bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of arginine and its “Downstream” molecules as potential markers of breast cancer
Authors: Hu Lu , Gao Yu , Cao Yunfeng , Zhang Yinxu , Xu Minghao , Wang Yuanyuan , Jing Yu , Guo Shengnan , Jing Fangyu , Hu Xiaodan , Zhu Zhitu
Published: September 2016

Breast cancer (BC) is the most commonly diagnosed cancer in women worldwide. Arginine is a semiessential amino acid in humans and is essential for several biological pathways in malignant and normal cells, such as ornithine and N1, N12‐diacetylspermine (DiAcSpm). This study aimed to determine the role of arginine and these downstream molecules in BC. Plasma arginine, ornithine, and arginine–to–ornithine ratio (AOR) were analysed by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Urine samples were measured by the colloid gold aggregation to test determination of urinary diAcSpm. A principal component analysis was performed to evaluate the results observed between breast tumor and control characteristics. Differences in individual metabolite concentrations between BC patients and controls were tested by receiver operating characteristics (ROC) analyses. Student's t tests were used to detect the differences between two groups of normally distributed variables, and Wilcoxon sign rank tests were performed for asymmetrically distributed variables. As we analyzed, BC patients had lower plasma arginine and arginine/ornithine level, and higher plasma ornithine and urinary DiAcSpm concentrations as compared with control patients (P = 0.028, 0.020, 0.002, and 0.011, respectively). And the ROC curve was drawn and the area under the curve of the metabolites was calculated to be 0.659 (P = 0.028), 0.645 (P = 0.045), 0.7233 (P = 0.002), 0.683 (P = 0.011), respectively. In addition, our analysis showed that arginine concentrations and AOR had a positive correlation with ER status, while ornithine had a negative correlation with T stage (P = 0.042, 0.083, 0.023, respectively).In conclusion, arginine and these downstream molecules were biomarkers for BC. More studies are needed to highlight the theoretical strengths. © 2016 IUBMB Life, 68(10):817–822, 2016
A Case Report of Harm‐Related Obsessions in Pediatric Obsessive‐Compulsive Disorder
Authors: Wu Monica S. , Storch Eric A.
Published: September 2016

Harm‐related, or “aggressive,” obsessions are a symptom subtype in obsessive‐compulsive disorder (OCD). Given the violent nature of these thoughts, the stark contrast between the child's character and the content of these obsessions often results in high levels of distress for not only the patient but also the family. This case report illustrates the application of family‐based exposure and response prevention (ERP) for a 15‐year‐old male presenting with harm‐related obsessions and mild depressive symptoms secondary to the OCD. The obsessions primarily revolved around the fear of acting on unwanted impulses (e.g., stabbing a family member, pushing a friend onto oncoming traffic), and the compulsions entailed avoidance (both mental and physical), excessive reassurance seeking, and ritualistic confessions. The client underwent a 14‐week course of ERP involving repeated imaginal and in vivo exposures and behavioral activation to alleviate depressive symptoms. Significant improvements in obsessive‐compulsive symptom severity and depressive symptoms were observed posttreatment, elucidating the efficacy of treating harm‐related obsessions with a course of ERP.
Managing Family Accommodation of OCD in the Context of Adolescent Treatment Refusal: A Case Example
Authors: Johnco Carly
Published: September 2016

Family accommodation is a common and widely studied phenomenon in families of youth with obsessive‐compulsive disorder (OCD). Family accommodation has been associated with increased symptom severity, poorer functional outcomes, and reduced treatment response. While family accommodation is increasingly targeted in family‐based treatment of OCD, there are cases where youth refuse treatment. In these circumstances, parent‐focused treatments that target reduction of family accommodation can be used to improve outcomes for youth with OCD. This case study illustrates the conceptualization and treatment of family accommodation in childhood OCD in the context of treatment refusal. Treatment was implemented without explicit involvement of the child. Parents reported moderate improvement in OCD symptoms at the end of treatment and a decrease in overall parent–child conflict. The findings illustrate how exposure and response principles can be implemented without direct involvement of the child in cases where youth show low motivation or refusal of treatment.
A Facile and Chemoselective Synthesis of Novel Pyrimido[5,4‐b][1,4]thiazines by exo‐dig Iodocyclization Reactions
Authors: Sharma Rashmi , Mohan Chander
Published: September 2016

The present manuscript involves the synthesis of 5‐prop‐2‐ynylsulfanyl‐pyrimidin‐4‐ones 3a–i by [4 + 2] cycloaddition reactions of 1,3‐diazabuta‐1,3‐dienes 1a–i with prop‐2‐ynyl‐sulfanyl ketene 2. These 5‐prop‐2‐ynylsulfanyl‐pyrimidin‐4‐ones 3a–i were explored in iodocyclization for the synthesis of novel pyrimido[5,4‐b][1,4]thiazines 4a–i in excellent yields. The iodocyclizations followed exo‐dig ring‐closure cyclizations to yield 6–6 bicyclic fused pyrimidinones, while corresponding endo‐dig ring‐closure iodoamination was not observed.
Strategy Induction Enhances Creativity in Figural Divergent Thinking
Authors: Forthmann Boris , Wilken Andrea , Doebler Philipp , Holling Heinz
Published: September 2016

Instructional effects in creative‐thinking tasks are important to understand in order to promote creative performance of individuals. In divergent‐thinking tasks, for example, instructional and strategic enhancement effects have been extensively studied for verbal tasks. However, while studies on instructional enhancement effects on creative drawing tasks exist, it is surprising that strategy enhancement in figural divergent thinking is still underresearched. In this study, we used a strategy manipulation approach to reassess the role of executive strategy implementation and the moderating role of an indicator of fluid intelligence, figural analogical reasoning, in two types of figural divergent‐thinking tasks (abstract vs. concrete). The sample comprised N = 75 high‐school students. Importantly, we found strategic enhancement effects by combining strategy instructions with a prompt to “be creative.” This combined instruction was contrasted with a standard instruction, and main effects were found for overall, concrete, and abstract creativity. Moreover, we found in a regression analysis a main effect for figural analogical reasoning on overall creativity and creativity for only the concrete object tasks. An expected interaction effect of instruction and figural analogical reasoning was not found. As another addition, the role of current motivation in figural divergent thinking was explored.
Conceptualizing Creativity: General and Cultural Biases in Gough's Creative Personality Scale
Authors: Luescher Raphael , Barthelmess Petra Young‐Zie , Kim Su‐Yeong , Richter Ulf Henning , Mittag Michael
Published: September 2016

This study analyzes the validity of Gough's Creative Personality Scale (CPS) for the Adjective Check List (ACL) by using 1773 Swiss, South Korean, and Mainland Chinese students as a sample. Four sources of potential bias were identified in Gough's CPS, two of which are general and two cultural in nature. The two general biases were investigated by conducting correlation analyses and evaluating alternative scoring methods for the CPS. As a result of the first bias, checking a large number of adjectives was found to be more important for achieving a high score than checking the relevant ones. Due to the second bias, the CPS score mostly depends on the number of positive adjectives checked while negative items have little impact. The two cultural biases were analyzed using an implicit version of the CPS (iCPS) and factor analysis. The latter revealed three different clusters of creativity type: exploratory‐type, socially responsible‐type, and intellectual‐type creativity. Based on cultural background, they are all weighted differently, causing a potential experiential bias in the CPS. Findings indicate that in South Korea and Mainland China socially responsible‐type creativity dominates whereas in Switzerland exploratory‐type creativity prevails. Findings from the iCPS suggest the second cultural bias, the socially desirable responding bias arising from differences in responding styles among the three cultures.
Value of routine staging imaging studies for patients with stage III breast cancer
Authors: Piatek Caroline I. , Ji Lingyun , Kaur Chandan , Russell Christy A. , Tripathy Debu , Church Terry , Sposto Richard , Sener Stephen F. , Garcia Agustin A.
Published: September 2016

Background and Objectives

Routine staging imaging studies (RSIS) are optional in stage III breast cancer (BC). The impact of RSIS on treatment decisions and patient outcomes has not been extensively studied. The goal of this study was to determine whether RSIS in stage III BC affected treatment or patient outcomes.

Methods

Stage III BC patients from 2000 to 2010 were retrospectively identified. RSIS results and treatment plan in response to RSIS results were recorded. Univariate and multivariate Cox proportional hazards regression models with time‐dependent covariates were used to assess associations between RSIS use and recurrence‐free survival (RFS).

Results

Of 420 patients, 362 (86.2%) received RSIS. RSIS were negative in 264 (72.9%), indeterminate in 77 (18.3%), and positive in 21 patients (5.0%) for metastatic disease. Treatment was altered in 21 (5.8%) patients based on RSIS results (20 with metastatic disease, 1 with indeterminate disease). There was no difference in RFS with RSIS use on multivariate analysis (hazard ratio 1.3; 95% confidence interval 0.73–2.5, P = 0.32).

Conclusions

Most stage III BC patients underwent RSIS, but RSIS results infrequently affected treatment decisions. There was no significant difference in RFS with RSIS use. RSIS to identify metastatic disease for stage III BC has limited value. J. Surg. Oncol. 2016;114:917–921. © 2016 Wiley Periodicals, Inc.
“Click”‐Triggered Self‐Healing Graphene Nanocomposites
Authors: Rana Sravendra , Döhler Diana , Nia Ali Shaygan , Nasir Mahmood , Beiner Mario , Binder Wolfgang H.
Published: September 2016

Strategies to compensate material fatigue are among the most challenging issues, being most prominently addressed by the use of nano‐ and microscaled fillers, or via new chemical concepts such as self‐healing materials. A capsule‐based self‐healing material is reported, where the adverse effect of reduced tensile strength due to the embedded capsules is counterbalanced by a graphene‐based filler, the latter additionally acting as a catalyst for the self‐healing reaction. The concept is based on “click”‐based chemistry, a universal methodology to efficiently link components at ambient reaction conditions, thus generating a “reactive glue” at the cracked site. A capsule‐based healing system via a graphene‐based Cu2O (TRGO‐Cu2O‐filler) is used, acting as both the catalytic species for crosslinking and the required reinforcement agent within the material, in turn compensating the reduction in tensile strength exerted by the embedded capsules. Room‐temperature self‐healing within 48 h is achieved, with the investigated specimen containing TRGO‐Cu2O demonstrating significantly faster self‐healing compared to homogeneous (Cu(PPh3)3F, Cu(PPh3)3Br), and heterogeneous (Cu/C) copper(I) catalysts.

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A Brief Nonmotor Screen Combined with Transcranial Ultrasound may Improve Diagnostic Accuracy of Parkinson's Disease
Authors: Hayes Michael , Puhl Peter , Hagenah Johann , Russo Robert
Published: September 2016

Background

The addition of a simple nonmotor symptom (NMS) screen and transcranial sonography (TCS) to standard clinical assessment may improve the diagnostic accuracy of Parkinson's disease (PD).

Methods

Sixty‐nine subjects (23 established PD group, 23 healthy controls, and 23 possible PD) were enrolled. All completed 3 “yes‐no” NMS questions (score, 0–3) and had a transcranial ultrasound assessing nigral hyperechogenicity (score, 0–1). A combined PD risk score of 0 to 4 was obtained for each subject. A PD risk score of ≥2 was used as the diagnostic cutoff for PD.

Results

In the established PD group, there was an average of 2 NMSs per person or a group total of 46 of 69 possible NMSs, but only 4 of 69 NMSs in the healthy control group. Of the technically satisfactory TCS, 16 of 20 (80%) of the established PD group and 2 of 16 (12.5%) of the healthy control group were TCS positive. Using ≥2 NMSs alone as the cutoff identified 17 of 23 (74%) of the established PD and 100% of the healthy controls. The PD risk score of ≥2 identified 21 of 23 (91%) of the established PD as PD and 22 of 23 (96%) of the healthy control group as non‐PD. In the possible PD group, the PD risk score identified 9 of 18 (50%) of those with a final clinical diagnosis of PD and 4 of 5 (80%) of non‐PD.

Conclusions

The combination of a brief NMS screen and TCS discriminated well between normal healthy controls and established PD. A positive TCS and one NMS, or a negative TCS with two NMSs, indicated a likely diagnosis of PD.
Prevalence and clinical aspects of immigrants with myasthenia gravis in northern Europe
Authors: Boldingh Marion Ingeborg , Maniaol Angelina , Brunborg Cathrine , Dekker Luuk , Lipka Alexander , Niks Erik Harmen , Verschuuren Jan , Tallaksen Chantal
Published: September 2016

Introduction: Multiethnic studies can provide etiological clues toward the genetic and environmental influence of a disease. The aim of this study was to determine prevalence and clinical features of myasthenia gravis (MG) in immigrants compared with native patients in 2 population‐based cohorts. Methods: This cross‐sectional study included 843 MG patients (375 from Norway and 468 from the Netherlands). Ethnic background was defined by questionnaires. Results: Among the participating MG patients, 163 of 843 (19.3%) were first or second generation immigrants, mainly from Europe, Asia, and South America. No marked prevalence differences were found between immigrants and native ethnic groups. MG with muscle specific kinase antibodies and MG with thymoma were more frequent in Asian MG immigrants compared with other ethnic groups (8% vs. 0–4%; P < 0.001 and 21% vs. 6–10%; P < 0.001), respectively. Conclusions: Our findings indicate that Asian immigrant MG patients carry genetic factors or environmental/lifestyle factors which contribute to their specific phenotype, even after migration. Muscle Nerve 55: 819–827, 2017
A fully coupled method for massively parallel simulation of hydraulically driven fractures in 3‐dimensions
Authors: Settgast Randolph R. , Fu Pengcheng , Walsh Stuart D.C. , White Joshua A. , Annavarapu Chandrasekhar , Ryerson Frederick J.
Published: September 2016

This paper describes a fully coupled finite element/finite volume approach for simulating field‐scale hydraulically driven fractures in three dimensions, using massively parallel computing platforms. The proposed method is capable of capturing realistic representations of local heterogeneities, layering and natural fracture networks in a reservoir. A detailed description of the numerical implementation is provided, along with numerical studies comparing the model with both analytical solutions and experimental results. The results demonstrate the effectiveness of the proposed method for modeling large‐scale problems involving hydraulically driven fractures in three dimensions. © 2016 The Authors. International Journal for Numerical and Analytical Methods in Geomechanics published by John Wiley & Sons Ltd.
Network pricing problem with unit toll
Authors: Castelli Lorenzo , Labbé Martine , Violin Alessia
Published: September 2016

In the so‐called network pricing problem an authority owns some arcs of the network and tolls them, while users travel between their origin and destination choosing their minimum cost path. In this article, we consider a unit toll scheme, and in particular the cases where the authority is imposing either the same toll on all of its arcs, or a toll proportional to a given parameter particular to each arc (for instance a per kilometer toll). We show that if tolls are all equal then the complexity of the problem is polynomial, whereas in case of proportional tolls it is pseudo‐polynomial, proposing ad‐hoc solution algorithms and relating these problems to the parametric shortest path problem. We then address a robust approach using an interval representation to take into consideration uncertainty on parameters. We show how to modify the algorithms for the deterministic case to solve the robust counterparts, maintaining their complexity class. © 2016 Wiley Periodicals, Inc. NETWORKS, Vol. 69(1), 83–93 2017
Aberrant methylation of protocadherin 17 and its prognostic value in pediatric acute lymphoblastic leukemia
Authors: Uyen Thanh Nha , Sakashita Kazuo , Al‐Kzayer Lika'a Fasih Y. , Nakazawa Yozo , Kurata Takashi , Koike Kenichi
Published: September 2016

Background

The outcome of approximately 20% of patients with acute lymphoblastic leukemia (ALL) remains poor because of disease recurrence. We examined whether DNA methylation of cadherin superfamily genes is a useful biomarker for ALL relapse.

Procedure

We used Infinium Methylation 450K Arrays to assess genome‐wide DNA methylation status. The methylation status of each individual gene was then determined by a combination of bisulfite restriction analysis and genome bisulfite sequencing. mRNA expression was evaluated by reverse‐transcriptase PCR (RT‐PCR) and quantitative real‐time PCR.

Results

Cadherin superfamily genes including cadherin (CDH) 1, protocadherin (PCDH) 8, and PCDH17 were selected for analysis of methylation status. In 40 patient samples with B‐cell precursor (BCP) ALL at diagnosis, the methylation frequencies of CDH1, PCDH8, and PCDH17 were 62.5, 55, and 30%, respectively. CDH1 and PCDH8 methylation was also detected in 80 and 20% of control bone marrow (BM) samples, respectively. On the contrary, PCDH17 was unmethylated in all control BM samples. There was a significant correlation between the methylation status of PCDH17 (but not CDH1 and PCDH8) and event‐free survival or overall survival. Univariate and multivariate analyses showed that only PCDH17 methylation was associated with an increased risk for relapse and mortality in patients with BCP ALL.

Conclusion

PCDH17 methylation at diagnosis was closely related to poor prognosis and thus could be used as a new biomarker to predict relapse in patients with BCP ALL.
Atomic modeling of the ITS2 ribosome assembly subcomplex from cryo‐EM together with mass spectrometry‐identified protein–protein crosslinks
Authors: Wu Shan , Tan Dan , Woolford John L. , Dong Meng‐Qiu , Gao Ning
Published: September 2016

The assembly of ribosomal subunits starts in the nucleus, initiated by co‐transcriptional folding of nascent ribosomal RNA (rRNA) transcripts and binding of ribosomal proteins and assembly factors. The internal transcribed spacer 2 (ITS2) is a precursor sequence to be processed from the intermediate 27S rRNA in the nucleoplasm; its removal is required for nuclear export of pre‐60S particles. The proper processing of the ITS2 depends on multiple associated assembly factors and RNases. However, none of the structures of the known ITS2‐binding factors is available. Here, we describe the modeling of the ITS2 subcomplex, including five assembly factors Cic1, Nop7, Nop15, Nop53, and Rlp7, using a combination of cryo‐electron microscopy and cross‐linking of proteins coupled with mass spectrometry approaches. The resulting atomic models provide structural insights into their function in ribosome assembly, and establish a framework for further dissection of their molecular roles in ITS2 processing.
Substitutions in Spodoptera exigua topoisomerase I modulate its relaxation activity and camptothecin sensitivity
Authors: Zhang Pei , Zhang Lan , Zhang Yanning , Mao Liangang , Jiang Hongyun
Published: September 2016

BACKGROUND

Topoisomerase I (Top I) is referred as the cellular target of the camptothecins (CPTs) which are now being explored as potential pesticides for insect control. Three amino acid substitutions, including L530P, A653T and S729T, in Top Is of insects were found in our previous studies. In order to investigate the effect of these three substitutions, a comparative analysis was conducted between the wild‐type and mutant Top Is in Spodoptera exigua Hübner.

RESULTS

The optimal salt concentration of A653T and S729T was 150 mm, which is consistent with that of the wild‐type Top I, while the mutant L530P showed maximum relaxation activity at a lower KCl concentration (100 mm). The mutated L530P and A653T Top Is showed a higher relaxation efficiency owing to an increased relaxation velocity toward the negatively supercoiled plasmid pBR322 DNA, which rendered L530P and A653T resistant to CPTs, whereas mutant S729T exhibited sensitivity to CPTs as a result of a decreased relaxation activity toward plasmid pBR322 DNA.

CONCLUSIONS

These results suggested that the polymorphism in Top I of insects was related to the biological activity of CPTs, which provided the basic information for reasonable usage of CPTs to control insect pests. © 2016 Society of Chemical Industry
Generation of gas‐phase ions from charged clusters: an important ionization step causing suppression of matrix and analyte ions in matrix‐assisted laser desorption/ionization mass spectrometry
Authors: Lou Xianwen , van Dongen Joost L.J. , Milroy Lech‐Gustav , Meijer E.W.
Published: September 2016

Rationale

Ionization in matrix‐assisted laser desorption/ionization mass spectrometry (MALDI‐MS) is a very complicated process. It has been reported that quaternary ammonium salts show extremely strong matrix and analyte suppression effects which cannot satisfactorily be explained by charge transfer reactions. Further investigation of the reasons causing these effects can be useful to improve our understanding of the MALDI process.

Methods

The dried‐droplet and modified thin‐layer methods were used as sample preparation methods. In the dried‐droplet method, analytes were co‐crystallized with matrix, whereas in the modified thin‐layer method analytes were deposited on the surface of matrix crystals. Model compounds, tetrabutylammonium iodide ([N(Bu)4]I), cesium iodide (CsI), trihexylamine (THA) and polyethylene glycol 600 (PEG 600), were selected as the test analytes given their ability to generate exclusively pre‐formed ions, protonated ions and metal ion adducts respectively in MALDI.

Results

The strong matrix suppression effect (MSE) observed using the dried‐droplet method might disappear using the modified thin‐layer method, which suggests that the incorporation of analytes in matrix crystals contributes to the MSE. By depositing analytes on the matrix surface instead of incorporating in the matrix crystals, the competition for evaporation/ionization from charged matrix/analyte clusters could be weakened resulting in reduced MSE. Further supporting evidence for this inference was found by studying the analyte suppression effect using the same two sample deposition methods.

Conclusions

By comparing differences between the mass spectra obtained via the two sample preparation methods, we present evidence suggesting that the generation of gas‐phase ions from charged matrix/analyte clusters may induce significant suppression of matrix and analyte ions. The results suggest that the generation of gas‐phase ions from charged matrix/analyte clusters is an important ionization step in MALDI‐MS. Copyright © 2016 John Wiley & Sons, Ltd.
Development and Evaluation of Different Methods for Preparation of Fluorine‐Containing (R)‐ and (S)‐N‐tert‐Butanesulfinyl–aldimines
Authors: Xie Chen , Zhang Lijun , Mei Haibo , Han Jianlin , Soloshonok Vadim A. , Pan Yi
Published: September 2016

This work is solely focused on the development of optimized procedures for preparation of various (S)‐N‐tert‐butanesulfinyl‐aldimines bearing CHF2, CClF2, CBrF2, CIF2, C2F5, C3F7, C4F9, C4HF8, C5F11 and C6HF12 groups, synthetically valuable reagents for preparation of fluorinated amino‐compounds of high pharmaceutical potential.
Unexpected Diversity within Solid‐State Structures of Methanetrisulfonate Salts
Authors: Oelkers Benjamin , Schaffner Dirk , Sun Yu
Published: September 2016

The structural properties of various salts of methanetrisulfonic acid (H3mts) are described, spanning the free acid, ammonium and alkali metals (Na, K, Cs), first row transition metals (Cr, Co−Zn), and lead. A number of different coordination modes is found, including unexpected motifs such as the κ3O1,4,7 coordination in the lead salt and anions of the type [M(H2O)4(κ2O1,4‐mts)]− (M=Co, Ni, Zn), which do not seem to be persistent in aqueous solution.
A Lysophosphatidic Acid Receptors 1 and 3 Axis Governs Cellular Senescence of Mesenchymal Stromal Cells and Promotes Growth and Vascularization of Multiple Myeloma
Authors: Kanehira Masahiko , Fujiwara Tohru , Nakajima Shinji , Okitsu Yoko , Onishi Yasushi , Fukuhara Noriko , Ichinohasama Ryo , Okada Yoshinori , Harigae Hideo
Published: September 2016

Mesenchymal stromal cells (MSCs) are multipotent progenitor cells and there is much interest in how MSCs contribute to the regulation of the tumor microenvironment. Whether MSCs exert a supportive or suppressive effect on tumor progression is still controversial, but is likely dependent on a variety of factors that are tumor-type dependent. Multiple myeloma (MM) is characterized by growth of malignant plasma cells in the bone marrow. It has been shown that the progression of MM is governed by MSCs, which act as a stroma of the myeloma cells. Although stroma is created via mutual communication between myeloma cells and MSCs, the mechanism is poorly understood. Here we explored the role of lysophosphatidic acid (LPA) signaling in cellular events where MSCs were converted into either MM-supportive or MM-suppressive stroma. We found that myeloma cells stimulate MSCs to produce autotaxin, an indispensable enzyme for the biosynthesis of LPA, and LPA receptor 1 (LPA1) and 3 (LPA3) transduce opposite signals to MSCs to determine the fate of MSCs. LPA3-silenced MSCs (siLPA3-MSCs) exhibited cellular senescence-related phenotypes in vitro, and significantly promoted progression of MM and tumor-related angiogenesis in vivo. In contrast, siLPA1-MSCs showed resistance to cellular senescence in vitro, and efficiently delayed progression of MM and tumor-related angiogenesis in vivo. Consistently, anti-MM effects obtained by LPA1-silencing in MSCs were completely reproduced by systemic administration of Ki6425, an LPA1 antagonist. Collectively, our results indicate that LPA signaling determines the fate of MSCs and has potential as a therapeutic target in MM.
Reactive Oxygen Species Impair the Function of CD90+ Hematopoietic Progenitors Generated from Human Pluripotent Stem Cells
Authors: Rönn Roger E. , Guibentif Carolina , Saxena Shobhit , Woods Niels-Bjarne
Published: September 2016

Cell stressors, such as elevated levels of reactive oxygen species (ROS), adversely affect hematopoietic stem cell (HSC) reconstituting ability. However, the effects of ROS have not been evaluated in the context of hematopoietic development from human pluripotent stem cells (hPSCs). Using our previously described in vitro system for efficient derivation of hematopoietic cells from hPSCs, we show that the vast majority of generated hematopoietic cells display supraphysiological levels of ROS compared to fresh cord blood cells. Elevated ROS resulted in DNA damage of the CD34+ hematopoietic fraction and, following functional assays, reduced colony formation and impaired proliferative capacity. Interestingly, all the proliferative potential of the most primitive hematopoietic cells was limited to a small fraction with low ROS levels. We show that elevation of ROS in hPSC-derived hematopoietic cells is contributed by multiple distinct cellular processes. Furthermore, by targeting these molecular processes with 4 unique factors, we could reduce ROS levels significantly, yielding a 22-fold increase in the most primitive CD90+ CD34+ hematopoietic cells with robust growth capacity. We demonstrate that the ROS reducing factors specifically reduced ROS in more primitive hematopoietic fractions, in contrast to endothelial cells that maintained low ROS levels in the cultures. We conclude that high levels of ROS in in vitro differentiation systems of hPSCs is a major determinant in the lack of ability to generate hematopoietic cells with similar proliferation/differentiation potential to in vivo hematopoietic progenitors, and suggest that elevated ROS is a significant barrier to generating hPSC-derived repopulating HSCs.
Progressive lesions of central nervous system in microcephalic fetuses with suspected congenital Zika virus syndrome
Authors: Sarno M. , Aquino M. , Pimentel K. , Cabral R. , Costa G. , Bastos F. , Brites C.
Published: September 2016

Objective

To describe the pattern and progression of central nervous system (CNS) lesions in microcephalic fetuses with suspected Zika virus (ZIKV) infection.

Methods

In this prospective study in Salvador, Brazil, we analyzed fetuses diagnosed with microcephaly and suspected ZIKV infection after a routine primary care ultrasound scan between July 2015 and February 2016 raised suspicion of fetal microcephaly. The pregnancies were followed with serial ultrasound scans until delivery at one of the three main referral centers for fetal abnormalities in Salvador, Brazil. Microcephaly was diagnosed when the head circumference was two or more SDs below the mean for gestational age and its relationship with ZIKV infection was defined according to the World Health Organization's criteria. All women were interviewed, to assess potential factors associated with fetal microcephaly. Serology test results for toxoplasmosis, cytomegalovirus, rubella, syphilis and human immunodeficiency virus (HIV) were recorded, as were previous routine ultrasound results. Signs/symptoms of infection during the pregnancy were noted.

Results

Of 60 cases of suspected ZIKV‐related fetal microcephaly seen during the study period, eight were excluded due to serological evidence of other congenital infections or major ultrasound chromosomal markers. In the remaining 52 fetuses, microcephaly was diagnosed between 19 and 40 (median, 27.7; interquartile range, 23.4–32.0) weeks of gestation. The main ultrasound findings were: ventriculomegaly (65.4% of cases), cerebral calcifications (44.2%) and posterior fossa abnormalities (32.7%). 9.6% presented with arthrogryposis as an associated finding. Microcephaly was an isolated finding in four cases (7.7%). While ventriculomegaly was progressive in 41.2% of cases with this finding, the velocity of head circumference increase decreased progressively in almost all cases. Exanthematic disease was present in the majority (86.5%) of the women, 67.3% presenting in the first trimester of pregnancy. Additional lesions were detected after birth in 71.4% of the 35 cases with neonatal follow‐up.

Conclusions

The majority of cases of congenital ZIKV syndrome have other ultrasonographic findings in addition to microcephaly. ZIKV‐related CNS anomalies present mainly as progressive CNS lesions and slowing rate of growth of the fetal head, and this seems to be evident only in the late second trimester, even when maternal infection occurs in the first trimester. Other ultrasound findings, such as ventriculomegaly, brain calcifications and posterior fossa destruction lesions, are also common in this congenital syndrome. Posterior fossa destruction lesions and arthrogryposis are an uncommon finding in other congenital infections, perhaps suggesting a novel severe congenital syndrome associated with fetal ZIKV. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.
Is curved three‐dimensional ultrasound reconstruction needed to assess the warped pelvic floor plane?
Authors: Youssef A. , Cavalera M. , Pacella G. , Salsi G. , Morganelli G. , Montaguti E. , Cataneo I. , Pilu G. , Rizzo N.
Published: September 2016

Objectives

Caudal distension of the female pelvic floor is common and results in perineal descent and a caudally curved levator hiatus (warping). Image reconstruction of the pelvic floor using currently available ultrasound techniques involves a linear approach (flat‐plane reconstruction). We aimed to evaluate the feasibility, reproducibility and potential usefulness of a new three‐dimensional (3D) technique capable of reconstructing a curved plane of the levator hiatus.

Methods

Primiparous women were recruited to undergo a 3D/four‐dimensional transperineal ultrasound examination 3–6 months after delivery. Levator ani muscle warping was evaluated on Valsalva maneuver by measuring the distance between the plane extending from the pubic rami to the anorectal angle and the plane of minimal hiatal dimensions on the coronal plane. Warping distance was used to reconstruct a curved plane of the levator hiatus using the curved OmniView volume contrast imaging (VCI) technique (C‐OV). Intra‐ and interobserver reproducibility of the C‐OV technique were assessed, as was intermethod agreement between the C‐OV technique and the linear OmniView‐VCI (L‐OV) technique, for the measurement of levator hiatal area on Valsalva maneuver.

Results

Measurement of the levator hiatal area using C‐OV was feasible in all 84 women recruited. The warping distance ranged from −3.5 to 9.7 mm, confirming that the 1–2‐cm slice thickness traditionally used for linear reconstruction was adequate for proper assessment of levator hiatal area in our population. C‐OV showed excellent intra‐ and interobserver reproducibility, as well as excellent agreement with the L‐OV technique for measuring levator hiatal area. No systematic difference was demonstrated in any of the reproducibility studies performed.

Conclusions

3D reconstruction of the warped levator hiatal plane is feasible and highly reproducible. In our population, reconstruction of a curved plane to correct for levator hiatal warping did not offer any benefit over the traditionally performed linear reconstruction. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.
Diagnostic accuracy of midtrimester antenatal ultrasound for multicystic dysplastic kidneys
Authors: Scala C. , McDonnell S. , Murphy F. , Leone Roberti Maggiore U. , Khalil A. , Bhide A. , Thilaganathan B. , Papageorghiou A. T.
Published: September 2016

Objectives

To establish the diagnostic accuracy of obstetric ultrasound at a tertiary fetal medicine center in the prenatal detection of unilateral and bilateral multicystic dysplastic kidney (MCDK) in fetuses in which this condition was suspected, and to undertake a systematic review of the relevant literature.

Methods

This was a retrospective observational study of all cases referred to a regional tertiary fetal medicine unit due to suspicion of either unilateral or bilateral MCDK between 1997 and 2015. Diagnosis was confirmed by postnatal ultrasound reports or postmortem examination. The accuracy of prenatal ultrasound in the diagnosis of MCDK was calculated. Using a systematic search strategy we also performed a review of the literature regarding the prenatal diagnosis and diagnostic accuracy of MCDK.

Results

We included 144 women in our analysis; 37 (25.7%) opted for pregnancy termination (TOP) (due to unilateral MCDK with additional abnormalities, suspected bilateral MCDK or severe obstructive uropathy). Complete pre‐ and postnatal data were available in 126 pregnancies, including 104 livebirths, 19 TOPs with postmortem findings available and three intrauterine fetal deaths. Two infants died shortly after birth (due to known bilateral MCDK or known cranial vault defect). The overall number of cases of MCDK confirmed postnatally was 100; of these, 98 were diagnosed prenatally (true positive), while two were thought to be hydronephrosis prenatally (false negative) and the diagnosis of MCDK was made after birth. In nine cases, the initial antenatal diagnosis of suspected MCDK was revised, either later in pregnancy (n = 2) or postnatally (n = 7) (false positive). Overall, the diagnostic accuracy in our population for the use of antenatal ultrasound to detect MCDK was 91.3%, while that reported in the existing literature was found to range from 53.3% to 100%. MCDK was isolated in the majority (71%) of cases, while in 29% of cases it was found to be associated with other renal and extrarenal fetal abnormalities.

Conclusions

Antenatal ultrasound had a diagnostic accuracy of about 91% in the prediction of postnatal MCDK and can therefore be used to guide antenatal counseling. However, prenatal or postnatal revision of the diagnosis occurred in about 7% of cases and parents should be counseled appropriately. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.
Ankle Reconstruction in Fibular Hemimelia: New Approach
Authors: Hefny Hany , Elmoatasem ElHussein M. , Mahran Mahmoud , Fayyad Tamer , Elgebeily Mohamed A. , Mansour Ahmed , Hefny Mamdouh
Published: September 2016

Background

Fibular hemimelia is a congenital disorder that is characterized by the absence of the fibula that could be either partial or complete. Successful management aims to restore normal weight bearing and normal limb length. The introduction of the Ilizarov method of limb lengthening has provided an attractive alternative to amputation. During lengthening, the tight posterolateral soft-tissue structures, the thick fibrous fibular band, and the shortened Achilles tendon become tighter and transfer a valgus force to the talus and calcaneus, further aggravating the deformity.

Questions/Purposes

We have developed a strategy to address this in patients with Paley type III fibular hemimelia via ankle reconstruction that provides posterolateral stability and buttressing of the ankle and hind foot by reconstructing the lateral buttress. This is achieved through excision of the fibrous fibular anlage, centralization of the ankle, restoring talocalcaneal coronal alignment, and reconstruction of the lateral malleolus by transplanting the cartilaginous remnant of the lateral malleolus or by crafting a bone block autograft taken from the iliac crest or tibia.

Methods

A prospective non-randomized clinical trial included ten ankles in eight patients with fibular hemimelia Paley type III (two patients had bilateral deformity). The patients’ ages ranged from 7 to 36 months.

Results

After a follow-up ranging from 48 to 96 months, a stable plantigrade foot was achieved in nine ankles; one ankle had residual equinus, five ankles had residual valgus heel, and eight ankles had complete range of motion of the ankle, whereas one patient lost 5° of dorsiflexion. One ankle had equinus deformity.

Conclusions

To achieve satisfactory results, a stable plantigrade foot and ankle is necessary in patients with fibular hemimelia before attempting to equalize limb length discrepancy. It is important to reconstruct the ankle through an extra-articular soft tissue release, anlage resection, osteotomies, and restoring the abnormal talocalcaneal relationship before any attempt to equalize LLD.
Akzeptanz als Rahmenbedingung für das erfolgreiche Management von Landnutzungen und biologischer Vielfalt in Großschutzgebieten
Authors: Ruschkowski Eick von , Nienaber Birte
Published: September 2016

Local acceptance and the resolution of conflicts that arise from conservation objectives are important tasks for the successful management of large protected areas. This paper focuses on the distinct genesis of acceptance research for German large protected areas compared to the global context where the comprehensive term “park-people relationships” prevails. Using multiple tasks and roles assigned to national parks and biosphere reserves, we illustrate the overall diversity of conflict potential. Four explorative case studies, based on media analysis and selected expert interviews, are used to elaborate on the individual local conditions that foster conflict or co-existence in Germany. Berchtesgaden National Park is currently mainly free of conflicts, but unforeseen events such as barkbeetle infestations could unsettle the situation. On the contrary, private land ownership and conflicts over zoning in the Senne-Teutoburger Wald-Eggegebirge region have halted plans to establish a national park. In the Bliesgau Biosphere Reserve, conflicts arose around conflicting land uses and overlapping planning responsibilities during the designation process, while in the Pfälzerwald Biosphere Reserve region, the development of renewable energies – mainly wind turbines – have shown to bear a specific conflict potential. The paper concludes with suggestions related to spatial and environmental planning, such as widening the mainly local focus on “acceptance” to active stakeholder management, including integrated, adaptive management approaches, in the sense of the term park-people relationships.
Carbonates and sources of fluids in ores and metasomatites of the Ermakovka fluorite-bertrandite-phenacite deposit (western Transbaikalia)
Authors: Ripp G.S. , Izbrodin I.A. , Doroshkevich A.G. , Rampilov M.O. , Lastochkin E.I. , Posokhov V.F.
Published: September 2016

We present results of isotope-geochemical study of the Ermakovka F–Be deposit, including data on the oxygen and carbon isotope compositions in dolomite and calcite marbles and in carbonates accompanying skarns, of early and late stages of ore formation and of post-ore parageneses. To elucidate the sources of fluids participated in the ore formation, we calculated the oxygen isotope composition in water and the hydrogen isotope composition in hydroxyl-containing minerals. Phlogopite in marbleized dolomites, vesuvianite and amphibole in skarns, eudidimite and bertrandite in ore parageneses, and bavenite formed during post-ore processes are analyzed. Most of the ore-stage minerals are depleted in heavy oxygen. Their δ18O values are lower than 5–6‰ (SMOW). Oxygen in carbonate minerals of the initial stage (dolomite and bastnaesite) is heavier (1.3–4.9‰) than that in calcite (+ 2 to –3.7‰). The δ18O values of water in equilibrium both with carbonate and with silicate minerals (–4 to –14‰) suggest the contribution of meteoric water to the mineral formation. A magmatic fluid (δ18O from + 6 to + 9‰) participated in the skarn formation at the initial stage, and a meteoric fluid, at the final stage (δ18O from –1 to –9‰). A meteoric source is confirmed by the depleted hydrogen isotope composition in minerals (δD from –119 to –192‰).
G/G/∞ queues with renewal alternating interruptions
Authors: Pang Guodong , Zhou Yuhang
Published: September 2016

We study G/G/∞ queues with renewal alternating service interruptions, where the service station experiences `up' and `down' periods. The system operates normally in the up periods, and all servers stop functioning while customers continue entering the system during the down periods. The amount of service a customer has received when an interruption occurs will be conserved and the service will resume when the down period ends. We use a two-parameter process to describe the system dynamics:Xr(t,y) tracking the number of customers in the system at timetthat have residual service times strictly greater thany. The service times are assumed to satisfy either of the two conditions: they are independent and identically distributed with a distribution of a finite support, or are a stationary and weakly dependent sequence satisfying the ϕ-mixing condition and having a continuous marginal distribution function. We consider the system in a heavy-traffic asymptotic regime where the arrival rate gets large and service time distribution is fixed, and the interruption down times are asymptotically negligible while the up times are of the same order as the service times. We show the functional law of large numbers and functional central limit theorem (FCLT) for the processXr(t,y) in this regime, where the convergence is in the space 𝔻([0,∞), (𝔻,L1)) endowed with the SkorokhodM1topology. The limit processes in the FCLT possess a stochastic decomposition property.
On the relation between graph distance and Euclidean distance in random geometric graphs
Authors: Díaz J. , Mitsche D. , Perarnau G. , Pérez-Giménez X.
Published: September 2016

Given any two vertices u, v of a random geometric graph G(n, r), denote by dE(u, v) their Euclidean distance and by dE(u, v) their graph distance. The problem of finding upper bounds on dG(u, v) conditional on dE(u, v) that hold asymptotically almost surely has received quite a bit of attention in the literature. In this paper we improve the known upper bounds for values of r=ω(√logn) (that is, for r above the connectivity threshold). Our result also improves the best known estimates on the diameter of random geometric graphs. We also provide a lower bound on dE(u, v) conditional on dE(u, v).
Degrees and distances in random and evolving apollonian networks
Authors: Kolossváry István , Komjáthy; Júlia , Vágó Lajos
Published: September 2016

In this paper we study random Apollonian networks (RANs) and evolving Apollonian networks (EANs), in d dimensions for any d≥2, i.e. dynamically evolving random d-dimensional simplices, looked at as graphs inside an initial d-dimensional simplex. We determine the limiting degree distribution in RANs and show that it follows a power-law tail with exponent τ=(2d-1)/(d-1). We further show that the degree distribution in EANs converges to the same degree distribution if the simplex-occupation parameter in the nth step of the dynamics tends to 0 but is not summable in n. This result gives a rigorous proof for the conjecture of Zhang et al. (2006) that EANs tend to exhibit similar behaviour as RANs once the occupation parameter tends to 0. We also determine the asymptotic behaviour of the shortest paths in RANs and EANs for any d≥2. For RANs we show that the shortest path between two vertices chosen u.a.r. (typical distance), the flooding time of a vertex chosen uniformly at random, and the diameter of the graph after n steps all scale as a constant multiplied by log n. We determine the constants for all three cases and prove a central limit theorem for the typical distances. We prove a similar central limit theorem for typical distances in EANs.
HOW ACCURATELY DOES 70% FINAL EMPLOYMENT EARNINGS REPLACEMENT MEASURE RETIREMENT INCOME (IN)ADEQUACY? INTRODUCING THE LIVING STANDARDS REPLACEMENT RATE (LSRR)
Authors: MacDonald Bonnie-Jeanne , Osberg Lars , Moore Kevin D.
Published: September 2016

Will 70% of a worker's final annual employment earnings sustain living standards after retirement? Despite increasing skepticism, the most dominant measure of retirement income adequacy by financial planners, pensions plan advisors, academics and public policy makers is the “final employment earnings replacement rate”, where 70% is considered the right target to ensure living standards remain at approximately the same level after retirement. Using Statistics Canada's LifePaths dynamic population micro-simulation model, this paper asks whether those individuals from the 1951–1958 Canadian birth cohort who attain roughly a 70% final employment earnings replacement rate (as conventionally measured) at retirement do, in fact, achieve approximate continuity in their living standards. We find that the conventional final earnings replacement rate measure has little predictive value for living standards continuity between working-life and retirement. The primary reason is that employment earnings in a single year is not a reliable representation of a worker's standard of living — it relies on an inadequate pre-retirement measurement period, does not incorporate important components of consumption sources (such as home equity), and ignores household size (particularly children). As a result, we find that the correlation between the conventional earnings replacement rate and actual living standards continuity is relatively low (0.11). The paper therefore suggests an alternative metric for assessing how well a worker's living standard is maintained after retirement — i.e., the Living Standards Replacement Rate, or the LSRR. The LSRR provides a more accurate, understandable and consistent measure of retirement income adequacy.