bluuebunny/crossref_metadata_2025 huggingface dataset:
Do Korean-Japanese Historical Disputes Generate Rally Effects?
Authors: Hwang Wonjae , Cho Wonbin , Wiegand Krista
Published: May 2018

Does ongoing animosity between South Korea and Japan over the disputed Dokdo Islands and other issues that originated from historical disputes generate rally effects in Korean domestic politics? This article argues that the Dokdo Islands dispute—and related disputed issues rooted in the colonial experience of Korea under Japan's rule historically—strongly influence Korean presidents’ abilities to effectively mobilize domestic support for not only the issues, but particularly the public opinion of presidents. Using data on Korean presidents’ approval ratings between 1993 and 2016, this article shows that Korea's bilateral disputes with Japan tend to promote Korean presidential popularity. The findings suggest that external crises with Japan related to historical disputes have positive political effects on leadership ratings in Korea.
Udder skin surface temperature variation pre- and post- milking in dairy cows as determined by infrared thermography
Authors: Yang Chunhe , Li Gan , Zhang Xiaojun , Gu Xianhong
Published: May 2018

The objectives of the research reported in this Research Communication were to compare the variation of hind quarter skin surface temperature pre- and post- milking in dairy cows and to determine the optimal time to capture images by infrared thermography for improving the sensitivity and specificity of mastitis detection in dairy cows. Hind quarter infrared images of 102 Holstein dairy cows were captured from the caudal view by an infrared camera pre-milking and post-milking. The udder skin surface temperature was measured with the help of the image processing software. No significant difference was found between the left and right quarter skin surface temperature pre- and post- milking. The hind quarter skin surface temperature pre-milking was not significantly influenced by milk yield, but exhibited a rising trend along with the increase of milk yield. The hind quarter skin surface temperature post-milking was significantly influenced by milk yield. This leads us to conclude that the sensitivity and specificity of IRT in mastitis detection may be influenced by milk yield and it may be better to capture the infrared images of cow udders pre-milking.
Local Political Uncertainty, Family Control, and Investment Behavior
Authors: Amore Mario Daniele , Minichilli Alessandro
Published: May 2018

Estimating difference-in-differences models on a comprehensive data set of Italian companies, we provide novel insights into the literature on political uncertainty and firm investment. We first establish thatlocalpolitical uncertainty leads to declining investment. Next, we show thatfamily controlneutralizes this effect: Family firms are more likely than other firms to invest during politically uncertain times, especially when operating in industries dependent on public spending and/or managed by family members. Finally, we document that this investment resilience of family firms under political uncertainty translates into significantly greater profitability and growth.
According to mitochondrial DNA evidence, Parascaris equorum and Parascaris univalens may represent the same species
Authors: Gao J.F. , Zhang X.X. , Wang X.X. , Li Q. , Li Y. , Xu W.W. , Gao Y. , Wang C.R.
Published: May 2018

Parascarosis is caused mainly by parasitic infections with Parascaris equorum and Parascaris univalens, the most common ascarid nematodes, in the small intestine of equines. Parascarosis often causes severe illness and even death in foals and yearlings. In this study, we obtained the complete sequence of the P. equorum mitochondrial (mt) genome and compared its organization and structure with that of P. equorum Japan isolate (nearly complete), and the complete mtDNA sequences of P. univalens Switzerland and USA isolates. The complete mtDNA genome of P. equorum China isolate is 13,899 base pairs (bp), making it the smallest of the four genomes. All four Parascaris mt genomes are circular, and all genes are transcribed in the same direction. The P. equorum mtDNA genome consists of 12 protein-coding genes, two ribosomal RNA genes, 22 transfer (t) RNA genes and one non-coding region, which is consistent with P. equorum Japan isolate and P. univalens Switzerland isolate but distinct from P. univalens USA isolate, which has 20 tRNA genes. Differences in nucleotide sequences of the four entire mt genomes range from 0.1–0.9%, and differences in total amino acid sequences of protein-coding genes are 0.2–2.1%. Phylogenetic analyses showed that the four Parascaris species clustered in a clade, indicating that P. equorum and P. univalens are very closely related. These mt genome datasets provide genetic evidence that P. equorum and P. univalens may represent the same species, which will be of use in further studies of the taxonomy, systematics and population genetics of ascarids and other nematodes.
Diffusive shock re-acceleration
Authors: Caprioli Damiano , Zhang Horace , Spitkovsky Anatoly
Published: May 2018

We have performed two-dimensional hybrid simulations of non-relativistic collisionless shocks in the presence of pre-existing energetic particles (‘seeds’); such a study applies, for instance, to the re-acceleration of galactic cosmic rays (CRs) in supernova remnant (SNR) shocks and solar wind energetic particles in heliospheric shocks. Energetic particles can be effectively reflected and accelerated regardless of shock inclination via a process that we call diffusive shock re-acceleration. We find that re-accelerated seeds can drive the streaming instability in the shock upstream and produce effective magnetic field amplification. This can eventually trigger the injection of thermal protons even at oblique shocks that ordinarily cannot inject thermal particles. We characterize the current in reflected seeds, finding that it tends to a universal value $J\simeq en_{\text{CR}}v_{\text{sh}}$, where $en_{\text{CR}}$ is the seed charge density and $v_{\text{sh}}$ is the shock velocity. When applying our results to SNRs, we find that the re-acceleration of galactic CRs can excite the Bell instability to nonlinear levels in less than ${\sim}10~\text{yr}$, thereby providing a minimum level of magnetic field amplification for any SNR shock. Finally, we discuss the relevance of diffusive shock re-acceleration also for other environments, such as heliospheric shocks, galactic superbubbles and clusters of galaxies.
Ambiguity, Ambivalence, Multiplicity: A Case Study of Late Pottery Neolithic Ceramic Assemblages from the Southern Levant
Authors: Nativ Assaf
Published: May 2018

This paper presents an experiment. Can a typologically inarticulate assemblage be accounted for by other means? What might such an articulation look like? What prospects would it offer? Focusing on three small late Pottery Neolithic assemblages from the southern Levant, the paper argues that they are typologically inarticulate, primarily because they possess considerable morphological fluidity that is at odds with the segmented structure demanded by this mode of classification. The paper presents an attempt to formulate an account of these assemblages that incorporates their morphological fluidity and ambiguity. Allowing for differential quantitative emphases across the assemblage, it is suggested that certain forms may be specified as types. In turn, the relations among these types are shown to constitute a structural order. Yet the assemblages are also fundamentally ambivalent, both constituting and de-constituting their order and logic. For the types are constituted in relative (rather than absolute) terms and the orderly structures are accompanied by elements that are incommensurable with it. Acknowledging these conflicting qualities, it is proposed that they are multiple, that the one assemblage is several. Finally, the paper explores some implications this understanding of the ceramic assemblages might have for the discussion of temporal development.
INFLATION TARGETING, PATTERN OF TRADE, AND ECONOMIC DYNAMICS
Authors: Chang Juin-jen , Chang Wen-ya , Tsai Hsueh-fang , Wang Ping
Published: May 2018

This paper develops an analytically tractable, two-country, two-traded-good dynamic general-equilibrium model of money to examine the long-run and short-run effects of a temporary change in the domestic inflation target on the trade pattern, the terms of trade, the foreign exchange rate, and the capital accumulation of each country and of the world economy. We find that such a temporary monetary innovation can generate permanent effects on the world distribution of capital and the pattern of trade, resulting in nonneutrality in an otherwise money-neutral cash-in-advance setting. This change also leads to very rich transitional dynamics that we fully characterize analytically. In particular, endogenous responses in transition can be monotone or nonmonotone and can exhibit over-shooting. Our analytic findings and quantitative results help explain some noticeable changes in the capital accumulation, output, and bilateral trade of several countries adopting inflation targeting. Since the permanent effects of a temporary change in the domestic inflation target on the pattern of international trade and the performance of the macroeconomy are driven by a new channel through the world distribution of capital, we add new insights to the literature.
Complexity in pediatric primary care
Authors: Nasir Arwa , Nasir Laeth , Tarrell Ariel , Finken David , Lacroix Amy , Pinninti Swetha , Pitner Sheryl , McCarthy Molly
Published: May 2018

Background

The management of patients in primary care is often complicated by the presence of multiple chronic conditions and psychosocial issues that increase the complexity of the encounter and have important impacts on care. There is a paucity of literature on this subject in the pediatric population.

Objectives

The aim of this study was to quantify the burden of chronic conditions in pediatric primary care.

Methods

The problem lists of 3995 randomly selected patients from a community pediatric clinic and an academic hospital-based pediatric clinic in the same metropolitan area were analyzed for the presence and number of any chronic condition.

Results

In total, 53% of patients suffered from at least one chronic problem, 25% had two or more chronic conditions and 5.1% had four or more conditions. Compared with the community clinic, the academic clinic had significantly more children with catastrophic complex conditions (P<0.001). A regression analysis showed a significant positive correlation between the number of chronic medical conditions and mental health diagnoses.

Conclusions

The burden of chronic disease in the pediatric primary care setting may be significantly higher than has been previously suggested. To ensure optimal quality of care, health planners should take into account the high burden of chronic illness, psychosocial issues and multimorbidity among patients in the pediatric primary care setting, as well as the higher complexity profile of patients attending academic clinics.
Parallelism, concurrency and distribution in constraint handling rules: A survey
Authors: FRÜHWIRTH THOM
Published: May 2018

Constraint Handling Rules (CHR) is both an effective concurrent declarative programming language and a versatile computational logic formalism. In CHR, guarded reactive rules rewrite a multi-set of constraints. Concurrency is inherent, since rules can be applied to the constraints in parallel. In this comprehensive survey, we give an overview of the concurrent, parallel as well as distributed CHR semantics, standard and more exotic, that have been proposed over the years at various levels of refinement. These semantics range from the abstract to the concrete. They are related by formal soundness results. Their correctness is proven as a correspondence between parallel and sequential computations. On the more practical side, we present common concise example CHR programs that have been widely used in experiments and benchmarks. We review parallel and distributed CHR implementations in software as well as hardware. The experimental results obtained show a parallel speed-up for unmodified sequential CHR programs. The software implementations are available online for free download and we give the web links. Due to its high level of abstraction, the CHR formalism can also be used to implement and analyse models for concurrency. To this end, the Software Transaction Model, the Actor Model, Colored Petri Nets and the Join-Calculus have been faithfully encoded in CHR. Finally, we identify and discuss commonalities of the approaches surveyed and indicate what problems are left open for future research.
HEAVEN
Authors: Cahn Steven M.
Published: May 2018

The concept of Heaven raises innumerable difficulties but is so attractive that many may wish to believe in the idea regardless of any arguments against it. Even though unreasonable, it might play a positive role in some lives.
ON BEING CONFIDENT
Authors: Haas Bruno
Published: May 2018

The ethically significant concept of being confident is analysed as the ability to face the void – an idea perhaps better studied in (Zen) Buddhism than in the West.
Industrial scale microwave applicator for high temperature alkaline hydrolysis of PET
Authors: Ramopoulos Vasileios , Link Guido , Soldatov Sergey , Jelonnek John
Published: May 2018

A microwave design for an industrial scale applicator of a continuous microwave assisted depolymerization of polyethylene terephthalate (PET) has been developed. The cavity is designed for use in combination with an Archimedean screw pump to transport the reaction material, surrounded by a cylindrical pipe with a diameter of 250 mm and a length of 250 mm at the 2.45 GHz ISM band. The proposed design is modular and can be easily expanded for the heating of longer reactor tubes. Simulation results show that a homogeneous heating of the process material along the screw axis can be achieved by using a novel cavity design which is based on theTE1,0,x– rectangular waveguide cavity mode. The achieved design provides high energy efficiency with a reflected power of less than 10%. It is robust against changes in the permittivity of the reactants. The electromagnetic design is based on the dielectric properties of the solvolytic reaction mixture measured in the relevant temperature range. It is verified over the full range of the expected permittivities.
Pharmacological properties of cannabidiol in the treatment of psychiatric disorders: a critical overview
Authors: Mandolini G. M. , Lazzaretti M. , Pigoni A. , Oldani L. , Delvecchio G. , Brambilla P.
Published: May 2018

Cannabidiol (CBD) represents a new promising drug due to a wide spectrum of pharmacological actions. In order to relate CBD clinical efficacy to its pharmacological mechanisms of action, we performed a bibliographic search on PUBMED about all clinical studies investigating the use of CBD as a treatment of psychiatric symptoms. Findings to date suggest that (a) CBD may exert antipsychotic effects in schizophrenia mainly through facilitation of endocannabinoid signalling and cannabinoid receptor type 1 antagonism; (b) CBD administration may exhibit acute anxiolytic effects in patients with generalised social anxiety disorder through modification of cerebral blood flow in specific brain sites and serotonin 1A receptor agonism; (c) CBD may reduce withdrawal symptoms and cannabis/tobacco dependence through modulation of endocannabinoid, serotoninergic and glutamatergic systems; (d) the preclinical pro-cognitive effects of CBD still lack significant results in psychiatric disorders. In conclusion, current evidences suggest that CBD has the ability to reduce psychotic, anxiety and withdrawal symptoms by means of several hypothesised pharmacological properties. However, further studies should include larger randomised controlled samples and investigate the impact of CBD on biological measures in order to correlate CBD's clinical effects to potential modifications of neurotransmitters signalling and structural and functional cerebral changes.
A Critical Investigation into How Year 8 Students’ Narrative Writing Skills are Developed Through the Medium of Oral Storytelling
Authors: Walker Hannah
Published: May 2018

This research project seeks to examine, using approaches drawn from a case study, how oral storytelling within the classroom can influence various aspects of narrative writing. Therefore, certain teaching strategies and oral activities were implemented in a sequence of lessons which aimed to develop the style and content base of students’ narrative writing.
Evaluating Decision-Making Capacity
Authors: Iseli Luzia M. , Wangmo Tenzin , Hermann Helena , Trachsel Manuel , Elger Bernice S.
Published: May 2018

Abstract. The study identified factors that make an evaluation of decision-making capacity (DMC) difficult for clinicians in their daily work. Semistructured interviews were carried out with 24 healthcare professionals from Switzerland and subsequently thematically analyzed. The challenges they faced when evaluating DMC stemmed from three main concerns: patient characteristics that impede DMC evaluation; differing opinions and consequences of DMC evaluation; and familial and legal situations that complicate such evaluations. Physicians must be adequately trained to evaluate DMC as it is closely related to basic ethical principles of respect for patients’ autonomy and beneficence. Extensive training on DMC evaluation and the legal concept of capacity should be part of pre- and postgraduate education.
Determining the Mode, Frequency, and Azimuthal Wave Number of ULF Waves During a HSS and Moderate Geomagnetic Storm
Authors: Murphy Kyle R. , Inglis Andrew R. , Sibeck David G. , Rae I. Jonathan , Watt Clare E. J. , Silveira Marcos , Plaschke Ferdinand , Claudepierre Seth G. , Nakamura Rumi
Published: May 2018

Ultralow frequency (ULF) waves play a fundamental role in the dynamics of the inner magnetosphere and outer radiation belt during geomagnetic storms. Broadband ULF wave power can transport energetic electrons via radial diffusion, and discrete ULF wave power can energize electrons through a resonant interaction. Using observations from the Magnetospheric Multiscale mission, we characterize the evolution of ULF waves during a high‐speed solar wind stream (HSS) and moderate geomagnetic storm while there is an enhancement of the outer radiation belt. The Automated Flare Inference of Oscillations code is used to distinguish discrete ULF wave power from broadband wave power during the HSS. During periods of discrete wave power and utilizing the close separation of the Magnetospheric Multiscale spacecraft, we estimate the toroidal mode ULF azimuthal wave number throughout the geomagnetic storm. We concentrate on the toroidal mode as the HSS compresses the dayside magnetosphere resulting in an asymmetric magnetic field topology where toroidal mode waves can interact with energetic electrons. Analysis of the mode structure and wave numbers demonstrates that the generation of the observed ULF waves is a combination of externally driven waves, via the Kelvin‐Helmholtz instability, and internally driven waves, via unstable ion distributions. Further analysis of the periods and toroidal azimuthal wave numbers suggests that these waves can couple with the core electron radiation belt population via the drift resonance during the storm. The azimuthal wave number and structure of ULF wave power (broadband or discrete) have important implications for the inner magnetospheric and radiation belt dynamics.
Could Machine Learning Break the Convection Parameterization Deadlock?
Authors: Gentine P. , Pritchard M. , Rasp S. , Reinaudi G. , Yacalis G.
Published: May 2018

Representing unresolved moist convection in coarse‐scale climate models remains one of the main bottlenecks of current climate simulations. Many of the biases present with parameterized convection are strongly reduced when convection is explicitly resolved (i.e., in cloud resolving models at high spatial resolution approximately a kilometer or so). We here present a novel approach to convective parameterization based on machine learning, using an aquaplanet with prescribed sea surface temperatures as a proof of concept. A deep neural network is trained with a superparameterized version of a climate model in which convection is resolved by thousands of embedded 2‐D cloud resolving models. The machine learning representation of convection, which we call the Cloud Brain (CBRAIN), can skillfully predict many of the convective heating, moistening, and radiative features of superparameterization that are most important to climate simulation, although an unintended side effect is to reduce some of the superparameterization's inherent variance. Since as few as three months' high‐frequency global training data prove sufficient to provide this skill, the approach presented here opens up a new possibility for a future class of convection parameterizations in climate models that are built “top‐down,” that is, by learning salient features of convection from unusually explicit simulations.
Self‐Organizing Fluid Convection Patterns in an en Echelon Fault Array
Authors: Patterson James W. , Driesner Thomas , Matthai Stephan K.
Published: May 2018

We present three‐dimensional numerical simulations of natural convection in buried, vertical en echelon faults in impermeable host rock. Despite the fractures being hydraulically disconnected, convection within each fracture alters the temperature field in the surrounding host rock, altering convection in neighboring fractures. This leads to self‐organization of coherent patterns of upward/downward flow and heating/cooling of the host rock spanning the entire fault array. This “synchronization” effect occurs when fracture spacing is less than the width of convection cells within the fractures, which is controlled by fracture transmissivity (permeability times thickness) and heterogeneity. Narrow fracture spacing and synchronization enhance convective fluid flow within fractures and cause convection to initiate earlier, even lowering the critical transmissivity necessary for convection initiation. Heat flow through the en echelon region, however, is enhanced only in low‐transmissivity fractures, while heat flow in high‐permeability fractures is reduced due to thermal interference between fractures.
Interpreting Precession‐Driven δ18O Variability in the South Asian Monsoon Region
Authors: Tabor Clay R. , Otto‐Bliesner Bette L. , Brady Esther C. , Nusbaumer Jesse , Zhu Jiang , Erb Michael P. , Wong Tony E. , Liu Zhengyu , Noone David
Published: May 2018

Speleothem records from the South Asian summer monsoon (SASM) region display variability in the ratio of 18O and 16O (δ18O) in calcium carbonate at orbital frequencies. The dominant mode of variability in many of these records reflects cycles of precession. There are several potential explanations for why SASM speleothem records show a strong precession signal, including changes in temperature, precipitation, and circulation. Here we use an Earth system model with water isotope tracers and water‐tagging capability to deconstruct the precession signal found in SASM speleothem records. Our results show that cycles of precession‐eccentricity produce changes in SASM intensity that correlate with local temperature, precipitation, and δ18O. However, neither the amount effect nor temperature differences are responsible for the majority of the SASM δ18O variability. Instead, changes in the relative moisture contributions from different source regions drive much of the SASM δ18O signal, with more nearby moisture sources during Northern Hemisphere summer at aphelion and more distant moisture sources during Northern Hemisphere summer at perihelion. Further, we find that evaporation amplifies the δ18O signal of soil water relative to that of precipitation, providing a better match with the SASM speleothem records. This work helps explain a significant portion of the long‐term variability found in SASM speleothem records.
Financial incentive strategies for maintenance of weight loss: results from an internet-based randomized controlled trial
Authors: Yancy William S. , Shaw Pamela A. , Wesby Lisa , Hilbert Victoria , Yang Lin , Zhu Jingsan , Troxel Andrea , Huffman David , Foster Gary D. , Wojtanowski Alexis C. , Volpp Kevin G.
Published: May 2018

Background/objective

Financial incentives can improve initial weight loss; we examined whether financial incentives can improve weight loss maintenance.

Subjects/methods

Participants aged 30–80 years who lost at least 5 kg during the first 4–6 months in a nationally available commercial weight loss program were recruited via the internet into a three-arm randomized trial of two types of financial incentives versus active control during months 1–6 (Phase I) followed by passive monitoring during months 7–12 (Phase II). Interventions were daily self-weighing and text messaging feedback alone (control) or combined with a lottery-based incentive or a direct incentive. The primary outcome was weight change 6 months after initial weight loss. Secondary outcomes included weight change 12 months after initial weight loss (6 months after cessation of maintenance intervention), and self-reported physical activity and eating behaviors.

Results

Of 191 participants randomized, the mean age was 49.0 (SD = 10.5) years and weight loss prior to randomization was 11.4 (4.7) kg; 92% were women and 89% were White. Mean weight changes during the next 6 months (Phase I) were: lottery −3.0 (5.8) kg; direct −2.8 (5.8) kg; and control −1.4 (5.8) kg (all pairwise comparisons p > 0.1). Weight changes through the end of 12 months post-weight loss (Phase II) were: lottery −1.8 (10.5) kg; direct −0.7 (10.7) kg; and control −0.3 (9.4) kg (all pairwise comparisons p > 0.1). The percentages of participants who maintained their weight loss (defined as gaining ≤1.36 kg) were: lottery 79%, direct 76%, and control 67% at 6 months and lottery 66%, direct 62%, and control 59% at 12 months (all pairwise comparisons p > 0.1). At 6 and 12 months after initial weight loss, changes in self-reported physical activity or eating behaviors did not differ across arms.

Conclusions

Compared with the active control of daily texting based on daily home weighing, lottery-based and direct monetary incentives provided no additional benefit for weight loss maintenance.
NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest
Authors: Diluvio Giulia , Del Gaudio Francesca , Giuli Maria Valeria , Franciosa Giulia , Giuliani Eugenia , Palermo Rocco , Besharat Zein Mersini , Pignataro Maria Gemma , Vacca Alessandra , d’Amati Giulia , Maroder Marella , Talora Claudio , Capalbo Carlo , Bellavia Diana , Checquolo Saula
Published: May 2018

Notch dysregulation has been implicated in numerous tumors, including triple-negative breast cancer (TNBC), which is the breast cancer subtype with the worst clinical outcome. However, the importance of individual receptors in TNBC and their specific mechanism of action remain to be elucidated, even if recent findings suggested a specific role of activated-Notch3 in a subset of TNBCs. Epidermal growth factor receptor (EGFR) is overexpressed in TNBCs but the use of anti-EGFR agents (including tyrosine kinase inhibitors, TKIs) has not been approved for the treatment of these patients, as clinical trials have shown disappointing results. Resistance to EGFR blockers is commonly reported. Here we show that Notch3-specific inhibition increases TNBC sensitivity to the TKI-gefitinib in TNBC-resistant cells. Mechanistically, we demonstrate that Notch3 is able to regulate the activated EGFR membrane localization into lipid rafts microdomains, as Notch3 inhibition, such as rafts depletion, induces the EGFR internalization and its intracellular arrest, without involving receptor degradation. Interestingly, these events are associated with the EGFR tyrosine dephosphorylation at Y1173 residue (but not at Y1068) by the protein tyrosine phosphatase H1 (PTPH1), thus suggesting its possible involvement in the observed Notch3-dependent TNBC sensitivity response to gefitinib. Consistent with this notion, a nuclear localization defect of phospho-EGFR is observed after combined blockade of EGFR and Notch3, which results in a decreased TNBC cell survival. Notably, we observed a significant correlation between EGFR and NOTCH3 expression levels by in silico gene expression and immunohistochemical analysis of human TNBC primary samples. Our findings strongly suggest that combined therapies of TKI-gefitinib with Notch3-specific suppression may be exploited as a drug combination advantage in TNBC treatment.
AIRE promotes androgen-independent prostate cancer by directly regulating IL-6 and modulating tumor microenvironment
Authors: Kalra Rashi , Bhagyaraj Ella , Tiwari Drishti , Nanduri Ravikanth , Chacko Anuja P. , Jain Monika , Mahajan Sahil , Khatri Neeraj , Gupta Pawan
Published: May 2018

Abstract

Early stage prostate cancers are dependent on androgens for their growth and survival and androgen withdrawal causes them to regress. Progressive prostate cancers eventually acquire androgen independence rendering anti-androgen therapy ineffective. However, the factors leading to this have not been adequately addressed. This study shows that AIRE finds differential expression in androgen-dependent and -independent prostate cancer cells. AIRE expression is more in androgen-independent cells due to its regulation by transcription factor Elk-1. These enhanced levels of AIRE modulate the prostate tumor microenvironment by transcriptionally activating a malignancy gene IL-6 in androgen-independent cells. Additionally, AIRE prevents the cancer cells from anticancer drug-induced death and enhances their invasiveness. Moreover, AIRE by modulating the cytokine milieu skews the tumor-associated macrophage polarization towards M2 phenotype with increased CD206 and CD163 expression. Subcutaneous mouse model of prostate cancer revealed AIRE+/+ mice forming a palpable tumor and presents lymphadenopathy however, only a small benign tumor is observed in AIRE−/− mice and lymph nodes appear normal in size. In conclusion, our findings suggest AIRE as a probable factor in promoting prostate cancer progression.
Longitudinal and cross-sectional investigations of long-term potentiation-like cortical plasticity in bipolar disorder type II and healthy individuals
Authors: Zak Nathalia , Moberget Torgeir , Bøen Erlend , Boye Birgitte , Waage Trine R. , Dietrichs Espen , Harkestad Nina , Malt Ulrik F. , Westlye Lars T. , Andreassen Ole A. , Andersson Stein , Elvsåshagen Torbjørn
Published: May 2018

Visual evoked potential (VEP) plasticity is a promising assay for noninvasive examination of long-term potentiation (LTP)-like synaptic processes in the cerebral cortex. We conducted longitudinal and cross-sectional investigations of VEP plasticity in controls and individuals with bipolar disorder (BD) type II. VEP plasticity was assessed at baseline, as described previously (Elvsåshagen et al. Biol Psychiatry 2012), and 2.2 years later, at follow-up. The longitudinal sample with VEP data from both time points comprised 29 controls and 16 patients. VEP data were available from 13 additional patients at follow-up (total n = 58). VEPs were evoked by checkerboard reversals in two premodulation blocks before and six blocks after a plasticity-inducing block of prolonged (10 min) visual stimulation. VEP plasticity was computed by subtracting premodulation VEP amplitudes from postmodulation amplitudes. Saliva samples for cortisol analysis were collected immediately after awakening in the morning, 30 min later, and at 12:30 PM, at follow-up. We found reduced VEP plasticity in BD type II, that impaired plasticity was present in the euthymic phases of the illness, and that VEP plasticity correlated negatively with depression severity. There was a positive association between VEP plasticity and saliva cortisol in controls, possibly reflecting an inverted U-shaped relationship between cortisol and synaptic plasticity. VEP plasticity exhibited moderate temporal stability over a period of 2.2 years. The present study provides additional evidence for impaired LTP-like cortical plasticity in BD type II. VEP plasticity is an accessible method, which may help elucidate the pathophysiological and clinical significance of synaptic dysfunction in psychiatric disorders.
Immunoglobulin light chain amyloidosis diagnosis and treatment algorithm 2018
Authors: Gertz Morie A.
Published: May 2018

Immunoglobulin light chain amyloidosis (AL) should be considered in any patient that presents to a cancer care provider with nephrotic range proteinuria, heart failure with preserved ejection fraction, non-diabetic peripheral neuropathy, unexplained hepatomegaly or diarrhea. More importantly, patients being monitored for smoldering multiple myeloma and a monoclonal gammopathy of undetermined significance (MGUS) are at risk for developing AL amyloidosis. MGUS and myeloma patients that have atypical features, including unexplained weight loss; lower extremity edema, early satiety, and dyspnea on exertion should be considered at risk for light chain amyloidosis. Overlooking the diagnosis of light chain amyloidosis leading to therapy delay is common, and it represents an error of diagnostic consideration. Algorithms will be provided on how to evaluate patients with suspected AL amyloid as well as how to manage patients referred from other medical specialties with biopsy-proven amyloid. An organized stepwise approach to the treatment of patients with light chain amyloidosis, including established and investigational therapies, will be reviewed.
Long non-coding RNA Gm2199 rescues liver injury and promotes hepatocyte proliferation through the upregulation of ERK1/2
Authors: Gao Qiang , Gu Yunyan , Jiang Yanan , Fan Li , Wei Zixiang , Jin Haobin , Yang Xirui , Wang Lijuan , Li Xuguang , Tai Sheng , Yang Baofeng , Liu Yan
Published: May 2018

Long non-coding RNAs (lncRNAs) are a new class of regulators of various human diseases. This study was designed to explore the potential role of lncRNAs in experimental hepatic damage. In vivo hepatic damage in mice and in vitro hepatocyte damage in AML12 and NCTC1469 cells were induced by carbon tetrachloride (CCl4) treatments. Expression profiles of lncRNAs and mRNAs were analyzed by microarray. Bioinformatics analyses were conducted to predict the potential functions of differentially expressed lncRNAs with respect to hepatic damage. Overexpression of lncRNA Gm2199 was achieved by transfection of the pEGFP-N1-Gm2199 plasmid in vitro and adeno-associated virus-Gm2199 in vivo. Cell proliferation and viability was detected by cell counting kit-8 and 5-ethynyl-2′-deoxyuridine assay. Protein and mRNA expressions of extracellular signal-regulated kinase-1/2 (ERK1/2) were detected by western blot and quantitative real-time reverse-transcription PCR (qRT-PCR). Microarray analysis identified 190 and 148 significantly differentially expressed lncRNAs and mRNAs, respectively. The analyses of lncRNA-mRNA co-expression and lncRNA-biological process networks unraveled potential roles of the differentially expressed lncRNAs including Gm2199 in the pathophysiological processes leading to hepatic damage. Gm2199 was downregulated in both damaged livers and hepatocyte lines. Overexpression of Gm2199 restored the reduced proliferation of damaged hepatocyte lines and increased the expression of ERK1/2. Overexpression of Gm2199 also promoted the proliferation and viability of normal hepatocyte lines and increased the level of p-ERK1/2. Overexpression of Gm2199 in vivo also protected mouse liver injury induced by CCl4, evidenced by more proliferating hepatocytes, less serum alanine aminotransferase, less serum aspartate aminotransferase, and decreased hepatic hydroxyproline. The ability of Gm2199 to maintain hepatic proliferation capacity indicates it as a novel anti-liver damage lncRNA.
Tamoxifen-induced knockdown of the mitochondrial calcium uniporter in Thy1-expressing neurons protects mice from hypoxic/ischemic brain injury
Authors: Nichols Matthew , Pavlov Evgeny V. , Robertson George S.
Published: May 2018

The mitochondrial calcium uniporter (MCU) mediates high-capacity mitochondrial calcium uptake that stimulates energy production. However, excessive MCU activity can cause ischemic heart injury. To examine if the MCU is also involved in hypoxic/ischemic (HI) brain injury, we have generated conditional MCU knockout mice by tamoxifen (TMX) administration to adult MCU-floxed (MCUfl/fl) mice expressing a construct encoding Thy1-cre/ERT2-eYFP. Relative to TMX/Thy1-cre/ERT2-eYFP controls, HI-induced sensorimotor deficits, forebrain neuron loss and mitochondrial damage were decreased for conditional MCU knockout mice. MCU knockdown by siRNA-induced silencing in cortical neuron cultures also reduced cell death and mitochondrial respiratory deficits following oxygen-glucose deprivation. Furthermore, MCU silencing did not produce metabolic abnormalities in cortical neurons observed previously for global MCU nulls that increased reliance on glycolysis for energy production. Based on these findings, we propose that brain-penetrant MCU inhibitors have strong potential to be well-tolerated and highly-efficacious neuroprotectants for the acute management of ischemic stroke.
The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses
Authors: Cao Yu , Chen Min , Tang Dehua , Yan Hongli , Ding Xiwei , Zhou Fan , Zhang Mingming , Xu Guifang , Zhang Weijie , Zhang Shu , Zhuge Yuzheng , Wang Lei , Zou Xiaoping
Published: May 2018

Proton pump inhibitors (PPIs) play a role in antitumor activity, with studies showing specialized impacts of PPIs on cancer cell apoptosis, metastasis, and autophagy. In this study, we demonstrated that pantoprazole (PPI) increased autophagosomes formation and affected autophagic flux depending on the pH conditions. PPI specifically elevated SQSTM1 protein levels by increasing SQSTM1 transcription via NFE2L2 activation independent of the specific effect of PPI on autophagic flux. Via decreasing proteasome subunits expression, PPI significantly impaired the function of the proteasome, accompanied by the accumulation of undegraded poly-ubiquitinated proteins. Notably, PPI-induced autophagy functioned as a downstream response of proteasome inhibition by PPI, while suppressing protein synthesis abrogated autophagy. Blocking autophagic flux in neutral pH condition or further impairing proteasome function with proteasome inhibitors, significantly aggravated PPI cytotoxicity by worsening protein degradation ability. Interestingly, under conditions of mitochondrial stress, PPI showed significant synergism when combined with Bcl-2 inhibitors. Taken together, these findings provide a new understanding of the impact of PPIs on cancer cells’ biological processes and highlight the potential to develop more efficient and effective combination therapies.
Long noncoding RNA gastric cancer-related lncRNA1 mediates gastric malignancy through miRNA-885-3p and cyclin-dependent kinase 4
Authors: Lin Zhijuan , Zhou Zhixia , Guo Hang , He Yuqi , Pang Xin , Zhang Xumei , Liu Ying , Ao Xiang , Li Peifeng , Wang Jianxun
Published: May 2018

Gastric cancer (GC) is one of the most common malignancy and the third leading cancer-related death in China. Long noncoding RNAs (lncRNAs) have been implicated in numerous tumors, including GC, however, the mechanism of many functional lncRNAs is still unclear. In this study, we identified the abundantly expressed lncRNA, RP11-290F20.3, in GC cells and patient tumor tissues. We named this lncRNA as GC-related lncRNA1 (GCRL1), which could regulate gastric cell proliferation and metastasis, both in vitro and in vivo. Mechanistically, miRNA-885-3p (miR-885-3p) could inhibit the cell proliferation and metastasis in GC by negatively regulating the expression of cyclin-dependent kinase 4 (CDK4) at the post-transcriptional level. Further, GCRL1 promoted the cell proliferation and metastasis by sponging miR-885-3p and hence, positively regulating CDK4 in GC cells. Taken together, our results demonstrate a novel regulatory axis of malignant cell proliferation and invasion in GC, comprising GCRL1, miR-885-3p, and CDK4, which may serve as a potential therapeutic target in GC.
Transcriptional and epigenetic modulation of autophagy promotes EBV oncoprotein EBNA3C induced B-cell survival
Authors: Bhattacharjee Shaoni , Bose Priyanka , Patel Krishna , Roy Shatadru Ghosh , Gain Chandrima , Gowda Harsha , Robertson Erle S. , Saha Abhik
Published: May 2018

Epstein-Barr virus (EBV) oncoprotein EBNA3C is indispensable for primary B-cell transformation and maintenance of lymphoblastoid cells outgrowth. EBNA3C usurps two putative cellular pathways—cell-cycle and apoptosis, essentially through modulating ubiquitin-mediated protein-degradation or gene transcription. In cancer cells, these two pathways are interconnected with autophagy,—a survival-promoting catabolic network in which cytoplasmic material including mis/un-folded protein aggregates and damaged organelles along with intracellular pathogens are degraded and recycled in lysosomal compartments. Studies have shown that tumor viruses including EBV can manipulate autophagy as a survival strategy. Here, we demonstrate that EBNA3C elevates autophagy, which serves as a prerequisite for apoptotic inhibition and maintenance of cell growth. Using PCR based micro-array we show that EBNA3C globally accelerates autophagy gene transcription under growth limiting conditions. Reanalyzing the ENCODE ChIP-sequencing data (GSE52632 and GSE26386) followed by ChIP-PCR demonstrate that EBNA3C recruits several histone activation epigenetic marks (H3K4me1, H3K4me3, H3K9ac, and H3K27ac) for transcriptional activation of autophagy genes, notably ATG3, ATG5, and ATG7 responsible for autophagosome formation. Moreover, under growth limiting conditions EBNA3C further stimulates the autophagic response through upregulation of a number of tumor suppressor genes, notably cyclin-dependent kinase inhibitors—CDKN1B (p27Kip1) and CDKN2A (p16INK4a) and autophagy mediated cell-death modulators—DRAM1 and DAPK1. Together our data highlight a new role of an essential EBV oncoprotein in regulating autophagy cascade as a survival mechanism and offer novel-targets for potential therapeutic expansion against EBV induced B-cell lymphomas.
Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cells
Authors: Winge Sofia Boeg , Dalgaard Marlene Danner , Belling Kirstine G , Jensen Jacob Malte , Nielsen John Erik , Aksglaede Lise , Schierup Mikkel Heide , Brunak Søren , Skakkebæk Niels Erik , Juul Anders , Rajpert-De Meyts Ewa , Almstrup Kristian
Published: May 2018

The most common human sex chromosomal disorder is Klinefelter syndrome (KS; 47,XXY). Adult patients with KS display a diverse phenotype but are nearly always infertile, due to testicular degeneration at puberty. To identify mechanisms causing the selective destruction of the seminiferous epithelium, we performed RNA-sequencing of 24 fixed paraffin-embedded testicular tissue samples. Analysis of informative transcriptomes revealed 235 differentially expressed transcripts (DETs) in the adult KS testis showing enrichment of long non-coding RNAs, but surprisingly not of X-chromosomal transcripts. Comparison to 46,XY samples with complete spermatogenesis and Sertoli cell-only-syndrome allowed prediction of the cellular origin of 71 of the DETs. DACH2 and FAM9A were validated by immunohistochemistry and found to mark apparently undifferentiated somatic cell populations in the KS testes. Moreover, transcriptomes from fetal, pre-pubertal, and adult KS testes showed a limited overlap, indicating that different mechanisms are likely to operate at each developmental stage. Based on our data, we propose that testicular degeneration in men with KS is a consequence of germ cells loss initiated during early development in combination with disturbed maturation of Sertoli- and Leydig cells.
Carnitine palmitoyltransferase gene upregulation by linoleic acid induces CD4+ T cell apoptosis promoting HCC development
Authors: Brown Zachary J. , Fu Qiong , Ma Chi , Kruhlak Michael , Zhang Haibo , Luo Ji , Heinrich Bernd , Yu Su Jong , Zhang Qianfei , Wilson Andrew , Shi Zhen-Dan , Swenson Rolf , Greten Tim F.
Published: May 2018

Hepatocellular carcinoma (HCC) is a common cause of cancer-related death worldwide. As obesity and diabetes become more prevalent, the contribution of non-alcoholic fatty liver disease (NAFLD) to HCC is rising. Recently, we reported intrahepatic CD4+ T cells are critical for anti-tumor surveillance in NAFLD. Lipid accumulation in the liver is the hallmark of NAFLD, which may perturb T cell function. We sought to investigate how the lipid-rich liver environment influences CD4+ T cells by focusing on carnitine palmitoyltransferase (CPT) family members, which control the mitochondrial β-oxidation of fatty acids and act as key molecules in lipid catabolism. Linoleic acid (C18:2) co-localized within the mitochondria along with a corresponding increase in CPT gene upregulation. This CPT upregulation can be recapitulated by feeding mice with a high-C18:2 diet or the NAFLD promoting methionine-choline-deficient (MCD) diet. Using an agonist and antagonist, the induction of CPT genes was found to be mediated by peroxisome proliferator-activated receptor alpha (PPAR-α). CPT gene upregulation increased mitochondrial reactive oxygen species (ROS) and led to cell apoptosis. In vivo, using liver-specific inducible MYC transgenic mice fed MCD diet, blocking CPT with the pharmacological inhibitor perhexiline decreased apoptosis of intrahepatic CD4+ T cells and inhibited HCC tumor formation. These results provide useful information for potentially targeting the CPT family to rescue intrahepatic CD4+ T cells and to aid immunotherapy for NAFLD-promoted HCC.
Cordycepin induces apoptosis of human ovarian cancer cells by inhibiting CCL5-mediated Akt/NF-κB signaling pathway
Authors: Cui Zhen Yang , Park Soo Jung , Jo Eunbi , Hwang In-Hu , Lee Kyung-Bok , Kim Sung-Woo , Kim Dae Joon , Joo Jong Chun , Hong Seok Hoon , Lee Min-Goo , Jang Ik-Soon
Published: May 2018

The chemokine, CCL5, is a key mediator for the recruitment of immune cells into tumors and tissues. Akt/NF-κB signaling is significantly activated by CCL5. However, the role of NF-κB inactivation in apoptosis induced by negative regulation of CCL5 remains unclear. Here, we analyzed the effect of cordycepin on NF-κB activity in SKOV-3 cells and found that cordycepin-mediated inhibition of NF-κB signaling induced apoptosis in SKOV-3 cells via the serial activation of caspases. In addition, immune-blotting analysis showed that CCL5 is highly expressed in SKOV-3 cells. In addition to activating caspases, we show that, cordycepin prevents TNF-α-induced increase in CCL5, Akt, NF-κB, and c-FLIPL activation and that CCL5 siRNA could inhibit Akt/NF-κB signaling. Moreover, cordycepin negatively regulated the TNF-α-mediated IκB/NF-κB pathway and c-FLIPL activation to promote JNK phosphorylation, resulting in caspase-3 activation and apoptosis. Also, we show that c-FLIPL is rapidly lost in NF-κB activation-deficient. siRNA mediated c-FLIP inhibition increased JNK. SP600125, a selective JNK inhibitor, downregulated p-JNK expression in cordycepin-treated SKOV-3 cells, leading to suppression of cordycepin-induced apoptosis. Thus, these results indicate that cordycepin inhibits CCL5-mediated Akt/NF-κB signaling, which upregulates caspase-3 activation in SKOV-3 cells, supporting the potential of cordycepin as a therapeutic agent for ovarian cancer.