bluuebunny/crossref_metadata_2025 huggingface dataset:
Distributed Graph Neural Network Training: A Survey
Authors: Shao Yingxia , Li Hongzheng , Gu Xizhi , Yin Hongbo , Li Yawen , Miao Xupeng , Zhang Wentao , Cui Bin , Chen Lei
Published: February 2024

Graph neural networks (GNNs) are a type of deep learning models that are trained on graphs and have been successfully applied in various domains. Despite the effectiveness of GNNs, it is still challenging for GNNs to efficiently scale to large graphs. As a remedy, distributed computing becomes a promising solution of training large-scale GNNs, since it is able to provide abundant computing resources. However, the dependency of graph structure increases the difficulty of achieving high-efficiency distributed GNN training, which suffers from the massive communication and workload imbalance. In recent years, many efforts have been made on distributed GNN training, and an array of training algorithms and systems have been proposed. Yet, there is a lack of systematic review of the optimization techniques for the distributed execution of GNN training. In this survey, we analyze three major challenges in distributed GNN training: massive feature communication, the loss of model accuracy, and workload imbalance. Then, we introduce a new taxonomy for the optimization techniques in distributed GNN training that address the above challenges. The new taxonomy classifies existing techniques into four categories: GNN data partition, GNN batch generation, GNN execution model, and GNN communication protocol. We carefully discuss the techniques in each category. In the conclusion, we summarize existing distributed GNN systems for multi–graphics processing units (GPUs), GPU-clusters and central processing unit (CPU)-clusters, respectively, and present a discussion about the future direction of distributed GNN training.
Architectural Support for Sharing, Isolating and Virtualizing FPGA Resources
Authors: Miliadis Panagiotis , Theodoropoulos Dimitris , Pnevmatikatos Dionisios , Koziris Nectarios
Published: February 2024

FPGAs are increasingly popular in cloud environments for their ability to offer on-demand acceleration and improved compute efficiency. Providers would like to increase utilization, by multiplexing customers on a single device, similar to how processing cores and memory are shared. Nonetheless, multi-tenancy still faces major architectural limitations including: (a) inefficient sharing of memory interfaces across hardware tasks (HT) exacerbated by technological limitations and peculiarities, (b) insufficient solutions for performance and data isolation and high quality of service, and (c) absent or simplistic allocation strategies to effectively distribute external FPGA memory across HT. This article presents a full-stack solution for enabling multi-tenancy on FPGAs. Specifically, our work proposes an intra-fpga virtualization layer to share FPGA interfaces and its resources across tenants. To achieve efficient inter-connectivity between virtual FPGAs (vFGPAs) and external interfaces, we employ a compact network-on-chip architecture to optimize resource utilization. Dedicated memory management units implement the concept of virtual memory in FPGAs, providing mechanisms to isolate the address space and enable memory protection. We also introduce a memory segmentation scheme to effectively allocate FPGA address space and enhance isolation through hardware-software support, while preserving the efficacy of memory transactions. We assess our solution on an Alveo U250 Data Center FPGA Card, employing 10 real-world benchmarks from the Rodinia and Rosetta suites. Our framework preserves the performance of HT from a non-virtualized environment, while enhancing the device aggregate throughput through resource sharing; up to 3.96x in isolated and up to 2.31x in highly congested settings, where an external interface is shared across four vFPGAs. Finally, our work ensures high-quality of service, with HT achieving up to 0.95x of their native performance, even when resource sharing introduces interference from other accelerators.
Mitigating Epistemic Injustice: The Online Construction of a Bisexual Culture
Authors: Taylor Jordan , Bruckman Amy
Published: February 2024

People participating in online groups often co-construct knowledge of what they believe and, sometimes, co-construct their understanding of
who they are
. Through participant observation and semi-structured interviews with 13 members of the online forum r/bisexual on Reddit, we found participants collaboratively constructing an understanding of bisexuality. We found that this knowledge-building fills an epistemic gap resulting from bisexuality often being poorly understood. When individuals do not possess knowledge key to understanding their own lives, this can be seen as
hermeneutical injustice
—a type of epistemic injustice. We use the lens of hermeneutical injustice to shed light on participants’ experiences on r/bisexual. Our work contributes to recent research on epistemic injustice in HCI by looking at how members of r/bisexual mitigate epistemic injustice by reclaiming residuality—the space outside the gay-straight binary. We also discuss considerations for hermeneutical injustice to inform the design of online communities and HCI research practice.
Unmasking the Power of Play Through TUI Designs
Authors: Nonnis A. , Bryan-Kinns N.
Published: February 2024

Research on the potential benefits of technology for autistic children is an emergent field in Human-Computer Interaction (HCI), especially within the Child-Computer Interaction Community. At the same time, there are concerns about what these interventions and technologies are for and who benefits. We present a research and design approach for Tangible User Interfaces (TUIs) for minimally verbal to nonverbal autistic children following a neurodiversity narrative through three field studies developed and evaluated with three groups of children within a semi-structured scholastic environment between 2018 and 2021 in the UK. We discuss our insights for research and TUI designs in the context of social play for nonverbal autistic children and critically reflect on the methods and approaches we used. We do this to disrupt the normalisation agenda that subtly permeates the field of HCI and to direct designers’ attention toward supporting autistic ways of being in the world.
TET Enzymes in the Immune System: From DNA Demethylation to Immunotherapy, Inflammation, and Cancer
Authors: López-Moyado Isaac F. , Ko Myunggon , Hogan Patrick G. , Rao Anjana
Published: February 2024

Ten-eleven translocation (TET) proteins are iron-dependent and α-ketoglutarate-dependent dioxygenases that sequentially oxidize the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). All three epigenetic modifications are intermediates in DNA demethylation. TET proteins are recruited by transcription factors and by RNA polymerase II to modify 5mC at enhancers and gene bodies, thereby regulating gene expression during development, cell lineage specification, and cell activation. It is not yet clear, however, how the established biochemical activities of TET enzymes in oxidizing 5mC and mediating DNA demethylation relate to the known association of TET deficiency with inflammation, clonal hematopoiesis, and cancer. There are hints that the ability of TET deficiency to promote cell proliferation in a signal-dependent manner may be harnessed for cancer immunotherapy. In this review, we draw upon recent findings in cells of the immune system to illustrate established as well as emerging ideas of how TET proteins influence cellular function.
The Immunobiology and Treatment of Food Allergy
Authors: Barshow Suzanne , Tirumalasetty Jyothi , Sampath Vanitha , Zhou Xiaoying , Seastedt Hana , Schuetz Jackson , Nadeau Kari
Published: February 2024

IgE-mediated food allergy (IgE-FA) occurs due to a breakdown in immune tolerance that leads to a detrimental type 2 helper T cell (TH2) adaptive immune response. While the processes governing this loss of tolerance are incompletely understood, several host-related and environmental factors impacting the risk of IgE-FA development have been identified. Mounting evidence supports the role of an impaired epithelial barrier in the development of IgE-FA, with exposure of allergens through damaged skin and gut epithelium leading to the aberrant production of alarmins and activation of TH2-type allergic inflammation. The treatment of IgE-FA has historically been avoidance with acute management of allergic reactions, but advances in allergen-specific immunotherapy and the development of biologics and other novel therapeutics are rapidly changing the landscape of food allergy treatment. Here, we discuss the pathogenesis and immunobiology of IgE-FA in addition to its diagnosis, prognosis, and treatment.
Impact of the trans-ancestry polygenic risk score on type 2 diabetes risk, onset age and progression among population in Taiwan
Authors: Wang Shi-Heng , Huang Yu-Chuen , Cheng Chun-Wen , Chang Ya-Wen , Liao Wen-Ling
Published: February 2024

Our findings indicated that diabetic polygenic risk score (PRS) which combined susceptibility variants from Asian and European population affect the onset age of type 2 diabetes (T2D) and could be used as a tool for early screening of T2D, especially for individuals with high genetic risk, and may be associated with the risk of diabetic complications among people in Taiwan.
Sex-based differences in short- and longer-term diet-induced metabolic heart disease
Authors: Croft Amanda J. , Kelly Conagh , Chen Dongqing , Haw Tatt Jhong , Balachandran Lohis , Murtha Lucy A. , Boyle Andrew J. , Sverdlov Aaron L. , Ngo Doan T. M.
Published: February 2024

Sex differences in obesity-associated cardiomyopathy are well documented but incompletely understood. We show for the first time that RNA methylation machinery genes may be regulated in response to obesogenic diet in a sex- and age-dependent manner and levels may correspond to cardiac systolic function. Our cardiac RNA-seq analysis suggests female, but not male mice may be protected from cardiac dysfunction by a protective cardiac remodeling response early during obesogenic stress.
Changes in Techno-Functional Characteristics of Cow Colostrum Powder Prepared by Freeze Drying
Authors: Das Anamika , Seth Raman , Tarafdar Ayon , Dey Swarnima , Kumar Yogesh , Sirohi Ranjna
Published: February 2024

The present study investigates the characteristics of freeze-dried bovine colostrum powder prepared from the first three milkings of Karan fries cattle at different intervals. Bioactive components of bovine colostrum are heat sensitive, and therefore, in order to retain the biological activity of different components, it should be subjected to minimal nonthermal treatment. In this study, the optimum temperature/time combination of 60°C/45 min was used for the processing of cow colostrum. At this temperature, the microbial count significantly decreased as compared to raw colostrum. In freeze-dried bovine skimmed colostrum powder (BSCP) and bovine colostrum whey powder (BCWP), IgG emerged as the highest fraction among immune factors, whereas in growth factors, insulin-like growth factor 1(IGF1) and transforming growth factor β2 (TGFβ2) were found in large proportion as compared to insulin-like growth factor 2 (IGF2) and transforming growth factor β1 (TGFβ1). The IgG content (per 100 g) of BSCP prepared from 1st, 2nd, and 3rd milking was found to be 36.62, 27.87, and 20.51 g, respectively, whereas IgG content (per 100 g) of BCWP prepared from 1st, 2nd, and 3rd milking was found to be 33.32, 24.53, and 16.81 g, respectively. The IGF1 content (per 100 g) of BSCP prepared from 1st, 2nd, and 3rd milking was found to be 921.6, 741.2, and 617.2 μg, respectively, whereas IGF1 content (per 100 g) of BCWP prepared from 1st, 2nd, and 3rd milking was found to be 869.8, 688, and 454.4 μg, respectively. The TGFβ2 content (per 100 g) of BSCP prepared from 1st, 2nd, and 3rd milking was found to be 1278, 1076, and 856.8 μg, respectively, whereas TGFβ2 content (per 100 g) of BCWP prepared from 1st, 2nd, and 3rd milking was found to be 1167, 950.2, and 769.2 μg, respectively. The microstructure of freeze-dried cow colostrum whey powder revealed that its pore size was more than that of skimmed colostrum powder. BCWP exhibited lower phagocytic activity as well as lymphocyte proliferation index as compared to BSCP which was carried out in vitro. The observations of the study provide an insight about the components present in BCWP and BSCP apart from the physical characteristics of the products which might pave the way for its utilization in various food formats.
Cyanidin-3-O-Glucoside Combined with PGC1α Inhibitor Promotes Cancer Cell Death by Inducing Excessive Levels of ROS in Cervical Squamous Cell Carcinoma
Authors: Liu Lili , Zhao Tao , Yang Huaping , Hu Zhenghui , Xie Caifeng
Published: February 2024

Cervical cancer is a global public health problem, particularly in the low-income and middle-income countries. Natural products, such as cyanidin and its derivative cyanidin-3-O-glucoside (C3G), are considered safe and nontoxic food additives, potent therapeutic options for cancer. The present study aims to evaluate the beneficial effects of C3G on cervical squamous cell carcinoma (CSCC) in vitro and explore more potential therapeutic strategies for CSCC. C3G significantly inhibited the cell growth of CSCC cells and induced cancer cell apoptosis in a dose-dependent manner. Meanwhile, C3G promoted cellular reactive oxygen species (ROS) accumulation and decreased mitochondrial membrane potential and mitochondrial mass. The antioxidant regent N-acetyl-L-cysteine (NAC) rescued the effect of C3G on CSCC cells, further demonstrating ROS’s important role in C3G treatment. To explore the underlying mechanism, autophagy-related signaling pathways were investigated, and the results showed that C3G induced cell autophagy but not mitophagy. More importantly, C3G caused a significant activation of mitochondria biogenesis through the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) signaling pathway. C3G synergized with PGC-1α inhibitor SR-18292 induced more severe ROS accumulation and showed more potent inhibition of cell proliferation and mitochondrial membrane potential than C3G treatment alone. Thus, the present study suggests a new potential therapeutic strategy for CSCC based on the synergistic effect of C3G and PGC1α inhibitors.
Mammoplasty Using Modified Superomedial Pedicle Technique in Severely Macromastia and Ptotic Breasts
Authors: Selamioğlu Engin , Agdoğan Özgür
Published: February 2024

Mammoplasty is a surgery commonly used for macromastia. Many mammoplasty techniques are described, all with their specific pros and cons. However, the concern to avoid serious complications sometimes takes precedence, and the ideal result cannot be. For macromastia and severely ptotic breasts, usually the free nipple-areolar complex (NAC) mammoplasty technique is implemented. The results, however, may only be completely satisfactory regarding cosmetics. Loss of NAC, poor appearance, flabbiness, flattening, and ptosis are among the disadvantages of this technique. This study aimed to present the results of mammoplasty employing the superomedial pedicle technique without interrupting a macromastia central base with a pedicle length of 8 to 18 cm. According to the literature, many plastic surgeons recommend the free NAC rather than the pedicle technique because of the high complication rates in mammoplasties planned for highly ptotic breasts and macromastia. On the other hand, many free NAC techniques and their modifications with pedicle mammoplasty are described. The general conviction is that a standard method, protocol, or technique good for all patients does not exist. Our results are more acceptable both cosmetically and physiologically. Therefore, the superomedial pedicle technique can be modified to achieve ideal results where free NAC mammoplasty is considered for severe macromastia and ptotic patients. This combined method contributes to the viability of NAC by increasing blood supply to breast tissue and providing an ideal breast appearance.
Supplementary Data from Fimepinostat Impairs NF­κB and PI3K/AKT Signaling and Enhances Gemcitabine Efficacy in H3.3K27M-Diffuse Intrinsic Pontine Glioma
Authors: Wang Dan , Yan Kun , Yu Hongxing , Li Haocheng , Zhou Wei , Hong Yaqiang , Guo Shuning , Wang Yi , Xu Cheng , Pan Changcun , Tang Yujie , Liu Nian , Wu Wei , Zhang Liwei , Xi Qiaoran
Published: February 2024

Supplementary Figures 1-7;
Supplementary Tables 1-8
Supplementary Data from FAM3C in Cancer-Associated Adipocytes Promotes Breast Cancer Cell Survival and Metastasis
Authors: Kim Sahee , Oh Jiyoung , Park Chanho , Kim Min , Jo Woobeen , Kim Chu-Sook , Cho Sun Wook , Park Jiyoung
Published: February 2024

Figure S1, S2, S3, S4, S5, S6, S7,Table S1, and S2
Supplementary Tables1-11 from CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility
Authors: Du Mulong , Xin Junyi , Zheng Rui , Yuan Qianyu , Wang Zhihui , Liu Hongliang , Liu Hanting , Cai Guoshuai , Albanes Demetrius , Lam Stephen , Tardon Adonina , Chen Chu , Bojesen Stig E. , Landi Maria Teresa , Johansson Mattias , Risch Angela , Bickeböller Heike , Wichmann H-Erich , Rennert Gad , Arnold Susanne , Brennan Paul , Field John K. , Shete Sanjay S. , Le Marchand Loïc , Liu Geoffrey , Andrew Angeline S. , Kiemeney Lambertus A. , Zienolddiny Shan , Grankvist Kjell , Johansson Mikael , Caporaso Neil E. , Cox Angela , Hong Yun-Chul , Yuan Jian-Min , Schabath Matthew B. , Aldrich Melinda C. , Wang Meilin , Shen Hongbing , Chen Feng , Zhang Zhengdong , Hung Rayjean J. , Amos Christopher I. , Wei Qingyi , Lazarus Philip , Christiani David C.
Published: February 2024

Supplementary Tables1-11
Supplementary Table S2 from A Large-Scale Meta-Analysis Reveals Positive Feedback between Macrophages and T Cells That Sensitizes Tumors to Immunotherapy
Authors: Yang Jing , Liu Qi , Shyr Yu
Published: February 2024

The odds ratio and significance of each biomarker in five independent validation datasets.
Supplementary Table S1 from A Large-Scale Meta-Analysis Reveals Positive Feedback between Macrophages and T Cells That Sensitizes Tumors to Immunotherapy
Authors: Yang Jing , Liu Qi , Shyr Yu
Published: February 2024

A detailed summary of the datasets used in this study, including download sources, data availability (raw or processed), and the total number of samples retained after quality control.
Supplementary Figure legends from Mesothelin Secretion by Pancreatic Cancer Cells Co-opts Macrophages and Promotes Metastasis
Authors: Luckett Teifion , Abudula Maidinaimu , Ireland Lucy , Glenn Mark , Bellomo Gaia , Stafferton Ruth , Halloran Chris , Ghaneh Paula , Jones Rob , Schmid Michael C. , Mielgo Ainhoa
Published: February 2024

Supplementary Figure legends
Supplementary Figure S2 from A Large-Scale Meta-Analysis Reveals Positive Feedback between Macrophages and T Cells That Sensitizes Tumors to Immunotherapy
Authors: Yang Jing , Liu Qi , Shyr Yu
Published: February 2024

Associations between gene mutations and ICI response before and after TMB adjustment.
Figure S8 from Phospholipase PLCE1 Promotes Transcription and Phosphorylation of MCM7 to Drive Tumor Progression in Esophageal Cancer
Authors: Shi Qi , Xu Guixuan , Jiang Yuliang , Yang Ju , Han Xueping , Wang Qian , Li Ya , Zhang Zhiyu , Wang Kaige , Peng Hao , Chen Fangfang , Ma Yandi , Zhao Linyue , Chen Yunzhao , Liu Zheng , Yang Lan , Jia Xingyuan , Wen Tao , Tong Zhaohui , Cui Xiaobin , Li Feng
Published: February 2024

Figure S8
Figure S7 from Phospholipase PLCE1 Promotes Transcription and Phosphorylation of MCM7 to Drive Tumor Progression in Esophageal Cancer
Authors: Shi Qi , Xu Guixuan , Jiang Yuliang , Yang Ju , Han Xueping , Wang Qian , Li Ya , Zhang Zhiyu , Wang Kaige , Peng Hao , Chen Fangfang , Ma Yandi , Zhao Linyue , Chen Yunzhao , Liu Zheng , Yang Lan , Jia Xingyuan , Wen Tao , Tong Zhaohui , Cui Xiaobin , Li Feng
Published: February 2024

Figure S7
Figure S6 from Phospholipase PLCE1 Promotes Transcription and Phosphorylation of MCM7 to Drive Tumor Progression in Esophageal Cancer
Authors: Shi Qi , Xu Guixuan , Jiang Yuliang , Yang Ju , Han Xueping , Wang Qian , Li Ya , Zhang Zhiyu , Wang Kaige , Peng Hao , Chen Fangfang , Ma Yandi , Zhao Linyue , Chen Yunzhao , Liu Zheng , Yang Lan , Jia Xingyuan , Wen Tao , Tong Zhaohui , Cui Xiaobin , Li Feng
Published: February 2024

Figure S6
Figure S4 from Phospholipase PLCE1 Promotes Transcription and Phosphorylation of MCM7 to Drive Tumor Progression in Esophageal Cancer
Authors: Shi Qi , Xu Guixuan , Jiang Yuliang , Yang Ju , Han Xueping , Wang Qian , Li Ya , Zhang Zhiyu , Wang Kaige , Peng Hao , Chen Fangfang , Ma Yandi , Zhao Linyue , Chen Yunzhao , Liu Zheng , Yang Lan , Jia Xingyuan , Wen Tao , Tong Zhaohui , Cui Xiaobin , Li Feng
Published: February 2024

Figure S4
Figure S3 from Phospholipase PLCE1 Promotes Transcription and Phosphorylation of MCM7 to Drive Tumor Progression in Esophageal Cancer
Authors: Shi Qi , Xu Guixuan , Jiang Yuliang , Yang Ju , Han Xueping , Wang Qian , Li Ya , Zhang Zhiyu , Wang Kaige , Peng Hao , Chen Fangfang , Ma Yandi , Zhao Linyue , Chen Yunzhao , Liu Zheng , Yang Lan , Jia Xingyuan , Wen Tao , Tong Zhaohui , Cui Xiaobin , Li Feng
Published: February 2024

Figure S3
Table S7 from R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts
Authors: Liu Zhiyan Silvia , Sinha Sayantani , Bannister Maxwell , Song Axia , Arriaga-Gomez Erica , McKeeken Alexander J. , Bonner Elizabeth A. , Hanson Benjamin K. , Sarchi Martina , Takashima Kouhei , Zong Dawei , Corral Victor M. , Nguyen Evan , Yoo Jennifer , Chiraphapphaiboon Wannasiri , Leibson Cassandra , McMahon Matthew C. , Rai Sumit , Swisher Elizabeth M. , Sachs Zohar , Chatla Srinivas , Stirewalt Derek L. , Deeg H. Joachim , Skorski Tomasz , Papapetrou Eirini P. , Walter Matthew J. , Graubert Timothy A. , Doulatov Sergei , Lee Stanley C. , Nguyen Hai Dang
Published: February 2024

Differential gene expression of K562 SRSF2-WT and SRSF2-P95H cells
Figure S2 from Phospholipase PLCE1 Promotes Transcription and Phosphorylation of MCM7 to Drive Tumor Progression in Esophageal Cancer
Authors: Shi Qi , Xu Guixuan , Jiang Yuliang , Yang Ju , Han Xueping , Wang Qian , Li Ya , Zhang Zhiyu , Wang Kaige , Peng Hao , Chen Fangfang , Ma Yandi , Zhao Linyue , Chen Yunzhao , Liu Zheng , Yang Lan , Jia Xingyuan , Wen Tao , Tong Zhaohui , Cui Xiaobin , Li Feng
Published: February 2024

Figure S2
Table S6 from R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts
Authors: Liu Zhiyan Silvia , Sinha Sayantani , Bannister Maxwell , Song Axia , Arriaga-Gomez Erica , McKeeken Alexander J. , Bonner Elizabeth A. , Hanson Benjamin K. , Sarchi Martina , Takashima Kouhei , Zong Dawei , Corral Victor M. , Nguyen Evan , Yoo Jennifer , Chiraphapphaiboon Wannasiri , Leibson Cassandra , McMahon Matthew C. , Rai Sumit , Swisher Elizabeth M. , Sachs Zohar , Chatla Srinivas , Stirewalt Derek L. , Deeg H. Joachim , Skorski Tomasz , Papapetrou Eirini P. , Walter Matthew J. , Graubert Timothy A. , Doulatov Sergei , Lee Stanley C. , Nguyen Hai Dang
Published: February 2024

BROCA-GO sequencing analysis
Table S11 from R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts
Authors: Liu Zhiyan Silvia , Sinha Sayantani , Bannister Maxwell , Song Axia , Arriaga-Gomez Erica , McKeeken Alexander J. , Bonner Elizabeth A. , Hanson Benjamin K. , Sarchi Martina , Takashima Kouhei , Zong Dawei , Corral Victor M. , Nguyen Evan , Yoo Jennifer , Chiraphapphaiboon Wannasiri , Leibson Cassandra , McMahon Matthew C. , Rai Sumit , Swisher Elizabeth M. , Sachs Zohar , Chatla Srinivas , Stirewalt Derek L. , Deeg H. Joachim , Skorski Tomasz , Papapetrou Eirini P. , Walter Matthew J. , Graubert Timothy A. , Doulatov Sergei , Lee Stanley C. , Nguyen Hai Dang
Published: February 2024

GSEA analysis for Homologous repair related gene set in K562 SRSF2-P95H and U2AF1-S34F cells
Data from Phospholipase PLCE1 Promotes Transcription and Phosphorylation of MCM7 to Drive Tumor Progression in Esophageal Cancer
Authors: Shi Qi , Xu Guixuan , Jiang Yuliang , Yang Ju , Han Xueping , Wang Qian , Li Ya , Zhang Zhiyu , Wang Kaige , Peng Hao , Chen Fangfang , Ma Yandi , Zhao Linyue , Chen Yunzhao , Liu Zheng , Yang Lan , Jia Xingyuan , Wen Tao , Tong Zhaohui , Cui Xiaobin , Li Feng
Published: February 2024

Abstract
Phospholipase C epsilon 1 (PLCE1) is a well-established susceptibility gene for esophageal squamous cell carcinoma (ESCC). Identification of the underlying mechanism(s) regulated by PLCE1 could lead to a better understanding of ESCC tumorigenesis. In this study, we found that PLCE1 enhances tumor progression by regulating the replicative helicase MCM7 via two pathways. PLCE1 activated PKCα-mediated phosphorylation of E2F1, which led to the transcriptional activation of MCM7 and miR-106b-5p. The increased expression of miR-106b-5p, located in intron 13 of MCM7, suppressed autophagy and apoptosis by targeting Beclin-1 and RBL2, respectively. Moreover, MCM7 cooperated with the miR-106b-25 cluster to promote PLCE1-dependent cell-cycle progression both in vivo and in vitro. In addition, PLCE1 potentiated the phosphorylation of MCM7 at six threonine residues by the atypical kinase RIOK2, which promoted MCM complex assembly, chromatin loading, and cell-cycle progression. Inhibition of PLCE1 or RIOK2 hampered MCM7-mediated DNA replication, resulting in G1–S arrest. Furthermore, MCM7 overexpression in ESCC correlated with poor patient survival. Overall, these findings provide insights into the role of PLCE1 as an oncogenic regulator, a promising prognostic biomarker, and a potential therapeutic target in ESCC.
Significance:
PLCE1 promotes tumor progression in ESCC by activating PKCα-mediated phosphorylation of E2F1 to upregulate MCM7 and miR-106b-5p expression and by potentiating MCM7 phosphorylation by RIOK2.
Data from R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription–Replication Conflicts
Authors: Liu Zhiyan Silvia , Sinha Sayantani , Bannister Maxwell , Song Axia , Arriaga-Gomez Erica , McKeeken Alexander J. , Bonner Elizabeth A. , Hanson Benjamin K. , Sarchi Martina , Takashima Kouhei , Zong Dawei , Corral Victor M. , Nguyen Evan , Yoo Jennifer , Chiraphapphaiboon Wannasiri , Leibson Cassandra , McMahon Matthew C. , Rai Sumit , Swisher Elizabeth M. , Sachs Zohar , Chatla Srinivas , Stirewalt Derek L. , Deeg H. Joachim , Skorski Tomasz , Papapetrou Eirini P. , Walter Matthew J. , Graubert Timothy A. , Doulatov Sergei , Lee Stanley C. , Nguyen Hai Dang
Published: February 2024

Abstract
RNA splicing factor (SF) gene mutations are commonly observed in patients with myeloid malignancies. Here we showed that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors (PARPi), despite being proficient in homologous recombination repair. Instead, SF-mutant leukemias exhibited R-loop accumulation that elicited an R-loop–associated PARP1 response, rendering cells dependent on PARP1 activity for survival. Consequently, PARPi induced DNA damage and cell death in SF-mutant leukemias in an R-loop-dependent manner. PARPi further increased aberrant R-loop levels, causing higher transcription–replication collisions and triggering ATR activation in SF-mutant leukemias. Ultimately, PARPi-induced DNA damage and cell death in SF-mutant leukemias could be enhanced by ATR inhibition. Finally, the level of PARP1 activity at R-loops correlated with PARPi sensitivity, suggesting that R-loop-associated PARP1 activity could be predictive of PARPi sensitivity in patients harboring SF gene mutations. This study highlights the potential of targeting different R-loop response pathways caused by spliceosome gene mutations as a therapeutic strategy for treating cancer.
Significance:
Spliceosome-mutant leukemias accumulate R-loops and require PARP1 to resolve transcription–replication conflicts and genomic instability, providing rationale to repurpose FDA-approved PARP inhibitors for patients carrying spliceosome gene mutations.
Biomarkers for Antibody–Drug Conjugates in Solid Tumors
Authors: Katrini Jalissa , Boldrini Laura , Santoro Celeste , Valenza Carmine , Trapani Dario , Curigliano Giuseppe
Published: February 2024

The clinical development and then the progressive entry in clinical practice of antibody–drug conjugates (ADC) have marked a transformative advancement in the overall cancer treatment. ADCs have been extensively tested for a large number of tumors, reporting heterogeneous clinical efficacy and safety results. In some diseases, the advent of ADCs has yielded significant changes in the prognostic trajectory, portending an improvement of the survival and/or quality of life. ADCs are targeted agents, capable of delivering highly cytotoxic payloads selectively to antigen-expressing cancer cells. As such, they have been intended as perfect “bullets” to enable the promise of precision medicine, toward high-efficacy and limited-toxicity treatment options. However, only some approved ADCs are intended for the use in biomarker-selected patient populations, restricting potentially the opportunity to be more precise. Yet, key characteristics of modern ADCs might allow the activity of ADCs in tumors with heterogeneous or low expression of cancer antigens, resulting in a clinical activity that could sublimate the classic paradigm of a drug-to-target perfect match. In our review, we portrayed the current landscape of approved ADCs, reporting data of activity as related to the expression of the cancer antigens, and elucidating possible determinants of the safety and efficacy, including when used in a therapeutic sequence.
Supplementary Figure 3 from Lingual Denervation Improves the Efficacy of Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinomas by Downregulating TGFβ Signaling
Authors: Tao Zhuo-Ying , Wang Leilei , Zhu Wang-Yong , Zhang Gao , Su Yu-Xiong
Published: February 2024

Supplementary Figure 3. Galunisertib reserves the tumor cell aggressiveness and downregulates TGFbeta signaling and PD-L1 expression of tumor cells in the neuron-tumor coculture system.
FIGURE 6 from Lingual Denervation Improves the Efficacy of Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinomas by Downregulating TGFβ Signaling
Authors: Tao Zhuo-Ying , Wang Leilei , Zhu Wang-Yong , Zhang Gao , Su Yu-Xiong
Published: February 2024

A, LD enhances CD8+ T-cell activities. B–F, The expression levels of CD4+, CD8+ T cells, Tregs, IFNγ, and TNFα in each group [each bar represents mean ± SD (n = 5–7); **,***, P < 0.01, 0.001 vs. MOC1+IgG; #,###, P < 0.05, 0.001 vs. MOC1+αPD-1; $,$$$, P < 0.05, 0.001 αPD-1 vs. IgG].
FIGURE 3 from Lingual Denervation Improves the Efficacy of Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinomas by Downregulating TGFβ Signaling
Authors: Tao Zhuo-Ying , Wang Leilei , Zhu Wang-Yong , Zhang Gao , Su Yu-Xiong
Published: February 2024

Coculturing with TG neurons activates TGFβ-SMAD2 pathway and upregulates PD-L1 expression of OSCC cells. A, KEGG pathway enrichment analysis of the coculture group 1. B, KEGG pathway enrichment analysis of the coculture group 2. C, Expression levels of TGFβ1, TGFβ2, TGFβ3, and PD-L1 determined by qRT-PCR (*,**, P < 0.05, 0.01 vs. control group). D, The TGFβ1 level in the supernatants of each group determined by ELISA (***, P < 0.001 vs. control group). E and F, Expression levels of TGFβ1, p-SMAD2, SMAD2, and PD-L1 determined by Western blot analysis (*,**, P < 0.05, 0.01 vs. control group).
PAR4 Antagonism in Patients With Coronary Artery Disease Receiving Antiplatelet Therapies
Authors: Nash Jennifer , Meah Mohammed N. , Whittington Beth , Debono Samuel , Raftis Jennifer , Miller Mark R. , Sorbie Andrew , Mills Nicholas L. , Nespoux Josselin , Bruce Lorraine , Duffin Rodger , Dhaun Neeraj , Brittan Mairi , Chao Longfei , Merali Samira , Kim Minji , Wang Zhaoqing , Zhang Yue , Jin Shiqiang , Wang Beqing , Kozinn Marc , Newby David E.
Published: February 2024

BACKGROUND:

BMS-986141 is a novel potent highly selective antagonist of PAR (protease-activated receptor) type 4. PAR4 antagonism has been demonstrated to reduce thrombus formation in isolation and in combination with factor Xa inhibition in high shear conditions in healthy people. We sought to determine whether PAR4 antagonism had additive antithrombotic effects in patients with coronary artery disease who were receiving antiplatelet therapy.

METHODS:

Forty-five patients with stable coronary heart disease and 10 healthy volunteers completed a phase 2a open-label 4-arm single-center study. Patients were allocated to 1 of 3 treatment arms for 7 days: (1) ticagrelor (90 mg BID), (2) aspirin (75 mg QD), or (3) the combination of ticagrelor and aspirin. Agonist-induced platelet aggregation, platelet activation, and ex vivo thrombus formation were measured before and 2 and 24 hours after a single oral 4-mg dose of BMS-986141 on the first study visit day in all participants.

RESULTS:

BMS-986141 demonstrated highly selective inhibition of PAR4-AP (agonist peptide)–induced platelet aggregation, P-selectin expression, and platelet-monocyte aggregate expression (
P
≤0.001 for all), which were unaffected by concomitant antiplatelet therapies. PAR4 antagonism reduced ex vivo thrombus area in high shear conditions in healthy volunteers (−21%;
P
=0.001) and in patients receiving ticagrelor alone (−28%;
P
=0.001), aspirin alone (−23%;
P
=0.018), or both in combination (−24%;
P
≤0.001). Plasma concentration of BMS-986141 correlated with PAR4-AP–induced platelet responses (
P
≤0.001 for all) and total thrombus area under high shear stress conditions (
P
≤0.01 for all).

CONCLUSIONS:

PAR4 antagonism has additive antithrombotic effects when used in addition to ticagrelor, aspirin, or their combination, in patients with stable coronary heart disease.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT05093790.
Sorbs2 Deficiency and Vascular BK Channelopathy in Diabetes
Authors: Sun Xiaojing , Lee Hon-Chi , Lu Tong
Published: February 2024

BACKGROUND:

Vascular large conductance Ca
2+
-activated K
+
(BK) channel, composed of the α-subunit (BK-α) and the β1-subunit (BK-β1), is a key determinant of coronary vasorelaxation and its function is impaired in diabetic vessels. However, our knowledge of diabetic BK channel dysregulation is incomplete. The Sorbs2 (Sorbin homology [SoHo] and Src homology 3 [SH3] domains-containing protein 2), is ubiquitously expressed in arteries, but its role in vascular pathophysiology is unknown.

METHODS:

The role of Sorbs2 in regulating vascular BK channel activity was determined using patch-clamp recordings, molecular biological techniques, and in silico analysis.

RESULTS:

Sorbs2 is not only a cytoskeletal protein but also an RNA-binding protein that binds to BK channel proteins and BK-α mRNA, regulating BK channel expression and function in coronary smooth muscle cells. Molecular biological studies reveal that the SH3 domain of Sorbs2 is necessary for Sorbs2 interaction with BK-α subunits, while both the SH3 and SoHo domains of Sorbs2 interact with BK-β1 subunits. Deletion of the SH3 or SoHo domains abolishes the Sorbs2 effect on the BK-α/BK-β1 channel current density. Additionally,
Sorbs2
is a target gene of the Nrf2 (nuclear factor erythroid-2-related factor 2), which binds to the promoter of
Sorbs2
and regulates Sorbs2 expression in coronary smooth muscle cells. In vivo studies demonstrate that
Sorbs2
knockout mice at 4 months of age display a significant decrease in BK channel expression and function, accompanied by impaired BK channel Ca
2+
-sensitivity and BK channel-mediated vasodilation in coronary arteries, without altering their body weights and blood glucose levels. Importantly, Sorbs2 expression is significantly downregulated in the coronary arteries of db/db type 2 diabetic mice.

CONCLUSIONS:

Sorbs2, a downstream target of Nrf2, plays an important role in regulating BK channel expression and function in vascular smooth muscle cells. Vascular Sorbs2 is downregulated in diabetes. Genetic knockout of
Sorbs2
manifests coronary BK channelopathy and vasculopathy observed in diabetic mice, independent of obesity and glucotoxicity.
Alternative Renin-Angiotensin System
Authors: Bader Michael , Steckelings U. Muscha , Alenina Natalia , Santos Robson A.S. , Ferrario Carlos M.
Published: February 2024

The renin-angiotensin system is the most important peptide hormone system in the regulation of cardiovascular homeostasis. Its classical arm consists of the enzymes, renin, and angiotensin-converting enzyme, generating angiotensin II from angiotensinogen, which activates its AT
1
receptor, thereby increasing blood pressure, retaining salt and water, and inducing cardiovascular hypertrophy and fibrosis. However, angiotensin II can also activate a second receptor, the AT
2
receptor. Moreover, the removal of the C-terminal phenylalanine from angiotensin II by ACE2 (angiotensin-converting enzyme 2) yields angiotensin-(1-7), and this peptide interacts with its receptor Mas. When the aminoterminal Asp of angiotensin-(1-7) is decarboxylated, alamandine is generated, which activates the Mas-related G-protein-coupled receptor D, MrgD (Mas-related G-protein-coupled receptor type D). Since Mas, MrgD, and the AT
2
receptor have opposing effects to the classical AT
1
receptor, they and the enzymes and peptides activating them are called the alternative or protective arm of the renin-angiotensin system. This review will cover the historical aspects and the current standing of this recent addition to the biology of the renin-angiotensin system.
South African government responses to Trump's Global Gag Rule: Silence, ignorance, and avoidance
Authors: Ndabula Yanela , Macleod Catriona Ida , du Plessis Ulandi , Moore Sarah
Published: February 2024

In 2017, Donald Trump signed the Protecting Life in Global Health Assistance (PLGHA), thereby reinstating the Global Gag Rule. The policy restricted all United States foreign funding from abortion-related activities. Little research reports the responses of recipients of this bilateral assistance. The study documents the South African government's responses to the PLGHA. We accessed Hansard parliamentary debates, interviewed four parliamentarians alongside one government official, and reviewed a USAID-funded initiative developed while the policy was in effect. We analysed the data using interpretive content analysis through a global social policy and gendered coloniality lens. Our research documents silence, ignorance, avoidance, and possible over-interpretation of the PLGHA within the South African government. The colonialist politics of global redistribution created the grounds for gendered regulation, resulting in a fundamental undermining of reproductive rights. Ironically, the solution – advocacy and parliamentarian briefing regarding sexual and reproductive issues – is generally led by civil society, the bodies weakened by the PLGHA.
Tree-ring hydrological research in the Himalaya: State of the art and future directions
Authors: Islam Nazimul , Vennemann Torsten , Büntgen Ulf , Cherubini Paolo , Lane Stuart N
Published: February 2024

Recent developments in tree-ring research offer great potential for reconstructing past climate changes; determining the frequencies of natural hazards; and assessing the availability of freshwater resources over timescales that extend well into the pre-instrumental period. Here, we review the state of dendrochronological research in the Himalaya and outline future directions for tree-ring-based hydrological reconstructions in a region that has a pressing societal need to understand the causes and consequences of past, present and future changes in the hydrological cycle. We used ‘tree ring’ and ‘Himalaya’ as keywords to identify scholarly articles from the Web of Science that were published between 1994 and 2022. The resulting 173 publications were separated by their spatial coverage into the western, central and eastern Himalaya, as well as their scientific purpose (e.g. reconstructing growth-climate relationships, temperature, precipitation, streamflow, floods, droughts, etc.). Our analysis shows that dendrochronological research in the Himalaya primarily focused on understanding growth-climate relationships using annual tree-ring widths measurements obtained for coniferous species, and their application in climate reconstructions. Reconstructions of hydrological processes such as streamflows, and extremes such as glacial and landslide lake outburst floods, have received less attention. Recent advances in dendrochronology, including blue intensity (BI), quantitative wood anatomy (QWA), and tree-ring stable isotopes (TRSI) should be combined to improve the resolution and accuracy of hydrological reconstructions in all parts of the Himalaya. Such studies may allow us to better understand the effects of climate change and the Himalayan water resources for its lowland surroundings. They may also facilitate decision-making processes for mitigating the impacts of climate change on natural hazards, and for better managing water resources in the region.
The tunnel infection in PD: Up in the air
Authors: Rakpithayanon Chanyanuch , Vacharathit Voranaddha , Manasnayakorn Sopark , Perl Jeffrey , Kanjanabuch Talerngsak
Published: February 2024

Catheter-related tunnel infection may lead to peritonitis and discontinuation of performing high-quality peritoneal dialysis (PD). Tunnel infection is commonly caused by Staphylococcus aureus. Gas-forming bacterial infection is rare in patients with PD and even exceedingly rare when such a infection spreads along the PD catheter tract. The first case of emphysematous PD catheter infection is presented here.
Recent development and engineering practices of space grid structures in China
Authors: Luo Yaozhi , Xue Yu
Published: February 2024

Space grid structures are widely used in the field of structural engineering due to their good mechanical properties and simple construction procedures. This paper reviews the development of space grid structures and mainly introduces the development of space grid structures in China in recent years. Some typical applications of space grid structures are introduced and the technical developments are summarized. It shows that China not only has a large number of engineering applications of space grid structures, but also a rapid development of related technologies. Finally, some prospects for space grid structures are discussed.
A Novel Necroptosis-Related Signature Can Predict Prognosis and Chemotherapy Sensitivity in Multiple Myeloma
Authors: Jiang Jun-Yao , Yao Fang-Yi , Liu Jing , Wang Xin-Lu , Huang Bo , Zhong Fang-Min , Wang Xiao-Zhong
Published: February 2024

Background

Necroptosis is an inflammatory cell death mode, and its association with multiple myeloma (MM) remains unclear.

Methods

This prospective study first analyzed the association between necroptosis-related signature as well as prognosis and chemotherapy sensitivity in MM using the necroptosis score. Consensus clustering was used to identify necroptosis-related molecular clusters. Least absolute shrinkage and selection operator analysis and multivariate Cox regression analysis were performed to establish the prognostic model of necroptosis-related genes (NRGs).

Results

A high necroptosis score was associated with poor prognosis and abundant immune infiltration. Two molecular clusters (clusters A and B) significantly differed in terms of prognosis and tumor microenvironment. Cluster B had a worse prognosis and higher tumor marker pathway activity than cluster A. The risk score model based on four NRGs can accurately predict the prognosis of patients with MM, which was validated in two validation cohorts. Receiver operating characteristic curve analysis showed that the area under the curves of the risk score in predicting the 1-, 3-, and 5-year survival rates were 0.710, 0.758, and 0.834, respectively. Further, the activity of pathways related to proliferation and genetic regulation in the high-risk group significantly increased. The drug prediction results showed that the low-risk score group was more sensitive to bortezomib, cytarabine, and doxorubicin than the high-risk score group. Meanwhile, the high-risk score group was more sensitive to lenalidomide and vinblastine than the low-risk score group. Finally, the upregulation of model genes CHMP1A, FAS, JAK3, and HSP90AA1 in clinical samples collected from patients with MM was validated via real-time polymerase chain reaction.

Conclusion

A systematic analysis of NRGs can help identify potential necroptosis-related mechanisms and provide novel biomarkers for MM prognosis prediction, tumor microenvironment evaluation, and personalized treatment planning.
Children’s production of place and (third) space during Covid 19: Den building, filmmaking and the postdigital in the Play Observatory
Authors: Potter John , Cannon Michelle , Cowan Kate
Published: February 2024

The Play Observatory was a COVID-19 rapid response project funded by UK Research and Innovation (UKRI) exploring children’s play experiences during the pandemic through an online survey, case studies and a filmmaking workshop. With access to many of the usual spaces and places of play curtailed during the lockdowns of the pandemic, in this article, we focus on children’s resourceful and playful placemaking during the restrictions, as well as their creation of mediated third spaces in their own homes and neighbourhoods. We discuss Play Observatory survey submissions centring on children’s use of space and place in their play. Images of den-building showed imaginative productions of worlds in the spaces of the home in which children felt secure. Arguably this was to do with the way they used material artefacts to move the locus of control closer to themselves, even as the world seemed out of control for many. In the same way, video clips and films submitted to the Observatory revealed much about everyday life during the pandemic, the third spaces that were enabled and the postdigital worlds of entanglement in which children played. This paper will present and discuss contributions to the Play Observatory’s archive which are revelatory of children’s exploration of time, space and placemaking during restrictions associated with the pandemics. In our explanation of how the pandemic influenced play, we offer insights into young people’s postdigital and collusive creative practices and their playful imbrication of material and cultural resources.
Improvement of generalized granuloma annulare with adalimumab: A case report
Authors: Horoub Yara Al , Walker Kirsten
Published: February 2024

Granuloma annulare is a benign, inflammatory condition of unknown etiology, characterized by erythematous annular plaques, frequently on distal extremities. Generalized granuloma annulare can be difficult to treat, with varying success in therapeutic approaches. We present the case of a 59-year-old female with refractory generalized granuloma annulare successfully managed with adalimumab, requiring ongoing 40 mg q2weekly treatment for 2 years. While there are a handful of published case reports/series suggesting that adalimumab can be used to treat generalized granuloma annulare, dosing regimens and the need for long-term use remain inconsistent. This case adds further evidence for considering adalimumab as a sustained therapeutic option for recalcitrant generalized granuloma annulare. The patient responded to adalimumab, a tumor necrosis factor-alpha antagonist, administered biweekly for a year, then switched to weekly intervals. Most granuloma annulare lesions improved within 2 months and continued to improve throughout the treatment. Adalimumab may be proposed as a therapeutic treatment for recalcitrant forms of generalized granuloma annulare.