bluuebunny/crossref_metadata_2025 huggingface dataset:
Arterial and venous thrombosis of the cerebral vasculature in GAPO syndrome
Authors: Zeydan Burcu , Benbir Gulcin , Uluduz Derya , Ince Birsen , Goksan Baki , Islak Civan
Published: March 2014

A 37‐year‐old male, previously diagnosed with GAPO syndrome, was admitted to our hospital complaining of recurrent episodes of transient weakness and numbness in his left arm for 3 months, and severe headache with progressive dysphagia for 15 days. His cranial magnetic resonance (MR) images showed multiple ischemic foci in the bilateral periventricular and supraventricular white matter. Cerebral MR‐angiography showed total occlusion of the right internal carotid artery and moderate stenosis in the left internal carotid. We also detected chronic thrombotic changes in the distal left sigmoid sinus, proximal right sigmoid sinus, and bilateral jugular veins on cerebral MR‐venography. He was diagnosed with dilated cardiomyopathy at age 31 years, which was reported as a novel association; and later he had a myocardial infarction at age 34 years. To the best of our knowledge, this is the first patient with GAPO syndrome and arterial atherosclerosis in cerebral—as well as coronary—arteries and intracranial venous thrombosis. We report the evolution of the disease in this patient, who died at age 38 years due to respiratory failure secondary to lower respiratory tract infection. © 2014 Wiley Periodicals, Inc.
Phenotype of a patient with contiguous deletion of TBX5 and TBX3: Expanding the disease spectrum
Authors: Bogarapu Soujanya , Bleyl Steven B. , Calhoun Amy , Viskochil David , Saarel Elizabeth V. , Everitt Melanie D. , Frank Deborah U.
Published: March 2014

The important roles that T‐box genes play in the morphogenesis of the heart and its conduction system has long been established, and a number of disorders are linked to mutations in these T‐box genes. Holt–Oram syndrome (HOS), the classic heart and hand syndrome, is clinically typified by radial ray upper limb abnormalities and cardiac malformations, and is caused by mutations involving TBX5. Another member of the T‐box gene family, TBX3, is found in close proximity to TBX5 on chromosome 12q24. Mutations in TBX3 cause ulnar–mammary syndrome (UMS), which is distinguished by upper limb malformations affecting the ulnar ray, apocrine, and mammary gland hypoplasia, and genital defects. While disorders involving isolated mutations of TBX5 and TBX3 have been well described, contiguous deletions of these T‐box genes remain exceptional. We report on a patient with features of both HOS and UMS consisting of bilateral symmetric limb malformations, congenital cardiac defects, and rapidly progressive cardiac conduction disease. © 2014 Wiley Periodicals, Inc.
Modeling AEC—New approaches to study rare genetic disorders
Authors: Koch Peter J. , Dinella Jason , Fete Mary , Siegfried Elaine C. , Koster Maranke I.
Published: March 2014

Ankyloblepharon‐ectodermal defects‐cleft lip/palate (AEC) syndrome is a rare monogenetic disorder that is characterized by severe abnormalities in ectoderm‐derived tissues, such as skin and its appendages. A major cause of morbidity among affected infants is severe and chronic skin erosions. Currently, supportive care is the only available treatment option for AEC patients. Mutations in TP63, a gene that encodes key regulators of epidermal development, are the genetic cause of AEC. However, it is currently not clear how mutations in TP63 lead to the various defects seen in the patients' skin. In this review, we will discuss current knowledge of the AEC disease mechanism obtained by studying patient tissue and genetically engineered mouse models designed to mimic aspects of the disorder. We will then focus on new approaches to model AEC, including the use of patient cells and stem cell technology to replicate the disease in a human tissue culture model. The latter approach will advance our understanding of the disease and will allow for the development of new in vitro systems to identify drugs for the treatment of skin erosions in AEC patients. Further, the use of stem cell technology, in particular induced pluripotent stem cells (iPSC), will enable researchers to develop new therapeutic approaches to treat the disease using the patient's own cells (autologous keratinocyte transplantation) after correction of the disease‐causing mutations. © 2014 Wiley Periodicals, Inc.
The intellectual disabilities evaluation and advice system (IDEAS): Outcome of the first 55 cases
Authors: Hunter Alasdair G.W. , Graham John M. , Neri Giovanni , Rogers R. Curtis , Stevenson Roger E. , Turner Gillian , Friez Michael J.
Published: March 2014

IDEAS (intellectual disabilities evaluation and advice system) provides the opportunity for physicians who are sending samples for the Greenwood Genetic Center (GGC) 92‐gene X‐linked intellectual disability (XLID) (formerly X‐linked mental retardation) panel to have their male patient's clinical features reviewed by an experienced panel of six Clinical Geneticists. They were asked to obtain parental consent, complete a one‐page information form, and provide A–P and lateral photographs. The panel members independently reviewed the material and forwarded comments about clinical features, possible diagnoses, and/or further testing for the patient. We present the results of the first 55 patients evaluated. In only a single case did all panelists agree on a non‐XLID diagnosis, later proven by genetic testing. The XLID gene panel diagnosed an additional five (9%) cases, but in only two cases did one panelist suggest the correct gene, which was one of four they suggested. This paper examines the possible reasons for the low rate of clinical diagnosis and suggests that, while the data received were often incomplete, the most important reasons for lack of diagnoses were the source of referral and selection of patients for review. We did note that there were a number of instances where we disagreed with the submitted information as to whether the individual was dysmorphic and with the stated presence of certain physical signs, most often downslanted palpebrae and posterior ear angulation. These differences in assessment of clinical signs and the general lack of completeness and detail provided in the standard data sheet, including that regarding the extended family history, lead us to raise concerns regarding the feasibility of establishing high quality central clinical databases designed to aid in the interpretation of exomic/genomic variants. © 2014 Wiley Periodicals, Inc.
Outfoxed by RBFOX1‐A caution about ascertainment bias
Authors: Kamien Benjamin , Lionel Anath C. , Bain Nicole , Scherer Stephen W. , Hunter Matthew
Published: March 2014

We report on two patients with intragenic deletions of RBFOX1 and one patient with an intragenic duplication of RBFOX1. These patients, by report, all had autism spectrum disorder and/or developmental delay and had strong family histories of these conditions. We initially hypothesized that RBFOX1 was another susceptibility locus for autism spectrum disorder or developmental delay. However, epidemiological evidence examining large numbers of individuals did not support this hypothesis and the data presented here suggests that RBFOX1 intragenic copy number variants are not pathogenic. This contradicts previous reports that examined smaller numbers of patients and controls. © 2014 Wiley Periodicals, Inc.
Chromosomal rearrangements in patients with clinical features of Silver–Russell syndrome
Authors: Fokstuen Siv , Kotzot Dieter
Published: March 2014

Silver–Russell syndrome (SRS) is characterized by pre‐ and postnatal growth retardation, relative macrocephaly, asymmetry, and a triangular facial gestalt. In 5–10% of the patients the phenotype is caused by maternal UPD 7, and 38–64% of the patients present with hypomethylation at the imprinting center region 1 (ICR1) on 11p15.5. The etiology of the remaining cases is so far not known and various (sub‐)microscopic chromosome aberrations with a phenotype resembling SRS have been published, especially duplication 11p15 (n = 15), deletion 12q14 (n = 19), ring chromosome 15, deletion 15qter, and various other mostly unique chromosomal aberrations (n = 30). In this study the phenotypes of these chromosomal aberrations were revisited and compared with the phenotypes of maternal UPD 7 and hypomethylation at ICR1 on 11p15.5. In some patients with a unique chromosomal aberration even the hallmarks of SRS were missing. Patients with duplication 11p15 show a more variable occipitofrontal head circumference at birth, a higher frequency of intellectual disability, and additional anomalies not reported in SRS. Deletion 12q14 is characterized by less severe pre‐ and postnatal growth retardation and less impressive relative macrocephaly. Patients with ring chromosome 15 and deletion 15qter have no relative macrocephaly (mostly even microcephaly) and more severe intellectual disability. Finally, deletion 15qter lacks the triangular facial gestalt. In summary, as SRS seems not an adequate diagnosis in many of these patients, diagnosis should focus on the chromosomal aberration than on SRS. © 2014 Wiley Periodicals, Inc.
Lymphedema in tuberous sclerosis complex
Authors: Geffrey Alexandra L. , Shinnick Julianna E. , Staley Brigid A. , Boronat Susana , Thiele Elizabeth A.
Published: March 2014

Congenital lymphedema has been described as a possible rare association of tuberous sclerosis complex (TSC), with only six previous cases reported in the literature. TSC is an autosomal dominant, multisystem disorder connected to aberrant regulation of the mammalian target of rapamycin (mTOR) pathway. The aim of this study is to review cases of lymphedema in a large cohort of TSC patients. The medical records of 268 patients seen at The Herscot Center for Children and Adults with Tuberous Sclerosis Complex at the Massachusetts General Hospital from 2002 to 2012 were retrospectively reviewed for reports of lymphedema or edema of unknown etiology. Genotypic and phenotypic data were collected in accordance with institutional review board (IRB) approval. This cohort presents two new cases of congenital lymphedema in TSC patients and acquired lymphedema was found in eight additional cases. Thus, we report 10 new cases of lymphedema in TSC (4%). The two patients with congenital lymphedema were female, as were the previous six reported cases. The frequency of lymphedema reported here (4%) is higher than the estimated prevalence in the general population (0.133–0.144%), suggesting a higher frequency of lymphedema in TSC. This study shows that patients with TSC and lymphedema are more likely to be females with renal AMLs and suggests that congenital lymphedema is a gender‐specific (female) manifestation of TSC. Exploration of the potential role of mTOR antagonists may be important in treatment of lymphedema in TSC patients. © 2014 Wiley Periodicals, Inc.
Craniofacial and dental development in Costello syndrome
Authors: Goodwin Alice F. , Oberoi Snehlata , Landan Maya , Charles Cyril , Massie Jessica C. , Fairley Cecilia , Rauen Katherine A. , Klein Ophir D.
Published: March 2014

Costello syndrome (CS) is a RASopathy characterized by a wide range of cardiac, musculoskeletal, dermatological, and developmental abnormalities. The RASopathies are defined as a group of syndromes caused by activated Ras/mitogen‐activated protein kinase (MAPK) signaling. Specifically, CS is caused by activating mutations in HRAS. Although receptor tyrosine kinase (RTK) signaling, which is upstream of Ras/MAPK, is known to play a critical role in craniofacial and dental development, the craniofacial and dental features of CS have not been systematically defined in a large group of individuals. In order to address this gap in our understanding and fully characterize the CS phenotype, we evaluated the craniofacial and dental phenotype in a large cohort (n = 41) of CS individuals. We confirmed that the craniofacial features common in CS include macrocephaly, bitemporal narrowing, convex facial profile, full cheeks, and large mouth. Additionally, CS patients have a characteristic dental phenotype that includes malocclusion with anterior open bite and posterior crossbite, enamel hypo‐mineralization, delayed tooth development and eruption, gingival hyperplasia, thickening of the alveolar ridge, and high palate. Comparison of the craniofacial and dental phenotype in CS with other RASopathies, such as cardio‐facio‐cutaneous syndrome (CFC), provides insight into the complexities of Ras/MAPK signaling in human craniofacial and dental development. © 2014 Wiley Periodicals, Inc.
Novel FBN1 gene mutation and maternal germinal mosaicism as the cause of neonatal form of Marfan syndrome
Authors: Šípek Antonín , Grodecká Lucie , Baxová Alice , Cibulková Petra , Dvořáková Magdaléna , Mazurová Stella , Magner Martin , Zeman Jiří , Honzík Tomáš , Freiberger Tomáš
Published: March 2014

Marfan syndrome (MFS) is an autosomal dominant disorder caused by mutations in the fibrillin 1 gene (FBN1). Neonatal form of MFS is rare and is associated with severe phenotype and a poor prognosis. We report on a newborn girl with neonatal MFS who displayed cyanosis and dyspnea on the first day of life. The main clinical features included mitral and tricuspid valve insufficiency, aortic root dilatation, arachnodactyly, and loose skin. Despite the presence of severe and inoperable heart anomalies, the girl was quite stable on symptomatic treatment and lived up to the 7th month of age when she died due to cardiorespiratory failure. Molecular‐genetic studies revealed a novel intronic c.4211‐32_‐13del mutation in the FBN1 gene. Subsequent in vitro splicing analysis showed this mutation led to exon 35 skipping, presumably resulting in a deletion of 42 amino acids (p.Leu1405_Asp1446del). Interestingly, this mutation is localized outside the region of exons 24–32, whose mutation is responsible for the substantial majority of cases of neonatal MFS. Although the family history of MFS was negative, the subsequent molecular genetic examination documented a mosaicism of the same mutation in the maternal blood cells (10–25% of genomic DNA) and the detailed clinical examination showed unilateral lens ectopy. © 2014 Wiley Periodicals, Inc.
Mutation spectrum of COL1A1 and COL1A2 genes in Indian patients with osteogenesis imperfecta
Authors: Stephen Joshi , Shukla Anju , Dalal Ashwin , Girisha Katta Mohan , Shah Hitesh , Gupta Neerja , Kabra Madhulika , Dabadghao Preeti , Phadke Shubha R.
Published: March 2014

Osteogenesis imperfecta (OI) is a condition of decreased bone density with heterogeneous etiologies. Most of the cases are inherited in an autosomal dominant fashion and are caused by mutations in the COL1A1 or COL1A2 genes. Since these two genes are very large, there are no data about mutations in Indian patients with OI. We selected 35 Indian patients who were clinically diagnosed with OI and all exons of both the genes were sequenced. Mutations in COL1A1 (14 cases, 6 novel) and COL1A2 (11 cases, 7 novel) were identified in 25 patients. A total of 55 polymorphisms were identified in both the genes with eight novel variants in the coding region, and nine novel variants in the non‐coding regions. No mutation was detected in 10 patients. Six of them were from consanguineous families, with one or two similarly affected siblings suggesting possible autosomal recessive inheritance. If we exclude families with consanguinity, mutations were identified in 25 out of 29 families giving 86% mutation detection rate. Mutations in COL1A1 accounted for 56% of the cases and COL1A2 44%, which is similar to the reported rate worldwide. © 2014 Wiley Periodicals, Inc.
A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency
Authors: Dubruc Estelle , Putoux Audrey , Labalme Audrey , Rougeot Christelle , Sanlaville Damien , Edery Patrick
Published: March 2014

A girl patient born to healthy nonconsanguineous parents was referred at age 3 years and 2 months to our genetics department for testing due to developmental delay and postnatal microcephaly. Initial clinical evaluation revealed an overall developmental delay, mildly dysmorphic features, thin, sparse fair hair, and fair skin. Postnatal microcephaly and progressive ataxia and spasticity appeared later. Array CGH karyotyping showed a 333 kb de novo microdeletion on 3p22 covering the entire genomic sequence of a single gene, CTNNB1, which codes for β‐catenin. β‐catenin is a sub‐unit of a multiprotein complex, which is part of the Wnt signaling pathway. In mice, a conditional homozygous β‐catenin knockout displays loss of neurons, impaired craniofacial development, and hair follicle defects, which is similar to the phenotype presented by the patient described in this clinical report. Thus, CTNNB1 haploinsufficiency causes neuronal loss, craniofacial anomalies and hair follicle defects in both humans and mice. Point mutations in CTNNB1 in human have recently been reported but this is the first observation of a new recognizable multiple congenital anomaly/mental retardation syndrome caused by CTNNB1 haploinsufficiency. This clinical report should prompt a search for point mutations in CTNNB1 in patients presenting developmental delay, mild hair, skin and facial anomalies, and neurodegeneration characterized by postnatal microcephaly, and progressive ataxia and spasticity. © 2014 Wiley Periodicals, Inc.
Efficient Solid‐Phase Synthesis of pppRNA by Using Product‐Specific Labeling
Authors: Goldeck M. , Tuschl T. , Hartmann G. , Ludwig J.
Published: March 2014

A novel solid‐phase synthesis and purification strategy for 5′‐triphosphate oligonucleotides by using lipophilic tagging of the triphosphate moiety is reported. This is based on triphosphate synthesis with 5′‐O‐cyclotriphosphate intermediates, whereby a lipophilic tag, such as decylamine, is introduced during the ring‐opening reaction to give a linear gamma‐phosphate‐tagged species. This method enables the highly efficient synthesis of 5′‐triphosphorylated RNA derivatives and their gamma‐phosphate‐substituted analogues and will especially facilitate the advancement of therapeutic approaches that make use of 5′‐triphosphate oligonucleotides as potent activators of the cytosolic immune sensor RIG‐I.
Carbon Fibers: Precursor Systems, Processing, Structure, and Properties
Authors: Frank Erik , Steudle Lisa M. , Ingildeev Denis , Spörl Johanna M. , Buchmeiser Michael R.
Published: March 2014

This Review gives an overview of precursor systems, their processing, and the final precursor‐dependent structure of carbon fibers (CFs) including new developments in precursor systems for low‐cost CFs. The following CF precursor systems are discussed: poly(acrylonitrile)‐based copolymers, pitch, cellulose, lignin, poly(ethylene), and new synthetic polymeric precursors for high‐end CFs. In addition, structure–property relationships and the different models for describing both the structure and morphology of CFs will be presented.
Separation of Photoactive Conformers Based on Hindered Diarylethenes: Efficient Modulation in Photocyclization Quantum Yields
Authors: Li Wenlong , Jiao Changhong , Li Xin , Xie Yongshu , Nakatani Keitaro , Tian He , Zhu Weihong
Published: March 2014

Endowing both solvent independency and excellent thermal bistability, the benzobis(thiadiazole)‐bridged diarylethene system provides an efficient approach to realize extremely high photocyclization quantum yields (Φo‐c, up to 90.6 %) by both separating completely pure anti‐parallel conformer and suppressing intramolecular charge transfer (ICT).
Bidirectional Chemical Communication between Nanomechanical Switches
Authors: Pramanik Susnata , De Soumen , Schmittel Michael
Published: March 2014

The interplay of biological machines depends critically on the bidirectionality of chemical information exchange. The implementation of such a communication procedure for abiological systems is achieved using two nanoswitches that both operate as transmitters and receivers by transfering copper ions in oxidation states +I and +II. Even at micromolar concentrations, communication in both directions is remarkably fast, occurring at t1/2=2–3 min. Metal ion translocation triggers a 20 Å relocation of the toggle at both nanoswitches, entailing major geometric and electronic changes.
Total Synthesis of Syringolin A and Improvement of Its Biological Activity
Authors: Chiba Takuya , Hosono Hidetaka , Nakagawa Koji , Asaka Masahiro , Takeda Hiroshi , Matsuda Akira , Ichikawa Satoshi
Published: March 2014

The development process for syringolin A analogues having improved proteasome inhibitory and antitumor activity is described. The strategy was to first establish a convergent synthesis of syringolin A using a rare intramolecular Ugi three‐component reaction in the last stage of the synthesis, so as to gain access toa set of structure‐based analogues. The inhibitory activity of chymotrypsin‐like activity of 20S proteasome was largely improved by targeting the S3 subsite of the β5 subunit. Cytotoxic activity was also improved by installing the membrane‐permeable substituent. These biological properties are comparable to those of bortezomib, a clinically used first‐line proteasome inhibitor.
Synthesis of a novel pH‐sensitive polyurethane–alginate blend with poly(ethylene terephthalate) waste for the oral delivery of protein
Authors: Bhattacharyya Aditi , Mukhopadhyay Piyasi , Kundu P. P.
Published: March 2014

With the aim of using poly(ethylene terephthalate) (PET) waste for the synthesis of a value added product, we prepared polyurethane (PU) from bishydrohxyethylene terephthalate (BHET), a byproduct obtained from the glycolysis of PET. Biodegradable, water‐swelling PU was synthesized by the reaction of BHET, hexamethylene diisocyanate, and poly(ethylene glycol) (PEG). Both BHET and PU were characterized by Fourier transform infrared spectroscopy, and the formation of PU was further confirmed by NMR analysis. The swelling behavior of PU in water was examined in terms of the various molecular weights of PEG. Semi‐interpenetrating network beads of PU and sodium alginate were prepared with calcium chloride (CaCl2) as a crosslinker to attain a pH sensitivity for successful oral protein/drug delivery. Bovine serum albumin (BSA) was used as a model protein. The pH‐responsive swelling behavior and protein (BSA) release kinetics in different pH media corresponding to the gastrointestinal tract (pH 1.2 and 7.4) were investigated. The degree of swelling in the case of the PU–alginate beads at pH 1.2 was found to be at a minimum, whereas the degree of swelling was significantly elevated (1080%) at pH 7.4. This substantiated the pH sensitivity of the polymeric beads with a minimum loss of encapsulated protein in the stomach and the almost complete release of encapsulated protein in the intestine. This revealed good opportunities for oral protein/drug delivery with a polymer derived from waste PET. Moreover, the fungal biodegradation study confirmed its compatibility with the ecological system. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40650.
Novel Acyclic Phosphonylated 1,2,3‐Triazolonucleosides with an Acetamidomethyl Linker: Synthesis and Biological Activity
Authors: Głowacka Iwona E. , Balzarini Jan , Wróblewski Andrzej E.
Published: March 2014

A new series of 4‐substituted [(1,2,3‐triazol‐1‐yl)acetamido]methylphosphonates as acyclic nucleotide analogs were synthesized from diethyl (2‐chloroacetamido)methylphosphonate via azidation followed by 1,3‐dipolar cycloaddition with selected alkynes derived from natural nucleobases or their mimetics. All compounds were tested for their antiviral activities against DNA and RNA viruses as well as for cytostatic activity or cytotoxicity. Among all tested compounds, [(1,2,3‐triazol‐1‐yl)acetamido]methylphosphonate 6e substituted with the N3‐Bz‐benzuracil moiety showed activity against the vesicular stomatitis virus (EC50 = 45 µM) in HeLa cell cultures.
Effect of Various Intercalators on the Fenton‐Type Oxidative Cleavage of Double‐Stranded DNA
Authors: Kim Hyeon Jeong , Sung Giwoong , Kim Gyeongwon , Park Jongjin , Jin Biao , Kim Seog K.
Published: March 2014

The intensity of the linear dichroism (LD) in the absorption region of DNA (about 260 nm) decreased with time in the presence of [Fe(EDTA)]2+ (EDTA=ethylenediaminetetraacetic acid), H2O2, and ascorbate. The decrease in the LD signal indicated either an increase in flexibility, a shortening of the DNA stem, or both, owing to oxidative cleavage, and was best described by the difference between the two single‐exponential‐decay curves, thereby suggesting the involvement of two sequential first‐order reactions. The fast reaction was assigned to cleavage of one of two DNA strands, which increased the flexibility of the DNA. The slow reaction corresponded to cleavage at or near the first cleavage site, thereby shortening the DNA stem. The presence of an intercalator, including ethidium, propidium, 9‐aminoacridine, and proflavine, inhibited the first step of the cleavage reaction. One of the possible reasons for the observed inhibition might be a change in the DNA conformation near the intercalation site. Intercalation caused an unwinding and elongation of the DNA and resulted in changes in the location of the H atoms of the sugar moiety, which is known to be the main site at which hydroxyl radicals react.
Progressing to university: hidden messages at two state schools
Authors: Donnelly Michael
Published: March 2014

This paper considers some of the ways that schools play a role in shaping higher education (HE) decision‐making. Through their everyday practices and processes, schools can carry hidden messages about progression to HE, including choice of university. The sorts of routine aspects of school life dealt with here include events and activities, interactions with teachers, as well as resources. The work of Basil Bernstein is particularly useful at elucidating the different kinds of messages about HE choice sent out by schools. By shining a light on the underlying structures of power and control, Bernstein's framework illuminates the mechanisms by which messages are sent out. To illustrate this, two case study schools (both based in the same urban locality in south Wales) are drawn upon here, purposefully selected on the basis of their variances in progression to HE and research‐intensive universities. The implications of the role played by schools are discussed in the context of the prevailing inequalities in HE participation, rising tuition fees, and an increasingly uncertain graduate labour market.
Bias in student survey findings from active parental consent procedures
Authors: Shaw Thérèse , Cross Donna , Thomas Laura T. , Zubrick Stephen R.
Published: March 2014

Increasingly, researchers are required to obtain active (explicit) parental consent prior to surveying children and adolescents in schools. This study assessed the potential bias present in a sample of actively consented students, and in the estimates of associations between variables obtained from this sample. Students (n = 3496) from 36 non‐government metropolitan schools in Perth, Western Australia completed an online survey in 2010 as part of the Cyber Friendly Schools Project. Students with active (35%) and passive (65%) parental consent were compared on a range of variables including demographic, bullying and social–emotional outcomes. The moderating effects of consent status were also tested. Comparisons of the two consent groups showed that older students and students involved in problem behaviours such as bullying others, with lower pro‐social scores, who lived with one parent and reported doing less well academically than their peers, were underrepresented in the sample with active parental consent. Additionally, consent status was a significant moderator of the associations between bullying victimisation and certain social–emotional variables. Active only parental consent leads to biased samples and biased estimates of associations between outcomes of interest, which could lead to miss‐targeted behavioural policies and interventions. Strategies to boost response rates to levels sufficient to warrant the conduct of the research are labour‐intensive and costly, and the obtained samples are still likely to be biased. For low risk research, such as bullying surveys, rigorous active–passive consent procedures which result in higher participation rates, lower costs and reduced burden on teachers and schools, are recommended.
The effect of oxygen tension on human articular chondrocyte matrix synthesis: Integration of experimental and computational approaches
Authors: Li S. , Oreffo R.O.C. , Sengers B.G. , Tare R.S.
Published: March 2014

Significant oxygen gradients occur within tissue engineered cartilaginous constructs. Although oxygen tension is an important limiting parameter in the development of new cartilage matrix, its precise role in matrix formation by chondrocytes remains controversial, primarily due to discrepancies in the experimental setup applied in different studies. In this study, the specific effects of oxygen tension on the synthesis of cartilaginous matrix by human articular chondrocytes were studied using a combined experimental‐computational approach in a “scaffold‐free” 3D pellet culture model. Key parameters including cellular oxygen uptake rate were determined experimentally and used in conjunction with a mathematical model to estimate oxygen tension profiles in 21‐day cartilaginous pellets. A threshold oxygen tension (pO2 ≈ 8% atmospheric pressure) for human articular chondrocytes was estimated from these inferred oxygen profiles and histological analysis of pellet sections. Human articular chondrocytes that experienced oxygen tension below this threshold demonstrated enhanced proteoglycan deposition. Conversely, oxygen tension higher than the threshold favored collagen synthesis. This study has demonstrated a close relationship between oxygen tension and matrix synthesis by human articular chondrocytes in a “scaffold‐free” 3D pellet culture model, providing valuable insight into the understanding and optimization of cartilage bioengineering approaches. Biotechnol. Bioeng. 2014;111: 1876–1885. © 2014 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.
Improved lipid accumulation by morphology engineering of oleaginous fungus Mortierella isabellina
Authors: Gao Difeng , Zeng Jijiao , Yu Xiaochen , Dong Tao , Chen Shulin
Published: March 2014

Oleaginous fungi capable of accumulating a considerable amount of lipids are promising sources for lipid‐based biofuel production. The specific productivities of filamentous fungi in submerged fermentation are often correlated with morphological forms. However, the relationship between morphological development and lipid accumulation is not known. In this study, distinct morphological forms of oleaginous fungus Mortierella isabellina including pellets of different sizes, free dispersed mycelia, and broken hyphal fragments were developed by additions of different concentrations of magnesium silicate microparticles. Different morphological forms led to different levels of lipid accumulation as well as different spatial patterns of lipid distribution within pellets/mycelial aggregates. Significant higher lipid content (0.75 g lipid/g cell biomass) and lipid yield (0.18 g lipid/g glucose consumed) were achieved in free dispersed mycelia than in pellets. Moreover, extracellular metabolite analysis showed that production of undesirable by‐product malate was repressed in free dispersed mycelium form. Unveiling the desired morphological form of M. isabellina for lipid accumulation provided insights into molecular mechanism of lipid biosynthesis linked with morphological development, as well as design and optimization of bioprocess to produce lipid‐based biofuels. Biotechnol. Bioeng. 2014;111: 1758–1766. © 2014 Wiley Periodicals, Inc.
Tuning single‐cell oil production in Ashbya gossypii by engineering the elongation and desaturation systems
Authors: Ledesma‐Amaro Rodrigo , Santos María‐Angeles , Jiménez Alberto , Revuelta José Luis
Published: March 2014

Microbial oils represent a sustainable alternative to vegetable oils and animal fats as feedstock for both the chemical and biofuel industries. The applications of microbial oils depend on their fatty acid composition, which is defined by the relative amount of each fatty acid, also considering the length and unsaturations of the acyl chain. These two properties are determined by elongases and desaturases. In the present study, we characterized the elongase and desaturase systems in the filamentous fungus Ashbya gossypii, which is able to accumulate high amounts of lipids. Additionally, both the elongation and desaturation systems were engineered in order to broaden the potential applications of A. gossypii oils. Finally, the properties of the strains engineered for biodiesel production were analyzed, with the observation that A. gossypii is a good candidate for the microbial production of renewable biofuels. Biotechnol. Bioeng. 2014;111: 1782–1791. © 2014 Wiley Periodicals, Inc.
Safety and outcome of combined liver and pancreatic resections
Authors: Addeo P , Oussoultzoglou E , Fuchshuber P , Rosso E , Nobili C , Langella S , Jaeck D , Bachellier P
Published: March 2014

Background

In Western countries, combined liver and pancreatic resections (CLPR) are performed rarely because of the perceived high morbidity and mortality rates. This study evaluated the safety and outcomes of CLPR at a tertiary European centre for hepatopancreatobiliary surgery.

Methods

A review of two prospectively maintained databases for pancreatic and liver resections was undertaken to identify patients undergoing CLPR between January 1994 and January 2012. Clinicopathological and surgical outcomes were analysed. Univariable and multivariable analyses for postoperative morbidity were performed.

Results

Fifty consecutive patients with a median age of 58 (range 20–81) years underwent CLPR. Indications for surgery were neuroendocrine carcinoma (16 patients), biliary cancer (15), colonic cancer (5), duodenal cancer (1) and others (13). The type of pancreatic resection included pancreaticoduodenectomy (30), distal pancreatectomy (17), spleen-preserving distal pancreatectomy (2) and total pancreatectomy (1). Twenty-three patients had associated major hepatectomies, 27 underwent minor liver resections and 11 had associated vascular resections. Mortality and morbidity rates were 4 and 46 per cent respectively. Univariable and multivariable analysis showed no differences in postoperative morbidity in relation to extent of liver resection or type of pancreatic resection. Use of preoperative chemotherapy was the only independent risk factor associated with postoperative morbidity (P = 0·021).

Conclusion

CLPR can be performed with fairly low morbidity and mortality rates. Postoperative outcomes were not affected by the extent of liver resection or the type of pancreatic resection. Patients receiving chemotherapy should be evaluated carefully before surgery is considered.
Validation of international consensus guidelines for the resection of branch duct-type intraductal papillary mucinous neoplasms
Authors: Jang J-Y , Park T , Lee S , Kang M J , Lee S Y , Lee K B , Chang Y R , Kim S-W
Published: March 2014

Background

Classifications of intraductal papillary mucinous neoplasm (IPMN) remain ambiguous, especially for the mixed type. Factors predicting malignancy remain unclear. The aim of this study was to evaluate the usefulness of factors predicting malignancy in the new international consensus guidelines for resection of branch duct-type (BD)-IPMN and to compare them with those in the previous version.

Methods

A prospectively collected database of patients with biopsy-proven BD-IPMN was analysed to compare factors between the first and second consensus guidelines, particularly as predictors of malignancy.

Results

Of 350 patients with BD-IPMN, sensitivity (0·724) and balanced accuracy (0·751) of the second guidelines were superior to those (0·639 and 0·730) in the first version at the expense of slightly reduced specificity (0·779 versus 0·822 for the first version) by random forest models. Multiple logistic regression analysis showed that main pancreatic duct dilatation greater than 5 mm (hazard ratio (HR) 4·54, 95 per cent confidence interval 2·45 to 8·41; P < 0·001), mural nodules (HR 6·27, 3·27 to 12·01; P < 0·001) and carbohydrate antigen 19–9 level above 37 units/ml (HR 4·03, 1·83 to 8·90; P = 0·001) were independent predictors of BD-IPMN malignancy.

Conclusion

The new consensus guidelines provide better sensitivity, performance of factors predicting malignancy, and balanced accuracy in the diagnosis of BD-IPMN malignancy. Size alone was limited in predicting malignancy. Variability in clinical significance of the individual factors associated with a risk of malignancy indicates the need for a tailored approach in the management of patients with BD-IPMN.
The impact of the distance from the interventional cardiologist's home to the hospital during off hours
Authors: Lotfi Amir , Alreja Gaurav , Kashef Mohammad Amin , Giugliano Gregory R. , Garb Jane , Schweiger Marc
Published: March 2014

Objectives

The impact of the distance from the interventional cardiologist's home to the hospital and door to balloon time (DTBT)

Background

The importance of DTBT is highlighted by its inclusion as one of the core quality measures collected by the center for Medicare and Medicaid services and by the Joint commission on Accreditation of Healthcare organizations. We investigated the effect of time of day on the DTBT in patients having primary percutaneous coronary intervention (pPCI) and the impact of distance of the on call interventional cardiologist from the hospital on the DTBT and major adverse cardiac events (MACE) in patients undergoing pPCI during the off hours

Methods

Patients enrolled in the study presented with STEMI either in the field or to the emergency department (ED) and underwent pPCI from October 2007 to July 2009

Results

Significant predictors of DTBT included a history of prior MI (P = 0.001), prior percutaneous coronary intervention (P = 0.021), prior coronary artery bypass grafting (P < 0.001), and history of diabetes mellitus (P = 0.004). The strongest predictor of DTBT was on versus off hours. Mean DTB was 18.5 min greater during off hours (72 min) compared to on‐hours (53.5 min). The distance from the cardiologist's home to the hospital was not associated with DTBT on multivariable analysis (P = 0.20)

Conclusion

When pPCI is performed in a highly organized STEMI center with broad staff support and expertise in cardiac care, the increase in the DTBT during off hours was not associated with increase MACE rates. © 2014 Wiley Periodicals, Inc.
Bisepoxide Cross‐Linked Enzyme Aggregates—New Immobilized Biocatalysts for Selective Biotransformations
Authors: Weiser Diána , Varga Andrea , Kovács Klaudia , Nagy Flóra , Szilágyi András , Vértessy Beáta G. , Paizs Csaba , Poppe László
Published: March 2014

Glycerol diglycidyl ether (GDE) is a convenient and inexpensive bisepoxide cross‐linker as demonstrated by the preparation of cross‐linked enzyme aggregates (CLEAs) from two enzyme classes. The GDE CLEAs of lipase from Pseudomonas fluorescens (AK), lipase from Burkholderia cepacia (PS), and lipase B from Candida antarctica (CaL B) as well as of phenylalanine ammonia‐lyase (PAL) from Petroselinum crispum demonstrated improved properties as compared with their glutaraldehyde (GA) cross‐linked counterparts. Ultrasonication studies indicated that the GDE CLEAs of lipase PS and PAL were mechanically more stable than the GA CLEAs. In the kinetic resolution of rac‐1‐phenylethanol, the catalytic activity of the GDE–lipase CLEAs (U=69.6, 134.8, and 127.4 U g−1 for AK, CaL B, and PS prepared at 22 °C, respectively) surpassed that of the corresponding GA–lipase CLEAs (U=24.4, 131.0, and 119.2 U g−1 for AK, CaL B, and PS prepared at 22 °C, respectively). The GDE co‐CLEAs from PAL and bovine serum albumin (BSA) could be recycled at least three times if used for the stereoselective ammonia addition in 6 M ammonia to (E)‐3‐(thiophen‐2‐yl)acrylic acid, whereas the recycling of the conventional GA–PAL CLEAs from this medium failed.
Facile Synthesis of Hybrid Core–Shell Nanospheres for the Asymmetric Transfer Hydrogenation of Aromatic Ketones
Authors: Wei Juan , Zhang Xiaomin , Zhang Xiaoming , Zhao Yaopeng , Li Ruixiang , Yang Qihua
Published: March 2014

The polymer–inorganic hybrid core–shell nanospheres with N‐(para‐toluenesulfonyl)‐1,2‐diphenylethylenediamine in the core and the poly(methyl acrylate) (PMA) polymer in the shell were prepared by using a sol–gel process. The surface properties of solid catalysts were modified by controlling PMA and the cetyltrimethylammonium bromide surfactant in the shell. The water contact angle results suggest that the presence of PMA and cetyltrimethylammonium bromide in the shell increases the surface hydrophobicity. In the Rh‐catalyzed transfer hydrogenation of aromatic ketones in aqueous HCOONa, the solid catalyst with higher surface hydrophobicity demonstrates higher activity, which suggests that suitable surface properties increase the reaction rate by increasing the diffusion rates of hydrophobic substrates. Furthermore, this heterogeneous catalyst can be reused conveniently without loss of ee values.
Whole‐Cell Biocatalysis in Deep‐Eutectic‐Solvents/Aqueous Mixtures
Authors: Maugeri Zaira , Domínguez de María Pablo
Published: March 2014

Whole‐cell biocatalysis with the use of baker’s yeast is demonstrated in different mixtures of water with deep eutectic solvents (DESs; choline chloride/glycerol, 1:2 mol/mol). Enantioselective ketone reduction is observed for long reaction times (>200 h), which suggests that the whole cells remain stable in these neoteric solvents. By changing the proportion of the DES added, a complete inversion of enantioselectivity is observed, from approximately 95 % enantiomeric excess (ee) (S) in pure water to approximately 95 % ee (R) in the pure DES. Presumably, some (S)‐oxidoreductases present in baker’s yeast are inhibited by DESs.
Correlated Coordination and Redox Activity of a Hemilabile Noninnocent Ligand in Nickel Complexes
Authors: Paretzki Alexa , Bubrin Martina , Fiedler Jan , Záliš Stanislav , Kaim Wolfgang
Published: March 2014

The compound [Ni(QM)2], QM=4,6‐di‐tert‐butyl‐N‐(2‐methylthiomethylphenyl)‐o‐iminobenzoquinone, is a singlet diradical species with approximately planar configuration at the tetracoordinate metal atom and without any NiS bonding interaction. One‐electron oxidation results in additional twofold NiS coordination (dNiS≈2.38 Å) to produce a complex cation of [Ni(QM)2](PF6) with hexacoordinate NiII and two distinctly different mer‐configurated tridentate ligands. The O,O′‐trans arrangement in the neutral precursor is changed to an O,O′‐cis configuration in the cation. The EPR signal of [Ni(QM)2](PF6) has a very large g anisotropy and the magnetic measurements indicate an S=3/2 state. The dication was structurally characterized as [Ni(QM)2](ClO4)2 to exhibit a similar NiN2O2S2 framework as the monocation. However, the two tridentate (O,N,S) ligands are now equivalent according to the formulation [NiII(QM0)2]2+. Cyclic voltammetry reflects the qualitative structure change on the first, but not on the second oxidation of [Ni(QM)2], and spectroelectrochemistry reveals a pronounced dependence of the 800–900 nm absorption on the solvent and counterion. Reduction of the neutral form occurs in an electrochemically reversible step to yield an anion with an intense near‐infrared absorption at 1345 nm (ε=10400 M−1 cm−1) and a conventional g factor splitting for a largely metal‐based spin (S=1/2), suggesting a [(QM.−)NiII(QM2−)]− configuration with a tetracoordinate metal atom with antiferromagnetic NiII–(QM.−) interactions and symmetry‐allowed ligand‐to‐ligand intervalence charge transfer (LLIVCT). Calculations are used to understand the NiS binding activity as induced by remote electron transfer at the iminobenzoquinone redox system.
Exploiting Aromatic Interactions for β‐Peptide Foldamer Helix Stabilization: A Significant Design Element
Authors: Mándity István M. , Monsignori Antonella , Fülöp Lívia , Forró Enikö , Fülöp Ferenc
Published: March 2014

Tetrameric H10/12 helix stabilization was achieved by the application of aromatic side‐chains in β‐peptide oligomers by intramolecular backbone–side chain CH–π interactions. Because of the enlarged hydrophobic surface of the oligomers, a further aim was the investigation of the self‐assembly in a polar medium for the β‐peptide H10/12 helices. NMR, ECD, and molecular modeling results indicated that the oligomers formed by cis‐[1S,2S]‐ or cis‐[1R,2R]‐1‐amino‐1,2,3,4‐tetrahydronaphthalene‐2‐carboxylic acid (ATENAC) and cis‐[1R,2S]‐ or cis‐[1S,2R]‐2‐aminocyclohex‐3‐enecarboxylic acid (ACHEC) residues promote stable H10/12 helix formation with an alternating backbone configuration even at the tetrameric chain length. These results support the view that aromatic side‐chains can be applied for helical structure stabilization. Importantly, this is the first observation of a stable H10/12 helix with tetrameric chain‐length. The hydrophobically driven self‐assembly was achieved for the helix‐forming oligomers, seen as vesicles in transmission electron microscopy images. The self‐association phenomenon, which supports the helical secondary structure of these oligomers, depends on the hydrophobic surface area, because a higher number of aromatic side‐chains yielded larger vesicles. These results serve as an essential element for the design of helices relating to the H10/12 helix. Moreover, they open up a novel area for bioactive foldamer construction, while the hydrophobic area gained through the aromatic side‐chains may yield important receptor–ligand interaction surfaces, which can provide amplified binding strength.
Nickel(I) Monomers and Dimers with Cyclopentadienyl and Indenyl Ligands
Authors: Wu Jianguo , Nova Ainara , Balcells David , Brudvig Gary W. , Dai Wei , Guard Louise M. , Hazari Nilay , Lin Po‐Heng , Pokhrel Ravi , Takase Michael K.
Published: March 2014

The reaction of (μ‐Cl)2Ni2(NHC)2 (NHC=1,3‐bis(2,6‐diisopropylphenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ylidene (IPr) or 1,3‐bis(2,6‐diisopropylphenyl)imidazolidin‐2‐ylidene (SIPr)) with either one equivalent of sodium cyclopentadienyl (NaCp) or lithium indenyl (LiInd) results in the formation of diamagnetic NHC supported NiI dimers of the form (μ‐Cp)(μ‐Cl)Ni2(NHC)2 (NHC=IPr (1 a) or SIPr (1 b); Cp=C5H5) or (μ‐Ind)(μ‐Cl)Ni2(NHC)2 (NHC=IPr (2 a) or SIPr (2 b); Ind=C7H9), which contain bridging Cp and indenyl ligands. The corresponding reaction between two equivalents of NaCp or LiInd and (μ‐Cl)2Ni2(NHC)2 (NHC=IPr or SIPr) generates unusual 17 valence electron NiI monomers of the form (η5‐Cp)Ni(NHC) (NHC=IPr (3 a) or SIPr (3 b)) or (η5‐Ind)Ni(NHC) (NHC=IPr (4 a) or SIPr (4 b)), which have nonlinear geometries. A combination of DFT calculations and NBO analysis suggests that the NiI monomers are more strongly stabilized by the Cp ligand than by the indenyl ligand, which is consistent with experimental results. These calculations also show that the monomers have a lone unpaired‐single‐electron in their valence shell, which is the reason for the nonlinear structures. At room temperature the Cp bridged dimer (μ‐Cp)(μ‐Cl)Ni2(NHC)2 undergoes homolytic cleavage of the NiNi bond and is in equilibrium with (η5‐Cp)Ni(NHC) and (μ‐Cl)2Ni2(NHC)2. There is no evidence that this equilibrium occurs for (μ‐Ind)(μ‐Cl)Ni2(NHC)2. DFT calculations suggest that a thermally accessible triplet state facilitates the homolytic dissociation of the Cp bridged dimers, whereas for bridging indenyl species this excited triplet state is significantly higher in energy. In stoichiometric reactions, the NiI monomers (η5‐Cp)Ni(NHC) or (η5‐Ind)Ni(NHC) undergo both oxidative and reductive processes with mild reagents. Furthermore, they are rare examples of active NiI precatalysts for the Suzuki–Miyaura reaction. Complexes 1 a, 2 b, 3 a, 4 a and 4 b have been characterized by X‐ray crystallography.