bluuebunny/crossref_metadata_2025 huggingface dataset:
Review of international clinical guidelines for adolescents on transition to Adult Mental Health Services and adults with attention-deficit hyperactivity disorder and their application to an irish context
Authors: Hughes G. C. , O’Hanrahan S. , Kavanagh G. , McNicholas F.
Published: January 2016

Objectives

To review the available clinical guidelines from Canada, North America, Europe and the United Kingdom for the diagnosis and management of attention-deficit hyperactivity disorder (ADHD) for adolescents previously diagnosed in Child and Adolescent Mental Health Services (CAMHS) on transition to Adult Mental Health Services (AMHS) and for adults presenting with a diagnostic query re-ADHD. This article seeks to apply the available guidelines to an Irish context.

Method

Various clinical guidelines and consensus statements were identified by a literature search of PubMed, incorporating literature from the past 10 years from English speaking countries and inclusion of any additional guidelines of clinical relevance. A clinical guideline with specific reference for Irish clinicians was proposed for the diagnosis and management of adults presenting for the first time with a diagnostic query re-ADHD and also to include those young adults previously diagnosed in CAMHS on transition to AMHS.

Conclusions

ADHD is a lifelong disorder, which if undiagnosed or untreated can lead to significant impairment resulting in a high economic cost for society. Stimulant medication is a first-line treatment option for adults with ADHD; however, some formulations are unlicensed in Ireland. Recent licensing of Atomoxetine, for both adolescents on transition and for adults with newly diagnosed ADHD is a welcome development. Third-line agents are rarely prescribed due to their side effect profiles and are prescribed off-label:

It is important to establish clinical guidelines for an Irish context incorporating a biopsychosocial approach. Further discussion amongst clinicians and stakeholders is needed to plan service development.
Transport by breaking internal gravity waves on slopes
Authors: Arthur Robert S. , Fringer Oliver B.
Published: January 2016

We use the results of a direct numerical simulation (DNS) with a particle-tracking model to investigate three-dimensional transport by breaking internal gravity waves on slopes. Onshore transport occurs within an upslope surge of dense fluid after breaking. Offshore transport occurs due to an intrusion of mixed fluid that propagates offshore and resembles an intermediate nepheloid layer (INL). Entrainment of particles into the INL is related to irreversible mixing of the density field during wave breaking. Maximum onshore and offshore transport are calculated as a function of initial particle position, and can be of the order of the initial wave length scale for particles initialized within the breaking region. An effective cross-shore dispersion coefficient is also calculated, and is roughly three orders of magnitude larger than the molecular diffusivity within the breaking region. Particles are transported laterally due to turbulence that develops during wave breaking, and this lateral spreading is quantified with a lateral turbulent diffusivity. Lateral turbulent diffusivity values calculated using particles are elevated by more than one order of magnitude above the molecular diffusivity, and are shown to agree well with turbulent diffusivities estimated using a generic length scale turbulence closure model. Based on a favourable comparison of DNS results with those of a similar two-dimensional case, we use two-dimensional simulations to extend our cross-shore transport results to additional wave amplitude and bathymetric slope conditions.
Relative Manin–Mumford for Semi-Abelian Surfaces
Authors: Bertrand D. , Masser D. , Pillay A. , Zannier U.
Published: January 2016

We show that Ribet sections are the only obstruction to the validity of the relative Manin–Mumford conjecture for one-dimensional families of semi-abelian surfaces. Applications include special cases of the Zilber–Pink conjecture for curves in a mixed Shimura variety of dimension 4, as well as the study of polynomial Pell equations with non-separable discriminants.
Take the Money and Run: The Determinants of Compliance with Aid Agreements
Authors: Girod Desha M. , Tobin Jennifer L.
Published: January 2016

Conditions on aid agreements aim to increase aid effectiveness, and are, therefore, an important component of aid agreements. Yet little is known about why aid-recipient governments comply with these conditions. Some scholars have suggested a strategic-importance hypothesis: recipients comply when donors enforce conditions—and donors enforce conditions when recipients are not strategically important. However, there are many cases where strategically important countries comply with conditions and strategically unimportant countries fail to do so. We argue that to explain compliance, we must also understand how the desire to maximize revenue from major income sources, such as FDI and natural resource rents, changes the recipient's incentive to comply. Using data on World Bank records of compliance from 1964 to 2010, we find strong support for our hypotheses even after accounting for different model specifications and potential endogeneity. Paradoxically, donors can secure compliance from recipients for reasons unrelated to the promise of additional aid.
From acting to being: Expressions of religious individuality in Aceh, ca. 1600–1900
Authors: Kloos David
Published: January 2016

This article discusses the early modern Acehnese epic tradition to demonstrate the emergence of an individualized Muslim ethics. From the late seventeenth century onwards, a protracted decline of Acehnese royal power initiated a process of political fragmentation as well as the gradual integration of rural areas in the globalizing economy. This shift coincided with the emergence of local religious teachers as a new and influential social group. Contingent upon these changes, the Acehnese epic tradition shifted from a dominant cosmological model based on ritual hierarchies to a paradigm of reflexive ethics based on individual responsibility to God.
BEFORE-AND-AFTER STUDY: DOES BARIATRIC SURGERY REDUCE HEALTHCARE UTILIZATION AND RELATED COSTS AMONG OPERATED PATIENTS?
Authors: Bruschi Kelles Silvana Marcia , Machado Carla Jorge , Barreto Sandhi Maria
Published: January 2016

Background: Healthcare use and costs are about 81% higher for morbidly obese individuals compared to non-obese persons, and 47% higher compared to the non-morbidly obese population. The benefits of bariatric surgery for health are well established, but its mid-term impact on healthcare use and costs remains controversial.

Methods: This study examines the trends in healthcare use and costs in a Brazilian cohort during a 4-year period before and after surgery. Healthcare use and direct costs related to inpatients and outpatients were retrieved from a healthcare insurance company database from which all cohort members were selected.

Results: Between 2004 and 2010, 4,006 individuals underwent bariatric surgery. Most patients were female (80%) with a mean age of 36.2 years and a mean body mass index of 42.8 kg/m2. Elevated blood pressure was present in 38% of cases and diabetes was found in 12.5% of subjects. Hospital admissions increased consistently after surgery, even after excluding hospitalizations for esthetic surgery and pregnancy-related care. The most prevalent conditions in this group were gastrointestinal diseases. Emergency department visits increased after bariatric procedures, in particular for genitourinary and hematologic problems. Adjusted costs were higher after surgery as assessed during a 4-year follow-up period.

Conclusion: Results indicate that costs and hospital admissions after bariatric surgery increase following this procedure, even when elective interventions are excluded. Healthcare providers and policy makers need to be aware that a decrease in obesity-related diseases following bariatric surgery does not reduce healthcare use and costs.
Relationships of wood density and wood chemical traits between stems and coarse roots across 53 Bornean tropical tree species
Authors: Nakagawa Michiko , Hori Megumi , Umemura Mitsutoshi , Ishida Takuya
Published: January 2016

Wood density and wood chemical traits are strong predictors of tree performance, carbon stock, and wood decomposition, which play important roles in ecosystem processes and carbon and nutrient cycling in forests. However, it remains unknown how root wood traits are related to stem wood traits. We examined the relationships of wood density and wood chemical traits (lignin and nitrogen concentrations, carbon-to-nitrogen ratio) between the stems and coarse roots of 90 individuals representing 53 tropical tree species in Malaysian Borneo. We developed regression equations of each wood trait using the standardized major axis method. Each root wood trait was highly correlated with the corresponding stem wood trait, and most regression equations fitted well (R2 > 0.5). The lignin concentration of roots was significantly greater than that of stems. We conclude that root wood traits can be estimated from the corresponding stem wood traits in South-East Asian tropical trees. Further analysis of coarse root decomposability will provide more accurate estimates of carbon and nutrient fluxes in tropical forest ecosystems.
Relationship between Sloan-Kettering virus expression and mammalian follicular development-RETRACTION
Authors: Kim Hyun , Cho Young Moo , Ko Yeoung-Gyu , Choe Changyong , Seong Hwan-Hoo
Published: January 2016

Zygotewishes to inform its readers that its Editor-in-Chief has decided to retract the above article after an investigation carried out in compliance with the Committee on Publication Ethics guidelines found that the authors duplicated substantial parts of the following two articles:

1.

Kim H, Yamanouchi K, Nishihara M. (2006) Expression of ski in the granulosa cells of atretic follicles in the rat ovary.J. Reprod. Dev.52, 715–721

2.

Kim H, Yamanouchi K, Matsuwaki T, Nishihara M. (2012) Induction of Ski protein expression upon luteinization in rat granulosa cells without a change in its mRNA expression.J. Reprod. Dev.58, 254–259
The curious incident of the franc in the Gambia: exchange rate instability and imperial monetary systems in the 1920s
Authors: Gardner Leigh
Published: January 2016

In 1922, British colonial Gambia demonetized the French 5-franc coin, which had been legal tender at a fixed rate in the colony since 1843. Until World War I, this rate was close to the international rate under the gold standard. When the franc began to depreciate in 1918, however, a gap emerged between the Gambian rate and the international rate, prompting a rapid influx of the coins. The demonetization cost the colonial administration over a year's revenue, affecting the later development of the colony. The 1920s have long been a fruitful period for the study of monetary history owing to the instability of exchange rates during and after the war. This article extends the study of this period to examine the impact of these changes on dependent colonies in West Africa, highlighting the importance of local compromises and particularities in colonial monetary systems.
POLISH MODELS AND SOFIC ENTROPY
Authors: Hayes Ben
Published: January 2016

We deduce properties of the Koopman representation of a positive entropy probability measure-preserving action of a countable, discrete, sofic group. Our main result may be regarded as a ‘representation-theoretic’ version of Sinaǐ’s factor theorem. We show that probability measure-preserving actions with completely positive entropy of an infinite sofic group must be mixing and, if the group is nonamenable, have spectral gap. This implies that if$\unicode[STIX]{x1D6E4}$is a nonamenable group and$\unicode[STIX]{x1D6E4}\curvearrowright (X,\unicode[STIX]{x1D707})$is a probability measure-preserving action which is not strongly ergodic, then no action orbit equivalent to$\unicode[STIX]{x1D6E4}\curvearrowright (X,\unicode[STIX]{x1D707})$has completely positive entropy. Crucial to these results is a formula for entropy in the presence of a Polish, but a priori noncompact, model.
THE ARITHMETIC OF THE EVEN AND THE ODD
Authors: PAMBUCCIAN VICTOR
Published: January 2016

We present several formal theories for the arithmetic of the even and the odd, show that the irrationality of$\sqrt 2$can be proved in one of them, that the proof must involve contradiction, and prove that the irrationality of$\sqrt {17}$cannot be proved inside any formal theory of the even and the odd.
Citizens’ Classics for the 21st Century
Authors: Hall Edith
Published: January 2016

The recent general election has exposed the danger inherent in vote-based democracies – that they inevitably entail large disaffected minorities being excluded from executive power. The ancient Greek inventors of democracy vigorously debated this issue, having painful historical experience of it (recorded by Thucydides) and theoretical solutions (discussed by Aristotle). Yet our state educational system almost completely deprives our secondary-school children of the opportunity to think about democracy afforded by the dazzling thought-world of the ancient Greeks. This is despite the availability of excellent translations of all their writings – free online – into modern English.
How do Different Types of Goals and Feedback Affect Student Motivation in Latin?
Authors: Hoath Harriet
Published: January 2016

This research studies whether different types of motivation have an effect on students' attitudes towards their own ability and success. This is assessed through a comparison of process goals and performance goals within a series of lessons, terms which have been adapted from the research of Dweck & Leggett (1988), amongst others as cited in the literature review. A study of such research has revealed that generally intrinsic motivation as ‘doing something because it is inherently interesting or enjoyable’ is preferable (Ryan & Deci, 2000, p. 55), and that this is encouraged through a focus on the process of an activity rather than an ultimate goal. The main issue here is whether students work more effectively if this goal is not made obvious to them during a lesson. The suggested benefit of focussing on process rather than performance is that students are encouraged to recognise enjoyment in each task, so that they spend time and effort improving their skills. In contrast a performance focus increases the chances of choosing an easy task or rushing through a piece of work in order to obtain the results expected (Dweck, 1999). Furthermore performance feedback seems more summative and less helpful for future work (Corpus & Lepper, 2007); comments such as “Well done you did it !” provide nothing useful, while process feedback reflects upon skills which can be applied repeatedly.
The Tirones Project
Authors: Pendergraft Mary
Published: January 2016

“There is a shortage of certified Latin teachers: Please spread the word!” This plea is the title of a recent article inAmphora, a publication of the Society for Classical Studies (Ancona & Durkin, 2015). Here the authors cite government statistics, reports from the placement service of the American Classical League, and personal experience to demonstrate that the demand for Latin teachers – whether or not certified – outstrips the supply. As they point out, this lack of teachers at the pre-collegiate level does not bode well for the health of our discipline.
Blitz Latin Revisited
Authors: White John F.
Published: January 2016

Development of the machine translator Blitz Latin between the years 2002 and 2015 is discussed. Key issues remain the ambiguity in meaning of Latin stems and inflections, and the word order of the Latin language. Attempts to improve machine translation of Latin are described by the programmer.
Factors that Affect Sugar Sweetened Beverage Intake in Rural, Southern College Students in the US
Authors: Kim Yeonsoo , Chau Tak Yan , Rutledge Julie M. , Erickson Dawn , Lim Yunsook
Published: January 2016

Abstract. The objective of the present study was to investigate factors that affect sugar sweetened beverage (SSB) intake in rural, southern college students in the US. The majority of the participants were male (58 %) and Caucasian (63 %). The average total SSB consumption was 79.4 fl oz/day (2.35 L/d). Results of binary logistic regression analyses of total SSB intake greater than 57.4 fl oz/day (1.8 L/d) versus less than 57.4 fl oz/day showed that factors associated with greater odds for high SSB intake were age greater than 20 years old (odds ratio [OR] = 3.551, 95 % confidence interval [CI] = 1.385 - 9.104, p = 0.008) and being African American (OR = 3.477, 95 % CI = 1.291 - 9.363, p = 0.013). Results of binary logistic regression analyses of total bottled water intake greater than 39.4 fl oz/day (median) versus less than 39.4 fl oz/day showed that consuming alcohol was significantly related to an increased probability of drinking more than 39.4 fl oz (1.17 L/d) of bottled water per day (median; OR = 2.914, 95 % CI = 1.223 - 6.943, p = 0.016). Culturally sensitive strategies are needed to raise awareness for making healthy beverage choices when dining on campus to effectively reduce college student’s SSB consumption.
Vitamin D Deficiency in Patients with Acute Myocardial Infarction: An Italian Single-Center Study
Authors: Aleksova Aneta , Belfiore Rita , Carriere Cosimo , Kassem Salam , La Carrubba Salvatore , Barbati Giulia , Sinagra Gianfranco
Published: January 2016

Abstract. Background: Hypovitaminosis D is a vitamin deficiency that has been increasing in developed countries; it was also suggested as an emerging risk factor for developing of atherosclerosis and acute myocardial infarction. The primary source of vitamin D is its cutaneous synthesis under exposure to sunlight. It has been suggested that 30 min of sun exposure twice weekly leads to sufficient vitamin D synthesis. The residents of Trieste (Italy) are well-known for their high exposure to sunlight in all seasons. We aimed to investigate the vitamin D status in subjects with acute myocardial infarction living in this area. Methods: Vitamin D status was identified in 478 subjects diagnosed with acute myocardial infarction. Results: The median serum 25-hydroxyvitamin D concentration was 14.5 [7.8 - 22.7] ng/mL. Vitamin D deficiency and insufficiency were present in 324 (68 %) and 107 (22 %) subjects, respectively. Vitamin D deficiency was less frequent among subjects enrolled in the period from July to the end of September (p < 0.001). In a multivariate analysis vitamin D deficiency was predicted by older age (p = 0.02), female gender (p = 0.002), higher body mass index (p = 0.05), autumn/winter sampling (p < 0.001), increased parathyroid hormone (p = 0.03) and alkaline phosphatase (p = 0.003). Conclusions: We observed very high prevalence of vitamin D deficiency among subjects with myocardial infarction in all seasons of enrollment. However, it was lower in the summer when sun exposure is higher. The exposure to sunlight may be a cost-saving therapeutic strategy for the management of vitamin D deficiency.
Impact of Micronutrient Malnutrition on the Health of Preschool Children: A Cross-Sectional Study
Authors: Shah Afzal , Ullah Shah Farid , Ud-Din Khan Salah , Ali Rana Usman , Shoaib Khan Muhammad , Ahmad Zahoor
Published: January 2016

Abstract. A cross-sectional study was designed to diagnose the prevalence of serum micronutrient deficiencies in apparently healthy preschool children in Pakistan. Children with any organic illnesses, abnormal blood parameters or genetic disorder were excluded. Amongst the studied samples, 56 % were healthy, 7 % were overweight, 7 % were obese, and 30 % were underweight. The body mass index (BMI) of female children was reduced compared to male children, which was statistically significant (p < 0.05). Similarly, zinc and iron deficiencies, ranging from moderate to severe, were found in 50 % and 25 % of the studied population, respectively. Copper and vitamin A concentrations were insufficient in 7 % and 25 % of the subject children, respectively. Micronutrient malnutrition is a recurrent health problem in children below the age of 5 years worldwide, particularly in developing countries. Serum micronutrient deficiencies and imbalances were more prevalent in children from rural than from urban areas.
Health Risks Associated with Meat Consumption: A Review of Epidemiological Studies
Authors: Battaglia Richi Evelyne , Baumer Beatrice , Conrad Beatrice , Darioli Roger , Schmid Alexandra , Keller Ulrich
Published: January 2016

Abstract. Recent evidence from large prospective US and European cohort studies and from meta-analyses of epidemiological studies indicates that the long-term consumption of increasing amounts of red meat and particularly of processed meat is associated with an increased risk of total mortality, cardiovascular disease, colorectal cancer and type 2 diabetes, in both men and women. The association persists after inclusion of known confounding factors, such as age, race, BMI, history, smoking, blood pressure, lipids, physical activity and multiple nutritional parameters in multivariate analysis. The association has not always been noted with red meat, and it has been absent with white meat. There is evidence of several mechanisms for the observed adverse effects that might be involved, however, their individual role is not defined at present. It is concluded that recommendations for the consumption of unprocessed red meat and particularly of processed red meat should be more restrictive than existing recommendations. Restrictive recommendations should not be applied to subjects above about 70 years of age, as the studies quoted herein did not examine this age group, and the inclusion of sufficient protein supply (e. g. in the form of meat) is particularly important in the elderly.
Dyspepsia is Associated with Low Protein and Caloric Intake among End-Stage Renal Disease Patients
Authors: Santos Paulo Roberto , Silveira Monteiro Diego Levi , de Paula Paulo Henrique Alexandre , Lopes Monte Neto Vicente , Ponte Monte Coelho Maria Leilah , Costa Arcanjo Cecília , Lopes Ponte Neto Fernando , Lopes Lima Marcela , Campos Arriaga Natacha , Mendes Vieira Coêlho Lília , Cavalcante Brito Wallena
Published: January 2016

Abstract. Background: Dyspepsia is highly prevalent and easily assessed in end-stage renal disease (ESRD) patients undergoing hemodialysis (HD) and is not a traditional predictor of malnutrition. We sought to establish an association between dyspeptic symptoms and nutritional status in ESRD patients undergoing maintenance HD. Methods: We studied 106 ESRD patients on HD. Dyspepsia was assessed through the Porto Alegre Dyspeptic Symptoms Questionnaire (PADYQ). Scores equal to or greater than 6 classified patients as dyspeptic. Nutritional status was evaluated using serum chemistry, total body mass, muscle mass, and dietary intake. Nutritional status was compared between dyspeptic and non-dyspeptic patients. The association of PADYQ scores and the presence of dyspepsia with nutritional variables were tested. Multivariate analysis was performed to test dyspepsia as an independent predictor for dietary intake. Results: There were 41 (38.7 %) dyspeptics. Protein intake (g/kg/day) and calorie intake (kcal/kg/day) were lower among dyspeptics compared to non-dyspeptics, 1.0 ± 0.5 vs 1.3 ± 0.5 (p = 0.01) and 23.0 ± 9.2 vs 27.4 ± 10.0 (p = 0.02), respectively. More dyspeptics than non-dyspeptics presenting protein-energy wasting based on protein and calorie intake, 41.4 vs 15.3 % (p = 0.01) and 68.2 vs 38.4 % (p = 0.02), respectively. PAQYQ score was negatively correlated with protein intake (r = - 0.20; p = 0.03) and calorie intake (r = - 0.19; p = 0.04). Dyspepsia was able to predict protein (b = - 0.26; p = 0.01) and calorie (b = - 4.42; p = 0.02) intake. Conclusions: Dyspepsia is associated with low protein and calorie intake. Screening of dyspeptic symptoms can be routinely performed aiming to improve HD patients’ nutritional status.
Minerals Intake Distributions in a Large Sample of Iranian at-Risk Population Using the National Cancer Institute Method: Do They Meet Their Requirements?
Authors: Heidari Zahra , Feizi Awat , Azadbakht Leila , Sarrafzadegan Nizal
Published: January 2016

Abstract. Background: Minerals are required for the body’s normal function. Aim: The current study assessed the intake distribution of minerals and estimated the prevalence of inadequacy and excess among a representative sample of healthy middle aged and elderly Iranian people. Methods: In this cross-sectional study, the second follow up to the Isfahan Cohort Study (ICS), 1922 generally healthy people aged 40 and older were investigated. Dietary intakes were collected using 24 hour recalls and two or more consecutive food records. Distribution of minerals intake was estimated using traditional (averaging dietary intake days) and National Cancer Institute (NCI) methods, and the results obtained from the two methods, were compared. The prevalence of minerals intake inadequacy or excess was estimated using the estimated average requirement (EAR) cut-point method, the probability approach and the tolerable upper intake levels (UL). Results: There were remarkable differences between values obtained using traditional and NCI methods, particularly in the lower and upper percentiles of the estimated intake distributions. A high prevalence of inadequacy of magnesium (50 - 100 %), calcium (21 - 93 %) and zinc (30 - 55 % for males > 50 years) was observed. Significant gender differences were found regarding inadequate intakes of calcium (21 - 76 % for males vs. 45 - 93 % for females), magnesium (92 % vs. 100 %), iron (0 vs. 15 % for age group 40 - 50 years) and zinc (29 - 55 % vs. 0 %) (all; p < 0.05). Conclusion: Severely imbalanced intakes of magnesium, calcium and zinc were observed among the middle-aged and elderly Iranian population. Nutritional interventions and population-based education to improve healthy diets among the studied population at risk are needed.
Homocysteine Levels Show Significant Differences among Mediterranean Dietary Quality Index Variables Compared to Folate and Vitamin B12 Status in Women
Authors: Višekruna Ivona , Rumbak Ivana , Samarin Ivana Rumora , Keser Irena , Ranilović Jasmina
Published: January 2016

Abstract. Results of epidemiologic studies and clinical trials have shown that subjects following the Mediterranean diet had lower inflammatory markers such as homocysteine (Hcy). Therefore, the aim of this cross-sectional study was to assess female diet quality with the Mediterranean diet quality index (MDQI) and to determine the correlation between MDQI, homocysteine, folate and vitamin B12 levels in the blood. The study participants were 237 apparently healthy women (96 of reproductive age and 141 postmenopausal) between 25 and 93 years. For each participant, 24-hour dietary recalls for 3 days were collected, MDQI was calculated, and plasma Hcy, serum and erythrocyte folate and vitamin B12 levels were analysed. Total MDQI ranged from 8 to 10 points, which represented a medium-poor diet for the subjects. The strength of correlation using biomarkers, regardless of group type, age, gender and other measured parameters, was ranked from best (0.11) to worst (0.52) for olive oil, fish, fruits and vegetables, grains, and meat, in this order. Hcy levels showed the best response among all markers across all groups and food types. Our study shows significant differences between variables of the MDQI and Hcy levels compared to levels of folate and vitamin B12 in participants with medium-poor diet quality, as evaluated according to MDQI scores.
P53 functional abnormality in mesenchymal stem cells promotes osteosarcoma development
Authors: Velletri T , Xie N , Wang Y , Huang Y , Yang Q , Chen X , Chen Q , Shou P , Gan Y , Cao G , Melino G , Shi Y
Published: January 2016

It has been shown that p53 has a critical role in the differentiation and functionality of various multipotent progenitor cells. P53 mutations can lead to genome instability and subsequent functional alterations and aberrant transformation of mesenchymal stem cells (MSCs). The significance of p53 in safeguarding our body from developing osteosarcoma (OS) is well recognized. During bone remodeling, p53 has a key role in negatively regulating key factors orchestrating the early stages of osteogenic differentiation of MSCs. Interestingly, changes in the p53 status can compromise bone homeostasis and affect the tumor microenvironment. This review aims to provide a unique opportunity to study the p53 function in MSCs and OS. In the context of loss of function of p53, we provide a model for two sources of OS: MSCs as progenitor cells of osteoblasts and bone tumor microenvironment components. Standing at the bone remodeling point of view, in this review we will first explain the determinant function of p53 in OS development. We will then summarize the role of p53 in monitoring MSC fidelity and in regulating MSC differentiation programs during osteogenesis. Finally, we will discuss the importance of loss of p53 function in tissue microenvironment. We expect that the information provided herein could lead to better understanding and treatment of OS.
Intrinsic and chemo-sensitizing activity of SMAC-mimetics on high-risk childhood acute lymphoblastic leukemia
Authors: Schirmer M , Trentin L , Queudeville M , Seyfried F , Demir S , Tausch E , Stilgenbauer S , Eckhoff S M , Meyer L H , Debatin K-M
Published: January 2016

SMAC-mimetics represent a targeted therapy approach to overcome apoptosis resistance in many tumors. Here, we investigated the efficacy of the SMAC-mimetic BV6 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In ALL cell lines, intrinsic apoptosis sensitivity was associated with rapid cIAP degradation, NF-κB activation, TNF-α secretion and induction of an autocrine TNF-α-dependent cell death loop. This pattern of responsiveness was also observed upon ex vivo analysis of 40 primograft BCP-ALL samples. Treatment with BV6 induced cell death in the majority of ALL primografts including leukemias with high-risk and poor-prognosis features. Inhibition of cell death by the TNF receptor fusion protein etanercept demonstrated that BV6 activity is dependent on TNF-α. In a preclinical NOD/SCID/huALL model of high-risk ALL, marked anti-leukemia effectivity and significantly prolonged survival were observed upon BV6 treatment. Interestingly, also in vivo, intrinsic SMAC-mimetic activity was mediated by TNF-α. Importantly, BV6 increased the effectivity of conventional induction therapy including vincristine, dexamethasone and asparaginase leading to prolonged remission induction. These data suggest SMAC-mimetics as an important addendum to efficient therapy of pediatric BCP-ALL.
Survivin, a novel target of the Hedgehog/GLI signaling pathway in human tumor cells
Authors: Vlčková K , Ondrušová L , Vachtenheim J , Réda J , Dundr P , Zadinová M , Žáková P , Poučková P
Published: January 2016

Survivin, an important antiapoptotic protein, is expressed in tumors, whereas in normal tissues the expression of this protein is extremely low, defining a role for survivin as a cancer gene. Survivin exhibits multifunctional activity in tumor cells. However, why survivin expression is sharply and invariably restricted to tumor tissue remains unclear. Here, we identified 11 putative consensus binding sites for GLI transcription factors in the survivin promoter and characterized the promoter activity. Inhibitors of the Hedgehog/GLI pathway, cyclopamine and GANT61, decreased the promoter activity in reporter assays. ΔNGLI2 (which lacks the repressor domain) was the most potent vector in activating the survivin promoter–reporter. Moreover, GANT61, a GLI1/2 inhibitor, repressed endogenous survivin protein and mRNA expression in most cells across a large panel of tumor cell lines. Chromatin immunoprecipitation showed GLI2 binding to the survivin promoter. The ectopic GLI2-evoked expression of endogenous survivin was observed in normal human fibroblasts. GANT61 decreased survivin level in nude mice tumors, mimicking the activity of GANT61 in cultured cells. The immunohistochemistry and double immunofluorescence of human tumors revealed a correlation between the tissue regions showing high GLI2 and survivin positivity. Thus, these results demonstrated that survivin is a classical transcriptional target of GLI2, a Hedgehog pathway signaling effector. This potentially reflects the high expression of survivin in human tumor cells. As the Hedgehog pathway is upregulated in virtually all types of cancer cells, these findings substantially contribute to the explanation of uniform survivin expression in tumors as a potential target for the development of a more effective treatment of cancers through the inhibition of GLI2 to restrain survivin activity.
Prediction of disease–gene–drug relationships following a differential network analysis
Authors: Zickenrott S , Angarica V E , Upadhyaya B B , del Sol A
Published: January 2016

Great efforts are being devoted to get a deeper understanding of disease-related dysregulations, which is central for introducing novel and more effective therapeutics in the clinics. However, most human diseases are highly multifactorial at the molecular level, involving dysregulation of multiple genes and interactions in gene regulatory networks. This issue hinders the elucidation of disease mechanism, including the identification of disease-causing genes and regulatory interactions. Most of current network-based approaches for the study of disease mechanisms do not take into account significant differences in gene regulatory network topology between healthy and disease phenotypes. Moreover, these approaches are not able to efficiently guide database search for connections between drugs, genes and diseases. We propose a differential network-based methodology for identifying candidate target genes and chemical compounds for reverting disease phenotypes. Our method relies on transcriptomics data to reconstruct gene regulatory networks corresponding to healthy and disease states separately. Further, it identifies candidate genes essential for triggering the reversion of the disease phenotype based on network stability determinants underlying differential gene expression. In addition, our method selects and ranks chemical compounds targeting these genes, which could be used as therapeutic interventions for complex diseases.
Deubiquitylating enzyme USP9x regulates radiosensitivity in glioblastoma cells by Mcl-1-dependent and -independent mechanisms
Authors: Wolfsperger F , Hogh-Binder S A , Schittenhelm J , Psaras T , Ritter V , Bornes L , Huber S M , Jendrossek V , Rudner J
Published: January 2016

Glioblastoma is a very aggressive form of brain tumor with limited therapeutic options. Usually, glioblastoma is treated with ionizing radiation (IR) and chemotherapy after surgical removal. However, radiotherapy is frequently unsuccessful, among others owing to resistance mechanisms the tumor cells have developed. Antiapoptotic B-cell leukemia (Bcl)-2 family members can contribute to radioresistance by interfering with apoptosis induction in response to IR. Bcl-2 and the closely related Bcl-xL and Mcl-1 are often overexpressed in glioblastoma cells. In contrast to Bcl-2 and Bcl-xL, Mcl-1 is a short-lived protein whose stability is closely regulated by ubiquitylation-dependent proteasomal degradation. Although ubiquitin ligases facilitate degradation, the deubiquitylating enzyme ubiquitin-specific protease 9x (USP9x) interferes with degradation by removing polyubiquitin chains from Mcl-1, thereby stabilizing this protein. Thus, an inability to downregulate Mcl-1 by enhanced USP9x activity might contribute to radioresistance. Here we analyzed the impact of USP9x on Mcl-1 levels and radiosensitivity in glioblastoma cells. Correlating Mcl-1 and USP9x expressions were significantly higher in human glioblastoma than in astrocytoma. Downregulation of Mcl-1 correlated with apoptosis induction in established glioblastoma cell lines. Although Mcl-1 knockdown by siRNA increased apoptosis induction after irradiation in all glioblastoma cell lines, USP9x knockdown significantly improved radiation-induced apoptosis in one of four cell lines and slightly increased apoptosis in another cell line. In the latter two cell lines, USP9x knockdown also increased radiation-induced clonogenic death. The massive downregulation of Mcl-1 and apoptosis induction in A172 cells transfected with USP9x siRNA shows that the deubiquitinase regulates cell survival by regulating Mcl-1 levels. In contrast, USP9x regulated radiosensitivity in Ln229 cells without affecting Mcl-1 levels. We conclude that USP9x can control survival and radiosensitivity in glioblastoma cells by Mcl-1-dependent and Mcl-1-independent mechanisms.
EMC6/TMEM93 suppresses glioblastoma proliferation by modulating autophagy
Authors: Shen X , Kan S , Hu J , Li M , Lu G , Zhang M , Zhang S , Hou Y , Chen Y , Bai Y
Published: January 2016

EMC6 (endoplasmic reticulum membrane protein complex subunit 6), also known as transmembrane protein 93, is a novel positive autophagy regulator. In this report, we evaluated the anti-tumor activity of EMC6 in glioblastoma cells in vitro and in vivo. Our data show that overexpression of EMC6 in three glioblastoma cell lines (SHG44, U87 and U251) suppresses tumor cell growth by activating autophagy, but fails to induce cell apoptosis. EMC6-mediated autophagy was associated with inactivation of the PIK3CA/AKT/mTOR signaling pathway. Accordingly, EMC6 knockdown in glioblastoma cells had the opposite effect; it promoted cell growth. Overexpression of EMC6 also sensitized glioblastoma cells to the chemotherapy drug, temozolomide, to further suppress tumor growth. Our data indicate that EMC6-induced autophagy may play a positive role in suppressing the development of glioblastoma.
Pdcd4 deficiency enhances macrophage lipoautophagy and attenuates foam cell formation and atherosclerosis in mice
Authors: Wang L , Jiang Y , Song X , Guo C , Zhu F , Wang X , Wang Q , Shi Y , Wang J , Gao F , Zhao W , Chen Y H , Zhang L
Published: January 2016

Macrophage foam cells, a major component of the atherosclerotic lesion, have vital roles in the development of atherosclerosis. Lipoautophagy, a type of autophagy characterized by selective delivery of lipid droplet for lysosomal degradation, may impact atherosclerosis by regulating macrophage foam cell formation. Previously, we reported that programmed cell death 4 (PDCD4), a tumor suppressor, negatively regulated autophagy in tumor cells. However, its roles in macrophage lipoautophagy, foam cell formation and atherosclerosis remain to be established. Here we found that Pdcd4 deficiency clearly improved oxidized low-density lipoproteins-impaired autophagy efflux, promoted autophagy-mediated lipid breakdown in murine macrophages and thus prevented macrophage conversion into foam cells. Importantly, Pdcd4 deficiency in mice significantly upregulated macrophage autophagy in local plaques along with attenuated lipid accumulation and atherosclerotic lesions in high-fat-fed Apolipoprotein E knockout mice. Bone marrow transplantation experiment demonstrated that PDCD4-mediated autophagy in hematopoietic cells contributed to the development of atherosclerosis. These results indicate that endogenous PDCD4 promotes for macrophage foam cell formation and atherosclerosis development via inhibiting autophagy and provides new insights into atherogenesis, suggesting that promoting macrophage autophagy through downregulating PDCD4 expression may be beneficial for treating atherosclerosis.
Overexpression of protein kinase C ɛ improves retention and survival of transplanted mesenchymal stem cells in rat acute myocardial infarction
Authors: He H , Zhao Z-H , Han F-S , Liu X-H , Wang R , Zeng Y-J
Published: January 2016

We assessed the effects of protein kinase C ɛ (PKCɛ) for improving stem cell therapy for acute myocardial infarction (AMI). Primary mesenchymal stem cells (MSCs) were harvested from rat bone marrow. PKCɛ-overexpressed MSCs and control MSCs were transplanted into infarct border zones in a rat AMI model. MSCs and PKCɛ distribution and expression of principal proteins involved in PKCɛ signaling through the stromal cell-derived factor 1 (SDF-1)/CXC chemokine receptor type 4 (CXCR4) axis and the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway were analyzed by immunofluorescence and western blot 1 day after transplantation. Echocardiographic measurements and histologic studies were performed at 4 weeks after transplantation, and MSC survival, expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor β (TGFβ), cardiac troponin I (cTnI), von Willebrand factor (vWF), smooth muscle actin (SMA) and factor VIII and apoptosis in infarct border zones were assessed. Rat heart muscles retained more MSCs and SDF-1, CXCR4, PI3K and phosphorylated AKT increased with PKCɛ overexpression 1 day after transplantation. MSC survival and VEGF, bFGF, TGFβ, cTnI, vWF, SMA and factor VIII expression increased in animals with PKCɛ-overexpressed MSCs at 4 weeks after transplantation and cardiac dysfunction and remodeling improved. Infarct size and apoptosis decreased as well. Inhibitory actions of CXCR4 or PI3K partly attenuated the effects of PKCɛ. Activation of PKCɛ may improve retention, survival and differentiation of transplanted MSCs in myocardia. Augmentation of PKCɛ expression may enhance the therapeutic effects of stem cell therapy for AMI.
Interleukin-33 enhances programmed oncosis of ST2L-positive low-metastatic cells in the tumour microenvironment of lung cancer
Authors: Akimoto M , Hayashi J-I , Nakae S , Saito H , Takenaga K
Published: January 2016

The proinflammatory interleukin-33 (IL-33) binds to its receptor ST2L on the surface of immune cells and stimulates the production of Th2 cytokines; however, the effects of IL-33 on tumour cells are poorly understood. Here we show that ST2 was significantly downregulated in human lung cancer tissues and cells compared with normal lung tissues and cells. IL-33 expression was also inversely correlated with the stages of human lung cancers. In accordance with this finding, low-metastatic cells but not high-metastatic cells derived from Lewis lung carcinoma expressed functional ST2L. IL-33 was abundantly present in the tumours established by the low-metastatic cells compared with those formed by the high-metastatic cells. Although the low-metastatic cells scarcely expressed IL-33 in vitro, these cells did expry 6ess this molecule in vivo, likely due to stimulation by intratumoural IL-1β and IL-33. Importantly, IL-33 enhanced the cell death of ST2L-positive low-metastatic cells, but not of ST2L-negative high-metastatic cells, under glucose-depleted, glutamine-depleted and hypoxic conditions through p38 MAPK and mTOR activation, and in a mitochondria-dependent manner. The cell death was characterised by cytoplasmic blisters and karyolysis, which are unique morphological features of oncosis. Inevitably, the low-metastatic cells, but not of the high-metastatic cells, grew faster in IL-33−/− mice than in wild-type mice. Furthermore, IL-33 selected for the ST2L-positive, oncosis-resistant high-metastatic cells under conditions mimicking the tumour microenvironment. These data suggest that IL-33 enhances lung cancer progression by selecting for more malignant cells in the tumour microenvironment.
Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration
Authors: Detaille D , Vial G , Borel A-L , Cottet-Rouselle C , Hallakou-Bozec S , Bolze S , Fouqueray P , Fontaine E
Published: January 2016

Imeglimin is the first in a new class of oral glucose-lowering agents, having recently completed its phase 2b trial. As Imeglimin did show a full prevention of β-cell apoptosis, and since angiopathy represents a major complication of diabetes, we studied Imeglimin protective effects on hyperglycemia-induced death of human endothelial cells (HMEC-1). These cells were incubated in several oxidative stress environments (exposure to high glucose and oxidizing agent tert-butylhydroperoxide) which led to mitochondrial permeability transition pore (PTP) opening, cytochrome c release and cell death. These events were fully prevented by Imeglimin treatment. This protective effect on cell death occurred without any effect on oxygen consumption rate, on lactate production and on cytosolic redox or phosphate potentials. Imeglimin also dramatically decreased reactive oxygen species production, inhibiting specifically reverse electron transfer through complex I. We conclude that Imeglimin prevents hyperglycemia-induced cell death in HMEC-1 through inhibition of PTP opening without inhibiting mitochondrial respiration nor affecting cellular energy status. Considering the high prevalence of macrovascular and microvascular complications in type 2 diabetic subjects, these results together suggest a potential benefit of Imeglimin in diabetic angiopathy.
Strongly frustrated triangular spin lattice emerging from triplet dimer formation in honeycomb Li2IrO3
Authors: Nishimoto Satoshi , Katukuri Vamshi M. , Yushankhai Viktor , Stoll Hermann , Rößler Ulrich K. , Hozoi Liviu , Rousochatzakis Ioannis , van den Brink Jeroen
Published: January 2016

Iridium oxides with a honeycomb lattice have been identified as platforms for the much anticipated Kitaev topological spin liquid: the spin-orbit entangled states of Ir4+ in principle generate precisely the required type of anisotropic exchange. However, other magnetic couplings can drive the system away from the spin-liquid phase. With this in mind, here we disentangle the different magnetic interactions in Li2IrO3, a honeycomb iridate with two crystallographically inequivalent sets of adjacent Ir sites. Our ab initio many-body calculations show that, while both Heisenberg and Kitaev nearest-neighbour couplings are present, on one set of Ir–Ir bonds the former dominates, resulting in the formation of spin-triplet dimers. The triplet dimers frame a strongly frustrated triangular lattice and by exact cluster diagonalization we show that they remain protected in a wide region of the phase diagram.
Magnetoelectric effect and phase transitions in CuO in external magnetic fields
Authors: Wang Zhaosheng , Qureshi Navid , Yasin Shadi , Mukhin Alexander , Ressouche Eric , Zherlitsyn Sergei , Skourski Yurii , Geshev Julian , Ivanov Vsevolod , Gospodinov Marin , Skumryev Vassil
Published: January 2016

Apart from being so far the only known binary multiferroic compound, CuO has a much higher transition temperature into the multiferroic state, 230 K, than any other known material in which the electric polarization is induced by spontaneous magnetic order, typically lower than 100 K. Although the magnetically induced ferroelectricity of CuO is firmly established, no magnetoelectric effect has been observed so far as direct crosstalk between bulk magnetization and electric polarization counterparts. Here we demonstrate that high magnetic fields of ≈50 T are able to suppress the helical modulation of the spins in the multiferroic phase and dramatically affect the electric polarization. Furthermore, just below the spontaneous transition from commensurate (paraelectric) to incommensurate (ferroelectric) structures at 213 K, even modest magnetic fields induce a transition into the incommensurate structure and then suppress it at higher field. Thus, remarkable hidden magnetoelectric features are uncovered, establishing CuO as prototype multiferroic with abundance of competitive magnetic interactions.