bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adverse Outcome Pathway Network–Based Assessment of the Interactive Effects of an Androgen Receptor Agonist and an Aromatase Inhibitor on Fish Endocrine Function
Authors: Ankley Gerald T. , Blackwell Brett R. , Cavallin Jenna E. , Doering Jon A. , Feifarek David J. , Jensen Kathleen M. , Kahl Michael D. , LaLone Carlie A. , Poole Shane T. , Randolph Eric C. , Saari Travis W. , Villeneuve Daniel L. 
Published: January 2020

Abstract
Predictive approaches to assessing the toxicity of contaminant mixtures have been largely limited to chemicals that exert effects through the same biological molecular initiating event. However, by understanding specific pathways through which chemicals exert effects, it may be possible to identify shared “downstream” nodes as the basis for forecasting interactive effects of chemicals with different molecular initiating events. Adverse outcome pathway (AOP) networks conceptually support this type of analysis. We assessed the utility of a simple AOP network for predicting the effects of mixtures of an aromatase inhibitor (fadrozole) and an androgen receptor agonist (17β-trenbolone) on aspects of reproductive endocrine function in female fathead minnows. The fish were exposed to multiple concentrations of fadrozole and 17β-trenbolone individually or in combination for 48 or 96 h. Effects on 2 shared nodes in the AOP network, plasma 17β-estradiol (E2) concentration and vitellogenin (VTG) production (measured as hepatic vtg transcripts) responded as anticipated to fadrozole alone but were minimally impacted by 17β-trenbolone alone. Overall, there were indications that 17β-trenbolone enhanced decreases in E2 and vtg in fadrozole-exposed fish, as anticipated, but the results often were not statistically significant. Failure to consistently observe hypothesized interactions between fadrozole and 17β-trenbolone could be due to several factors, including lack of impact of 17β-trenbolone, inherent biological variability in the endpoints assessed, and/or an incomplete understanding of interactions (including feedback) between different pathways within the hypothalamic–pituitary–gonadal axis. Environ Toxicol Chem 2020;39:913–922. © 2020 SETAC
Hiding in Plain Sight: Historical Fish Collections Aid Contemporary Parasite Research
Authors: Murphy Christina A , Gerth William , Pauk Kelci , Konstantinidis Peter , Arismendi Ivan 
Published: January 2020

Abstract
Natural history collections provide a wealth of information beyond the scope of their initial purpose, including a historical window into host–parasite relationships. For example, collections can reveal historical infections of fishes by the freshwater gill-maggot Salmincola californiensis, a parasite of increasing concern because of negative effects on salmonids that use large reservoirs in western North America. Here, we examined 1,241 preserved specimens collected between 1933 and 2014 from the Willamette River Basin, Oregon and deposited in the Oregon State Ichthyology Collection. We confirmed the historical presence and broad distribution of freshwater gill-maggot species affecting Cutthroat Trout Oncorhynchus clarkii, Rainbow Trout O. mykiss, Chinook Salmon O. tshawytscha, and Mountain Whitefish Prosopium williamsoni. In particular, S. californiensis was found infecting Pacific trout and Chinook Salmon. In addition, a previously undocumented freshwater gill-maggot species was discovered on Mountain Whitefish. The ability to both detect historical infections as well as to identify previously undocumented parasites demonstrates the value of historical collections for modern explorations of fish infections and highlights a need to keep archival representatives in mind when collecting fish.
Adherence to medical follow‐up recommendations reduces hospital admissions: Evidence from diabetic patients in France
Authors: Bussière Clémence , Sirven Nicolas , Rapp Thomas , Sevilla‐Dedieu Christine 
Published: January 2020

AbstractThe aim of this study was to document the extent to which diabetic patients who adhered to required medical follow‐ups in France experienced reduced hospital admissions over time. The main assumption was that enhanced monitoring and follow‐up of diabetic patients in the primary care setting could be a substitute for hospital use. Using longitudinal claim data of diabetic patients between 2010 and 2015 from MGEN, a leading mutuelle insurance company in France, we estimated a dynamic logit model with lagged measures of the quality of adherence to eight medical follow‐up recommendations. This model allowed us to disentangle follow‐up care in hospitals from other forms of inpatient care that could occur simultaneously. We found that a higher adherence to medical guidance is associated with a lower probability of hospitalization and that the take‐up of each of the eight recommendations may help reduce the rates of hospital admission. The reasons for the variation in patient adherence and implications for health policy are discussed.
Cooperation Between MYC and β‐Catenin in Liver Tumorigenesis Requires Yap/Taz
Authors: Bisso Andrea , Filipuzzi Marco , Gamarra Figueroa Gianni Paolo , Brumana Giulia , Biagioni Francesca , Doni Mirko , Ceccotti Giorgia , Tanaskovic Nina , Morelli Marco Jacopo , Pendino Vera , Chiacchiera Fulvio , Pasini Diego , Olivero Daniela , Campaner Stefano , Sabò Arianna , Amati Bruno 
Published: January 2020

Background and Aims
Activation of MYC and catenin beta‐1 (CTNNB1, encoding β‐catenin) can co‐occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear.

Approach and Results
We generated a mouse model allowing conditional activation of MYC and WNT/β‐catenin signaling (through either β‐catenin activation or loss of APC ‐ adenomatous polyposis coli) upon expression of CRE recombinase in the liver and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles, and tumorigenesis. Activation of WNT/β‐catenin signaling strongly accelerated MYC‐driven carcinogenesis in the liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell‐autonomous action. Short‐term induction of MYC and β‐catenin in hepatocytes, followed by RNA‐sequencing profiling, allowed the identification of a “Myc/β‐catenin signature,” composed of a discrete set of Myc‐activated genes whose expression increased in the presence of active β‐catenin. Notably, this signature enriched for targets of Yes‐associated protein (Yap) and transcriptional coactivator with PDZ‐binding motif (Taz), two transcriptional coactivators known to be activated by WNT/β‐catenin signaling and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β‐catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β‐catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.

Conclusions
Myc and β‐catenin show a strong cooperative action in liver carcinogenesis, with Yap and Taz serving as mediators of this effect. These findings warrant efforts toward therapeutic targeting of Yap/Taz in aggressive liver tumors marked by elevated Myc/β‐catenin activity.
Assessing the Time‐Dependent Impact of Performance Status on Outcomes After Liver Transplantation
Authors: Wallace David , Cowling Thomas , McPhail Mark J. , Brown Sarah E. , Aluvihare Varuna , Suddle Abid , Auzinger Georg , Heneghan Michael A. , Rowe Ian A. , Walker Kate , Heaton Nigel , van der Meulen Jan , Bernal William 
Published: January 2020

Background and Aims
Identifying how the prognostic impact of performance status (PS) differs according to indication, era, and time period (“epoch”) after liver transplantation (LT) could have implications for selection and treatment of patients on the waitlist. We used national data from the United Kingdom and Ireland to assess impact of PS on mortality separately for HCC and non‐HCC recipients.

Approach and Results
We assessed pre‐LT PS using the 5‐point modified Eastern Cooperative Oncology Group scale and used Cox regression methods to estimate hazard ratios (HRs) that compared posttransplantation mortality in different epochs of follow‐up (0‐90 days and 90 days to 1 year) and in different eras of transplantation (1995‐2005 and 2006‐2016). 2107 HCC and 10,693 non‐HCC patients were included. One‐year survival decreased with worsening PS in non‐HCC recipients where 1‐year survival was 91.9% (95% confidence interval [CI], 88.3‐94.4) in those able to carry out normal activity (PS1) compared to 78.7% (95% CI, 76.7‐80.5) in those completely reliant on care (PS5). For HCC patients, these estimates were 89.9% (95% CI, 85.4‐93.2) and 83.1% (95% CI, 61.0‐93.3), respectively. Reduction in survival in non‐HCC patients with poorer PS was in the first 90 days after transplant, with no major effect observed between 90 days and 1 year. Adjustment for donor and recipient characteristics did not change the findings. Comparing era, post‐LT mortality improved for HCC (adjusted HR, 0.55; 95% CI, 0.40‐0.74) and non‐HCC recipients (0.48; 95% CI, 0.42‐0.55), but this did not differ according to PS score (P = 0.39 and 0.61, respectively).

Conclusions
Impact on mortality of the recipient’s pretransplant PS is principally limited to the first 3 months after LT. Over time, mortality has improved for both HCC and non‐HCC recipients and across the full range of PS.
Serum metabonomics analysis of quercetin against the toxicity induced by cadmium in rats
Authors: Jia Siqi , Guan Tong , Zhang Xia , Liu Yajing , Liu Yanli , Zhao Xiujuan 
Published: January 2020

AbstractThis study aimed to investigate the protective effect of quercetin against the toxicity induced by chronic exposure to low levels of cadmium in rats by an ultra performance liquid chromatography mass spectrometer. Rats were randomly divided into six groups as follows: control group (C), low dose of quercetin group (Q1: 10 mg/kg·bw), high dose of quercetin group (Q2: 50 mg/kg·bw), cadmium chloride group (D), low dose of quercetin plus cadmium chloride group (DQ1), and high dose of quercetin plus cadmium chloride group (DQ2). Cadmium chloride (CdCl2) was administered to rats by drinking water ad libitum in a concentration of 40 mg/L. The final amount of CdCl2 ingested was estimated from the water consumption data to be 4.85, 4.91, and 4.89 mg/kg·bw/day, for D, DQ1, and DQ2 groups, respectively. After a 12‐week treatment, the serum samples of rats were collected for metabonomics analysis. Ten potential biomarkers were identified for which intensities were significantly increased or reduced as a result of the treatment. These metabolites included isorhamnetin 4′‐O‐glucuronide, 3‐indolepropionic acid, tetracosahexaenoic acid, lysophosphatidylcholine (LysoPC) (20:5), lysoPC (18:3), lysophosphatidylethanolamine (LysoPE) (20:5/0:0), bicyclo‐prostaglandin E2, sulpholithocholylglycine, lithocholyltaurine, and glycocholic acid. Results indicated that quercetin exerted a protective effect against cadmium‐induced toxicity by regulating lipid and amino acid metabolism, enhancing the antioxidant defense system and protecting liver and kidney function.
Improving the predictive quality of time‐dependent density functional theory calculations of the X‐ray emission spectroscopy of organic molecules
Authors: Fouda Adam A. E. , Besley Nicholas A. 
Published: January 2020

AbstractThe simulation of X‐ray emission spectra of organic molecules using time‐dependent density functional theory (TDDFT) is explored. TDDFT calculations using standard hybrid exchange‐correlation functionals in conjunction with large basis sets can predict accurate X‐ray emission spectra provided an energy shift is applied to align the spectra with experiment. The relaxation of the orbitals in the intermediate state is an important factor, and neglect of this relaxation leads to considerably poorer predicted spectra. A short‐range corrected functional is found to give emission energies that required a relatively small energy shift to align with experiment. However, increasing the amount of Hartree–Fock exchange in this functional to remove the need for any energy shift led to a deterioration in the quality of the calculated spectral profile. To predict accurate spectra without reference to experimental measurements, we use the CAM‐B3LYP functional with the energy scale determined with reference to a Δself‐consistent field calculation for the highest energy emission transition.
Plasma level of miR‐99b may serve as potential diagnostic and short‐term prognostic markers in patients with acute cerebral infarction
Authors: Wu Xiaomu , Zhang Xiaohong , Li Dongqing , Zhu Ziyang 
Published: January 2020

AbstractObjectiveThe aim of the present study is to explore the potential diagnostic and prognostic value of plasma levels of miR‐99 family for patients with acute cerebral infarction (ACI).MethodsA total of 112 patients who have been diagnosed with ACI were enrolled in this study, and 112 healthy volunteers were served as the controls. The plasma of the patients and controls were collected, and total RNAs were isolated, and the expression levels of miR‐99a, miR‐99b, and miR‐100 in the plasma of patients and controls were compared determined by RT‐qPCR methods; moreover, the receiver operating characteristic (ROC) curve has been drawn to determine whether the plasma levels of miR‐99b can distinguish patients with ACI from the controls; furthermore, the short‐term prognosis of the patients was evaluated by glasgow outcome scale (GOS), and the correlation between the plasma levels of miR‐99b and the GOS of the patients was evaluated. Finally, the correlation between the plasma level of miR‐99 and VEGF of ACI patients was analyzed.ResultsIt was observed that miR‐99b was significantly decreased in the plasma of ACI patients compared with the healthy controls (P < .01), while the plasma levels of miR‐99a and miR‐100 showed no significant differences between the patients with ACI and the healthy controls; moreover, the area under the curve (AUC) of miR‐99b for the diagnosis of ACI was 0.8882 (95% confidence interval (CI), 0.8451‐0.9313), suggesting that plasma level of miR‐99b is a sensitive marker to distinguish patients with ACI from the healthy volunteers; furthermore, the serum level of miR‐99b was negatively correlated with GOS score of the patients (r = −.56, P < .001); finally, the plasma level of miR‐99b was negatively correlated with the levels of VEGF (r = −.3013, P = .0012).ConclusionmiR‐99b was down‐regulated in plasma of patients with ACI, and plasma level of miR‐99b may be a potential diagnostic and prognostic marker for the diagnosis and treatment of ACI.
Low‐intensity pulsed ultrasound affects growth, differentiation, migration, and epithelial‐to‐mesenchymal transition of colorectal cancer cells
Authors: Lucchetti Donatella , Perelli Luigi , Colella Filomena , Ricciardi‐Tenore Claudio , Scoarughi Gian Luca , Barbato Gaetano , Boninsegna Alma , De Maria Ruggero , Sgambato Alessandro 
Published: January 2020

AbstractUltrasound (US) offers potentially important opportunities from a therapeutic point of view. Thus, the study of the biological effects of US on cancer cells is important to understand the consequences of these changes on the malignant phenotype. This study aimed to investigate the effects of low‐intensity ultrasound (LIPUS) on the phenotype of colorectal cancer cell lines. Cell proliferation was evaluated by viability test and by evaluation of pERK expression, while cell motility using the scratch test. Cell differentiation was evaluated assessing alkaline phosphatase activity. Epithelial mesenchymal transition was assessed by analyzing the expression of Vimentin and E‐Cadherin. Release and uptake of extracellular vesicles (EVs) were evaluated by flow cytometry. LIPUS effects on the organization of cytoskeleton were analyzed by confocal microscopy and by evaluation of Rho GTPase expression. No alterations in vitality and clonogenicity were observed when the intermediate (0.4 MPa) and the lowest (0.035 MPa) acoustic intensities were administered while the treatment with high intensity (1 MPa) induced a reduction of both cell viability and clonogenicity in both cell lines in a frequency‐dependent manner. LIPUS promoted the differentiation of colon cancer cells, affected epithelial‐to‐mesenchymal transition, promoted the closure of a wound as well as increased the release of EVs compared with untreated cells. LIPUS‐induced increase in cell motility was likely due to a Rho GTPase‐dependent mechanism. Overall, the results obtained warrant further studies on the potential combined effect of LIPUS with differentiating agents and on their potential use in a clinical setting.
Transcriptional memory in skeletal muscle. Don't forget (to) exercise
Authors: Beiter Thomas , Nieß Andreas M. , Moser Dirk 
Published: January 2020

AbstractTranscriptional memory describes an ancient and highly conserved form of cellular learning that enables cells to benefit from recent experience by retaining a mitotically inheritable but reversible memory of the initial transcriptional response when encountering an environmental or physiological stimulus. Herein, we will review recent progress made in the understanding of how cells can make use of diverse constituents of the epigenetic toolbox to retain a transcriptional memory of past states and perturbations. Specifically, we will outline how these mechanisms will help to improve our understanding of skeletal muscle plasticity in health and disease. We describe the epigenetic road map that allows skeletal muscle fibers to navigate through training‐induced adaptation processes, and how epigenetic memory marks can preserve an autobiographical history of lifestyle behavior changes, pathological challenges, and aging. We will further consider some key findings in the field of exercise epigenomics to emphasize major challenges when interpreting dynamic changes in the chromatin landscape in response to acute exercise and training.
Organizational readiness to implement population‐based screening and genetic service delivery for hereditary cancer prevention and control
Authors: Knerr Sarah , West Kathleen M. , Angelo Frank A. 
Published: January 2020

AbstractDespite clinical guidelines, programs conducting population‐based screening and genetic service delivery for hereditary cancer prevention and control are rare in practice. We interviewed individuals (n = 13) instrumental in implementing seven unique clinical programs conducting either universal tumor screening for Lynch Syndrome or routine family history screening and provision of genetic services for hereditary breast and ovarian cancer in the United States. To characterize determinants of readiness to implement population‐based cancer genetic service delivery models, interviews and deductive codes drew on Weiner's theory of organizational readiness for change. Qualitative analysis identified themes across programs. The degree to which organizational stakeholders valued moving to a population‐based genetic service delivery model depended on the existence of aligned clinical guidelines at the time of program implementation. However, judgments of implementation capacity within the organization, particularly with respect to task demands and resource concerns, were more often barriers to readiness. Program champions were essential to facilitating readiness, frequently taking on substantial uncompensated work. These data suggest that developing interventions targeting change efficacy and cultivating practice change champions may be two promising ways to increase uptake of population‐based hereditary cancer screening and genetic service delivery in clinical practice.
Mortality of Japanese patients with Leigh syndrome: Effects of age at onset and genetic diagnosis
Authors: Ogawa Erika , Fushimi Takuya , Ogawa‐Tominaga Minako , Shimura Masaru , Tajika Makiko , Ichimoto Keiko , Matsunaga Ayako , Tsuruoka Tomoko , Ishige Mika , Fuchigami Tatsuo , Yamazaki Taro , Kishita Yoshihito , Kohda Masakazu , Imai‐Okazaki Atsuko , Okazaki Yasushi , Morioka Ichiro , Ohtake Akira , Murayama Kei 
Published: January 2020

AbstractLeigh syndrome is a major phenotype of mitochondrial diseases in children. With new therapeutic options being proposed, assessing the mortality and clinical condition of Leigh syndrome patients is crucial for evaluating therapeutics. As data are scarce in Japan, we analysed the mortality rate and clinical condition of Japanese Leigh syndrome patients that we diagnosed since 2007. Data from 166 Japanese patients diagnosed with Leigh syndrome from 2007 to 2017 were reviewed. Patients' present status, method of ventilation and feeding, and degree of disability as of April 2018 was analysed. Overall, 124 (74.7%) were living, 40 (24.1%) were deceased, and 2 (1.2%) were lost to follow‐up. Median age of living patients was 8 years (1‐39 years). Median length of disease course was 91 months for living patients and 23.5 months for deceased patients. Nearly 90% of deaths occurred by age 6. Mortality rate of patients with onset before 6 months of age was significantly higher than that of onset after 6 months. All patients with neonatal onset were either deceased or bedridden. MT‐ATP6 deficiency caused by m.8993T>G mutation and MT‐ND5 deficiency induced a severe form of Leigh syndrome. Patients with NDUFAF6, ECHS1, and SURF1 deficiency had relatively mild symptoms and better survival. The impact of onset age on prognosis varied across the genetic diagnoses. The clinical condition of many patients was poor; however, few did not require mechanical ventilation or tube‐feeding and were not physically dependent. Early disease onset and genetic diagnosis may have prognostic value.
p67phox binds to a newly identified site in Nox2 following the disengagement of an intramolecular bond—Canaan sighted?
Authors: Bechor Edna , Zahavi Anat , Amichay Maya , Fradin Tanya , Federman Aya , Berdichevsky Yevgeny , Pick Edgar 
Published: January 2020

Abstract
Activation of the phagocyte NADPH oxidase involves a conformational change in Nox2. The effector in this process is p67phox and there is evidence for a change in the configuration of p67phox being required for binding to Nox2. To study this, we measured binding of p67phox to a library of Nox2 peptides and binding of NusA–Nox2 fusion proteins to p67phox. We found, serendipitously, that deletion of residues 259–279 in p67phox (p67phoxΔ(259–279)), endowed it with the ability to bind selectively to Nox2 peptide 369–383 (peptide 28). There was no binding to scrambled Nox2 peptide 28 and to Nox4 peptide 28. Binding was cysteine independent and resistant to reducing and alkylating agents. Truncations of peptide 28 revealed that the actual binding site consisted of residues 375–383. Binding of p67phoxΔ(259–279) to peptide 28 was mimicked by that of a (p67phox-RacGTP) chimera. Both p67phoxΔ(259–279) and the (p67pho–RacGTP) chimera bound a NusA–Nox2 fusion protein, comprising residues 375–383. Specific single residue deletion mutants, within the p67phox sequence 259–279, were also bound to Nox2 peptide 28. Peptides synthesized to correspond to the 259–279 sequence in p67phox, were found to autobind p67phox, suggesting that an intramolecular bond exists in p67phox, one pole of which was located within residues 259–279. We conclude that “resting” p67phox exists in a “closed” conformation, generated by an intramolecular bond. Deletion of specific residues within the 259–279 sequence, in vitro, or interaction with RacGTP, in vivo, causes “opening” of the bond and results in binding of p67phox to a specific, previously unknown, site in Nox2.