bluuebunny/crossref_metadata_2025 huggingface dataset:
Genotypic Variation in Nickel Accumulation and Translocation and Its Relationships with Silicon, Phosphorus, Iron, and Manganese among 72 Major Rice Cultivars from Jiangsu Province, China
Authors: Wang Ya , Shi Chengqiao , Lv Kang , Li Youqing , Cheng Jinjin , Chen Xiaolong , Fang Xianwen , Yu Xiangyang
Published: September 2019

Nickel (Ni) is a ubiquitous environmental toxicant and carcinogen, and rice is a major dietary source of Ni for the Chinese population. Recently, strategies to decrease Ni accumulation in rice have received considerable attention. This study investigated the variation in Ni accumulation and translocation, and also multi-element (silicon (Si), phosphorus (P), iron (Fe), and manganese (Mn)) uptake and transport among 72 rice cultivars from Jiangsu Province, China, that were grown under hydroponic conditions. Our results showed a 2.2-, 4.2-, and 5.3-fold variation in shoot Ni concentrations, root Ni concentrations, and translocation factors (TFs) among cultivars, respectively. This suggests that Ni accumulation and translocation are significantly influenced by the genotypes of the different rice cultivars. Redundancy analysis of the 72 cultivars revealed that the uptake and transport of Ni were more similar to those of Si and Fe than to those of P and Mn. The Ni TFs of high-Ni cultivars were significantly greater than those of low-Ni cultivars (p < 0.001). However, there were no significant differences in root Ni concentrations of low-Ni and high-Ni cultivars, suggesting that high-Ni cultivars could translocate Ni to shoots more effectively than low-Ni cultivars. In addition, the cultivars HD8 and YD8 exhibited significantly lower levels of Ni accumulation than their parents (p < 0.05). Our results suggest that breeding can be an effective strategy for mitigating excessive Ni accumulation in rice grown in Ni-contaminated environments.
Acute Health Impacts of the Southeast Asian Transboundary Haze Problem—A Review
Authors: Cheong Kang Hao , Ngiam Nicholas Jinghao , Morgan Geoffrey G. , Pek Pin Pin , Tan Benjamin Yong-Qiang , Lai Joel Weijia , Koh Jin Ming , Ong Marcus Eng Hock , Ho Andrew Fu Wah
Published: September 2019

Air pollution has emerged as one of the world’s largest environmental health threats, with various studies demonstrating associations between exposure to air pollution and respiratory and cardiovascular diseases. Regional air quality in Southeast Asia has been seasonally affected by the transboundary haze problem, which has often been the result of forest fires from “slash-and-burn” farming methods. In light of growing public health concerns, recent studies have begun to examine the health effects of this seasonal haze problem in Southeast Asia. This review paper aims to synthesize current research efforts on the impact of the Southeast Asian transboundary haze on acute aspects of public health. Existing studies conducted in countries affected by transboundary haze indicate consistent links between haze exposure and acute psychological, respiratory, cardiovascular, and neurological morbidity and mortality. Future prospective and longitudinal studies are warranted to quantify the long-term health effects of recurrent, but intermittent, exposure to high levels of seasonal haze. The mechanism, toxicology and pathophysiology by which these toxic particles contribute to disease and mortality should be further investigated. Epidemiological studies on the disease burden and socioeconomic cost of haze exposure would also be useful to guide policy-making and international strategy in minimizing the impact of seasonal haze in Southeast Asia.
Emergency Care for Women Irregular Migrants Who Arrive in Spain by Small Boat: A Qualitative Study
Authors: López-Domene Esperanza , Granero-Molina José , Fernández-Sola Cayetano , Hernández-Padilla José Manuel , López-Rodríguez María del Mar , Fernández-Medina Isabel María , Guerra-Martín Maria Dolores , Jiménez-Lasserrrotte María del Mar
Published: September 2019

Background: this study aimed to describe and understand the experiences and health needs of women irregular migrants during emergency care provision upon arrival in Spain by small boat. Methods: a qualitative study based on Gadamer’s phenomenology was used. The data collection included 13 in-depth interviews with women irregular migrants and 10 in-depth interviews with key informants. The study took place in the Spanish Red Cross’ facilities between February 2017 and April 2018. Results: two main themes emerged from the data analysis: the need for emergency care focused on women irregular migrants with the sub-themes ‘Women irregular migrants as objects of sexual exploitation’ and ‘The mother-child dyad as the axis in human trafficking’; and developing an emergency care gender policy for women irregular migrants, with the subthemes ‘Healthcare in a police-controlled setting: detecting weaknesses’ and ‘Promoting screening and safety protocols focused on women irregular migrants’. Conclusions: women irregular migrants who arrive in Spain by small boat have specific needs and healthcare problems. Due to strict safety conditions during emergency care provision, rape and human trafficking can go unnoticed. Implications: interdisciplinary care protocols and new health policies that have a gender perspective are needed to improve the emergency care provided to women irregular migrants.
What Is the Experience of Practitioners in Health, Education or Social Care Roles Following a Death by Suicide? A Qualitative Research Synthesis
Authors: Causer Hilary , Muse Kate , Smith Jo , Bradley Eleanor
Published: September 2019

Recent research has highlighted that the number of people impacted by a death by suicide is far greater than previously estimated and includes wider networks beyond close family members. It is important to understand the ways in which suicide impacts different groups within these wider networks so that safe and appropriate postvention support can be developed and delivered. A systematic review in the form of a qualitative research synthesis was undertaken with the aim of addressing the question ‘what are the features of the experiences of workers in health, education or social care roles following the death by suicide of a client, patient, student or service user?’ The analysis developed three categories of themes, ‘Horror, shock and trauma’, ‘Scrutiny, judgement and blame’, and ‘Support, learning and living with’. The mechanisms of absolution and incrimination were perceived to impact upon practitioners’ experiences within social and cultural contexts. Practitioners need to feel prepared for the potential impacts of a suicide and should be offered targeted postvention support to help them in processing their responses and in developing narratives that enable continued safe practice. Postvention responses need to be contextualised socially, culturally and organisationally so that they are sensitive to individual need.
Neural Classification of Compost Maturity by Means of the Self-Organising Feature Map Artificial Neural Network and Learning Vector Quantization Algorithm
Authors: Boniecki Piotr , Idzior-Haufa Małgorzata , Pilarska Agnieszka , Pilarski Krzysztof , Kolasa-Wiecek Alicja
Published: September 2019

Self-Organising Feature Map (SOFM) neural models and the Learning Vector Quantization (LVQ) algorithm were used to produce a classifier identifying the quality classes of compost, according to the degree of its maturation within a period of time recorded in digital images. Digital images of compost at different stages of maturation were taken in a laboratory. They were used to generate an SOFM neural topological map with centres of concentration of the classified cases. The radial neurons on the map were adequately labelled to represent five suggested quality classes describing the degree of maturation of the composted organic matter. This enabled the creation of a neural separator classifying the degree of compost maturation based on easily accessible graphic information encoded in the digital images. The research resulted in the development of original software for quick and easy assessment of compost maturity. The generated SOFM neural model was the kernel of the constructed IT system.
Adsorption of Malachite Green with Sodium Dodecylbenzene Sulfonate Modified Sepiolite: Characterization, Adsorption Performance and Regeneration
Authors: Yu Jian , Zhang Lirong , Liu Bin
Published: September 2019

The adsorption of malachite green (MG) onto sodium dodecylbenzene sulfonate (SDBS)-modified sepiolite was investigated with respect to pH, oscillation rate, MG dosage and adsorbent dosage. The modification condition and modified sepiolite characterization were examined. The conditions of 100% cation exchange capacity (CEC), pH value of 9, contact time of 60 min and 25 °C were deemed as the optimal conditions. The interlayer spacing of sepiolite was expanded and the surface hydrophobicity improved due to the entering of SDBS into the interlayer structure of the sepiolite ore. This is probably the reason for its adsorption enhancement. The adsorption of malachite green by organic sepiolite is in line with the quasi-secondary kinetic model. The results from the regeneration procedure suggest that a superior regeneration property obtained with 0.2 mol/L HCl concentration.
Multi-Service Programs for Pregnant and Parenting Women with Substance Use Concerns: Women’s Perspectives on Why They Seek Help and Their Significant Changes
Authors: Hubberstey Carol , Rutman Deborah , Schmidt Rose A. , Van Bibber Marilyn , Poole Nancy
Published: September 2019

Within Canada, several specialized multi-service prevention programs work with highly vulnerable pregnant and early parenting women with substance use issues. Experiences of trauma, mental health, poverty, and other factors associated with the social determinants of health complete the picture. Program evaluations have demonstrated their value, but less has been said as to women’s reasons for choosing to seek help from these programs, what they were hoping to gain, or what difference they believe has occurred as a result. The Co-creating Evidence project is a multi-year (2017–2020) national evaluation of holistic programs serving women at high risk of having an infant with prenatal alcohol or substance exposure. The evaluation uses a mixed methods design involving quarterly program output and “snapshot” client data, as well as in-person, semi-structured interviews and questionnaires with clients, program staff, and program partners. This article presents findings from interviews with women regarding why they sought help, how they used the services, and what they perceived to be the most significant change in their lives as a result. Obtaining help with substance use was the top theme for what women hoped to get from their participation in their program; however, women’s reasons were often intertwined. Additional motivations included wanting information, support or assistance with: child welfare; pregnancy; housing; getting connected to health care or prenatal care; and opportunities for peer support. With respect to the most significant life change, themes included: reduced substance use; improved housing; stronger mother–child connection; and improved wellness and social connections. Findings demonstrated that vulnerable, marginalized pregnant and parenting women who are using substances will seek help when health and social care services are configured in such a way as to take into consideration and address their unique roles, responsibilities, and realities.
Impact of an Innovative Securement Dressing and Tourniquet in Peripheral Intravenous Catheter-Related Complications and Contamination: An Interventional Study
Authors: Parreira Pedro , Serambeque Beatriz , Costa Paulo S. , Mónico Lisete S. , Oliveira Vânia , Sousa Liliana B. , Gama Fernando , Bernardes Rafael A. , Adriano David , Marques Inês A. , Braga Luciene M. , Graveto João , Osório Nádia , Salgueiro-Oliveira Anabela
Published: September 2019

Reusable tourniquets and conventional securement dressings are considered risk factors for the occurrence of reported complications and catheter-related bloodstream infections. This study’s purpose is to assess the impact of single-use disposable tourniquets and advanced occlusive polyurethane dressings with reinforced cloth borders on peripheral intravenous catheter (PIVC)-related complications and contamination. A pre- and post-interventional prospective observational study was conducted in a cardiology ward of a tertiary hospital between April 2018 and February 2019. Overall, demographic and clinical data from 156 patients and PIVC-related outcomes were collected (n = 296) as well as PIVC tips for microbiological analysis (n = 90). In the pre-intervention phase (n = 118), complication rates of 62.1% were reported, while 44.1% of the PIVCs were contaminated (n = 34). In the post-intervention phase (n = 178), complication rates decreased to 57.3%, while contamination rates significantly decreased to 17.9% (p = 0.014; n = 56). Through a logistic regression, it was found that the use of innovative technologies reduces the chance of PIVC contamination by 79% (odds ratio (OR): 0.21; 95% confidence interval (CI): 0.05–0.98; p = 0.046). Meanwhile, PIVC-related complications and fluid therapy emerged as predictors for PIVC contamination. Findings suggest that the adoption of these innovative devices in nurses’ practice contributes to the significant reduction of PIVC contamination.
Analysis of the Effects of the River Network Structure and Urbanization on Waterlogging in High-Density Urban Areas—A Case Study of the Pudong New Area in Shanghai
Authors: Liu Song , Lin Mengnan , Li Chunlin
Published: September 2019

In the process of urbanization, high-intensity human activities have seriously disturbed the river networks, especially in the core urban areas of large cities. At present, a series of urban water environmental problems, such as urban waterlogging and non-point pollution, caused by damage to the river network structure and the decrease in surface permeability conditions in high-density urban areas have received widespread attention. In this study, the effects of the river network structure and urbanization on urban waterlogging were analyzed in the Pudong New Area by using the data of waterlogging sites on the Amap. The results showed that the average water surface ratio is 10.9%, the average river network density is 4.59 km/km2, and the comprehensive impervious ratio is 42.8%. From northwest to southeast, the impervious ratio of the Pudong New Area decreases gradually, and the water surface ratio and the river density increase gradually, while the areas with high waterlogging density are mainly concentrated in the northwest districts. The correlation coefficients indicate that the river network structure (−0.710 and −0.716) has a greater impact on waterlogging than urbanization (0.608) does. The current water surface ratio (10.9%) of the study area generally meets the requirements of the suitable water surface ratio (10.0%) in a rainfall return period of 50 years. However, the water surface ratio and the river density in about half of the districts did not meet the requirements of the suitable river network structure.
Residents’ Awareness of Family Doctor Contract Services, Status of Contract with a Family Doctor, and Contract Service Needs in Zhejiang Province, China: A Cross-Sectional Study
Authors: Shang Xiaopeng , Huang Yangmei , Li Bi’e , Yang Qing , Zhao Yanrong , Wang Wei , Liu Yang , Lin Junfen , Hu Chonggao , Qiu Yinwei
Published: September 2019

In China, family doctor services originated in 2009. After two years, the Chinese government proposed the establishment of a family doctor contract system suitable for China’s national conditions. Then, in 2016, a multi-department jointly issued an important document, which further clarified the development goals of family doctor contract services in the next five years. Zhejiang Province has been exploring responsible doctor contract services since 2012, which was promoted throughout the province in 2015. Objectives: The aim of this study was to investigate the residents’ awareness of Zhejiang Province, China, of family doctor contract services, the status of signing such a contract, and the demand for service items in the contracted service package. Further, we sought to explore the relevant influential factors in order to provide a reference and evidence-based recommendations for the further development of family doctor contract services. Design: We enrolled 3960 residents from nine counties in Zhejiang Province using a multistage stratified random sampling method. A survey using a self-designed questionnaire was used to collect the demographic data, residents’ awareness of family doctor contract services, the status of contracting, and demand for different items from October to December 2017. Data were analyzed by SPSS 21.0. Results: In total, 3871 residents returned valid questionnaires, with a response rate of 97.75%. The awareness rate of residents of family doctor contract services was 71.58% (2771/3871). Age, education level, and chronic medical history status were the influencing factors affecting residents’ awareness. The contracted rate was 50.43% (1952/3871). Age, education level, personal monthly income, chronic disease history, and awareness of family doctor contract services were the influencing factors. Residents who have a contract with family doctors have a higher demand for family doctor contract services, and different residents have different needs for the project because of their physical condition, education level, marital status, household registration, and personal monthly income level. The top three needs of the residents for contracted services were health consultation (84.64%), regular physical examination (81.71%), and increasing the proportion of medical insurance reimbursements (80.06%). Conclusions: The awareness rate of family doctor contract services and the contracting rate are unsatisfactory among residents of Zhejiang Province. It is suggested that the government should more heavily publicize family doctor contract services, expand the coverage, introduce personalized contract schemes to meet the needs of different groups, and promote the rapid development of family doctor contract services in Zhejiang Province.
Maternal Undernutrition and Breast Milk Macronutrient Content Are Not Associated with Weight in Breastfed Infants at 1 and 3 Months after Delivery
Authors: Minato Takafumi , Nomura Kyoko , Asakura Hitomi , Aihara Ayaka , Hiraike Haruko , Hino Yuko , Isojima Tsuyoshi , Kodama Hiroko
Published: September 2019

This study examined whether maternal nutritional intake and breast milk macronutrient content influence the weight of breastfed infants. We investigated 129 healthy mothers with singleton babies born from July 2016 to December 2017 in a university hospital in Tokyo, Japan. Information was obtained by a self-administered food frequency questionnaire at 1 (valid response n = 92; mean age, 34 years) and 3 (n = 57) months after delivery. Breast milk was sampled at 1 and 3 months and the macronutrient contents were analyzed. The average pre-pregnancy body mass index and weight gain during pregnancy were 20.7 ± 2.6 kg/m2 and 9.6 ± 3.7 kg, respectively. At 1 month, average maternal calorie intake was 1993 ± 417 kcal/day, which was lower than the intake recommended by Japanese Dietary Reference Intakes for breastfeeding mothers. There were no significant differences with regard to maternal calorie and protein intake, and breast milk macronutrient content between breastfed infants with weight above and below the 25th percentile of its distribution at both 1 and 3 months. This study suggests that suboptimal calorie intake by breastfeeding mothers and breast milk macronutrient content were not associated with weight of their infants at 1 and 3 months after delivery.
Individual and Environmental Factors Associated with Proteinuria in Korean Children: A Multilevel Analysis
Authors: Kim Suhee , Uhm Ju-Yeon
Published: September 2019

Proteinuria is a significant sign of childhood renal disorders. However, little is known about how sociodemographic and environmental factors are related to the presence of proteinuria among children and adolescents. This paper focuses on the prevalence of proteinuria and its risk factors among children and adolescents. This study conducted a secondary analysis of data from the 2016 Sample Schools Raw Data of Health Examination for School Students (SSRDHESS). Data collected from 27,081 students who had undergone a health screening were analyzed using Chi-square tests, independent t-tests, and multilevel logistic regression analysis. The prevalence of proteinuria was higher in the thin group than in the normal weight group (adjusted odds ratio (aOR) = 1.77; 95% confidence interval (CI) = 1.34–2.33) and lower in the overweight/obese group (aOR = 0.64; 95% CI = 0.51–0.80). Additionally, those in metropolitan and small–medium sized cities had a proteinuria prevalence about 1.5-fold higher than that of those in rural areas (95% CI = 1.08–2.02, 95% CI = 1.19–1.92, respectively). Proteinuria was associated with environmental pollution, including smoking rate, ambient particulate matter and heavy metals in drinking water (aOR = 1.10; 95% CI = 1.01–1.20; aOR = 1.06; 95% CI = 1.01–1.11, aOR = 1.001; 95% CI = 1.0001–1.0015). These results suggest that to improve health management effectiveness, kidney disease prevention efforts for children and adolescents should focus on geographical area and environmental pollution, as well as body weight as individual factors.
Striving for Confidence and Satisfaction in Everyday Life with Chronic Obstructive Pulmonary Disease: Rationale and Content of the Tele-Rehabilitation Programme >C☺PD-Life>>
Authors: Simonÿ Charlotte , Riber Claus , Bodtger Uffe , Birkelund Regner
Published: September 2019

Background: More feasible rehabilitation programmes for patients with chronic obstructive pulmonary disease (COPD) are warranted. Even so, still in its infancy, telerehabilitation to COPD patients reveals promising results, wherefore it is anticipated to contribute significant value to the current challenges of rehabilitation to these patients. To expand useful knowledge in the field, more sophisticated telerehabilitation interventions must be developed and appraised, but first and foremost, thoroughly described. Aims and methods: The aim of this article is to give a detailed description of the rationale and content of the >C☺PD-Life>> programme, within the bounds of the checklist of Template for Intervention Description and Replication (TIDieR). Approach: >C☺PD-Life>> is a telerehabilitation programme for COPD patients delivered as a study intervention by an interprofessional team of clinicians collaborating from both the hospital and the municipal healthcare system. Making use of two-way audio and visual communication software, 15 patients participated in the intervention via a tablet computer from their private setting. The programme was a six-month-long empowerment-based rehabilitation that aimed to support COPD patients in leading a satisfactory and confident life with appropriate physical activity and high disease management. Conclusions: A long-term interprofessional cross-sectoral telerehabilitation programme has been justified and described. The intervention was tested in 2017–2018 and the qualitative appraisal, along with an analysis of case-based measurements of development in physical capacity, COPD Assesment Test, and health management, is currently under production.
School Absenteeism, Health-Related Quality of Life [HRQOL] and Happiness among Young Adults Aged 16–26 Years
Authors: van den Toren Suzanne J. , van Grieken Amy , Mulder Wico C. , Vanneste Yvonne TM , Lugtenberg Marjolein , de Kroon Marlou LA , Tan Siok Swan , Raat Hein
Published: September 2019

This study examines the association between school absenteeism, health-related quality of life (HRQOL) and happiness among young adults aged 16–26 years attending vocational education. Cross-sectional data from a survey among 676 young adults were analyzed. School absenteeism was measured by the self-reported number of sick days in the past eight weeks and hours of truancy in the past four weeks. HRQOL was measured by the 12-item Short Form Health Survey; physical and mental component summary scores were calculated. General happiness was assessed on a scale of 0–10, higher scores indicating greater happiness. Linear regression analyses were performed. The study population had a mean age of 18.5 years (SD 2.2); 26.1% were boys. Young adults with ≥5 sick days or ≥6 h of truancy reported lower mental HRQOL compared to young adults without sickness absence or truancy (p < 0.05). Young adults with 1–4 and ≥5 sick days reported lower physical HRQOL compared to young adults who had not reported to be sick (p < 0.05). Young adults with 1–5 h and ≥6 h of truancy reported higher physical HRQOL compared to young adults who were not truant (p < 0.05). No associations were observed between school absence and happiness. Lower self-reported mental HRQOL was observed among young adults with more school absenteeism due to sickness or truancy. Sickness absence was additionally associated with lower physical HRQOL.
Impact of Composting Methods on Nitrogen Retention and Losses during Dairy Manure Composting
Authors: Yang Xiao , Liu Enke , Zhu Xinmeng , Wang Hongyuan , Liu Hongbin , Liu Xiu , Dong Wenyi
Published: September 2019

Currently, composting is one of the most effective methods for treating fecal waste on large-scale livestock and poultry farms, but the quality effects of different composting methods are different. In this study, we implemented four composting methods, including farmer compost (FC), anaerobic compost (AnC), mixed compost (MC), and aerobic compost (AC), to study the effects of different composting methods on nitrogen (N) losses while composting dairy manure. Our results showed that the germination indexes (GIs) of three of the composting treatments (AnC, MC, and AC) exceeded 80%, which met the maturity requirements for composted products. Ammonia (NH3) emissions were the main contributor to nitrogen losses, while accumulated nitrous oxide (N2O) emissions accounted for the lowest proportion of nitrogen losses. The cumulative N losses via the leachate of the AC treatment were the lowest and accounted for 0.38% of the initial total nitrogen (TN). The accumulated N losses of the AC, FC, AnC, and MC treatments accounted for 13.13% 15.98%, 15.08%, and 19.75%, respectively, of the initial TN. Overall, the AC method significantly reduced N losses via leachates, further reducing TN losses. This observation suggests that AC might be an appropriate method for highly efficient nitrogen management during dairy manure composting.
Impact of PPAR-Alpha Polymorphisms—The Case of Metabolic Disorders and Atherosclerosis
Authors: Ruscica Massimiliano , Busnelli Marco , Runfola Enrico , Corsini Alberto , Sirtori Cesare R.
Published: September 2019

Peroxisome proliferator activated receptor α (PPARα) has the most relevant biological functions among PPARs. Activation by drugs and dietary components lead to major metabolic changes, from reduced triglyceridemia to improvement in the metabolic syndrome. Polymorphisms of PPARα are of interest in order to improve our understanding of metabolic disorders associated with a raised or reduced risk of diseases. PPARα polymorphisms are mainly characterized by two sequence changes, L162V and V227A, with the latter occurring only in Eastern nations, and by numerous SNPs (Single nucleotide polymorphisms) with a less clear biological role. The minor allele of L162V associates with raised total cholesterol, LDL-C (low-density lipoprotein cholesterol), and triglycerides, reduced HDL-C (high-density lipoprotein metabolism), and elevated lipoprotein (a). An increased cardiovascular risk is not clear, whereas a raised risk of diabetes or of liver steatosis are not well supported. The minor allele of the V227A polymorphism is instead linked to a reduction of steatosis and raised γ-glutamyltranspeptidase levels in non-drinking Orientals, the latter being reduced in drinkers. Lastly, the minor allele of rs4353747 is associated with a raised high-altitude appetite loss. These and other associations indicate the predictive potential of PPARα polymorphisms for an improved understanding of human disease, which also explain variability in the clinical response to specific drug treatments or dietary approaches.
Flow Cytometry Reveals the Nature of Oncotic Cells
Authors: Vossenkamper Anna , Warnes Gary
Published: September 2019

The term necrosis is commonly applied to cells that have died via a non-specific pathway or mechanism but strictly is the description of the degradation processes involved once the plasma membrane of the cell has lost integrity. The signalling pathways potentially involved in accidental cell death (ACD) or oncosis are under-studied. In this study, the flow cytometric analysis of the intracellular antigens involved in regulated cell death (RCD) revealed the phenotypic nature of cells undergoing oncosis or necrosis. Sodium azide induced oncosis but also classic apoptosis, which was blocked by zVAD (z-Vla-Ala-Asp(OMe)-fluoromethylketone). Oncotic cells were found to be viability+ve/caspase-3–ve/RIP3+ve/–ve (Receptor-interacting serine/threonine protein kinase 3). These two cell populations also displayed a DNA damage response (DDR) phenotype pH2AX+ve/PARP–ve, cleaved PARP induced caspase independent apoptosis H2AX–ve/PARP+ve and hyper-activation or parthanatos H2AX+ve/PARP+ve. Oncotic cells with phenotype cell viability+ve/RIP3–ve/caspase-3–ve showed increased DDR and parthanatos. Necrostatin-1 down-regulated DDR in oncotic cells and increased sodium azide induced apoptosis. This flow cytometric approach to cell death research highlights the link between ACD and the RCD processes of programmed apoptosis and necrosis.
Contribution of Corticotropin-Releasing Factor Receptor 1 (CRF1) to Serotonin Receptor 5-HT2CR Function in Amygdala Neurons in a Neuropathic Pain Model
Authors: Ji Guangchen , Neugebauer Volker
Published: September 2019

The amygdala plays a key role in emotional-affective aspects of pain and in pain modulation. The central nucleus (CeA) serves major amygdala output functions related to emotional-affective behaviors and pain modulation. Our previous studies implicated the corticotropin-releasing factor (CRF) system in amygdala plasticity and pain behaviors in an arthritis model. We also showed that serotonin (5-HT) receptor subtype 5-HT2CR in the basolateral amygdala (BLA) contributes to increased CeA output and neuropathic pain-like behaviors. Here, we tested the novel hypothesis that 5-HT2CR in the BLA drives CRF1 receptor activation to increase CeA neuronal activity in neuropathic pain. Extracellular single-unit recordings of CeA neurons in anesthetized adult male rats detected increased activity in neuropathic rats (spinal nerve ligation model) compared to sham controls. Increased CeA activity was blocked by local knockdown or pharmacological blockade of 5-HT2CR in the BLA, using stereotaxic administration of 5-HT2CR short hairpin RNA (shRNA) viral vector or a 5-HT2CR antagonist (SB242084), respectively. Stereotaxic administration of a CRF1 receptor antagonist (NBI27914) into the BLA also decreased CeA activity in neuropathic rats and blocked the facilitatory effects of a 5-HT2CR agonist (WAY161503) administered stereotaxically into the BLA. Conversely, local (BLA) knockdown of 5-HT2CR eliminated the inhibitory effect of NBI27914 and the facilitatory effect of WAY161503 in neuropathic rats. The data suggest that 5-HT2CR activation in the BLA contributes to neuropathic pain-related amygdala (CeA) activity by engaging CRF1 receptor signaling.
Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes as Models for Genetic Cardiomyopathies
Authors: Brodehl Andreas , Ebbinghaus Hans , Deutsch Marcus-André , Gummert Jan , Gärtner Anna , Ratnavadivel Sandra , Milting Hendrik
Published: September 2019

In the last few decades, many pathogenic or likely pathogenic genetic mutations in over hundred different genes have been described for non-ischemic, genetic cardiomyopathies. However, the functional knowledge about most of these mutations is still limited because the generation of adequate animal models is time-consuming and challenging. Therefore, human induced pluripotent stem cells (iPSCs) carrying specific cardiomyopathy-associated mutations are a promising alternative. Since the original discovery that pluripotency can be artificially induced by the expression of different transcription factors, various patient-specific-induced pluripotent stem cell lines have been generated to model non-ischemic, genetic cardiomyopathies in vitro. In this review, we describe the genetic landscape of non-ischemic, genetic cardiomyopathies and give an overview about different human iPSC lines, which have been developed for the disease modeling of inherited cardiomyopathies. We summarize different methods and protocols for the general differentiation of human iPSCs into cardiomyocytes. In addition, we describe methods and technologies to investigate functionally human iPSC-derived cardiomyocytes. Furthermore, we summarize novel genome editing approaches for the genetic manipulation of human iPSCs. This review provides an overview about the genetic landscape of inherited cardiomyopathies with a focus on iPSC technology, which might be of interest for clinicians and basic scientists interested in genetic cardiomyopathies.
A Fragmenting Protocol with Explicit Hydration for Calculation of Binding Enthalpies of Target-Ligand Complexes at a Quantum Mechanical Level
Authors: Horváth István , Jeszenői Norbert , Bálint Mónika , Paragi Gábor , Hetényi Csaba
Published: September 2019

Optimization of the enthalpy component of binding thermodynamics of drug candidates is a successful pathway of rational molecular design. However, the large size and missing hydration structure of target-ligand complexes often hinder such optimizations with quantum mechanical (QM) methods. At the same time, QM calculations are often necessitated for proper handling of electronic effects. To overcome the above problems, and help the QM design of new drugs, a protocol is introduced for atomic level determination of hydration structure and extraction of structures of target-ligand complex interfaces. The protocol is a combination of a previously published program MobyWat, an engine for assigning explicit water positions, and Fragmenter, a new tool for optimal fragmentation of protein targets. The protocol fostered a series of fast calculations of ligand binding enthalpies at the semi-empirical QM level. Ligands of diverse chemistry ranging from small aromatic compounds up to a large peptide helix of a molecular weight of 3000 targeting a leukemia protein were selected for systematic investigations. Comparison of various combinations of implicit and explicit water models demonstrated that the presence of accurately predicted explicit water molecules in the complex interface considerably improved the agreement with experimental results. A single scaling factor was derived for conversion of QM reaction heats into binding enthalpy values. The factor links molecular structure with binding thermodynamics via QM calculations. The new protocol and scaling factor will help automated optimization of binding enthalpy in future molecular design projects.
Roles of Glutamate Receptors in Parkinson’s Disease
Authors: Zhang Zhu , Zhang Shiqing , Fu Pengfei , Zhang Zhang , Lin Kaili , Ko Joshua Ka-Shun , Yung Ken Kin-Lam
Published: September 2019

Parkinson’s disease is a progressive neurodegenerative disorder resulting from the degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta. It induces a series of functional modifications in the circuitry of the basal ganglia nuclei and leads to severe motor disturbances. The amino acid glutamate, as an excitatory neurotransmitter, plays a key role in the disruption of normal basal ganglia function regulated through the interaction with its receptor proteins. It has been proven that glutamate receptors participate in the modulation of neuronal excitability, transmitter release, and long-term synaptic plasticity, in addition to being related to the altered neurotransmission in Parkinson’s disease. Therefore, they are considered new targets for improving the therapeutic strategies used to treat Parkinson’s disease. In this review, we discuss the biological characteristics of these receptors and demonstrate the receptor-mediated neuroprotection in Parkinson’s disease. Pharmacological manipulation of these receptors during anti-Parkinsonian processes in both experimental studies and clinical trials are also summarized.
Downregulation of POFUT1 Impairs Secondary Myogenic Fusion Through a Reduced NFATc2/IL-4 Signaling Pathway
Authors: Der Vartanian Audrey , Chabanais Julien , Carrion Claire , Maftah Abderrahman , Germot Agnès
Published: September 2019

Past work has shown that the protein O-fucosyltransferase 1 (POFUT1) is involved in mammal myogenic differentiation program. Pofut1 knockdown (Po –) in murine C2C12 cells leads to numerous elongated and thin myotubes, suggesting significant defects in secondary fusion. Among the few pathways involved in this process, NFATc2/IL-4 is described as the major one. To unravel the impact of POFUT1 on secondary fusion, we used wild-type (WT) C2C12 and Po – cell lines to follow Myf6, Nfatc2, Il-4 and Il-4rα expressions during a 120 h myogenic differentiation time course. Secreted IL-4 was quantified by ELISA. IL-4Rα expression and its labeling on myogenic cell types were investigated by Western blot and immunofluorescence, respectively. Phenotypic observations of cells treated with IL-4Rα blocking antibody were performed. In Po –, we found a decrease in nuclei number per myotube and a downexpression of Myf6. The observed downregulation of Nfatc2 is correlated to a diminution of secreted IL-4 and to the low level of IL-4Rα for reserve cells. Neutralization of IL-4Rα on WT C2C12 promotes myonuclear accretion defects, similarly to those identified in Po –. Thus, POFUT1 could be a new controller of myotube growth during myogenesis, especially through NFATc2/IL-4 signaling pathway.
Role of a RhoA/ROCK-Dependent Pathway on Renal Connexin43 Regulation in the Angiotensin II-Induced Renal Damage
Authors: Gómez Gonzalo I. , Velarde Victoria , Sáez Juan C.
Published: September 2019

In various models of chronic kidney disease, the amount and localization of Cx43 in the nephron is known to increase, but the intracellular pathways that regulate these changes have not been identified. Therefore, we proposed that: “In the model of renal damage induced by infusion of angiotensin II (AngII), a RhoA/ROCK-dependent pathway, is activated and regulates the abundance of renal Cx43”. In rats, we evaluated: 1) the time-point where the renal damage induced by AngII is no longer reversible; and 2) the involvement of a RhoA/ROCK-dependent pathway and its relationship with the amount of Cx43 in this irreversible stage. Systolic blood pressure (SBP) and renal function (urinary protein/urinary creatinine: Uprot/UCrea) were evaluated as systemic and organ outcomes, respectively. In kidney tissue, we also evaluated: 1) oxidative stress (amount of thiobarbituric acid reactive species), 2) inflammation (immunoperoxidase detection of the inflammatory markers ED-1 and IL-1β), 3) fibrosis (immune detection of type III collagen; Col III) and 4) activity of RhoA/ROCK (amount of phosphorylated MYPT1; p-MYPT1). The ratio Uprot/UCrea, SBP, oxidative stress, inflammation, amount of Cx43 and p-MYPT1 remained high 2 weeks after suspending AngII treatment in rats treated for 4 weeks with AngII. These responses were not observed in rats treated with AngII for less than 4 weeks, in which all measurements returned spontaneously close to the control values after suspending AngII treatment. Rats treated with AngII for 6 weeks and co-treated for the last 4 weeks with Fasudil, an inhibitor of ROCK, showed high SBP but did not present renal damage or increased amount of renal Cx43. Therefore, renal damage induced by AngII correlates with the activation of RhoA/ROCK and the increase in Cx43 amounts and can be prevented by inhibitors of this pathway.
A Yersinia ruckeri TIR Domain-Containing Protein (STIR-2) Mediates Immune Evasion by Targeting the MyD88 Adaptor
Authors: Liu Tao , Wei Wen-Yan , Wang Kai-Yu , Wang Er-Long , Yang Qian
Published: September 2019

TIR domain-containing proteins are essential for bacterial pathogens to subvert host defenses. This study describes a fish pathogen, Yersinia ruckeri SC09 strain, with a novel TIR domain-containing protein (STIR-2) that affects Toll-like receptor (TLR) function. STIR-2 was identified in Y. ruckeri by bioinformatics analysis. The toxic effects of this gene on fish were determined by in vivo challenge experiments in knockout mutants and complement mutants of the stir-2 gene. In vitro, STIR-2 downregulated the expression and secretion of IL-6, IL-1β, and TNF-α. Furthermore, the results of NF-κB-dependent luciferase reporter system, co-immunoprecipitation, GST pull-down assays, and yeast two-hybrid assay indicated that STIR-2 inhibited the TLR signaling pathway by interacting with myeloid differentiation factor 88 (MyD88). In addition, STIR-2 promoted the intracellular survival of pathogenic Yersinia ruckeri SC09 strain by binding to the TIR adaptor protein MyD88 and inhibiting the pre-inflammatory signal of immune cells. These results showed that STIR-2 increased virulence in Y. ruckeri and suppressed the innate immune response by inhibiting TLR and MyD88-mediated signaling, serving as a novel strategy for innate immune evasion.
Production of IFNβ by Conventional Dendritic Cells after Stimulation with Viral Compounds and IFNβ-Independent IFNAR1-Signaling Pathways are Associated with Aggravation of Polymicrobial Sepsis
Authors: Howe Magdalena , Bauer Jens , Schulze Anja , Kropp Sonja , Locksley Richard M. , Alferink Judith , Weighardt Heike , Scheu Stefanie
Published: September 2019

Viral infections are associated with increased incidence of severe sepsis. Particularly during the early stages, type I interferons (IFNs) are known mediators of detrimental effects. However, the functional role of early interferon β (IFNβ) and its cellular source during sepsis in the context of preexisting viral infections has not been defined. Using the colon ascendens stent peritonitis (CASP) model, we demonstrate that IFNβ−/− and type I IFN receptor (IFNAR1)−/− mice were less susceptible to sepsis after pre-stimulation with the viral mimetic poly(I:C). Wild type (WT) mice treated with poly(I:C) exhibited altered expression patterns of TNF and IL-12p40 during CASP which were dependent on IFNβ or IFNAR1, suggesting a mechanism for the increased sepsis susceptibility of WT mice. Using a double cytokine reporter mouse model, we present novel data on the simultaneous expression of IFNβ and IL-12p40 on a single cell level during polymicrobial sepsis in vivo. Conventional dendritic cells (cDCs) were identified as primary source of IFNβ and the protective cytokine IL-12p40 after CASP surgery irrespective of poly(I:C) pre-stimulation. These data demonstrated that if polymicrobial sepsis is preceded by a viral infection, IFNβ and IL-12p40 are expressed by polyfunctional cDCs suggesting that these cells can play both detrimental and beneficial roles during sepsis development.
Vascular Endothelial Cell Biology: An Update
Authors: Krüger-Genge Anne , Blocki Anna , Franke Ralf-Peter , Jung Friedrich
Published: September 2019

The vascular endothelium, a monolayer of endothelial cells (EC), constitutes the inner cellular lining of arteries, veins and capillaries and therefore is in direct contact with the components and cells of blood. The endothelium is not only a mere barrier between blood and tissues but also an endocrine organ. It actively controls the degree of vascular relaxation and constriction, and the extravasation of solutes, fluid, macromolecules and hormones, as well as that of platelets and blood cells. Through control of vascular tone, EC regulate the regional blood flow. They also direct inflammatory cells to foreign materials, areas in need of repair or defense against infections. In addition, EC are important in controlling blood fluidity, platelet adhesion and aggregation, leukocyte activation, adhesion, and transmigration. They also tightly keep the balance between coagulation and fibrinolysis and play a major role in the regulation of immune responses, inflammation and angiogenesis. To fulfill these different tasks, EC are heterogeneous and perform distinctly in the various organs and along the vascular tree. Important morphological, physiological and phenotypic differences between EC in the different parts of the arterial tree as well as between arteries and veins optimally support their specified functions in these vascular areas. This review updates the current knowledge about the morphology and function of endothelial cells, particularly their differences in different localizations around the body paying attention specifically to their different responses to physical, biochemical and environmental stimuli considering the different origins of the EC.
Apoptotic Effects of Drug Targeting Conjugates Containing Different GnRH Analogs on Colon Carcinoma Cells
Authors: Lajkó Eszter , Hegedüs Rózsa , Mező Gábor , Kőhidai László
Published: September 2019

The wide range of cellular target reactions (e.g., antitumor) of gonadotropin-releasing hormone (GnRH) variants provides the possibility to develop multifunctional GnRH conjugates. The aim of our work was to compare the cytotoxic/apoptotic activity of different GnRH-based, daunorubicin (Dau)-linked conjugates with or without butyrated Lys in position 4 (4Lys(Bu)) at a molecular level in a human colorectal carcinoma cell line. Cell viability was measured by impedimetry, cellular uptake and apoptosis were studied by flow cytometry, and the expression of apoptosis-related genes was analyzed by qRT-PCR. The modification with 4Lys(Bu) resulted in an increased cytotoxic and apoptotic effects and cellular uptake of the GnRH-I and GnRH-III conjugates. Depending on the GnRH isoform and the presence of 4Lys(Bu), the conjugates could regulate the expression of several apoptosis-related genes, especially tumor necrosis factor (TNF), tumor protein p53 (TP53) and the members of growth-factor signaling. The stronger cytotoxicity of GnRH-I and GnRH-III conjugates containing 4Lys(Bu) was associated with a stronger inhibitory effect on the expression of growth-factor signaling elements in comparison with their 4Ser counterparts, in which the upregulation of TP53 and caspases (e.g., CASP9) seemed to play a more important role. We were able to provide further evidence that targeting the GnRH receptor could serve as a successful therapeutic approach in colon cancer, and GnRH-III-[4Lys(Bu),8Lys(Dau=Aoa)] proved to be the best candidate for this purpose.