bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of dynamic changes in retinoid-induced transcription and epigenetic profiles of murine Hox clusters in ES cells
Authors: De Kumar Bony , Parrish Mark E. , Slaughter Brian D. , Unruh Jay R. , Gogol Madelaine , Seidel Christopher , Paulson Ariel , Li Hua , Gaudenz Karin , Peak Allison , McDowell William , Fleharty Brian , Ahn Youngwook , Lin Chengqi , Smith Edwin , Shilatifard Ali , Krumlauf Robb
Published: May 2015

The clustered Hox genes, which are highly conserved across metazoans, encode homeodomain-containing transcription factors that provide a blueprint for segmental identity along the body axis. Recent studies have underscored that in addition to encoding Hox genes, the homeotic clusters contain key noncoding RNA genes that play a central role in development. In this study, we have taken advantage of genome-wide approaches to provide a detailed analysis of retinoic acid (RA)-induced transcriptional and epigenetic changes within the homeotic clusters of mouse embryonic stem cells. Although there is a general colinear response, our analyses suggest a lack of strict colinearity for several genes in the HoxA and HoxB clusters. We have identified transcribed novel noncoding RNAs (ncRNAs) and their cis-regulatory elements that function in response to RA and demonstrated that the expression of these ncRNAs from both strands represent some of the most rapidly induced transcripts in ES cells. Finally, we have provided dynamic analyses of chromatin modifications for the coding and noncoding genes expressed upon activation and suggest that active transcription can occur in the presence of chromatin modifications and machineries associated with repressed transcription state over the clusters. Overall, our data provide a resource for a better understanding of the dynamic nature of the coding and noncoding transcripts and their associated chromatin marks in the regulation of homeotic gene transcription during development.
Lipid Peroxide-Derived Short-Chain Carbonyls Mediate Hydrogen Peroxide-Induced and Salt-Induced Programmed Cell Death in Plants
Authors: Biswas Md. Sanaullah , Mano Jun’ichi
Published: May 2015

Lipid peroxide-derived toxic carbonyl compounds (oxylipin carbonyls), produced downstream of reactive oxygen species (ROS), were recently revealed to mediate abiotic stress-induced damage of plants. Here, we investigated how oxylipin carbonyls cause cell death. When tobacco (Nicotiana tabacum) Bright Yellow-2 (BY-2) cells were exposed to hydrogen peroxide, several species of short-chain oxylipin carbonyls [i.e. 4-hydroxy-(E)-2-nonenal and acrolein] accumulated and the cells underwent programmed cell death (PCD), as judged based on DNA fragmentation, an increase in terminal deoxynucleotidyl transferase dUTP nick end labeling-positive nuclei, and cytoplasm retraction. These oxylipin carbonyls caused PCD in BY-2 cells and roots of tobacco and Arabidopsis (Arabidopsis thaliana). To test the possibility that oxylipin carbonyls mediate an oxidative signal to cause PCD, we performed pharmacological and genetic experiments. Carnosine and hydralazine, having distinct chemistry for scavenging carbonyls, significantly suppressed the increase in oxylipin carbonyls and blocked PCD in BY-2 cells and Arabidopsis roots, but they did not affect the levels of ROS and lipid peroxides. A transgenic tobacco line that overproduces 2-alkenal reductase, an Arabidopsis enzyme to detoxify α,β-unsaturated carbonyls, suffered less PCD in root epidermis after hydrogen peroxide or salt treatment than did the wild type, whereas the ROS level increases due to the stress treatments were not different between the lines. From these results, we conclude that oxylipin carbonyls are involved in the PCD process in oxidatively stressed cells. Our comparison of the ability of distinct carbonyls to induce PCD in BY-2 cells revealed that acrolein and 4-hydroxy-(E)-2-nonenal are the most potent carbonyls. The physiological relevance and possible mechanisms of the carbonyl-induced PCD are discussed.
Monochromatic computed microtomography using laboratory and synchrotron sources and X-ray fluorescence analysis for comprehensive analysis of structural changes in bones
Authors: Buzmakov Alexey , Chukalina Marina , Nikolaev Dmitry , Gulimova Victoriya , Saveliev Sergey , Tereschenko Elena , Seregin Alexey , Senin Roman , Zolotov Denis , Prun Victor , Shaefer Gerald , Asadchikov Victor
Published: May 2015

A combination of X-ray tomography at different wavelengths and X-ray fluorescence analysis was applied in the study of two types of bone tissue changes: prolonged presence in microgravity conditions and age-related bone growth. The proximal tail vertebrae of geckos were selected for investigation because they do not bear the supporting load in locomotion, which allows them to be considered as an independent indicator of gravitational influence. For the vertebrae of geckos no significant differences were revealed in the elemental composition of the flight samples and the synchronous control samples. In addition, the gecko bone tissue samples from the jaw apparatus, spine and shoulder girdle were measured. The dynamics of structural changes in the bone tissue growth was studied using samples of a human fetal hand. The hands of human fetuses of 11–15 weeks were studied. Autonomous zones of calcium accumulation were found not only in individual fingers but in each of the investigated phalanges. The results obtained are discussed.
Crystallography of grain refinement in cast zinc–copper alloys
Authors: Liu Zhilin , Qiu Dong , Wang Feng , Taylor John A. , Zhang Mingxing
Published: May 2015

Adding the peritectic forming element Cu effectively reduced the average grain size of cast Zn by over 85%. At a specified cast condition, the smallest grain size was obtained at 2 wt% Cu addition. A further increase in Cu content led to grain coarsening in the cast Zn–Cu alloys. Although the solute effect of Cu was predominately responsible for the grain refinement through restriction of the grain growth, it was found that the variation of grain size is also closely related to the formation of the pro-peritectic phase, ɛ-CuZn4. Crystallographic calculations using the edge-to-edge matching model showed low interatomic misfit and interplanar mismatch between Zn and the ɛ-CuZn4 phase. In addition, a reproducible h.c.p.–h.c.p. (h.c.p. denotes hexagonal close-packed) orientation relationship between Zn and the ɛ-CuZn4 particles (located within the Zn grain centres) was also experimentally determined using the electron backscattered diffraction method. This indicated the high potency of the pro-peritectic ɛ-CuZn4 particles as effective heterogeneous nucleation sites for η-Zn, which further refined the Zn grains. However, when the Cu content was over 2.0 wt%, formation of large ɛ-CuZn4 particles resulted in grain coarsening of the cast alloys.
Quantitative evaluation of microtwins and antiphase defects in GaP/Si nanolayers for a III–V photonics platform on silicon using a laboratory X-ray diffraction setup
Authors: Ping Wang Yan , Letoublon Antoine , Nguyen Thanh Tra , Bahri Mounib , Largeau Ludovic , Patriarche Gilles , Cornet Charles , Bertru Nicolas , Le Corre Alain , Durand Olivier
Published: May 2015

This study is carried out in the context of III–V semiconductor monolithic integration on silicon for optoelectronic device applications. X-ray diffraction is combined with atomic force microscopy and scanning transmission electron microscopy for structural characterization of GaP nanolayers grown on Si. GaP has been chosen as the interfacial layer, owing to its low lattice mismatch with Si. But, microtwins and antiphase boundaries are still difficult to avoid in this system. Absolute quantification of the microtwin volume fraction is used for optimization of the growth procedure in order to eliminate these defects. Lateral correlation lengths associated with mean antiphase boundary distances are then evaluated. Finally, optimized growth conditions lead to the annihilation of antiphase domains within the first 10 nm.
Time to diagnosis of Type I or II invasive epithelial ovarian cancers: a multicentre observational study using patient questionnaire and primary care records
Authors: Lim AWW , Mesher D , Gentry‐Maharaj A , Balogun N , Widschwendter M , Jacobs I , Sasieni P , Menon U
Published: May 2015

Objective

To compare time to diagnosis of the typically slow‐growing Type I (low‐grade serous, low‐grade endometrioid, mucinous, clear cell) and the more aggressive Type II (high‐grade serous, high‐grade endometrioid, undifferentiated, carcinosarcoma) invasive epithelial ovarian cancer (iEOC).

Design

Multicentre observational study.

Setting

Ten UK gynaecological oncology centres.

Population

Women diagnosed with primary EOC between 2006 and 2008.

Methods

Symptom data were collected before diagnosis using patient questionnaire and primary‐care records. We estimated patient interval (first symptom to presentation) using questionnaire data and diagnostic interval (presentation to diagnosis) using primary‐care records. We considered the impact of first symptom, referral and stage on intervals for Type I and Type II iEOC.

Main outcome measures

Patient and diagnostic intervals.

Results

In all, 78% of 60 Type I and 21% of 134 Type II iEOC were early‐stage. Intervals were comparable and independent of stage [e.g. median patient interval for Type I: early‐stage 0.3 months (interquartile range 0.3–3.0) versus late‐stage 0.3 months (interquartile range 0.3–4.5), P = 0.8]. Twenty‐seven percent of women with Type I and Type II had diagnostic intervals of at least 9 months. First symptom (questionnaire) was also similar, except for the infrequent abnormal bleeding (Type I 15% versus Type II 4%, P = 0.01). More women with Type I disease (57% versus 41%, P = 0.04) had been referred for suspected gynaecological cancer. Median time from referral to diagnosis was 1.4 months for women with iEOC referred via a 2‐week cancer referral to any specialty compared with 2.6 months (interquartile range 2.0–3.7) for women who were referred routinely to gynaecology.

Conclusion

Overall, shorter diagnostic delays were seen when a cancer was suspected, even if the primary tumour site was not recognised to be ovarian. Despite differences in carcinogenesis and stage for Type I and Type II iEOC, time to diagnosis and symptoms were similar. Referral patterns were different, implying subtle symptom differences. If symptom‐based interventions are to impact on ovarian cancer survival, it is likely to be through reduced volume rather than stage‐shift. Further research on histological subtypes is needed.

Tweetable abstract

No difference in time to diagnosis for Type I versus Type II invasive epithelial ovarian cancers.
Gestational weight gain and the risk of offspring obesity at 10 and 16 years: a prospective cohort study in low‐income women
Authors: Diesel JC , Eckhardt CL , Day NL , Brooks MM , Arslanian SA , Bodnar LM
Published: May 2015

Objective

To study the association between gestational weight gain (GWG) and offspring obesity risk at ages chosen to approximate prepuberty (10 years) and postpuberty (16 years).

Design

Prospective pregnancy cohort.

Setting

Pittsburgh, PA, USA.

Sample

Low‐income pregnant women (n = 514) receiving prenatal care at an obstetric residency clinic and their singleton offspring.

Methods

Gestational weight gain was classified based on maternal GWG‐for‐gestational‐age Z‐score charts and was modelled using flexible spline terms in modified multivariable Poisson regression models.

Main outcome measures

Obesity at 10 or 16 years, defined as body mass index (BMI) Z‐scores ≥95th centile of the 2000 CDC references, based on measured height and weight.

Results

The prevalence of offspring obesity was 20% at 10 years and 22% at 16 years. In the overall sample, the risk of offspring obesity at 10 and 16 years increased when GWG exceeded a GWG Z‐score of 0 SD (equivalent to 30 kg at 40 weeks); but for gains below a Z‐score of 0 SD there was no relationship with child obesity risk. The association between GWG and offspring obesity varied by prepregnancy BMI. Among mothers with a pregravid BMI <25 kg/m2, the risk of offspring obesity increased when GWG Z‐score exceeded 0 SD, yet among overweight women (BMI ≥25 kg/m2), there was no association between GWG Z‐scores and offspring obesity risk.

Conclusions

Among lean women, higher GWG may have lasting effects on offspring obesity risk.

Tweetable abstract

Maternal weight gain is associated with offspring obesity at 10 and 16 years in a prospective study.
Previous caesarean delivery and the risk of unexplained stillbirth: retrospective cohort study and meta‐analysis
Authors: Moraitis AA , Oliver‐Williams C , Wood AM , Fleming M , Pell JP , Smith GCS
Published: May 2015

Objective

To determine whether caesarean delivery in the first pregnancy is a risk factor for unexplained antepartum stillbirth in a second pregnancy.

Design

A population‐based retrospective cohort study and meta‐analysis.

Setting

All maternity units in Scotland.

Participants

A cohort of 128 585 second births, 1999–2008.

Methods

Time‐to‐event analysis and random‐effects meta‐analysis.

Main outcome measure

Risk of unexplained antepartum stillbirth in a second pregnancy.

Results

There were 88 stillbirths among 23 688 women with a previous caesarean delivery (2.34 per 10 000 women per week) and 288 stillbirths in 104 897 women who had previously delivered vaginally (1.67 per 10 000 women per week, P = 0.002). When analysed by cause, women with a previous caesarean delivery had an increased risk of unexplained stillbirth (hazard ratio, HR 1.47; 95% confidence interval, 95% CI 1.12–1.94; P = 0.006) and, as previously observed, the excess risk was apparent from 34 weeks of gestation onwards. The risk did not differ in relation to the indication of the caesarean delivery, and was independent of maternal characteristics and previous obstetric complications. We identified three other comparable studies (two in North America and one in Europe), and meta‐analysis of these studies showed a statistically significant association between previous caesarean delivery and the risk of antepartum stillbirth in the second pregnancy (pooled HR 1.40; 95% CI 1.10–1.77; P = 0.006).

Conclusions

Women who have had a previous caesarean delivery are at increased risk of unexplained stillbirth in the second pregnancy.

Tweetable abstract

Caesarean first delivery is associated with an increased risk of unexplained stillbirth in the next pregnancy.
Effectiveness of Rinse Water during In‐Place Cleaning of Stainless Steel Pipe Lines
Authors: Fan Mengyuan , Phinney David M. , Heldman Dennis R.
Published: May 2015

The 1st step of any Clean‐In‐Place (CIP) operation is a prerinse with water. The purpose of this step is to remove the bulk of food material remaining in the processing lines after production period has ended. It is known that this prerinse step can be a very water intensive process. The objective of this investigation was to measure the influence of CIP parameters (flow characteristics, water temperature, and contact time) on the effectiveness of prerinse water in removing dairy‐based deposits from stainless steel pipe surfaces and to compare the rinse effectiveness of unused to reused rinse water. A pilot‐scale CIP system was operated to rinse 304 stainless steel pipe sections of 3 different pipe diameters. The velocity of the rinse water was varied from 0.72 to 2.26 m/s. The rinse water temperatures were 22 °C, 45 °C, and 67 °C. The contact times between rinse water and deposited film were 20 and 60 s. Rinse effectiveness was expressed as the ratio of the amount of protein residue removed from the pipe surface during rinsing, as compared to the magnitude of the initial protein deposit. The rinse effectiveness varied from 73.1% to 94.9% for the range of the CIP parameters investigated. High velocities of rinse water provided a higher level of rinse effectiveness. Increasing the rinse water temperature from 23 °C to 45 °C improved rinse effectiveness significantly (P < 0.05). This impact was not significant when the water temperature was increased from 45 °C to 67 °C and at higher rinse water velocities. Similarly, longer contact time provided less improvement in rinse effectiveness at higher temperatures and velocities as compared to lower temperatures and velocities. There were no significant differences in rinse effectiveness when comparing reused and unused water (normal tap water) within the range of velocities evaluated.
Nursing Students' and Tutors' Satisfaction With a New Clinical Competency System Based on the Nursing Interventions Classification
Authors: Iglesias‐Parra Maria Rosa , García‐Mayor Silvia , Kaknani‐Uttumchandani Shakira , León‐Campos Álvaro , García‐Guerrero Alfonso , Morales‐Asencio José Miguel
Published: May 2015

Purpose

To assess students' satisfaction with their clinical tutors, their clinical practices, and tutors' satisfaction with the new approach of clinical placements and tutorship.

Methods

A cross‐sectional study was used, with a study population of second and third year nursing students and clinical tutors.

Results

Global satisfaction was 7.47 (SD 1.61) (range from 1 to 9). Regarding students' satisfaction, 75.67% of the items were equal to or greater than 4 (range from 1 to 5). The overall mean score was 4.05 (DE 1.08).

Conclusions and implications for nursing practice

A competency‐structured practicum, assessed through the Nursing Interventions Classification and supported on information and communications technologies, is a reliable and valid method that encourages students and tutors to an active participation, and implies a high degree of satisfaction in both tutors and students.
Caring for Residents of Eldercare Facilities: A Concept Analysis
Authors: Hwang Huei‐lih
Published: May 2015

Purpose

To report the results of an evolutionary concept analysis of caring in facilities that provide care for elders.

Sources

Cumulative indices for CINAHL, ERIC, Academic Search Complete, PsychINFO, Medline, and CEPTS.

Results

Caring is an interactive process characterized by seeing, helping, and communicating, which are analogous to two wheels with one axle. Caring is preceded by individuality and followed by well‐being.

Conclusion

The findings explicate the core components of caring in facilities that provide care for elders.

Implications

The metaphor of an axle and wheel can guide caregivers in delivering effective care as the demand for improved well‐being of residents of eldercare facilities increases.
Voluntary exercise protects against ulcerative colitis by up‐regulating glucocorticoid‐mediated PPAR‐γ activity in the colon in mice
Authors: Liu W.‐X. , Zhou F. , Wang Y. , Wang T. , Xing J.‐W. , Zhang S. , Sang L.‐X. , Gu S.‐Z. , Wang H.‐L.
Published: May 2015

Aim

Voluntary exercise has been shown to protect against the development of ulcerative colitis, but the mechanism is not fully understood. We hypothesized that prior voluntary exercise would attenuate colonic inflammation and ameliorate clinical symptoms in dextran sulphate sodium (DSS)‐induced ulcerative colitis by increasing glucocorticoid production and up‐regulating PPAR‐γ activity in the colon.

Methods

Male C57Bl/6J mice were assigned to sedentary, exercise, exercise with PPAR‐γ antagonist GW9662 or glucocorticoid synthesis inhibitor metyrapone. Following the completion of the 30 days’ exercise training programme, they were treated with or without 2% DSS in drinking water for 5 days, followed by 5 days of regular water.

Results

Compared with sedentary mice, exercise mice exhibited improved clinical symptoms (weight loss and diarrhoea) and less inflammation (expression of pro‐inflammatory cytokines and histological injury) in response to DSS, whereas these beneficial effects were abolished by both GW9662 and metyrapone treatment. Molecular studies revealed that exercise significantly increased the expression of PPAR‐γ, augmented the expression of steroidogenic enzymes (CYP11A1 and CYP11B1) and elevated corticosterone levels in the colon. GW9662 treatment reversed the expression of PPAR‐γ without altering the expression of steroidogenic enzymes and corticosterone secretion in the colon, while metyrapone treatment blocked glucocorticoid secretion and abrogated the increase in PPAR‐γ expression in the colon.

Conclusion

These findings suggest that prior voluntary exercise suppresses the expression of pro‐inflammatory cytokines in the colon in response to inflammatory challenge by up‐regulating glucocorticoid‐mediated PPAR‐γ activity, contributing to protection against the development of ulcerative colitis.
Children's understanding of embarrassment: Integrating mental time travel and mental state information
Authors: Chobhthaigh Sorcha Ni , Wilson Charlotte
Published: May 2015

The current study investigated 4‐ to 8‐year‐olds’ (N = 81) understanding of embarrassment and their ability to integrate temporal and mental state information to predict and explain emotions. Participants heard stories describing characters commit trivial social transgressions, and then the next day, characters found themselves in the same situation that led to the previous transgression. For some story endings, participants were asked to predict and explain how the character felt, and for others, participants were told the character started to feel embarrassed and they were asked to explain why. Participants’ responses were coded and analysed using nonparametric statistical tests. Kruskal–Wallis analyses revealed significant developments occur between 6 and 8 years in children's understanding of embarrassment and their ability to explain individual's emotion as caused by anticipating the reoccurrence of a previous embarrassing event. Younger children demonstrated a basic knowledge of embarrassment but failed to demonstrate more advanced understanding of the emotion. Findings from the current study indicate children reach a more mature understanding of embarrassment and the implications of committing social transgressions between 7 and 8 years. Finally, the current study contributes to the literature on children's ability to infer mental states and temporally connect experiences.
Quantitative proteomic analysis of mitochondria from human ovarian cancer cells and their paclitaxel‐resistant sublines
Authors: Chen Ming , Huang Hong , He Haojie , Ying Wantao , Liu Xin , Dai Zhiqin , Yin Jie , Mao Ning , Qian Xiaohong , Pan Lingya
Published: May 2015

Paclitaxel resistance is a major obstacle for the treatment of ovarian cancer. The chemoresistance mechanisms are partly related to the mitochondria. Identification of the relevant proteins in mitochondria will help in clarifying the possible mechanisms and in selecting effective chemotherapy for patients with paclitaxel resistance. In the present study, mitochondria from two paclitaxel‐sensitive human ovarian cancer cell lines (SKOV3 and A2780) and their corresponding resistant cell lines (SKOV3‐TR and A2780‐TR) were isolated. Guanidine‐modified acetyl‐stable isotope labeling and liquid chromatography‐hybrid linear ion trap Fourier‐transform ion cyclotron resonance mass spectrometry (LC‐FTICR MS) were performed to find the expressed differential proteins. Comparative proteomic analysis revealed eight differentially expressed proteins in the ovarian cancer cells and their paclitaxel‐resistant sublines. Among them, mimitin and 14‐3‐3 ζ/δ were selected for further research. The effects of mimitin and 14‐3‐3 ζ/δ were explored using specific siRNA interference in ovarian cancer cell lines and immunohistochemistry in human tissue specimens. The downregulation of mimitin and 14‐3‐3 ζ/δ using specific siRNA in paclitaxel‐resistant ovarian cancer cells led to an increase in the resistance index to paclitaxel. Multivariate analyses demonstrated that lower expression levels of the mimitin and 14‐3‐3 ζ/δ proteins were positively associated with shorter progression‐free survival (PFS) and overall survival (OS) in patients with primary ovarian cancer (mimitin: PFS: P = 0.041, OS: P = 0.003; 14‐3‐3 ζ/δ: PFS: P = 0.031, OS: P = 0.011). Mimitin and 14‐3‐3 protein ζ/δ are potential markers of paclitaxel resistance and prognostic factors in ovarian cancer.
Discovery of New 4‐Alkoxyquinazoline‐Based Derivatives as Potent VEGFR2 Inhibitors
Authors: Yin Yong , Sha Shao , Wang Yan‐Ting , Wu Xun , Wang She‐Feng , Qiao Fang , Lv Peng‐Cheng , Zhu Hai‐Liang
Published: May 2015

VEGFR2 has been proved to play a major role in the regulation of tumor angiogenesis. Twenty‐one 4‐alkoxyquinazoline‐based derivatives have been designed and synthesized as vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors, and their biological activities were evaluated. Among these compounds, compound 3h exhibited the most potent inhibitory activities against VEGFR2 tyrosine kinase and cell proliferation, with the IC50 values of 2.89 nm (for VEGFR2) and 0.25 μm (for MCF‐7), which were comparable with the control compound. Docking simulation was performed to position compound 3h into the 4ASE active site, and the result showed that compound 3h could bind well at the 4ASE active site.
Synthesis and Biological Evaluation of Benzo[d][1,3]Dioxol‐5‐yl Chalcones as Antiproliferating Agents
Authors: Kamal Ahmed , Balakrishna Moku , Loka Reddy Velatooru , Riyaz Syed , Bagul Chandrakant , Satyanarayana Bethu Murali , Venkateswar Rao Janapala
Published: May 2015

A series of chalcone derivatives were designed, synthesized, and evaluated for their cytotoxic potential. These molecules have showed promising cytotoxic activity with IC50 values ranging from 5.24 to 63.12 μm. Among them, conjugates 16k, 16m and 16t showed significant antiproliferative activity with IC50 values ranging from 5.24 to 10.39 μm in MDA‐MB‐231 cell line. These compounds were further investigated for their effect on cell membrane blebbing, chromatin condensation, DNA fragmentation, Hoechst staining, annexin V, and cell cycle arrest (G2/M). The Western blot experiments revealed up regulation of pro‐apoptotic Bax and downregulation of antiapoptotic Bcl‐2. The studies also indicated reduction of mitochondrial membrane potential and increase in the levels of caspase‐3 and caspase‐7.
Characterizing the Free‐Energy Landscape of MDM2 Protein–Ligand Interactions by Steered Molecular Dynamics Simulations
Authors: Hu Guodong , Xu Shicai , Wang Jihua
Published: May 2015

Inhibition of p53–MDM2 interaction by small molecules is considered to be a promising approach to re‐activate wild‐type p53 for tumor suppression. Several inhibitors of the MDM2–p53 interaction were designed and studied by the experimental methods and the molecular dynamics simulation. However, the unbinding mechanism was still unclear. The steered molecular dynamics simulations combined with Brownian dynamics fluctuation–dissipation theorem were employed to obtain the free‐energy landscape of unbinding between MDM2 and their four ligands. It was shown that compounds 4 and 8 dissociate faster than compounds 5 and 7. The absolute binding free energies for these four ligands are in close agreement with experimental results. The open movement of helix II and helix IV in the MDM2 protein‐binding pocket upon unbinding is also consistent with experimental MDM2‐unbound conformation. We further found that different binding mechanisms among different ligands are associated with H‐bond with Lys51 and Glu25. These mechanistic results may be useful for improving ligand design.
Antimalarial Effect of 3‐Methoxy‐1,2‐Dioxetanes on the Erythrocytic Cycle of Plasmodium falciparum
Authors: Lopes Nicolas S. , Yoshitake Ariane M. , Silva Adriana F. , Oliveira Vani X. , Silva Leandro S. , Pinheiro Ana A. S. , Ciscato Luiz Francisco M. L.
Published: May 2015

The antimalarial activity of peroxides most likely originates from their interaction with iron(II) species located inside the malaria parasite, which forms destructive radical species through a Fenton‐like mechanism. This article reports the first evaluation of the in vitro antimalarial activity of three peroxides of the class 1,2‐dioxetanes against Plasmodium falciparum; the results reveal that the studied 3‐methoxy‐1,2‐dioxetanes display significant antimalarial activity, at a similar level as artemisinin and also that their reactivity toward iron(II) correlate linearly with their antimalarial activity.
Tertiary paediatric hospital admissions in children and young people with cerebral palsy
Authors: Meehan E. , Freed G. L. , Reid S. M. , Williams K. , Sewell J. R. , Rawicki B. , Reddihough D. S.
Published: May 2015

Background

Many previous studies that have investigated hospital admissions in children and young people with cerebral palsy lack information on cerebral palsy severity and complexity. Consequently, little is known about factors associated with the frequency and type of hospital admissions in this population. This study used hospital admission data available for all children and young people known to a population‐based cerebral palsy register to describe the patterns of use of tertiary paediatric hospital services over a 5‐year period.

Methods

This was a retrospective cohort analysis of routinely collected admission data from the two tertiary paediatric hospitals in the Australian state of Victoria. Data on admissions of individuals born between 1993 and 2008 registered on the Victorian Cerebral Palsy Register were analysed (n = 2183).

Results

Between 2008 and 2012, 53% of the cohort (n = 1160) had at least one same‐day admission, and 46% (n = 996) had one or more multi‐day admissions. Those with a moderate to severe motor impairment and those with a co‐diagnosis of epilepsy had more admissions, and for multi‐day admissions, longer lengths of stay, P < 0.05. Across all severity levels, respiratory and musculoskeletal diseases were the most frequently reported reasons for medical and surgical admissions, respectively. All‐cause readmission rates for urgent multi‐day stays within 7, 30 and 365 days of an index admission were 10%, 23% and 63%, respectively.

Conclusions

The reasons for hospital admissions reported here reflect the range of comorbidities experienced by children and young people with cerebral palsy. This study highlights priority areas for prevention, early diagnosis and medical management in this group. Improved primary and secondary prevention measures may decrease non‐elective hospital admissions and readmissions in this group and reduce paediatric inpatient resource use and healthcare expenditure attributable to cerebral palsy.
Initial immunological changes as predictors for house dust mite immunotherapy response
Authors: Gómez E. , Fernández T. D. , Doña I. , Rondon C. , Campo P. , Gomez F. , Salas M. , Gonzalez M. , Perkins J. R. , Palomares F. , Blanca M. , Torres M. J. , Mayorga C.
Published: May 2015

Background

Although specific immunotherapy is the only aetiological treatment for allergic disorders, the underlying mechanisms are not fully understood. Specific immunotherapy induces changes in lymphocyte Th subsets from Th2 to Th1/Treg. Whether differences in immunological patterns underlie patient response to immunotherapy has not yet been established.

Objectives

We studied the immunological changes occurring during a 1‐year period of Dermatophagoides pteronyssinus (DP) immunotherapy and their relation with clinical outcome.

Methods

We included 34 patients with DP allergy who received subcutaneous specific immunotherapy (SCIT) for 1 year. Following treatment, patients were classified as responders or non‐responders. Fourteen allergic subjects who did not receive SCIT were included as controls. Peripheral blood was obtained at 0, 1, 3, 6 and 12 months and cultured with nDer p 1. Phenotypic changes, cytokine production and basophil response were analysed by flow cytometry; transcription factors were measured by mRNA quantification. Serum immunoglobulin levels were also measured.

Results

After 1 year of SCIT, 82% of cases showed improved symptoms (responders). Although increases in sIgG4 were observed, BAT reactivity was not modified in these patients. Increases in T‐BET/FOXP3 as well as nDer p 1‐specific Th1/Treg frequencies were also observed, along with a decrease in Th2, Th9 and Th17. These changes corresponded to changes in cytokine levels.

Conclusion

Patients who respond well to DP‐SCIT show immunological differences compared to non‐responders. In responders, basal differences include a lower frequency of Th1 and higher frequencies of Th2, Th9 and Th17 cells. After 1 year of treatment, an increased production of sIgG4 was observed in responders, along with a change in Th2 response towards Th1/Treg.
Hormonal ‘minipuberty’ influences the somatic development of boys but not of girls up to the age of 6 years
Authors: Becker Marianne , Oehler Klaus , Partsch Carl‐Joachim , Ulmen Ulrike , Schmutzler Renate , Cammann Henning , Hesse Volker
Published: May 2015

Objective

Hormonal ‘minipuberty’ refers to a transient sex‐specific surge of LH, FSH, testosterone (T) and estradiol (E2) in the first few months of life. We hypothesized a potential long‐term effect of this hormonal surge on somatic parameters in the following years and therefore designed this longitudinal study.

Design

A hierarchical multiple regression analysis was used to analyse the potential influence of hormone concentrations during minipuberty on anthropometric measurements conducted in the first 6 years of life.

Patients

Thirty‐five healthy babies (17 male, 18 female) were the participants.

Measurements

Testosterone, E2, SHBG, LH and FSH were measured at the ages of four, eight and 20 weeks. Anthropometric measurements were taken eight times in the first 12 months, then every 6 months up to the age of 6 years.

Results

A significant negative effect was found in boys between testosterone and LH levels at 8 weeks and body weight up to the age of 6 years and BMI up to 6 years (LH) and 3 years (T), respectively. A further negative effect was found between E2 levels at the age of 20 weeks and body weight as well as body length in the years that followed. A positive effect was observed between E2 at the age of 4 weeks and skinfold thickness up to the age of 6 years in boys. No significant effects were found in girls.

Conclusions

The findings seem to reflect an up to now unknown long‐term influence of the physiological early hormonal surge on the subsequent male but not female somatic development.
Quality‐of‐life and functional outcomes following pharyngolaryngectomy: a systematic review of literature
Authors: Mahalingam S. , Srinivasan R. , Spielmann P.
Published: May 2015

Background

The long‐term prognosis of hypopharyngeal cancer is poor. Surgery necessitates pharyngolaryngectomy with flap reconstruction. For such patients, it is important that functional outcomes are preserved to maintain a respectable quality of life.

Objective of review

To identify the functional outcomes following pharyngolaryngectomy with respect to quality of life, speech and swallow through a systematic review of literature.

Search strategy

Searches of EBM databases and literature databases using key words: pharyngolaryngectomy, laryngopharyngectomy, swallow, dysphagia, speech and dysphonia from 1970 to August 2014. Articles were screened for relevance using pre‐determined inclusion and exclusion criteria.

Evaluation method

Articles reviewed by authors and data compiled in tables for analysis.

Results

No previous systematic reviews assessing functional outcomes were identified. Seventeen studies reported speech outcomes (576 patients) and fifteen reported swallow outcomes (1076 patients). The data suggests that patients who underwent trachea‐oesophageal puncture developed more favourable speech outcomes than those rehabilitated using other measures. Overall stricture incidence was 11.4% and 6.5% of patients required long‐term enteral nutrition. Four studies used validated speech measures, and three used validated swallow measures. They suggest an overall level of perceived impairment in quality of life. Speech and swallow outcomes were significantly poorer than patients who underwent total laryngectomy.

Conclusions

Overall, there is an impairment in speech and swallow outcomes following pharyngolaryngectomy; however, the exact extent is unclear. There is a need for a general consensus on assessment measures and prospective multicentre studies to be conducted. This study compiles the available data to improve caregiver and patient awareness of functional outcomes.
Divergence in sink contributions to population persistence
Authors: Heinrichs Julie A. , Lawler Joshua J. , Schumaker Nathan H. , Wilsey Chad B. , Bender Darren J.
Published: May 2015

Population sinks present unique conservation challenges. The loss of individuals in sinks can compromise persistence; but conversely, sinks can improve viability by improving connectivity and facilitating the recolonization of vacant sources. To assess the contribution of sinks to regional population persistence of declining populations, we simulated source–sink dynamics for 3 very different endangered species: Black‐capped Vireos (Vireo atricapilla) at Fort Hood, Texas, Ord's kangaroo rats (Dipodomys ordii) in Alberta, and Northern Spotted Owls (Strix occidentalis caurina) in the northwestern United States. We used empirical data from these case studies to parameterize spatially explicit individual‐based models. We then used the models to quantify population abundance and persistence with and without long‐term sinks. The contributions of sink habitats varied widely. Sinks were detrimental, particularly when they functioned as strong sinks with few emigrants in declining populations (e.g., Alberta's Ord's kangaroo rat) and benign in robust populations (e.g., Black‐capped Vireos) when Brown‐headed Cowbird (Molothrus ater) parasitism was controlled. Sinks, including ecological traps, were also crucial in delaying declines when there were few sources (e.g., in Black‐capped Vireo populations with no Cowbird control). Sink contributions were also nuanced. For example, sinks that supported large, variable populations were subject to greater extinction risk (e.g., Northern Spotted Owls). In each of our case studies, new context‐dependent sinks emerged, underscoring the dynamic nature of sources and sinks and the need for frequent re‐assessment. Our results imply that management actions based on assumptions that sink habitats are generally harmful or helpful risk undermining conservation efforts for declining populations.
Impact of functional training on cardiac autonomic modulation, cardiopulmonary parameters and quality of life in healthy women
Authors: Rezende Barbosa Marianne Penachini da Costa de , Netto Júnior Jayme , Cassemiro Bruna Montechieze , de Souza Naiara Maria , Bernardo Aline Fernanda Barbosa , da Silva Anne Kastelianne França , Pastre Carlos Marcelo , Vanderlei Luiz Carlos Marques
Published: May 2015

Functional training (FT) promotes benefits in various physical abilities; however, its effect on autonomic modulation, cardiorespiratory parameters and quality of life in the healthy adult population is unknown, and thus, the aim of this study was to evaluate the influence of  FT on these variables in healthy young women. The study consisted of 29 women, distributed into two groups: the FT Group (FTG; n = 13; 23 ± 2·51 years; 21·90 ± 2·82 kg m−²) and the Control Group (CG; n = 16; 20·56 ± 1·03 years; 22·12 ± 3·86 kg m−²). The FTG performed periodized FT for 12 weeks, three times a week. The following were evaluated: autonomic modulation (heart rate variability), cardiorespiratory parameters and quality of life (SF‐36 Questionnaire). The Student's t‐test for unpaired data or the Mann–Whitney test was used to compare the differences obtained between the final moment and the initial moment of the studied groups (P<0·05). The FTG demonstrated significant improvements in quality of life and autonomic modulation (P<0·05), but not in the cardiorespiratory parameters. Functional training was able to produce improvements in autonomic modulation and quality of life.
Editorial Introduction to the Special Section: Deconstructing Offshore Finance
Authors: Clark Gordon L. , Lai Karen P. Y. , Wójcik Dariusz
Published: May 2015

Recent scandals involving large corporations including Amazon, Apple, Google, Starbucks, and HSBC have highlighted the problems of tax avoidance, evasion, and offshore financial activities. Considering their significance to growing inequality and financial instability, renewed media and public attention is well justified, and new research on these topics urgent. At the same time, however, there is confusion in the very use of the term offshore finance. Some apply it interchangeably with tax havens; others go as far as to use it as a synonym of international finance. We argue that offshore finance needs a precise definition and careful positioning in a broader economic geographical framework. We suggest a definition based on the legal and accounting, in addition to financial, aspects of offshore finance, and we propose the concept of global financial networks to situate offshore jurisdictions and offshore finance in the firm–territory nexus and in relation to global production networks. This sets the stage for the three research articles presented in this issue, which map offshore financial networks at global and regional scales, and investigate their causes and mechanisms.
Functional and phylogenetic structure of forest and savanna bird assemblages across spatial scales
Authors: Sobral Fernando L. , Cianciaruso Marcus V.
Published: May 2015

Ecological and evolutionary mechanisms that drive community assembly vary in space and time. However, little is known about how such mechanisms act in contrasting habitats. Here, we estimated the functional and phylogenetic structure of forest and savanna bird assemblages across different spatial scales to understand: 1) the mechanisms that govern the structure of assemblages in these habitats; 2) the relationship between phylogenetic and functional structure; and 3) the influence of species richness on the functional and phylogenetic structure of assemblages. We used a null model where forest and savanna bird species were allowed to occur in the same null assemblages and other where species were separated based on their habitats. According to the first null model, forest bird assemblages were functionally and phylogenetically clustered at all spatial scales, whereas savanna bird assemblages generally showed random functional and phylogenetic structure. These results can be explained by the low dispersal rate of forest species across of the patchy habitats and the widespread distribution of savanna species. However, in the second null model, both forest and savanna bird assemblages showed random functional and phylogenetic structure at regional and local scales. This suggests that trait‐based assembly might not play an important role in both habitats and across different spatial scales. In addition, the phylogenetic and functional structure of assemblages were not correlated, evidencing that caution is necessary when using phylogenetic relationships as a surrogate to functional distances among species. Finally, the relationships between species richness and functional and phylogenetic structure indicated that an increase in the number of species can promote both clustering and overdispersion, depending on the studied habitat and scale. Our study shows that integrating different types of habitat, spatial scales and biodiversity components in a single framework can shed light on the mechanisms that determine the community assembly.
Characterization of host–fungus interactions among wood decay fungi associated with Khaya senegalensis (Desr.) A. Juss (Meliaceae) in Singapore
Authors: Burcham D. C. , Wong J.‐Y. , Ali M. I. M. , Abarrientos N. V. , Fong Y.‐K. , Schwarze F. W. M. R.
Published: May 2015

Tree pruning creates wounds that are amenable for wood decay fungi colonization. To characterize the dynamic host–fungus interactions at this location in Senegal mahogany (Khaya senegalensis), in vitro and in vivo pathogenicity tests were conducted with wood decay fungi associated with this tropical tree species. Fomitiporella caryophylii, Hymenochaete murina and Phellinus noxius isolates were included in this experiment following their frequent isolation from Senegal mahogany pruning wounds. The evaluated isolates demonstrated unique host interactions in laboratory tests that suggest equally divergent prognoses for living Senegal mahoganies affected by these fungi. Although all evaluated fungal isolates successfully breached naturally induced reaction zones, P. noxius alone caused significant mass loss to incubated wood blocks. In addition, P. noxius caused extensive wood decay after inoculation in living hosts, successfully illustrating Koch's postulates for this host–fungus relationship. The wood decay ability, invasiveness and facultative parasitism demonstrated by P. noxius suggest its dominant role in wood decay columns below pruning wounds on living Senegal mahoganies. These results highlight the importance of characterizing specific host–fungus interactions and their implications for wood decay severity below pruning wounds in living trees.
Evaluation of Pinus radiata seed treatments to control Fusarium circinatum: effects on seed emergence and disease incidence
Authors: Berbegal M. , Landeras E. , Sánchez D. , Abad‐Campos P. , Pérez‐Sierra A. , Armengol J.
Published: May 2015

In this study, the effects of hot water (HWT), hydrogen peroxide and fungicides on the incidence of Fusarium circinatum on artificially inoculated Pinus radiata seeds were evaluated. Fifteen commercial fungicide formulations were screened in vitro for inhibitory activity on mycelial growth and conidial germination of F. circinatum. With half‐maximal effective concentration (EC50) lower than 0.5 ppm, fluazinam, imazalil and tebuconazole were the most effective fungicides on mycelial growth, while captan, mancozeb or pyraclostrobin were the most effective (EC50 < 0.3 ppm) on conidial germination. Based on the results obtained, imazalil, fluazinam, mancozeb and pyraclostrobin were selected for further testing. The effects of HWT, hydrogen peroxide and fungicide treatments on seed emergence and the incidence of F. circinatum were assessed. Seed treatments with fungicides prior to sowing were less effective and inconsistent in reducing the incidence of F. circinatum on seedlings. In contrast, hot water and hydrogen peroxide treatments significantly reduced F. circinatum contamination on P. radiata seeds with an overall disease incidence lower than 0.8% on seedlings. Furthermore, subsequent application of fungicides on seedlings did not improve the effectiveness of HWT. These results, therefore, suggest that hot water is a better alternative to hydrogen peroxide and fungicides as Pinus seed treatment against F. circinatum and could easily be implemented as standard in commercial nurseries to control the spread of the pitch canker disease.
Northward displacement of optimal climate conditions for ecotypes ofEriophorum vaginatumL. across a latitudinal gradient inAlaska
Authors: McGraw James B. , Turner Jessica B. , Souther Sara , Bennington Cynthia C. , Vavrek Milan C. , Shaver Gaius R. , Fetcher Ned
Published: May 2015

Plants are often genetically specialized as ecotypes attuned to local environmental conditions. When conditions change, the optimal environment may be physically displaced from the local population, unless dispersal orin situevolution keep pace, resulting in a phenomenon called adaptational lag. Using a 30‐year‐old reciprocal transplant study across a 475 km latitudinal gradient, we tested the adaptational lag hypothesis by measuring both short‐term (tiller population growth rates) and long‐term (17‐year survival) fitness components ofEriophorum vaginatumecotypes in Alaska, where climate change may have already displaced the optimum. Analyzing the transplant study as a climate transfer experiment, we showed that the climate optimum for plant performance was displaced ca. 140 km north of home sites, although plants were not generally declining in size at home sites. Adaptational lag is expected to be widespread globally for long‐lived, ecotypically specialized plants, with disruptive consequences for communities and ecosystems.