bluuebunny/crossref_metadata_2025 huggingface dataset:
Wandering along the epigenetic timeline
Authors: Topart Clémence , Werner Emilie , Arimondo Paola B.
Published: July 2020

Background

Increasing life expectancy but also healthspan seems inaccessible as of yet but it may become a reality in the foreseeable future. To extend lifespan, it is essential to unveil molecular mechanisms involved in ageing. As for healthspan, a better understanding of the mechanisms involved in age-related pathologies is crucial.

Main body

We focus on the epigenetic side of ageing as ageing is traced by specific epigenetic patterns and can be measured by epigenetic clocks. We discuss to what extent exposure to environmental factor, such as alcohol use, unhealthy diet, tobacco and stress, promotes age-related conditions. We focused on inflammation, cancer and Alzheimer’s disease. Finally, we discuss strategies to reverse time based on epigenetic reprogramming.

Conclusions

Reversibility of the epigenetic marks makes them promising targets for rejuvenation. For this purpose, a better understanding of the epigenetic mechanisms underlying ageing is essential. Epigenetic clocks were successfully designed to monitor these mechanisms and the influence of environmental factors. Further studies on age-related diseases should be conducted to determine their epigenetic signature, but also to pinpoint the defect in the epigenetic machinery and thereby identify potential therapeutic targets. As for rejuvenation, epigenetic reprogramming is still at an early stage.

Graphical abstract
Nonadherent culture method promotes MSC-mediated vascularization in myocardial infarction via miR-519d/VEGFA pathway
Authors: Deng Baoping , Zhang Xianlan , Liang Yi , Jiang Haiming , Huang Weizhao , Wu Yinmeng , Deng Weiping
Published: July 2020

Background

Mesenchymal stem cells (MSCs) can provide therapeutic benefits for myocardial infarction (MI) recovery; however, the molecular mechanism by which MSCs improve the heart function is unclear.

Methods

Microarray analysis was performed to examine the expression profiling of human MSCs (hMSCs) grown as adherent cultures (AC-hMSCs) or nonadherent cultures on ultra-low-adherent plates (nonAC-hMSCs). Real-time quantitative polymerase chain reaction (RT-qPCR), western blotting, and enzyme-linked immunosorbent assays (ELISA) were used to assess VEGFA expression and secretion in the AC-hMSCs and nonAC-hMSCs. The paracrine effect of VEGFA-overexpressing AC-MSCs (AC-VEGFA-hMSCs) or VEGFA-knockdown nonAC-hMSCs (nonAC-shVEGFA-hMSCs) on the angiogenic ability of human umbilical vein endothelial cells (HUVECs) was evaluated using tube formation assay. AC-VEGFA-hMSCs or nonAC-shVEGFA-hMSCs were transplanted into myocardial infarction rats to investigate the therapeutic effect of AC-VEGFA-hMSCs or nonAC-shVEGFA-hMSCs. Luciferase reporter assay was used to confirm the association of VEGFA with miR-519d.

Results

Microarray analysis revealed that VEGFA is downregulated in AC-hMSCs compared to nonAC-hMSCs. Functional assays revealed that high levels of VEGFA produced from AC-VEGFA-hMSCs increased the tube formation capacity of HUVECs in vitro, improved angiogenesis and cardiac performance, and reduced infarct size in a rat MI model. Low levels of VEGFA secretion from nonAC-shVEGFA-hMSCs had the opposite effects. Mechanistically, we found that miR-519d directly targets VEGFA. High levels of VEGFA secreted from VEGFA-overexpressing nonAC-hMSCs abolished the repressive effect of miR-519d on HUVEC angiogenesis.

Conclusion

Our findings indicate that nonadherent culture-induced secretion of VEGFA plays an important role in MSCs via the miR-519d/VEGFA pathway and may provide a novel therapeutic strategy for MI treatment.
Comparison of fuzzy Adomian decomposition method with fuzzy VIM for solving fuzzy heat-like and wave-like equations with variable coefficients
Authors: Osman Mawia , Gong Zengtai , Mustafa Altyeb Mohammed
Published: July 2020

In this work, we investigate the fuzzy Adomian decomposition method (ADM) and fuzzy variational iteration method (VIM) applied to solving fuzzy heat-like and wave-like equations with variable coefficients, in the sense of gH-differentiability. The methods clearly are very efficient and powerful techniques in finding the solutions to the proposed equations. We also illustrate them by some examples. The results reveal that the methods are very effective, convenient, and accurate mathematical tools for solving fuzzy heat-like and wave-like equations with variable coefficients.
Parameterized algorithms of fundamental NP-hard problems: a survey
Authors: Li Wenjun , Ding Yang , Yang Yongjie , Sherratt R. Simon , Park Jong Hyuk , Wang Jin
Published: July 2020

Parameterized computation theory has developed rapidly over the last two decades. In theoretical computer science, it has attracted considerable attention for its theoretical value and significant guidance in many practical applications. We give an overview on parameterized algorithms for some fundamental NP-hard problems, including MaxSAT, Maximum Internal Spanning Trees, Maximum Internal Out-Branching, Planar (Connected) Dominating Set, Feedback Vertex Set, Hyperplane Cover, Vertex Cover, Packing and Matching problems. All of these problems have been widely applied in various areas, such as Internet of Things, Wireless Sensor Networks, Artificial Intelligence, Bioinformatics, Big Data, and so on. In this paper, we are focused on the algorithms’ main idea and algorithmic techniques, and omit the details of them.
Tumor-associated collagen signatures: pushing tumor boundaries
Authors: Brett Elizabeth A. , Sauter Matthias A. , Machens Hans-Günther , Duscher Dominik
Published: July 2020

In 2006, a new model of invasive breast tumor emerged and, since 2011, is gaining recognition and research momentum. “Tumor-associated collagen signatures” describe 3 distinct layers of collagen which radiate outward in shells from the main body of the tumor. The outermost layer (TACS3) features branches of collagen radiating away from the tumor, 90° perpendicular to the tumor surface. TACS3 increases tumor span and correlates directly with metastasis, though presently difficult to detect in breast tissue. TACS is an emerging model but has been validated by multiple labs in vitro and in vivo, specifically for breast cancer prognostics. Newly recognized and accepted tumor borders will impact both R0 resections and downstream surgical reconstruction. This review aims to comprehensively introduce and connect the ranging literature on linearized collagen of invasive tumor borders. Using PubMed keyword searches containing “aligned,” “linear,” “oriented,” and “organized,” we have gathered the studies on TACS, integrated the concept into the clinic, and projected future platforms.
Quantitative patterns of motor cortex proteinopathy across ALS genotypes
Authors: Nolan Matthew , Scott Connor , Gamarallage Menuka Pallebage , Lunn Daniel , Carpenter Kilda , McDonough Elizabeth , Meyer Dan , Kaanumalle Sireesha , Santamaria-Pang Alberto , Turner Martin R. , Talbot Kevin , Ansorge Olaf
Published: July 2020

Degeneration of the primary motor cortex is a defining feature of amyotrophic lateral sclerosis (ALS), which is associated with the accumulation of microscopic protein aggregates in neurons and glia. However, little is known about the quantitative burden and pattern of motor cortex proteinopathies across ALS genotypes. We combined quantitative digital image analysis with multi-level generalized linear modelling in an independent cohort of 82 ALS cases to explore the relationship between genotype, total proteinopathy load and cellular vulnerability to aggregate formation. Primary motor cortex phosphorylated (p)TDP-43 burden and microglial activation were more severe in sporadic ALS-TDP disease than C9-ALS. Oligodendroglial pTDP-43 pathology was a defining feature of ALS-TDP in sporadic ALS, C9-ALS and ALS with OPTN, HNRNPA1 or TARDBP mutations. ALS-FUS and ALS-SOD1 showed less cortical proteinopathy in relation to spinal cord pathology than ALS-TDP, where pathology was more evenly spread across the motor cortex-spinal cord axis. Neuronal pTDP-43 aggregates were rare in GAD67+ and Parvalbumin+ inhibitory interneurons, consistent with predominant accumulation in excitatory neurons. Finally, we show that cortical microglia, but not astrocytes, contain pTDP-43. Our findings suggest divergent quantitative, genotype-specific vulnerability of the ALS primary motor cortex to proteinopathies, which may have implications for our understanding of disease pathogenesis and the development of genotype-specific therapies.
Performance estimate of some prototypes of inertial platform and strapdown marine gravimeters
Authors: Yuan Yuan , Gao Jinyao , Wu Zhaocai , Shen Zhongyan , Wu Guochao
Published: July 2020

Marine gravimeter has been proved to be the primary technique to efficiently obtain middle-to-short wavelength signals of the earth’s gravity field in geodesy, geodynamics and marine sciences research. In recent years, some prototypes of inertial platform and strapdown marine gravimeters have been developed, where the inertial platform gravimeter systems include CHZ-II and ZL11, and strapdown gravimeter systems include SAG-2M and SGA-WZ. In order to validate the performance of these marine gravimeter prototypes, a synchronous test with the widely used gravimeters GT-2M and LCR arranged on the same vessel was carried out in the north of South China Sea. All the data are processed according to the survey standard flow, and the performance is estimated by analyzing the errors of the repeat lines and the crossover points under the same environment. The compared results show that all the six gravimeters can meet the precision requirement of marine gravity survey. Meanwhile, the precision results of the improved gravimeters can get close to the precision of gravimeter GT-2M, higher than the precision gravimeter LCR.
Allometric models for estimating aboveground biomass in the tropical woodlands of Ghana, West Africa
Authors: Aabeyir Raymond , Adu-Bredu Stephen , Agyare Wilson Agyei , Weir Michael J. C.
Published: July 2020

Background

Modelling aboveground biomass (AGB) in forest and woodland ecosystems is critical for accurate estimation of carbon stocks. However, scarcity of allometric models for predicting AGB remains an issue that has not been adequately addressed in Africa. In particular, locally developed models for estimating AGB in the tropical woodlands of Ghana have received little attention. In the absence of locally developed allometric models, Ghana will continue to use Tier 1 biomass data through the application of pantropic models. Without local allometric models it is not certain how Ghana would achieve Tier 2 and 3 levels under the United Nations programme for reducing emissions from deforestation and forest degradation. The objective of this study is to develop a mixed-species allometric model for use in estimating AGB for the tropical woodlands in Ghana. Destructive sampling was carried out on 745 trees (as part of charcoal production) for the development of allometric equations. Diameter at breast height (dbh, i.e. 1.3 m above ground level), total tree height (H) and wood density (ρ) were used as predictors for the models. Seven models were compared and the best model selected based on model efficiency, bias (%) and corrected Akaike Information Criterion. The best model was validated by comparing its results with those of the pantropic model developed by Chave et al. (Glob Chang Biol 20:3177–3190, 2014) using equivalence test and conventional paired t-test.

Results

The results revealed that the best model for estimating AGB in the tropical woodlands is AGB = 0.0580ρ((dbh)2H)0.999. The equivalence test showed that this model and the pantropic model developed by Chave et al. (Glob Chang Biol 20:3177–3190, 2014) were equivalent within ±10% of their mean predictions (p-values < 0.0001 for one-tailed t-tests for both lower and upper bounds at 5% significant level), while the paired t-test revealed that the mean (181.44 ± 18.25 kg) of the model predictions of the best model of this study was significantly (n = 745, mean diff. = 16.50 ± 2.45 kg; S.E. = 1.25 kg; p < 0.001) greater than that (164.94 ± 15.82 kg) of the pantropic model of Chave et al. (Glob Chang Biol 20:3177–3190, 2014).

Conclusion

The model developed in this study fills a critical gap in estimating AGB in tropical woodlands in Ghana and other West African countries with similar ecological conditions. Despite the equivalence with the pantropic model it remains superior to the model of Chave et al. (Glob Chang Biol 20:3177–3190, 2014) for the estimation of AGB in local tropical woodlands. It is a relevant tool for the attainment of Tier 2 and 3 levels for REDD+. The model is recommended for use in the tropical woodlands in Ghana and other West African countries in place of the use of pantropic models.
Guidance on authorship with and acknowledgement of patient partners in patient-oriented research
Authors: Richards Dawn P. , Birnie Kathryn A. , Eubanks Kathleen , Lane Therese , Linkiewich Delane , Singer Lesley , Stinson Jennifer N. , Begley Kimberly N.
Published: July 2020

The Strategy for Patient-Oriented Research Chronic Pain Network was founded in 2016 and is a patient-oriented research network funded by the Canadian Institutes of Health Research. The Network incorporates patient partners throughout its governance and operations meaning that patient partners may contribute to research projects in ways that warrant scientific authorship as defined by the International Committee of Medical Journal Editors. The Network did a brief informal review of guidance on patient authorship in 2019, but could not find any practical documentation to guide its members on this topic. Note the term patient partner here refers to a patient (or caregiver or other person with lived experience) who is a partner or collaborator on a research team. This guidance does not address patients as participants in a research study.

This guidance has been co-written by a group of researchers and patient partners of the Chronic Pain Network in an effort to address this gap. It is intended for both researchers and patient partner audiences. This guidance is meant to facilitate conversations between researchers and patient partners about authorship and/or acknowledgement regarding research projects on which they collaborate. While the overall principles of academic authorship and acknowledgement remain unchanged, nuances for interpreting these principles through the lens of patient engagement or patient-oriented research is provided.

Teams that carry out patient-oriented research projects will require different preparation to empower all team members (researchers and patient partners) to discuss authorship and acknowledgement. To facilitate these conversations, we have included an overview of the scientific publishing process, explanation of some common terms, and sets of considerations are provided for both patient partners and researchers in determining the range of team member contribution from acknowledgement to authorship. Conversations about authorship can be difficult, even for established research teams. This guidance, and the resources discussed within it, are provided with the intention of making these conversations easier and more thoughtful.
Pluto gas field: Successful placement of an infill well based on 4D seismic monitoring
Authors: Peterson Benjamin , Gerhardt André
Published: July 2020

Seismic 4D monitoring technology has not been as widely employed for gas fields as it has for oil. Many gas fields rely on depletion drive, which has a 4D seismic response that can be uncertain and difficult to predict. On the other hand, aquifer-supported gas fields with measurable water ingress have a reasonable chance of success in terms of generating an interpretable 4D amplitude signal. Pluto gas field in the North West Shelf of Australia falls into this category. Following discovery in 2005, Pluto was appraised by five wells, which found a consistent gas gradient and gas-water contact across the entire field and its various reservoirs. Gas production began in 2012. Time-lapse seismic feasibility studies concluded that gas-saturation changes could be observed with a monitor seismic survey acquired three to four years after first gas. The Pluto 4D Monitor 1 survey was acquired at the start of 2016 and revealed both hardening and softening anomalies. Hardening is interpreted as water ingress (expected) and softening as gas expansion (unexpected). The Pluto 4D results provided important insights into reservoir connectivity and discontinuities. Large hardening anomalies at the TR27 (lower) level can be clearly seen in the data, showing avenues for water ingress. More importantly, a large softening anomaly below the original gas-water contact in the TR29 (upper) reservoir is interpreted to be gas expansion into the aquifer created by a U-tubing effect around a possible barrier in the gas leg. This suggests that the entire TR29 reservoir may not be accessed by the producing PLA04 well. Based on this 4D interpretation, the PLA07 well was drilled and completed in 2019 to produce the TR29 gas updip from the gas expansion anomaly and to increase Pluto field recovery.
A time-lapse seismic repeatability test using the P-Cable high-resolution 3D marine acquisition system
Authors: Smith Patrick , Mattox Brandon
Published: July 2020

The P-Cable high-resolution 3D marine acquisition system tows many short, closely separated streamers behind a small source. It can provide 3D seismic data of very high temporal and spatial resolution. Since the system is containerized and has small dimensions, it can be deployed at short notice and relatively low cost, making it attractive for time-lapse seismic reservoir monitoring. During acquisition of a 3D high-resolution survey in the Gulf of Mexico in 2014, a pair of sail lines were repeated to form a time-lapse seismic test. We processed these in 2019 to evaluate their geometric and seismic repeatability. Geometric repetition accuracy was excellent, with source repositioning errors below 10 m and bin-based receiver positioning errors below 6.25 m. Seismic data comparisons showed normalized root-mean-square difference values below 10% between 40 and 150 Hz. Refinements to the acquisition system since 2014 are expected to further improve repeatability of the low-frequency components. Residual energy on 4D difference seismic data was low, and timing stability was good. We conclude that the acquisition system is well suited to time-lapse seismic surveying in areas where the reservoir and time-lapse seismic signal can be adequately imaged by small-source, short-offset, low-fold data.
Repeat well logging using earthquake wave amplitudes measured by distributed acoustic sensors
Authors: Pevzner Roman , Gurevich Boris , Pirogova Anastasia , Tertyshnikov Konstantin , Glubokovskikh Stanislav
Published: July 2020

Well-based technologies for seismic subsurface monitoring increasingly utilize fiber-optic cables installed in boreholes as distributed acoustic sensing (DAS) systems. A DAS cable allows measuring linear strain of the fiber and can serve as an array of densely spaced seismic receivers. The strain amplitudes recorded by the DAS cable depend on the near-well formation properties (the softer the medium, the larger the strain). Thus, these properties can be estimated by measuring relative variations of the amplitudes of seismic waves propagating along the well. An advantage of such an approach to subsurface characterization and monitoring is that no active seismic source is required. Passive sources such as earthquakes can be utilized. A synthetic data example demonstrates viability of the approach for monitoring of small-scale CO2 injection into an aquifer. Two field DAS data examples based on signal recordings from several distant earthquakes show that the relevant properties of the near-well formation can be estimated with an accuracy of approximately 5%.
When self-harm is about preventing harm: emergency management of obsessive–compulsive disorder and associated self-harm
Authors: Palombini Erika , Richardson Joel , McAllister Emma , Veale David , Thomson Alex B.
Published: July 2020

Mental health staff may have limited exposure to emergencies associated with obsessive–compulsive disorder (OCD) during postgraduate training. The first time they encounter a person in the midst of severe obsessions, or one who has compulsively self-harmed in response to such obsessions, might be when working on call covering the emergency department. This educational article presents the lived experience of one of the authors as a clinical scenario. The scenario is then used to illustrate the severity of disability and the rates of self-harm and suicide-related mortality caused by OCD. The recognition and assessment of OCD is described, along with what helps in emergency situations. Written informed consent was obtained for the publication of clinical details.
Pyrotinib in HER2-Mutant Advanced Lung Adenocarcinoma After Platinum-Based Chemotherapy: A Multicenter, Open-Label, Single-Arm, Phase II Study
Authors: Zhou Caicun , Li Xingya , Wang Qiming , Gao Guanghui , Zhang Yiping , Chen Jianhua , Shu Yongqian , Hu Yanping , Fan Yun , Fang Jian , Chen Gongyan , Zhao Jun , He Jianxing , Wu Fengying , Zou Jianjun , Zhu Xiaoyu , Lin Xiang
Published: July 2020

PURPOSE

Targeted therapies against non–small-cell lung cancer (NSCLC) harboring HER2 mutations remain an unmet need. In this study, we assessed the efficacy and safety of pyrotinib in patients with HER2-mutant advanced NSCLC in a prospective, multicenter, open-label, single-arm, phase II study.

PATIENTS AND METHODS

Patients with stage IIIB or IV HER2-mutant lung adenocarcinoma who were previously treated with platinum-based chemotherapy were enrolled to receive pyrotinib at a dose of 400 mg/d for 21-day cycles. The primary end point was objective response rate per independent review committee (IRC).

RESULTS

Between October 20, 2016, and December 10, 2018, 60 patients received pyrotinib monotherapy. At baseline, 58 (96.7%) were stage IV, and 25 (41.7%) received at least 2 lines of prior chemotherapy. As of data cutoff on June 20, 2019, IRC-assessed objective response rate was 30.0% (95% CI, 18.8% to 43.2%). All subgroups of patients with different HER2 mutation types showed a favorable objective response rate. The objective response rates were similar between patients with and without brain metastases (25.0% v 31.3%). The median duration of response was 6.9 months (95% CI, 4.9 to 11.1 months). The median progression-free survival was 6.9 months (95% CI, 5.5 to 8.3 months) per IRC. The median overall survival was 14.4 months (95% CI, 12.3 to 21.3 months). Treatment-related adverse events of grade 3 or 4 occurred in 28.3% of patients, with the most common being diarrhea (20.0%; all grade 3). No treatment-related deaths were reported.

CONCLUSION

Pyrotinib showed promising antitumor activity and an acceptable safety profile in chemotherapy-treated patients with HER2-mutant NSCLC.
Landscape of Oncology Clinical Trials in Africa
Authors: Odedina Folakemi T. , Shamley Delva , Okoye Ifeoma , Ezeani Adaora , Ndlovu Ntokozo , Dei-Adomakoh Yvonne , Meza Kimberly , Agaba Ruth , Fathi Parisa , Askins Nissa
Published: July 2020

PURPOSE

The burden of cancer in Africa is of significant concern for several reasons, including that incidence of cancer in Africa continues to rise while Africa is also dealing with communicable diseases. To combat cancer in Africa, oncology clinical trials are needed to develop innovative interventions for cancer prevention, screening, diagnosis, treatment, and survivorship. Unfortunately, there is a paucity of clinical trials in Africa and it is difficult for African clinicians to get information on open oncology clinical trials and impossible for African patients with cancer to access this information. The primary objective of this study was to identify open oncology clinical trials in Africa.

METHODS

This project was part of a large-scale study to develop an African Virtual Platform for Oncology Clinical Trials Registry. The study was a quantitative, web-based, retrospective review of clinical trials registries.

RESULTS

A total of 109 open oncology clinical trials were identified. Most of the trials were in Egypt, South Africa, Algeria, and Kenya. The top cancer types for oncology clinical trials in Africa were breast, cervical, and lung cancers. The top sponsor of oncology clinical trials in Africa was academic institutions, especially institutions in the United States.

CONCLUSION

The paucity of clinical trials in Africa will continue to magnify the global disparities of cancer in the African population. Clinical trials are needed to ensure therapeutic interventions are safe and effective in the African population. In the era of personalized and precision health, it no longer suffices to assume that drugs developed in North America, Europe, or Asia will be effective in the African population.
Engaging Patients for Clinical Trials in Africa: Patient-Centered Approaches
Authors: Mutebi Miriam , Scroggins Dicey , Simons Virgil , Oti Naomi Ohene , Hammad Nazik
Published: July 2020

Clinical trials in oncology are an emergent field in sub-Saharan Africa. There is a long history of clinical trials in high-income countries (HICs), with increasing attempts to develop patient-centric approaches and to evaluate patient-centered outcomes. The challenge remains as to how these trends could be adopted in low-resource settings and adapted to best fit the different health ecosystems that coexist on the African continent. Models that evaluate patient-related outcomes and measures and that are used in HICs must be modified, adopted, and adapted to suit the diverse populations and the low-resource settings in most of the continent. Patient engagement in clinical trials in Africa must be well nuanced, and it demands innovation and application of models that consider established but tailored notions/principles of patient and community engagement and the unique sociocultural aspects of different populations. It also must be linked to strategies that aim to improve patient education, health literacy, and access to services and to encourage and protect patient autonomy.
Innovative Use of mHealth and Clinical Technology for Oncology Clinical Trials in Africa
Authors: Mutebi Miriam , Bhatia Rohini , Salako Omolola , Rubagumya Fidel , Grover Surbhi , Hammad Nazik
Published: July 2020

Utilization of clinical technology and mobile health (mHealth) is expanding globally. It is important to reflect on how their usage and application could translate in low- and middle-income country (LMIC) settings. With the exponential growth and advancements of mobile and wireless technologies, LMICs are prime to adapt such technologies to potentially democratize and create solutions to health-related challenges. The role of these technologies in oncology clinical trials continues to expand. The lure of mHealth promises disruptive technology that may change the way clinical trials are designed and conducted in many settings. Its applicability in the African context is currently under consideration. Although potentially of expanding benefit, the role of these technologies requires careful and nuanced evaluation of the context in which they might be applied to harness their full potential, while mitigating possible harms or preventing further deepening of disparities within populations. Moreover, technology and digital innovations are no substitute for poor referral pathways and dysfunctional health systems and can only complement or enhance definite strategies aimed at strengthening these health systems.
Saddle-Reset for Robust Parameter Estimation and Identifiability Analysis of Nonlinear Mixed Effects Models
Authors: Bjugård Nyberg Henrik , Hooker Andrew C. , Bauer Robert J. , Aoki Yasunori
Published: July 2020

Parameter estimation of a nonlinear model based on maximizing the likelihood using gradient-based numerical optimization methods can often fail due to premature termination of the optimization algorithm. One reason for such failure is that these numerical optimization methods cannot distinguish between the minimum, maximum, and a saddle point; hence, the parameters found by these optimization algorithms can possibly be in any of these three stationary points on the likelihood surface. We have found that for maximization of the likelihood for nonlinear mixed effects models used in pharmaceutical development, the optimization algorithm Broyden–Fletcher–Goldfarb–Shanno (BFGS) often terminates in saddle points, and we propose an algorithm, saddle-reset, to avoid the termination at saddle points, based on the second partial derivative test. In this algorithm, we use the approximated Hessian matrix at the point where BFGS terminates, perturb the point in the direction of the eigenvector associated with the lowest eigenvalue, and restart the BFGS algorithm. We have implemented this algorithm in industry standard software for nonlinear mixed effects modeling (NONMEM, version 7.4 and up) and showed that it can be used to avoid termination of parameter estimation at saddle points, as well as unveil practical parameter non-identifiability. We demonstrate this using four published pharmacometric models and two models specifically designed to be practically non-identifiable.
Postmodern Paper Tiger
Authors: Goodfield Eric
Published: July 2020

For most contemporary theorists, the death of postmodern thought as a theoretical impulse and critical divide has become a given. Yet, since the end of the 1990s a variety of important strands of social and political thought—queer theory, feminism, and postcolonialism to name but a few—have taken up and advanced poststructuralist emphases on language and discourse that are derivative of postmodern theory. In this context, the article considers two of the most central and original postmodern thinkers, Jean-François Lyotard and Jean Baudrillard, to illustrate the political entanglements of postmodern and liberal thought. Through this investigation the article illuminates the way these authors’ works on the political potencies of language raise important questions for the relevancy of poststructuralist political thought for contemporary critical thinking in the context of the global expanse of neoliberal capital. The article initiates an original dialogue between two poststructuralist authors and raises this to a second engagement with current debates over the crises of critical thought and, by extension, carries contemporary relevance as well.
Of Emptiness and Revolution
Authors: Huang Yiju
Published: July 2020

Lu Xun 魯迅 (1881–1936) has remained a most prominent figure in modern Chinese literary studies, but not so in modern Buddhism scholarship. This article shows the interlacing of Lu Xun's revolutionary vision with Buddhism on three primary terrains: his indebtedness to his teacher Zhang Taiyan 章太炎 (1868–1936), his immersion in a wide range of Buddhist texts before the May Fourth movement, and a close reading of selected poems from Yecao 野草 (Wild Grass) in light of Buddhist philosophy. The author argues that Yogācāra conceptions promoted by Zhang, wanfa weixin 萬法唯心 (all phenomena are nothing but mind), bushi 佈施 (the bodhisattva ideal of sacrificial giving), and kong 空 (emptiness as boundless potentiality), greatly influenced Lu Xun's aesthetics. Ultimately, this article shows how revolution, the dominant mode of secularism, is theistically conditioned. The Buddhist notion of emptiness, rather than an impediment to modernity, informs the worldly action of revolution and the phenomenal possibility of change.
The Failure of the May Fourth Movement and My Two Struggles
Authors: Zaifu Liu , Guo Yijiao
Published: July 2020

In this speech, Liu Zaifu thoroughly discusses the history of the May Fourth movement and the New Culture movement in the whole last century and the circumstances of humanity in China. In his explanation, May Fourth could be conceptualized through three different groups of concepts: the cultural May Fourth and the political May Fourth, the New Culture movement and the New Literature movement, and the masculine May Fourth and the feminine May Fourth. Liu regards the May Fourth spirit as a complete failure, in terms of six symbolic signs: (1) the mass spiritual suicide of Guo Moruo and the Creation Society, (2) the failure of humanity, (3) the elimination of individuality and personality, (4) the reversal of the enlightenment subject, (5) the devastation of the world vision, and (6) the failure of aesthetic practice. Liu also shares his two struggles. The first struggle in the 1980s was to reconstruct the subjectivity and dignity of people. After going abroad, he started the second struggle in exiling the gods, by which he endeavored to free himself from the four major spiritual chains: revolutionary thinking, the idolatry of nation, all the political ideologies, and dualistic thinking.
“Standing Alone atop the Mountain, Walking Freely under the Sea”
Authors: Wang David Der-wei
Published: July 2020

Liu Zaifu is one of the most influential critics in the New Era after the Cultural Revolution. His works, such as On Literary Subjectivity (1985) and A Treatise of Character Composition (1986), inspired a generation of Chinese youth yearning for intellectual breakthroughs. After June 4, 1989, however, Liu's life took unexpected twists and turns. He exiled himself overseas, finally settling down in the United States. In the ensuing three decades, he has produced dozens of books, articles, and essays, some of which—including Farwell to Revolution (1995)—have become instant classics. However, in terms of personal engagement and reflective intensity, his forthcoming Five Autobiographical Accounts outstrips his other, prior work. This article seeks to describe Liu's intellectual and personal adventures in light of his autobiography. The year 2019 marks the thirtieth anniversary of the June Fourth democracy movement, as well as Liu's self-exile; the seventieth anniversary of the founding of the People's Republic of China (1949); and most important, the centennial of the May Fourth movement (1919). Juxtaposed against one another, these dates compel us to reflect on the high hopes and bitter outcomes, grand projects and failed expectations, that informed China's century-long pursuit of modernity.
Neural crest cells require Meis2 for patterning the mandibular arch via the Sonic hedgehog pathway
Authors: Fabik Jaroslav , Kovacova Katarina , Kozmik Zbynek , Machon Ondrej
Published: July 2020

Cranial neural crest cells (cNCCs) originate in the anterior neural tube and populate pharyngeal arches in which they contribute to formation of bone and cartilage. This cell population also provides molecular signals for the development of tissues of non-neural crest origin, such as the tongue muscles, teeth enamel or gland epithelium. Here we show that the transcription factor Meis2 is expressed in the oral region of the first pharyngeal arch (PA1) and later in the tongue primordium. Conditional inactivation of Meis2 in cNCCs resulted in loss of Sonic hedgehog signalling in the oropharyngeal epithelium and impaired patterning of PA1 along the lateral–medial and oral–aboral axis. Failure of molecular specification of PA1, illustrated by altered expression of Hand1/2, Dlx5, Barx1, Gsc and other markers, led to hypoplastic tongue and ectopic ossification of the mandible. Meis2-mutant mice thus display craniofacial defects that are reminiscent of several human syndromes and patients with mutations in the Meis2 gene.
Post-traumatic osteoarthritis development is not modified by postnatal chondrocyte deletion of Ccn2
Authors: Keenan Craig M. , Ramos-Mucci Lorenzo , Kanakis Ioannis , Milner Peter I. , Leask Andrew , Abraham David , Bou-Gharios George , Poulet Blandine
Published: July 2020

CCN2 is a matricellular protein involved in several crucial biological processes. In particular, CCN2 is involved in cartilage development and in osteoarthritis. Ccn2 null mice exhibit a range of skeletal dysmorphisms, highlighting its importance in regulating matrix formation during development; however, its role in adult cartilage remains unclear. The aim of this study was to determine the role of CCN2 in postnatal chondrocytes in models of post-traumatic osteoarthritis (PTOA). Ccn2 deletion was induced in articular chondrocytes of male transgenic mice at 8 weeks of age. PTOA was induced in knees either surgically or non-invasively by repetitive mechanical loading at 10 weeks of age. Knee joints were harvested, scanned with micro-computed tomography and processed for histology. Sections were stained with Toluidine Blue and scored using the Osteoarthritis Research Society International (OARSI) grading system. In the non-invasive model, cartilage lesions were present in the lateral femur, but no significant differences were observed between wild-type (WT) and Ccn2 knockout (KO) mice 6 weeks post-loading. In the surgical model, severe cartilage degeneration was observed in the medial compartments, but no significant differences were observed between WT and Ccn2 KO mice at 2, 4 and 8 weeks post-surgery. We conclude that Ccn2 deletion in chondrocytes does not modify the development of PTOA in mice, suggesting that chondrocyte expression of CCN2 in adults is not a crucial factor in protecting cartilage from the degeneration associated with PTOA.

This article has an associated First Person interview with the first author of the paper.
How zebrafish turn: analysis of pressure force dynamics and mechanical work
Authors: Thandiackal Robin , Lauder George V.
Published: July 2020

Whereas many fish swim steadily, zebrafish regularly exhibit unsteady burst-and-coast swimming, which is characterized by repeated sequences of turns followed by gliding periods. Such a behavior offers the opportunity to investigate the hypothesis that negative mechanical work occurs in posterior regions of the body during early phases of the turn near the time of maximal body curvature. Here we use a modified Particle Image Velocimetry (PIV) technique to obtain high-resolution flow fields around the zebrafish body during turns. Using detailed swimming kinematics coupled with body surface pressure computations, we estimated fluid-structure interaction forces and the pattern of forces and torques along the body during turning. We then calculated the mechanical work done by each body segment. We used estimated patterns of positive and negative work along the body to evaluate the hypothesis (based on fish midline kinematics) that the posterior body region would experience predominantly negative work. Between 10 and 20% of the total mechanical work was done by the fluid on the body (negative work), and negative work was concentrated in the anterior and middle areas of the body, not along the caudal region. Energetic costs of turning were calculated by considering the sum of positive and negative work and were compared to previous metabolic estimates of turning energetics in fishes. The analytical workflow presented here provides a rigorous way to quantify hydrodynamic mechanisms of fish locomotion and facilitates the understanding how body kinematics generates locomotor forces in freely-swimming fishes.
Cinderella and Pandora’s box – Autoethnographic Reflections on My Early Career Research Trajectory between Australia and China
Authors: Lu Jinjin
Published: July 2020

In the last decade, the world has witnessed significant changes in terms of economic, educational, and cultural development both inside and outside China, creating valuable opportunities to better understand the cultural stereotypes Asians and Westerners have regarding each other. In this paper, I examine my immigrant experiences as a female, bilingual early-career researcher in multilingual and multicultural environments and my subsequent re-entry into China to work as a leading researcher within a span of ten years. My series of auto-ethnographic dialogues between a cast of characters, in which they recall experiences, perceptions, and emotions, provides readers with ample opportunities to actively respond to the text. Through this autoethnographic memoir and performance, I hope to contribute to new directions for narrative research in intercultural contexts.
’Oh, of course, one accepts the Gospels, naturally’: Subversive Use of the Bible in Graham Greene’s Monsignor Quixote
Authors: Valverde Beatriz
Published: July 2020

When Graham Greene wrote Monsignor Quixote (published in 1982), one of his aims was to reflect critically on the role of the Catholic Church in the Spain of the late 1970s, as well as on the support this institution offered to the former dictatorship of Franco within the so called ‘National Catholicism.’ In this novel, the reader witnesses the evolution of the protagonist, Father Quixote, from a religious living a complacent life in a small village in La Mancha to a priest in rebellion against the conservative hierarchy of the Catholic Church in Spain. Drawing upon Gerard Genette’s theory of transtextuality, I will examine Greene’s use of different religious texts to fight a model of conservative Catholic Church that he rejects. I will focus my analysis especially on the intertextual and metatextual references to the Gospels that the Bishop of La Mancha/Father Herrera and Father Quixote make in their dialogic interactions, references that portray their different vision of the role that the Church should have in society.
Scientific Educational Center – an Effective Form of Organization of Research in Continuous Technological Education
Authors: Tatko G.
Published: July 2020

The article identifies the problems of continuous technological education of the Moscow Region, describes the main directions of scientific research activity of the REC at the Department of Theory and Methods of Professional Education, Faculty of Technology and Entrepreneurship of Moscow Region State University, presents the results reflecting the positive dynamics of solving the set educational and research problems.
Is the Child Free in M. Montessori's Class?
Authors: Sumnitel'nyy K.
Published: July 2020

The article is devoted to the views of M. Montessori on the freedom of the child. It is already well known that she believed that freedom is not permissiveness. But how this principle is implemented and why in its system there is no conflict between freedom and discipline, which also distinguishes children in Montessori classes. What the ideas look like laying in Montessori's pedagogy in the context of modern psychology, which recognized that freedom is not an unambiguous and unquestioned value, and adaptation can be of a different nature and have different consequences.
Prospects for the Development of Artificial Intelligence in the Current Agenda of Political and Social Risks of Global Transformations
Authors: Bagdasaryan V. , Baldin P.
Published: July 2020

The purpose of this research was to identify political and social risks for humanity and Russia in connection with the development of artificial intelligence technologies. Methodologically, the research correlates with the direction of political scientific futurology. When identifying political risks of the development of artificial intelligence, the method of scenario forecasting is used. Based on the study of scientific literature and public discourse, the main positions in understanding the threats to the development of artificial intelligence for humanity are identified. In the course of the study, eleven possible groups of political and social risks were identified based on the analysis of various futurological models. The conclusion is made about the production of risks by the modern system of the world social structure, its contradictions and conflicts. It is emphasized that the need for developments in the field of artificial intelligence is due to the threats of falling behind potential opponents and competitors, which may mean the loss of Russia's sovereign status. The results of the research can be used as a basis for practical developments on the modernization of the national security system of Russia in connection with the actualization of the risks of the development of artificial intelligence technologies. In theoretical and methodological meaning the presented research can be used for further understanding of new technological realities and prospects through the prism of political science analysis.
The Oxford Marston and The Dutch Courtesan
Authors: Butler Martin
Published: July 2020

This paper situates the play in the context of the ongoing Complete Works of John Marston, under preparation for Oxford University Press, the first such collected critical edition ever to have been created. It discusses the edition’s aims and working practices as well as the new picture of Marston we expect to emerge from it. Scholars now often encounter The Dutch Courtesan in isolation, as Marston’s single best-known and most-read play. This paper approaches the play in the context of Marston’s career and publication history as a whole, in addition to the textual and theatrical relationships which work on the edition is gradually coming to disclose.
The Dutch Courtesan and 'The Soul of Lively Action'
Authors: Cordner Michael
Published: July 2020

The Dutch Courtesan has traditionally been the subject of critical interpretations which offer simplified accounts of both its overall design and its scene-by-scene complexities. This article charts some of the recurrent problems that have, in particular, affected scholarly accounts of the Freevill/Malheureux/Franceschina plot, which became apparent as the author worked on the play in production. The aim is to map more clearly some of the key givens of the script, but not to dictate performance outcomes, since the play is sufficiently rich to invite and to accommodate contrasting realizations on stage.
'Our hurtless mirth': What’s Funny about The Dutch Courtesan?
Authors: Julian Erin
Published: July 2020

This paper reflects on the performance work of the Toronto Dutch Courtesan to explore what is potentially funny in the play and how this comic potential might be used to explore inequities filtering through misogyny, religious intolerance, and xenophobia. Marston’s play operates in series of comic registers eliciting a range of emotional responses from audiences – from cruel laughter to cathartic pathos to light-hearted pleasure to anxiety. While the play’s critical and moral ‘point’ is impossible to pin down, the Toronto Courtesan demonstrated the capacity of the play’s comic ambiguity to critique social inequity and to invite audiences to ask reflectively: what are we laughing at and why?
Introduction: Strangers and Aliens in London ca 1605 -- Is Anyone Stranger than a London Gallant?
Authors: Ostovich Helen M.
Published: July 2020

This special issue on John Marston's The Dutch Courtesan illustrates the various tensions in London at the start of James I's reign. This city comedy deploys satire to urge its audience to see the anxiety and fears caused by misogyny, xenophobia, religious dissent, and contact with European foreigners, all of which create an alien environment infecting those who live in it. Each of the ten essays that make up the issue touches on these anxieties, or at least elements of strangeness that need arguing away or accepting as unresolvable in Marston's view of human nature.
Leslie Thomson. Discoveries on the Early Modern Stage: Contexts and Conventions. Cambridge: Cambridge University Press, 2018. Pp. 265.
Authors: Hamlet Jess
Published: July 2020

This review considers Discoveries on the Early Modern Stage: Contexts and Conventions.