bluuebunny/crossref_metadata_2025 huggingface dataset:
Observed jet power and radiative efficiency of black hole candidates in the Kerr+PFDM model
Authors: Narzilloev Bakhtiyor , Abdujabbarov Ahmadjon , Ahmedov Bobomurat , Bambi Cosimo
Published: September 2024

In this research, we explore the electromagnetic energy emitted by astrophysical black holes within the Kerr+PFDM (Kerr + perfect fluid dark matter) spacetime, a model comprising rotating black holes surrounded by dark matter. Our investigation focuses on black holes within X-ray binary systems, namely GRS 1915+105, GRO J1655-40, XTE J1550-564, A0620-00, H1743-322, and GRS 1124-683. Our findings indicate that the Kerr+PFDM spacetime can account for the radiative efficiency of these sources as determined through the continuum-fitting method (CFM). Additionally, employing the Blandford–Znajek mechanism, we demonstrate the ability to replicate the observed jet power. By combining the outcomes of both analyses for the selected objects, we establish more rigorous constraints on the spacetime parameters. Notably, our results reveal that, similar to the Kerr spacetime, the Kerr+PFDM spacetime cannot simultaneously account for the observed jet power and radiative efficiency of GRS 1915+105.
Fast Unsupervised Cross-Modal Hashing with Robust Factorization and Dual Projection
Authors: Liu Xingbo , Li Jiamin , Nie Xiushan , Zhang Xuening , Yin Yilong
Published: September 2024

Unsupervised hashing has attracted extensive attention in effectively and efficiently tackling large-scale cross-modal retrieval task. Existing methods typically try to mine the latent common subspace across multimodal data without any category annotation. Despite the exciting progress, there are still three challenges that need to be further addressed: (1) efficiently improving the robustness during latent common subspace learning; (2) harmoniously embedding the intra-modal inherence and inter-modal relevance of multimodal data into Hamming space; and (3) effectively reducing the training time complexity and making the model scalable for large-scale datasets. To well address the above challenges, this study proposes a method named Fast Unsupervised Cross-Modal Hashing (FUCH). Specifically, FUCH proposes a semantic-aware collective matrix factorization to learn robust representation via exploiting latent category-specific attributes, and introduces Cauchy loss to measure the factorization process. Accordingly, the above process can effectively embed potential discriminative information into common space, while making the model insensitive for outliers. Moreover, FUCH designs a dual projection learning scheme, which not only learns modality-unique hash functions to excavate individual properties but also learns modality-mutual hash functions to multimodal correlational properties. Experimental results on three benchmark datasets verify the effectiveness of FUCH under various scenarios.
Personality Expression Using Co-Speech Gesture
Authors: Sonlu Sinan , Demir Halil Özgür , Güdükbay Uğur
Published: September 2024

We express our personality through verbal and nonverbal behavior. While verbal cues are mostly related to the semantics of what we say, nonverbal cues include our posture, gestures, and facial expressions. Appropriate expression of these behavioral elements improves conversational virtual agents’ communication capabilities and realism. Although previous studies focus on co-speech gesture generation, they do not consider the personality aspect of the synthesized animations. We show that automatically generated co-speech gestures naturally express personality traits, and heuristics-based adjustments for such animations can further improve personality expression. To this end, we present a framework for enhancing co-speech gestures with the different personalities of the Five-Factor model. Our experiments suggest that users perceive increased realism and improved personality expression when combining heuristics-based motion adjustments with co-speech gestures.
Time-Sensitive Networking (TSN) for Industrial Automation: Current Advances and Future Directions
Authors: Zhang Tianyu , Wang Gang , Xue Chuanyu , Wang Jiachen , Nixon Mark , Han Song
Published: September 2024

With the introduction of Cyber-Physical Systems (CPS) and Internet of Things (IoT) technologies, the automation industry is undergoing significant changes, particularly in improving production efficiency and reducing maintenance costs. Industrial automation applications often need to transmit time- and safety-critical data to closely monitor and control industrial processes. Several Ethernet-based fieldbus solutions, such as PROFINET IRT, EtherNet/IP, and EtherCAT, are widely used to ensure real-time communications in industrial automation systems. These solutions, however, commonly incorporate additional mechanisms to provide latency guarantees, making their interoperability a grand challenge. The IEEE 802.1 Time-Sensitive Networking (TSN) task group was formed to enhance and optimize IEEE 802.1 network standards, particularly for Ethernet-based networks. These solutions can be evolved and adapted for cross-industry scenarios, such as large-scale distributed industrial plants requiring multiple industrial entities to work collaboratively. This paper provides a comprehensive review of current advances in TSN standards for industrial automation. It presents the state-of-the-art IEEE TSN standards and discusses the opportunities and challenges of integrating TSN into the automation industry. Some promising research directions are also highlighted for applying TSN technologies to industrial automation applications.
Approaches to Conflict-free Replicated Data Types
Authors: Almeida Paulo Sérgio
Published: September 2024

Conflict-free Replicated Data Types (CRDTs) allow optimistic replication in a principled way. Different replicas can proceed independently, being available even under network partitions and always converging deterministically: Replicas that have received the same updates will have equivalent state, even if received in different orders. After a historical tour of the evolution from sequential data types to CRDTs, we present in detail the two main approaches to CRDTs, operation-based and state-based, including two important variations, the pure operation-based and the delta-state based. Intended for prospective CRDT researchers and designers, this article provides solid coverage of the essential concepts, clarifying some misconceptions that frequently occur, but also presents some novel insights gained from considerable experience in designing both specific CRDTs and approaches to CRDTs.
Reversible Data Hiding in Shared JPEG Images
Authors: Yu Chunqiang , Cheng Shichao , Zhang Xianquan , Zhang Xinpeng , Tang Zhenjun
Published: September 2024

Reversible data hiding (RDH) in encrypted images has emerged as an effective technique for securely storing and managing confidential images in the cloud. However, most RDH methods in shared images (RDHSI) are designed for uncompressed images and cannot be applied for JPEG images. To address this issue, we propose a novel RDH in shared JPEG images. Our method consists of JPEG image sharing and data hiding in JPEG shares, which are both conducted on JPEG bit-stream. Specifically, the DC appended bits (DCA) and AC appended bits (ACA) derived from the original JPEG bit-stream are shared by (

\(k\)

,

\(n\)

) threshold Chinese remainder theorem-based secret sharing (CRTSS) with two different constraints, one for DC sharing and another for AC sharing. The constraint of DC sharing ensures that the DC coefficient shares do not overflow. The constraint of AC sharing ensures the sizes of ACA shares are less than the sizes of the original ACA so that the embedding room can be vacated from each shared JPEG bit-stream. Each data-hider can embed the secret data into the personal JPEG share. The original JPEG image can be recovered losslessly from any

\(k\)

JPEG shares. The proposed sharing and data hiding are both well compatible with the JPEG standard. Experimental results demonstrate that the proposed method not only well preserves the file size whether the JPEG shares or marked JPEG shares but also achieves outstanding security performance and a high embedding capacity.
Multi-Label and Evolvable Dataset Preparation for Web-Based Object Detection
Authors: Li Shucheng , Zhu Jingzhou , Chang Boyu , Wu Hao , Xu Fengyuan , Zhong Sheng
Published: September 2024

In this article, we focus on the emerging field of web-based object detection, which has gained considerable attention due to its ability to utilize large amounts of web data for training, thus eliminating the need for labor-intensive manual annotations. However, the noisy and ever-evolving nature of web data poses challenges in preparing high-quality datasets for web-based object detection. To address these challenges, we propose a fully automatic dataset preparation method in this article. Our proposed method incorporates a hierarchical clustering module that assigns multiple precise labels to each image. This module is based on our observation that web image data exhibits different distributions at varying granularities. Furthermore, an evolutionary relabeling module ensures the adaptability of both the prepared dataset and trained detection models to the ever-evolving web data. Extensive experiments demonstrate that our method outperforms other web-based methods, and achieves a comparable performance to those manually labeled benchmark datasets.
Localized Surface Modification during Alternating Current Scanning Electrochemical Microscopy: Origin and Mechanism
Authors: Pal Ankita , Krishna Nanda Gopala , A. Ravi Shankar , Philip John
Published: September 2024

In the current study, we report for the first time the observation of unintended localized surface modification on commercially pure aluminum (Al) during an alternating current scanning electrochemical microscopy (AC-SECM) analysis, its origin, and the probable mechanism responsible for it. Application of an AC perturbation potential (∼100 mV amplitude at ∼100 kHz frequency) to the Platinum ultramicroelectrode (Pt UME), during AC-SECM in acidic, neutral chloride, tap water, and alkaline electrolytes was found to cause surface modification on the scanned region of Al. An increase in the local pH of the electrolyte between the UME and the Al substrate, irrespective of the electrolyte pH (3–11) and UME biasing conditions, led to the local surface modification. The reason for the enhancement of local pH is attributed to the occurrence of higher rates of cathodic reduction reactions than that of anodic oxidation reactions. The reduction of dissolved oxygen/protons/water in the electrolytes led to the generation or consumption of OH−/H+ ions, respectively, and thus increased the pH, whereas the oxidation of Pt UME/Al surfaces decreased the pH with the generation of H+ or consumption of OH− ions. These results contribute significantly to accurately analyzing Al and its alloys using the AC-SECM technique.
Physical effects of 3-D microenvironments on confined cell behaviors
Authors: Lan Bao-Qiong , Wang Ya-Jun , Yu Sai-Xi , Liu Wei , Liu Yan-Jun
Published: September 2024

Cell migration is a fundamental and functional cellular process, influenced by a complex microenvironment consisting of different cells and extracellular matrix. Recent research has highlighted that, besides biochemical cues from the microenvironment, physical cues can also greatly alter cellular behavior. However, due to the complexity of the microenvironment, little is known about how the physical interactions between migrating cells and surrounding microenvironment instructs cell movement. Here, we explore various examples of three-dimensional microenvironment reconstruction models in vitro and describe how the physical interplay between migrating cells and the neighboring microenvironment controls cell behavior. Understanding this mechanical cooperation will provide key insights into organ development, regeneration, and tumor metastasis.
CD8+ tissue-resident memory T cells are essential in bleomycin-induced pulmonary fibrosis
Authors: Feng Xiao , Yu Fan , He Xin-Liang , Cheng Pei-Pei , Niu Qian , Zhao Li-Qin , Li Qian , Cui Xiao-Lin , Jia Zi-Heng , Ye Shu-Yi , Liang Li-Mei , Song Lin-Jie , Xiong Liang , Xiang Fei , Wang Xiaorong , Ma Wan-Li , Ye Hong
Published: September 2024

The role of CD8+ TRM cells in the development of pulmonary fibrosis was validated and studied in the classic model of pulmonary fibrosis. It was proposed for the first time that CCL18 has a chemotactic effect on CD8+ TRM cells, thereby exacerbating pulmonary fibrosis.
Pik3c3 expression profiling in the mouse kidney and its role in proximal tubule cell physiology
Authors: Liu Ting , Yuan Jialing , Dai Caihong , Chen Mystie X. , Fan Jerry , Humphreys Benjamin D. , Fulton David J. R. , Kleven Daniel T. , Fan Xingjun , Dong Zheng , Chen Jian-Kang
Published: September 2024

This is the first report defining the class 3 phosphatidylinositol 3-kinase (Pik3c3) expression profile in the kidney. Pik3c3 is nearly absent in renal interstitial cells, glomerular mesangial cells, and endothelial cells. Remarkably, glomerular podocytes express the highest Pik3c3 level in the kidney. However, the proximal tubule exhibits the highest expression level among all renal tubules. This study also unveils the pivotal role of Pik3c3 in regulating EGFR degradation and signaling termination in RPTCs, furthering our understanding of Pik3c3 in renal cell physiology.
Bacterial lipopolysaccharide inhibits free thiamin uptake along the intestinal tract via interference with membrane expression of thiamin transporters 1 and 2
Authors: Anthonymuthu Selvaraj , Sabui Subrata , Manzon Kameron Isaiah , Sheikh Alaullah , Fleckenstein James M. , Said Hamid M.
Published: September 2024

This study shows that the exposure of gut epithelial cells to bacterial LPS negatively impact the uptake process of the free form of vitamin B1 (i.e., thiamin). This appears to be mediated via suppression in the level of thiamin transporters 1 and 2 (THTR-1 and -2) expression at the cell membrane and involves a protein kinase A (PKA) signaling pathway.
Mitragynine and morphine produce dose-dependent bimodal action on food but not water intake in rats
Authors: Zuarth Gonzalez Julio D. , Mottinelli Marco , McCurdy Christopher R. , de Lartigue Guillaume , McMahon Lance R. , Wilkerson Jenny L.
Published: September 2024

This study reveals that morphine and the kratom alkaloid mitragynine produce dose-dependent effects on feeding in rats. Low doses stimulate food intake via opioid pathways, while high doses decrease consumption through nonopioid mechanisms. Morphine potently suppresses water intake at all doses, whereas only high doses of mitragynine reduce drinking. These findings provide novel insights into the complex opioid and nonopioid mechanisms underlying the effects of mitragynine on ingestive behaviors.
Consideration of absolute intensity when examining sex differences in blood pressure responses during static exercise
Authors: Lee Jordan B. , Millar Philip J.
Published: September 2024

Low- to moderate-intensity submaximal static contractions are commonly used to study the effects of biological sex on the cardiovascular response to exercise. Under this paradigm, premenopausal females frequently demonstrate smaller blood pressure responses than age-matched males. These differences are preserved during postexercise circulatory occlusion, implicating the muscle metaboreflex as an important driver of sex differences in the blood pressure response to static exercise. The mechanisms responsible for these differences are incompletely understood but often attributed to innate sex differences in skeletal muscle fiber type distribution, muscle metabolism, and/or sympathetic control of the circulation. However, one potential confounding factor is that the majority of studies use relative intensity exercise (e.g., 30% of maximal voluntary contraction), such that on average, females are completing static contractions at a lower absolute intensity. In this review, we summarize human evidence showing that sex differences in blood pressure responses to static exercise are attenuated or abolished when controlling for absolute intensity and muscle strength, either by statistical methods or strength-matched cohorts. We highlight evidence that the effect of higher absolute contraction intensity on exercise blood pressure likely occurs through increased mechanical occlusion of skeletal muscle microvasculature, leading to greater activation of the muscle metaboreflex. These findings highlight an important need to account for absolute intensity when studying and interpreting sex differences in cardiovascular responses to exercise.
Salinity and prolactin regulate anoctamin 1 in the model teleost, Fundulus heteroclitus
Authors: Breves Jason P. , Posada Mariana A. , Tao Yixuan T. , Shaughnessy Ciaran A.
Published: September 2024

In this study, we provide evidence in a teleost fish that the Ca2+-activated Cl− channel, anoctamin 1 may provide an additional path for Cl− secretion by seawater-type ionocytes. Not only is this the first report of a Cftr-independent Cl−-secreting pathway conferring survival in seawater but also the first description of its regulation by the pituitary hormone prolactin.
Effects of the anti-inflammatory drug budesonide on the gut microbiota and cytokine production of 13-lined ground squirrels during prehibernation fattening
Authors: Grond Kirsten , Zur Tulod Jewel , Kurtz Courtney C. , Duddleston Khrystyne N.
Published: September 2024

Disruptions of gut microbiota can lead to inflammation, resulting in weight gain. Inflammation can be treated with budesonide, but how budesonide affects gut microbiota is unclear. Thirteen-lined ground squirrels experience low-grade gut inflammation during prehibernation fattening, which compares with human inflammation-weight gain mechanisms. We showed that budesonide treatment decreased microbiome diversity and lead to a shift in community in the cecum lumen. Our study supports developing ground squirrels as a model for studying microbiome-inflammation interactions.
Identification of shared and disease-specific intratumoral microbiome-host gene associations in gastrointestinal tumors
Authors: Liu Jing , Wang Hongyan , Zhang Shuai , Liu Jinyang
Published: September 2024

Our study constitutes a pivotal advancement in elucidating the intricate relationship between the intratumoral microbiome and host gene regulation, thereby gaining insights into the pivotal role that the intratumoral microbiome plays in the etiology of gastrointestinal tumors.
Investigative power of genomic informational field theory relative to genome-wide association studies for genotype-phenotype mapping
Authors: Kyratzi Panagiota , Matika Oswald , Brassington Amey H. , Clare Connie E. , Xu Juan , Barrett David A. , Emes Richard D. , Archibald Alan L. , Paldi Andras , Sinclair Kevin D. , Wattis Jonathan , Rauch Cyril
Published: September 2024

The genetic basis of complex traits remains challenging to investigate using classic genome-wide association studies (GWASs). Given the success of gene editing technologies, this point needs to be addressed urgently since there can only be useful editing technologies whether precise genotype-phenotype mapping information is available initially. Genomic informational field theory (GIFT) is a new mapping method designed to increase the investigative power of biological/medical datasets suggesting, in turn, the need to rethink the conceptual bases of quantitative genetics.
Lost in translation? Evidence for a muted proteomic response to thermal stress in a stenothermal Antarctic fish and possible evolutionary mechanisms
Authors: Dowd W. Wesley , Kültz Dietmar
Published: September 2024

Antarctic fishes have some of the lowest known heat tolerances among vertebrates, but the molecular mechanisms underlying this pattern are not fully understood. By combining detailed analyses of protein expression patterns in several tissues under various heat treatments with a broader evolutionary perspective, this study offers a novel hypothesis to explain the narrow range of temperature tolerance in this extraordinary group of fishes.
Characterization of Lactic Acid Bacteria Isolated From Rotting Oranges and Use of Agropastoral Processing By‐products as Carbon and Nitrogen Sources Alternative for Lactic Acid Production
Authors: Ngouénam Romial Joel , Nofal Ghadir , Patra Sanjukta , Njapndounke Bilkissou , Kouam Edith Marius Foko , Kaktcham Pierre Marie , Ngoufack François Zambou
Published: September 2024

This study investigated the ability of lactic acid bacteria (LAB) isolated from oranges to use fish by‐products (FB) and chicken by‐products (CB) as nitrogen sources alternative to yeast extract for lactic acid (LA) production in a papaya by‐product medium as a carbon source. Once the fermentation agents had been isolated, they were subjected to biochemical and molecular characterization. Inexpensive nitrogen sources, precisely CB and FB, were prepared, freeze‐dried, and yield evaluated. Also, before to the fermentation experiments, the Total Kjehdahl Nitrogen (TKN) of these by‐products and that of the yeast extract were determined. Then, three production media differing in terms of nitrogen source were formulated from these nitrogen sources. From the 22 LAB isolated from orange, two isolates of interest (NGO25 and NGO23) were obtained; all belonging to the Lactiplantibacillus plantarum species based on 16S rRNA gene sequencing. Furthermore, the production yield powder obtained after lyophilization of 1 L of CB and FB surpernatant were, respectively, 16.6 g and 12.933 g. The TKN of different nitrogen sources powder were 71.4 ± 0.000% DM (FB), 86.145 ± 0.001% DM (CB), and 87.5 ± 0.99% DM (yeast extract). The best kinetic parameters of LA production (LA (g/L): 31.945 ± 0.078; volumetric productivity (g/L.h): 1.331 ± 0.003; LA yield (mg/g) 63.89 ± 0.156; biomass (g/L) 7.925 ± 0.035; cell growth rate (g/L.h): 0.330 ± 0.001) were recorded by Lactiplantibacillus plantarum NGO25 after 24 h of fermentation. The latter data were obtained in the production medium containing CB as nitrogen sources. In addition, this production medium cost only $0.152 to formulate, compared to yeast extract which required $1.692 to formulate. Thus, freeze‐dried CB can be used as an alternative to yeast extract in large‐scale production of LA.
New Lindley Generator Based on T‐X Family of Distributions: Properties and Reliability Applications
Authors: Eissa Fatehi Yahya , Sonar Chhaya Dhanraj
Published: September 2024

The generalization of probability distributions has a rich history, with various techniques employed to introduce new families of distributions. One notable approach is the transformed‐transformer (T‐X) method, which has been used by several authors to introduce many of novel probability distributions. In this study, we present the new Lindley‐X class, a novel family of continuous probability distributions, and we introduce some submodels within this framework. Our research involves deriving mathematical expressions for various statistical measures, including moments, the generating function, the quantile function, and Renyi entropy. To estimate the parameters of the new family of distributions, we utilize a range of methods, including maximum likelihood, maximum product spacing, least squares, Cramer‐von Mises, and Anderson–Darling estimations. Furthermore, we illustrate the practical applicability of this new family of distributions through the analysis of real‐life datasets.
Targeting NTRK1 Enhances Immune Checkpoint Inhibitor Efficacy in NTRK1 Wild-Type Non–Small Cell Lung Cancer
Authors: Smith Margaret R. , Dixon Caroline B. , Wang Yuezhu , Liu Yin , D’Agostino Ralph , Ruiz Jimmy , Oliver George , Miller Lance D. , Topaloglu Umit , Chan Michael D. , Farris Michael , Su Jing , Mileham Kathryn F. , Zhao Dawen , Li Wencheng , Sexton Tammy , Lycan Thomas , Haas Karen M. , Grayson Jason M. , Xing Fei
Published: September 2024

Treatment of non–small cell lung cancer (NSCLC) has drastically changed in recent years owing to the robust anticancer effects of immune checkpoint inhibitors (ICI). However, only 20% of the patients with NSCLC benefit from ICIs, highlighting the need to uncover the mechanisms mediating resistance. By analyzing the overall survival (OS) and mutational profiles of 424 patients with NSCLC who received ICI treatments between 2015 and 2021, we determined that patients carrying a loss-of-function mutation in neurotrophic tyrosine kinase receptor 1 (NTRK1) had a prolonged OS when compared with patients with wild-type NTRK1. Notably, suppression of the NTRK1 pathway by knockdown or entrectinib treatment significantly enhanced ICI efficacy in mouse NSCLC models. Comprehensive T-cell population analyses demonstrated that stem-like CD4+ T cells and effector CD4+ and CD8+ T cells were highly enriched in anti–PD-1–treated mice bearing tumors with decreased NTRK1 signaling. RNA sequencing revealed that suppression of NTRK1 signaling in tumor cells increased complement C3 expression, which enhanced the recruitment of T cells and myeloid cells and stimulated M1-like macrophage polarization in the tumor. Together, this study demonstrates a role for NTRK1 signaling in regulating cross-talk between tumor cells and immune cells in the tumor microenvironment and provides a potential therapeutic approach to overcome immunotherapy resistance in patients with NSCLC with NTRK1 wild-type.

Significance: Inhibition of NTRK1 signaling confers sensitivity to immunotherapy by enhancing complement C3-mediated T-cell and macrophage functions, leading to improved responses to immune checkpoint inhibitors in patients with lung cancer with NTRK1 mutations.
ctDNA Dynamics and Mechanisms of Acquired Resistance in Patients Treated with Osimertinib with or without Bevacizumab from the Randomized Phase II ETOP-BOOSTER Trial
Authors: Soo Ross A. , Dafni Urania , Han Ji-Youn , Cho Byoung Chul , Nadal Ernest , Yeo Chong Ming , Carcereny Enric , de Castro Javier , Sala Maria Angeles , Coate Linda , Provencio Mariano , Britschgi Christian , Vagenknecht Patrick , Dimopoulou Georgia , Kammler Roswitha , Finn Stephen P. , Peters Solange , Stahel Rolf A. ,   for the ETOP 10-16 BOOSTER Collaborators
Published: September 2024

Purpose:

The ETOP 10-16 BOOSTER study was a randomized phase II trial of osimertinib and bevacizumab therapy versus osimertinib therapy in patients with an acquired EGFR T790M mutation. The mechanisms of acquired resistance to osimertinib and bevacizumab have not been described previously.

Experimental Design:

Next-generation sequencing (Guardant360) was conducted in serial plasma samples. The association between ctDNA and efficacy outcomes was explored, and molecular alterations at progression were described.

Results:

A total of 136 patients (88% of 155 randomized) had plasma samples at baseline (68 per arm), 110 (71%) at week 9, and 65 (42%) at progression. In a multivariable model for progression-free survival (PFS), the treatment effect was found to differ by smoking status (interaction P = 0.046), with the effect of smoking also differing by baseline EGFR T790M (interaction P = 0.033), whereas both TP53 at baseline and the tissue EGFR exon 21 L858R mutation were significantly associated with worse PFS outcome. Smokers (current/former) without baseline EGFR T790M showed a significant improvement in PFS under combination treatment, albeit with small numbers (P = 0.015). Week-9 EGFR T790M clearance was associated with improved PFS in the osimertinib arm (P = 0.0097). Acquired EGFR C797S mutations were detected in 22% and 13% of patients in the combination and osimertinib arms, respectively.

Conclusions:

The differential effect of treatment by smoking was not explained by TP53 mutations or other molecular alterations examined. Molecular mechanisms of acquired resistance were detected, but no novel molecular alterations were identified in the combination arm.
Supplementary Tables from Activation of Cell-Intrinsic Signaling in CAR-T Cells via a Chimeric IL7R Domain
Authors: Vorri Stamatia C. , Holl Natalie J. , Leeming Michael , Apostolova Petya , Marple Andrew , Ravich Jonas W. , Canbaz Ata , Rahnama Ruyan , Choe Jun , Modi Arjun , Fearnow Adam D. , Walsh Scott T.R. , Pearce Erika L. , Varadhan Ravi , Bonifant Challice L.
Published: September 2024

Supplemental Table 1 and 2
Figure S3 from Activation of Cell-Intrinsic Signaling in CAR-T Cells via a Chimeric IL7R Domain
Authors: Vorri Stamatia C. , Holl Natalie J. , Leeming Michael , Apostolova Petya , Marple Andrew , Ravich Jonas W. , Canbaz Ata , Rahnama Ruyan , Choe Jun , Modi Arjun , Fearnow Adam D. , Walsh Scott T.R. , Pearce Erika L. , Varadhan Ravi , Bonifant Challice L.
Published: September 2024

Supplementary Figure 3
Figure S1 from Activation of Cell-Intrinsic Signaling in CAR-T Cells via a Chimeric IL7R Domain
Authors: Vorri Stamatia C. , Holl Natalie J. , Leeming Michael , Apostolova Petya , Marple Andrew , Ravich Jonas W. , Canbaz Ata , Rahnama Ruyan , Choe Jun , Modi Arjun , Fearnow Adam D. , Walsh Scott T.R. , Pearce Erika L. , Varadhan Ravi , Bonifant Challice L.
Published: September 2024

Supplementary Figure 1
Figure 6 from Activation of Cell-Intrinsic Signaling in CAR-T Cells via a Chimeric IL7R Domain
Authors: Vorri Stamatia C. , Holl Natalie J. , Leeming Michael , Apostolova Petya , Marple Andrew , Ravich Jonas W. , Canbaz Ata , Rahnama Ruyan , Choe Jun , Modi Arjun , Fearnow Adam D. , Walsh Scott T.R. , Pearce Erika L. , Varadhan Ravi , Bonifant Challice L.
Published: September 2024

Single-chain IL7Rα signaling stimulates STAT5 activation in CAR-T cells. A, Schema of the compared T-cell conditions. A: CAR and sIL7; B: CAR with the distal IL7Rα domain; C: CAR with the proximal IL7Rα domain. B, Levels of STAT5 phosphorylation before and after exposure to plate-bound recombinant antigen (rhCD123) for 30 minutes, measured with a TR-FRET assay. Comparison between conditions with and without rhCD123 stimulation. n = 3 donors, performed in duplicate. C, Relative ECAR and (D) relative OCR of T cells measured after 24-hour rhCD123 stimulation in cytokine-free media. n = 4 individual donors tested in five replicates per assay. For each donor, normalization of all values to the baseline (NT control) was performed. E, Cytotoxic activity measured by luminescence-based assay. CD123-negative K562 cell line and NT T cells included as controls. n = 4 T-cell donors, E:T. Comparison of cytotoxicity of engineered T cells against all CD123-expressing targets with that from NT T cells was very significant (P < 0.0001 in K562.CD123, MV-4-11, and Molm-13). Differences between engineered T cells noted only with MV-4-11 target. ****, P < 0.0001; **, P < 0.01. F, Long-term cytotoxicity measured with six 48-hour serial stimulations with indicated NLS eGFP-modified AML cell lines with initial plating at 1:1 E:T (n = 4 individual donors in technical triplicate each normalized to timepoint 0). G, Half-life decay of each target cell line calculated at each stimulation. Shaded bars, 95% confidence intervals for decay calculated at each timepoint. NT, nontransduced.
Data from Activation of Cell-Intrinsic Signaling in CAR-T Cells via a Chimeric IL7R Domain
Authors: Vorri Stamatia C. , Holl Natalie J. , Leeming Michael , Apostolova Petya , Marple Andrew , Ravich Jonas W. , Canbaz Ata , Rahnama Ruyan , Choe Jun , Modi Arjun , Fearnow Adam D. , Walsh Scott T.R. , Pearce Erika L. , Varadhan Ravi , Bonifant Challice L.
Published: September 2024

Abstract
Chimeric antigen receptor (CAR) T cells can effectively treat leukemias, but sustained antitumor responses can be hindered by a lack of CAR T-cell persistence. Cytotoxic effector T cells are short-lived, and establishment of CAR-T cells with memory to ensure immune surveillance is important. Memory T cells depend on cytokine support, with IL7 activation of the IL7 receptor (IL7R) being critical. However, IL7R surface expression is negatively regulated by exposure to IL7. We aimed to support CAR T-cell persistence by equipping CAR-T cells with a sustained IL7Rα signal. We engineered T cells to constitutively secrete IL7 or to express an anti–acute myeloid leukemia–targeted IL7Rα–chimeric cytokine receptor (CCR) and characterized the phenotype of these cell types. Canonical downstream signaling was activated in CCR-T cells with IL7R activation. When coexpressed with a cytotoxic CAR, functionality of both the CCR and CAR was maintained. We designed hybrid CAR–CCR and noted membrane proximity of the intracellular domains as vital for signaling. These data show cell-intrinsic cytokine support with canonical signaling, and functionality can be provided via expression of an IL7Rα domain whether independently expressed or incorporated into a cytotoxic CAR for use in anticancer therapy.
Significance:
To improve the phenotype of tumor-directed T-cell therapy, we show that provision of cell-intrinsic IL7R-mediated signaling is preferable to activation of cells with exogenous IL7. We engineer this signaling via independent receptor engineering and incorporation into a CAR and validate maintained antigen-specific cytotoxic activity.
Exploring Diagnostic and Therapeutic Odyssey in Pulmonary Arterial Hypertension: Insights from In-Depth Semi-Structured Interviews
Authors: Swietlik Emilia M. , Fay Michaela , Morrell Nicholas W.
Published: September 2024

Introduction: Establishing a diagnosis is paramount in medical practice as it shapes patients’ experiences and guides treatment. Patients grappling with rare diseases face a triple challenge: prolonged diagnostic journeys, limited responses to existing therapies, and the absence of effective monitoring tools. Genetic diagnosis often provides crucial diagnostic and prognostic information, opening up possibilities for genotype-targeted treatments and facilitating counselling and relative testing. The NIHR BioResource – Rare Diseases (NBR) Study and the Cohort Study in Idiopathic and Hereditary Pulmonary Arterial Hypertension (PAH Cohort study) aimed to enhance diagnosis and treatment for PAH, successfully identifying the genetic cause in 25% of idiopathic cases. However, the diagnostic and therapeutic odyssey in patients with PAH remains largely unexplored. Methods: Stakeholders from the NBR and PAH Cohort studies were recruited using purposive sampling. In-depth interviews and focus groups were recorded, transcribed, anonymised, and analysed thematically using MAXQDA software. Results: The study involved 53 interviews and focus groups with 63 participants, revealing key themes across five stages of the diagnostic odyssey: initial health concerns and interactions with general practitioners, experiences of misdiagnosis, relief upon receiving the correct diagnosis, and mixed emotions regarding genetic results and the challenges of living with the disease. Following the diagnosis, participants embarked on a therapeutic journey, facing various challenges, including the disease’s impact on professional and social lives, the learning curve associated with understanding the disease, shifts in communication dynamics with healthcare providers, therapeutic hurdles, and insurance-related issues. Building on these insights, we identified areas of unmet needs, such as improved collaboration with primary care providers and local hospitals, the provision of psychological support and counselling, and the necessity for ongoing patient education in the ever-evolving realms of research and therapy. Conclusions: The study highlights the significant challenges encountered throughout the diagnostic and therapeutic journey in PAH. To enhance patient outcomes, it is crucial to raise awareness of the disease, establish clear diagnostic pathways, and seamlessly integrate genetic diagnostics into clinical practice. Streamlining the diagnostic process can be achieved by utilising existing clinical infrastructure to support research and fostering better communication within the NHS. Moreover, there is an urgent need for more effective therapies alongside less burdensome drug delivery methods.
Ovarian Insufficiency in Adolescent Females with Transfusion-Dependent β-Thalassemia: Pituitary versus Ovarian Iron Overload
Authors: Matter Randa M. , Farid Laila A. , Madkour Sherihane S. , Yassin Alshimaa H. , Salah Nouran Y.
Published: September 2024

Introduction: Females with transfusion-dependent β-thalassemia (TDT) display menstrual irregularities and subfertility at certain points in their lives, even if well-chelated, representing a significant physical and psychological burden. Little is known about the effects of pituitary and ovarian iron contents on ovarian reserve and function. Hence, this study aimed to assess ovarian reserve and pituitary-gonadal axis function in adolescent females with TDT and correlate them with pituitary and ovarian volume, pituitary iron load, and serum ferritin. Methods: Fifty adolescent females with TDT were compared to 50 age-matched healthy females. Age of diagnosis of TDT, transfusion index, type of chelation therapy, age at menarche, and Tanner breast stage were assessed. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), and ferritin were measured. Magnetic resonance imaging (MRI) pituitary iron content R2* and T2* were measured, and 3-D transabdominal ovarian ultrasound performed. Results: The mean age of the studied females with TDT was 14.54 ± 2.24 years. Ovarian insufficiency was found in 20 of them (40%). Compared to controls, adolescent females with TDT had significantly delayed age of menarche, AMH, FSH, LH, antral follicle count (AFC), and ovarian volume. Upon comparing those with ovarian insufficiency and those without, adolescents with TDT having ovarian insufficiency had significantly higher serum ferritin and pituitary MRI-R2* than those without insufficiency. Multivariate-logistic regression showed that pituitary MRI-R2* was the most significant independent variable associated with ovarian insufficiency among adolescent females with TDT. Conclusion: Adolescent females with TDT have decreased ovarian reserve, AFC, and gonadotropins that are correlated with serum ferritin, pituitary iron load, and ovarian volume. Hence, regular ovarian reserve assessment should be implemented as a part of endocrinological follow-up of females with TDT advising procedures to preserve fertility to those who are likely to have ovarian insufficiency.
Insights from ARCOS-V’s Transition to Remote Data Collection during the COVID-19 Pandemic: A Descriptive Study
Authors: Henry Nathan I.N. , Nair Balakrishnan , Ranta Anna , Krishnamurthi Rita , Bhatia Anjali , Feigin Valery
Published: September 2024

Introduction: The ARCOS-V study, an epidemiological study on stroke and transient ischaemic attack (TIA), faced the challenge of continuing data collection amidst the COVID-19 pandemic. This study aimed to describe the methodological changes and challenges encountered during the transition from paper-based methods to digital data collection for the ARCOS-V study and to provide insights into the potential of using digital tools to transform epidemiological research. Methods: The study adapted to remote data collection using REDCap and Zoom, involving daily health record reviews, direct data entry by trained researchers, and remote follow-up assessments. The process was secured with encryption and role-based access controls. The transition period was analysed to evaluate the effectiveness and challenges of the new approach. Results: The digital transition allowed for uninterrupted monitoring of stroke and TIA cases during lockdowns. Using REDCap and Zoom improved data reach, accuracy, and security. However, it also revealed issues such as the potential for systematic data entry errors and the need for robust security measures to protect sensitive health information. Conclusion: The ARCOS-V study’s digital transformation exemplifies the resilience of epidemiological research in the face of a global crisis. The successful adaptation to digital data collection methods highlights the potential benefits of such tools, particularly as we enter a new age of artificial intelligence (AI).
Do Children's Health Behaviors Buffer the Impact of Cumulative Environmental Stress on Emerging Cardiometabolic Risk?
Authors: Kunin‐Batson Alicia S. , Crain A. Lauren , Sherwood Nancy E. , Kelly Aaron S. , Kharbanda Elyse O. , Gunnar Megan R. , Haapala Jacob , Seburg Elisabeth M. , French Simone A.
Published: September 2024

Background

Previous studies have found that exposure to childhood environmental stress is associated with cardiometabolic risk. However, it is not known whether individual health behaviors disrupt this relationship. This study prospectively evaluated the relationship between cumulative environmental stress in a low‐income sample and cardiometabolic risk in middle childhood and examined whether child health behaviors attenuated this relationship.

Methods and Results

In a cohort of children (n=338; 57% Hispanic children; 25% Black children), environmental stressors (family and neighborhood factors representing disadvantage/deprivation) and child health behaviors (accelerometry measured physical activity; parent‐reported screen time and diet recalls) were measured over 5 time points beginning when children were aged 2 to 4 years and ending when they were aged 7 to 11 years. Children's cardiometabolic risk factors (body mass index, blood pressure, triglyceride/high‐density lipoprotein ratio, glucose, hemoglobin A
1c
, C‐reactive protein) were measured at 7 to 11 years. Emerging cardiometabolic risk was defined as having ≥1 elevations that exceeded clinical thresholds. In adjusted path analyses, greater cumulative environmental stress was associated with higher likelihood of emerging cardiometabolic risk in middle childhood (
P
<0.001). Higher levels of moderate to vigorous physical activity and fewer sedentary minutes attenuated the positive relationship between stress and cardiometabolic risk (
P
<0.05). Children with
>
2 hours of average daily screen time had a higher likelihood of elevated cardiometabolic risk (
P
<0.01), but screen time did not moderate the stress–cardiometabolic risk relationship. Dietary intake was not related to cardiometabolic risk.

Conclusions

Interventions that promote moderate to vigorous physical activity and limit sedentary behavior may have particular importance for the cardiometabolic health of children exposed to high levels of cumulative environmental stress.
Relationship Between Infarct Artery, Myocardial Injury, and Outcomes After Primary Percutaneous Coronary Intervention in ST‐Segment–Elevation Myocardial Infarction
Authors: de Waha Suzanne , Patel Manesh R. , Thiele Holger , Udelson James E. , Granger Christopher B. , Ben‐Yehuda Ori , Kotinkaduwa Lak , Redfors Björn , Eitel Ingo , Selker Harry P. , Maehara Akiko , Stone Gregg W.
Published: September 2024

Background

The extent to which infarct artery impacts the extent of myocardial injury and outcomes in patients with ST‐segment–elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention is uncertain.

Methods and Results

We performed a pooled analysis using individual patient data from 7 randomized STEMI trials in which myocardial injury within 30 days after primary percutaneous coronary intervention was assessed in 1774 patients by cardiac magnetic resonance (n=1318) or technetium‐99m sestamibi single‐photon emission computed tomography (n=456). Clinical follow‐up was performed at a median duration of 351 days (interquartile range, 184–368 days). Infarct size and outcomes were assessed in anterior (infarct vessel=left anterior descending) versus nonanterior (non–left anterior descending) STEMI. Median infarct size (percentage left ventricular myocardial mass) was larger in patients with anterior compared with nonanterior STEMI (19.7% [interquartile range, 9.4%–31.7%] versus 12.6% [interquartile range, 5.1%–20.5%];
P
<0.001). Patients with anterior compared with nonanterior STEMI were at higher risk for 1‐year all‐cause mortality (6.2% versus 3.6%; adjusted hazard ratio [HR], 1.66 [95% CI, 1.02–2.69];
P
=0.04) and heart failure hospitalization (4.4% versus 2.6%; adjusted HR, 1.96 [95% CI, 1.15–3.36];
P
=0.01). Infarct size was a predictor of subsequent all‐cause mortality or heart failure hospitalization in anterior STEMI (adjusted HR per 1% increase, 1.05 [95% CI, 1.03–1.07];
P
<0.001), but not in nonanterior STEMI (adjusted HR, 1.02 [95% CI, 0.99–1.05];
P
=0.19). The
P
value for this interaction was 0.04.

Conclusions

Anterior STEMI was associated with substantially greater myonecrosis after primary percutaneous coronary intervention compared with nonanterior STEMI, contributing in large part to the worse prognosis in patients with anterior infarction.
Long‐Term Risk of Cardiovascular Death in Patients With Mildly Reduced Ejection Fraction After Acute Myocardial Infarction: A Multicenter, Prospective Registry Study
Authors: Kim Hwajung , Lee Kwan Yong , Choo Eun Ho , Hwang Byeong‐Hee , Kim Jin Jin , Kim Chan Joon , Chang Kiyuk , Hong Young Joon , Kim Ju Han , Ahn Youngkeun , Choi Young ,   KAMIR‐NIH Investigators
Published: September 2024

Background

The prognostic implication of mildly reduced ejection fraction (mrEF) after acute myocardial infarction has not been clearly demonstrated. We investigated the long‐term risk of cardiovascular death and its predictors in patients with mrEF following acute myocardial infarction.

Methods and Results

A total of 18 668 patients who presented with acute myocardial infarction were included in 2 prospective, multicenter registries. The incidence of adverse cardiovascular events according to the left ventricular ejection fraction (EF) strata at index admission were evaluated. A score system consisting of clinical variables were developed to predict long‐term cardiovascular death in the mrEF group. There were 2548 patients with reduced EF (EF ≤40%), 4266 patients with mrEF (EF 41%–49%), and 11 854 patients with preserved EF (EF ≥50%). During a median follow‐up period of 37.9 months, the cardiovascular death rate was 22.3% in the reduced EF group, 10.3% in the mrEF group, and 7.3% in the preserved EF group (
P
<0.001). In the mrEF group, age>65 years, hypertension, stroke, severe renal insufficiency, and Killip class ≥3 were independent predictors for cardiovascular death. Presence of >2 predictors best discriminated the high‐risk patients for cardiovascular death with an area under the curve of 0.746. Incidence of cardiovascular death in the high‐risk mrEF group was comparable with the rEF group, while it was lower in the low‐risk mrEF group than in the pEF group.

Conclusions

Patients with mrEF after acute myocardial infarction had a modest risk of cardiovascular death. Clinical predictors could help discriminate a high‐risk subpopulation with cardiovascular death risks comparable with those in the reduced EF group.