bluuebunny/crossref_metadata_2025_split huggingface dataset:
Melioidosis fatalities in captive slender-tailed meerkats (Suricata suricatta): combining epidemiology, pathology and whole-genome sequencing supports variable mechanisms of transmission with one health implications
Authors: Rachlin Audrey , Shilton Cathy , Webb Jessica R. , Mayo Mark , Kaestli Mirjam , Kleinecke Mariana , Rigas Vanessa , Benedict Suresh , Gurry Ian , Currie Bart J. 
Published: December 2019

AbstractBackgroundMelioidosis is a tropical infectious disease which is being increasingly recognised throughout the globe. Infection occurs in humans and animals, typically through direct exposure to soil or water containing the environmental bacteriumBurkholderia pseudomallei. Case clusters of melioidosis have been described in humans following severe weather events and in exotic animals imported into melioidosis endemic zones. Direct transmission ofB. pseudomalleibetween animals and/or humans has been documented but is considered extremely rare. Between March 2015 and October 2016 eight fatal cases of melioidosis were reported in slender-tailed meerkats (Suricata suricatta)on display at a Wildlife Park in Northern Australia. To further investigate the melioidosis case cluster we sampled the meerkat enclosure and adjacent park areas and performed whole-genome sequencing (WGS) on all culture-positiveB. pseudomalleienvironmental and clinical isolates.ResultsWGS confirmed that the fatalities were caused by two differentB. pseudomalleisequence types (STs) but that seven of the meerkat isolates were highly similar on the whole-genome level. Used concurrently with detailed pathology data, our results demonstrate that the seven cases originated from a single original source, but routes of infection varied amongst meerkats belonging to the clonal outbreak cluster. Moreover, in some instances direct transmission may have transpired through wounds inflicted while fighting.ConclusionsCollectively, this study supports the use of high-resolution WGS to enhance epidemiological investigations into transmission modalities and pathogenesis of melioidosis, especially in the instance of a possible clonal outbreak scenario in exotic zoological collections. Such findings from an animal outbreak have important One Health implications.
Differential analysis of nutrient intake, insulin resistance and lipid profiles between healthy and premature thelarche Chinese girls
Authors: Xu Yueqin , Li Yan , Liang Shuang , Li Guimei 
Published: December 2019

AbstractBackgroundPremature thelarche (PT) is a benevolent ailment affecting young girls. Multiple factors are reported to correlate with this condition, but the mechanisms responsible for the onset of PT have not yet been fully investigated. This study aimed to evaluate the relationship of nutrient intake, insulin resistance and lipid profile with PT.MethodsTwo hundred sixty-three girls with PT, and 222 healthy girls of similar age were enrolled into this study. Their demographics, Tanner stage of breast development, nutrient intake, insulin resistance and lipid profiles were compared.ResultsDaily protein and fat intakes, insulin resistance parameters including serum insulin-like growth factor 1, fasting glucose to insulin ratio, quantitative insulin check index and homeostasis model of assessment of insulin resistance, as well as serum levels of triacylglycerol, total cholesterol and low-density lipoprotein, were all significantly altered in PT patients. Daily intake of energy and carbohydrate, and serum level of high-density lipoprotein protein were statistically indistinguishable between PT patients and healthy controls.ConclusionChinese girls with PT are potentially insulin resistant, which warrants more clinical attention and further investigation to address the underlying etiology.
Ethical issues in the design and conduct of stepped-wedge cluster randomized trials in low-resource settings
Authors: Joag Kaustubh , Ambrosio Guillermo , Kestler Edgar , Weijer Charles , Hemming Karla , Van der Graaf Rieke 
Published: December 2019

Abstract
Background
Stepped-wedge cluster randomized trials (SW-CRTs) are increasingly popular in health-related research in both high- and low-resource settings. There may be specific ethical issues that researchers face when designing and conducting SW-CRTs in low-resource settings. Knowledge of these issues can help to improve the ethical conduct of SW-CRTs in a global health context.

Methods
We performed an ethical analysis of two studies using SW-CRT designs in low-resource settings: the Que Vivan Las Madres study conducted from 2014 to 2017 in Guatemala and the Atmiyata study conducted from 2017 to 2018 in rural parts of India. For both case studies, we identified and evaluated the classification of the study as research or nonresearch and the ethical issues regarding the justification of the design, including the delayed rollout of an intervention that had a promising effect.

Results
In our case studies, some minor ethical issues surfaced about the registration and stakeholder pressure on the order of randomization, but both included good justification for the design and delayed rollout. Our analysis did, however, demonstrate that careful consideration of the role of randomization and registration of the trials is important.

Discussion
SW-CRTs can provide an opportunity for rigorous evaluation of interventions destined to be rolled out on the basis of limited evidence. Furthermore, in SW-CRTs, the underlying objective is often to provide a robust evaluation of the effectiveness for generalized dissemination, and this makes the SW-CRT no less a research study than any other form of cluster randomized trial.

Conclusion
The design and conduct of stepped-wedge cluster randomized trials raises at least two ethical issues that need special consideration in both high- and low-resource settings: the justification for using the design, specifically the delayed rollout of the intervention to the control group, and the classification of the study as research or nonresearch. In our case studies, these issues did not seem to raise special ethical scrutiny in low-resource settings. Further ethical evaluation will hopefully result in specific ethical guidelines for the use of SW-CRTs in both high- and low-resource settings to contribute to responsible functioning of these trials and adequate protection of participants.
Reduced H3K27me3 leads to abnormal Hox gene expression in neural tube defects
Authors: Yu Juan , Wang Lei , Pei Pei , Li Xue , Wu Jianxin , Qiu Zhiyong , Zhang Juan , Ao Ruifang , Wang Shan , Zhang Ting , Xie Jun 
Published: December 2019

Abstract
Background
Neural tube defects (NTDs) are severe, common birth defects that result from failure of normal neural tube closure during early embryogenesis. Accumulating strong evidence indicates that genetic factors contribute to NTDs etiology, among them, HOX genes play a key role in neural tube closure. Although abnormal HOX gene expression can lead to NTDs, the underlying pathological mechanisms have not fully been understood.

Method
We detected that H3K27me3 and expression of the Hox genes in a retinoic acid (RA) induced mouse NTDs model on E8.5, E9.5 and E10.5 using RNA-sequencing and chromatin immunoprecipitation sequencing assays. Furthermore, we quantified 10 Hox genes using NanoString nCounter in brain tissue of fetuses with 39 NTDs patients including anencephaly, spina bifida, hydrocephaly and encephalocele.

Results
Here, our results showed differential expression in 26 genes with a > 20-fold change in the level of expression, including 10 upregulated Hox genes. RT-qPCR revealed that these 10 Hox genes were all upregulated in RA-induced mouse NTDs as well as RA-treated embryonic stem cells (ESCs). Using ChIP-seq assays, we demonstrate that a decrease in H3K27me3 level upregulates the expression of Hox cluster A–D in RA-induced mouse NTDs model on E10.5. Interestingly, RA treatment led to attenuation of H3K27me3 due to cooperate between UTX and Suz12, affecting Hox gene regulation. Further analysis, in human anencephaly cases, upregulation of 10 HOX genes was observed, along with aberrant levels of H3K27me3. Notably, HOXB4, HOXC4 and HOXD1 expression was negatively correlated with H3K27me3 levels.

Conclusion
Our results indicate that abnormal HOX gene expression induced by aberrant H3K27me3 levels may be a risk factor for NTDs and highlight the need for further analysis of genome-wide epigenetic modification in NTDs.
The effect of cassia seed extract on the regulation of the LKB1–AMPK–GLUT4 signaling pathway in the skeletal muscle of diabetic rats to improve the insulin sensitivity of the skeletal muscle
Authors: Wang Qiu-Ying , Tong Ai-Hua , Pan Ying-Ying , Zhang Xian-Dang , Ding Wen-Yu , Xiong Wen 
Published: December 2019

Abstract
Background
This study aimed to observe the hypoglycemic effect of cassia seed extract in rats with type-2 diabetes mellitus and its effect on reducing insulin resistance in the skeletal muscle.

Methods
50 rats were randomly divided into the normal, model, high-dose, middle-dose, and low-dose groups of cassia seed extract (n = 10 each). A high-fat diet combined with streptozotocin administration was adopted to build type 2 diabetes models. The cassia seed extract groups were fed different concentrations cassia seed extract while the normal and model groups were fed the same volume of normal saline. The weight, FINS, GIR, insulin tolerance, blood glucose and blood lipid level, oxidative stress indices and expressions related to the LKB1–AMPK–GLUT4 pathway were detected and compared between the two groups.

Results
Compared with the normal group, the model group showed lower weight, glucose infusion rate and expressions related to LKB1–AMPK–GLUT4 pathway and higher FINS, insulin tolerance, blood glucose and blood lipid level and oxidative stress indices (all P < 0.05). Compared with the model group, higher weight, glucose infusion rate and expressions related to LKB1–AMPK–GLUT4 pathway and lower FINS, insulin tolerance, blood glucose and blood lipid level and oxidative stress indices were observed in all groups that were administered cassia see extract (all P < 0.05).

Conclusion
Cassia seed extract could noticeably improve the insulin resistance of diabetic rats and enhance the insulin sensitivity of their skeletal muscles. Its mechanism may be related to damage repair of the LKB1–AMPK–GLUT4 signaling pathway and oxidative stress in the skeletal muscle.
Effects of exercise training on markers of adipose tissue remodeling in patients with coronary artery disease and type 2 diabetes mellitus: sub study of the randomized controlled EXCADI trial
Authors: Zaidi Hani , Byrkjeland Rune , Njerve Ida U. , Åkra Sissel , Solheim Svein , Arnesen Harald , Seljeflot Ingebjørg , Opstad Trine B. 
Published: December 2019

Abstract
Background
Investigate effects of long-term exercise on the remodeling markers MMP-9, TIMP-1, EMMPRIN and Galectin-3 in combined type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) patients. Any associations between these biomarkers and glucometabolic variables were further assessed at baseline.

Methods
137 patients (age 41–81 years, 17.2% females) were included and randomized to a 12-months exercise program or to a control group. Fasting blood samples and subcutaneous adipose tissue (AT) samples were taken at inclusion and after 12-months. The intervention was a combination of aerobic and strength training for a minimum of 150 min per week. Circulating protein levels were measured by ELISA methods and RNA was extracted from AT and circulating leukocytes. Expression levels were relatively quantified by PCR.

Results
After 12 months of intervention, both AT-expression and circulating levels of EMMPRIN were increased in the exercise group (p < 0.05, both) with significant difference in change between the two groups (p < 0.05 both). No significant effect was observed on MMP-9, TIMP-1 and Galectin-3. Levels of TIMP-1 (AT-expression and circulating) were significantly correlated to insulin, and HOMA2- after Bonferroni correction (p = 0.001, by 48 performed correlations).

Conclusion
The increase in levels of EMMPRIN after long-term exercise training, might indicate some degree of AT remodeling in these patients after 12-months of exercise, whether beneficial or not. The remodeling markers were to some extent associated with glucometabolic variables in our population with the combined disease.
Trial registration clinicaltrials.gov, NCT01232608. Registered 2 November 2010
Genome-wide assessment of DNA methylation in mouse oocytes reveals effects associated with in vitro growth, superovulation, and sexual maturity
Authors: Saenz-de-Juano Maria Desemparats , Ivanova Elena , Billooye Katy , Herta Anamaria-Cristina , Smitz Johan , Kelsey Gavin , Anckaert Ellen 
Published: December 2019

Abstract
Background
In vitro follicle culture (IFC), as applied in the mouse system, allows the growth and maturation of a large number of immature preantral follicles to become mature and competent oocytes. In the human oncofertility clinic, there is increasing interest in developing this technique as an alternative to ovarian cortical tissue transplantation and to preserve the fertility of prepubertal cancer patients. However, the effect of IFC and hormonal stimulation on DNA methylation in the oocyte is not fully known, and there is legitimate concern over epigenetic abnormalities that could be induced by procedures applied during assisted reproductive technology (ART).

Results
In this study, we present the first genome-wide analysis of DNA methylation in MII oocytes obtained after natural ovulation, after IFC and after superovulation. We also performed a comparison between prepubertal and adult hormonally stimulated oocytes. Globally, the distinctive methylation landscape of oocytes, comprising alternating hyper- and hypomethylated domains, is preserved irrespective of the procedure. The conservation of methylation extends to the germline differential methylated regions (DMRs) of imprinted genes, necessary for their monoallelic expression in the embryo. However, we do detect specific, consistent, and coherent differences in DNA methylation in IFC oocytes, and between oocytes obtained after superovulation from prepubertal compared with sexually mature females. Several methylation differences span entire transcription units. Among these, we found alterations in Tcf4, Sox5, Zfp521, and other genes related to nervous system development.

Conclusions
Our observations show that IFC is associated with altered methylation at specific set of loci. DNA methylation of superovulated prepubertal oocytes differs from that of superovulated adult oocytes, whereas oocytes from superovulated adult females differ very little from naturally ovulated oocytes. Importantly, we show that regions other than imprinted gDMRs are susceptible to methylation changes associated with superovulation, IFC, and/or sexual immaturity in mouse oocytes. Our results provide an important reference for the use of in vitro growth and maturation of oocytes, particularly from prepubertal females, in assisted reproductive treatments or fertility preservation.
18F-Fluorodeoxyglucose positron emission tomography may not visualize radiation pneumonitis
Authors: Guo Meiying , Qi Liang , Zhang Yun , Shang Dongping , Yu Jinming , Yue Jinbo 
Published: December 2019

Abstract
Background
Radiation pneumonitis is a common and potentially fatal complication of radiotherapy (RT). Some patients with radiation pneumonitis show increases in uptake of fluorodeoxyglucose (FDG) on positron emission tomography (PET), but others do not. The exact relationship between radiation pneumonitis and 18F-FDG PET findings remains controversial.

Methods
We used an animal model of radiation pneumonitis involving both radiation and simulated bacterial infection in Wistar rats. Treatment groups (10 rats/group) were as follows: control, RT-only, lipopolysaccharide (LPS)-only, and RT+LPS. All rats had micro-PET scans at 7 weeks after RT (or sham). Histologic, immunohistochemical, and biochemical analyses were performed to evaluate potential mechanisms.

Results
Irradiated rats had developed radiation pneumonitis at 7 weeks after RT based on pathology and CT scans. Maximum and mean standardized uptake values (SUVmax and SUVmean) at that time were significantly increased in the LPS group (P < 0.001 for both) and the RT+LPS group (P < 0.001 for both) relative to control, but were not different in the RT-only group (P = 0.156 SUVmax and P = 0.304 SUVmean). The combination of RT and LPS increased the expression of the aerobic glycolysis enzyme PKM2 (P < 0.001) and the glucose transporter GLUT1 (P = 0.004) in lung tissues. LPS alone increased the expression of PKM2 (P = 0.018), but RT alone did not affect PKM2 (P = 0.270) or GLUT1 (P = 0.989).

Conclusions
Aseptic radiation pneumonitis could not be accurately assessed by 18F-FDG PET, but was visualized after simulated bacterial infection via LPS. The underlying mechanism of the model of bacterial infection causing increased FDG uptake may be the Warburg effect.
Melatonin-loaded lipid-core nanocapsules protect against lipid peroxidation caused by paraquat through increased SOD expression in Caenorhabditis elegans
Authors: Charão Mariele F. , Goethel Gabriela , Brucker Natália , Paese Karina , Eifler-Lima Vera L. , Pohlmann Adriana R. , Guterres Silvia S. , Garcia Solange C. 
Published: December 2019

AbstractBackgroundMelatonin has been described in the literature as a potent antioxidant. However, melatonin presents variable, low bioavailability and a short half-life. The use of polymeric nanoparticulated systems has been proposed for controlled release. Thus, the purpose of this study was to investigate the action of melatonin-loaded lipid-core nanocapsules (Mel-LNC) in the antioxidant system ofCaenorhabditis elegans,and the possible protective effect of this formulation against lipid peroxidation caused by paraquat (PQ).MethodsThe suspensions were prepared by interfacial deposition of the polymer and were physiochemically characterized.C. elegansN2 wild type and transgenic worm CF1553, muls84 [sod-3p::gfp; rol6(su1006)] were obtained from the Caenorhabditis Genetics Center (CGC). The worms were divided into 5 groups: Control, PQ 0.5 mM, PQ 0.5 mM + Mel-LNC 10 μg/mL, PQ + unloaded lipid-core nanocapsules (LNC), and PQ + free melatonin (Mel) 10 μg/mL. The lipid peroxidation was assessed through thiobarbituric acid (TBARS) levels and the fluorescence levels of the transgenic worms expressing GFP were measured.ResultsThe LNC and Mel-LNC presented a bluish-white liquid, with pH values of 5.56 and 5.69, respectively. The zeta potential was − 6.4 ± 0.6 and − 5.2 ± 0.2, respectively. The mean particle diameter was 205 ± 4 nm and 203 ± 3 nm, respectively. The total melatonin content was 0.967 mg/ml. The TBARS levels were significantly higher in the PQ group when compared to the control group (p < 0.001). Mel-LNC reduced TBARS levels to similar levels found in the control group. Moreover, only Mel-LNC significantly enhanced the SOD-3 expression (p < 0.05). Mel-LNC was capable of protectingC. elegansfrom lipid peroxidation caused by PQ and this was not observed when free melatonin was used. Moreover, Mel-LNC increased the fluorescence intensity of the transgenic strain that encodes the antioxidant enzyme SOD-3, demonstrating a possible mechanism of protection from PQ-induced damage.ConclusionThese findings demonstrated that melatonin, when associated with nanocapsules, had improved antioxidant properties and the protective activity against PQ-induced lipid peroxidation could be associated with the activation of antioxidant enzymes by Mel-LNC inC. elegans.
Hormonal status affects plasma exposure of tamoxifen and its main metabolites in tamoxifen-treated breast cancer patients
Authors: Ximenez João Paulo Bianchi , de Andrade Jurandyr Moreira , Marques Maria Paula , Coelho Eduardo Barbosa , Suarez-Kurtz Guilherme , Lanchote Vera Lucia 
Published: December 2019

Abstract
Background
Tamoxifen is considered a prodrug of its active metabolite endoxifen, which is dependent on the CYP2D6 and CYP3A enzymes. Tamoxifen pharmacokinetic variability influences endoxifen exposure and, consequently, its clinical outcome. This study investigated the impact of hormonal status on the pharmacokinetics of tamoxifen and its metabolites in TAM-treated breast cancer patients.

Methods
TAM-treated breast cancer patients (n = 40) previously believed to have CYP3A activity within the normal range based on oral midazolam and phenotyped as CYP2D6 normal metabolizers using oral metoprolol were divided into two groups according to premenopausal (n = 20; aged 35–50 years) or postmenopausal (n = 20; aged 60–79 years) status. All patients were treated with 20 mg/day tamoxifen for at least three months. Serial plasma samples were collected within the 24 h dose interval for analysis of unchanged tamoxifen, endoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen quantified by LC-MS/MS. CYP activities were assessed using midazolam apparent clearance (CYP3A) and the metoprolol/alfa-hydroxymetoprolol plasma metabolic ratio (CYP2D6). CYP3A4, CYP3A5 and CYP2D6 SNPs and copy number variation were investigated using TaqMan assays.

Results
Postmenopausal status increased steady-state plasma concentrations (Css) of tamoxifen (116.95 vs 201.23 ng/mL), endoxifen (8.01 vs 18.87 ng/mL), N-desmethyltamoxifen (485.16 vs 843.88 ng/mL) and 4-hydroxytamoxifen (2.67 vs 4.11 ng/mL). The final regression models included hormonal status as the only predictor for Css of tamoxifen [β-coef ± SE, p-value (75.03 ± 17.71, p = 0.0001)] and 4-hydroxytamoxifen (1.7822 ± 0.4385, p = 0.0002), while endoxifen Css included hormonal status (8.578 ± 3.402, p = 0.02) and race (11.945 ± 2.836, p = 0.007). For N-desmethyltamoxifen Css, the final model was correlated with hormonal status (286.259 ± 76.766, p = 0.0007) and weight (− 8.585 ± 3.060, p = 0.008).

Conclusion
The premenopausal status was associated with decreased endoxifen plasma concentrations by 135% compared to postmenopausal status. Thus, the endoxifen plasma concentrations should be monitored mainly in the premenopausal period to maintain plasma levels above the efficacy threshold value.

Trial registration
RBR-7tqc7k.
The impact assessment of technologies diffusion: a mixed methods analysis
Authors: Rezaei-Moghaddam Kurosh , Tohidyan Far Somayeh 
Published: December 2019

AbstractBackgroundImpact assessment is an important process that helps the policy makers to understand the consequences of possible and actual government interventions. Assessing the impacts and consequences is considered as applicable means for policy makers and planners of projects, since not only it measures and presents the plans’ developments, but also for determining their impacts on the target group. Therefore, the purpose of this paper was to assess the impacts of laser-land-leveling technology in Iran, comparing the impacts among two groups of farmers adopting traditional-leveling and laser-land-leveling projects and identifying factors influencing perception regarding laser-land-leveling technology impacts.MethodologyThe research draws on a mixed-methods approach, which includes two distinct research phases. First, 375 farmers were selected using survey based on stratified random sampling for quantitative part. Twenty-Seven farmers were also interviewed in the qualitative phase.ResultsThe most important impacts of laser-land leveling were uniform germination of the crop, uniform distribution of water, decrease of soil erosion, increasing positive competition, and increasing net income. In addition, the results revealed that adopters of laser-land leveling expressed more impacts than another group.ConclusionsAttitude towards water and soil resources’ conservation was the most important variable to predict the impacts’ perception among traditional-leveling adopters. It is necessary to officials to increase the information of farmers regarding different consequences of the project and contributing them to make proper decisions for farm management.