bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRAF4 Maintains Deubiquitination of Caveolin-1 to Drive Glioblastoma Stemness and Temozolomide Resistance
Authors: Li Yongxu , Wang Tiepeng , Wan Quan , Wang Qing , Chen Zhenzhong , Gao Yuan , Ye Yuchen , Lin Jiusheng , Zhao Bihuan , Wang Huaile , Yang Jinming , Zhao Kai , Lu Na 
Published: July 2022

Abstract

Glioblastoma (GBM) is the most common type of primary adult brain tumor. Glioma stem cell (GSC) residence and temozolomide (TMZ) resistance in GBM both contribute to poor patient outcome. TRAF4 is a scaffold protein with E3 ubiquitin ligase activity that has recently been discovered to promote invasion and metastasis in several malignancies, but the effects and functions of TRAF4 in GBM remain to be determined. Here, we report that TRAF4 is preferentially overexpressed in GSCs and is required for stem-like properties as well as TMZ sensitivity in GBM cells. TRAF4 specifically interacted with the N-terminal tail of Caveolin-1 (CAV1), an important contributor to the tumorigenicity of GBM cells. TRAF4 regulated CAV1 stability by preventing ZNRF1-mediated ubiquitination and facilitating USP7-mediated deubiquitination independently of its E3 ubiquitin ligase catalytic activity. TRAF4-mediated stabilization of CAV1 activated protumorigenic AKT/ERK1/2 signaling, and disruption of this axis resulted in defects in stemness maintenance. In addition, expression of TRAF4 and CAV1 was positively correlated and predicted poor prognosis in human GBM samples. Screening of common nervous system drugs identified risperidone interaction with TRAF4, and risperidone treatment resulted in the dissociation of TRAF4 and CAV1. Importantly, pharmacologic inhibition of TRAF4 with risperidone potently inhibited self-renewal, abrogated tumorigenicity, and reversed TMZ resistance in GBM. Overall, TRAF4-mediated stabilization of CAV1 promotes stemness and TMZ resistance in GBM, providing a therapeutic strategy that could improve patient outcomes.

Significance:
The identification of a TRAF4/Caveolin-1 axis that plays a crucial role in malignant progression of glioblastoma provides new insights into the function of TRAF4 in ubiquitin signaling and suggests TRAF4 as a potential therapeutic target.
GLS2 Is a Tumor Suppressor and a Regulator of Ferroptosis in Hepatocellular Carcinoma
Authors: Suzuki Sawako , Venkatesh Divya , Kanda Hiroaki , Nakayama Akitoshi , Hosokawa Hiroyuki , Lee Eunyoung , Miki Takashi , Stockwell Brent R. , Yokote Koutaro , Tanaka Tomoaki , Prives Carol 
Published: July 2022

Abstract

Glutamine synthase 2 (GLS2) is a key regulator of glutaminolysis and has been previously implicated in activities consistent with tumor suppression. Here we generated Gls2 knockout (KO) mice that develop late-occurring B-cell lymphomas and hepatocellular carcinomas (HCC). Further, Gls2 KO mice subjected to the hepatocarcinogenic Stelic Animal Model (STAM) protocol produce larger HCC tumors than seen in wild-type (WT) mice. GLS2 has been shown to promote ferroptosis, a form of cell death characterized by iron-dependent accumulation of lipid peroxides. In line with this, GLS2 deficiency, either in cells derived from Gls2 KO mice or in human cancer cells depleted of GLS2, conferred significant resistance to ferroptosis. Mechanistically, GLS2, but not GLS1, increased lipid reactive oxygen species (ROS) production by facilitating the conversion of glutamate to α-ketoglutarate (αKG), thereby promoting ferroptosis. Ectopic expression of WT GLS2 in a human hepatic adenocarcinoma xenograft model significantly reduced tumor size; this effect was nullified by either expressing a catalytically inactive form of GLS2 or by blocking ferroptosis. Furthermore, analysis of cancer patient datasets supported a role for GLS2-mediated regulation of ferroptosis in human tumor suppression. These data suggest that GLS2 is a bona fide tumor suppressor and that its ability to favor ferroptosis by regulating glutaminolysis contributes to its tumor suppressive function.

Significance:
This study demonstrates that the key regulator of glutaminolysis, GLS2, can limit HCC in vivo by promoting ferroptosis through αKG-dependent lipid ROS, which in turn might lay the foundation for a novel therapeutic approach.
GOT2 Silencing Promotes Reprogramming of Glutamine Metabolism and Sensitizes Hepatocellular Carcinoma to Glutaminase Inhibitors
Authors: Li Yunzheng , Li Binghua , Xu Yanchao , Qian Liyuan , Xu Tiancheng , Meng Gang , Li Huan , Wang Ye , Zhang Laizhu , Jiang Xiang , Liu Qi , Xie Yuanyuan , Cheng Chunxiao , Sun Beicheng , Yu Decai 
Published: July 2022

Abstract

Hepatocellular carcinoma (HCC) is one of the primary liver malignancies with a poor prognosis. Glutamic-oxaloacetic transaminase 2 (GOT2) is a highly tissue-specific gene in the liver, but the roles GOT2 plays in the progression of HCC remain unclear. Here, we report that GOT2 is downregulated in HCC tumor tissues and that low expression of GOT2 is associated with advanced progression and poor prognosis. In HCC cells, knockdown of GOT2 promoted proliferation, migration, and invasion. In mouse models of HCC, loss of GOT2 promoted tumor growth as well as hematogenous and intrahepatic metastasis. Mechanistically, silencing of GOT2 enhanced glutaminolysis, nucleotide synthesis, and glutathione synthesis by reprogramming glutamine metabolism to support the cellular antioxidant system, which activated the PI3K/AKT/mTOR pathway to contribute to HCC progression. Furthermore, HCC with low expression of GOT2 was highly dependent on glutamine metabolism and sensitive to the glutaminase inhibitor CB-839 in vitro and in vivo. Overall, GOT2 is involved in glutamine metabolic reprogramming to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC.

Significance:
Altered glutamine metabolism induced by GOT2 loss supports HCC growth and metastasis but confers a targetable vulnerability to glutaminase inhibitors.
Association Between Baseline C-Reactive Protein and the Risk of Lung Cancer: A Prospective Population-Based Cohort Study
Authors: Yin Jian , Wang Gang , Wu Zheng , Lyu Zhangyan , Su Kai , Li Fang , Feng Xiaoshuang , Guo Lan-Wei , Chen Yuheng , Xie Shuanghua , Cui Hong , Li Jiang , Ren Jiansong , Shi Ju-Fang , Chen Shuohua , Wu Shouling , Dai Min , Li Ni , He Jie 
Published: July 2022

Abstract

C-reactive protein (CRP), a systemic marker of diagnosing chronic inflammation, has been associated with the incidence of multiple types of cancer. However, little is known about the impact of CRP on lung cancer incidence in Chinese population. A total of 97,950 participants without cancer at baseline (2006–2007) of the Kailuan Cohort Study were followed up. The concentration of plasma high-sensitivity CRP (hsCRP) was tested for all participants at baseline interview. Multivariable Cox proportional hazards regression models were used to assess the association between levels of hsCRP and incident lung cancer. During 8.7-year follow-up, 890 incident lung cancer cases occurred and were divided into three groups according to the level of hsCRP. The risk of incident lung cancer was significantly increased with elevated levels of hsCRP [HRMedium/Low, 1.21; 95% confidence interval (CI), 1.03–1.42; HRHigh/Low, 1.42, 95% CI, 1.20–1.68; Ptrend &lt; 0.001], compared with the low group after adjusting confounders. Moreover, after stratifying by BMI, the significantly positive associations between the hsCRP level and the risk of lung cancer were found among those with BMI &lt; 24 (HRHigh/Low, 1.51; 95% CI, 1.18–1.94; Ptrend = 0.001) and BMI = 24–28 (HRHigh/Low, 1.47; 95% CI, 1.13–1.92; Ptrend = 0.003), but not among those with BMI ≥ 28 (HRHigh/Low, 1.01; 95% CI, 0.64–1.57; Ptrend = 0.991). There was an antagonistic interaction between hsCRP levels and BMI that contributed to development of lung cancer (Pinteraction = 0.049). In conclusion, these findings indicate a dose-dependent relationship between hsCRP and lung cancer risk among Chinese population, especially in nonobese participants, suggesting that CRP could serve as a potential biomarker for prediction of lung cancer risk and identification of high-risk population.

Prevention Relevance:
In this prospective population-based cohort study, we found an association between higher plasma hsCRP and an increased risk of developing lung cancer, with stronger associations observed among nonobese participants.
CAR T-cell Therapy Meets Clonal Hematopoiesis
Authors: Uslu Ugur , June Carl H. 
Published: July 2022

Summary:
Clonal hematopoiesis of indeterminate potential (CHIP) is common in patients with hematologic malignancies. Recent publications provide evidence that CHIP may affect chimeric antigen receptor T-cell therapy efficacy and that the incidence of treatment-related toxicities such as cytokine release syndrome and immune effector-cell associated neurotoxicity syndrome may be affected.
See related article by Saini et al., p. 385 (8).
Effects of Walking Exercise at a Pace With Versus Without Ischemic Leg Symptoms on Functional Performance Measures in People With Lower Extremity Peripheral Artery Disease: The LITE Randomized Clinical Trial
Authors: Hammond Michael M. , Spring Bonnie , Rejeski W. Jack , Sufit Robert , Criqui Michael H. , Tian Lu , Zhao Lihui , Xu Shujun , Kibbe Melina R. , Leeuwenburgh Christiaan , Manini Todd , Forman Daniel E. , Treat‐Jacobson Diane , Polonsky Tamar S. , Bazzano Lydia , Ferrucci Luigi , Guralnik Jack , Lloyd‐Jones Donald M. , McDermott Mary M. 
Published: July 2022

Background
In people with peripheral artery disease, post hoc analyses of the LITE (Low Intensity Exercise Intervention in Peripheral Artery Disease) randomized trial were conducted to evaluate the effects of walking exercise at a pace inducing ischemic leg symptoms on walking velocity and the Short Physical Performance Battery, compared with walking exercise without ischemic leg symptoms and compared with a nonexercising control group.

Methods and Results

Participants with peripheral artery disease were randomized to: home‐based walking exercise that induced ischemic leg symptoms; home‐based walking exercise conducted without ischemic leg symptoms; or a nonexercising control group for 12 months. Outcomes were change of walking velocity over 4 m and change of the Short Physical Performance Battery (0–12, with 12=best) at 6‐ and 12‐month follow‐up. A total of 264 participants (48% women, 61% Black race) were included. Compared with walking exercise without ischemic symptoms, walking exercise that induced ischemic symptoms improved change in usual‐paced walking velocity over 4 m at 6‐month (0.056 m/s [95% CI, 0.019–0.094 m/s];
P
<0.01) and 12‐month follow‐up (0.084 m/s [95% CI, 0.049–0.120 m/s];
P
<0.01), change in fast‐paced of walking velocity over 4 m at 6‐month follow‐up (
P
=0.03), and change in the Short Physical Performance Battery at 12‐month follow‐up (0.821 [95% CI, 0.309–1.334];
P
<0.01). Compared with control, walking exercise at a pace inducing ischemic symptoms improved change in usual‐paced walking velocity over 4 m at 6‐month follow‐up (0.066 m/s [95% CI, 0.021–0.111 m/s];
P
<0.01).

Conclusions
In people with peripheral artery disease, those who walked for exercise at a comfortable pace without ischemic leg symptoms slowed their walking speed during daily life and worsened the Short Physical Performance Battery score, a potentially harmful effect, compared with people who walked for exercise at a pace inducing ischemic leg symptoms. Compared with a control group who did not exercise, home‐based walking exercise at a pace inducing ischemic leg symptoms significantly improved change of walking velocity over 4 m at 6‐month follow‐up, but this benefit did not persist at 12‐month follow‐up.

Registration
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02538900.
A Model of Semantic Completion in Generative Episodic Memory
Authors: Fayyaz Zahra , Altamimi Aya , Zoellner Carina , Klein Nicole , Wolf Oliver T. , Cheng Sen , Wiskott Laurenz 
Published: July 2022

Abstract
Many studies have suggested that episodic memory is a generative process, but most computational models adopt a storage view. In this article, we present a model of the generative aspects of episodic memory. It is based on the central hypothesis that the hippocampus stores and retrieves selected aspects of an episode as a memory trace, which is necessarily incomplete. At recall, the neocortex reasonably fills in the missing parts based on general semantic information in a process we call semantic completion. The model combines two neural network architectures known from machine learning, the vector-quantized variational autoencoder (VQ-VAE) and the pixel convolutional neural network (PixelCNN). As episodes, we use images of digits and fashion items (MNIST) augmented by different backgrounds representing context. The model is able to complete missing parts of a memory trace in a semantically plausible way up to the point where it can generate plausible images from scratch, and it generalizes well to images not trained on. Compression as well as semantic completion contribute to a strong reduction in memory requirements and robustness to noise. Finally, we also model an episodic memory experiment and can reproduce that semantically congruent contexts are always recalled better than incongruent ones, high attention levels improve memory accuracy in both cases, and contexts that are not remembered correctly are more often remembered semantically congruently than completely wrong. This model contributes to a deeper understanding of the interplay between episodic memory and semantic information in the generative process of recalling the past.
Permitted Sets and Convex Coding in Nonthreshold Linear Networks
Authors: Collazos Steven , Nykamp Duane 
Published: July 2022

Abstract
Hebbian theory proposes that ensembles of neurons form a basis for neural processing. It is possible to gain insight into the activity patterns of these neural ensembles through a binary analysis, regarding neurons as either active or inactive. The framework of permitted and forbidden sets, introduced by Hahnloser, Seung, and Slotine (2003), is a mathematical model of such a binary analysis: groups of coactive neurons can be permitted or forbidden depending on the network's structure.
In order to widen the applicability of the framework of permitted sets, we extend the permitted set analysis from the original threshold-linear regime. Specifically, we generalize permitted sets to firing rate models in which Φ is a nonnegative continuous piecewise C1 activation function. In our framework, the focus is shifted from a neuron's firing rate to its responsiveness to inputs; if a neuron's firing rate is sufficiently sensitive to changes in its input, we say that the neuron is responsive. The algorithm for categorizing a neuron as responsive depends on thresholds that a user can select arbitrarily and that are independent of the dynamics.
Given a synaptic weight matrix W, we say that a set of neurons is permitted if it is possible to find a stimulus where those neurons, and no others, remain responsive. The main coding property we establish about PΦ(W), the collection of all permitted sets of the network, is that PΦ(W) is a convex code when W is almost rank one. This means that PΦ(W) in the low-rank regime can be realized as a neural code resulting from the pattern of overlaps of receptive fields that are convex.
Periodisation and the futūḥ: Making Sense of Muḥammad’s Leadership of the Conquests in Non-Muslim Sources
Authors: Shaddel Mehdy 
Published: July 2022

Abstract
The past few decades have witnessed a proliferation of theories on the origins of Islam which have called into question long-held scholarly axioms. One such axiom is the traditional date of 632 CE for the death of the prophet Muḥammad, which some scholars have now sought to redate to after the beginning of the Muslim conquests on the basis of the evidence of non-Muslim sources. The present contribution aims to demonstrate that the prima facie disharmony between these sources and Muslim accounts of Muḥammad’s life and the conquests is a product of the reading imposed on both sets of data, which primarily has to do with the fact that, more often than not, modern scholarship unsuspectingly operates within the rigid framework of the classical periodisation of early Islamic history. Therefore, a revision of either the traditional date of Muḥammad’s death or the starting date of the conquests based on this evidence is uncalled for.
Restoring the King’s Creditworthiness in Troubled Times: The Mission of a Polish Prince in Genoa (1776–1777)
Authors: Zanini Andrea 
Published: July 2022

Abstract
The rumors that accompanied the arrival of Polish nobleman Prince Antoni Sułkowski in Genoa in 1776 offer an opportunity to examine, from a new perspective, the overall complexity behind the challenges a monarch faces when attempting to inspire and regain the faith of foreign investors after a liquidity crisis. Managing creditworthiness became crucial for the Polish king during a period characterized by increasing geopolitical tensions in which the appetites of powerful neighboring states undermined the survival of the Polish-Lithuanian Commonwealth. However, despite several economic and financial reforms implemented during those years, it was the growing uncertainty that made it difficult for both the king and the state to negotiate new loans, thus triggering a vicious cycle that contributed to the further weakening of Poland and led to its disappearance from the European political map.
Just Another Physical Wreck on the Shores of Time
Authors: Millen Lisa 
Published: July 2022

Abstract
This article investigates the various ways in which Pentecostals read and interpreted the narrative of the woman whom Jesus healed of an “issue of blood.” It explores the manner in which she and her experience are described and explained by Pentecostals in articles and sermons from the beginning of the movement to the present day. The article attempts to survey and analyze the different interpretations and how they have changed over time. While early pentecostal literature used the narrative as an opportunity to engage in anti-physician rhetoric and to defend the doctrine of healing in the atonement, later literature expanded the interpretation of the woman’s issue beyond physical healing to include other “issues” a person might face. Present throughout the literature is an emphasis on the woman’s faith and her personal agency to bring about the miracle. However, also present are negative interpretations of the woman and her “issue of blood.” Finally, the article looks forward to other possible interpretive strategies.
How Leibniz Read Pascal’s Geometry
Authors: Dumas Primbault Simon 
Published: July 2022

Abstract
Between 1675 and 1676, while in Paris, Gottfried Wilhelm Leibniz (1646–1716) got privileged access to some geometric manuscripts from late Blaise Pascal’s hand. Although said manuscripts are not extant, Leibniz’s reading notes were preserved, together with his personal papers in Hannover, under the heading “Pascaliana.” The mathematical content of these notes and the influence they had on Leibniz’s later work are quite known nowadays. At the crossroads of the history of ideas, historical epistemology, and material history, this contribution looks at Leibniz’s Pascaliana through the prism of their materiality—format, layout, organization, corrections, and additions—, and the practices it betrays—copying, commenting, excerpting. Parallel to knowing what Leibniz read in Pascal, this perspective allows us to shed light on how Leibniz read Pascal, on the very intellectual-material operations that allowed him to incorporate a foreign thought and, eventually, start developing his own.
Not Anymore in Politics: Theorising the Young Egyptian Muslim Brothers’ Political Disengagement in the aftermath of the 2013 Military Coup
Authors: Abdelgawad Doha Samir , Magued Shaimaa 
Published: July 2022

Abstract
This study relies on the life story narratives of 48 young members of the Egyptian Muslim Brothers in identifying the different reasons behind their political disengagement in the aftermath of the 2013 military coup. Unlike the smt scholarly writings addressing Islamists’ political disengagement within a limited scope of analysis that focuses on members leaving their groups rather than politics, this study presents a multi-layered approach that examines the interplay between youth’s personal experiences, the repressive macro political conditions, and the organizational decay in shaping young Muslim Brothers’ positions towards political activism.
Peasants’ Serfdom, Freedom and Mobility in the Cracow Province (1501–1800)
Authors: Wyżga Mateusz 
Published: July 2022

Abstract
The article analyses the mobility of peasants, especially in the context of their relations with their landlords. It considers the role of serfdom and demesne lordship, and the circumstances in which peasants left their villages, whether legally or illegally. It then examines measurements of geographical distances covered in such movements. In the period under review, the predominance of short-distance mobility was characteristic of the peasant population in the Polish Lands; the average scope of the geography of their everyday life was about 15 kilometres. What is important for today’s understanding of both serfdom in Polish history and peasant mobility, is the relationship between the landlord, the leaseholder and the serf. Another key circumstance is that, while limiting the serfs’ mobility by restricting their personal freedom, serfdom also generated mobility through various orders given to peasants with respect to transport services.
Moving up the Hill? Peasant Strategies in Times of Plague and Climate Change
Authors: Svensson Eva , Nilsson Stefan , Pettersson Susanne , Johansson Annie 
Published: July 2022

Abstract
The Late Medieval Agrarian Crisis is associated with a desertion of rural settlements. Farmsteads in agriculturally-marginal locations are presumed to have been among the first to be deserted. In recent decades, interdisciplinary research has instead shown several examples of increased agrarian activity, including cereal cultivation, in the fourteenth and fifteenth centuries in forested upland areas of boreal inland Scandinavia. Farmsteads and hamlets established in forested upland areas in the fourteenth century have also been discovered. The recent excavation of one such farmstead, Ivarsbråten, shows that both settlement and agrarian production at the site had been adapted to the new climatic conditions of the Little Ice Age, which involved colder and wetter weather. It is here suggested that micro-mobility, moving out of a hamlet to an upland position, was a climate adaptation strategy pursued by a small number of peasants.