Hansford Jordan , Michael Michael , Ashley David
Published: June 2022

BACKGROUND: Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumours (MRT) and atypical teratoid rhabdoid tumours (ATRT) in pre-clinical models. We report results of the open label, phase II study of oral panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumour activity of low dose, continuous oral panobinostat as well as its associated toxicities. To assess the biological activity of low dose panobinostat by measuring histone H4 acetylation status in peripheral mononuclear cells (PMNC), and differentiation markers. METHODS: Following primary institutional standard of care induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2/day, with a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat at different dosing levels. Patients were monitored for toxicity; dose reductions were in decrements of 2mg/m2/day. RESULTS: A total of 13 patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled. The average age at enrollment was 3.6 years (range 0.8-6.8 years). The mean treatment duration was 206 days (13-344 days). Currently, six patients (42.9%) remain on study with a mean study duration of 531 days (range 13-895 days). 6/14 patients (42.9%) were removed due to disease progression at a mean study duration of 245 days (44-560 days). 2/14 patients (14.3%) withdrew due to toxicity. 12/14 patients (85.7%) required dose reductions. The main toxicities were thrombocytopaenia and leukopaenia (Grade III-IV). Real-time pharmacodynamic assessment of panobinostat, at a dose as low as 6mg/m2/day resulted in significant acetylation of histone H4 in PMNC. CONCLUSIONS: Treatment with low dose panobinostat is well tolerated in infants and children with MRT/ATRT, with significant acetylation of histone H4 in PMNC.
RARE-32. Phase 0 and feasibility single-institution clinical trial of intravenous tocilizumab for adamantinomatous craniopharyngioma
Authors: Dorris Kathleen , Mettetal Ashley , Dahl Nathan , Hemenway Molly , Winzent-Oonk Shelby , Prince Eric , Vijmasi Trinka , McWilliams Jennifer , Jordan Kimberly , Mirsky David , Hoffman Lindsey , Hankinson Todd
Published: June 2022

BACKGROUND: Adamantinomatous craniopharyngioma (ACP) is a devastating skull-base tumor believed to derive from epithelial remnants of the primordial craniopharyngeal duct (Rathke’s pouch), which gives rise to the anterior pituitary gland. ACP lacks medical antitumor therapies. Current standard therapy with surgery and radiation is associated with poor quality of life. Clinical and preclinical data indicate that IL-6 blockade may contribute to ACP tumor control. METHODS: Children aged 2–21 years with newly diagnosed or previously treated ACP with measurable disease are eligible for the Phase 0/feasibility single-institution clinical trial (NCT03970226) of intravenous (IV) tocilizumab at Children’s Hospital Colorado. The phase I stratum involves IV tocilizumab prior to a standard-of-care surgical resection. The feasibility portion of the trial involves IV tocilizumab every two weeks for up to 13 28-day cycles. Tocilizumab is administered at the established weight-based pediatric dosage of 8 mg/kg for patients who weigh ≥30kg or 12 mg/kg for patients who weigh <30kg. RESULTS: To date, three patients have been enrolled on the Phase 0 component of the trial. These patients demonstrated clinically relevant levels of tocilizumab (≥ 4µg/mL) in serum, cyst fluid, and/or tumor tissue, compared to undetectable levels in control samples. Two patients (1 male and 1 female; median age 10.5 years) have enrolled on the feasibility stratum; one patient had best response of minor response but met definition of progressive disease at cycle 11. One patient with extensive disease required dose reduction for myelosuppression. CONCLUSION: Systemic delivery of tocilizumab at the established pediatric dosage is promising for treatment of ACP based on preclinical work and its demonstrated penetration into cystic and solid portions of ACP tumors. The therapy to date has been well tolerated overall. Further study is planned through a CONNECT consortium international Phase II trial.
DIPG-07. Preclinical and case study results underpinning the phase II clinical trial testing the combination of ONC201 and paxalisib for the treatment of patients with diffuse midline glioma (NCT05009992)
Authors: Dun Matthew D , Jackson Evangeline R , Duchatel Ryan J , Persson Mika L , Mannan Abdul , Yadavilli Sridevi , Parackal Sarah , Game Shaye , Chong Wai Chin , Jayasekara Samantha , Le Grand Marion , Kearney Padraic S , Douglas Alicia M , Findlay Izac J , Staudt Dilana , Germon Zacary P , Skerrett-Byrne David A , Nixon Brett , Smith Nathan D , Hulleman Esther , Day Bryan , McCowage Geoff B , Alvaro Frank , Waszak Sebastian M , Larsen Martin R , Colino-Sanguino Yolanda , Valdes-Mora Fatima , Rakotomalala Andria , Meignan Samuel , Pasquier Eddy , Vitanza Nicholas A , Nazarian Javad , Koschmann Carl , Cain Jason , Mueller Sabine
Published: June 2022

Diffuse midline gliomas (DMG), including those of the brainstem (diffuse intrinsic pontine glioma - DIPG), are pediatric CNS tumors recognized as the most lethal of all children’s cancers. Palliative radiotherapy is the only approved treatment, with survival just 9-11–months post-diagnosis. ONC201 shows preclinical and emerging clinical efficacy in early-stage clinical trials, extending survival of DIPG patients by ~9-11–months compared to historic controls. However, patients invariably develop resistance, with some patients completely refractory to treatment. Using a multi-omics approach, including pharmacology, proteomics, genomics, epigenetics, in vitro and in vivo modeling, across ten international laboratories, we have uncovered the inherent mechanisms of resistance to ONC201. We find ONC201 elicits antagonism of the Dopamine receptor D2 (DRD2), whilst also causing mitochondrial degradation through potent agonism of the Mitochondrial protease CLPP, that drives proteolysis of the electron transport chain (ETC) protein Succinate dehydrogenase A (SDHA) and degradation of critical mitochondrial tricarboxylic acid (TCA) cycle regulator Isocitrate dehydrogenase 3B (IDH3B). Loss mitochondrial respiration increased hypoxia and reduced α-ketoglutarate, inhibiting lysine demethylation, increasing methylation of H3K4me3 and H3K27me3, thus altering the epigenome of primary DIPG cells. Loss of SDHA caused oxidation of succinate forming superoxide driving redox regulated PI3K/AKT signaling, counteracted using the PI3K/AKT inhibitor paxalisib. The combination of ONC201 and paxalisib synergically extended survival of two aggressive DIPG PDX models (SU-SIPG-VI vehicle=73 vs. combination=100-days, p=0.0027; SF8626 vehicle=36 vs. combination=43-days, p=0.0002). Compassionate access to this combination (n=2 patients; immediately post-RT and following re-RT) resulted in reductions in tumor volume and complete resolution of disease symptoms, extending overall survival (e.g., diagnosis patient MR axial scan=1554 mm2 , following eight months on the combination, current tumor volume=464 mm2 (<70%), patient remains on treatment). Our findings harness the powerful anti-DMG/DIPG pharmacokinetic/dynamic properties of ONC201 and paxalisib, a combination that is currently in clinical trials (NCT05009992).
DIPG-15. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T-cells
Authors: Monje Michelle , Majzner Robbie , Mahdi Jasia , Ramakrishna Sneha , Patel Shabnum , Chinnasamy Harshini , Yeom Kristen , Schultz Liora , Barsan Valentin , Richards Rebecca , Campen Cynthia , Reschke Agnes , Toland Angus Martin , Baggott Christina , Mavroukakis Sharon , Egeler Emily , Moon Jennifer , Jacobs Ashley , Yamabe-Kwong Karen , Rasmussen Lindsey , Nie Esther , Green Sean , Kunicki Michael , Fujimoto Michele , Ehlinger Zach , Reynolds Warren , Prabhu Snehit , Warren Katherine E , Cornell Tim , Partap Sonia , Fisher Paul , Grant Gerald , Vogel Hannes , Sahaf Bita , Davis Kara , Feldman Steven , Mackall Crystal
Published: June 2022

BACKGROUND: H3K27M-mutated DMGs express high levels of the disialoganglioside GD2 and GD2-CAR T-cells (GD2-CART) regress DMG in preclinical models. METHODS: NCT04196413 is a 3 + 3 Phase I dose escalation trial testing GD2-CART in patients with biopsy-proved H3K27M DMG, with dose-limiting toxicities (DLT) considered independently for DIPG and spinal DMG (sDMG). Arm A tested escalating doses of IV GD2-CART (DL1=1e6 GD2-CART/kg; DL2=3e6 GD2-CART/kg) following lymphodepletion (LD). After the DLT period, patients with clinical and/or radiographic benefit were eligible for subsequent ICV GD2-CART infusions (10-30e6 GD2-CART) administered via Ommaya without LD. RESULTS: Twelve subjects were treated after standard radiotherapy, 7 of whom began treatment at the time of progression [n=4 DL1 (3 DIPG/1 sDMG); n=8 DL2 (6 DIPG/2 sDMG)]. No DLTs were observed on DL1. Three subjects experienced DLT on DL2 (2 DIPG/1 sDMG) due to grade-4 cytokine release syndrome (CRS). On both dose levels, all subjects exhibited transient symptoms related to on-tumor inflammation, termed Tumor Inflammation-Associated Neurotoxicity (TIAN); no DLT due to TIAN has occurred. Ten subjects experienced radiographic and/or clinical benefit after IV infusion and received subsequent ICV infusions (median=4 ICV infusions/pt, range=1-7). ICV infusions were not associated with high-grade CRS. Four patients continue to receive ICV infusions on study and have experienced continued clinical and radiographic benefit, currently 7-11 months following enrollment. Two patients (one sDMG, one DIPG) have experienced near-complete (>95%) tumor volume reduction. CONCLUSIONS: IV treatment of DIPG and sDMG with GD2-CART is safe at a dose of 1e6/kg, but associated with frequent high-grade CRS at 3e6/kg. ICV GD2-CART has been well tolerated and has mediated impressive sustained clinical benefit in some patients with DIPG/sDMG. Given these findings, we are launching a new arm to assess safety and activity and to define the recommended phase 2 dose for ICV delivery of GD2-CART without LD.