bluuebunny/crossref_metadata_2025 huggingface dataset:
Circuit Structure and Control Method to Reduce Size and Harmonic Distortion of Interleaved Dual Buck Inverter
Authors: Cho Min-Gi , Lee Sang-Hoon , Lee Hyeon-Seok , Choi Yoon-Geol , Kang Bongkoo
Published: March 2020

A new circuit structure and control method for a high power interleaved dual-buck inverter are proposed. The proposed inverter consists of six switches, four diodes and two inductors, uses a dual-buck structure to eliminate zero-cross distortion, and operates in an interleaved mode to reduce the current stress of switch. To reduce the total harmonic distortion at low output power, the inverter is controlled using discontinuous-current-mode control combined with continuous-current-mode control. The experimental inverter had a power-conversion efficiency of 98.5% at output power = 1300 W and 98.3% at output power = 2 kW, when the inverter was operated at an input voltage of 400 VDC, output voltage of 220 VAC/60 Hz, and switching frequency of 20 kHz. The total harmonic distortion was < 0.66%, which demonstrates that the inverter is suitable for high-power dc-ac power conversion.
Responses of Parameters for Electrical Impedance Spectroscopy and Pressure–Volume Curves to Drought Stress in Pinus bungeana Seedlings
Authors: Wang Ai-Fang , Di Bao , Repo Tapani , Roitto Marja , Zhang Gang
Published: March 2020

Background and Objectives: Drought occurs more frequently in Northern China with the advent of climate change, which might increase the mortality of tree seedlings after afforestation due to hydraulic failure. Therefore, investigating water relations helps us understand the drought tolerance of tree seedlings. Electrical impedance spectroscopy (EIS) is widely used to assess the responses of plant tissues to stress factors and may potentially reveal the water relations of cells. The aim of this study is to reveal the relationships between EIS and water related parameters, produced by pressure–volume (PV) curves in lacebark pine (Pinus bungeana Zucc.) seedlings reacting to drought stress. Materials and Methods: Four-year-old pot seedlings were divided into three parts (0, 5, and 10 days of drought) before planting, the treated seedlings were then replanted, and finally exposed to post-planting drought treatments with the following soil relative water contents: (i) adequate irrigation (75%–80%), (ii) light drought (55%–60%), (iii) moderate drought (35%–40%), and (iv), severe drought (15%–20%). During the post-planting growth phase, the EIS parameters of needles and shoots, and the parameters of PV curves, were measured coincidently; thus, the correlations between them could be obtained. Results: The extracellular resistance (re) of needles and shoots were substantially reduced after four weeks of severe post-planting drought stress. Meanwhile, the osmotic potential at the turgor-loss point (ψtlp) and the saturation water osmotic potential (ψsat) of shoots decreased after drought stress, indicating an osmotic adjustment in acclimating to drought. The highest correlations were found between the intracellular resistance (ri) of the shoots and ψtlp and ψsat. Conclusions: EIS parameters can be used as a measure of drought tolerance. The change in intracellular resistance is related to the osmotic potential of the cell and cell wall elasticity. Extracellular resistance is a parameter that shows cell membrane damage in response to drought stress in lacebark pine seedlings.
How to Deal with Uninvited Guests in Wine: Copper and Copper-containing Oxidases
Authors: Claus Harald
Published: March 2020

Copper is one of the most frequently occurring heavy metals in must and wine. It is introduced by pesticides, brass fittings, and as copper sulphate for treatment of reductive off-flavors. At higher concentrations, copper has harmful effects on the wine. It contributes to the oxidation of wine ingredients, browning reactions, cloudiness, inhibition of microorganisms, and wine fermentation. Last but not least, there is also a danger to the consumer. At present, some physicochemical methods exist to reduce the copper content in must and wine, but they all have their shortcomings. A possible solution is the biosorption of metals by yeasts or lactobacilli. Copper can also reach must and wine in the form of copper-containing phenol oxidases (grape tyrosinase, Botrytis cinerea laccases). Similar to free copper, they oxidize phenolic wine compounds, and thus lead to considerable changes in color and nutritional value, making the product ultimately unsaleable. All measurements for enzyme inactivation such as heat treatment, and addition of sulphites or bentonite are either problematic or not effective enough. The application of oenological tannins could offer a way out but needs further research.
“Nomen Omen”: Exploring Connected Healthcare through the Perspective of Name Omen
Authors: Chen Sonia Chien-I , Liu Chenglian , Hu Ridong , Mo Yiyi , Ye Xiupin
Published: March 2020

Background: The evolution of names, from “medical informatics” to “connected health”, implies that the evolvement of technology in health care has been shifted from technology-oriented to healthcare-oriented implementation. Connected healthcare, a healthcare platform of remote monitoring and self-management through technological measures, is suggested to contribute to the efficiency, cost-effectiveness, and satisfaction of healthcare recipient enhancement. However, limited understanding of related connected health (CH) terminology may constrain its implementation. Whether CH is a buzzword only or a practice that can contribute to an aging society is controversial. Objective: This study aims to distinguish CH-related terminology and to identify the trend of CH through reviewing its definition, initiation, development, and evolvement, in order to offer management insights and implications. The objective is to understand what is connected and who is cared about in the connected health model so that better applications can be addressed for the benefit of society. Method: This study reviews the evolution of names, from “medical informatics” in the 1970s to “connected health” after 2000, as well as relevant literature of CH, including e-health, telemedicine, telehealth, telecare, and m-health, to discover the trend of technology-related healthcare innovations. Results: The current status and issues facing accessibility, quality, and cost were presented. Its future trends will be explored through reviewing how changes in healthcare are managed, in addition to its operation and practice. Pre-conditions and requirements for implementing CH are identified to select a typical case to study. Findings suggest that areas with a complete business ecosystem—isolated locations, advanced information technology, aging in population, integrated health, and social care system—are prevalent for designing friendly CH environments. Conclusion: The evidence and tendency of technological convergence create a demand for innovation and partnering with start-up companies that offer a competitive advantage in innovation.
Isolation and Identification of Chromium Reducing Bacillus Cereus Species from Chromium-Contaminated Soil for the Biological Detoxification of Chromium
Authors: Li Ming-hao , Gao Xue-yan , Li Can , Yang Chun-long , Fu Chang-ai , Liu Jie , Wang Rui , Chen Lin-xu , Lin Jian-qiang , Liu Xiang-mei , Lin Jian-qun , Pang Xin
Published: March 2020

Chromium contamination has been an increasing threat to the environment and to human health. Cr(VI) and Cr(III) are the most common states of chromium. However, compared with Cr(III), Cr(VI) is more toxic and more easily absorbed, therefore, it is more harmful to human beings. Thus, the conversion of toxic Cr(VI) into Cr(III) is an accepted strategy for chromium detoxification. Here, we isolated two Bacillus cereus strains with a high chromium tolerance and reduction ability, named B. cereus D and 332, respectively. Both strains demonstrated a strong pH and temperature adaptability and survival under 8 mM Cr(VI). B. cereus D achieved 87.8% Cr(VI) removal in 24 h with an initial 2 mM Cr(VI). Cu(II) was found to increase the removal rate of Cr(VI) significantly. With the addition of 0.4 mM Cu(II), 99.9% of Cr(VI) in the culture was removed by B. cereus 332 in 24 h. This is the highest removal efficiency in the literature that we have seen to date. The immobilization experiments found that sodium alginate with diatomite was the better method for immobilization and B. cereus 332 was more efficient in immobilized cells. Our research provided valuable information and new, highly effective strains for the bioremediation of chromium pollution.
How to Value Digital Health Interventions? A Systematic Literature Review
Authors: Kolasa Katarzyna , Kozinski Grzegorz
Published: March 2020

In Europe, there were almost twice as many patents granted for medical technology (13,795) compared to pharmaceuticals (7441) in 2018. It is important to ask how to integrate such an amount of innovations into routine clinical practice and how to measure the value it brings to the healthcare system. Given the novelty of digital health interventions (DHI), one can even question whether the quality-adjusted life years (QALY) approach developed for pharmaceuticals can be used or whether we need to develop a new DHI’s value assessment framework. We conducted a systematic literature review of published DHIs’ assessment guidelines. Each publication was analyzed with a 12-items checklist based on a EUnetHTA core model enriched with additional criteria such as usability, interoperability, and data security. In total, 11 value assessment guidelines were identified. The review revealed that safety, clinical effectiveness, usability, economic aspects, and interoperability were most often discussed (seven out of 11). More than half of the guidelines addressed organizational impact, data security, choice of comparator, and technical considerations (six out of 11). The unmet medical needs (three out of 11), along with the ethical (two out of 11) and legal aspects (one out of 11), were given the least attention. No author provided an analytical framework for the calculation of clinical and economic outcomes. We elicited five recommendations for the choice of DHI’s value criteria and a methodological suggestion for the pricing and reimbursement framework. Our conclusions lead to the need for a new DHI’s value assessment framework instead of a QALY approach.
Global Research on Quality of Life of Patients with HIV/AIDS: Is It Socio-Culturally Addressed? (GAPRESEARCH)
Authors: Vu Giang Thu , Tran Bach Xuan , Hoang Chi Linh , Hall Brian J. , Phan Hai Thanh , Ha Giang Hai , Latkin Carl A. , Ho Cyrus S.H. , Ho Roger C.M.
Published: March 2020

Quality of life (QOL) has been considered as an important outcome indicator in holistic care for HIV-infected people, especially as HIV/AIDS transforms from a fatal illness to a chronic condition. This study aimed to identify trends and emerging topics among research concerning the QOL of people living with HIV/AIDS (PLWHA). The analyzed data were English papers published from 1996 to 2017, searched and extracted from the Web of Science Core Collection. Collaborations between countries and the correlation between the keywords were visualized by VOSviewer while the abstracts’ content was analyzed using exploratory factor analysis and Jaccard’s’ similarity index. There has been an increase in both the number of publications and citations. The United Nations of America leads in terms of paper volume. The cross-nation collaborations are mainly regional. Despite a rather comprehensive coverage of topics relating to QOL in PLWHA, there has evidently been a lack of studies focusing on socio-cultural factors and their impacts on the QOL of those who are HIV-infected. Further studies should consider investigating the role of socio-cultural factors, especially where long-term treatment is involved. Policy-level decisions are recommended to be made based on the consideration of cultural factors, while collaborations between developed and developing nations, in particular in HIV/AIDS-ridden countries, are strongly recommended.
Diarrhea in Under Five Year-old Children in Nepal: A Spatiotemporal Analysis Based on Demographic and Health Survey Data
Authors: Li Ruixue , Lai Yingsi , Feng Chenyang , Dev Rubee , Wang Yijing , Hao Yuantao
Published: March 2020

Background: Diarrhea in children under five years of age remains a challenge in reducing child mortality in Nepal. Understanding the spatiotemporal patterns and influencing factors of the disease is important for control and intervention. Methods: Data regarding diarrhea prevalence and its potential influencing factors were extracted from the Demographic and Health Surveys in Nepal and other open-access databases. A Bayesian logistic regression model with district-specific spatio-temporal random effects was applied to explore the space and time patterns of diarrhea risk, as well as the relationships between the risk and the potential influencing factors. Results: Both the observed prevalence and the estimated spatiotemporal effects show a decreasing diarrhea risk trend from 2006 to 2016 in most districts of Nepal, with a few exceptions, such as Achham and Rasuwa. The disease risk decreased with mothers’ years of education (OR 0.93, 95% Bayesian Credible Interval (BCI) 0.87, 0.997). Compared to spring, autumn and winter had lower risks of diarrhea. The risk firstly increased and then decreased with age and children under 12–24 months old were the highest risk group (OR 1.20, 95% BCI 1.04, 1.38). Boys had higher risk than girls (OR 1.24, 95% BCI 1.13, 1.39). Even though improved sanitation wasn’t found significant within a 95% BCI, there was 93.2% of chance of it being a protective factor. There were no obvious spatiotemporal clusters among districts and each district tended to have its own spatiotemporal diarrhea prevalence pattern. Conclusions: The important risk factors identified by our Bayesian spatial-temporal modeling provide insights for control and intervention on children diarrhea in Nepal. Special attention should be paid to high risk groups of children and high risk seasons, as well as districts with high risk or increased trend of risk. Effective actions should be implemented to improve sanitation and women’s education level. District-specific control planning is recommended for local governments for effective control of children diarrhea in Nepal.
Total Worker Health Leadership and Business Strategies Are Related to Safety and Health Climates in Small Business
Authors: Schwatka Natalie V. , Dally Miranda , Tenney Liliana , Shore Erin , Brown Carol E. , Newman Lee S.
Published: March 2020

The purpose of this study was to investigate the relationship between Total Worker Health® (TWH) business strategies and employee perceptions of leadership commitment and safety and health climates. Using data from 53 small enterprises and 1271 of their workers collected as part of the Small + Safe + Well (SSWell) Study, we confirm the primacy of the relationship between leadership commitment to safety and workplace safety climate. After accounting for leadership commitment to safety, business-reported policies and practices that promote the health, safety, and well-being of workers (i.e., TWH strategies) were no longer related to safety climate. In contrast, the relationship between TWH strategies and health climate were significantly associated with the level of small business leadership commitment to worksite wellness. Relatedly, our results demonstrate that leadership is a common correlate to both safety climate and health climate. Future research should investigate integrated TWH leadership development strategies as a means of simultaneously improving safety and health climates.
The Age-Related Performance Decline in Ironman 70.3
Authors: Jäckel Kristian , Sousa Caio , Villiger Elias , Nikolaidis Pantelis , Knechtle Beat
Published: March 2020

Although the age-related decline in sport events has been well studied, little is known on such a decline in recreational triathletes for the Half Ironman distance. Indeed, the few existing studies concentrated on specific aspects such as top events, elite groups, some consecutive years, single locations, or age categories instead of analyzing all the data available. Therefore, the aim of the present study was to examine recreational triathletes’ performance in three split disciplines (swimming, cycling, and running) as well as in overall race time by analyzing all data of Half Ironman finishers found on ironman.com (i.e., 690 races; years 2004 through 2018; 206,524 women (24.6%) and 633,576 men (75.4%), in total 840,100 athletes). The age-dependent decline in Half Ironman started earliest in swimming (from the very first age group on) with a smallest age group delta between 35–49 years in men and 40–54 years in women. The performance decline started at 26 and 28 years in men and women for running; at 34 years for men and 35 years for women in cycling; and at 32 years for men and 31 years for women with regard to overall race time. The results may be used by coaches and recreational athletes alike to plan a triathlon career.
Health Literacy Associations with Periodontal Disease among Slovak Adults
Authors: Timková Silvia , Klamárová Tatiana , Kovaľová Eva , Novák Bohuslav , Kolarčik Peter , Madarasová Gecková Andrea
Published: March 2020

Periodontal disease is inflammation of the gums and without good oral hygiene, it can progress to periodontitis. Oral hygiene might be related to a patient’s health literacy (HL), defined as ability to gain access, understand, and use information to promote and maintain good health. The aim of our study is to examine the associations of HL with indicators of periodontal disease. A cross-sectional study on 1117 adults (36.2% males; mean age = 36.4, SD = 14.2) attending dental hygiene treatment was conducted. Data on demographics, socioeconomic status, and nine domains of HL (Health Literacy Questionnaire, HLQ) were collected by questionnaire, and Community Periodontal Index of Treatment Needs (CPITN) was established by the dental hygienist. Data were analysed using t-tests and logistic regression. Respondents with periodontal disease (N = 152) had statistically significantly lower levels of HL in seven out of nine HLQ domains compared to intact patients (N = 818) (t from 3.03 to 4.75, p < 0.01). Association of higher HL in seven domains with lower chance of diagnosed periodontal disease remain significant even after adjustment for age, gender and educational attainment (adjusted ORs 0.55–0.67, p < 0.05). Our findings confirm that an individual’s lower HL is significantly associated with higher chance of periodontal disease incidence, specifically among Slovak adults attending oral hygiene clinics. HL might be a promising factor in the improvement of oral health in this population, worthy of consideration in intervention and preventive activities.
Dynamic Navigation in Dental Implantology: The Influence of Surgical Experience on Implant Placement Accuracy and Operating Time. An in Vitro Study
Authors: Pellegrino Gerardo , Bellini Pierantonio , Cavallini Pier Francesco , Ferri Agnese , Zacchino Andrea , Taraschi Valerio , Marchetti Claudio , Consolo Ugo
Published: March 2020

Aim: the aim of this in vitro study was to test whether the implant placement accuracy and the operating time can be influenced by the operator’s experience. Materials and methods: sixteen models underwent a (Cone Beam Computer Tomography) CBCT and implant positioning was digitally planned on this. The models were randomly assigned to four operators with different levels of surgical experience. One hundred and twelve implant sites were drilled using a dynamic navigation system and operating times were measured. Based on postoperative CBCTs, dental implants were virtually inserted and superimposed over the planned ones. Two-dimensional and 3D deviations between planned and virtually inserted implants were measured at the entry point and at the apical point. Angular and vertical errors were also calculated. Results: considering coronal and apical 3D deviations, no statistically significant differences were found between the four operators (p = 0.27; p = 0.06). Some vectorial components of the deviation at the apical point and the angular errors of some operators differed from each other. Conclusions: within the limitations of this study, dynamic navigation can be considered a reliable technique both for experienced and novice clinicians.
Population Attributable Fraction of Early Age of Onset of Alcohol Use in Alcohol Abuse and Dependence: A 3-Year Follow-Up Study in University Students
Authors: Caamano-Isorna Francisco , Adkins Amy , Aliev Fazil , Moure-Rodríguez Lucía , Dick Danielle M.
Published: March 2020

Background: we aimed to determine the risk factors and associated population attributable fractions (PAFs) for the age of onset of alcohol use and also to identify protective factors. Methods: we analyzed follow-up data collected between autumn 2011 and spring 2016 (n = 5170) from the first two cohorts (2011, 2012) of the Spit for ScienceTM project. The dependent variables were alcohol abuse and dependence, and the independent variables were age of drinking onset, residence, ethnicity, religiosity, sexual orientation and work status. We determined the odds ratios (OR) using multilevel logistic regression for repeated measures in SPSSv.20. Results: the early onset of alcohol use was associated with an increased risk of alcohol abuse and dependence among females (OR = 14.98; OR = 11.83) and males (OR = 7.41; OR = 6.24). The PAFs for the early onset of alcohol use in alcohol abuse and dependence were respectively 80.9% and 71.7% in females and 71.0% and 63.5% in males. Among females, being white (OR = 1.58; OR = 1.51), living off-campus (OR = 1.73; OR = 2.76) and working full-time (OR = 1.69; OR = 1.78) were also risk factors. Strong religious beliefs were found to protect males from alcohol abuse (OR = 0.58), while same-gender sexual orientation increased the risk among females (OR = 2.09). Conclusion: delaying the age of onset by one year would reduce alcohol abuse among young adults.
Ranking Preventive Interventions from Different Policy Domains: What Are the Most Cost-Effective Ways to Improve Public Health?
Authors: van der Vliet Nina , Suijkerbuijk Anita W.M. , de Blaeij Adriana T. , de Wit G. Ardine , van Gils Paul F. , Staatsen Brigit A.M. , Maas Rob , Polder Johan J.
Published: March 2020

It is widely acknowledged that in order to promote public health and prevent diseases, a wide range of scientific disciplines and sectors beyond the health sector need to be involved. Evidence-based interventions, beyond preventive health interventions targeting disease risk factors and interventions from other sectors, should be developed and implemented. Investing in these preventive health policies is challenging as budgets have to compete with other governmental expenditures. The current study aimed to identify, compare and rank cost-effective preventive interventions targeting metabolic, environmental, occupational and behavioral risk factors. To identify these interventions, a literature search was performed including original full economic evaluations of Western country interventions that had not yet been implemented in the Netherlands. Several workshops were held with experts from different disciplines. In total, 51 different interventions (including 13 cost saving interventions) were identified and ranked based on their incremental cost-effectiveness ratio (ICER) and potential averted disability-adjusted life years (DALYs), resulting in two rankings of the most cost-effective interventions and one ranking of the 13 cost saving interventions. This approach, resulting in an intersectoral ranking, can assist policy makers in implementing cost-effective preventive action that considers not only the health sector, but also other sectors.
Use of Multiple Tobacco and Tobacco-Like Products Including Heated Tobacco and E-Cigarettes in Japan: A Cross-Sectional Assessment of the 2017 JASTIS Study
Authors: Sugiyama Takefumi , Tabuchi Takahiro
Published: March 2020

Information on the use of multiple tobacco and tobacco-like products (hereafter multiple tobacco products use, i.e., use of more than one product) is important for tobacco control. Use of heated tobacco products (HTPs), which first became popular in Japan, has been spreading over the world, while information about use of multiple tobacco products, including HTPs, is insufficient. We analyzed data of 10,114 responders from the 2017 Japan “Society and New Tobacco” Internet Survey (JASTIS) study. The prevalence and adjusted odds ratio (aOR) of multiple tobacco products use were estimated with inverse probability weighting using multivariable logistic regression models to approximate the results to whole Japanese estimates. Tobacco and tobacco-like products included cigarettes, cigars, e-cigarettes, HTPs, pipes/water pipes, and smokeless tobacco products. Among Japanese adults, 18.4% were single tobacco product users and 3.2% were multiple tobacco product users in 2017. Among current product users (100%), cigarettes were the most popular product in single (78.8%) and multiple (14.2%) tobacco products use, while HTPs were the second most popular product in single (5.2%) and multiple (10.6%) tobacco products use. People with no perception of risk regarding e-cigarettes/HTPs were more likely to use multiple tobacco products (aOR = 1.47, 95% CI = 1.12–1.92) than those who perceived a risk. Prevalence rates and predictors of multiple tobacco products use, including HTPs, were studied first. In multiple tobacco products use, high popularity of HTPs among current product users was revealed. Risk perception of e-cigarettes/HTPs was associated with multiple tobacco products use. This study provides baseline information on multiple tobacco products use in Japan, which will enable the examination of trends in the future.
Specific NDM-1 Inhibitor of Isoliquiritin Enhances the Activity of Meropenem against NDM-1-positive Enterobacteriaceae in vitro
Authors: Wang Yanling , Sun Xiaodi , Kong Fanrong , Xia Lining , Deng Xuming , Wang Dacheng , Wang Jianfeng
Published: March 2020

NDM-1-positive Enterobacteriaceae have caused serious clinical infections, with high mortality rates. Carbapenem was the ultimate expectation for the treatment of such infections in clinical practice. However, since the discovery of plasmid-mediated New Delhi metallo-β-lactamase-1 (NDM-1), the efficient therapeutic effects of carbapenems have been increasingly restricted. Here, we identified isoliquiritin, a novel specific inhibitor of the NDM-1 enzyme that restored the activity of carbapenem against NDM-1-producing E. coli isolates and K. pneumoniae isolates without affecting the growth of bacteria. A checkerboard test, growth curve assays and time-kill assays confirmed the significant synergistic effect of isoliquiritin combined with meropenem in vitro. It is worth noting that isoliquiritin only inhibited the activity of NDM-1 and had no obvious inhibitory effect on other class B metallo-β-lactamases (VIM-1) or NDM-1 mutants (NDM-5). The FIC indices of meropenem with isoliquiritin on NDM-1-positive E. coli and K. pneumoniae were all less than 0.5. Isoliquiritin had no influences on the expression of NDM-1-positive strains at concentrations below 64 µg/mL. Collectively, our results show that isoliquiritin is a potential adjuvant therapy drug that could enhance the antibacterial effect of carbapenems, such as meropenem, on NDM-1-positive Enterobacteria and lay the foundation for subsequent clinical trials.
OsINV3 and Its Homolog, OsINV2, Control Grain Size in Rice
Authors: Deng Xiaoshu , Han Xiaohang , Yu Shicong , Liu Zhijian , Guo Daiming , He Yao , Li Wenyi , Tao Yu , Sun Chaowei , Xu Peizhou , Liao Yongxiang , Chen Xiaoqiong , Zhang Hongyu , Wu Xianjun
Published: March 2020

Vacuolar invertase is involved in sugar metabolism and plays a crucial role in plant growth and development, thus regulating seed size. However, information linking vacuolar invertase and seed size in rice is limited. Here we characterized a small grain mutant sg2 (grain size on chromosome 2) that showed a reduced in grain size and 1000-grain weight compared to the wild type. Map-based cloning and genetic complementation showed that OsINV3 is responsible for the observed phenotype. Loss-of-function of OsINV3 resulted in grains of smaller size when compared to the wild type, while overexpression showed increased grain size. We also obtained a T-DNA insertion mutant of OsINV2, which is a homolog of OsINV3 and generated double knockout (KO) mutants of OsINV2 and OsINV3 using CRISPR/Cas9. Genetic data showed that OsINV2, that has no effect on grain size by itself, reduces grain length and width in the absence of OsINV3. Altered sugar content with increased sucrose and decreased hexose levels, as well as changes vacuolar invertase activities and starch constitution in INV3KO, INV2KO, INV3KOINV2KO mutants indicate that OsINV2 and OsINV3 affect sucrose metabolism in sink organs. In summary, we identified OsINV3 as a positive regulator of grain size in rice, and while OsINV2 has no function on grain size by itself. In the absence of OsINV3, it is possible to detect a role of OsINV2 in the regulation of grain size. Both OsINV3 and OsINV2 are involved in sucrose metabolism, and thus regulate grain size. Our findings increase our understanding of the role of OsINV3 and its homolog, OsINV2, in grain size development and also suggest a potential strategy to improve grain yield in rice.
Myocyte Enhancer Factor 2A (MEF2A) Defines Oxytocin-Induced Morphological Effects and Regulates Mitochondrial Function in Neurons
Authors: Meyer Magdalena , Kuffner Kerstin , Winter Julia , Neumann Inga D. , Wetzel Christian H. , Jurek Benjamin
Published: March 2020

The neuropeptide oxytocin (OT) is a well-described modulator of socio-emotional traits, such as anxiety, stress, social behavior, and pair bonding. However, when dysregulated, it is associated with adverse psychiatric traits, such as various aspects of autism spectrum disorder (ASD). In this study, we identify the transcription factor myocyte enhancer factor 2A (MEF2A) as the common link between OT and cellular changes symptomatic for ASD, encompassing neuronal morphology, connectivity, and mitochondrial function. We provide evidence for MEF2A as the decisive factor defining the cellular response to OT: while OT induces neurite retraction in MEF2A expressing neurons, OT causes neurite outgrowth in absence of MEF2A. A CRISPR-Cas-mediated knockout of MEF2A and retransfection of an active version or permanently inactive mutant, respectively, validated our findings. We also identified the phosphatase calcineurin as the main upstream regulator of OT-induced MEF2A signaling. Further, MEF2A signaling dampens mitochondrial functioning in neurons, as MEF2A knockout cells show increased maximal cellular respiration, spare respiratory capacity, and total cellular ATP. In summary, we reveal a central role for OT-induced MEF2A activity as major regulator of cellular morphology as well as neuronal connectivity and mitochondrial functioning, with broad implications for a potential treatment of disorders based on morphological alterations or mitochondrial dysfunction.
Apical Sodium-Dependent Bile Acid Cotransporter, A Novel Transporter of Indocyanine Green, and Its Application in Drug Screening
Authors: Wu Menq-Rong , Hsiao Jong-Kai
Published: March 2020

Bile acid plays critical roles in the elimination of inorganic compounds such as bilirubin, heavy metals, and drug metabolites. Apical sodium-dependent bile acid cotransporter (ASBT), a solute carrier membrane transport protein, transports bile acids. Several inhibitors of ASBT have been evaluated in clinical trials. Sodium taurocholate cotransporting polypeptide (NTCP), belonging to the same family as ASBT, has fluorescein 5(6)-isothiocyanate (FITC) and indocyanine green (ICG) transportability. ICG, a Food and Drug Administration-approved fluorophore at near-infrared range, has perfect optical characteristics, so it can be applied in cell tracking and drug screening. In this study, ASBT and NTCP were transduced into the HT-1080 cell line. Nude mice were subcutaneously xenografted with control and ASBT-expressing cells. ICG transportability was observed through flow cytometry, fluorescent microscopy, multi-mode plate readers, and an in vivo imaging system. Several molecules, including taurocholate, sodium deoxycholate, cyclosporine A, nifedipine, and Primovist, were used to evaluate an in vitro drug-screening platform by using the combination of ICG and ASBT through flow cytometry. ICG and FITC were validated and shown to be transported by ASBT. NTCP had a higher ICG intensity compared with ASBT. For cell tracking, the ASBT xenograft had similar ICG signals as the control. For a drug-screening platform, the ICG intensity decreased with 186 μM taurocholate (56.8%), deoxycholate (83.8%), and increased with nifedipine (133.2%). These findings are suggestive of opportunities for the high-throughput drug screening of cholestasis and other diseases that are related to the dynamics of bile acid reabsorption.
SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation
Authors: Erazo Tatiana , Espinosa-Gil Sergio , Diéguez-Martínez Nora , Gómez Néstor , Lizcano Jose M
Published: March 2020

The MAP kinase ERK5 contains an N-terminal kinase domain and a unique C-terminal tail including a nuclear localization signal and a transcriptional activation domain. ERK5 is activated in response to growth factors and stresses and regulates transcription at the nucleus by either phosphorylation or interaction with transcription factors. MEK5-ERK5 pathway plays an important role regulating cancer cell proliferation and survival. Therefore, it is important to define the precise molecular mechanisms implicated in ERK5 nucleo-cytoplasmic shuttling. We previously described that the molecular chaperone Hsp90 stabilizes and anchors ERK5 at the cytosol and that ERK5 nuclear shuttling requires Hsp90 dissociation. Here, we show that MEK5 or overexpression of Cdc37—mechanisms that increase nuclear ERK5—induced ERK5 Small Ubiquitin-related Modifier (SUMO)-2 modification at residues Lys6/Lys22 in cancer cells. Furthermore, mutation of these SUMO sites abolished the ability of ERK5 to translocate to the nucleus and to promote prostatic cancer PC-3 cell proliferation. We also show that overexpression of the SUMO protease SENP2 completely abolished endogenous ERK5 nuclear localization in response to epidermal growth factor (EGF) stimulation. These results allow us to propose a more precise mechanism: in response to MEK5 activation, ERK5 SUMOylation favors the dissociation of Hsp90 from the complex, allowing ERK5 nuclear shuttling and activation of the transcription.
VLA-4 Expression and Activation in B Cell Malignancies: Functional and Clinical Aspects
Authors: Härzschel Andrea , Zucchetto Antonella , Gattei Valter , Hartmann Tanja Nicole
Published: March 2020

Lineage commitment and differentiation of hematopoietic cells takes place in well-defined microenvironmental surroundings. Communication with other cell types is a vital prerequisite for the normal functions of the immune system, while disturbances in this communication support the development and progression of neoplastic disease. Integrins such as the integrin very late antigen-4 (VLA-4; CD49d/CD29) control the localization of healthy as well as malignant B cells within the tissue, and thus determine the patterns of organ infiltration. Malignant B cells retain some key characteristics of their normal counterparts, with B cell receptor (BCR) signaling and integrin-mediated adhesion being essential mediators of tumor cell homing, survival and proliferation. It is thus not surprising that targeting the BCR pathway using small molecule inhibitors has proved highly effective in the treatment of B cell malignancies. Attenuation of BCR-dependent lymphoma–microenvironment interactions was, in this regard, described as a main mechanism critically contributing to the efficacy of these agents. Here, we review the contribution of VLA-4 to normal B cell differentiation on the one hand, and to the pathophysiology of B cell malignancies on the other hand. We describe its impact as a prognostic marker, its interplay with BCR signaling and its predictive role for novel BCR-targeting therapies, in chronic lymphocytic leukemia and beyond.
Rapamycin Re-Directs Lysosome Network, Stimulates ER-Remodeling, Involving Membrane CD317 and Affecting Exocytosis, in Campylobacter Jejuni-Lysate-Infected U937 Cells
Authors: Canonico Barbara , Cesarini Erica , Montanari Mariele , Di Sario Gianna , Campana Raffaella , Galluzzi Luca , Sola Federica , Gundogdu Ozan , Luchetti Francesca , Diotallevi Aurora , Baffone Wally , Giordano Antonio , Papa Stefano
Published: March 2020

The Gram-negative Campylobacter jejuni is a major cause of foodborne gastroenteritis in humans worldwide. The cytotoxic effects of Campylobacter have been mainly ascribed to the actions of the cytolethal distending toxin (CDT): it is mandatory to put in evidence risk factors for sequela development, such as reactive arthritis (ReA) and Guillain–Barré syndrome (GBS). Several researches are directed to managing symptom severity and the possible onset of sequelae. We found for the first time that rapamycin (RM) is able to largely inhibit the action of C. jejuni lysate CDT in U937 cells, and to partially avoid the activation of specific sub-lethal effects. In fact, we observed that the ability of this drug to redirect lysosomal compartment, stimulate ER-remodeling (highlighted by ER–lysosome and ER–mitochondria contacts), protect mitochondria network, and downregulate CD317/tetherin, is an important component of membrane microdomains. In particular, lysosomes are involved in the process of the reduction of intoxication, until the final step of lysosome exocytosis. Our results indicate that rapamycin confers protection against C. jejuni bacterial lysate insults to myeloid cells.
Analysis of Selenoprotein Expression in Response to Dietary Selenium Deficiency During Pregnancy Indicates Tissue Specific Differential Expression in Mothers and Sex Specific Changes in the Fetus and Offspring
Authors: Hofstee Pierre , Cuffe James S.M. , Perkins Anthony V.
Published: March 2020

The human selenoproteome is comprised of ~25 genes, which incorporate selenium, in the form of selenocysteine, into their structure. Since it is well known that selenium is important to maternal health and foetal development during pregnancy, this study aimed at defining the impact of selenium deficiency on maternal, placental, foetal and offspring selenoprotein gene expression. Female C57BL/6 mice were randomly allocated to control (>190 μg/kg) or low selenium (<50 μg/kg) diets four weeks prior to mating and throughout gestation. At embryonic day (E)18.5, pregnant mice were sacrificed followed by collection of maternal and foetal tissues. A subset of mice littered down, and offspring were monitored from postnatal day (PN) 8, weaned at PN24 and sacrificed at PN180, followed by tissue collection. Following RNA extraction, the expression of 14 selenoproteins was assessed with qPCR in liver, kidneys, muscle and placenta. Selenium deficiency downregulated expression (Ptrt < 0.05) of many selenoproteins in maternal tissues and the placenta. However, foetal selenoprotein expression was upregulated (Ptrt < 0.05) in all tissues, especially the kidneys. This was not reflected at PN180; however, a sexually dimorphic relationship in selenoprotein expression was observed in offspring. This study demonstrates the selenoproteome is sensitive to dietary selenium levels, which may be exacerbated by pregnancy. We concluded that transcriptional regulation of selenoproteins is complex and multifaceted, with expression exhibiting tissue-, age- and sex-specificities.
Preparation and Characterization of Aptamers Against O,p’-DDT
Authors: Zhang Wei , Li Danyang , Zhang Jianguang , Jiang Lingli , Li Zhaofa , Lin Jun Sheng
Published: March 2020

The compound 1,1,1-trichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl) ethane (o,p’-DDT) has been identified as one of the endocrine-disrupting chemicals causing adverse effects on wildlife and even humans through bioaccumulation. Its detection has become increasingly important. We have obtained candidate aptamers binding to o,p’-DDT by a systematic evolution of ligands by exponential enrichment (SELEX) protocol. Five out of seventeen candidate sequences were selected for preliminary characterization by SYBR Green I assay. One sequence with highest fluorescence response with o,p’-DDT, designated DDT_13, was chosen for further characterization. Its dissociation constant (Kd) was determined to be 412.3 ± 124.6 nM. DDT_13 exhibited low cross-binding activities on other tested small molecules. The good bioactivities of DDT_13 were demonstrated for the analysis of spiked lake water and tap water samples. This study provides a novel o,p’-DDT-specific probe for its future applications.
Metabolites Produced by the Oral Commensal Bacterium Corynebacterium durum Extend the Lifespan of Caenorhabditis elegans via SIR-2.1 Overexpression
Authors: Kim Jun Hyeong , Bang In Hyuk , Noh Yun Jeong , Kim Dae Keun , Bae Eun Ju , Hwang In Hyun
Published: March 2020

Human microbiota is heavily involved in host health, including the aging process. Based on the hypothesis that the human microbiota manipulates host aging via the production of chemical messengers, lifespan-extending activities of the metabolites produced by the oral commensal bacterium Corynebacterium durum and derivatives thereof were evaluated using the model organism Caenorhabditis elegans. Chemical investigation of the acetone extract of a C. durum culture led to the identification of monoamines and N-acetyl monoamines as major metabolites. Phenethylamine and N-acetylphenethylamine induced a potent and dose-dependent increase of the C. elegans lifespan, up to 21.6% and 19.9%, respectively. A mechanistic study revealed that the induction of SIR-2.1, a highly conserved protein associated with the regulation of lifespan, was responsible for the observed increased longevity.
The IL-17A/IL-17RA Axis Is Not Related to Overall Survival and Cancer Stem Cell Modulation in Pancreatic Cancer
Authors: Li Jiahui , Betzler Christopher , Lohneis Philipp , Popp Marie Christine , Qin Jiwei , Kalinski Thomas , Wartmann Thomas , Bruns Christiane J. , Zhao Yue , Popp Felix C.
Published: March 2020

(1) Background: IL-17A accelerates pancreatic intraepithelial neoplasia (PanIN) progression. In this study, we examined whether IL-17A/IL-17RA promotes pancreatic ductal adenocarcinoma (PDAC) aggressiveness in terms of survival and cancer stem cell modulation. (2) Methods: In vitro, the wound-healing assay, the sphere formation assay, and flow cytometry were applied to assess cancer stem cell features. In vivo, pancreatic tumors were induced in C57BL/6 mice using electroporation with oncogenic plasmids (P53-/- R172H; KrasG12V). Anti-IL-17 antibodies were administered as immunotherapy. We analyzed IL-17A/IL-17RA related survival using publicly available transcriptomic data (n = 903). (3) Results: IL-17A/IL-17RA expression was not related to survival in PDAC patients. IL-17A neither induces stem cell markers nor increases sphere formation and cell motility in vitro. Blocking the IL-17A/IL-17RA axis in a murine pancreatic cancer model did not improve the survival of mice, but reduced the tumor burden slightly. (4) Conclusions: IL-17A does not promote stem cell expansion in PDAC cell lines. Blocking IL-17A/IL-17RA signaling does not interfere with pancreatic cancer development and progression and may not be considered as a promising monotherapy for PDAC.
Fli-1 Activation through Targeted Promoter Activity Regulation Using a Novel 3’, 5’-diprenylated Chalcone Inhibits Growth and Metastasis of Prostate Cancer Cells
Authors: Ma Youfen , Xu Bixue , Yu Jia , Huang Lirong , Zeng Xiaoping , Shen Xiangchun , Ren Chunyan , Ben-David Yaacov , Luo Heng
Published: March 2020

The friend leukemia integration 1 (Fli-1) gene is involved in the expression control of key genes in multiple pathogenic/physiological processes, including cell growth, differentiation, and apoptosis; this implies that Fli-1 is a strong candidate for drug development. In our previous study, a 3′,5′-diprenylated chalcone, (E)-1-(2-hydroxy-4-methoxy-3,5-diprenyl) phenyl-3-(3-pyridinyl)-propene-1-one (C10), was identified as a novel anti-prostate cancer (PCa) agent. Here, we investigated the molecular mechanisms underlying the anti-cancer effects of C10 on the growth, metastasis, and invasion of PC3 cells in vitro. Our results show that C10 exhibited a strong inhibitory effect on proliferation and metastasis of PC3 cells via several cellular and flow cytometric analyses. Further mechanism studies revealed that C10 likely serves as an Fli-1 agonist for regulating the expression of Fli-1 target genes including phosphatidylinositol 3-kinase (P110), murine double minute2 (MDM2), B-cell lymphoma-2 (Bcl-2), Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP-1), and globin transcription factor-1 (Gata-1) as well as the phosphorylation of extracellular-regulated protein kinases 1 (ERK1). Further, we confirmed that C10 can regulate the expressions of vascular endothelial growth factor 1 (VEGF-1), transforming growth factor-β2 (TGF-β2), intercellular cell adhesion molecule-1 (ICAM-1), p53, and matrix metalloproteinase 1 (MMP-1) genes associated with tumor apoptosis, migration, and invasion. Thus, C10 exhibits stronger anticancer activity with novel molecular targets and regulatory molecular mechanisms, indicating its great potency for development as a novel targeted anticancer drug.
Plant-Based Antidiabetic Nanoformulations: The Emerging Paradigm for Effective Therapy
Authors: Dewanjee Saikat , Chakraborty Pratik , Mukherjee Biswajit , De Feo Vincenzo
Published: March 2020

Diabetes mellitus is a life-threatening metabolic syndrome. Over the past few decades, the incidence of diabetes has climbed exponentially. Several therapeutic approaches have been undertaken, but the occurrence and risk still remain unabated. Several plant-derived small molecules have been proposed to be effective against diabetes and associated vascular complications via acting on several therapeutic targets. In addition, the biocompatibility of these phytochemicals increasingly enhances the interest of exploiting them as therapeutic negotiators. However, poor pharmacokinetic and biopharmaceutical attributes of these phytochemicals largely restrict their clinical usefulness as therapeutic agents. Several pharmaceutical attempts have been undertaken to enhance their compliance and therapeutic efficacy. In this regard, the application of nanotechnology has been proven to be the best approach to improve the compliance and clinical efficacy by overturning the pharmacokinetic and biopharmaceutical obstacles associated with the plant-derived antidiabetic agents. This review gives a comprehensive and up-to-date overview of the nanoformulations of phytochemicals in the management of diabetes and associated complications. The effects of nanosizing on pharmacokinetic, biopharmaceutical and therapeutic profiles of plant-derived small molecules, such as curcumin, resveratrol, naringenin, quercetin, apigenin, baicalin, luteolin, rosmarinic acid, berberine, gymnemic acid, emodin, scutellarin, catechins, thymoquinone, ferulic acid, stevioside, and others have been discussed comprehensively in this review.