bluuebunny/crossref_metadata_2025 huggingface dataset:
Coaxial electrospun biomimetic copolymer fibres for application in diffusion magnetic resonance imaging
Authors: Zhou Feng-Lei , McHugh Damien J , Li Zhanxiong , Gough Julie E , Williams Gareth R , Parker Geoff J M
Published: March 2021

Objective. The use of diffusion magnetic resonance imaging (dMRI) opens the door to characterizing brain microstructure because water diffusion is anisotropic in axonal fibres in brain white matter and is sensitive to tissue microstructural changes. As dMRI becomes more sophisticated and microstructurally informative, it has become increasingly important to use a reference object (usually called an imaging phantom) for validation of dMRI. This study aims to develop axon-mimicking physical phantoms from biocopolymers and assess their feasibility for validating dMRI measurements. Approach. We employed a simple and one-step method—coaxial electrospinning—to prepare axon-mimicking hollow microfibres from polycaprolactone-b-polyethylene glycol (PCL-b-PEG) and poly(D, L-lactide-co-glycolic) acid (PLGA), and used them as building elements to create axon-mimicking phantoms. Electrospinning was firstly conducted using two types of PCL-b-PEG and two types of PLGA with different molecular weights in various solvents, with different polymer concentrations, for determining their spinnability. Polymer/solvent concentration combinations with good fibre spinnability were used as the shell material in the following co-electrospinning process in which the polyethylene oxide polymer was used as the core material. Following the microstructural characterization of both electrospun and co-electrospun fibres using optical and electron microscopy, two prototype phantoms were constructed from co-electrospun anisotropic hollow microfibres after inserting them into water-filled test tubes. Main results. Hollow microfibres that mimic the axon microstructure were successfully prepared from the appropriate core and shell material combinations. dMRI measurements of two phantoms on a 7 tesla (T) pre-clinical scanner revealed that diffusivity and anisotropy measurements are in the range of brain white matter. Significance. This feasibility study showed that co-electrospun PCL-b-PEG and PLGA microfibre-based axon-mimicking phantoms could be used in the validation of dMRI methods which seek to characterize white matter microstructure.
Fabrication and characterization of an injectable reinforced composite scaffold for cartilage tissue engineering: an in vitro study
Authors: Ravari Mojtaba Khozaei , Mashayekhan Shohreh , Zarei Fatemeh , Sayyahpour Forough Azam , Taghiyar Leila , Baghban Eslaminejad Mohamadreza
Published: March 2021

There are limitations in current medications of articular cartilage injuries. Although injectable bioactive hydrogels are promising options, they have decreased biomechanical performance. Researchers should consider many factors when providing solutions to overcome these challenges. In this study, we created an injectable composite hydrogel from chitosan and human acellular cartilage extracellular matrix (ECM) particles. In order to enhance its mechanical properties, we reinforced this hydrogel with microporous microspheres composed of the same materials as the structural building blocks of the scaffold. Articular cartilage from human donors was decellularized by a combination of physical, chemical, and enzymatic methods. The decellularization efficiency was assessed by histological analysis and assessment of DNA content. We characterized the composite constructs in terms of storage modulus, gelation time, biocompatibility, and differentiation potential. The results showed that mechanical behavior increased with an increase in microsphere content. The sample that contained 10% microsphere had an enhanced storage modulus of up to 90 kPa. Biocompatibility and preliminary differentiation investigations revealed that this composite hydrogel might have potential benefits for cartilage tissue engineering.
Anthropogenic warming of Tibetan Plateau and constrained future projection
Authors: Zhou Tianjun , Zhang Wenxia
Published: March 2021

Serving as ‘the water tower of Asia’, the Tibetan Plateau (TP) supplies water resources to more than 1.4 billion people. It is warming more rapidly than the global average over the past decades, affecting regional hydrological cycle and ecosystem services. However, the anthropogenic (ANT) influence remains unknown. Here we assessed the human contribution to the observed TP warming based on coupled climate simulations and an optimal fingerprinting detection and attribution analysis. We show that the observed rapid warming on the TP (1.23 °C over 1961–2005) is attributable to human influence, and particularly, to the greenhouse gases with a contribution of 1.37 °C by the best estimate, which was slightly offset by anthropogenic aerosols. As the multi-model ensemble tends to underestimate the ANT warming trend, the constraint from the attribution results suggests an even warmer future on the TP than previously expected, implying further increased geohazard risks in the Asian water tower.
Perspectives of application of simultaneous water and gas injection for utilizing associated petroleum gas and enhancing oil recovery in the Arctic fields
Authors: Drozdov Alexander , Gorbyleva Yana , Drozdov Nikolay , Gorelkina Evgeniya
Published: March 2021

At present, it is becoming more relevant to use other displacing agents, which are more effective in comparison with waterflooding, for increasing oil and gas condensate deposits component recovery. One of such promising methods is simultaneous water and gas injection. In this article, we present the principal options for using simultaneous water and gas injection in Arctic fields, case study of the Urengoyskoye and Prirazlomnoye fields. Technological schemes for its implementation in the Urengoyskoye field at low reservoir pressures are considered. Filtration studies of oil from reservoir models with water-gas mixtures at various gas contents allow increasing hydrocarbon recovery efficiency by determining the area of rational gas contents. For the conditions of the Prirazlomnoye field, the possibility of using pump-ejector system for the utilization of associated petroleum gas has been established.
Experimental investigation of the tool radius and micro-cutting speed influence on micro-cutting mechanisms for marble based material
Authors: Pjević Miloš , Popović Mihajlo , Tanović Ljubodrag
Published: March 2021

In this paper, a detailed experimental analysis of the effect of tool tip radius and cutting speed on the proposed mechanism of micro-cutting Plavi tok marble was performed. Although Plavi tok marble belongs to extremely brittle materials, experiments have shown that it can be processed in ductile mode (plastic deformation mode), i.e. without the presence of brittle fracturing of the material. Moreover, it has been established that the range of plastic deformation zone is a function of the tool tip radius and the cutting speed. The diamond tools used during the experiments had tip radius values of r = 0.15 and r = 0.2 mm, while cutting speeds were 15 and 25 m s−1. When using tools with higher tip radius values, with increasing cutting speed, the critical penetration depth (ductile-brittle transition) increased from 8.8 to 9.3 μm. On the other hand, tools with lower radius value led to a reduction of the plastic deformation zone range. This declining trend of plastic deformation zone continued during increased cutting speed, with critical penetration depths of 8.6 and 8.3 μm for cutting speeds of 15 and 25 m s−1, respectively. The intensity of lateral/radial destruction in the brittle fracturing mode was also directly dependent on the processing conditions. The reduction was achieved by using tools with a lower value of the tip radius while processing at lower speeds. In this paper, the identification of the components of the cutting force was carried out, whose intensities indicate the occurrence of the brittle destruction within the material.
A closed-loop feature-based FTS patterning and characterisation of functional structured surfaces
Authors: Tong Zhen , Zeng Wenhan , Zhong Wenbin , Jiang Xiangqian
Published: March 2021

To improve the feasibility and efficiency of ultra-precision surface structuring, a closed-loop fast-tool-servo (FTS) surface patterning and measurement system is developed with functional modules of feature-based tool path generation, embedded surface measurement and integrated surface characterisation toolkit. A dedicate controller HUDCNC is developed for the process control of FTS surface patterning and on-machine surface measurement (OMSM). Algorithms are developed for data formatting and transformation of designed patterns into the FTS cutting points (maximum number of 5 million points). The feasibility and performance of the proposed closed-loop FTS machining system are demonstrated by successfully generating typical functional structured surfaces including periodic structures, patterns and tessellations, biological surfaces, profile and character combinations. The results indicate that the feature-based FTS patterning and surface characterisation system provides a promising solution to the design and manufacturing of high-precision functional structured surfaces. The integrated OMSM system and the surface characterisation toolkit allow the fast inspection and quality control of the machined functional surfaces.
In-situ reduction by Joule heating and measurement of electrical conductivity of graphene oxide in a transmission electron microscope
Authors: Hettler Simon , Sebastian David , Pelaez-Fernandez Mario , Benito Ana M , Maser Wolfgang K , Arenal Raul
Published: March 2021

Graphene oxide (GO) is reduced by Joule heating using in-situ transmission electron microscopy (TEM). The approach allows the simultaneous study of GO conductivity by electrical measurements and of its composition and structural properties throughout the reduction process by TEM, electron diffraction and electron energy-loss spectroscopy. The small changes of GO properties observed at low applied electric currents are attributed to the promotion of diffusion processes. The actual reduction process starts from an applied power density of about 2 × 1014 Wm−3 and occurs in a highly uniform and localized manner. The conductivity increases more than 4 orders of magnitude reaching a value of 3 × 103 Sm−1 with a final O content of less than 1%. We discuss differences between the reduction by thermal annealing and Joule heating.
Enhanced single-ion conduction and free-standing properties of solid polymer electrolyte by incorporating a polyelectrolyte
Authors: Mengistie Tewuhibo S , Ko Jang Myoun , Kim Jung Yong
Published: March 2021

A free-standing solid polymer electrolyte (SPE) composed of poly(ethylene oxide) (PEO), bis(trifluoromethanesulfonyl)imide (LiTFSI), and poly(lithium 4-styrenesulfonate) (PLSS) was developed in this work. Thermal analysis indicated that the melting points of PEO were depressed with increasing the salt additives, LiTFSI and PLSS. At the composition of [EO]:LiTFSI:[LSS] = 14:1:1, the SPE exhibited a crystallinity of 7.75%, and a crystallite size of 30.62 nm on the (120) crystallographic plane. [EO] and [LSS] represent the structural unit of PEO and PLSS, respectively. This SPE also exhibited an ionic conductivity (σ) of 1.70 × 10−5 S cm−1 at 25 °C and 1.04 × 10−4 S cm−1 at 45 °C. For analyzing the temperature dependence of σ, the Vogel-Tammann-Fulcher equation was employed. Resultantly, a pseudo activation energy (E

a
 = 0.1552 eV), a prefactor (A = 206.0338 S cm−1 K1/2), and an empirical constant (B = 1800.5879 K) were obtained using the optimized [EO]:[Li+] = 7:1 complex. The SPE showed an electrochemical stability window of ∼4.7 ± 0.1 V versus Li/Li+. Through DC polarization and AC impedance, the Li-ion transference number of 0.66 was obtained at 70 °C. Finally, when a Li/SPE/LiFePO4 cell was prepared, the device exhibited a discharge capacity of 121 mAh g−1 at 50 °C with a coulombic efficiency close to 100%.
Corruption: An Impediment to Delivering Pathology and Laboratory Services in Resource-Limited Settings
Authors: Glynn Emily H , Amukele Timothy , Vian Taryn
Published: March 2021

Objectives

Corruption is a widely acknowledged problem in the health sector of low- and middle-income countries (LMICs). Yet, little is known about the types of corruption that affect the delivery of pathology and laboratory medicine (PALM) services. This review is a first step at examining corruption risks in PALM.

Methods

We performed a critical review of medical literature focused on health sector corruption in LMICs. To provide context, we categorized cases of laboratory-related fraud and abuse in the United States.

Results

Forms of corruption in LMICs that may affect the provision of PALM services include informal payments, absenteeism, theft and diversion, kickbacks, self-referral, and fraudulent billing.

Conclusions

Corruption represents a functional reality in many LMICs and hinders the delivery of services and distribution of resources to which individuals and entities are legally entitled. Further study is needed to estimate the extent of corruption in PALM and develop appropriate anticorruption strategies.
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

Glioblastoma (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

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

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

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

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

The 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

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

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 < 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

This 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

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

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 >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

Aims

Fabry 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 results

A 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 > 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.

Conclusions

Treatment 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.
Surgical outcomes of infective endocarditis in children: should we delay surgery for infective endocarditis?
Authors: Lee Jae Hong , Kwak Jae Gun , Cho Sungkyu , Kim Woong-Han , Lee Jeong Ryul , Kwon Hye Won , Song Mi Kyoung , Lee Sang-Yun , Kim Gi Beom , Bae Eun Jung
Published: March 2021

OBJECTIVES

We compared the surgical outcomes of infective endocarditis (IE) between early surgery and non-early surgery groups in children.

METHODS

From January 2000 to April 2020, we retrospectively reviewed 50 patients <18years of age who underwent first surgery for IE. Early surgery was defined as that performed within 2 days for left-sided IE and 7 days for right-sided IE after diagnosis.

RESULTS

The median age and body weight at operation were 7.7 years [interquartile range (IQR), 2.3–13.2] and 23.7 kg (IQR, 10.3–40.7), respectively. The median follow-up duration was 9.5 years (IQR, 4.0–14.5). In 28 patients with native valve endocarditis, the native valve was preserved in 23 (82.1%). The most common causative microorganism was Streptococcus viridans (32.0%). The operative mortality was 2.0%, and 13 (26.0%) patients required reoperation most commonly for prosthesis failure (n = 7). There were no significant differences in patient characteristics and perioperative data between early surgery (n = 9) and non-early surgery (n = 36) groups, except for the interval between diagnosis and surgery (early surgery < non-early surgery, P < 0.001) and preoperative negative blood culture conversion (early surgery < non-early surgery, P = 0.025). There were no significant differences in overall survival, recurrent IE, and reoperation rate between the groups. Early surgery and preoperative negative blood culture conversion were not found as significant factors for surgical adverse outcomes.

CONCLUSIONS

Surgical outcomes for IE in children were acceptable irrespective of the time of surgery. Our results suggest that it may not be required to delay surgery for IE and the potential benefit of early surgery could be expected in children.
Functional capacity assessment and Minimal Clinically Important Difference in post-acute cardiac patients: the role of Short Physical Performance Battery
Authors: Rinaldo Linda , Caligari Marco , Acquati Claudia , Nicolazzi Sabrina , Paracchini Giulio , Sardano Daniela , Giordano Andrea , Marcassa Claudio , Corrà Ugo
Published: March 2021

Background

The Short Physical Performance Battery (SPPB) test is a well-established tool to assess physical performance, and to identify frail patients. Assessment of the SPPB in a specific population of elder patients in cardiac rehabilitation phase after a cardiac event is missing.

Aim

The aim of this study was to correlate SPPB and the cardiac rehabilitation outcome in a group of elder patients after a cardiac event and to identify the Minimal Clinically Important Difference (MCID) of the SPPB.

Methods

Consecutive (n = 392) patients aged ≥75 years, in the rehabilitation phase after cardiac surgery (70.1%), congestive heart failure (7.4%), or acute coronary syndrome (22.5%), were enrolled. SPPB was performed twice: on admission and discharge. The MCID was assessed with the ‘anchor method’, and the Patient Global Impression of Change was employed as the anchor.

Results

On admission, SPPB classified 56, 117, 116, and 94 patients as severe, moderate, mild, or minimal/no limitations, respectively. Patients with the lower SPPB had the longer length of stay, and the higher complications rate. At receiver operating characteristic analysis, an SPPB improvement >1 was identified as the MCID (area-under-curve 0.77, 95% CI 0.67–0.85). Overall, 285 patients (74.2%) had a ‘clinically significant’ improvement in SPPB, with a rate of improvement higher in patients with severe/moderate limitations (83.0%) and lower in those with mild (78.9%) or minimal/no limitations (53.6%).

Conclusion

A lower SPPB score is associated with a higher complications rate in the post-acute phase. An improvement >1 point of SPPB was identified as the MCID; this reference value could serve as the goal for rehabilitation interventions.
Comparative transcriptome analyses of theDrosophilapupal eye
Authors: DeAngelis Miles W , Coolon Joseph D , Johnson Ruth I
Published: March 2021

Tissue function is dependent on correct cellular organization and behavior. As a result, the identification and study of genes that contribute to tissue morphogenesis is of paramount importance to the fields of cell and developmental biology. Many of the genes required for tissue patterning and organization are highly conserved between phyla. This has led to the emergence of several model organisms and developmental systems that are used to study tissue morphogenesis. One such model is the Drosophila melanogaster pupal eye that has a highly stereotyped arrangement of cells. In addition, the pupal eye is postmitotic that allows for the study of tissue morphogenesis independent from any effects of proliferation. While the changes in cell morphology and organization that occur throughout pupal eye development are well documented, less is known about the corresponding transcriptional changes that choreograph these processes. To identify these transcriptional changes, we dissected wild-type Canton S pupal eyes and performed RNA-sequencing. Our analyses identified differential expression of many loci that are documented regulators of pupal eye morphogenesis and contribute to multiple biological processes including signaling, axon projection, adhesion, and cell survival. We also identified differential expression of genes not previously implicated in pupal eye morphogenesis such as components of the Toll pathway, several non-classical cadherins, and components of the muscle sarcomere, which could suggest these loci function as novel patterning factors.
Chromosome inheritance and meiotic stability in allopolyploidBrassica napus
Authors: Xiong Zhiyong , Gaeta Robert T , Edger Patrick P , Cao Yao , Zhao Kanglu , Zhang Siqi , Pires J Chris
Published: March 2021

Homoeologous recombination, aneuploidy, and other genetic changes are common in resynthesized allopolyploid Brassica napus. In contrast, the chromosomes of cultivars have long been considered to be meiotically stable. To gain a better understanding of the underlying mechanisms leading to stabilization in the allopolyploid, the behavior of chromosomes during meiosis can be compared by unambiguous chromosome identification between resynthesized and natural B. napus. Compared with natural B. napus, resynthesized lines show high rates of nonhomologous centromere association, homoeologous recombination leading to translocation, homoeologous chromosome replacement, and association and breakage of 45S rDNA loci. In both natural and resynthesized B. napus, we observed low rates of univalents, A–C bivalents, and early sister chromatid separations. Reciprocal homoeologous chromosome exchanges and double reductions were photographed for the first time in meiotic telophase I. Meiotic errors were non-uniformly distributed across the genome in resynthesized B. napus, and in particular homoeologs sharing synteny along their entire length exhibited multivalents at diakinesis and polysomic inheritance at telophase I. Natural B. napus appeared to resolve meiotic errors mainly by suppressing homoeologous pairing, resolving nonhomologous centromere associations and 45S rDNA associations before diakinesis, and reducing homoeologous cross-overs.
A zero altered Poisson random forest model for genomic-enabled prediction
Authors: Montesinos-López Osval Antonio , Montesinos-López Abelardo , Mosqueda-Gonzalez Brandon A , Montesinos-López José Cricelio , Crossa José , Ramirez Nerida Lozano , Singh Pawan , Valladares-Anguiano Felícitas Alejandra
Published: March 2021

In genomic selection choosing the statistical machine learning model is of paramount importance. In this paper, we present an application of a zero altered random forest model with two versions (ZAP_RF and ZAPC_RF) to deal with excess zeros in count response variables. The proposed model was compared with the conventional random forest (RF) model and with the conventional Generalized Poisson Ridge regression (GPR) using two real datasets, and we found that, in terms of prediction performance, the proposed zero inflated random forest model outperformed the conventional RF and GPR models.
Generalized gametic relationships for flexible analyses of parent-of-origin effects
Authors: Reinsch Norbert , Mayer Manfred , Blunk Inga
Published: March 2021

A class of epigenetic inheritance patterns known as genomic imprinting allows alleles to influence the phenotype in a parent-of-origin-specific manner. Various pedigree-based parent-of-origin analyses of quantitative traits have attempted to determine the share of genetic variance that is attributable to imprinted loci. In general, these methods require four random gametic effects per pedigree member to account for all possible types of imprinting in a mixed model. As a result, the system of equations may become excessively large to solve using all available data. If only the offspring have records, which is frequently the case for complex pedigrees, only two averaged gametic effects (transmitting abilities) per parent are required (reduced model). However, the parents may have records in some cases. Therefore, in this study, we explain how employing single gametic effects solely for informative individuals (i.e., phenotyped individuals), and only average gametic effects otherwise, significantly reduces the complexity compared with classical gametic models. A generalized gametic relationship matrix is the covariance of this mixture of effects. The matrix can also make the reduced model much more flexible by including observations from parents. Worked examples are present to illustrate the theory and a realistic body mass data set in mice is used to demonstrate its utility. We show how to set up the inverse of the generalized gametic relationship matrix directly from a pedigree. An open-source program is used to implement the rules. The application of the same principles to phased marker data leads to a genomic version of the generalized gametic relationships.
Copper Availability Influences the Transcriptomic Response of Candida albicans to Fluconazole Stress
Authors: Hunsaker Elizabeth W , Yu Chen-Hsin Albert , Franz Katherine J
Published: March 2021

The ability of pathogens to maintain homeostatic levels of essential biometals is known to be important for survival and virulence in a host, which itself regulates metal availability as part of its response to infection. Given this importance of metal homeostasis, we sought to address how the availability of copper in particular impacts the response of the opportunistic fungal pathogen Candida albicans to treatment with the antifungal drug fluconazole. The present study reports whole transcriptome analysis via time-course RNA-seq of C. albicans cells exposed to fluconazole with and without 10 µM supplemental CuSO4 added to the growth medium. The results show widespread impacts of small changes in Cu availability on the transcriptional response of C. albicans to fluconazole. Of the 2359 genes that were differentially expressed under conditions of cotreatment, 50% were found to be driven uniquely by exposure to both Cu and fluconazole. The breadth of metabolic processes that were affected by cotreatment illuminates a fundamental intersectionality between Cu metabolism and fungal response to drug stress. More generally, these results show that seemingly minor fluctuations in Cu availability are sufficient to shift cells’ transcriptional response to drug stress. Ultimately, the findings may inform the development of new strategies that capitalize on drug-induced vulnerabilities in metal homeostasis pathways.