bluuebunny/crossref_metadata_2025 huggingface dataset:
Mining-Induced Failure Criteria of Interactional Hard Roof Structures: A Case Study
Authors: Shen Wenlong , Wang Meng , Cao Zhengzheng , Su Faqiang , Nan Hua , Li Xuelong
Published: August 2019

Due to the additional abutment stress, interactional hard roof structures (IHRS) affect the normal operation of the coal production system in underground mining. The movement of IHRS may result in security problems, such as the failure of supporting body, large deformation, and even roof caving for nearby openings. According to the physical configuration and loading conditions of IHRS in a simple two-dimensional physical model under the plane stress condition, mining-induced failure criteria were proposed and validated by the mechanical behavior of IHRS in a mechanical analysis model. The results indicate that IHRS, consisting of three interactional parts—the lower key structure, the middle soft interlayer, and the upper key structure—are governed by the additional abutment stress induced by the longwall mining working face. The fracture of the upper key structure in IHRS can be explained as follows: Due to the crushing failure, lower key structure, and middle soft interlayer yield, the action force between the upper and lower key structures vanishes, resulting in fracture of the upper key structure in IHRS. In a field case, when additional abutment stress reaches 7.37 MPa, the energy of 2.35 × 105 J is generated by the fracture of the upper key structure in IHRS. Under the same geological and engineering conditions, the energy generated by IHRS is much larger than that generated by a single hard roof. The mining-induced failure criteria are successfully applied in a field case. The in-situ mechanical behavior of the openings nearby IHRS under the mining abutment stress can be clearly explained by the proposed criteria.
Empirical Conductivity Equation for the Simulation of the Stationary Space Charge Distribution in Polymeric HVDC Cable Insulations
Authors: Jörgens Christoph , Clemens Markus
Published: August 2019

Many processes are involved in the accumulation of space charges within the insulation materials of high voltage direct current (HVDC) cables, e.g., the local electric field, a conductivity gradient inside the insulation, and the injection of charges at both electrodes. An accurate description of the time dependent charge distribution needs to include these effects. Furthermore, using an explicit Euler method for the time integration of a suitably formulated transient model, low time steps are used to resolve fast charge dynamics and to satisfy the Courant–Friedrichs–Lewy (CFL) stability condition. The long lifetime of power cables makes the use of a final stationary charge distribution necessary to assess the reliability of the cable insulations. For an accurate description of the stationary space charge and electric field distribution, an empirical conductivity equation is developed. The bulk conductivity, found in literature, is extended with two sigmoid functions to represent a conductivity gradient near the electrodes. With this extended conductivity equation, accumulated bulk space charges and hetero charges are simulated. New introduced constants to specify the sigmoid functions are determined by space charge measurements, taken from the literature. The measurements indicate accumulated hetero charges in about one quarter of the insulation thickness in the vicinity of both electrodes. The simulation results conform well to published measurements and show an improvement to previously published models, i.e., the developed model shows a good approximation to simulate the stationary bulk and hetero charge distribution.
Transcriptomic Responses of Dove Tree (Davidia involucrata Baill.) to Heat Stress at the Seedling Stage
Authors: Liu Qinsong , Vetukuri Ramesh R. , Xu Wenjuan , Xu Xiao
Published: August 2019

The dove tree (Davidia involucrata Baill.), a tertiary relic species, is adapted to cool climates. With the progression of global warming, high-temperature stress has become the primary environmental factor restricting geographic distribution, ex situ conservation, and landscape application for D. involucrata resources. However, the detailed molecular events underlying D. involucrata responses to heat stress are poorly understood. Here, we conducted RNA-Seq-based gene expression profiling in D. involucrata seedlings during the time course of a 42 °C heat treatment (0, 1, 6, and 12 h). After de novo assembly, we obtained 138,923 unigenes, of which 69,743 were annotated in public databases. Furthermore, 19,532, 20,497 and 27,716 differentially expressed genes (DEGs) were identified after 1 h (HS1), 6 h (HS6), and 12 h (HS12) of heat treatment in comparison to 0 h (HS0), respectively. Based on a KEGG enrichment analysis, the two pathways “protein processing in endoplasmic reticulum” and “plant hormone signal transduction” are hypothesized to play vital roles during heat response in D. involucrata, and their potential interactions during heat stress are also discussed. In addition, 32 genes encoding putative heat shock transcription factors (Hsfs) were found to be associated with the response of D. involucrata to heat stress. Finally, the expression patterns of eight heat-responsive genes derived from qRT-PCR were in agreement with their transcript level alterations, as determined by a transcriptome analysis. Taken together, our transcriptomic data provide the first comprehensive transcriptional profile affected by heat stress in D. involucrata, which will facilitate further studies on the improvement of heat tolerance in this rare and endangered species.
Mount Taishan Forest Ecosystem Health Assessment Based on Forest Inventory Data
Authors: Meng Yan , Cao Banghua , Dong Chao , Dong Xiaofeng
Published: August 2019

Forest health is an important aspect of sustainable forest management. The practical significance of health assessments of forest ecosystems is becoming more and more prominent because good knowledge about the health level of forests and the causes of unhealthy forests enables the identification of proper actions for enhancing sustainable development of forest ecosystems. This paper evaluated the health status of the forest ecosystem of Mount Taishan using the spatial analysis technique of GIS (Geographic Information System) and local forest inventory data. A comprehensive indicator system that reflects the health status of forestsin the study areawas established. Based on this indicator system, the health level of each sub-compartment of the forests in the study area was assessed. The results show that the high-quality grade forest (80.4 ha) and healthy grade forest (2671 ha) accounted for only 23.5% of the total forest area of Mount Taishan. About 60.5% of Mount Taishan forest was in a sub-health status. The area of unhealthy forests was 1865 ha (accounting for 16% of the total forest area), of which about 98 ha was inextremely unhealthy conditions.Asmore than two-thirds of the forests in Mount Taishan are in a sub-health or unhealthy state, effective measures for improving forest health are in urgent need in the study area.
Enological Repercussions of Non-Saccharomyces Species in Wine Biotechnology
Authors: Morata Antonio
Published: August 2019

The use of non-Saccharomyces yeasts in enology has increased since the beginning of the current century because of the potential improvements they can produce in wine sensory quality [...]
Breed, Diet, and Interaction Effects on Adipose Tissue Transcriptome in Iberian and Duroc Pigs Fed Different Energy Sources
Authors: Benítez Rita , Trakooljul Nares , Núñez Yolanda , Isabel Beatriz , Murani Eduard , De Mercado Eduardo , Gómez-Izquierdo Emilio , García-Casco Juan , López-Bote Clemente , Wimmers Klaus , Óvilo Cristina
Published: August 2019

In this study, we analyzed the effects of breed, diet energy source, and their interaction on adipose tissue transcriptome in growing Iberian and Duroc pigs. The study comprised 29 Iberian and 19 Duroc males, which were kept under identical management conditions except the nutritional treatment. Two isoenergetic diets were used with 6% high oleic sunflower oil (HO) or carbohydrates (CH) as energy sources. All animals were slaughtered after 47 days of treatment at an average live weight of 51.2 kg. Twelve animals from each breed (six fed each diet) were employed for ham subcutaneous adipose tissue RNA-Seq analysis. The data analysis was performed using two different bioinformatic pipelines. We detected 837 and 1456 differentially expressed genes (DEGs) according to breed, depending on the pipeline. Due to the strong effect of breed on transcriptome, the effect of the diet was separately evaluated in the two breeds. We identified 207 and 57 DEGs depending on diet in Iberian and Duroc pigs, respectively. A joint analysis of both effects allowed the detection of some breed–diet interactions on transcriptome, which were inferred from RNA-Seq and quantitative PCR data. The functional analysis showed the enrichment of functions related to growth and tissue development, inflammatory response, immune cell trafficking, and carbohydrate and lipid metabolism, and allowed the identification of potential regulators. The results indicate different effects of diet on adipose tissue gene expression between breeds, affecting relevant biological pathways.
Joint RNA-Seq and miRNA Profiling Analyses to Reveal Molecular Mechanisms in Regulating Thickness of Pod Canopy in Brassica napus
Authors: Chen Zhiyou , Huo Qiang , Yang Hong , Jian Hongju , Qu Cunmin , Lu Kun , Li Jiana
Published: August 2019

Oilseed rape (Brassica napus) is the second largest oilseed crop worldwide. As an architecture component of B. napus, thickness of pod canopy (TPC) plays an important role in yield formation, especially under high-density cultivation conditions. However, the mechanisms underlying the regulation of TPC remain unclear. RNA and microRNA (miRNA) profiling of two groups of B. napus lines with significantly different TPC at the bolting with a tiny bud stage revealed differential expressions of numerous genes involved in nitrogen-related pathways. Expression of several nitrogen-related response genes, including ASP5, ASP2, ASN3, ATCYSC1, PAL2, APT2, CRTISO, and COX15, was dramatically changed in the thick TPC lines compared to those in the thin TPC lines. Differentially expressed miRNAs also included many involved in nitrogen-related pathways. Expression of most target genes was negatively associated with corresponding miRNAs, such as miR159, miR6029, and miR827. In addition, 12 (including miR319, miR845, and miR158) differentially expressed miRNAs between two plant tissues sampled (stem apex and flower bud) were identified, implying that they might have roles in determining overall plant architecture. These results suggest that nitrogen signaling may play a pivotal role in regulating TPC in B. napus.
Late Holocene Glacial Fluctuations of Schiaparelli Glacier at Monte Sarmiento Massif, Tierra del Fuego (54°24′ S)
Authors: Meier Wolfgang Jens-Henrik , Aravena Juan-Carlos , Grießinger Jussi , Hochreuther Philipp , Soto-Rogel Pamela , Zhu Haifeng , Pol-Holz Ricardo De , Schneider Christoph , Braun Matthias Holger
Published: August 2019

The Magallanes–Tierra del Fuego region, Southern Patagonia (53–56° S) features a plethora of fjords and remote and isolated islands, and hosts several thousand glaciers. The number of investigated glaciers with respect to the multiple Neoglacial advances is based on a few individual studies and is still fragmentary, which complicates the interpretation of the glacial dynamics in the southernmost part of America. Schiaparelli Glacier (54°24′ S, 70°50′ W), located at the western side of the Cordillera Darwin, was selected for tree-ring-based and radiocarbon dating of the glacial deposits. One focus of the study was to address to the potential dating uncertainties that arise by the use of Nothofagus spp. as a pioneer species. A robust analysis of the age–height relationship, missing the pith of the tree (pith offset), and site-specific ecesis time revealed a total uncertainty value of ±5–9 years. Three adjacent terminal moraines were identified, which increasingly tapered towards the glacier, with oldest deposition dates of 1749 ± 5 CE, 1789 ± 5 CE, and 1867 ± 5 CE. Radiocarbon dates of trunks incorporated within the terminal moraine system indicate at least three phases of cumulative glacial activity within the last 2300 years that coincide with the Neoglacial phases of the Southern Patagonian Icefield and adjacent mountain glaciers. The sub-recent trunks revealed the first evidence of a Neoglacial advance between ~600 BCE and 100 CE, which so far has not been substantiated in the Magallanes–Tierra del Fuego region.
Physical Activity and Quality of Life of Healthy Children and Patients with Hematological Cancers
Authors: Kowaluk Aleksandra , Woźniewski Marek , Malicka Iwona
Published: August 2019

The aim was to assess the level of physical activity and the quality of life of children undergoing cancer treatment, during and after the completion of the treatment. Eighty-eight children aged 11–15 were enrolled. Three groups of children were assessed, i.e., children undergoing cancer treatment (n = 30), children after cancer treatment (n = 28), and healthy children (n = 30). The level of physical activity in children was assessed using the questions from the Health Behavior in School-Aged Children (HBSC) questionnaire. The assessment of children’s quality of life was conducted using the KIDSCREEN-10 Index. The chi-square test was used to assess the statistical significance of the differences in the results between the study groups in the case of both HBSC and KIDSCREEN-10 questionnaires. Children undergoing cancer treatment did not perform any physical activity of at least 60 min (in total) per day, during the week. Therefore, they did not meet the recommendations related to the appropriate level of daily physical activity (Moderate-to-Vigorous Physical Activity; MVPA). Children after cancer treatment and healthy children significantly more frequently undertook physical activity. The quality of life of children with cancer is significantly lower and different from the quality of life of healthy children.
Costs of Hospitalization for Dementia in Urban China: Estimates from Two Urban Health Insurance Scheme Claims Data in Guangzhou City
Authors: Zhang Hui , Zhang Donglan , Yin Yujie , Zhang Chao , Huang Yixiang
Published: August 2019

Background: Dementia is one of the public health priorities in China. This study aimed to examine the hospitalization costs of patients with dementia and analyzed the factors associated with their inpatient costs. Methods: This was a prevalence-based, observational study using claims data derived from two urban insurance schemes during the period from 2008 through 2013 in Guangzhou. The extended estimating equations model was performed to identify the main drivers of total inpatient costs. Results: We identified 5747 dementia patients with an average age of 77.4. The average length of stay (LOS) was 24.2 days. The average hospitalization costs per inpatient was Chinese Yuan (CNY) 9169.0 (CNY 9169.0 = US$1479.8 in 2013). The mean inpatient costs for dementia patients with the Urban Employee-based Basic Medical Insurance (UEBMI) scheme (CNY 9425.0 = US$1521.1) were higher than those for patients with the Urban Resident-based Basic Medical Insurance scheme (CNY 7420.5 = US$1197.6) (p < 0.001). Having UEBMI coverage, dementia subtypes, having hypertension, being admitted in larger hospitals, and longer LOS were significantly associated with hospitalization costs of dementia. Conclusions: The costs of hospitalization for dementia were high and differed by types of insurance schemes. Dementia was associated with substantial hospitalization costs, mainly driven by insurance type and long LOS. These findings provided economic evidence for evaluating the burden of dementia in China.
Children Exposure-Related Behavior Patterns and Risk Perception Associated with Recreational Beach Use
Authors: Ferguson Alesia , Del Donno Courtney , Obeng-Gyasi Emmanuel , Mena Kristina , Kaur Altomare Tanu , Guerrero Rosalía , Gidley Maribeth , Montas Larissa , Solo-Gabriele Helena M.
Published: August 2019

Background: Oil spill chemicals (OSCs) result not only from the crude oil components but also from dispersants used in the clean-up activities, where some may result in adverse health effects under certain exposure and dosage conditions. One of the main populations of concern for exposure to OSCs are children, who are frequent beach users. Activities such as ingestion of and digging in sand can increase dermal and ingestion exposure. Longer times spent at the beach can also increase exposures for all routes. Objectives: The Beach Exposure and Child Health Study (BEaCHeS) was initiated to evaluate the risk of exposure to children from oil contaminants. Reported here are results for surveys collected, as a part of the project, to address exposure-related behavior patterns and risk perception for parents or guardians who visit the beach. Methods: Over 400 parental surveys were collected at four beaches, two in Miami and two in Texas, to evaluate children’s exposure related activities. Surveys consisted of three general sections: demographics, exposure, and risk perception. Surveys were analyzed in REDcap and Stata to evaluate demographic and regional differences on activities related to beach behavior and potential exposures to oil contaminants (e.g., how much time spent on beach, cleaning habits following beach activities). The statistical analysis included the mean and standard errors, along with regressions to evaluate associations between parameters. Results: Overall, the data showed high variability in how children play on the beach, influenced more by age and less by gender. Variations were also seen in certain variables by beach region (e.g., hygiene practices). By race, variations were seen in income, distance of travel to beach, and preferred method of communication for beach warning. Other important findings are reflected in the article. Discussion: The data presented here may prove useful for those evaluating children exposures to a variety of contaminants, chemical, or bacterial in origin. In addition, coastal managers may find the risk perception and general behaviors useful for planning and maintenance of beach areas.
Understanding the Chinese Hui Ethnic Minority’s Information Seeking on Cardiovascular Diseases: A Focus Group Study
Authors: Yang Lei , Mao Yuping , Jansz Jeroen
Published: August 2019

The Chinese Hui ethnic minority group is an Islamic minority. The Hui people comprise the third largest minority population in China and are widely distributed throughout the country. Previous research shows that the Hui had a higher prevalence of cardiovascular risk factors (CVRFs) than most other ethnic groups. Therefore, the availability of health information relating to these factors is especially important for the Hui minority’s preventive healthcare. They do, however, experience difficulties in obtaining health-related information. The current research aims to identify the needs of the Hui people on where and how they obtain cardiovascular disease (CVD) related information from the media and other sources. Six focus groups were conducted in Shenyang City. The results revealed that the participants relied on different sources to get advice about CVDs, of which the internet and television were the most prominent ones. The participants expressed a desire for credible and professional information from different sources and asked for mediated health communication programs specifically targeted at the Hui. In addition, the participants felt ignored by the Chinese mainstream media at large, which created barriers for them to get health information.
Public Perception of the Range of Roles Played by Professional Pharmacists
Authors: Majchrowska Anita , Bogusz Renata , Nowakowska Luiza , Pawlikowski Jakub , Piątkowski Włodzimierz , Wiechetek Michał
Published: August 2019

Background: Professional pharmacists should be directly involved in patient healthcare as members of therapeutic teams are not the only dispensers of medication. Public perceptions of the professional role of pharmacists is expressed through patients’ attitudes, trust, and expectations as health and illness consultants, or qualified retailers of medicines. This perception is influenced by numerous determinants, both health-related and social. Objective: This research intends to describe the range of social roles pharmacists play from the perspective of potential pharmacy customers/patients. Methods: The data presented in the article comes from cross-sectional survey-based research, undertaken in 2018, on a representative sample of 600 Polish adults. Results: Over-the-counter medication is purchased by almost all Polish adults, but they do not tend to ask for advice at pharmacies. Most respondents consider a pharmacist to be “a person qualified to sell medicines”, with some of the participants regarding pharmacists as “ordinary retailers”. A small number of respondents are interested in benefiting from pharmaceutical care, but the pharmacy is still perceived to be a point of purchase for medication. Conclusions: Respondents do not treat pharmacists as health advisors and reduce its role to that of dispensing medication. Sociodemographic variables have no significant effect on social perception of pharmacists.
Application of the Theory of Planned Behavior in Environmental Science: A Comprehensive Bibliometric Analysis
Authors: Si Hongyun , Shi Jian-gang , Tang Daizhong , Wen Shiping , Miao Wei , Duan Kaifeng
Published: August 2019

Since the theory of planned behavior (TPB) was proposed by Ajzen in 1985, it has attracted extensive interest and been widely applied worldwide. Although an increasing number of studies have employed the TPB in the domain of environmental science, there have been no attempts to retrospectively analyze existing articles. The current study aimed to holistically understand the application status of the TPB in environmental science from a knowledge domain visualization perspective. A total of 531 journal articles were obtained through the Scopus database to perform a bibliometric analysis and content analysis. The results showed that waste management, green consumption, climate and environment, saving and conservation, and sustainable transportation are the primary research topics; the United States (U.S.), Mainland China, the United Kingdom (UK), and Malaysia are the most productive countries/regions. Moreover, the cross-disciplinary situations, main source journals, and key articles were revealed. Furthermore, the extended factors, integrated theories, major methods, specific groups, and control variables of environmental science research using the TPB were elaborated and integrated into a comprehensive application framework. Constructive criticisms were ultimately discussed. The findings contribute in several ways to help relevant researchers learn about the application of TPB to environmental science and provide new insights and holistic references for further research on environment-related behavior.
Comment on Choi, Y.-J.; Choi, H.-B.; O’Donnell, M. Disaster Reintegration Model: A Qualitative Analysis on Developing Korean Disaster Mental Health Support Model. Int. J. Environ. Res. Public Health 2018, 15, 362
Authors: Allahbakhshi Kiyoumars , Jahangiri Katayoun , Khorasani-Zavareh Davoud
Published: August 2019

Recently, Choi et al. published an article in the International Journal of Environmental Research and Public Health, indicating that mental health disorders were experienced by disaster survivors in Korea. [...]
Assessment of River Water Quality Based on an Improved Fuzzy Matter-Element Model
Authors: Wang Yumin , Ran Weijian , Wu Lei , Wu Yifeng
Published: August 2019

In this paper, an improved fuzzy matter-element (IFME) method was proposed, which integrates the classical matter-element (ME) method, set pair analysis (SPA), and variable coefficient method (VCM). The method was applied to evaluate water quality of five monitor stations along Caoqiao River in Yixing city, Jiangsu Province, China. The levels of river water quality were determined according to fuzzy closeness degree. Compared with the traditional evaluation methods, the IFME method has several characteristics as follows: (i) weights were determined by the VCM method, which can reduce workload and overcome the adverse effects of abnormal values, (ii) membership degrees were defined by SPA, which can utilize monitored data more scientifically and comprehensively, and (iii) IFME is more suitable for seriously polluted rivers. Overall, these findings reinforce the notion that an integrated approach is essential for attaining scientific and objective assessment of river water quality.
Education and Training in Applied Remote Sensing in Africa: The ARCSSTE-E Experience
Authors: Agbaje Ganiyu , Alabi Omowumi , Offiong Etim
Published: August 2019

In Africa, there is growing knowledge regarding the use of data obtained by remote sensing and analysed while using Geographic Information Systems for solving myriad problems. The awareness has largely arisen through the efforts of the Programme on Space Applications (PSA) of the United Nations Office for Outer Space Affairs (UNOOSA), and the subsequent UN resolutions for the establishment of Regional Centres for Space Science and Technology Education, to train scientists and researchers in different thematic areas of space, including Remote Sensing/Geographic Information Systems (RS/GIS). The African Regional Centre for Space Science and Technology Education in English (ARCSSTE-E) is one of these regional centres. The Centre has successfully trained 474 professionals from 18 countries since its inception in 1998; about 14% of these trainees have been female. This paper highlights the training programmes of ARCSSTE-E from its inception, and discusses the potential areas of improvement with a focus on the RS/GIS area. In 2019, a survey was conducted on alumni of the Postgraduate Diploma (PGD) programme of ARCSSTE-E. Based on the analysis of their responses and the progression of the PGD programme to a new Masters programme in RS/GIS at the university, there is clear evidence regarding the impact of the UNOOSA-assisted capacity building programme on the work and career of alumni, which has already produced an appreciable number of trained personnel in developing countries in Africa.
Peroxisomes and Innate Immunity: Antiviral Response and Beyond
Authors: Ferreira Ana Rita , Marques Mariana , Ribeiro Daniela
Published: August 2019

Peroxisomes are ubiquitous organelles with well-defined functions in lipid and reactive oxygen species metabolism, having a significant impact on a large number of important diseases. Growing evidence points to them, in concert with mitochondria, as important players within the antiviral response. In this review we summarize and discuss the recent findings concerning the relevance of peroxisomes within innate immunity. We not only emphasize their importance as platforms for cellular antiviral signaling but also review the current information concerning their role in the control of bacterial infections. We furthermore review the recent data that pinpoints peroxisomes as regulators of inflammatory processes.
Optical Investigation of Action Potential and Calcium Handling Maturation of hiPSC-Cardiomyocytes on Biomimetic Substrates
Authors: Pioner Josè Manuel , Santini Lorenzo , Palandri Chiara , Martella Daniele , Lupi Flavia , Langione Marianna , Querceto Silvia , Grandinetti Bruno , Balducci Valentina , Benzoni Patrizia , Landi Sara , Barbuti Andrea , Ferrarese Lupi Federico , Boarino Luca , Sartiani Laura , Tesi Chiara , Mack David L. , Regnier Michael , Cerbai Elisabetta , Parmeggiani Camilla , Poggesi Corrado , Ferrantini Cecilia , Coppini Raffaele
Published: August 2019

Cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) are the most promising human source with preserved genetic background of healthy individuals or patients. This study aimed to establish a systematic procedure for exploring development of hiPSC-CM functional output to predict genetic cardiomyopathy outcomes and identify molecular targets for therapy. Biomimetic substrates with microtopography and physiological stiffness can overcome the immaturity of hiPSC-CM function. We have developed a custom-made apparatus for simultaneous optical measurements of hiPSC-CM action potential and calcium transients to correlate these parameters at specific time points (day 60, 75 and 90 post differentiation) and under inotropic interventions. In later-stages, single hiPSC-CMs revealed prolonged action potential duration, increased calcium transient amplitude and shorter duration that closely resembled those of human adult cardiomyocytes from fresh ventricular tissue of patients. Thus, the major contribution of sarcoplasmic reticulum and positive inotropic response to β-adrenergic stimulation are time-dependent events underlying excitation contraction coupling (ECC) maturation of hiPSC-CM; biomimetic substrates can promote calcium-handling regulation towards adult-like kinetics. Simultaneous optical recordings of long-term cultured hiPSC-CMs on biomimetic substrates favor high-throughput electrophysiological analysis aimed at testing (mechanistic hypothesis on) disease progression and pharmacological interventions in patient-derived hiPSC-CMs.
Flexible and Expedited Regulatory Review Processes for Innovative Medicines and Regenerative Medical Products in the US, the EU, and Japan
Authors: Nagai Sumimasa
Published: August 2019

Several expedited regulatory review projects for innovative drugs and regenerative medical products have been developed in the US, the EU, and Japan. Each regulatory agency has elaborated an original regulatory framework and adopted regulatory projects developed by the other regulatory agencies. For example, the Food and Drug Administration (FDA) first developed the breakthrough therapy designation, and then the Pharmaceuticals and Medical Devices Agency (PMDA) and European Medicines Agency (EMA) introduced the Sakigake designation and the priority medicines (PRIME) designation, respectively. In addition, the necessity of the product being first development in Japan is the original feature of the Sakigake designation, while actively supporting the development of advanced-therapy medicinal products (ATMPs) by academia or small/medium-sized sponsors is the original feature of the PRIME; these particular features are different from the breakthrough therapy designation in the US. In this review article, flexible and expedited review processes for new drugs, and cell and gene therapies in the US, the EU, and Japan are described. Moreover, all the drugs and regenerative medical products that were granted conditional approval or Sakigake designation in Japan are listed and analyzed herein.
Arabidopsis Trichome Contains Two Plasma Membrane Domains with Different Lipid Compositions Which Attract Distinct EXO70 Subunits
Authors: Kubátová Zdeňka , Pejchar Přemysl , Potocký Martin , Sekereš Juraj , Žárský Viktor , Kulich Ivan
Published: August 2019

Plasma membrane (PM) lipid composition and domain organization are modulated by polarized exocytosis. Conversely, targeting of secretory vesicles at specific domains in the PM is carried out by exocyst complexes, which contain EXO70 subunits that play a significant role in the final recognition of the target membrane. As we have shown previously, a mature Arabidopsis trichome contains a basal domain with a thin cell wall and an apical domain with a thick secondary cell wall, which is developed in an EXO70H4-dependent manner. These domains are separated by a cell wall structure named the Ortmannian ring. Using phospholipid markers, we demonstrate that there are two distinct PM domains corresponding to these cell wall domains. The apical domain is enriched in phosphatidic acid (PA) and phosphatidylserine, with an undetectable amount of phosphatidylinositol 4,5-bisphosphate (PIP2), whereas the basal domain is PIP2-rich. While the apical domain recruits EXO70H4, the basal domain recruits EXO70A1, which corresponds to the lipid-binding capacities of these two paralogs. Loss of EXO70H4 results in a loss of the Ortmannian ring border and decreased apical PA accumulation, which causes the PA and PIP2 domains to merge together. Using transmission electron microscopy, we describe these accumulations as a unique anatomical feature of the apical cell wall—radially distributed rod-shaped membranous pockets, where both EXO70H4 and lipid markers are immobilized.
Nanomaterials as Promising Alternative in the Infection Treatment
Authors: Vallet-Regí María , González Blanca , Izquierdo-Barba Isabel
Published: August 2019

Both the prevalence of antibiotic resistance and the increased biofilm-associated infections are boosting the demand for new advanced and more effective treatment for such infections. In this sense, nanotechnology offers a ground-breaking platform for addressing this challenge. This review shows the current progress in the field of antimicrobial inorganic-based nanomaterials and their activity against bacteria and bacterial biofilm. Herein, nanomaterials preventing the bacteria adhesion and nanomaterials treating the infection once formed are presented through a classification based on their functionality. To fight infection, nanoparticles with inherent antibacterial activity and nanoparticles acting as nanovehicles are described, emphasizing the design of the carrier nanosystems with properties targeting the bacteria and the biofilm.
Posttranscriptional Regulation of RhBRC1 (Rosa hybrida BRANCHED1) in Response to Sugars is Mediated via its Own 3′ Untranslated Region, with a Potential Role of RhPUF4 (Pumilio RNA-Binding Protein Family)
Authors: Wang Ming , Ogé Laurent , Voisine Linda , Perez-Garcia Maria-Dolores , Jeauffre Julien , Hibrand Saint-Oyant Laurence , Grappin Philippe , Hamama Latifa , Sakr Soulaiman
Published: August 2019

The shoot branching pattern is a determining phenotypic trait throughout plant development. During shoot branching, BRANCHED1 (BRC1) plays a master regulator role in bud outgrowth, and its transcript levels are regulated by various exogenous and endogenous factors. RhBRC1 (the homologous gene of BRC1 in Rosa hybrida) is a main branching regulator whose posttranscriptional regulation in response to sugar was investigated through its 3′UTR. Transformed Rosa calluses containing a construction composed of the CaMV35S promoter, the green fluorescent protein (GFP) reporter gene, and the 3′UTR of RhBRC1 (P35S:GFP::3′UTRRhBRC1) were obtained and treated with various combinations of sugars and with sugar metabolism effectors. The results showed a major role of the 3′UTR of RhBRC1 in response to sugars, involving glycolysis/the tricarboxylic acid cycle (TCA) and the oxidative pentose phosphate pathway (OPPP). In Rosa vegetative buds, sequence analysis of the RhBRC1 3′UTR identified six binding motifs specific to the Pumilio/FBF RNA-binding protein family (PUF) and probably involved in posttranscriptional regulation. RhPUF4 was highly expressed in the buds of decapitated plants and in response to sugar availability in in-vitro-cultured buds. RhPUF4 was found to be close to AtPUM2, which encodes an Arabidopsis PUF protein. In addition, sugar-dependent upregulation of RhPUF4 was also found in Rosa calluses. RhPUF4 expression was especially dependent on the OPPP, supporting its role in OPPP-dependent posttranscriptional regulation of RhBRC1. These findings indicate that the 3′UTR sequence could be an important target in the molecular regulatory network of RhBRC1 and pave the way for investigating new aspects of RhBRC1 regulation.
Glial Dysfunction in MeCP2 Deficiency Models: Implications for Rett Syndrome
Authors: Kahanovitch Uri , Patterson Kelsey C. , Hernandez Raymundo , Olsen Michelle L.
Published: August 2019

Rett syndrome (RTT) is a rare, X-linked neurodevelopmental disorder typically affecting females, resulting in a range of symptoms including autistic features, intellectual impairment, motor deterioration, and autonomic abnormalities. RTT is primarily caused by the genetic mutation of the Mecp2 gene. Initially considered a neuronal disease, recent research shows that glial dysfunction contributes to the RTT disease phenotype. In the following manuscript, we review the evidence regarding glial dysfunction and its effects on disease etiology.
Protein Phosphatase Ppz1 Is Not Regulated by a Hal3-Like Protein in Plant Pathogen Ustilago maydis
Authors: Zhang Chunyi , de la Torre Antonio , Pérez-Martín José , Ariño Joaquín
Published: August 2019

Ppz enzymes are type-1 related Ser/Thr protein phosphatases that are restricted to fungi. In S. cerevisiae and other fungi, Ppz1 is involved in cation homeostasis and is regulated by two structurally-related inhibitory subunits, Hal3 and Vhs3, with Hal3 being the most physiologically relevant. Remarkably, Hal3 and Vhs3 have moonlighting properties, as they participate in an atypical heterotrimeric phosphopantothenoyl cysteine decarboxylase (PPCDC), a key enzyme for Coenzyme A biosynthesis. Here we identify and functionally characterize Ppz1 phosphatase (UmPpz1) and its presumed regulatory subunit (UmHal3) in the plant pathogen fungus Ustilago maydis. UmPpz1 is not an essential protein in U. maydis and, although possibly related to the cell wall integrity pathway, is not involved in monovalent cation homeostasis. The expression of UmPpz1 in S. cerevisiae Ppz1-deficient cells partially mimics the functions of the endogenous enzyme. In contrast to what was found in C. albicans and A. fumigatus, UmPpz1 is not a virulence determinant. UmHal3, an unusually large protein, is the only functional PPCDC in U. maydis and, therefore, an essential protein. However, when overexpressed in U. maydis or S. cerevisiae, UmHal3 does not reproduce Ppz1-inhibitory phenotypes. Indeed, UmHal3 does not inhibit UmPpz1 in vitro (although ScHal3 does). Therefore, UmHal3 might not be a moonlighting protein.
Activity Coefficients for Liquid Organic Reactions: Towards a Better Understanding of True Kinetics with the Synthesis of Jasmin Aldehyde as Showcase
Authors: Heynderickx Philippe M.
Published: August 2019

The aldol condensation of benzaldehyde and heptanal is taken as an example of reversible liquid phase organic reactions to show that inclusion of activity coefficients reveal distinct differences in conversion and product distribution when different solvents methanol, ethanol, n-propanol, or n-butanol are used. The purpose of this work is to show a pronounced solvent effect for a given set of identical kinetic parameters, i.e., the same liquid phase kinetics can result in different conversion and yield values, depending on the choice of solvent. It was shown that subsequent parameter estimation without inclusion of the activity coefficients resulted in a pronounced deviation from the ‘true’ kinetics, up to a factor of 30. It is proposed that the usage of average activity coefficients gives already a significant improvement, resulting in acceptable parameter estimates.
Anti-Proliferative and Pro-Apoptotic Effects of Licochalcone A through ROS-Mediated Cell Cycle Arrest and Apoptosis in Human Bladder Cancer Cells
Authors: Hong Su , Cha Hee-Jae , Hwang-Bo Hyun , Kim Min , Kim So , Ji Seon , Cheong JaeHun , Park Cheol , Lee Hyesook , Kim Gi-Young , Moon Sung-Kwon , Yun Seok , Chang Young-Chae , Kim Wun-Jae , Choi Yung
Published: August 2019

Licochalcone A (LCA) is a chalcone that is predominantly found in the root of Glycyrrhiza species, which is widely used as an herbal medicine. Although previous studies have reported that LCA has a wide range of pharmacological effects, evidence for the underlying molecular mechanism of its anti-cancer efficacy is still lacking. In this study, we investigated the anti-proliferative effect of LCA on human bladder cancer cells, and found that LCA induced cell cycle arrest at G2/M phase and apoptotic cell death. Our data showed that LCA inhibited the expression of cyclin A, cyclin B1, and Wee1, but increased the expression of cyclin-dependent kinase (Cdk) inhibitor p21WAF1/CIP1, and increased p21 was bound to Cdc2 and Cdk2. LCA activated caspase-8 and -9, which are involved in the initiation of extrinsic and intrinsic apoptosis pathways, respectively, and also increased caspase-3 activity, a typical effect caspase, subsequently leading to poly (ADP-ribose) polymerase cleavage. Additionally, LCA increased the Bax/Bcl-2 ratio, and reduced the integrity of mitochondria, which contributed to the discharge of cytochrome c from the mitochondria to the cytoplasm. Moreover, LCA enhanced the intracellular levels of reactive oxygen species (ROS); however, the interruption of ROS generation using ROS scavenger led to escape from LCA-mediated G2/M arrest and apoptosis. Collectively, the present data indicate that LCA can inhibit the proliferation of human bladder cancer cells by inducing ROS-dependent G2/M phase arrest and apoptosis.
Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC)
Authors: Hsu Ping-Chih , Jablons David M. , Yang Cheng-Ta , You Liang
Published: August 2019

The epidermal growth factor receptor (EGFR) pathway is a well-studied oncogenic pathway in human non-small cell lung cancer (NSCLC). A subset of advanced NSCLC patients (15–55%) have EGFR-driven mutations and benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) targeting the PD-1/PDL-1 axis are a new anti-cancer therapy for metastatic NSCLC. The anti-PD-1/PDL-1 ICIs showed promising efficacy (~30% response rate) and improved the survival of patients with metastatic NSCLC, but the role of anti-PD-1/PDL-1 ICIs for EGFR mutant NSCLC is not clear. YAP (yes-associated protein) is the main mediator of the Hippo pathway and has been identified as promoting cancer progression, drug resistance, and metastasis in NSCLC. Here, we review recent studies that examined the correlation between the EGFR, YAP pathways, and PD-L1 and demonstrate the mechanism by which EGFR and YAP regulate PD-L1 expression in human NSCLC. About 50% of EGFR mutant NSCLC patients acquire resistance to EGFR-TKIs without known targetable secondary mutations. Targeting YAP therapy is suggested as a potential treatment for NSCLC with acquired resistance to EGFR-TKIs. Future work should focus on the efficacy of YAP inhibitors in combination with immune checkpoint PD-L1/PD-1 blockade in EGFR mutant NSCLC without targetable resistant mutations.
Liquid Biopsy as a Tool for Differentiation of Leiomyomas and Sarcomas of Corpus Uteri
Authors: Dvorská Dana , Škovierová Henrieta , Braný Dušan , Halašová Erika , Danková Zuzana
Published: August 2019

Utilization of liquid biopsy in the management of cancerous diseases is becoming more attractive. This method can overcome typical limitations of tissue biopsies, especially invasiveness, no repeatability, and the inability to monitor responses to medication during treatment as well as condition during follow-up. Liquid biopsy also provides greater possibility of early prediction of cancer presence. Corpus uteri mesenchymal tumors are comprised of benign variants, which are mostly leiomyomas, but also a heterogenous group of malignant sarcomas. Pre-surgical differentiation between these tumors is very difficult and the final description of tumor characteristics usually requires excision and histological examination. The leiomyomas and malignant leiomyosarcomas are especially difficult to distinguish and can, therefore, be easily misdiagnosed. Because of the very aggressive character of sarcomas, liquid biopsy based on early diagnosis and differentiation of these tumors would be extremely helpful. Moreover, after excision of the tumor, liquid biopsy can contribute to an increased knowledge of sarcoma behavior at the molecular level, especially on the formation of metastases which is still not well understood. In this review, we summarize the most important knowledge of mesenchymal uterine tumors, the possibilities and benefits of liquid biopsy utilization, the types of molecules and cells that can be analyzed with this approach, and the possibility of their isolation and capture. Finally, we review the typical abnormalities of leiomyomas and sarcomas that can be searched and analyzed in liquid biopsy samples with the final aim to pre-surgically differentiate between benign and malignant mesenchymal tumors.
Biochemistry of Copper Site Assembly in Heme-Copper Oxidases: A Theme with Variations
Authors: Llases María-Eugenia , Morgada Marcos N. , Vila Alejandro J.
Published: August 2019

Copper is an essential cofactor for aerobic respiration, since it is required as a redox cofactor in Cytochrome c Oxidase (COX). This ancient and highly conserved enzymatic complex from the family of heme-copper oxidase possesses two copper sites: CuA and CuB. Biosynthesis of the oxidase is a complex, stepwise process that requires a high number of assembly factors. In this review, we summarize the state-of-the-art in the assembly of COX, with special emphasis in the assembly of copper sites. Assembly of the CuA site is better understood, being at the same time highly variable among organisms. We also discuss the current challenges that prevent the full comprehension of the mechanisms of assembly and the pending issues in the field.
The Activation Status of the TGF-β Transducer Smad2 Is Associated with a Reduced Survival in Gastrointestinal Cancers: A Systematic Review and Meta-Analysis
Authors: Girolami Ilaria , Veronese Nicola , Smith Lee , Caruso Maria G. , Reddavide Rosa , Leandro Gioacchino , Demurtas Jacopo , Nottegar Alessia
Published: August 2019

Aberrant function of Smad2, a crucial member of transforming growth factor beta (TGF-β) signaling, is associated with the development of malignancies, particularly in the gastrointestinal district. However, little is known about its possible prognostic role in such tumor types. With the first meta-analysis on this topic, we demonstrated that the lack of the activated form of Smad2 (phosphor-Smad2 or pSmad2), which was meant to be the C-terminally phosphorylated form, showed a statistically significant association with an increased risk of all-cause mortality in patients with gastrointestinal cancers (RR, 1.58; 95% CI, 1.05–2.37, p = 0.029, I2 = 84%), also after having adjusted for potential confounders (RR, 1.65; 95% CI, 1.24–2.18; p < 0.001; I2 = 4%). This finding highlights the importance of the TGF-β signaling in this type of cancer. In this line, further studies are needed to explore more in depth this important molecular pathway, focusing also on potential therapeutic strategies based on its effectors or molecular targets.
Activities and Operations with Cryptocurrencies and Their Taxation Implications: The Spanish Case
Authors: Náñez Alonso Sergio Luis
Published: August 2019

The purpose of this article was to attempt to shed light on the taxation of activities or actions related to cryptocurrencies. For this purpose, a small analysis was carried out on the nature, operation, and characteristics of cryptocurrencies. Subsequently, from the point of view of the Spanish tax system, the tax implications of the use, actions, and operations carried out with this virtual medium were discussed. The most recent information derived from the binding inquiries issued by the general directorate of taxes in Spain, an institution under the Ministry of Finance, was reviewed. This article analyzed whether the activities related to Bitcoin should be declared for the purposes of personal income tax, property tax, inheritance tax and finally, in the tax on transmissions of assets and documented legal acts. Finally, special mention was made of activities, such as the mining of Bitcoins in “Bitcoin farms” and the exploitation of websites for buying and selling cryptocurrencies and vending machines. Other collateral situations were also analyzed, such as the system to be used.