bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk Factors Affecting Traffic Accidents at Urban Weaving Sections: Evidence from China
Authors: Mao Xinhua , Yuan Changwei , Gan Jiahua , Zhang Shiqing
Published: May 2019

As a critical configuration of interchanges, the weaving section is inclined to be involved in more traffic accidents, which may bring about severe casualties. To identify the factors associated with traffic accidents at the weaving section, we employed the multinomial logistic regression approach to identify the correlation between six categories of risk factors (drivers’ attributes, weather conditions, traffic characteristics, driving behavior, vehicle types and temporal-spatial distribution) and four types of traffic accidents (rear-end, side wipe, collision with fixtures and rollover) based on 768 accident samples of an observed weaving section from 2016 to 2018. The modeling results show that drivers’ gender and age, weather condition, traffic density, weaving ratio, vehicle speed, lane change behavior, private cars, season, time period, day of week and accident location are important factors affecting traffic accidents at the weaving section, but they have different contributions to the four traffic accident types. The results also show that traffic density of ≥31 vehicle/100 m has the highest risk of causing rear-end accidents, weaving ration of ≥41% has the highest possibility to bring about a side wipe incident, collision with fixtures is the most likely to happen in snowy weather, and rollover is the most likely incident to occur in rainy weather.
Long-Acting Reversible Contraception Uptake and Associated Factors among Women of Reproductive Age in Rural Kenya
Authors: Ontiri Susan , Ndirangu Gathari , Kabue Mark , Biesma Regien , Stekelenburg Jelle , Ouma Collins
Published: May 2019

In the last two decades, the use of short-acting methods of contraception has driven the increase of contraceptive use in Kenya. We assessed the factors associated with uptake of long-acting reversible contraception by women seeking family planning services in public health facilities in Kakamega County, Kenya. A mixed methods cross-sectional study through client exit surveys among 423 women seeking family planning services was done at 12 public health facilities in Kakamega County. Twelve in-depth interviews with health care providers from the study facilities further explored practices in provision of long-acting reversible contraception (LARC). Among women initiating contraceptive use, LARC method utilization was 20.6%. Women’s tertiary education level, Protestant Christian religion, age at first birth, and having no desire for more children were significantly associated with utilization of LARC. Structural factors including shortage of human resource, provider bias and lack of adequate skills on provision of services were identified as key barriers to uptake of long-acting reversible contraception services.
The Relationship between the HLA-G Polymorphism and sHLA-G Levels in Parental Pairs with High-Risk Pregnancy
Authors: Sipak Olimpia , Rył Aleksandra , Grzywacz Anna , Laszczyńska Maria , Zimny Małgorzata , Karakiewicz Beata , Rotter Iwona , Kosik-Bogacka Danuta , Cybulski Cezary
Published: May 2019

Human leukocyte antigen G (HLA-G) is observed in immune system cells and other organs. It is a class Ib molecule, which plays a pivotal role in the implantation and maintenance of pregnancy. The aim of this study was to assess the relationship between serum sHLA-G levels and the HLA-G allele in parental pairs with complicated obstetric histories. The clinical material consisted of 210 women and 190 men with the experience of a complicated or an unsuccessful pregnancy. The control group included parents―89 women and 86 men―lacking complicated obstetric histories. We applied genetic analysis methods: isolation of genomic DNA, sequencing, and determination of serum sHLA-G levels. There were no statistically significant differences in the frequencies of the HLA-G −725 C>G polymorphism between particular experimental groups compared with the control group (p > 0.05). The median sHLA-G levels in the women with the HLA-G10101 allele (15.4 U/mL) were significantly higher than in the women with other alleles (p < 0.05). The HLA-G 10101 allele seems to protect against antiphospholipid syndrome, which may be associated with increased serum sHLA-G levels in its carriers. The relationship between serum sHLA-G levels and the HLA-G polymorphisms in the Polish population requires further investigation.
Factors Leading Municipal Authorities to Implement Preventive Interventions for Lyme Disease
Authors: Jacob Johann , Valois Pierre , Aenishaenslin Cécile , Bouchard Catherine , Briand Sandie , Talbot Denis , Tessier Maxime
Published: May 2019

The aim of this study is to document climate change adaptation interventions targeting Lyme disease at the municipal level in the province of Quebec (Canada). This exploratory study relies on the theory of planned behavior and certain constructs from the health belief model to identify the factors leading municipal authorities to implement preventive interventions for Lyme disease (PILD). Data were obtained from an online survey sent, during the summer of 2018, to municipal officers in 820 municipalities in Quebec, in all health regions where the population is at risk of contracting Lyme disease (response rate = 36%). The questionnaire was used to measure the implementation of PILD, the intention to implement these interventions, attitudes, perceived social pressure, perceived control (levers and barriers) over interventions, perceived effectiveness of preventive measures, risk, and perceived vulnerability. Results of structural equation analyses showed that attitudes were significantly associated with municipal authorities’ intention to implement PILD, while the intention to implement PILD was a significant predictor of the implementation of PILD. Additional analyses showed that perceived barriers added a moderating effect in the intention-implementation relationship. The prediction of behaviors or practices that municipal authorities could implement to prevent Lyme disease will enable the evaluation over time of the evolution of Quebec municipalities’ adaptation to Lyme disease. Moreover, the examination of the associations of specific psychosocial factors revealed important implications for the design of effective behavior-change interventions, which would allow health officials doing awareness work to create personalized interventions better suited to municipal officers and their specific contexts.
Key Messages in an Early Childhood Obesity Prevention Intervention: Are They Recalled and Do They Impact Children’s Behaviour?
Authors: Ray Carola , Campbell Karen , Hesketh Kylie D.
Published: May 2019

Knowledge of the impact of health messages as an intervention strategy is sparse. The aim of this study was to explore recall and use of health behaviour messages among mothers, and whether recall is associated with child health behaviours. Intervention group data from the 15 months Melbourne Infant Feeding, Activity and Nutrition Trial (InFANT) were used (n = 127, children 4 months at commencement). Mothers recalled (unprompted then prompted) at 2 and 3.5 years post-intervention six key messages used in the program, and reported whether they had used them. Children’s food intake was measured by three days of 24-h recall; physical activity by accelerometers; and television viewing by parent report. Unprompted recall ranged between 1–56% across messages and follow-up points, and 37–90% for prompted recall. The most commonly recalled messages “tap into water”, “parents provide, kids decide” and “color every meal with fruit and veg” were also most commonly used. There were few associations between recall and children’s health behaviours. Given the association between recall and reported use, it is important to plan messages so they resonate well with the target group and its needs. Messages should be used as one of multiple strategies within health promotion programs.
Capturing and Characterizing Human Activities Using Building Locations in America
Authors: Ren Zheng , Jiang Bin , Seipel Stefan
Published: May 2019

Capturing and characterizing collective human activities in a geographic space have become much easier than ever before in the big era. In the past few decades it has been difficult to acquire the spatiotemporal information of human beings. Thanks to the boom in the use of mobile devices integrated with positioning systems and location-based social media data, we can easily acquire the spatial and temporal information of social media users. Previous studies have successfully used street nodes and geo-tagged social media such as Twitter to predict users’ activities. However, whether human activities can be well represented by social media data remains uncertain. On the other hand, buildings or architectures are permanent and reliable representations of human activities collectively through historical footprints. This study aims to use the big data of US building footprints to investigate the reliability of social media users for human activity prediction. We created spatial clusters from 125 million buildings and 1.48 million Twitter points in the US. We further examined and compared the spatial and statistical distribution of clusters at both country and city levels. The result of this study shows that both building and Twitter data spatial clusters show the scaling pattern measured by the scale of spatial clusters, respectively, characterized by the number points inside clusters and the area of clusters. More specifically, at the country level, the statistical distribution of the building spatial clusters fits power law distribution. Inside the four largest cities, the hotspots are power-law-distributed with the power law exponent around 2.0, meaning that they also follow the Zipf’s law. The correlations between the number of buildings and the number of tweets are very plausible, with the r square ranging from 0.53 to 0.74. The high correlation and the similarity of two datasets in terms of spatial and statistical distribution suggest that, although social media users are only a proportion of the entire population, the spatial clusters from geographical big data is a good and accurate representation of overall human activities. This study also indicates that using an improved method for spatial clustering is more suitable for big data analysis than the conventional clustering methods based on Euclidean geometry.
Spatial Pattern Consistency among Different Remote-Sensing Land Cover Datasets: A Case Study in Northern Laos
Authors: Kang Junmei , Sui Lichun , Yang Xiaomei , Wang Zhihua , Huang Chong , Wang Jun
Published: May 2019

Comparisons of the accuracy and consistency of different remote-sensing land cover datasets are important for the rational application of multi-source land cover datasets to regional development, or to studies of global or local environmental change. Existing comparisons of accuracy or spatial consistency among land cover datasets primarily use confusion or transfer matrices and focus on the type and area consistency of land cover. However, less attention has been paid to the consistency of spatial patterns, and quantitative analyses of spatial pattern consistency are rare. However, when proportions of land cover types are similar, spatial patterns are essential for studies of the ecological functions of a landscape system. In this study, we used classical landscape indices that quantifies spatial patterns to analyze the spatial pattern consistency among different land cover datasets, and chose three datasets (GlobeLand30-2010, FROM-GLC2010, and SERVIR MEKONG2010) in northern Laos as a case study. We also analyzed spatial pattern consistency at different scales after comparing the landscape indices method with the confusion matrix method. We found that the degree of consistency between GlobeLand30-2010 and SERVIR MEKONG2010 was higher than that of GlobeLand30-2010 and FROM-GLC2010, FROM-GLC2010, and SERVIR MEKONG2010 based on the confusion matrix, mainly because of the best forest consistency and then water. However, the spatial consistency results of the landscape indices analysis show that the three datasets have large differences in the number of patches (NP), patch density (PD), and landscape shape index (LSI) at the original scale of 30 m, and decrease with the increase of the scale. Meanwhile, the aggregation index (AI) shows different changes, such as the changing trend of the forest aggregation index increasing with the scale. Our results suggested that, when using or producing land cover datasets, it is necessary not only to ensure the consistency of landscape types and areas, but also to ensure that differences among spatial patterns are minimized, especially those exacerbated by scale. Attention to these factors will avoid larger deviations and even erroneous conclusions from these data products.
Biochemical Characterization of a New β-Agarase from Cellulophaga algicola
Authors: Han Zhenggang , Zhang Yuxi , Yang Jiangke
Published: May 2019

Cellulophaga algicola DSM 14237, isolated from the Eastern Antarctic coastal zone, was found to be able to hydrolyze several types of polysaccharide materials. In this study, a predicted β-agarase (CaAga1) from C. algicola was heterologously expressed in Escherichia coli. The purified recombinant CaAga1 showed specific activities of 29.39, 20.20, 14.12, and 8.99 U/mg toward agarose, pure agar, and crude agars from Gracilaria lemaneiformis and Porphyra haitanensis, respectively. CaAga1 exhibited an optimal temperature and pH of 40 °C and 7, respectively. CaAga1 was stable over a wide pH range from 4 to 11. The recombinant enzyme showed an unusual thermostability, that is, it was stable at temperature below or equal to 40 °C and around 70 °C, but was thermolabile at about 50 °C. With the agarose as the substrate, the Km and Vmax values for CaAga1 were 1.19 mg/mL and 36.21 U/mg, respectively. The reducing reagent (dithiothreitol) enhanced the activity of CaAga1 by more than one fold. In addition, CaAga1 was salt-tolerant given that it retained approximately 70% of the maximum activity in the presence of 2 M NaCl. The thin layer chromatography results indicated that CaAga1 is an endo-type β-agarase and efficiently hydrolyzed agarose into neoagarotetraose (NA4) and neoagarohexaose (NA6). A structural model of CaAga1 in complex with neoagarooctaose (NA8) was built by homology modeling and explained the hydrolysis pattern of CaAga1.
Multifaceted Functional Role of Semaphorins in Glioblastoma
Authors: Angelucci Cristiana , Lama Gina , Sica Gigliola
Published: May 2019

Glioblastoma (GBM) is the most malignant tumor type affecting the adult central nervous system. Despite advances in therapy, the prognosis for patients with GBM remains poor, with a median survival of about 15 months. To date, few treatment options are available and recent trials based on the molecular targeting of some of the GBM hallmark pathways (e.g., angiogenesis) have not produced any significant improvement in overall survival. The urgent need to develop more efficacious targeted therapies has led to a better molecular characterization of GBM, revealing an emerging role of semaphorins in GBM progression. Semphorins are a wide group of membrane-bound and secreted proteins, originally identified as axon guidance cues, signaling through their receptors, neuropilins, and plexins. A number of semaphorin signals involved in the control of axonal growth and navigation during development have been found to furthermore participate in crosstalk with different dysfunctional GBM pathways, controlling tumor cell proliferation, migration, and invasion, as well as tumor angiogenesis or immune response. In this review, we summarize the regulatory activities mediated by semaphorins and their receptors on the oncogenic pathways implicated in GBM growth and invasive/metastatic progression.
MicroRNA Involvement in Allergic and Non-Allergic Mast Cell Activation
Authors: Shefler Irit , Salamon Pazit , Mekori Yoseph A.
Published: May 2019

Allergic inflammation is accompanied by the coordinated expression of numerous genes and proteins that initiate, sustain, and propagate immune responses and tissue remodeling. MicroRNAs (miRNAs) are a large class of small regulatory molecules that are able to control the translation of target mRNAs and consequently regulate various biological processes at the posttranscriptional level. MiRNA profiles have been identified in multiple allergic inflammatory diseases and in the tumor microenvironment. Mast cells have been found to co-localize within the above conditions. More specifically, in addition to being essential in initiating the allergic response, mast cells play a key role in both innate and adaptive immunity as well as in modulating tumor growth. This review summarizes the possible role of various miRNAs in the above-mentioned processes wherein mast cells have been found to be involved. Understanding the role of miRNAs in mast cell activation and function may serve as an important tool in developing diagnostic as well as therapeutic approaches in mast cell-dependent pathological conditions.
Calcium-Binding Proteins as Determinants of Central Nervous System Neuronal Vulnerability to Disease
Authors: Fairless Richard , Williams Sarah K. , Diem Ricarda
Published: May 2019

Neuronal subpopulations display differential vulnerabilities to disease, but the factors that determine their susceptibility are poorly understood. Toxic increases in intracellular calcium are a key factor in several neurodegenerative processes, with calcium-binding proteins providing an important first line of defense through their ability to buffer incoming calcium, allowing the neuron to quickly achieve homeostasis. Since neurons expressing different calcium-binding proteins have been reported to be differentially susceptible to degeneration, it can be hypothesized that rather than just serving as markers of different neuronal subpopulations, they might actually be a key determinant of survival. In this review, we will summarize some of the evidence that expression of the EF-hand calcium-binding proteins, calbindin, calretinin and parvalbumin, may influence the susceptibility of distinct neuronal subpopulations to disease processes.
Antioxidant and Photoprotective Activity of Apigenin and its Potassium Salt Derivative in Human Keratinocytes and Absorption in Caco-2 Cell Monolayers
Authors: Sánchez-Marzo Noelia , Pérez-Sánchez Almudena , Ruiz-Torres Verónica , Martínez-Tébar Adrián , Castillo Julián , Herranz-López María , Barrajón-Catalán Enrique
Published: May 2019

Ultraviolet (UV) radiation, especially types A (UVA) and B (UVB), is one of the main causes of skin disorders, including photoaging and skin cancer. Ultraviolent radiation causes oxidative stress, inflammation, p53 induction, DNA damage, mutagenesis, and oxidation of various molecules such as lipids and proteins. In recent decades, the use of polyphenols as molecules with an antioxidant and anti-inflammatory capacity has increased. However, some of these compounds are poorly soluble, and information regarding their absorption and bioavailability is scarce. The main objective of this study was to compare the intestinal absorption and biological activity of apigenin and its more soluble potassium salt (apigenin-K) in terms of antioxidant and photoprotective capacity. Photoprotective effects against UVA and UVB radiation were studied in human keratinocytes, and antioxidant capacity was determined by different methods, including trolox equivalent antioxidant capacity (TEAC), ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays. Finally, the intestinal absorption of both apigenins was determined using an in vitro Caco-2 cell model. Apigenin showed a slightly higher antioxidant capacity in antioxidant activity assays when compared with apigenin-K. However, no significant differences were obtained for their photoprotective capacities against UVA or UVB. Results indicated that both apigenins protected cell viability in approximately 50% at 5 J/m2 of UVA and 90% at 500 J/m2 of UVB radiation. Regarding intestinal absorption, both apigenins showed similar apparent permeabilities (Papp), 1.81 × 10−5 cm/s and 1.78 × 10−5 cm/s, respectively. Taken together, these results suggest that both apigenins may be interesting candidates for the development of oral (nutraceutical) and topical photoprotective ingredients against UVA and UVB-induced skin damage, but the increased water solubility of apigenin-K makes it the best candidate for further development.
β3-Adrenoreceptor Activity Limits Apigenin Efficacy in Ewing Sarcoma Cells: A Dual Approach to Prevent Cell Survival
Authors: Pasha Amada , Vignoli Marina , Subbiani Angela , Nocentini Alessio , Selleri Silvia , Gratteri Paola , Dabraio Annalisa , Casini Tommaso , Filippi Luca , Fotzi Ilaria , Favre Claudio , Calvani Maura
Published: May 2019

Ewing Sarcoma (ES) is an aggressive paediatric tumour where oxidative stress and antioxidants play a central role in cancer therapy response. Inhibiting antioxidants expression, while at the same time elevating intracellular reactive oxygen species (ROS) levels, have been proposed as a valid strategy to overcome ES cancer progression. Flavonoid intake can affect free radical and nutritional status in children receiving cancer treatment, but it is not clear if it can arrest cancer progression. In particular, apigenin may enhance the effect of cytotoxic chemotherapy by inducing cell growth arrest, apoptosis, and by altering the redox state of the cells. Little is known about the use of apigenin in paediatric cancer. Recently, β3-adrenergic receptor (β3-AR) antagonism has been proposed as a possible strategy in cancer therapy for its ability to induce apoptosis by increasing intracellular levels of ROS. In this study we show that apigenin induces cell death in ES cells by modulating apoptosis, but not increasing ROS content. Since ES cells are susceptible to an increased oxidative stress to reduce cell viability, here we demonstrate that administration of β3-ARs antagonist, SR59230A, improves the apigenin effect on cell death, identifying β3-AR as a potential discriminating factor that could address the use of apigenin in ES.
Changes of Circulating Extracellular Vesicles from the Liver after Roux-en-Y Bariatric Surgery
Authors: Rega-Kaun Gersina , Ritzel Dorothea , Kaun Christoph , Ebenbauer Benjamin , Thaler Barbara , Prager Manfred , Demyanets Svitlana , Wojta Johann , Hohensinner Philipp J.
Published: May 2019

Circulating extracellular vesicles are small particles enclosed by a phospholipid bilayer. Vesicles deriving directly from the cellular membrane by an active budding process retain cell origin specific proteins and RNA. These vesicles carry pathophysiological information from their parental cell and hold the potential to allow analysis of organs without the need for a biopsy. We included in our study 27 patients undergoing bariatric surgery. Hepatic extracellular vesicles were determined by flow cytometry. mRNA specific for hepatic cellular origin was determined in the extracellular vesicle fraction using qPCR. Surgery led to a massive reduction of weight and overall hepatic stress as determined by alanine transaminase (ALT), aspartate transaminase (AST) and γ-glutamyltransferase (GGT). Total extracellular vesicle numbers were reduced after bariatric surgery. Liver specific vesicles identified by HepPar1 or asialoglycoprotein receptor (ASGPR) were significantly reduced after bariatric surgery in both AnnexinV+ and AnnexinV− subgroups. When analyzing circulating liver-specific mRNAs, we found reduced levels of these mRNAs after surgery even though total circulating RNA remained unchanged. We conclude that circulating hepatic extracellular vesicles are detectable in samples from patients undergoing gastric bypass surgery. These vesicles are reduced after a reduction of hepatic stress also observed with classic liver enzyme measurements. We conclude that ASGPR or HepPar positive vesicles hold the potential to serve as liver specific vesicle markers.
Inflammatory, Serological and Vascular Determinants of Cardiovascular Disease in Systemic Lupus Erythematosus Patients
Authors: Mercurio Valentina , Lobasso Antonio , Barbieri Letizia , Parrella Paolo , Ciervo Deasy , Liccardo Bianca , Bonaduce Domenico , Tocchetti Carlo G. , De Paulis Amato , Rossi Francesca W.
Published: May 2019

Background and aim: Systemic lupus erythematosus (SLE) is associated with increased risk of cardiovascular disease (CVD). Among many mechanisms, accelerated atherosclerosis, endothelial dysfunction, and hypercoagulability play a main role. Here, we investigate whether inflammatory, serological and clinical markers of SLE determine and correlate with arterial stiffness in SLE patients. Materials and methods: Routine blood samples, inflammatory mediators, specific antibodies, and 24 h proteinuria were measured in 43 SLE patients and 43 age and sex-matched controls using routine laboratory assays. We also assessed arterial stiffness by measuring radial artery applanation tonometry-derived augmentation index (AI), normalized AI (AIx@75), aortic pulse pressure, central systolic, diastolic and peripheral blood pressure. Results: SLE patients showed a significantly greater arterial stiffness vs. controls, as demonstrated by the significantly higher AIx@75 and aortic pulse pressure. Interestingly, regression analysis showed that age, systolic pulse pressure, inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), daily dose of glucocorticoids, and cumulative organ damage positively correlated with arterial stiffness. Conclusions: SLE patients show increased arterial stiffness which correlates with markers of inflammation, that is involved in early alterations in arterial walls. Applanation tonometry can be used to screen SLE patients for subclinical vascular damage to implement prevention strategies for CVD.
Resveratrol and Vascular Function
Authors: Li Huige , Xia Ning , Hasselwander Solveig , Daiber Andreas
Published: May 2019

Resveratrol increases the production of nitric oxide (NO) in endothelial cells by upregulating the expression of endothelial NO synthase (eNOS), stimulating eNOS enzymatic activity, and preventing eNOS uncoupling. At the same time, resveratrol inhibits the synthesis of endothelin-1 and reduces oxidative stress in both endothelial cells and smooth muscle cells. Pathological stimuli-induced smooth muscle cell proliferation, vascular remodeling, and arterial stiffness can be ameliorated by resveratrol as well. In addition, resveratrol also modulates immune cell function, inhibition of immune cell infiltration into the vascular wall, and improves the function of perivascular adipose tissue. All these mechanisms contribute to the protective effects of resveratrol on vascular function and blood pressure in vivo. Sirtuin 1, AMP-activated protein kinase, and estrogen receptors represent the major molecules mediating the vascular effects of resveratrol.
Dendritic Cell-Mediated Th2 Immunity and Immune Disorders
Authors: Kumar Sunil , Jeong Yideul , Ashraf Muhammad Umer , Bae Yong-Soo
Published: May 2019

Dendritic cells (DCs) are the professional antigen-presenting cells that recognize and present antigens to naïve T cells to induce antigen-specific adaptive immunity. Among the T-cell subsets, T helper type 2 (Th2) cells produce the humoral immune responses required for protection against helminthic disease by activating B cells. DCs induce a Th2 immune response at a certain immune environment. Basophil, eosinophil, mast cells, and type 2 innate lymphoid cells also induce Th2 immunity. However, in the case of DCs, controversy remains regarding which subsets of DCs induce Th2 immunity, which genes in DCs are directly or indirectly involved in inducing Th2 immunity, and the detailed mechanisms underlying induction, regulation, or maintenance of the DC-mediated Th2 immunity against allergic environments and parasite infection. A recent study has shown that a genetic defect in DCs causes an enhanced Th2 immunity leading to severe atopic dermatitis. We summarize the Th2 immune-inducing DC subsets, the genetic and environmental factors involved in DC-mediated Th2 immunity, and current therapeutic approaches for Th2-mediated immune disorders. This review is to provide an improved understanding of DC-mediated Th2 immunity and Th1/Th2 immune balancing, leading to control over their adverse consequences.
Bisphenol A Activates Calcium Influx in Immortalized GnRH Neurons
Authors: Ruffinatti Federico Alessandro , Gilardino Alessandra , Secchi Valter , Cottone Erika , Lovisolo Davide , Bovolin Patrizia
Published: May 2019

Bisphenol A (BPA) is one of the most widely used chemicals worldwide, e.g., as a component of plastic containers for food and water. It is considered to exert an estrogenic effect, by mimicking estradiol (E2) action. Because of this widespread presence, it has attracted the interest and concern of researchers and regulators. Despite the vast amount of related literature, the potential adverse effects of environmentally significant doses of BPA are still object of controversy, and the mechanisms by which it can perturb endocrine functions, and particularly the neuroendocrine axis, are not adequately understood. One of the ways by which endocrine disruptors (EDCs) can exert their effects is the perturbation of calcium signaling mechanisms. In this study, we addressed the issue of the impact of BPA on the neuroendocrine system with an in vitro approach, using a consolidated model of immortalized Gonadotropin-Releasing Hormone (GnRH) expressing neurons, the GT1–7 cell line, focusing on the calcium signals activated by the endocrine disruptor. The investigation was limited to biologically relevant doses (nM–µM range). We found that BPA induced moderate increases in intracellular calcium concentration, comparable with those induced by nanomolar doses of E2, without affecting cell survival and with only a minor effect on proliferation.
Targeting Apolipoprotein E for Alzheimer’s Disease: An Industry Perspective
Authors: Suidan Georgette L. , Ramaswamy Gayathri
Published: May 2019

Apolipoprotein E (apoE), a key lipid transport protein in the brain, is predominantly produced by astrocytes. Astrocytes are the most numerous cell type in the brain and are the main support network for neurons. They play a critical role in the synthesis and delivery of cholesterol in the brain. Humans have three common apoE isoforms, apoE2, apoE3 and apoE4, that show a strong genotype effect on the risk and age of onset for sporadic and late onset forms of Alzheimer’s disease (AD). Carriers of an ε4 allele have an increased risk of developing AD, while those with an ε2 allele are protected. Investigations into the contribution of apoE to the development of AD has yielded conflicting results and there is still much speculation about the role of this protein in disease. Here, we review the opposing hypotheses currently described in the literature and the approaches that have been considered for targeting apoE as a novel therapeutic strategy for AD. Additionally, we provide our perspective on the rationale for targeting apoE and the challenges that arise with respect to “drug-ability” of this target.
Extracellular Vesicles in Human Oogenesis and Implantation
Authors: Andronico Francesca , Battaglia Rosalia , Ragusa Marco , Barbagallo Davide , Purrello Michele , Di Pietro Cinzia
Published: May 2019

Reproduction, the ability to generate offspring, represents one of the most important biological processes, being essential for the conservation of the species. In mammals, it involves different cell types, tissues and organs, which, by several signaling molecules, coordinate the different events such as gametogenesis, fertilization and embryo development. In the last few years, the role of Extracellular Vesicles, as mediators of cell communication, has been investigated in every phase of these complex processes. Microvesicles and exosomes, identified in the fluid of ovarian follicles during egg maturation, are involved in communication between the developing oocyte and the somatic follicular cells. More recently, it has been demonstrated that, during implantation, Extracellular Vesicles could participate in the complex dialog between the embryo and maternal tissues. In this review, we will focus our attention on extracellular vesicles and their cargo in human female reproduction, mainly underlining the involvement of microRNAs in intercellular communication during the several phases of the reproductive process.
Tetrahydrocannabinol Reduces Hapten-Driven Mast Cell Accumulation and Persistent Tactile Sensitivity in Mouse Model of Allergen-Provoked Localized Vulvodynia
Authors: Boo Beebie , Kamath Rohit , Arriaga-Gomez Erica , Landry Jasmine , Emanuel Elizabeth , Joo Sookyong , Saldías Montivero Marietta , Martinov Tijana , Fife Brian T. , Chatterjea Devavani
Published: May 2019

Vulvodynia is a remarkably prevalent chronic pain condition of unknown etiology. An increase in numbers of vulvar mast cells often accompanies a clinical diagnosis of vulvodynia and a history of allergies amplifies the risk of developing this condition. We previously showed that repeated exposures to oxazolone dissolved in ethanol on the labiar skin of mice led to persistent genital sensitivity to pressure and a sustained increase in labiar mast cells. Here we sensitized female mice to the hapten dinitrofluorobenzene (DNFB) dissolved in saline on their flanks, and subsequently challenged them with the same hapten or saline vehicle alone for ten consecutive days either on labiar skin or in the vaginal canal. We evaluated tactile ano-genital sensitivity, and tissue inflammation at serial timepoints. DNFB-challenged mice developed significant, persistent tactile sensitivity. Allergic sites showed mast cell accumulation, infiltration of resident memory CD8+CD103+ T cells, early, localized increases in eosinophils and neutrophils, and sustained elevation of serum Immunoglobulin E (IgE). Therapeutic intra-vaginal administration of Δ9-tetrahydrocannabinol (THC) reduced mast cell accumulation and tactile sensitivity. Mast cell-targeted therapeutic strategies may therefore provide new ways to manage and treat vulvar pain potentially instigated by repeated allergenic exposures.
Ectopic Expression of Jatropha curcas TREHALOSE-6-PHOSPHATE PHOSPHATASE J Causes Late-Flowering and Heterostylous Phenotypes in Arabidopsis but not in Jatropha
Authors: Zhao Mei-Li , Ni Jun , Chen Mao-Sheng , Xu Zeng-Fu
Published: May 2019

Trehalose-6-phosphate (T6P) phosphatase (TPP), a dephosphorylating enzyme, catalyzes the dephosphorylation of T6P, generating trehalose. In Jatropha, we found six members of the TPP family. Five of them JcTPPA, JcTPPC, JcTPPD, JcTPPG, and JcTPPJ are highly expressed in female flowers or male flowers, or both, suggesting that members of the JcTPP family may participate in flower development in Jatropha. The wide expression of JcTPPJ gene in various organs implied its versatile roles and thus was chosen for unraveling its biological functions during developmental process. We constructed an overexpression vector of JcTPPJ cDNA driven by the cauliflower mosaic virus (CaMV) 35S promoter for genetic transformation. Compared with control Arabidopsis plants, 35S:JcTPPJ transgenic Arabidopsis plants presented greater sucrose contents in their inflorescences and displayed late-flowering and heterostylous phenotypes. Exogenous application of sucrose to the inflorescence buds of wild-type Arabidopsis repressed the development of the perianth and filaments, with a phenocopy of the 35S:JcTPPJ transgenic Arabidopsis. These results suggested that the significantly increased sucrose level in the inflorescence caused (or induced) by JcTTPJ overexpression, was responsible for the formation of heterostylous flower phenotype. However, 35S:JcTPPJ transgenic Jatropha displayed no obvious phenotypic changes, implying that JcTPPJ alone may not be sufficient for regulating flower development in Jatropha. Our results are helpful for understanding the function of TPPs, which may regulate flower organ development by manipulating the sucrose status in plants.
A New Analytical Method for Determination of Cathepsin L Based on the Surface Plasmon Resonance Imaging Biosensor
Authors: Tokarzewicz Anna , Romanowicz Lech , Sankiewicz Anna , Hermanowicz Adam , Sobolewski Krzysztof , Gorodkiewicz Ewa
Published: May 2019

The purpose of this study was to develop a new method for a determination of the cathepsin L—biosensor based on the Surface Plasmon Resonance Imaging technique. The cathepsin L is an endopeptidase, which degrades proteins and plays an important role in various processes occurring in the human body. The detection technique, Surface Plasmon Resonance Imaging, is an optical, label-free technique, which can be used for quantitative determination of the different proteins. In order to bind the enzyme, the cathepsin L inhibitor—RKLLW-NH2 was used. The validation process showed that parameters: precision, accuracy, and selectivity of the method were acceptable. The analytically useful range of the standard curve was 0.50 ng/mL—15.00 ng/mL. The detection and quantification limit of method was 1.67 pg/mL and 5.07 pg/mL, respectively. The usefulness of the developed method was confirmed by the determination of the cathepsin L concentration in the blood plasma of some healthy persons and in the blood plasma of patients. The obtained results were compared with the results obtained by the ELISA. It was found that the correlation between these two methods was very strong, what suggest that the developed method can be used as the competitive method to the ELISA.
Membrane Lipid Composition: Effect on Membrane and Organelle Structure, Function and Compartmentalization and Therapeutic Avenues
Authors: Casares Doralicia , Escribá Pablo V. , Rosselló Catalina Ana
Published: May 2019

Biological membranes are key elements for the maintenance of cell architecture and physiology. Beyond a pure barrier separating the inner space of the cell from the outer, the plasma membrane is a scaffold and player in cell-to-cell communication and the initiation of intracellular signals among other functions. Critical to this function is the plasma membrane compartmentalization in lipid microdomains that control the localization and productive interactions of proteins involved in cell signal propagation. In addition, cells are divided into compartments limited by other membranes whose integrity and homeostasis are finely controlled, and which determine the identity and function of the different organelles. Here, we review current knowledge on membrane lipid composition in the plasma membrane and endomembrane compartments, emphasizing its role in sustaining organelle structure and function. The correct composition and structure of cell membranes define key pathophysiological aspects of cells. Therefore, we explore the therapeutic potential of manipulating membrane lipid composition with approaches like membrane lipid therapy, aiming to normalize cell functions through the modification of membrane lipid bilayers.
Anti-Cancer Activity of Novel Dihydrotestosterone-Derived Ring A-Condensed Pyrazoles on Androgen Non-Responsive Prostate Cancer Cell Lines
Authors: Mótyán Gergő , Gopisetty Mohana Krishna , Kiss-Faludy Réka Eleonóra , Kulmány Ágnes , Zupkó István , Frank Éva , Kiricsi Mónika
Published: May 2019

Regioselective synthesis of novel ring A-fused arylpyrazoles of dihydrotestosterone (DHT) was carried out in two steps under facile reaction conditions. Aldol condensation of DHT with acetaldehyde afforded a 2-ethylidene derivative regio- and stereo-selectively, which was reacted with different arylhydrazines in the presence of iodine via microwave-assisted oxidative cyclization reactions. The 17-keto analogs of steroidal pyrazoles were also synthesized by simple oxidation in order to enlarge the compound library available for pharmacological studies and to obtain structure–activity relationship. The antiproliferative activities of the structurally related heteroaromatic compounds were tested in vitro on human cervical and breast adenocarcinoma cell lines (HeLa, MCF-7 and MDA-MB-231) and on two androgen-independent malignant prostate carcinoma cell lines (PC-3 and DU 145). Based on primary cytotoxicity screens and IC50 assessment, a structure-function relationship was identified, as derivatives carrying a hydroxyl group on C-17 exhibit stronger activity compared to the 17-one counterparts. Cancer cell selectivity of the derivatives was also determined using non-cancerous MRC-5 cells. Furthermore, the proapoptotic effects of some selected derivatives were verified on androgen therapy refractive p53-deficient PC-3 cells. The present study concludes that novel DHT-derived arylpyrazoles exert cancer cell specific antiproliferative activity and activate apoptosis in PC-3 cells.
Stereotactic Ablative Radiotherapy Combined with Immune Checkpoint Inhibitors Reboots the Immune Response Assisted by Immunotherapy in Metastatic Lung Cancer: A Systematic Review
Authors: Chicas-Sett Rodolfo , Morales-Orue Ignacio , Castilla-Martinez Juan , Zafra-Martin Juan , Kannemann Andrea , Blanco Jesus , Lloret Marta , Lara Pedro C
Published: May 2019

Background: Immune checkpoint inhibitors (ICI) have represented a revolution in the treatment of non-small-cell lung cancer (NSCLC). To improve these results, combined approaches are being tested. The addition of stereotactic ablative radiotherapy (SABR) to ICI seems promising. A systematic review was performed in order to assess the safety and efficacy of SABR-ICI combination. Material and Methods: MEDLINE databases from 2009 to March 3, 2019 were reviewed to obtain English language studies reporting clinical outcomes of the combination of ICI-SABR in NSCLC. 18 out of the 429 initial results fulfilled the inclusion criteria and were selected for review. Results: Eighteen articles, including six prospective studies, describing 1736 patients treated with an ICI-SABR combination fulfilled the selection criteria. The reported mean rates for local control and distant/abscopal response rates were 71% and 41%, respectively. Eleven studies reported progression-free survival and overall survival, with a mean of 4.6 and 12.4 months, respectively. Toxicity rates were consistent with the ones attributable to ICI treatment alone. Conclusions: The ICI-SABR combination has a good safety profile and achieves high rates of local control and greater chances of obtaining abscopal responses than SABR alone, with a relevant impact on PFS. More studies are needed to improve patient selection for an optimal benefit from this approach.
Discovery of Novel Potential Reversible Peptidyl Arginine Deiminase Inhibitor
Authors: Aliko Ardita , Kamińska Marta , Falkowski Katherine , Bielecka Ewa , Benedyk-Machaczka Malgorzata , Malicki Stanisław , Kozieł Joanna , Wong Alicia , Bryzek Danuta , Kantyka Tomasz , Mydel Piotr
Published: May 2019

Citrullination, a posttranslational modification, is catalyzed by peptidylarginine deiminases (PADs), a unique family of enzymes that converts peptidyl-arginine to peptidyl-citrulline. Overexpression and/or increased PAD activity is observed in rheumatoid arthritis (RA), Alzheimer’s disease, multiple sclerosis, and cancer. Moreover, bacterial PADs, such as Porphyromonas gingivalis PAD (PPAD), may have a role in the pathogenesis of RA, indicating PADs as promising therapeutic targets. Herein, six novel compounds were examined as potential inhibitors of human PAD4 and PPAD, and compared to an irreversible PAD inhibitor, Cl-amidine. Four of the tested compounds (compounds 2, 3, 4, and 6) exhibited a micromolar-range inhibition potency against PAD4 and no effect against PPAD in the in vitro assays. Compound 4 was able to inhibit the PAD4-induced citrullination of H3 histone with higher efficiency than Cl-amidine. In conclusion, compound 4 was highly effective and presents a promising direction in the search for novel RA treatment strategies.
Exploring the Potential of Spherical Harmonics and PCVM for Compounds Activity Prediction
Authors: Wiercioch Magdalena
Published: May 2019

Biologically active chemical compounds may provide remedies for several diseases. Meanwhile, Machine Learning techniques applied to Drug Discovery, which are cheaper and faster than wet-lab experiments, have the capability to more effectively identify molecules with the expected pharmacological activity. Therefore, it is urgent and essential to develop more representative descriptors and reliable classification methods to accurately predict molecular activity. In this paper, we investigate the potential of a novel representation based on Spherical Harmonics fed into Probabilistic Classification Vector Machines classifier, namely SHPCVM, to compound the activity prediction task. We make use of representation learning to acquire the features which describe the molecules as precise as possible. To verify the performance of SHPCVM ten-fold cross-validation tests are performed on twenty-one G protein-coupled receptors (GPCRs). Experimental outcomes (accuracy of 0.86) assessed by the classification accuracy, precision, recall, Matthews’ Correlation Coefficient and Cohen’s kappa reveal that using our Spherical Harmonics-based representation which is relatively short and Probabilistic Classification Vector Machines can achieve very satisfactory performance results for GPCRs.
Polysome Profiling of a Human Glioblastoma Reveals Intratumoral Heterogeneity
Authors: Lupinacci Fernanda Cristina Sulla , Kuasne Hellen , Roffé Martin , Vassalakis Julia Avian , da Silva Fernanda Ferreira , Santos Tiago Góss , Andrade Victor Piana , Sanematsu Paulo , Martins Vilma Regina , Rogatto Silvia Regina , Hajj Glaucia Noeli Maroso
Published: May 2019

Glioblastoma (GBM) is one of the most aggressive cancers, with median survival of less than 2 years. Despite of considerable advance in molecular classification of GBMs, no improvements in therapy have been described. The scenario is further complicated by tumor heterogeneity and the relationship among genetic, transcriptional and functional findings. Classically, gene expression has been evaluated by steady-state mRNA, however, this does not take translational control into consideration, which contributes considerably to the composition of the proteome. In this study, we evaluated the transcriptomic and translatomic signature of a GBM obtained from a single patient focusing in tumor heterogeneity. In a sampling of eight fragments, we investigated the translation rates, mTORC1 and ERK1/2 pathways and identified both total and polysome associated mRNAs. An increased translation rate was observed in fragments with high-grade histological features. High-grade histology was also associated with the expression of genes related to extracellular matrix (ECM) and angiogenesis, in both transcriptomes and translatomes. However, genes associated with epithelial to mesenchymal transition and stress response, were observed only in translatomes from high-grade fragments. Overall, our results demonstrate that isolation of translated mRNA can be used to identify biomarkers and reveal previously unrecognized determinants of heterogeneity in GBMs.