bluuebunny/crossref_metadata_2025_split huggingface dataset:
Machine learning revealed stemness features and a novel stemness-based classification with appealing implications in discriminating the prognosis, immunotherapy and temozolomide responses of 906 glioblastoma patients
Authors: Wang Zihao , Wang Yaning , Yang Tianrui , Xing Hao , Wang Yuekun , Gao Lu , Guo Xiaopeng , Xing Bing , Wang Yu , Ma Wenbin 
Published: March 2021

AbstractGlioblastoma (GBM) is the most malignant and lethal intracranial tumor, with extremely limited treatment options. Immunotherapy has been widely studied in GBM, but none can significantly prolong the overall survival (OS) of patients without selection. Considering that GBM cancer stem cells (CSCs) play a non-negligible role in tumorigenesis and chemoradiotherapy resistance, we proposed a novel stemness-based classification of GBM and screened out certain population more responsive to immunotherapy. The one-class logistic regression algorithm was used to calculate the stemness index (mRNAsi) of 518 GBM patients from The Cancer Genome Atlas (TCGA) database based on transcriptomics of GBM and pluripotent stem cells. Based on their stemness signature, GBM patients were divided into two subtypes via consensus clustering, and patients in Stemness Subtype I presented significantly better OS but poorer progression-free survival than Stemness Subtype II. Genomic variations revealed patients in Stemness Subtype I had higher somatic mutation loads and copy number alteration burdens. Additionally, two stemness subtypes had distinct tumor immune microenvironment patterns. Tumor Immune Dysfunction and Exclusion and subclass mapping analysis further demonstrated patients in Stemness Subtype I were more likely to respond to immunotherapy, especially anti-PD1 treatment. The pRRophetic algorithm also indicated patients in Stemness Subtype I were more resistant to temozolomide therapy. Finally, multiple machine learning algorithms were used to develop a 7-gene Stemness Subtype Predictor, which were further validated in two external independent GBM cohorts. This novel stemness-based classification could provide a promising prognostic predictor for GBM and may guide physicians in selecting potential responders for preferential use of immunotherapy.
Inference of dynamic spatial GRN models with multi-GPU evolutionary computation
Authors: Mousavi Reza , Konuru Sri Harsha , Lobo Daniel 
Published: March 2021

Abstract
Reverse engineering mechanistic gene regulatory network (GRN) models with a specific dynamic spatial behavior is an inverse problem without analytical solutions in general. Instead, heuristic machine learning algorithms have been proposed to infer the structure and parameters of a system of equations able to recapitulate a given gene expression pattern. However, these algorithms are computationally intensive as they need to simulate millions of candidate models, which limits their applicability and requires high computational resources. Graphics processing unit (GPU) computing is an affordable alternative for accelerating large-scale scientific computation, yet no method is currently available to exploit GPU technology for the reverse engineering of mechanistic GRNs from spatial phenotypes. Here we present an efficient methodology to parallelize evolutionary algorithms using GPU computing for the inference of mechanistic GRNs that can develop a given gene expression pattern in a multicellular tissue area or cell culture. The proposed approach is based on multi-CPU threads running the lightweight crossover, mutation and selection operators and launching GPU kernels asynchronously. Kernels can run in parallel in a single or multiple GPUs and each kernel simulates and scores the error of a model using the thread parallelism of the GPU. We tested this methodology for the inference of spatiotemporal mechanistic gene regulatory networks (GRNs)—including topology and parameters—that can develop a given 2D gene expression pattern. The results show a 700-fold speedup with respect to a single CPU implementation. This approach can streamline the extraction of knowledge from biological and medical datasets and accelerate the automatic design of GRNs for synthetic biology applications.
Increased SUMOylation of TCF21 improves its stability and function in human endometriotic stromal cells
Authors: Zhu Jingwen , Wu Peili , Zeng Cheng , Xue Qing 
Published: March 2021

Abstract
Endometriosis is an estrogen-dependent disease. Our previous study demonstrated that elevated levels of transcription factor 21 (TCF21) in endometriotic tissues enhanced steroidogenic factor-1 (SF-1) and estrogen receptor β (ERβ) expression by forming a heterodimer with upstream stimulatory factor 2 (USF2), allowing these TCF21/USF2 complexes to bind to the promoters of SF-1 and ERβ. Furthermore, TCF21 contributed to the increased proliferation of endometriotic stromal cells (ESCs), suggesting that TCF21 may play a vital role in the pathogenesis of endometriosis. SUMOylation is a posttranslational modification that has emerged as a crucial molecular regulatory mechanism. However, the mechanism regulating TCF21 SUMOylation in endometriosis is incompletely characterized. Thus, this study aimed to explore the effect of TCF21 SUMOylation on its expression and regulation in ovarian endometriosis. We found that the levels of SUMOylated TCF21 were increased in endometriotic tissues and stromal cells compared with eutopic endometrial tissues and stromal cells and enhanced by estrogen. Treatment with the SUMOylation inhibitor ginkgolic acid and the results of a protein half-life assay demonstrated that SUMOylation can stabilize the TCF21 protein. A coimmunoprecipitation assay showed that SUMOylation probably increased its interaction with USF2. Further analyses elucidated that SUMOylation of TCF21 significantly increased the binding activity of USF2 to the SF-1 and ERβ promoters. Moreover, the SUMOylation motifs in TCF21 affected the proliferation ability of ESCs. The results of this study suggest that SUMOylation plays a critical role in mediating the high expression of TCF21 in ESCs and may participate in the development of endometriosis.
Paternally expressed retrotransposon Gag-like 1 gene, RTL1, is one of the crucial elements for placental angiogenesis in horses
Authors: Dini Pouya , Carossino Mariano , Balasuriya Udeni B R , El-Sheikh Ali Hossam , Loux Shavahn C , Esteller-Vico Alejandro , Scoggin Kirsten E , Loynachan Alan T , Kalbfleisch Theodore , De Spiegelaere Ward , Daels Peter , Ball Barry A 
Published: March 2021

Abstract
RTL1 (retrotransposon Gag-like 1) is an essential gene in the development of the human and murine placenta. Several fetal and placental abnormalities such as intrauterine growth restriction (IUGR) and hydrops conditions have been associated with altered expression of this gene. However, the function of RTL1 has not been identified. RTL1 is located on a highly conserved region in eutherian mammals. Therefore, the genetic and molecular analysis in horses could hold important implications for other species, including humans. Here, we demonstrated that RTL1 is paternally expressed and is localized within the endothelial cells of the equine (Equus caballus) chorioallantois. We developed an equine placental microvasculature primary cell culture and demonstrated that RTL1 knockdown leads to loss of the sprouting ability of these endothelial cells. We further demonstrated an association between abnormal expression of RTL1 and development of hydrallantois. Our data suggest that RTL1 may be essential for placental angiogenesis, and its abnormal expression can lead to placental insufficiency. This placental insufficiency could be the reason for IUGR and hydrops conditions reported in other species, including humans.
Chronic overload of concentration-dependent iron exerts different effects on ovarian function in C57BL/6J mice
Authors: Qin Xian , Liang Deku , Hu Min , Lv Zi , Duan Zhaoning , Liu Xiaohan , Tang Liangdan 
Published: March 2021

Abstract
Overloaded iron can deposit in the reproductive system and impair ovarian function. But few studies have identified the exact effect of overloaded iron on the endocrine function and fertility capacity in female mice. Here, we established iron-overloaded mouse models by intraperitoneal injection of iron dextran to adult female C57BL/6J mice at 0.1 g/kg (LF group), 0.5 g/kg (MF group), and 1.0 g/kg (HF group) concentrations once a week for eight consecutive weeks. We found that overloaded iron resulted in smaller ovaries, as well as accumulated oxidative damages. The endocrine function and follicle development were also impeded in the MF and HF groups. The 10-month breeding trial indicated that (1) Low concentration of iron (0.1 g/kg) wasn’t detrimental to the ovary; (2) Middle concentration of iron (0.5 g/kg) impeded the childbearing process, though it could be recovered following the iron excretion; and (3) High concentration of iron (1.0 g/kg) damaged the fertility, even gave rise to sterility. Yet for those fertile mice, litter number and litter size were smaller and the ovarian reserve of their offspring was impaired. Transcriptome profiling results indicated that overloaded iron could compromise ovarian function by disrupting ovarian steroidogenesis, interfering with ovarian microenvironment, and inhibiting Wnt signaling. Taken together, we have demonstrated the effect that chronic concentration-dependent iron overload exerted on mouse ovarian function, which may act as a preliminary basis for further mechanism and intervention investigations.
Why Coordinated Distributed Experiments Should Go Global
Authors: Yahdjian Laura , Sala Osvaldo E , PiÑEiro-Guerra Juan Manuel , Knapp Alan K , Collins Scott L , Phillips Richard P , Smith Melinda D 
Published: March 2021

AbstractThe performance of coordinated distributed experiments designed to compare ecosystem sensitivity to global-change drivers depends on whether they cover a significant proportion of the global range of environmental variables. In the present article, we described the global distribution of climatic and soil variables and quantified main differences among continents. Then, as a test case, we assessed the representativeness of the International Drought Experiment (IDE) in parameter space. Considering the global environmental variability at this scale, the different continents harbor unique combinations of parameters. As such, coordinated experiments set up across a single continent may fail to capture the full extent of global variation in climate and soil parameter space. IDE with representation on all continents has the potential to address global scale hypotheses about ecosystem sensitivity to environmental change. Our results provide a unique vision of climate and soil variability at the global scale and highlight the need to design globally distributed networks.
Systemic sclerosis and microscopic polyangiitis after systemic exposure to silicone
Authors: Carrera Muñoz Claudia , González Rodríguez Jorge , Abó Rivera Annabel , Estarán Elena , Roig Cárcel Jordi , Segarra Medrano Alfons 
Published: March 2021

Abstract
The relationship between silicon breast implants (SBIs) and autoimmune/inflammatory syndrome induced by adjuvants (ASIA) has been extensively analysed, with discordant results. We present a 45-year-old woman with confirmed systemic exposure to SBI who developed systemic sclerosis (SSc) followed by anti-neutrophil cytoplasmic antibody anti-myeloperoxidase vasculitis with renopulmonary syndrome. The novelty of our case is, first, confirmation of systemic exposure to SBI and, second, chronologic development of not one, but two severe autoimmune diseases. Controversy may still remain regarding SBIs and ASIA because it is unclear that previous studies confirmed systemic exposure to silicon in their cohort of patients.
Remodelling of adult cardiac tissue subjected to physiological and pathological mechanical load in vitro
Authors: Pitoulis Fotios G , Nunez-Toldra Raquel , Xiao Ke , Kit-Anan Worrapong , Mitzka Saskia , Jabbour Richard J , Harding Sian E , Perbellini Filippo , Thum Thomas , de Tombe Pieter P , Terracciano Cesare M 
Published: March 2021

Abstract

Aims
Cardiac remodelling is the process by which the heart adapts to its environment. Mechanical load is a major driver of remodelling. Cardiac tissue culture has been frequently employed for in vitro studies of load-induced remodelling; however, current in vitro protocols (e.g. cyclic stretch, isometric load, and auxotonic load) are oversimplified and do not accurately capture the dynamic sequence of mechanical conformational changes experienced by the heart in vivo. This limits translational scope and relevance of findings.

Methods and results
We developed a novel methodology to study chronic load in vitro. We first developed a bioreactor that can recreate the electromechanical events of in vivo pressure–volume loops as in vitro force–length loops. We then used the bioreactor to culture rat living myocardial slices (LMS) for 3 days. The bioreactor operated based on a 3-Element Windkessel circulatory model enabling tissue mechanical loading based on physiologically relevant parameters of afterload and preload. LMS were continuously stretched/relaxed during culture simulating conditions of physiological load (normal preload and afterload), pressure-overload (normal preload and high afterload), or volume-overload (high preload & normal afterload). At the end of culture, functional, structural, and molecular assays were performed to determine load-induced remodelling. Both pressure- and volume-overloaded LMS showed significantly decreased contractility that was more pronounced in the latter compared with physiological load (P &lt; 0.0001). Overloaded groups also showed cardiomyocyte hypertrophy; RNAseq identified shared and unique genes expressed in each overload group. The PI3K-Akt pathway was dysregulated in volume-overload while inflammatory pathways were mostly associated with remodelling in pressure-overloaded LMS.

Conclusion
We have developed a proof-of-concept platform and methodology to recreate remodelling under pathophysiological load in vitro. We show that LMS cultured in our bioreactor remodel as a function of the type of mechanical load applied to them.
Reconciliation of anti-money laundering instruments and European data protection requirements in permissionless blockchain spaces
Authors: Karasek-Wojciechowicz Iwona 
Published: March 2021

AbstractThis article is an attempt to reconcile the requirements of the EU General Data Protection Regulation (GDPR) and anti-money laundering and combat terrorist financing (AML/CFT) instruments used in permissionless ecosystems based on distributed ledger technology (DLT). Usually, analysis is focused only on one of these regulations. Covering by this research the interplay between both regulations reveals their incoherencies in relation to permissionless DLT. The GDPR requirements force permissionless blockchain communities to use anonymization or, at the very least, strong pseudonymization technologies to ensure compliance of data processing with the GDPR. At the same time, instruments of global AML/CFT policy that are presently being implemented in many countries following the recommendations of the Financial Action Task Force, counteract the anonymity-enhanced technologies built into blockchain protocols. Solutions suggested in this article aim to induce the shaping of permissionless DLT-based networks in ways that at the same time would secure the protection of personal data according to the GDPR rules, while also addressing the money laundering and terrorist financing risks created by transactions in anonymous blockchain spaces or those with strong pseudonyms. Searching for new policy instruments is necessary to ensure that governments do not combat the development of all privacy-blockchains so as to enable a high level of privacy protection and GDPR-compliant data processing. This article indicates two AML/CFT tools which may be helpful for shaping privacy-blockchains that can enable the feasibility of such tools. The first tool is exceptional government access to transactional data written on non-transparent ledgers, obfuscated by advanced anonymization cryptography. The tool should be optional for networks as long as another effective AML/CFT measures are accessible for the intermediaries or for the government in relation to a given network. If these other measures are not available and the network does not grant exceptional access, the regulations should allow governments to combat the development of those networks. Effective tools in that scope should target the value of privacy-cryptocurrency, not its users. Such tools could include, as a tool of last resort, state attacks which would undermine the trust of the community in a specific network.
Why international law and norms do little in preventing non-state cyber attacks
Authors: Katagiri Nori 
Published: March 2021

Abstract
In this article, I investigate why international law and norms have failed to keep cyberspace peaceful. The problem comes mainly from their failure to address what non-state actors, such as individual hackers and technology firms, do in cyberspace. Created by the extensive input of government officials decades ago with heavy focus on states as primary actors of international politics, international law is incoherent with the dominance of non-state actors as de facto operators of cyberspace. The critical problem shared by international law and institutions of having no “teeth” to penalize non-state violence extends to cyberspace. As a result, noncompliance with international law has become practical, and it has even bolstered the private sector, especially major technology firms, to assert themselves in the legal void, leverage their digital products to reshape norms, and become norm entrepreneurs in the business of digital defense. However, the multiplication of norm entrepreneurs has accelerated in an uncoordinated manner, and the way they built their interests does not neatly align with those of the states. While some norms of cyberspace behavior have been accepted, many others remain contested. In the meantime, norm discourse in diplomatic venues, including in multilateral debates at the United Nations, has become highly undemocratic, dominated by a small mix of great powers and active middle powers that are also split over what norms should guide state and nonstate behaviors.
Awake venoarterial extracorporeal membrane oxygenation for refractory cardiogenic shock
Authors: Montero Santiago , Huang Florent , Rivas-Lasarte Mercedes , Chommeloux Juliette , Demondion Pierre , Bréchot Nicolas , Hékimian Guillaume , Franchineau Guillaume , Persichini Romain , Luyt Charles-Édouard , Garcia-Garcia Cosme , Bayes-Genis Antoni , Lebreton Guillaume , Cinca Juan , Leprince Pascal , Combes Alain , Alvarez-Garcia Jesus , Schmidt Matthieu 
Published: March 2021

Abstract

Background
Venoarterial-extracorporeal membrane oxygenation (VA-ECMO) is currently one of the first-line therapies for refractory cardiogenic shock (CS), but its applicability is undermined by the high morbidity associated with its complications, especially those related to mechanical ventilation (MV). We aimed to assess the prognostic impact of keeping patients in refractory CS awake at cannulation and during the VA-ECMO run.

Methods
A 7-year database of patients given peripheral VA-ECMO support was used to conduct a propensity-score (PS)-matched analysis to balance their clinical profiles. Patients were classified as ‘awake ECMO’ or ‘non-awake ECMO’, respectively, if invasive MV was used during ≤50% or &gt;50% of the VA-ECMO run. Primary outcomes included ventilator-associated pneumonia and ECMO-related complication rates, and secondary outcomes were 60-day and 1-year mortality. A multivariate logistic-regression analysis was used to identify whether MV at cannulation was independently associated with 60-day mortality.

Results
Among 231 patients included, 91 (39%) were ‘awake’ and 140 (61%) ‘non-awake’. After PS-matching adjustment, the ‘awake ECMO’ group had significantly lower rates of pneumonia (35% vs. 59%, P = 0.017), tracheostomy, renal replacement therapy, and less antibiotic and sedative consumption. This strategy was also associated with reduced 60-day (20% vs. 41%, P = 0.018) and 1-year mortality rates (31% vs. 54%, P = 0.021) compared to the ‘non-awake’ group, respectively. Lastly, MV at ECMO cannulation was independently associated with 60-day mortality.

Conclusion
An ‘awake ECMO’ management in VA-ECMO-supported CS patients is feasible, safe, and associated with improved short- and long-term outcomes.
Treatment of Fabry Disease management with migalastat—outcome from a prospective 24 months observational multicenter study (FAMOUS)
Authors: Lenders Malte , Nordbeck Peter , Kurschat Christine , Eveslage Maria , Karabul Nesrin , Kaufeld Jessica , Hennermann Julia B , Patten Monica , Cybulla Markus , Müntze Jonas , Üçeyler Nurcan , Liu Dan , Das Anibh M , Sommer Claudia , Pogoda Christian , Reiermann Stefanie , Duning Thomas , Gaedeke Jens , von Cossel Katharina , Blaschke Daniela , Brand Stefan-Martin , Mann W Alexander , Kampmann Christoph , Muschol Nicole , Canaan-Kühl Sima , Brand Eva 
Published: March 2021

AbstractAimsFabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (GLA/AGAL), resulting in the lysosomal accumulation of globotriaosylceramide (Gb3). Patients with amenable GLA mutations can be treated with migalastat, an oral pharmacological chaperone increasing endogenous AGAL activity. In this prospective observational multicentre study, safety as well as cardiovascular, renal, and patient-reported outcomes and disease biomarkers were assessed after 12 and 24 months of migalastat treatment under ‘real-world’ conditions.Methods and resultsA total of 54 patients (26 females) (33 of these [61.1%] pre-treated with enzyme replacement therapy) with amenable mutations were analysed. Treatment was generally safe and well tolerated. A total of 153 events per 1000 patient-years were detected. Overall left ventricular mass index decreased after 24 months (all: −7.5 ± 17.4 g/m2, P = 0.0118; females: −4.6 ± 9.1 g/m2, P = 0.0554; males: −9.9 ± 22.2 g/m2, P = 0.0699). After 24 months, females and males presented with a moderate yearly loss of estimated glomerular filtration rate (−2.6 and −4.4 mL/min/1.73 m2 per year; P = 0.0317 and P = 0.0028, respectively). FD-specific manifestations/symptoms remained stable (all P &gt; 0.05). A total of 76.9% of females and 50% of males suffered from pain, which has not improved under treatment. FD-specific disease scores (Disease Severity Scoring System and Mainz Severity Score Index) remained stable during treatment. AGAL activities and plasma lyso-Gb3 values remained stable, although some male patients presented with increasing lyso-Gb3 levels over time.ConclusionsTreatment with migalastat was generally safe and resulted in most patients in an amelioration of left ventricular mass. However, due to the heterogeneity of FD phenotypes, it is advisable that the treating physician monitors the clinical response regularly.