bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Reference Genes for Quantitative Gene Expression Studies in Three Tissues of Japanese Quail
Authors: Vitorino Carvalho Anaïs , Couroussé Nathalie , Crochet Sabine , Coustham Vincent
Published: March 2019

RT-qPCR is the gold standard for candidate gene expression analysis. However, the interpretation of RT-qPCR results depends on the proper use of internal controls, i.e., reference genes. Japanese quail is an agronomic species also used as a laboratory model, but little is known about RT-qPCR reference genes for this species. Thus, we investigated 10 putative reference genes (ACTB, GAPDH, PGK1, RPS7, RPS8, RPL19, RPL32, SDHA, TBP and YWHAZ) in three different female and male quail tissues (liver, brain and pectoral muscle). Gene expression stability was evaluated with three different algorithms: geNorm, NormFinder and BestKeeper. For each tissue, a suitable set of reference genes was defined and validated by a differential analysis of gene expression between females and males (CCNH in brain and RPL19 in pectoral muscle). Collectively, our study led to the identification of suitable reference genes in liver, brain and pectoral muscle for Japanese quail, along with recommendations for the identification of reference gene sets for this species.
The Impact of Stellar Surface Magnetoconvection and Oscillations on the Detection of Temperate, Earth-Mass Planets Around Sun-Like Stars
Authors: Cegla H. M.
Published: March 2019

Detecting and confirming terrestrial planets is incredibly difficult due to their tiny size and mass relative to Sun-like host stars. However, recent instrumental advancements are making the detection of Earth-like exoplanets technologically feasible. For example, Kepler and TESS photometric precision means we can identify Earth-sized candidates (and PLATO in the future will add many long-period candidates to the list), while spectrographs such as ESPRESSO and EXPRES (with an aimed radial velocity precision [RV] near 10 cm s − 1 ) mean we will soon reach the instrumental precision required to confirm Earth-mass planets in the habitable zones of Sun-like stars. However, many astrophysical phenomena on the surfaces of these host stars can imprint signatures on the stellar absorption lines used to detect the Doppler wobble induced by planetary companions. The result is stellar-induced spurious RV shifts that can mask or mimic planet signals. This review provides a brief overview of how stellar surface magnetoconvection and oscillations can impact low-mass planet confirmation and the best-tested strategies to overcome this astrophysical noise. These noise reduction strategies originate from a combination of empirical motivation and a theoretical understanding of the underlying physics. The most recent predications indicate that stellar oscillations for Sun-like stars may be averaged out with tailored exposure times, while granulation may need to be disentangled by inspecting its imprint on the stellar line profile shapes. Overall, the literature suggests that Earth-analog detection should be possible, with the correct observing strategy and sufficient data collection.
The Role of Vitamin D in the Pathogenesis of Inflammatory Bowel Disease
Authors: Nobile Stefano , Tenace Michela A. , Pappa Helen M.
Published: March 2019

Vitamin D has a complex role in the pathogenesis of inflammatory bowel disease (IBD), which is still under investigation. We conducted a literature search using PubMed through December 2018 through the use of relevant search terms. We found an abundance of evidence to support the role of vitamin D in regulating the innate and adaptive arms of the immune system. The pathogenesis of IBD implicates the immune dysregulation of these immune system components. Proof of concept of the vitamin’s role in the pathogenesis of IBD is the mapping of the vitamin D receptor in a region of chromosome 12, where IBD is also mapped, and specific VDR polymorphisms’ link to IBD phenotypes. Further research is needed to better delineate vitamin D’s role in preventing IBD and its potential as a therapeutic target for this disease.
The Voice of Skogula in ‘Beasts Royal’ and a Story of the Tagus Estuary (Lisbon, Portugal) as Seen through a Whale’s-Eye View
Authors: Brito Cristina
Published: March 2019

Patrick O’Brian inspired this work, with his 1934 book of chronicles “Beasts Royal,” where he gives a voice to animals. Therein, among other animals, we find Skogula, a young sperm whale journeying with his family group across the South Seas and his views on the surrounding world, both underwater and on land. This paper tells a story of historical natural events, from the viewpoint of a fin whale that travelled, rested and stranded in the Tagus estuary mouth (Lisbon, Portugal) during the early 16th century. It allows us to move across time and explore the past of this estuarine ecosystem. What kind of changes took place and how can literature and heritage contribute to understand peoples’ constructions of past environments, local maritime histories and memories? In the second part of this essay we present a fictional short story, supported on historical documental sources and imagery research where Lily, the whale, is the main character. Thus, we see the Tagus estuary as perceived through this whale’s-eye view. Finally, we discuss past earthquakes, whale strandings, the occurrence of seals and dolphins and peoples’ perceptions of the Tagus coastal environment across time. We expect to make a contribution to the field of the marine environmental humanities. We will do so both by addressing, by means of this literary approach, the writing of “new thalassographies,” oceanic historiographies and “historicities” and by including all intervening actors—people, animals and the physical space—in the understanding of the past of more-than-human aquatic worlds.
Management of Endocrinopathies in Pregnancy: A Review of Current Evidence
Authors: Calina Daniela , Docea Anca Oana , Golokhvast Kirill Sergeyevich , Sifakis Stavros , Tsatsakis Aristides , Makrigiannakis Antonis
Published: March 2019

Pregnancy in women with associated endocrine conditions is a therapeutic challenge for clinicians. These disorders may be common, such us thyroid disorders and diabetes, or rare, including adrenal and parathyroid disease and pituitary dysfunction. With the development of assisted reproductive techniques, the number of pregnancies with these conditions has increased. It is necessary to recognize symptoms and correct diagnosis for a proper pharmacotherapeutic management in order to avoid adverse side effects both in mother and fetus. This review summarizes the pharmacotherapy of these clinical situations in order to reduce maternal and fetal morbidity.
A Multiplicative Approach to Polyvictimization: A Study of Intimate Partner Violence Types as Risk Factors for Child Polyvictimization in South Korea
Authors: Emery Clifton R. , Yang Hyerin , Kim Oksoo , Ko Yoonjeong
Published: March 2019

Drawing on a new typology of intimate partner violence (IPV), this paper tests the relationship between indicators of totalitarian and anarchic IPV and child polyvictimization incidence and severity. The paper argues for and utilizes a quantitative approach to study polyvictimization severity. Polyvictimization is operationalized as a multiplicative relationship between physical abuse and neglect in a random sample of 204 children from Kyunggi province, South Korea. The indicator of totalitarian IPV significantly predicted polyvictimization severity and incidence even when a traditional measure of intimate terrorism was held constant. The indicator of anarchic IPV significantly predicted polyvictimization severity but not incidence when a traditional measure of intimate terrorism was held constant. Implications are discussed.
Spatiotemporal Variations in Gastric Cancer Mortality and Their Relations to Influencing Factors in S County, China
Authors: Cui Cheng , Wang Baohua , Ren Hongyan , Wang Zhen
Published: March 2019

Increasingly stricter and wider official efforts have been made by multilevel Chinese governments for seeking the improvements of the environment and public health status. However, the contributions of these efforts to environmental changes and spatiotemporal variations in some environmental diseases have been seldom explored and evaluated. Gastric cancer mortality (GCM) data in two periods (I: 2004–2006 and II: 2012–2015) was collected for the analysis of its spatiotemporal variations on the grid scale across S County in Central China. Some environmental and socioeconomic factors, including river, farmlands, topographic condition, population density, and gross domestic products (GDP) were obtained for the exploration of their changes and their relationships with GCM’s spatiotemporal variations through a powerful tool (GeoDetector, GD). During 2004–2015, S County achieved environmental improvement and socioeconomic development, as well as a clear decline of the age-standardized mortality rate of gastric cancer from 35.66/105 to 23.44/105. Moreover, the GCM spatial patterns changed on the grid scale, which was spatially associated with the selected influencing factors. Due to the improvement of rivers’ water quality, the distance from rivers posed relatively larger but reversed impacts on the gridded GCM. In addition, higher population density and higher economic level (GDP) acted as important protective factors, whereas the percentage of farmlands tended to have adverse effects on the gridded GCM in period II. It can be concluded that the decline of GCM in S County was spatiotemporally associated with increasingly strengthened environmental managements and socioeconomic developments over the past decade. Additionally, we suggest that more attentions should be paid to the potential pollution caused by excessive pesticides and fertilizers on the farmlands in S County. This study provided a useful clue for local authorities adopting more targeted measures to improve environment and public health in the regions similar to S County.
Chronic Kidney Disease: The Complex History of the Organization of Long-Term Care and Bioethics. Why Now, More Than Ever, Action is Needed
Authors: Versino Elisabetta , Piccoli Giorgina Barbara
Published: March 2019

Chronic kidney disease (CKD) has been redefined in the new millennium as any alteration of kidney morphology, function, blood, or urine composition lasting for at least 3 months. This broad definition also encompasses diseases or conditions that are associated with normal kidney function, such as a kidney scarring from an acute pyelonephritis episode or a single kidney, as a result of kidney donation. CKD is a relevant public health problem. According to the 2015 Global Burden of Disease Study, it was the 12th leading cause of death, leading to 1.1 million deaths, worldwide, each year. The role of CKD as a cause of death is evident where renal replacement therapy (RRT) is not available, however, its role in increasing death risk is not easily calculated. RRT consumes about 3–5% of the global healthcare budget where dialysis is available without restrictions. While the prevalence of CKD is increasing overall as lifespans extend, being linked to diabetes, hypertension, obesity, and atherosclerosis, CKD is at least partly preventable and its effects may be at least partly counterbalanced by early and appropriate care. We will welcome papers on all aspects of CKD, including organization, cost, and models of care. Papers from developing countries will be particularly welcomed.
Associations of Genetic Variations in ABCA1 and Lifestyle Factors with Coronary Artery Disease in a Southern Chinese Population with Dyslipidemia: A Nested Case-Control Study
Authors: Zhao Tian-Yu , Lei Song , Huang Liu , Wang Yi-Nan , Wang Xiao-Ni , Zhou Ping-Pu , Xu Xiao-Jun , Zhang Long , Xu Liang-Wen , Yang Lei
Published: March 2019

Coronary artery disease has become a major health concern over the past several decades. We aimed to explore the association of single nucleotide polymorphisms (SNPs) in the ATP-binding cassette subfamily A member 1 (ABCA1) and lifestyle factors with coronary artery disease (CAD) in dyslipidemia. This nested case-control study included 173 patients with CAD and 500 matched control individuals (1:3, case: control) from a district in southern China. We collected medical reports, lifestyle details, and blood samples of individuals with dyslipidemia and used the polymerase chain reaction-ligase detection reaction method to genotype the SNPs. The CC genotype of the additive and recessive models of rs4149339, together with regular intake of fried foods or dessert, increased the risk of CAD (adjusted odd ratio (OR) = 1.91, p = 0.030; adjusted OR = 1.97, p = 0.017; adjusted OR = 1.80, p = 0.002; adjusted OR = 1.98, p = 0.001). The AT + AA genotype of the dominant model of rs4743763 and moderate/heavy physical activity reduced the risk of CAD (adjusted OR = 0.66, p = 0.030; adjusted OR = 0.44, p = 0.001). The CT + CC genotype of the dominant model of rs2472386 reduced the risk of CAD only in males (adjusted OR = 0.36, p = 0.001). The interaction between rs4149339 and rs4743763 of ABCA1 and haplotype CTT (comprising rs4149339, rs4743763, and rs2472386) appeared to increase the risk of CAD (relative excess risk due to interaction (RERI) = 3.19, p = 0.045; OR = 1.49, p = 0.019). Polymorphisms of rs4149339, rs4743763 and rs2472386 in ABCA1 and three lifestyle factors (physical activity, fried food intake, and dessert intake) were associated with CAD in people with dyslipidemia in southern China. These results provide the theoretical basis for gene screening and the prevention of chronic cardiovascular diseases.
The Intervention Effect of SMS Delivery on Chinese Adolescent’s Physical Activity
Authors: Lau Patrick W. C. , Pitkethly Amanda J. , Leung Beeto W. C. , Lau Erica Y. , Wang Jing-Jing
Published: March 2019

To examine the effects of short messaging service (SMS) frequency and timing on the efficacy of an SMS-intervention for Hong Kong Chinese adolescents, sixty nine students aged between 12 and 16 (mean age 13.75 ± 0.90) were recruited from five schools in Hong Kong. Participants were randomly assigned into one of five groups: high-frequency + self-selected timing (HST), low-frequency + self-selected timing (LST), high-frequency + assigned timing (HAT), low-frequency + assigned timing (LAT) and the control group. The total duration of the intervention was four weeks. No significant intervention effects were detected in adolescent’s PA among the five groups (F = 1.14, p = 0.346). No significant differences were observed in the stage movement among the five groups (χ2 = 6.18, p = 0.627). No significant differences appeared in the exercise benefits, barriers and benefits/barriers differential scores. However, a growth trend in the exercise benefits score in the LST and HAT groups was found in contrast to the downswing in the control group. The exercise barriers score in the HST group showed the largest reduction after intervention. The benefits/barriers differential score in all the intervention groups increased, whereas it decreased in the control group. Although an increase is demonstrated in the high dosage SMS frequency and timing, no significant intervention effects were found among the five groups in PA behavior, stage of change and exercise benefits and barriers among Hong Kong Chinese adolescents.
Perception of the Effectiveness of Health-Related Campaigns among the Adult Population: An Analysis of Determinants
Authors: Duplaga Mariusz
Published: March 2019

Background: Social campaigns focusing on health are commonly used within an attempt to change behavior. To date, there has not been a targeted analysis of societies’ general perception about social campaigns. The aim of this study is to assess citizens’ opinions on the effectiveness of health-related social campaigns. Methods: The data set used in the analysis was obtained from Poland’s nationwide “Social Diagnosis” study. The determinants of public opinion were assessed using a multivariate logistic regression. The independent variables included socio-demographic characteristics, lifestyle, social participation, and the use of digital media. Results: The logistic regression model was developed using 23,593 cases. Opinions about the effectiveness of campaigns depended on all the predictors included in the socio-demographic cluster, smoking, self-declared excessive alcohol consumption, physical activity, the use of mobile phones, and watching TV. A significant impact was found in all but one variable related to social participation. Conclusions: The analysis revealed that opinions about social campaigns present in the media “landscape” are influenced by many factors. Interestingly, persons exhibiting unhealthy behaviors are more resistant to health-related campaigns and surprisingly the need to make use of healthcare resources is not accompanied by an acceptance of the interventions.
Isotemporal Substitution as the Gold Standard Model for Physical Activity Epidemiology: Why It Is the Most Appropriate for Activity Time Research
Authors: Mekary Rania A. , Ding Eric L.
Published: March 2019

Isotemporal substitution model was first developed in 2009 [...]
Coupling Computational Fluid Dynamics Simulations and Statistical Moments for Designing Healthy Indoor Spaces
Authors: Hoque Shamia , Omar Firoza B.
Published: March 2019

Cross-contamination between occupants in an indoor space may occur due to transfer of infectious aerosols. Computational fluid dynamics (CFD) provides detailed insight into particle transport in indoor spaces. However, such simulations are site-specific. This study couples CFD with statistical moments and establishes a framework that transitions site-specific results to generating guidelines for designing “healthy” indoor spaces. Eighteen cases were simulated, and three parameters were assessed: inlet/outlet location, air changes per hour, and the presence/absence of desks. Aerosol release due to a simulated “sneeze” in a two-dimensional ventilated space was applied as a test case. Mean, standard deviation, and skewness of the velocity profiles and particle locations gave an overall picture of the spread and movement of the air flow in the domain. A parameter or configuration did not dominate the values, confirming the significance of considering the combined influence of multiple parameters for determining localized air-flow characteristics. Particle clustering occurred more when the inlet was positioned above the outlet. The particle dispersion pattern could be classified into two time zones: “near time”, <60 s, and “far time”, >120 s. Based on dosage, the 18 cases were classified into three groups ranging from worst case scenario to best case scenario.
Impacting Microbial Communities and Absorbing Pollutants by Canna Indica and Cyperus Alternifolius in a Full-Scale Constructed Wetland System
Authors: Wu Yinghai , He Tao , Chen Chen , Fang Xiaohang , Wei Dongyang , Yang Jing , Zhang Renduo , Han Rui
Published: March 2019

Wetland plants that cover the wetlands play an important role in reducing pollutants. The aim of this study was to investigate the effect of two plant species on microbial communities and nitrogen-removal genes and to evaluate the contributions of absorbing pollutants by Canna indica (CI) and Cyperus alternifolius (CA) to the removal performance in both a vertical subsurface flow constructed wetland and a horizontal subsurface flow constructed wetland, which were part of a full-scale hybrid constructed wetland system. The microbial assemblages were determined using 16S rRNA high-throughput sequencing. Results showed that the presence of CI and CA positively affected microbial abundance and community in general and which was positive for the total bacteria and ammonia nitrogen removal in the CWs. The higher abundance of Nitrospirae appeared in the non-rhizosphere sediment (NRS) than that in the rhizosphere sediment (RS). More denitrification genes were found in NRS than in RS. The copy numbers of narG, nirS and nosZ genes for CA were higher than those for CI. Wetland plant species can significantly (P < 0.05) affect the distribution of microbial communities in RS. Plant selection is important to promote the development of microbial communities with a more active and diverse catabolic capability and the contribution of plant absorption to the overall removal rate of wetland system can be neglected.
Analysis of the Differential Relationship between the Perception of One’s Life and Coping Resources among Three Generations of Bedouin Women
Authors: Braun-Lewensohn Orna , Abu-Kaf Sarah , Al-Said Khaled , Huss Ephrat
Published: March 2019

Bedouin society has undergone rapid changes over the past decade. The younger generation of Bedouin women is better educated, which has enabled them to enter different professions, increased their incomes and elevated their social status. We examined the sense of coherence (SOC) and its components of meaningfulness, manageability and comprehensibility as well as the use of coping strategies among Bedouin women from three age groups. We also investigated the coping resources and strategies before determining the relationships between these variables in the three groups. One hundred ninety-six women participated in the study. Differences were found mostly between the oldest age group (61 years and older) and the two younger groups (21–40 and 41–60 years old). The oldest women reported less meaningfulness and used less positive reframing, planning, humor and acceptance. In terms of coping strategies, venting was used more by the youngest group whereas behavioral disengagement was used more by the oldest group. In the younger groups, SOC and its components were positively correlated with the use of coping strategies that are considered to be adaptive and with emotional support. However, the correlations between these factors were negative among the oldest group, which points to non-adaptive coping strategies used by these women. These results are discussed in light of the salutogenic, stress-appraisal and coping theories.
Trauma Exposure in Relation to the Content of Mother-Child Emotional Conversations and Quality of Interaction
Authors: Overbeek Mathilde M. , Koren-Karie Nina , Ben-Haim Adi Erez , de Schipper J. Clasien , Dreier Gligoor Patricia D. , Schuengel Carlo
Published: March 2019

Parent-child conversations contribute to understanding and regulating children’s emotions. Similarities and differences in discussed topics, quality of interaction and coherence/elaboration in mother-child conversations about emotional experiences of the child were studied in dyads who had been exposed to interpersonal trauma (N = 213) and non-trauma-exposed dyads (N = 86). Results showed that in conversations about negative emotions, trauma-exposed children more often discussed trauma topics and focused less on relationship topics than non-trauma-exposed children. Trauma-exposed dyads found it more difficult to come up with a story. The most common topics chosen by dyads to discuss for each emotion were mostly similar between trauma-exposed dyads and non-trauma-exposed dyads. Dyads exposed to interpersonal traumatic events showed lower quality of interaction and less coherence/elaboration than dyads who had not experienced traumatic events. Discussion of traumatic topics was associated with lower quality of mother-child interaction and less coherent dialogues. In conclusion, the effect of the trauma is seen at several levels in mother-child interaction: topics, behavior and coherence. A focus on support in developing a secure relationship after trauma may be important for intervention.
The UNICEF/Washington Group Child Functioning Module—Accuracy, Inter-Rater Reliability and Cut-Off Level for Disability Disaggregation of Fiji’s Education Management Information System
Authors: Sprunt Beth , McPake Barbara , Marella Manjula
Published: March 2019

This paper explores the validity (sensitivity and specificity) of different cut-off levels of the UNICEF/Washington Group Child Functioning Module (CFM) and the inter-rater reliability between teachers and parents as proxy respondents, for disaggregating Fiji’s education management information system (EMIS) by disability. The method used was a cross-sectional diagnostic accuracy study comparing CFM items to standard clinical assessments for 472 primary school aged students in Fiji. Whilst previous domain-specific results showed “good” to “excellent” accuracy of the CFM domains seeing, hearing, walking and speaking, newer analysis shows only “fair” to “poor” accuracy of the cognitive domains (learning, remembering and focusing attention) and “fair” of the overall CFM (area under the Receiver Operating Characteristic curve: 0.763 parent responses, 0.786 teacher responses). Severe impairments are reported relatively evenly across CFM response categories “some difficulty”, “a lot of difficulty” and “cannot do at all”. Most moderate impairments are reported as “some difficulty”. The CFM provides a core component of data required for disaggregating Fiji’s EMIS by disability. However, choice of cut-off level and mixture of impairment severity reported across response categories are challenges. The CFM alone is not accurate enough to determine funding eligibility. For identifying children with disabilities, the CFM should be part of a broader data collection including learning and support needs data and undertaking eligibility verification visits.
Micro-Space Complexity and Context in the Space-Time Variation in Enteric Disease Risk for Three Informal Settlements of Port au Prince, Haiti
Authors: Curtis Andrew , Squires Robert , Rouzier Vanessa , Pape Jean William , Ajayakumar Jayakrishnan , Bempah Sandra , Taifur Alam Meer , Alam Md. Mahbubul , Rashid Mohammed H. , Ali Afsar , Morris, Jr John Glenn
Published: March 2019

Diffusion of cholera and other diarrheal diseases in an informal settlement is a product of multiple behavioral, environmental and spatial risk factors. One of the most important components is the spatial interconnections among water points, drainage ditches, toilets and the intervening environment. This risk is also longitudinal and variable as water points fluctuate in relation to bacterial contamination. In this paper we consider part of this micro space complexity for three informal settlements in Port au Prince, Haiti. We expand on more typical epidemiological analysis of fecal coliforms at water points, drainage ditches and ocean sites by considering the importance of single point location fluctuation coupled with recording micro-space environmental conditions around each sample site. Results show that spatial variation in enteric disease risk occurs within neighborhoods, and that while certain trends are evident, the degree of individual site fluctuation should question the utility of both cross-sectional and more aggregate analysis. Various factors increase the counts of fecal coliform present, including the type of water point, how water was stored at that water point, and the proximity of the water point to local drainage. Some locations fluctuated considerably between being safe and unsafe on a monthly basis. Next steps to form a more comprehensive contextualized understanding of enteric disease risk in these environments should include the addition of behavioral factors and local insight.
Short-Term Consumption of Cuban Policosanol Lowers Aortic and Peripheral Blood Pressure and Ameliorates Serum Lipid Parameters in Healthy Korean Participants: Randomized, Double-Blinded, and Placebo-Controlled Study
Authors: Park Hye-Jeong , Yadav Dhananjay , Jeong Da-Jeong , Kim Suk-Jeong , Bae Myung-Ae , Kim Jae-Ryong , Cho Kyung-Hyun
Published: March 2019

The current study was designed to investigate the short-term effects of policosanol consumption on blood pressure (BP) and the lipid parameters in healthy Korean participants with prehypertension. A total of 84 healthy participants were randomly allocated to three groups receiving placebo, 10 mg of policosanol, or 20 mg of policosanol for 12 weeks. Based on an average of three measurements of peripheral BP, the policosanol 20 mg group exhibited the most significant reduction, that is, up to 7.7% reduction of average systolic BP (SBP) from 136.3 ± 6.1 mmHg (week 0) to 125.9 ± 8.6 mmHg (week 12, p < 0.001). Between group comparisons using repeated measures ANOVA showed that the policosanol 20 mg group had a significant reduction of SBP at 12 weeks (p = 0.020) and a reduction of diastolic BP (DBP) at 8 weeks (p = 0.041) and 12 weeks (p = 0.035). The policosanol 10 mg and 20 mg groups showed significant reductions in aortic SBP of 7.4% and 8.3%, respectively. The policosanol groups showed significant reductions of total cholesterol (TC) of 9.6% and 8.6% and low-density lipoproteins (LDL-C) of 21% and 18% for 10 mg and 20 mg of policosanol, respectively. Between group comparisons using repeated measures ANOVA showed that the policosanol (10 mg and 20 mg) groups at 12 weeks had a significant reduction of TC (p = 0.0004 and p = 0.001) and LDL-C (p = 0.00005 and p = 0.0001) and elevation of %HDL-C (p = 0.048 and p = 0.014). In conclusion, 12-week consumption of policosanol resulted in significant reductions of peripheral SBP and DBP, aortic SBP and DBP, mean arterial pressure (MAP), and serum TC and LDL-C with elevation of % HDL-C.
Salidroside Ameliorates Renal Interstitial Fibrosis by Inhibiting the TLR4/NF-κB and MAPK Signaling Pathways
Authors: Li Rui , Guo Yujuan , Zhang Yiming , Zhang Xue , Zhu Lingpeng , Yan Tianhua
Published: March 2019

Salidroside (Sal) is an active ingredient that is isolated from Rhodiola rosea, which has been reported to have anti-inflammatory activities and a renal protective effect. However, the role of Sal on renal fibrosis has not yet been elucidated. Here, the purpose of the current study is to test the protective effects of Sal against renal interstitial fibrosis (RIF), and to explore the underlying mechanisms using both in vivo and in vitro models. In this study, we establish the unilateral ureteric obstruction (UUO) or folic acid (FA)-induced mice renal interstitial fibrosis in vivo and the transforming growth factor (TGF)-β1-stimulated human proximal tubular epithelial cell (HK-2) model in vitro. The levels of kidney functional parameters and inflammatory cytokines in serum are examined. The degree of renal damage and fibrosis is determined by histological assessment. Immunohistochemistry and western blotting are used to determine the mechanisms of Sal against RIF. Our results show that treatment with Sal can ameliorate tubular injury and deposition of the extracellular matrix (ECM) components (including collagen Ш and collagen I). Furthermore, Sal administration significantly suppresses epithelial-mesenchymal transition (EMT), as evidenced by a decreased expression of α-SMA, vimentin, TGF-β1, snail, slug, and a largely restored expression of E-cadherin. Additionally, Sal also reduces the levels of serum biochemical markers (serum creatinine, Scr; blood urea nitrogen, BUN; and uric acid, UA) and decreases the release of inflammatory cytokines (IL-1β, IL-6, TNF-α). Further study revealed that the effect of Sal on renal interstitial fibrosis is associated with the lower expression of TLR4, p-IκBα, p-NF-κB and mitogen-activated protein kinases (MAPK), both in vivo and in vitro. In conclusion, Sal treatment improves kidney function, ameliorates the deposition of the ECM components and relieves the protein levels of EMT markers in mouse kidneys and HK-2 cells. Furthermore, Sal treatment significantly decreases the release of inflammatory cytokines and inhibits the TLR4/NF-κB and MAPK signaling pathways. Collectively, these results suggest that the administration of Sal could be a novel therapeutic strategy in treating renal fibrosis.
Identification of miRNA Reference Genes in Extracellular Vesicles from Adipose Derived Mesenchymal Stem Cells for Studying Osteoarthritis
Authors: Ragni Enrico , Perucca Orfei Carlotta , De Luca Paola , Colombini Alessandra , Viganò Marco , Lugano Gaia , Bollati Valentina , de Girolamo Laura
Published: March 2019

Osteoarthritis (OA) leads to chronic pain and disability, and traditional conservative treatments are not effective in the long term. The intra-articular injection of mesenchymal stem cells (MSCs) is considered a novel therapy for OA whose efficacy mainly relies on the adaptive release of paracrine molecules which are either soluble or extracellular vesicles (EVs) embedded. The correct quantification of EV-miRNAs using reliable reference genes (RGs) is a crucial step in optimizing this future therapeutic cell-free approach. The purpose of this study is to rate the stabilities of literature-selected proposed RGs for EV-miRNAs in adipose derived-MSCs (ASCs). EVs were isolated by ultracentrifugation from ASCs cultured with or without inflammatory priming mimicking OA synovial fluid condition. Expression of putative RGs (let-7a-5p, miR-16-5p, miR-23a-3p, miR-26a-5p, miR-101-3p, miR-103a-3p, miR-221-3p, miR-423-5p, miR-425-5p, U6 snRNA) was scored by using the algorithms geNorm, NormFinder, BestKeeper and ΔCt method. miR-16a-5p/miR-23a-3p yielded the most stable RGs, whereas let-7a-5p/miR-425-5p performed poorly. Outcomes were validated by qRT-PCR on miR-146a-5p, reported to be ASC-EVs enriched and involved in OA. Incorrect RG selection affected the evaluation of miR-146a-5p abundance and modulation by inflammation, with both values resulting strongly donor-dependent. Our findings demonstrated that an integrated approach of multiple algorithms is necessary to identify reliable, stable RGs for ASC-EVs miRNAs evaluation. A correct approach would increase the accuracy of embedded molecule assessments aimed to develop therapeutic strategies for the treatment of OA based on EVs.
HDAC Inhibitors Induce BDNF Expression and Promote Neurite Outgrowth in Human Neural Progenitor Cells-Derived Neurons
Authors: Bagheri Amir , Habibzadeh Parham , Razavipour Seyedeh Fatemeh , Volmar Claude-Henry , Chee Nancy T. , Brothers Shaun P. , Wahlestedt Claes , Mowla Seyed Javad , Faghihi Mohammad Ali
Published: March 2019

Besides its key role in neural development, brain-derived neurotrophic factor (BDNF) is important for long-term potentiation and neurogenesis, which makes it a critical factor in learning and memory. Due to the important role of BDNF in synaptic function and plasticity, an in-house epigenetic library was screened against human neural progenitor cells (HNPCs) and WS1 human skin fibroblast cells using Cell-to-Ct assay kit to identify the small compounds capable of modulating the BDNF expression. In addition to two well-known hydroxamic acid-based histone deacetylase inhibitors (hb-HDACis), SAHA and TSA, several structurally similar HDAC inhibitors including SB-939, PCI-24781 and JNJ-26481585 with even higher impact on BDNF expression, were discovered in this study. Furthermore, by using well-developed immunohistochemistry assays, the selected compounds were also proved to have neurogenic potential improving the neurite outgrowth in HNPCs-derived neurons. In conclusion, we proved the neurogenic potential of several hb-HDACis, alongside their ability to enhance BDNF expression, which by modulating the neurogenesis and/or compensating for neuronal loss, could be propitious for treatment of neurological disorders.
Regulation of Chemokines and Cytokines by Histone Deacetylases and an Update on Histone Decetylase Inhibitors in Human Diseases
Authors: Gatla Himavanth Reddy , Muniraj Nethaji , Thevkar Prashanth , Yavvari Siddhartha , Sukhavasi Sahithi , Makena Monish Ram
Published: March 2019

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) counteract with each other to regulate gene expression by altering chromatin structure. Aberrant HDAC activity was reported in many human diseases including wide range of cancers, viral infections, cardiovascular complications, auto-immune diseases and kidney diseases. HDAC inhibitors are small molecules designed to block the malignant activity of HDACs. Chemokines and cytokines control inflammation, immunological and other key biological processes and are shown to be involved in various malignancies. Various HDACs and HDAC inhibitors were reported to regulate chemokines and cytokines. Even though HDAC inhibitors have remarkable anti-tumor activity in hematological cancers, they are not effective in treating many diseases and many patients relapse after treatment. However, the role of HDACs and cytokines in regulating these diseases still remain unclear. Therefore, understanding exact mechanisms and effector functions of HDACs are urgently needed to selectively inhibit them and to establish better a platform to combat various malignancies. In this review, we address regulation of chemokines and cytokines by HDACs and HDAC inhibitors and update on HDAC inhibitors in human diseases.
Bioproduction of Quercetin and Rutinose Catalyzed by Rutinosidase: Novel Concept of “Solid State Biocatalysis”
Authors: Kapešová Jana , Petrásková Lucie , Markošová Kristína , Rebroš Martin , Kotik Michael , Bojarová Pavla , Křen Vladimír
Published: March 2019

Quercetin is a flavonoid largely employed as a phytochemical remedy and a food or dietary supplement. We present here a novel biocatalytic methodology for the preparation of quercetin from plant-derived rutin, with both substrate and product being in mostly an undissolved state during biotransformation. This “solid-state” enzymatic conversion uses a crude enzyme preparation of recombinant rutinosidase from Aspergillus niger yielding quercetin, which precipitates from virtually insoluble rutin. The process is easily scalable and exhibits an extremely high space-time yield. The procedure has been shown to be robust and was successfully tested with rutin concentrations of up to 300 g/L (ca 0.5 M) at various scales. Using this procedure, pure quercetin is easily obtained by mere filtration of the reaction mixture, followed by washing and drying of the filter cake. Neither co-solvents nor toxic chemicals are used, thus the process can be considered environmentally friendly and the product of “bio-quality.” Moreover, rare disaccharide rutinose is obtained from the filtrate at a preparatory scale as a valuable side product. These results demonstrate for the first time the efficiency of the “Solid-State-Catalysis” concept, which is applicable virtually for any biotransformation involving substrates and products of low water solubility.
Synthesis, Microtubule-Binding Affinity, and Antiproliferative Activity of New Epothilone Analogs and of an EGFR-Targeted Epothilone-Peptide Conjugate
Authors: Gaugaz Fabienne Zdenka , Chicca Andrea , Redondo-Horcajo Mariano , Barasoain Isabel , Díaz J. Fernando , Altmann Karl-Heinz
Published: March 2019

A new simplified, epoxide-free epothilone analog was prepared incorporating an N-(2-hydroxyethyl)-benzimidazole side chain, which binds to microtubules with high affinity and inhibits cancer cell growth in vitro with nM potency. Building on this scaffold, a disulfide-linked conjugate with the purported EGFR-binding (EGFR, epidermal growth factor receptor) peptide GE11 was then prepared. The conjugate retained significant microtubule-binding affinity, in spite of the size of the peptide attached to the benzimidazole side chain. The antiproliferative activity of the conjugate was significantly lower than for the parent scaffold and, surprisingly, was independent of the EGFR expression status of cells. Our data indicate that the disulfide-based conjugation with the GE11 peptide is not a viable approach for effective tumor-targeting of highly potent epothilones and probably not for other cytotoxics.
Extracellular Vesicles from Thyroid Carcinoma: The New Frontier of Liquid Biopsy
Authors: Rappa Germana , Puglisi Caterina , Santos Mark F. , Forte Stefano , Memeo Lorenzo , Lorico Aurelio
Published: March 2019

The diagnostic approach to thyroid cancer is one of the most challenging issues in oncology of the endocrine system because of its high incidence (3.8% of all new cancer cases in the US) and the difficulty to distinguish benign from malignant non-functional thyroid nodules and establish the cervical lymph node involvement during staging. Routine diagnosis of thyroid nodules usually relies on a fine-needle aspirate biopsy, which is invasive and often inaccurate. Therefore, there is an urgent need to identify novel, accurate, and non-invasive diagnostic procedures. Liquid biopsy, as a non-invasive approach for the detection of diagnostic biomarkers for early tumor diagnosis, prognosis, and disease monitoring, may be of particular benefit in this context. Extracellular vesicles (EVs) are a consistent source of tumor-derived RNA due to their prevalence in circulating bodily fluids, the well-established isolation protocols, and the fact that RNA in phospholipid bilayer-enclosed vesicles is protected from blood-borne RNases. Recent results in other types of cancer, including our recent study on plasma EVs from glioblastoma patients suggest that information derived from analysis of EVs from peripheral blood plasma can be integrated in the routine diagnostic tumor approach. In this review, we will examine the diagnostic and prognostic potential of liquid biopsy to detect tumor-derived nucleic acids in circulating EVs from patients with thyroid carcinoma.
HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer
Authors: Rinnerthaler Gabriel , Gampenrieder Simon Peter , Greil Richard
Published: March 2019

Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed therapies, the prognosis of HER2 amplified breast cancers has improved meaningfully. Next to monoclonal anti-HER2 antibodies and tyrosine kinase inhibitors, the antibody-drug conjugate T-DM1 is a pillar of targeted treatment of advanced HER2-positive breast cancers. Currently, several HER2 directed antibody-drug conjugates are under clinical investigation for HER2 amplified but also HER2 expressing but not amplified breast tumors. In this article, we review the current preclinical and clinical evidence of the investigational drugs A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522.
Bone Marrow Aspirate Concentrate for the Treatment of Avascular Meniscus Tears in a One-Step Procedure—Evaluation of an In Vivo Model
Authors: Koch Matthias , Hammer Selma , Fuellerer Julian , Lang Siegmund , Pfeifer Christian G. , Pattappa Girish , Weber Johannes , Loibl Markus , Nerlich Michael , Angele Peter , Zellner Johannes
Published: March 2019

Avascular meniscus tears show poor intrinsic regenerative potential. Thus, lesions within this area predispose the patient to developing knee osteoarthritis. Current research focuses on regenerative approaches using growth factors or mesenchymal stem cells (MSCs) to enhance healing capacity within the avascular meniscus zone. The use of MSCs especially as progenitor cells and a source of growth factors has shown promising results. However, present studies use bone-marrow-derived BMSCs in a two-step procedure, which is limiting the transfer in clinical praxis. So, the aim of this study was to evaluate a one-step procedure using bone marrow aspirate concentrate (BMAC), containing BMSCs, for inducing the regeneration of avascular meniscus lesions. Longitudinal meniscus tears of 4 mm in size of the lateral New Zealand White rabbit meniscus were treated with clotted autologous PRP (platelet-rich plasma) or BMAC and a meniscus suture or a meniscus suture alone. Menisci were harvested at 6 and 12 weeks after initial surgery. Macroscopical and histological evaluation was performed according to an established Meniscus Scoring System. BMAC significantly enhanced regeneration of the meniscus lesions in a time-dependent manner and in comparison to the PRP and control groups, where no healing could be observed. Treatment of avascular meniscus lesions with BMAC and meniscus suturing seems to be a promising approach to promote meniscus regeneration in the avascular zone using a one-step procedure.
Intake of Red and Processed Meat, Use of Non-Steroid Anti-Inflammatory Drugs, Genetic Variants and Risk of Colorectal Cancer: A Prospective Study of the Danish “Diet, Cancer and Health” Cohort
Authors: Andersen Vibeke , Halekoh Ulrich , Tjønneland Anne , Vogel Ulla , Kopp Tine Iskov
Published: March 2019

Red and processed meat have been associated with increased risk of colorectal cancer (CRC), whereas long-term use of non-steroid anti-inflammatory drugs (NSAIDs) may reduce the risk. The aim was to investigate potential interactions between meat intake, NSAID use, and gene variants in fatty acid metabolism and NSAID pathways in relation to the risk of CRC. A nested case-cohort study of 1038 CRC cases and 1857 randomly selected participants from the Danish prospective “Diet, Cancer and Health” study encompassing 57,053 persons was performed using the Cox proportional hazard model. Gene variants in SLC25A20, PRKAB1, LPCAT1, PLA2G4A, ALOX5, PTGER3, TP53, CCAT2, TCF7L2, and BCL2 were investigated. CCAT2 rs6983267 was associated with the risk of CRC per se (p < 0.01). Statistically significant interactions were found between intake of red and processed meat and CCAT2 rs6983267, TP53 rs1042522, LPCAT1 rs7737692, SLC25A20 rs7623023 (pinteraction = 0.04, 0.04, 0.02, 0.03, respectively), and the use of NSAID and alcohol intake and TP53 rs1042522 (pinteraction = 0.04, 0.04, respectively) in relation to the risk of CRC. No other consistent associations or interactions were found. This study replicated an association of CCAT2 rs6983267 with CRC and an interaction between TP53 rs1042522 and NSAID in relation to CRC. Interactions between genetic variants in fatty acid metabolism and NSAID pathways and the intake of red and processed meat were found. Our results suggest that meat intake and NSAID use affect the same carcinogenic mechanisms. All new findings should be sought replicated in independent prospective studies. Future studies on the cancer-protective effects of aspirin/NSAID should include gene and meat assessments.
The Potential Beneficial Effects of Resveratrol on Cardiovascular Complications in Marfan Syndrome Patients–Insights from Rodent-Based Animal Studies
Authors: van Andel Mitzi M. , Groenink Maarten , Zwinderman Aeilko H. , Mulder Barbara J.M. , de Waard Vivian
Published: March 2019

Marfan syndrome (MFS) patients are at risk for cardiovascular disease. In particular, for aortic aneurysm formation, which ultimately can result in a life-threatening aortic dissection or rupture. Over the years, research into a sufficient pharmacological treatment option against aortopathy has expanded, mostly due to the development of rodent disease models for aneurysm formation and dissections. Unfortunately, no optimal treatment strategy has yet been identified for MFS. The biologically-potent polyphenol resveratrol (RES), that occurs in nuts, plants, and the skin of grapes, was shown to have a positive effect on aortic repair in various rodent aneurysm models. RES demonstrated to affect aortic integrity and aortic dilatation. The beneficial processes relevant for MFS included the improvement of endothelial dysfunction, extracellular matrix degradation, and smooth muscle cell death. For the wide range of beneficial effects on these mechanisms, evidence was found for the following involved pathways; alleviating oxidative stress (change in eNOS/iNOS balance and decrease in NOX4), reducing protease activity to preserve the extracellular matrix (decrease in MMP2), and improving smooth muscle cell survival affecting aortic aging (changing the miR21/miR29 balance). Besides aortic features, MFS patients may also suffer from manifestations concerning the heart, such as mitral valve prolapse and left ventricular impairment, where evidence from rodent models shows that RES may aid in promoting cardiomyocyte survival directly (SIRT1 activation) or by reducing oxidative stress (increasing superoxide dismutase) and increasing autophagy (AMPK activation). This overview discusses recent RES studies in animal models of aortic aneurysm formation and heart failure, where different advantageous effects have been reported that may collectively improve the aortic and cardiac pathology in patients with MFS. Therefore, a clinical study with RES in MFS patients seems justified, to validate RES effectiveness, and to judge its suitability as potential new treatment strategy.