bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphic KIR3DL3 expression modulates tissue-resident and innate-like T cells
Authors: Palmer William H. , Leaton Laura Ann , Campos Codo Ana , Crute Bergren , Roest James , Zhu Shiying , Petersen Jan , Tobin Richard P. , Hume Patrick S. , Stone Matthew , van Bokhoven Adrie , Gerich Mark E. , McCarter Martin D. , Zhu Yuwen , Janssen William J. , Vivian Julian P. , Trowsdale John , Getahun Andrew , Rossjohn Jamie , Cambier John , Loh Liyen , Norman Paul J.
Published: June 2023

Most human killer cell immunoglobulin-like receptors (KIR) are expressed by natural killer (NK) cells and recognize HLA class I molecules as ligands. KIR3DL3 is a conserved but polymorphic inhibitory KIR recognizing a B7 family ligand, HHLA2, and is implicated for immune checkpoint targeting. The expression profile and biological function of KIR3DL3 have been somewhat elusive, so we searched extensively for KIR3DL3 transcripts, revealing highly enriched expression in γδ and CD8
+
T cells rather than NK cells. These KIR3DL3-expressing cells are rare in the blood and thymus but more common in the lungs and digestive tract. High-resolution flow cytometry and single-cell transcriptomics showed that peripheral blood KIR3DL3
+
T cells have an activated transitional memory phenotype and are hypofunctional. The T cell receptor (TCR) usage is biased toward genes from early rearranged TCR-α variable segments or Vδ1 chains. In addition, we show that TCR-mediated stimulation can be inhibited through KIR3DL3 ligation. Whereas we detected no impact of KIR3DL3 polymorphism on ligand binding, variants in the proximal promoter and at residue 86 can reduce expression. Together, we demonstrate that KIR3DL3 is up-regulated alongside unconventional T cell stimulation and that individuals may vary in their ability to express KIR3DL3. These results have implications for the personalized targeting of KIR3DL3/HHLA2 checkpoint inhibition.
IBD-related mental health disorders: where do we go from here?
Authors: Gomez David Augusto , Ahmad-Waqar Muhammad , Brookes Matthew James , Kumar Aditi
Published: June 2023

Inflammatory bowel disease is a complex and debilitating disease which is known to cause mental burden for patients. Even though few studies look at mental health disease in this cohort of patients, there is growing evidence of a correlation between disease activity and prevalence of mental health conditions such as anxiety, depression and post-traumatic stress disorder. In this literature review, the relationship between inflammatory bowel disease and mental health disorders is explored, with an emphasis on recognition, screening and therapeutic options and special considerations for these complex comorbidities. The relationship between medical and psychological disease is not often considered and less well understood and there is a need for further research in these fields. Patients would have much to gain both medically and psychologically from a multidisciplinary approach to this chronic disease association.
Association between gene expression signatures and clinical outcomes of pembrolizumab versus paclitaxel in advanced gastric cancer: exploratory analysis from the randomized, controlled, phase III KEYNOTE-061 trial
Authors: Shitara Kohei , Di Bartolomeo Maria , Mandala Mario , Ryu Min-Hee , Caglevic Christian , Olesinski Tomasz , Chung Hyun Cheol , Muro Kei , Goekkurt Eray , McDermott Raymond S , Mansoor Wasat , Wainberg Zev A , Shih Chie-Schin , Kobie Julie , Nebozhyn Michael , Cristescu Razvan , Cao Z Alexander , Loboda Andrey , Özgüroğlu Mustafa
Published: June 2023

Background

In the randomized, controlled, phase III KEYNOTE-061 trial, second-line pembrolizumab did not significantly prolong overall survival (OS) versus paclitaxel in patients with PD-L1-positive (combined positive score ≥1) advanced gastric/gastroesophageal junction (G/GEJ) cancer but did elicit a longer duration of response and offered a favorable safety profile. This prespecified exploratory analysis was conducted to evaluate associations between tumor gene expression signatures and clinical outcomes in the phase III KEYNOTE-061 trial.

Methods

Using RNA sequencing data obtained from formalin-fixed, paraffin-embedded baseline tumor tissue samples, we evaluated the 18-gene T-cell-inflamed gene expression profile (TcellinfGEP) and 10 non-TcellinfGEP signatures (angiogenesis, glycolysis, granulocytic myeloid-derived suppressor cell (gMDSC), hypoxia, monocytic MDSC (mMDSC), MYC, proliferation, RAS, stroma/epithelial-to-mesenchymal transition/transforming growth factor-β, WNT). The association between each signature on a continuous scale and outcomes was analyzed using logistic (objective response rate (ORR)) and Cox proportional hazards regression (progression-free survival (PFS) and OS). One-sided (pembrolizumab) and two-sided (paclitaxel) p values were calculated for TcellinfGEP (prespecified α=0.05) and the 10 non-TcellinfGEP signatures (multiplicity-adjusted; prespecified α=0.10).

Results

RNA sequencing data were available for 137 patients in each treatment group. TcellinfGEP was positively associated with ORR (p=0.041) and PFS (p=0.026) for pembrolizumab but not paclitaxel (p>0.05). The TcellinfGEP-adjusted mMDSC signature was negatively associated with ORR (p=0.077), PFS (p=0.057), and OS (p=0.033) for pembrolizumab, while the TcellinfGEP-adjusted glycolysis (p=0.018), MYC (p=0.057), and proliferation (p=0.002) signatures were negatively associated with OS for paclitaxel.

Conclusions

This exploratory analysis of tumor TcellinfGEP showed associations with ORR and PFS for pembrolizumab but not for paclitaxel. TcellinfGEP-adjusted mMDSC signature was negatively associated with ORR, PFS, and OS for pembrolizumab but not paclitaxel. These data suggest myeloid-driven suppression may play a role in resistance to PD-1 inhibition in G/GEJ cancer and support a strategy of considering immunotherapy combinations which target this myeloid axis.

Trial registration number

NCT02370498.
On the mechanics of filtered compacted consolidated and overconsolidated iron ore tailings at high pressures
Authors: Silva João Paulo de Sousa , Carvalho João Vítor de Azambuja , Wagner Alexia Cindy , Cacciari Pedro Pazzoto , Consoli Nilo Cesar
Published: June 2023

The mechanics of filtered compacted normally consolidated (NC) and overconsolidated (OC) iron ore tailings (IOTs) was studied by performing triaxial testing at high pressures of up to 120 MPa. The OC specimens were obtained by isotropically compressing compacted IOT to 120 MPa, unloading it to distinct confining pressures, and shearing at constant radial stress. Particle size distribution analyses were used to examine the effect of compression and shear stresses on particle breakage. Additionally, the triaxial test results illustrate the stress history influence on the deviatoric stress–axial strain–volumetric strain curves, as well as on the IOT peak strength. Furthermore, these results also show that the amount of breakage during the shearing stage plays an essential role in the geomaterial’s response, marking the existence of curved critical state locus in both v–ln p′ and q– p′ planes, which is unique in the studied confined stress range (4–120 MPa) for the compacted NC and OC (considering OC ratio up to 30) IOTs.
Transport-related enzymes and osmo-ionic regulation in a euryhaline freshwater shrimp after transfer to saline media
Authors: Asaro Antonela , Pinoni Silvina A. , Lorin-Nebel Catherine , Ituarte Romina B.
Published: June 2023

To understand the response of freshwater organisms to rising environmental salinity, it is essential to investigate their osmo-ionic regulatory physiology. Our laboratory experiment investigated the transfer of Palaemon argentinus (Nobili, 1901) from 2‰ (control condition) to concentrated salinity (15 and 25‰) for short- (6 h), medium- (48 h), and long-term (>504 h) acclimation periods. We measured relevant parameters in the shrimp’s haemolymph, the time course of the response of branchial V–H+–ATPase (VHA), Na+, K+–ATPase (NKA), carbonic anhydrase (CA) activity, and muscle water content. Upon prolonged acclimation to 15‰ (hyper-regulating condition), shrimp reached a new steady state of haemolymph osmolality by tightly adjusting ion concentrations to levels higher than the external medium. While NKA and CA activities recovered their pre-transfer levels, the downregulation of VHA suggests other functions rather than ion uptake after prolonged acclimation to 15‰. The activity of the three transport-related enzymes remained almost unchanged at the highest salinity (isosmotic condition), leading to increasing osmotic pressure and ion concentration after prolonged acclimation to 25‰. Although the freshwater shrimp studied here retains a certain degree of tolerance to high salinity, a common trait in palaemonid shrimps, our results highlight that 25‰ represents a significant hypertonic challenge for this species.
Exclusive photo- and electroproduction of excited light vector mesons via holographic model
Authors: Henkels Cheryl , de Oliveira Emmanuel G. , Pasechnik Roman , Trebien Haimon
Published: June 2023

In this paper, we study total and differential observables of electro- and photoproduction of light $$\rho $$
ρ
, $$\omega $$
ω
and $$\phi $$
ϕ
mesons as functions of the center-of-mass energy of the $$\gamma p$$

γ
p

collision and momentum transfer squared |t|. The corresponding vector mesons wave functions have been computed in the framework of relativistic AdS/QCD holographic approach. A satisfactory description of all available data on ground-state $$\rho (1S)$$

ρ
(
1
S
)

, $$\omega (1S)$$

ω
(
1
S
)

and $$\phi (1S)$$

ϕ
(
1
S
)

mesons production cross sections has been achieved in the color dipole picture. Finally, the key observables of excited $$\rho (2S)$$

ρ
(
2
S
)

, $$\omega (2S)$$

ω
(
2
S
)

and $$\phi (2S)$$

ϕ
(
2
S
)

states production in $$\gamma ^{(*)} p$$

γ

(

∗
)

p

collisions have been presented here using a common wave function formalism. This study reveals a large theoretical uncertainty coming from the modeling of the partial dipole amplitude in the nonperturbative kinematical domain. Hence, the latter could benefit from future measurements of photoproduction of the excited states.
Probing supermassive black hole binaries with orbital resonances of laser-ranged satellites
Authors: Du Minghui , Deng Qiong , Bian Yifan , Luo Ziren , Xu Peng
Published: June 2023

Coalescing supermassive black hole binaries (SMBHBs) are the primary source candidates for low frequency gravitational wave (GW) detections, which could bring us deep insights into galaxy evolutions over cosmic time and violent processes of spacetime dynamics. Promising candidates had been found based on optical and X-ray observations, which claims for new and ready-to-use GW detection approaches before the operations of space-borne antennas. We show that, satellite laser ranging (SLR) missions could serve as probes of coalescing SMBHBs through the GW-induced resonant effects. Lasting and characteristic imprints caused by such resonances in the residual distances or accelerations from SLR measurements are studied, and the detection SNR is analyzed with both the current and future improved ranging precisions. Within redshift $$z \sim 1$$

z
∼
1

, the threshold SNR = 5 requires 1–2 years of accumulated data for the current precision and months of data for improved precision, which are workable for the data processing of SLR missions. Meanwhile, joint detections with multiple SLR missions could further improve the total SNR and the confidence level. Such a detection scheme could fulfill the requirement of a tentative SMBHB probe during the preparing stage of LISA and Taiji, and it requires no further investment to any new and advanced facilities. It is also worthwhile to look back and re-process the archived data from the past decades, in where resonant signals from SMBHBs might be hidden.
Correlated Queues with Inter-Arrival Times Depending on Service Times
Authors: Jia Zhenzhen , Dai Weimin , Hu Jian-Qiang
Published: June 2023

We consider a type of correlated queue in which the inter-arrival time between two consecutive customers linearly depends on the service time of the first customer. We first derive infinite systems of linear equations for the moments of the waiting time in two special cases, based on which we then develop several methods to calculate the moments of the waiting time by using MacLaurin series approximation, Padé approximation and truncation method. In addition, we show how the moments and covariances of the inter-departure times of the correlated queue can be calculated based on the moments of the waiting time. Finally, extensive numerical examples are provided to validate our methods.
Performance analysis of annular disks with non-Newtonian Rabinowitsch fluid model: Influence of squeeze film pressure, surface roughness, porosity and viscosity variation
Authors: Rahul Amit Kumar , Singh Manoj Kumar , Paul Sourabh , Tiwari Ravi , Rao Pentyala Srinivasa , Saha Sandip
Published: June 2023

In various systems of energy, such as turbo-machinery and viscous-lock system, squeeze film plays a crucial role for improving transport systems. The importance of the aforementioned applications led us to explore the physical behavior of Rabinowitsch fluid flow for several values of viscosity, [Formula: see text], load capacity [Formula: see text], nonlinear factor, [Formula: see text], dimensionless film thickness [Formula: see text], dimensionless radius of the capillary tube [Formula: see text], dimensionless thickness of porous pad [Formula: see text]), inner and outer radius ratio [Formula: see text], roughness parameter [Formula: see text] through a squeeze film with two rough porous annular discs. Five-point Gauss quadrature integral formula has been used to examine the characteristics of annular discs, and small perturbation method has been used to discretize the governing Rabinowitsch fluid flow (RFF) equations. The modified Reynolds equation for rough, porous and viscosity change with film thickness is developed using Christensen’s stochastic theory, modified Darcy’s theory and the association between viscosity and film thickness agreement. The impacts of [Formula: see text] on the behavior of porosity and viscosity variability of RFF have been visually depicted in terms of film pressure, load capacity and squeeze reaction time of annular discs. It has been determined that for RFF with variable viscosity and roughness parameter on a porous media, the performance of the annular disks enhances for [Formula: see text] (dilatant lubricant), and diminishes for [Formula: see text] (pseudo-plastic lubricant). It has been found that the film pressure in case of dilatant lubricant is increased by the influence of Rabinowitsch fluids on porous walls, but the behavior of pseudo-plastic lubricants has an opposite tendency relative to Newtonian lubricants. It has also been found that the impact of variability in porosity, roughness and viscosity diminishes the load-carrying capacity (LCC) with increased film thickness than the case of nonporous, smooth surface and constant viscosity of Rabinowitsch fluid.
Calculation of the neutron cross-section for iron group nuclei in ℓ≠0 case
Authors: Alshamy A. M. , Musthafa M. M.
Published: June 2023

Total neutron cross-sections for iron group nuclei with energies [Formula: see text] have been theoretically calculated, for [Formula: see text] case. In this work, the collision matrix has been modified for a smooth spherical optical potential, which varies slowly with distance inside of target nucleus. Results agree well with the experimental data and TALYS 1.9 code. It has been found that a finite number of the angular momentum will contribute appreciably to the nuclear reaction. This study on smooth optical potential leads to useful insights into the mechanisms of neutron induced reactions, particularly for medium nuclei at high energies.
Analysis and Optimization of Gait Cycle of 25-DOF NAO Robot Using Particle Swarm Optimization and Genetic Algorithms
Authors: Gupta Pushpendra , Pratihar Dilip Kumar , Deb Kalyanmoy
Published: June 2023

The gait cycle of 25-degree of freedom (DOF) humanoid robot, namely NAO robot, consists of single support phase (SSP) and double support phase (DSP). Both dynamic and stability analyses are carried out for this robot to determine its power consumption and dynamic stability margin, respectively. Constrained single-objective optimization problems are formulated for the SSP and DSP separately and solved using particle swarm optimization (PSO) and genetic algorithms (GA). A performance index, other than the fitness function, consisting of constraint values and maximum swing height, is also considered to compare PSO and GA-obtained optimal solutions. PSO is able to find the trajectories that offer higher swing height for nearly similar power consumption during SSP. A performance assessment of each algorithm based on the best fitness values in each generation across several runs is also carried out. These values are compared using the Wilcoxon rank-sum test, and PSO is found to be statistically better than GA. The optimal solutions from the simulations are tested using the Webots simulator to validate their efficacy on stability. Moreover, an investigation of the influence of gait parameters on power consumption during SSP and DSP reveals that the humanoid robot with a higher hip height, lower swing height, and slow pace consumes less power. The methodology developed in this is generic and can be easily extended to other robots.
KEY FACTORS AFFECTING SOCIAL ENTERPRISE PERFORMANCE: A LITERATURE REVIEW
Authors: ISKANDAR YUSUF , JOELIATY JOELIATY , KALTUM UMI , YUDOMARTONO HILMIANA
Published: June 2023

This study aims to understand performance of social enterprises and assess the most influential factors affecting this performance based on a Systematic Literature Review (SLR). The study extracted data (articles) from three prominent databases (Scopus, Web of Science and Google Scholar). Four main determinant groups of performance are identified, namely, technology and innovation, investment considerations, overall organization orientation and a general category of other influential factors. The results indicate that fiscal, environmental, social contexts, creative methods and employee contributions have a major influence on the performance of social enterprises. It was also revealed that strategic and business orientation has proven to be a significant contributor as well. The findings contribute to social entrepreneurship literature in terms of performance improvement of hybrid enterprises. Future research suggestions are provided based on the findings.
Digital twin for a robot assembly line: Architecture and implementation
Authors: Liu Yongkui , Zhao Qing , Feng Jianyong , Zhong Chunfu , Zhang Lin
Published: June 2023

As an enabling technology and means to practice the concept of intelligent manufacturing, digital twin has attracted extensive attention from both industry and academia. In view of the lack of concrete implementation methods of digital twin robot assembly lines, and the complex implementation process, and long development cycle using existing methods, the implementation of digital twin robot assembly lines is a significant research problem. In view of this, this paper proposes an architecture as well as an implementation method of a digital twin system for a robot assembly line. Taking a robot assembly production line as an example, a digital twin architecture and modular development approach are proposed, and three key technologies for implementing the digital twin system, namely virtual model construction, real-time data acquisition and accurate virtual-real mapping, are elaborated. The architecture and implementation method can quickly and effectively facilitate building a digital twin system of the robot assembly line, and realizing real-time monitoring and intelligent analysis of all elements of the physical robot production line.
The Development of Competencies for Use in Online Learning During the Covid-19 Pandemic: Insights from the hospitality management degree program at the Universidad Panamericana, Mexico City campus
Authors: Vázquez Gómez Rosa Adriana , Galindo Correa Claudia , Espinosa Martínez Pedro Pablo
Published: June 2023

This study aims to comparatively analyze students and professors' perceptions regarding the development of competencies through the online format of a bachelor's degree program in hospitality management during three semesters of stay-at-home learning. The goal is to understand whether the tools and teaching resources used by faculty adequately met the objectives of the bachelor program, which has as one of its main objectives the development of competencies. Using the two variables from the TAM Model (i.e., perceived ease of use and perceived usefulness) and the types of technological resources that students and professors used, we found both groups saw the accessibility and ease of use of technological tools as simple and believe that they are useful or very useful for learning. Likewise, they agree that teamwork and change management were the competences they most developed during the pandemic, which play an important role in digital literacy.
Arabic ChatGPT Tweets Classification Using RoBERTa and BERT Ensemble Model
Authors: Mujahid Muhammad , Kanwal Khadija , Rustam Furqan , Aljedaani Wajdi , Ashraf Imran
Published: June 2023

ChatGPT OpenAI, a large-language chatbot model, has gained a lot of attention due to its popularity and impressive performance in many natural language processing tasks. ChatGPT produces superior answers to a wide range of real-world human questions and generates human-like text. The new OpenAI ChatGPT technology may have some strengths and weaknesses at this early stage. Users have reported early opinions about the ChatGPT features, and their feedback is essential to recognize and fix its shortcomings and issues. This study uses the ChatGPT tweets Arabic dataset to automatically find user opinions and sentiments about ChatGPT technology. The dataset is preprocessed and labeled using the TextBlob Arabic Python library into positive, negative, and neutral tweets. Despite extensive works for the English language, languages like Arabic are less studied regarding tweet analysis. Existing literature about Arabic tweet sentiment analysis has mainly focused on machine learning and deep learning models. We collected a total of 27,780 unstructured tweets from Twitter using the Tweepy SNscrape Python library using various hash-tags such as # Chat-GPT, #OpenAI, #Chatbot, Chat-GPT3, and so on. To enhance the model’s performance and reduce computational complexity, unstructured tweets are converted into structured and normalized forms. Tweets contain missing values, URL and HTML tags, stop words, punctuation, diacritics, elongations, and numeric values that have no impact on the model performance; hence, these increase the computational cost. So, these steps are removed with the help of Python preprocessing libraries to enhance text quality and consistency. This study adopts Transformer-based models such as RoBERTa, XLNet, and DistilBERT that automatically classify the tweets. Additionally, a hybrid transformer-based model is proposed to obtain better results. The proposed hybrid model is developed by combining the hidden outputs of the RoBERTA and BERT models using a concatenation layer, then adding dense layers with “Relu” activation employed as a hidden layer to create non-linearity and a “softmax” activation function for multiclass classification. They differ from existing state-of-the-art models due to the enhanced capabilities of both models in text classification. Hybrid models combine the different models to make accurate predictions and reduce bias and enhanced the overall results, while state-of-the-art models are incapable of making accurate predictions. Experiments show that the proposed hybrid model achieves 96.02% accuracy, 100% precision on negative tweets, and 99% recall for neutral tweets. The performance of the proposed model is far better than existing state-of-the-art models.
Document Image Quality Assessment: A Survey
Authors: Alaei Alireza , Bui Vinh , Doermann David , Pal Umapada
Published: June 2023

The rapid emergence of new portable capturing technologies has significantly increased the number and diversity of document images acquired for business and personal applications. The performance of document image processing systems and applications depends directly on the quality of the document images captured. Therefore, estimating the document's image quality is an essential step in the early stages of the document analysis pipeline. This article surveys research on Document Image Quality Assessment (DIQA). We first provide a detailed analysis of both subjective and objective DIQA methods. Subjective methods, including ratings and pair-wise comparison-based approaches, are based on human opinions. Objective methods are based on quantitative measurements, including document modeling and human perception-based methods. Second, we summarize the types and sources of document degradations and techniques used to model degradations. In addition, we thoroughly review two standard measures to characterize document image quality: Optical Character Recognition (OCR)-based and objective human perception-based. Finally, we outline open challenges regarding developing DIQA methods and provide insightful discussion and future research directions for this problem. This survey will become an essential resource for the document analysis research community and serve as a basis for future research.
Distributed MPC-ILC Thermal Control Design for Large-Scale Multi-Zone Building HVAC System
Authors: Liang Wei , Ma Sizhe , Cochran Erica , Flanigan Katherine A.
Published: June 2023

With building heating, ventilation, and air conditioning (HVAC) systems accounting for 50% the energy consumption in the building sector in the United States, there is a need to develop and implement optimal control strategies for building HVAC systems that reduce energy consumption while achieving thermal comfort for users. In the author's previous work, an integrated model predictive control (MPC) and iterative learning control (ILC) design approach was presented that took advantage of both controllers. It did not rely on model accuracy compared to conventional MPC and reduced the learning curve compared to conventional ILC. Albeit the previous numerical results showed fast convergence in most of the VAV subsystems, the gap between room air temperature and its set point remains noticeable in several zones. This paper further proposes an approach to extend the centralized MPC-ILC controller to take into account the distributed factor and the spatial distribution of the thermal zones of the VAV system. The improved control strategy allows all VAVs to interact with each other and contribute collectively to the overall convergence of the whole system. The proposed controller is implemented on a thirty-two zone VAV reheat system and compared with different controllers, including our previous MPC-ILC design. The outcomes show that the proposed controller results in faster and closer convergence among all zones even when the number of subsystems is large.
Coupling OMNeT++ and Mosaik for Integrated Co-Simulation of ICT-Reliant Smart Grids
Authors: Oest Frauke , Frost Emilie , Radtke Malin , Lehnhoff Sebastian
Published: June 2023

The increasing integration of renewable energy resources requires so-called smart grid services for monitoring, control and automation tasks. Simulation environments are vital for evaluating and developing innovative solutions and algorithms. Especially in smart energy systems, we face a variety of heterogeneous simulators representing, e.g., power grids, analysis or control components and markets. The co-simulation framework mosaik can be used to orchestrate the data exchange and time synchronization between individual simulators. So far, the underlying communication infrastructure has often been assumed to be optimal and therefore, the influence of e.g., communication delays has been neglected. This paper presents the first results of the project cosima, which aims at connecting the communication simulator OMNeT++ to the co-simulation framework mosaik to analyze the resilience and robustness of smart grid services, e.g., multi-agent-based services with respect to adaptivity, scalability, extensibility and usability. This facilitates simulations with realistic communication technologies (such as 5G) and the analysis of dynamic communication characteristics by simulating multiple messages. We show the functionality and benefits of cosima in experiments with 50 agents.
Chronic testosterone deficiency increases late inward sodium current and promotes triggered activity in ventricular myocytes from aging male mice
Authors: Banga Shubham , Mishra Manish , Heinze-Milne Stefan D. , Jansen Hailey J. , Rose Robert A. , Howlett Susan E.
Published: June 2023

Older men with low testosterone levels are at increased risk of developing cardiac arrhythmias. We found aged mice chronically exposed to low testosterone had more arrhythmias and ventricular myocytes had prolonged repolarization, abnormal electrical activity, larger late sodium currents, and increased expression of NaV1.8 sodium channels. Drugs that inhibit late sodium current or NaV1.8 channels abolished abnormal electrical activity and shortened repolarization. This suggests the late sodium current may be a novel target to treat arrhythmias in older testosterone-deficient men.
Bridge Frequency Scanning Using the Contact-Point Response of an Instrumented 3D Vehicle: Theory and Numerical Simulation
Authors: Li Zhenkun , Lin Weiwei , Zhang Youqi
Published: June 2023

Scanning the bridge’s frequencies from the passing vehicle’s vibration data has been frequently investigated recently. However, in previous studies, vehicles were typically simplified to quarter- or half-car models, and apparent disparity could be observed between the models and real vehicles. To make the vehicle model more practical, in this study, a 3D vehicle model is built to extract the bridge’s frequencies from vehicle vibrations. For the first time, equations for calculating the contact-point (CP) response of the 3D vehicle model are derived with tire damping. Furthermore, residual CP responses between front and rear wheels are utilized to eliminate the inverse effects of road roughness, making the bridge frequencies outstanding in the frequency domain. The robustness of the proposed method is tested under different influence factors, and two possible measurement errors are as follows: the sensor position and axle distance when applying the proposed method in engineering. Results show that the proposed method performs stably under the influence of different road roughness classes and tire damping. Bridge frequencies can be identified when the vehicle is travelling at a highway speed (108 km/h in this study). Environmental noises can submerge the bridge’s high-order frequencies but have little influence on the low-frequency range. High bridge damping will restrain the transmission of bridge vibration to the vehicle, making high-order bridge frequencies less visible. In addition, the errors introduced by a vehicle body sensor position can be eliminated when calculating the CP responses for tires, thus will not influence bridge frequency identification. To avoid possible errors induced by manual measurement of the axle distance, a novel cross-correlation function-based method is employed, which is verified effective and practical for calculating residual CP responses.
Tangent Hyperbolic Fluid Flow under Condition of Divergent Channel in the Presence of Porous Medium with Suction/Blowing and Heat Source: Emergence of the Boundary Layer
Authors: Choudhary Sushila , Choudhary Prasun , Pattanaik Balachandra
Published: June 2023

A boundary layer’s appearance in a diverging permeable channel for a non‐Newtonian hyperbolic tangent fluid with heat transfer in the availability of a heat source and suction or injection is investigated. By controlling backflow, nonlinearly associated ODEs are derived from flow‐regulating PDEs, and the restrictions under which the formation of a boundary layer for tangent hyperbolic fluid emerges are investigated. It is obtained that mass suction is an expression of the Hartmann number, porosity parameter, and power law index parameter, and when it surpasses a specific quantity, flow within a boundary layer is conceivable. “Bvp4c,” a MATLAB solver, is used to obtain numerical solutions of flow problem, and for validation of results obtained via Bvp4c, a comparison is made with the methodology of the Runge–Kutta fourth order. As the Weissenberg number enhances, flow in a boundary layer decreases. Furthermore, radiation and heat source parameters have a significant influence on the overall temperature pattern, and as the findings, the thermal boundary layer enhances.
Educación en pacientes adultos mayores sometidos a endoprótesis total de cadera: Un enfoque centrado en las preferencias de los pacientes
Authors: Morales Sergio , Valdivia Gonzalo , Botello Eduardo , Klaber Ianiv , Carmona Maximiliano , Lira María-Jesús
Published: June 2023

Propósito del estudio: Describir las preferencias educativas de los beneficiarios de las Garantías Explicitas en Salud (GES) que fueron sometidos a una cirugía de endoprótesis total de cadera. Material y método: Se diseñó una encuesta que exploró las preferencias educativas referentes a cada etapa del proceso quirúrgico de adultos mayores sometidos a endoprótesis total de cadera en un centro hospitalario universitario. Se seleccionó el total de pacientes operados en el centro durante el año 2019. La encuesta se aplicó de manera telefónica por un encuestador entrenado. El tiempo entre la aplicación de la encuesta y la cirugía fue entre 2 y 14 meses. Resultados: Se incluyeron 63 pacientes, cuya edad promedio fue 72,5 años y el 69,8% correspondía al sexo femenino. Con respecto a su cobertura de salud el 57,2% era beneficiario de FONASA y el 42,7% de ISAPRE. Las preferencias de información descritas en nuestra muestra con respecto al proceso quirúrgico desde su inicio a fin, señalan la cirugía (40,4%) y los cuidados post operatorios (29,3%) como los temas de más interés. Los temas de menor interés fueron los cuidados preoperatorios (45,2%) y la información relacionada a la hospitalización (31,7%). Los pacientes encuestados valoraron la información entregada previa a su cirugía como adecuada, útil y fácil de entender. Conclusiones: Los adultos mayores sometidos a endoprótesis señalaron la información específica referente a la cirugía y los cuidados post operatorios como los temas educativos de mayor interés. La información estándar entregada por los médicos tratantes fue bien recibida por los pacientes.
Supplementary Table S2 from Thyroid Cancers Exhibit Oncogene-Enhanced Macropinocytosis that Is Restrained by IGF1R and Promote Albumin–Drug Conjugate Response
Authors: Hu Huiyu , Ng Thomas S.C. , Kang Mikyung , Scott Ella , Li Ran , Quintana Jeremy M. , Matvey Dylan , Vantaku Venkata R. , Weissleder Ralph , Parangi Sareh , Miller Miles A.
Published: June 2023

Pharmacologic screening, over-representation analysis, and gene expression of macropinocytosis screen hits
Supplementary Figure 3 from Targeting BCL2 Overcomes Resistance and Augments Response to Aurora Kinase B Inhibition by AZD2811 in Small Cell Lung Cancer
Authors: Ramkumar Kavya , Tanimoto Azusa , Della Corte Carminia M. , Stewart C. Allison , Wang Qi , Shen Li , Cardnell Robert J. , Wang Jing , Polanska Urszula M. , Andersen Courtney , Saeh Jamal , Pease J. Elizabeth , Travers Jon , Fabbri Giulia , Gay Carl M. , Urosevic Jelena , Byers Lauren A.
Published: June 2023

Supplementary Figure 3 shows the combination of AZD2811 and BCL2 inhibitor enhances apoptosis and cell death.
Supplementary Figure 2 from Targeting BCL2 Overcomes Resistance and Augments Response to Aurora Kinase B Inhibition by AZD2811 in Small Cell Lung Cancer
Authors: Ramkumar Kavya , Tanimoto Azusa , Della Corte Carminia M. , Stewart C. Allison , Wang Qi , Shen Li , Cardnell Robert J. , Wang Jing , Polanska Urszula M. , Andersen Courtney , Saeh Jamal , Pease J. Elizabeth , Travers Jon , Fabbri Giulia , Gay Carl M. , Urosevic Jelena , Byers Lauren A.
Published: June 2023

Supplementary Figure 2 shows polyploidy and apoptosis are inhibited by high BCL2 levels
Supplementary Figure 1 from Targeting BCL2 Overcomes Resistance and Augments Response to Aurora Kinase B Inhibition by AZD2811 in Small Cell Lung Cancer
Authors: Ramkumar Kavya , Tanimoto Azusa , Della Corte Carminia M. , Stewart C. Allison , Wang Qi , Shen Li , Cardnell Robert J. , Wang Jing , Polanska Urszula M. , Andersen Courtney , Saeh Jamal , Pease J. Elizabeth , Travers Jon , Fabbri Giulia , Gay Carl M. , Urosevic Jelena , Byers Lauren A.
Published: June 2023

Supplementary Figure 1 shows BCL2 is a strong biomarker of resistance to AURK inhibition in SCLC.
Supplementary Figure S5 from Thyroid Cancers Exhibit Oncogene-Enhanced Macropinocytosis that Is Restrained by IGF1R and Promote Albumin–Drug Conjugate Response
Authors: Hu Huiyu , Ng Thomas S.C. , Kang Mikyung , Scott Ella , Li Ran , Quintana Jeremy M. , Matvey Dylan , Vantaku Venkata R. , Weissleder Ralph , Parangi Sareh , Miller Miles A.
Published: June 2023

IGF1R inhibition augments macropinocytosis and is blocked by IGF1
Supplementary Data 1 from Targeting BCL2 Overcomes Resistance and Augments Response to Aurora Kinase B Inhibition by AZD2811 in Small Cell Lung Cancer
Authors: Ramkumar Kavya , Tanimoto Azusa , Della Corte Carminia M. , Stewart C. Allison , Wang Qi , Shen Li , Cardnell Robert J. , Wang Jing , Polanska Urszula M. , Andersen Courtney , Saeh Jamal , Pease J. Elizabeth , Travers Jon , Fabbri Giulia , Gay Carl M. , Urosevic Jelena , Byers Lauren A.
Published: June 2023

Supplementary table shows AZD2811 sensitivity, transcriptomic and proteomic profiles of SCLC cell lines
Supplementary Figure S4 from Thyroid Cancers Exhibit Oncogene-Enhanced Macropinocytosis that Is Restrained by IGF1R and Promote Albumin–Drug Conjugate Response
Authors: Hu Huiyu , Ng Thomas S.C. , Kang Mikyung , Scott Ella , Li Ran , Quintana Jeremy M. , Matvey Dylan , Vantaku Venkata R. , Weissleder Ralph , Parangi Sareh , Miller Miles A.
Published: June 2023

MAPK pathway kinase inhibitors show little effect on albumin uptake in non-tumor tissues, and lectin and dextran uptakes in tumor tissues
Supplementary Figure S3 from Thyroid Cancers Exhibit Oncogene-Enhanced Macropinocytosis that Is Restrained by IGF1R and Promote Albumin–Drug Conjugate Response
Authors: Hu Huiyu , Ng Thomas S.C. , Kang Mikyung , Scott Ella , Li Ran , Quintana Jeremy M. , Matvey Dylan , Vantaku Venkata R. , Weissleder Ralph , Parangi Sareh , Miller Miles A.
Published: June 2023

MAPK/ERK and PTEN/PI3K modulation of macropinocytosis and albumin uptake
Supplementary Figure S2 from Thyroid Cancers Exhibit Oncogene-Enhanced Macropinocytosis that Is Restrained by IGF1R and Promote Albumin–Drug Conjugate Response
Authors: Hu Huiyu , Ng Thomas S.C. , Kang Mikyung , Scott Ella , Li Ran , Quintana Jeremy M. , Matvey Dylan , Vantaku Venkata R. , Weissleder Ralph , Parangi Sareh , Miller Miles A.
Published: June 2023

Assessment of albumin-bound chemotherapy efficacy and toxicity
Supplementary Figure S4 from The DRD2 Antagonist Haloperidol Mediates Autophagy-Induced Ferroptosis to Increase Temozolomide Sensitivity by Promoting Endoplasmic Reticulum Stress in Glioblastoma
Authors: Shi Linyong , Chen Hanning , Chen Kunxiang , Zhong Chengzong , Song Chong , Huang Yifeng , Wang Tong , Chen Lei , Li Chiyang , Huang Annie , Qi Songtao , Li Hong , Lu Yuntao
Published: June 2023

Fig. S4. Autophagy, endoplasmic reticulum stress and cAMP pathway are involved in TMZ+HP-induced ferroptosis in GBM cells.
Data from The DRD2 Antagonist Haloperidol Mediates Autophagy-Induced Ferroptosis to Increase Temozolomide Sensitivity by Promoting Endoplasmic Reticulum Stress in Glioblastoma
Authors: Shi Linyong , Chen Hanning , Chen Kunxiang , Zhong Chengzong , Song Chong , Huang Yifeng , Wang Tong , Chen Lei , Li Chiyang , Huang Annie , Qi Songtao , Li Hong , Lu Yuntao
Published: June 2023

AbstractPurpose:
Temozolomide resistance remains a major obstacle in the treatment of glioblastoma (GBM). The combination of temozolomide with another agent could offer an improved treatment option if it could overcome chemoresistance and prevent side effects. Here, we determined the critical drug that cause ferroptosis in GBM cells and elucidated the possible mechanism by which drug combination overcomes chemoresistance.
Experimental Design:
Haloperidol/temozolomide synergism was assessed in GBM cell lines with different dopamine D2 receptor (DRD2) expression in vitro and in vivo. Inhibitors of ferroptosis, autophagy, endoplasmic reticulum (ER) stress and cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) were used to validate the specific mechanisms by which haloperidol and temozolomide induce ferroptosis in GBM cells.
Results:
In the present work, we demonstrate that the DRD2 level is increased by temozolomide in a time-dependent manner and is inversely correlated with temozolomide sensitivity in GBM. The DRD2 antagonist haloperidol, a butylbenzene antipsychotic, markedly induces ferroptosis and effectively enhances temozolomide efficacy in vivo and in vitro. Mechanistically, haloperidol suppressed the effect of temozolomide on cAMP by antagonizing DRD2 receptor activity, and the increases in cAMP/PKA triggered ER stress, which led to autophagy and ferroptosis. Furthermore, elevated autophagy mediates downregulation of FTH1 expression at the posttranslational level in an autophagy-dependent manner and ultimately leads to ferroptosis.
Conclusions:
Our results provide experimental evidence for repurposing haloperidol as an effective adjunct therapy to inhibit adaptive temozolomide resistance to enhance the efficacy of chemoradiotherapy in GBM, a strategy that may have broad prospects for clinical application.
Trackable Intratumor Microdosing and Spatial Profiling Provide Early Insights into Activity of Investigational Agents in the Intact Tumor Microenvironment
Authors: Derry Jonathan M.J. , Burns Connor , Frazier Jason P. , Beirne Emily , Grenley Marc , DuFort Christopher C. , Killingbeck Emily , Leon Michael , Williams Claire , Gregory Mark , Houlton Jeffrey , Clayburgh Daniel , Swiecicki Paul , Huszar Dennis , Berger Allison , Klinghoffer Richard A.
Published: June 2023

Purpose:

Cancer drug development is currently limited by a paradigm of preclinical evaluation that does not adequately recapitulate the complexity of the intact human tumor microenvironment (TME). To overcome this, we combined trackable intratumor microdosing (CIVO) with spatial biology readouts to directly assess drug effects in patient tumors in situ.

Experimental Design:

In a first-of-its-kind phase 0 clinical trial, we explored the effects of an investigational stage SUMOylation-activating enzyme (SAE) inhibitor, subasumstat (TAK-981) in 12 patients with head and neck carcinoma (HNC). Patients scheduled for tumor resection received percutaneous intratumor injections of subasumstat and vehicle control 1 to 4 days before surgery, resulting in spatially localized and graded regions of drug exposure (∼1,000–2,000 μm in diameter). Drug-exposed (n = 214) and unexposed regions (n = 140) were compared by GeoMx Digital Spatial Profiler, with evaluation at single-cell resolution in a subset of these by CosMx Spatial Molecular Imager.

Results:

Localized regions of subasumstat exposure revealed SUMO pathway inhibition, elevation of type I IFN response, and inhibition of cell cycle across all tumor samples. Single-cell analysis by CosMx demonstrated cell-cycle inhibition specific to the tumor epithelium, and IFN pathway induction commensurate with a TME shift from immune-suppressive to immune-permissive.

Conclusions:

Pairing CIVO with spatial profiling enabled detailed investigation of response to subasumstat across a diverse sampling of native and intact TME. We demonstrate that drug mechanism of action can be directly evaluated in a spatially precise manner in the most translationally relevant setting: an in situ human tumor.
VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders
Authors: Bogue Danielle , Ryan Gavin , Wassmer Evangeline ,   Genomics England Research Consortiume, Naik Swati
Published: June 2023

Introduction: VAMP2 is an instrumental protein in neuronal synaptic transmission in the brain, facilitating neurotransmitter release. It is encoded by the VAMP2 gene, and pathogenic variants in this gene cause neurodevelopmental features including early onset axial hypotonia, intellectual disability, and features of autism spectrum disorder. To date, only three types of allelic variants (loss of function, in-frame deletions, and missense variants) in the VAMP2 gene have been previously reported in 11 patients with learning difficulties. Here, we describe a patient in whom a novel de novo pathogenic variant in the VAMP2 gene was identified. Case Presentation: A 15-month-old girl presented with early onset hypotonia, global developmental delay, learning difficulties, microcephaly, nystagmus, strabismus, and stereotypies. Later, she developed a sleep disorder, challenging behaviour with self-injury, and scoliosis. Gene agnostic analysis of whole genome sequencing data identified a novel de novo heterozygous missense variant c.197G>C (p.Arg66Pro) in the VAMP2 gene SNARE motif region. Discussion: This is the fourth report describing VAMP2 gene-related neurodevelopmental disorder. This report adds to the genotype-phenotype correlation and highlights this condition as an important differential diagnosis of Rett/Angelman-type spectrum of disorders. Patients presenting with features of either Rett syndrome or Angelman syndrome, in whom genetic testing is not suggestive, should be evaluated for variants in the VAMP2 gene, given the significant overlap in clinical presentation of these disorders.
The Introduction of an MR-Conditional Prototype for Cardiopulmonary Bypass Support: Technical Aspects and System Requirements
Authors: Hofmann Michael , Schmiady Martin , Schulte Dominik , Sollberger Samuel , Carrel Thierry , Hasenclever Peter , Werner Beat , Meboldt Mirko , Huebler Michael , Schmid Daners Marianne
Published: June 2023

Introduction: The use of cardiopulmonary bypass (CBP; also known as a heart-lung machine) in newborns with complex congenital heart defects may result in brain damage. Magnetic resonance imaging (MRI) assessments cannot be performed safely because the metal components used to construct CBP devices may elicit adverse effects on patients when they are placed in a magnetic field. Thus, this project aimed to develop a prototype MR-conditional circulatory support system that could be used to perform cerebral perfusion studies in animal models. Methods: The circulatory support device includes a roller pump with two rollers. The ferromagnetic and most of the metal components of the roller pump were modified or replaced, and the drive was exchanged by an air-pressure motor. All materials used to develop the prototype device were tested in the magnetic field according to the American Society for Testing and Materials (ASTM) Standard F2503-13. The technical performance parameters, including runtime/durability as well as achievable speed and pulsation behavior, were evaluated and compared to standard requirements. The behavior of the prototype device was compared with a commercially available pump. Results: The MRI-conditional pump system produced no image artifacts and could be safely operated in the presence of the magnetic field. The system exhibited minor performance-related differences when compared to a standard CPB pump; feature testing revealed that the prototype meets the requirements (i.e., operability, controllability, and flow range) needed to proceed with the planned animal studies. Conclusion: This MR-conditional prototype is suitable to perform an open-heart surgery in an animal model to assess brain perfusion in an MR environment.