bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hotspots of aberrant enhancer activity in fibrolamellar carcinoma reveal molecular mechanisms of oncogenesis and intrinsic drug resistance
Authors: Dinh Timothy A. , Sritharan Ramja , Smith F. Donelson , Francisco Adam B. , Ma Rosanna K. , Bunaciu Rodica P. , Kanke Matt , Danko Charles G. , Massa Andrew P. , Scott John D. , Sethupathy Praveen 
Published: January 2020

AbstractFibrolamellar carcinoma (FLC) is a rare, therapeutically intractable liver cancer that disproportionately affects youth. Although FLC tumors exhibit a distinct gene expression profile, the causative transcriptional mechanisms remain unclear. Here we used chromatin run-on sequencing to discover approximately 7,000 enhancers and 141 enhancer hotspots activated in FLC relative to non-malignant liver. Detailed bioinformatic analyses revealed aberrant ERK/MEK signaling and candidate master transcriptional regulators. We also defined the genes most strongly associated with aberrant FLC enhancer activity, includingCA12andSLC16A14. Treatment of FLC cell models with inhibitors of CA12 or SLC16A14 independently reduced cell viability and/or significantly enhanced the effect of MEK inhibitor cobimetinib. These findings highlight new molecular targets for drug development as well as novel drug combination approaches.
Selective Postnatal Excitation of Neocortical Pyramidal Neurons Results in Distinctive Behavioral and Circuit Deficits in Adulthood
Authors: Medendorp William E. , Pal Akash , Waddell Madison , Björefeldt Andreas , Moore Christopher I. , Hochgeschwender Ute 
Published: January 2020

SummaryIn leading models of Autism Spectrum Disorder, and in human data, the efficacy of outgoing cortical connectivity transitions from overly exuberant to languid from early development to adulthood. This transition begs the question of whether the early enhancement in excitation might be a common driver, across etiologies, of these symptoms. We directly tested this concept by chemogenetically driving neuronal activity in neocortical neurons during postnatal days 4-14. Hyperexcitation of Emx1-, but not dopamine transporter-, parvalbumin-, or Dlx5/6-expressing neurons led to decreased social interaction and increased grooming activity in adult animals.In vivooptogenetic interrogation in adults revealed decreased baseline but increased stimulus-evoked firing rates of pyramidal neurons, impaired recruitment of inhibitory neurons and reduced cortico-striatal communication. These results directly support the prediction that changed firing in developing circuits irreversibly alters adult circuit function that leads to maladaptive changes in behaviors. This experimental approach offers a valuable platform to study the impact of disruption of developmental neural activity on the formation and function of adult neural circuits and behavior.
Visuo-proprioceptive control of the hand in older adults
Authors: Block Hannah J. , Sexton Brandon M. 
Published: January 2020

AbstractTo control hand movement, we have both vision and proprioception, or position sense. The brain is known to integrate these to reduce variance. Here we ask whether older adults integrate vision and proprioception in a way that minimizes variance as young adults do, and whether older subjects compensate for an imposed visuo-proprioceptive mismatch as young adults do. Ten healthy older adults (mean age 69) and 10 healthy younger adults (mean age 19) participated. Subjects were asked to estimate the position of visual, proprioceptive, and combined targets, with no direct vision of either hand. After a veridical baseline block, a spatial visuo-proprioceptive misalignment was gradually imposed by shifting the visual component forward from the proprioceptive component without the subject’s awareness. Older subjects were more variable than young subjects at estimating both visual and proprioceptive target positions (F1,18= 6.14, p = 0.023). Older subjects tended to rely more heavily on vision than proprioception compared to younger subjects. However, the weighting of vision vs. proprioception was correlated with minimum variance predictions for both older (r = 0.71, p = 0.021) and younger (r = 0.81, p = 0.0047) adults, suggesting that variance-minimizing mechanisms are present to some degree in older adults. Visual and proprioceptive realignment were similar for young and older subjects in the misalignment block, suggesting older subjects are able to realign as much as young subjects. These results suggest that intact multisensory processing in older adults should be explored as a potential means of mitigating degradation in individual sensory systems.
Multidimensional hydrogel models reveal endothelial network angiocrine signals increase glioblastoma cell number, invasion, and temozolomide resistance
Authors: Ngo Mai T. , Karvelis Elijah , Harley Brendan A.C. 
Published: January 2020

ABSTRACTGlioblastoma is the most common primary malignant brain tumor. The tissue microenvironment adjacent to vasculature, termed the perivascular niche, has been implicated in promoting biological processes involved in glioblastoma progression such as invasion, proliferation, and therapeutic resistance. However, the exact nature of the cues that support tumor cell aggression in this niche are largely unknown. Soluble angiocrine factors secreted by tumor-associated vasculature have been shown to support such behaviors in other cancer types. Here, we exploit macroscopic and microfluidic gelatin hydrogel platforms to profile angiocrine factors secreted by self-assembled endothelial networks and evaluate their relevance to glioblastoma biology. Aggregate angiocrine factors support increases in U87-MG cell number, migration, and therapeutic resistance to temozolomide. We also identify a novel role for TIMP1 in facilitating glioblastoma tumor cell migration. Overall, this work highlights the use of multidimensional hydrogel models to evaluate the role of angiocrine signals in glioblastoma progression.Insight, Innovation, and IntegrationGlioblastoma progression is linked to interactions between tumor and vascular cells, which can influence invasion and therapeutic response. In co-culture studies to investigate tumor-vascular crosstalk, endothelial cells often are not presented in three-dimensional structures mimicking vasculature and the exact identity of secreted factors is not explored. Here, we use tissue engineering strategies to generate three-dimensional endothelial networks from which to collect soluble angiocrine signals and assess the impact of these signals on glioblastoma behavior. Furthermore, we use secretomic analysis to identify specific factors influencing glioblastoma invasion. We identify a novel role for TIMP1 in supporting glioblastoma migration and demonstrate that soluble angiocrine signals support chemoresistance to temozolomide.
The New South Wales Teachers Federation, the Conciliation Committee of 1927-1929, and the Formation of the Educational Workers League
Authors: Kass Dorothy , Sullivan Martin 
Published: January 2020

Purpose
Originally written in the 1990s but unpublished, the paper is now revised; the purpose of this paper is to examine the context of the formation of the Educational Workers League of NSW in 1931 with particular emphasis on the NSW Crown Employees (Teachers) Conciliation Committee and the enactment of its agreement in the worsening economic conditions of the Depression. The aims, reception and possible influence of the League on Federation policy and practice are addressed.

Design/methodology/approach
Primary source material consulted includes the minutes of the Conciliation Committee’s sittings from September 1927 to July 1929; papers relating to the Educational Workers League held in the Teachers Federation Library; and the Teachers Federation journal, Education.

Findings
The Conciliation Committee’s proceedings and outcomes had far reaching implications. The resultant salary agreement received a hostile reception from assistant teachers and fuelled distrust between assistants and headmasters. As economic depression deepened, dissatisfaction with the conservative leadership and tactics of the Federation increased. One outcome was the formation of the radical, leftist Educational Workers League by teachers, including Sam Lewis, who would later play key roles within the Federation itself.

Originality/value
While acknowledging the extensive earlier work of Bruce Mitchell, the paper contributes to a deeper understanding of teacher unionism and teacher activism in the 1920s and 1930s. Apart from brief attention by Federation historians in the 1960s and 1970s, there has been no history of the formation, reception and significance of the Educational Workers League.
Current climate overrides historical effects on species richness and range size of freshwater plants in Europe and North America
Authors: Alahuhta Janne , Antikainen Harri , Hjort Jan , Helm Aveliina , Heino Jani 
Published: January 2020

Abstract

The latitudinal diversity gradient hypothesis suggests that species richness should be highest at low latitudes, whereas Rapoport's rule states that largest ranges ought to be found for species at high latitudes. However, there is no consensus over these patterns and their underlying drivers in the freshwater realm.

We investigated species richness and mean range size of freshwater plants in 50 × 50 km grid cells across Europe (40°N–71°N) and North America (25°N–78°N), supplemented with data based on 1° latitudinal bands for mean range size. We were especially interested to find out whether there are similarities and differences in these ecogeographical patterns and their underlying drivers between the continents due to their contrasting historical characteristics, spatial extent and topography.

First, we used partial regression to reveal whether species richness and mean range size of freshwater plants have a linear or quadratic relationship with latitude. Second, we employed variation partitioning based on partial regression to model relationships between plant species richness and mean range size and four explanatory variable groups (i.e. environmental features, current climate, historical climate and geographical location). Third, we utilized boosted regression tree analysis to further investigate species richness and mean range size of freshwater plants in relation to a set of explanatory variables.

Our results revealed that species richness showed relatively similar patterns in relation to latitude between the continents. Similarly, mean range size trends were alike in North America whether we used 50 × 50 km grid cell data or 1° latitudinal bands. Instead, different patterns in mean range size emerged between the used datasets in Europe. For both species richness and mean range size, current climate (with different individual predictor variables) was the main driver in both the continents, but historical effects had a small influence on the response variables.

Synthesis. Our findings indicated that major ecogeographical rules can strongly vary for the same taxonomic group across broad scales between continents. It is also premature to rely solely on well‐known terrestrial taxonomic groups when drawing generalizations about ecogeographical rules.
Effect of physiological and production activities on the concentration of naturally occurring steroid hormones in raw milk
Authors: Xu Bozhou , Zhang Feng , Xu Xiuli , Li Xiaoming , He Muyi , Nie Xuemei , Liu Tong 
Published: January 2020

This study aimed to collect comprehensive experimental data and evaluate the effects of physiological and production activities on the concentration of naturally occurring steroid hormones in raw cow milk. The average levels of the hormones analysed (progesterone = 12 680 ng/kg and cortisol = 284 ng/kg) were comparable with data reported in the literature. Oestradiol, testosterone and methyltestosterone were not detected at their respective limits of quantification. Progesterone concentrations from individual cows have shown large variations ranging from 204 to 26 503 ng/kg, linked to the gestational status (pregnant/nonpregnant), lactation stages and gestational ages of the mammals. The average concentration of cortisol reaches a peak in the morning, decreases in the afternoon and reaches the lowest level at midnight. It is therefore evidenced that physiological and production activities have an effect on some hormonal levels in raw cow milk.
Does the Single Supervisory Mechanism Reduce Overall Risk in the European Stock Market?
Authors: Abad Pilar , García‐Olalla Myriam , Robles M. Dolores 
Published: January 2020

AbstractThe aim of this paper is to investigate the economic impact of the single supervisory mechanism (SSM) as measured by the reaction of the major stock market indexes of the European Union (EU) countries. To capture the market reaction, we analyse the impact of news related to the development and implementation of the SSM on the broad stock indexes and their banking and non‐financial sector indexes. Moreover, we not only investigate stock returns, but also study the impact on systematic risk, overall risk and the degree of integration among markets. The results of an event study and stability tests show significant market reactions that decrease value and increase risk for some of the news, specifically the beginning and end of the process. The main effects are heterogeneous across different EU countries. The observed response is also more evident in the banking sector than in the non‐financial sector.
World Trading System under Stress: Scenarios for the Future
Authors: Akman Mehmet Sait , Armstrong Shiro , Dadush Uri , Gonzalez Anabel , Kimura Fukunari , Nakagawa Junji , Rashish Peter , Tamura Akihiko , Primo Braga Carlos A. 
Published: January 2020

AbstractThe world trading system has been remarkably successful in many respects but is now under great strain. The causes are deep‐seated and require a strategic response. The future of the system depends critically on reinvigorating the WTO and policy change in the largest trading nations. Important measures are required to sustain the multilateral trading system, and urgent action is needed to avoid a scenario where the system fragments. The worst scenarios will disrupt global trade and see a world which splinters into large trading blocs (most likely centered on China, the European Union and the United States) and where trade relations are based to a large extent on relative power instead of rules. In such a world the smallest players – especially those whose trade is least covered by bilateral or regional agreements – will be at the greatest disadvantage. All countries will incur enormous costs only to try and reinvent a system that is already in place today under the WTO.
Transplanting cells from old but not young donors causes physical dysfunction in older recipients
Authors: Wang Binsheng , Liu Zukai , Chen Vicky P. , Wang Lichao , Inman Christina L. , Zhou Yueying , Guo Chun , Tchkonia Tamar , Rowe David W. , Kuchel George A. , Robson Paul , Kirkland James L. , Xu Ming 
Published: January 2020

AbstractAdipose‐derived mesenchymal stem cell (ADSC)‐based regenerative therapies have shown potential for use in many chronic diseases. Aging diminishes stem cell regenerative potential, yet it is unknown whether stem cells from aged donors cause adverse effects in recipients. ADSCs can be obtained using minimally invasive approaches and possess low immunogenicity. Nevertheless, we found that transplanting ADSCs from old donors, but not those from young donors, induces physical dysfunction in older recipient mice. Using single‐cell transcriptomic analysis, we identified a naturally occurring senescent cell‐like population in ADSCs primarily from old donors that resembles in vitro‐generated senescent cells with regard to a number of key pathways. Our study reveals a previously unrecognized health concern due to ADSCs from old donors and lays the foundation for a new avenue of research to devise interventions to reduce harmful effects of ADSCs from old donors.
Digital depression: a new disease of the millennium?
Authors: Ghaemi S. N. 
Published: January 2020

ObjectiveIn the past decade, since the innovation of the smartphone, there has been an increase in depression, anxiety, and suicidality among teenagers and young adults. The objective of this article was to review the current evidence for these associations and to provide initial clinical guidance.MethodsA narrative review of the available literature on digital technology, social media, and psychiatric outcomes in adolescents.ResultsPsychiatric outcomes have worsened in adolescents in the past decade, correlating with the invention of the smartphone and the rise of social media. Depressive symptoms among American teenagers rose rapidly around 2012 and now are reported in 22% of adolescents, which is at least double the rate in adults. Suicide rates have risen, especially among teenage girls in the United States, in whom there has been a doubling of completed suicide in the past decade. A causal relationship between social media use and these harmful psychiatric outcomes is supported by emerging randomized data showing reduced depressive symptoms associated with a decrease in social media use in college students.ConclusionsSocial media and digital technology correlate with harmful psychiatric outcomes in adolescents and young adults. Clinical recommendations should include limitations in social media use.
Simvastatin alleviated diabetes mellitus‐induced erectile dysfunction in rats by enhancing AMPK pathway‐induced autophagy
Authors: Ding Fan , Shan Changyu , Li Hongwei , Zhang Yuping , Guo Chunling , Zhou Zhansong , Zheng Ji , Shen Wenhao , Dai Qiang , Ouyang Qin , Wu Xiaojun 
Published: January 2020

AbstractBackgroundDiabetes mellitus‐induced erectile dysfunction is a common diabetic complication, and new therapeutics and the pathogenesis of diabetes mellitus‐induced erectile dysfunction need to be investigated.ObjectivesThe aim was to investigate the pathogenesis of diabetes mellitus‐induced erectile dysfunction and the pharmacological mechanism of simvastatin treatment in diabetes mellitus‐induced erectile dysfunction model rats.Materials and methodsA total of 86 male Sprague Dawley rats aged 8 weeks old were used in this study. The rats were divided into three groups: control (normal), diabetes mellitus‐induced erectile dysfunction (streptozotocin‐injected), and diabetes mellitus‐induced erectile dysfunction + simvastatin (sim). Each group was subdivided into two subgroups for in vitro and in vivo analyses. A bioinformatics method was used to detect differences in gene expression in the corpus cavernosum between normal and diabetes mellitus‐induced erectile dysfunction rats. Erectile function was measured by a cavernous nerve electrostimulation test. Corpus cavernosum fibrosis was assessed by Masson staining and Western blotting. Immunofluorescence and Western blotting were performed to explore the differential expression of autophagy‐related genes and the AMPK‐SKP2‐CARM1 pathway genes in rat cavernous smooth muscle cells and the corpus cavernosum. The autophagosomes of the corpus cavernosum tissue were observed by transmission electron microscopy.ResultsAutophagy‐related genes and pathways (the AMPK and FoxO pathway) were identified by bioinformatics analysis and confirmed at the protein level. Simvastatin, an AMPK agonist, was used to treat diabetes mellitus‐induced erectile dysfunction rats for 8 weeks, demonstrating that erectile function was improved for 80.5% (P < .05) of rats. Corpus cavernosum fibrosis was alleviated (P < .05), and autophagy was further enhanced (P < .05); these results might be partially caused by AMPK‐SKP2‐CARM1 pathway activation (P < .05).Discussion and conclusionSimvastatin could enhance protective autophagy by activating the AMPK‐SKP2‐CARM1 pathway to improve erectile function in diabetes mellitus‐induced erectile dysfunction rats.
The physician's gender influences the results of the diagnostic workup for erectile dysfunction
Authors: Rastrelli Giulia , Cipriani Sarah , Craparo Andrea , De Vincentis Sara , Granata Antonio R. M. , Spaggiari Giorgia , Simoni Manuela , Maggi Mario , Santi Daniele 
Published: January 2020

AbstractBackgroundDespite the well‐known influence of psychological and situational factors on erectile dysfunction, the influence of the physician's gender on the andrological workup has never been investigated so far.ObjectivesTo investigate physician's gender influence on the erectile dysfunction diagnostic workup.Materials and methodsCross‐sectional study with retrospective data collection. We evaluate a consecutive series of erectile dysfunction patients: 95 at the University of Modena and Reggio Emilia (UNIMORE) and 1808 at the University of Florence (UNIFI). In the UNIMORE cohort (Cohort 1), intracavernousal injection test was performed in case of suspected vascular pathogenic component. In the UNIFI cohort (Cohort 2), patients were evaluated by structured interview on erectile dysfunction and ANDROTEST. Both cohorts were divided into two groups according to the gender of the physician who performed the intracavernousal injection test or the structured interview.ResultsIn Cohort 1, patients who had the intracavernousal injection test performed by a female physician had a significantly higher probability of obtaining a better intracavernousal injection test response. In Cohort 2, patients interviewed by female physician more frequently reported to have a conflictual couple relationship and a reduced frequency of climax in their partners. However, they reported less difficulties in achieving and maintaining erection, higher frequency of autoeroticism, lower occurrence of erectile dysfunction during masturbation and lower impairment in morning erections.ConclusionsPhysician's gender affects the results obtained during the erectile dysfunction diagnostic workup. Men interviewed by a female physician describe a less severe erectile dysfunction probably as attempt to defend their own virility. On the other hand, the presence of a male physician during intracavernousal injection test is associated to a worse response suggesting a possible unconscious competition.
Identification of malignant early repolarization pattern by late QRS activity in high‐resolution magnetocardiography
Authors: Iwakami Naotsugu , Aiba Takeshi , Kamakura Shiro , Takaki Hiroshi , Furukawa Toshiaki A. , Sato Tosiya , Sun Wenxu , Shishido Toshiaki , Nishimura Kunihiro , Yamada‐Inoue Yuko , Nagase Satoshi , Shimizu Wataru , Yasuda Satoshi , Sugimachi Masaru , Kusano Kengo 
Published: January 2020

AbstractBackgroundThe early repolarization pattern (ERP) in electrocardiography (ECG) has been considered as a risk for ventricular fibrillation (VF), but effective methods for identification of malignant ERP are still required. We investigated whether high spatiotemporal resolution 64‐channel magnetocardiography (MCG) would enable distinction between benign and malignant ERPs.MethodsAmong all 2,636 subjects who received MCG in our facility, we identified 116 subjects (43 ± 18 years old, 54% male) with inferior and/or lateral ERP in ECG and without structural heart disease, including 13 survivors of VF (ERP‐VF(+)) and 103 with no history of VF (ERP‐VF(−)). We measured the following MCG parameters in a time‐domain waveform of relative current magnitude: (a) QRS duration (MCG‐QRSD), (b) root‐mean‐square of the last 40 ms (MCG‐RMS40), and (c) low amplitude (<10% of maximal) signal duration (MCG‐LAS).ResultsCompared to ERP‐VF(−), ERP‐VF(+) subjects presented a significantly longer MCG‐QRS (108 ± 24 vs. 91 ± 23 ms, p = .02) and lower MCG‐RMS40 (0.10 ± 0.08 vs. 0.25 ± 0.20, p = .01) but no difference in MCG‐LAS (38 ± 22 vs. 29 ± 23 ms, p = .17). MCG‐QRSD and MCG‐RMS40 showed significantly larger area under the ROC curve compared to J‐peak amplitude in ECG (0.72 and 0.71 vs. 0.50; p = .04 and 0.03). The sensitivity, specificity, and odds ratio for identifying VF(+) based on MCG‐QRSD ≥ 100 ms and MCG‐RMS40 ≤ 0.24 were 69%, 74%, and 6.33 (95% CI, 1.80–22.3), and 92%, 48%, and 10.9 (95% CI, 1.37–86.8), respectively.ConclusionMagnetocardiography is an effective tool to distinguish malignant and benign ERPs.