bluuebunny/crossref_metadata_2025 huggingface dataset:
Gain‐of‐Function Mutants of p53 and Their Role in Tumourigenesis
Authors: Vaughan Catherine A , Deb Swati P , Deb Sumitra
Published: February 2014

The p53 gene is a tumour suppressor that is widely mutated in human cancers. Wild‐type p53 plays a pivotal role in preventingdeoxyribonucleic acid (DNA)damage and maintaining the integrity of the cell. Cells that contain mutant p53, however, are unable to prevent this damage and, in fact, become more oncogenic. Gain‐of‐function (GOF) mutant p53 has been shown to transactivate a number of genes that are part of cell growth and survival pathways and cause an increase in tumourigenicity. Knockin and transgenic mouse models have been utilised to explore the GOF phenotype of mutant p53. Currently, p53 cannot be targeted for cancer therapy, but recent studies have demonstrated the ability to reduce tumourigenicity in lung cancer cells addicted to their endogenous GOF mutant p53.

Key Concepts:

The p53 gene is the most frequently mutated tumour suppressor gene in cancer.

WT p53 plays an active role in the cell cycle, DNA repair, apoptosis, and can function as a transcriptional activator.

A wide array of functions of WT p53 are dependent on its transcriptional ability.

Gain‐of‐function mutations are characterised by loss of the wild‐type tumour suppressor functions of p53 as well as gain of new oncogenic functions.

Several groups have utilized mouse models to study mutant p53 gain of function in cancer.
B1‐ and CD5‐Positive B Cells
Authors: Renaudineau Yves , Bariller Edwige , Olivier Pers Jacques
Published: February 2014

B1 (B1a/B1b) cells represent a population distinct from conventional B2 cells, which predominates the coelomic cavities. In contrast to B2 cells, B1 cells are selected by self‐antigens, and are chronically active in an autonomous B cell receptor pathway. B1 cells produce circulating IgM natural antibodies that provide ‘innate‐like’ protection against pathogens, contribute to the elimination of apoptotic cells and prevent B1 cell expansion. Furthermore, B1 cells are effective both in presenting autoantigens to T cells, and in inducing T cell activation and differentiation. The vast majority of B1 cells express CD5 and the new findings suggest that part of the B1 cell properties, as well as the capacity of B1 cells to contribute to the development of autoimmune diseases and chronic lymphocytic leukaemia, is related to the expression of the CD5 molecule.

Key Concepts:

B1 cells are a subclass of B cells.

B1 cells are involved in the innate protection.

B1 cells are first produced in the foetus.

B1 cells predominate in the coelomic cavities in adults.

B1 cells overlap incompletely with CD5+B cells in humans.
Incidental Findings in Genetic Research and Genetic Testing
Authors: Jackson Leigh
Published: February 2014

Incidental findings arise when clinically relevant genetic information about a research participant or patient is identified outside the scope of the original research objective or diagnostic test being performed. These findings can relate to carrier status for a heritable condition, misattributed paternity or increased susceptibility to a medical condition. The decision whether to disclose these findings to the research subject or patient is underpinned by many ethical, moral and potentially legal considerations. There is an urgent need for definitive guidelines for researchers and healthcare professionals. Major themes surrounding this issue include patient autonomy, patient welfare, harmful secrets and genetic literacy. The lack of relevant studies emphasises the urgent need for empirical investigations into the disclosure or nondisclosure of genetic incidental findings and the provision of guidelines to assist healthcare professionals and researchers.

Key Concepts:

Incidental findings are most likely to become more frequent due to advances in genome‐wide technology and decreases in the cost of testing.

Patient and participant autonomy must be considered in any strategy designed to manage incidental findings.

Patient and participant welfare should be a driving factor in decisions regarding disclosure of incidental findings.

Genetic secrets can be harmful to both the patient/participant and the healthcare professional.

The genetic literacy of healthcare professionals and public alike need to be considered when discussing genome‐wide testing technologies and attempts need to be made to increase knowledge across the board.

There is a lack of primary research data concerning patient and participant preferences regarding the management of incidental findings in research and the clinic.

Many clinician researchers have difficulty in separating their clinical and research obligations when genomic testing straddles the research–clinic interface.

There is an urgent need for coherent and ethical guidelines to address the management of incidental findings and assist researchers and clinicians in defining their legal, professional and ethical obligations.
Capillary Network‐Like Organization of Endothelial Cells in PEGDA Scaffolds Encoded with Angiogenic Signals via Triple Helical Hybridization
Authors: Stahl Patrick J. , Chan Tania R. , Shen Yu‐I , Sun Guoming , Gerecht Sharon , Yu S. M.
Published: February 2014

Survival of tissue engineered constructs after implantation depends on proper vascularization. The differentiation of endothelial cells into mature microvasculature requires dynamic interactions between cells, scaffold, and growth factors, which are difficult to recapitulate in artificial systems. Previously, photocrosslinked poly(ethylene glycol) diacrylate (PEGDA) hydrogels displaying collagen mimetic peptides (CMPs), dubbed PEGDA‐CMP, that can be further conjugated with bioactive molecules via CMP‐CMP triple helix hybridization were reported. Here, it is shown that a bifunctional peptide featuring pro‐angiogenic domain mimicking vascular endothelial growth factor (VEGF) and a collagen mimetic domain that can fold into a triple helix conformation can hybridize with CMP side chains of the PEGDA‐CMP hydrogel, which results in presentation of insoluble VEGF‐like signals to endothelial cells. Presentation of VEGF‐like signals on the surface of micropatterned scaffolds in this way transforms cells from a quiescent state to elongated and aligned phenotype suggesting that this system could be used to engineer organized microvasculature. It is also shown that the pro‐angiogenic peptide, when applied topically in combination with modified dextran/PEGDA hydrogels, can enhance neovascularization of burn wounds in mice demonstrating the potential clinical use of CMP‐mediated matrix‐bound bioactive molecules for dermal injuries.
Track‐Etched Magnetic Micropores for Immunomagnetic Isolation of Pathogens
Authors: Muluneh Melaku , Shang Wu , Issadore David
Published: February 2014

A microfluidic chip is developed to selectively isolate magnetically tagged cells from heterogeneous suspensions, the track‐etched magnetic micropore (TEMPO) filter. The TEMPO consists of an ion track‐etched polycarbonate membrane coated with soft magnetic film (Ni20Fe80). In the presence of an applied field, provided by a small external magnet, the filter becomes magnetized and strong magnetic traps are created along the edges of the micro­pores. In contrast to conventional microfluidics, fluid flows vertically through the porous membrane allowing large flow rates while keeping the capture rate high and the chip compact. By utilizing track‐etching instead of conventional semiconductor fabrication, TEMPOs can be fabricated with microscale pores over large areas A > 1 cm2 at little cost (< 5 C| cm−2). To demonstrate the utility of this platform, a TEMPO with 5 μm pore size is used to selectively and rapidly isolate immunomagnetically targeted Escherichia coli from heterogeneous suspensions, demonstrating enrichment of ζ > 500 at a flow rate of Φ = 5 mL h−1. Furthermore, the large density of micropores (ρ = 106 cm–2) allows the TEMPO to sort E. coli from unprocessed environmental and clinical samples, as the blockage of a few pores does not significantly change the behavior of the device.
25th Anniversary Article: 25 Years of Fullerene Research in Electron Transfer Chemistry
Authors: Kirner Sabrina , Sekita Michael , Guldi Dirk M.
Published: February 2014

The past 25 years have served as a test bed for exploring the chemistry and physics, in general, and the electron transfer chemistry, in particular, of low‐dimensional carbon. Nevertheless, the new realm started with the advent of fullerenes, followed in chronological order by carbon nanotubes, and, more recently, by graphene. The major thrust of this Review article is to historically recap the versatility of fullerenes regarding the design, the synthesis, and the tests as an electroactive building block in photosynthetic reaction mimics, photovoltaics, and catalysis.
Recent Developments in Microfluidics for Cell Studies
Authors: Xiong Bin , Ren Kangning , Shu Yiwei , Chen Yin , Shen Bo , Wu Hongkai
Published: February 2014

As a technique for precisely manipulating fluid at the micrometer scale, the field of microfluidics has experienced an explosive growth over the past two decades, particularly owing to the advances in device design and fabrication. With the inherent advantages associated with its scale of operation, and its flexibility in being incorporated with other microscale techniques for manipulation and detection, microfluidics has become a major enabling technology, which has introduced new paradigms in various fields involving biological cells. A microfluidic device is able to realize functions that are not easily imaginable in conventional biological analysis, such as highly parallel, sophisticated high‐throughput analysis, single‐cell analysis in a well‐defined manner, and tissue engineering with the capability of manipulation at the single‐cell level. Major advancements in microfluidic device fabrication and the growing trend of implementing microfluidics in cell studies are presented, with a focus on biological research and clinical diagnostics.
Influence of atomizer exit area ratio on the breakup morphology of coaxial air and round water jets
Authors: Zhao Hui , Liu Hai‐Feng , Tian Xiu‐Shan , Xu Jian‐Liang , Li Wei‐Feng , Lin Kuang‐Fei
Published: February 2014

The goal of this article is to study the effect of atomizer exit area ratio on atomizer performance. The experiments are performed on the round liquid jet breakup of seven coaxial air‐blast atomizers with water–air systems. The breakup morphology of liquid jet is observed first. The membrane‐type breakup can be divided into two subregimes called bag‐type breakup and membrane‐fiber breakup, and a correlation of characteristic length on bag‐type breakup regime is obtained. Then, we analyze the influence of atomizer exit area ratio on the breakup morphology of water‐air jets. To obtain reasonable atomization morphology criterions, the atomizer exit area ratio is used to modify the Weber number and momentum flux ratio per unit volume. This method is found to be able to explain different experimental results in the literature, which is also close to the results of round liquid jet in cross air flow and secondary atomization. © 2014 American Institute of Chemical Engineers AIChE J, 60: 2335–2345, 2014
Correlation analysis of genetic admixture and social identification with body mass index in a Native American Community
Authors: Norden‐Krichmar Trina M. , Gizer Ian R. , Libiger Ondrej , Wilhelmsen Kirk C. , Ehlers Cindy L. , Schork Nicholas J.
Published: February 2014

Objectives

Body mass index (BMI) is a well‐known measure of obesity with a multitude of genetic and non‐genetic determinants. Identifying the underlying factors associated with BMI is difficult because of its multifactorial etiology that varies as a function of geoethnic background and socioeconomic setting. Thus, we pursued a study exploring the influence of the degree of Native American admixture on BMI (as well as weight and height individually) in a community sample of Native Americans (n = 846) while accommodating a variety of socioeconomic and cultural factors.

Methods

Participants' degree of Native American (NA) ancestry was estimated using a genome‐wide panel of markers. The participants also completed an extensive survey of cultural and social identity measures: the Indian Culture Scale (ICS) and the Orthogonal Cultural Identification Scale (OCIS). Multiple linear regression was used to examine the relation between these measures and BMI.

Results

Our results suggest that BMI is correlated positively with the proportion of NA ancestry. Age was also significantly associated with BMI, while gender and socioeconomic measures (education and income) were not. For the two cultural identity measures, the ICS showed a positive correlation with BMI, while OCIS was not associated with BMI.

Conclusions

Taken together, these results suggest that genetic and cultural environmental factors, rather than socioeconomic factors, account for a substantial proportion of variation in BMI in this population. Further, significant correlations between degree of NA ancestry and BMI suggest that admixture mapping may be appropriate to identify loci associated with BMI in this population. Am. J. Hum. Biol. 26:347–360, 2014. © 2014 Wiley Periodicals, Inc.
Engaging bodies in the public imagination: Bioarchaeology as social science, science, and humanities
Authors: Stojanowski Christopher M. , Duncan William N.
Published: February 2014

Bioarchaeology is the contextual analysis of biological remains from past societies. It is a young and growing discipline born during the latter half of the twentieth century from its roots in physical anthropology and archaeology. Although often associated with the study of ancient diet and disease, bioarchaeology leverages variable temporal scales and its global scope to provide a uniquely comparative perspective on human life that transcends traditional boundaries of the natural sciences, social sciences, and humanities. Here, we explore the public face of bioarchaeology and consider the trends in publication practices that reflect diversifying research strategies.

Bioarchaeology is a popular topic on web‐based science news aggregators. However, we identify a disconnect between bioarchaeology's traditional research emphases, emerging research foci, and findings that actually spark the public imagination. A majority of popular news articles emphasize basic discovery or “natural curiosities.” Publication data indicate the field also remains regionally focused with relatively little emphasis on nomothetic goals. Nevertheless, bioarchaeology can do more to leverage its historical perspective and corporeal emphasis to engage a number of topics with importance across traditional academic boundaries. Big data, comparative, multi‐investigator, interdisciplinary projects on violence, colonialism, and health offer the most obvious potential for driving research narratives in the biological and social sciences. Humanistic approaches that explore emotional connections to the past can also have merit. The diversity of research outlets and products indicates the field must embrace the importance of nontraditional activities in its value structure to maximize our potential in public arenas. Am. J. Hum. Biol. 27:51–60, 2015. © 2014 Wiley Periodicals, Inc.
Food and nutrition policy: A biological anthropologist's experiences from an academic platform
Authors: Pelletier David
Published: February 2014

Objectives

Biological anthropologists within academia and in other sectors are increasingly engaged in a variety of problem‐oriented research and in the design, implementation, or evaluation of policies and programs, domestically and abroad. Such work can have distinctive requirements in terms of disciplinary background, professional orientation, and professional development. This article explores these issues through the author's autobiographical account of a career in food and nutrition policy from within an academic nutrition department.

Methods

The article is guided by an analytical framework that compares eight projects in terms of their mode of knowledge production, academic impact, public impacts, and personal rewards. The projects range from village‐based surveys in Samoa and Malawi to food security planning in upstate New York communities, US policies on genetically engineered (GE) foods, and participant–observer research on nutrition policy development in low‐income countries.

Results and Conclusions

The cumulative experience reveals the importance of a commitment to problem‐solving, a transdisciplinary orientation, intellectual and methodological dexterity, ongoing engagement with policy actors and openness to emergent research questions, new research settings, and nontraditional funding sources. Am. J. Hum. Biol. 27:16–26, 2015. © 2014 Wiley Periodicals, Inc.
Mountain gorilla ranging patterns: Influence of group size and group dynamics
Authors: Caillaud Damien , Ndagijimana Felix , Giarrusso Anthony J. , Vecellio Veronica , Stoinski Tara S.
Published: February 2014

Since the 1980s, the Virunga mountain gorilla population has almost doubled, now reaching 480 individuals living in a 430‐km2 protected area. Analysis of the gorillas' ranging patterns can provide critical information on the extent and possible effects of competition for food and space. We analyzed 12 years of daily ranging data and inter‐group encounter data collected on 11 gorilla groups monitored by the Karisoke Research Center in Rwanda. During that period, the study population increased in size by almost 50% and the number of groups tripled. Groups had small yearly home ranges compared to other known gorilla populations, with an average 90% kernel density estimate of 8.07 km2 and large between‐group variations (3.17–23.59 km2). Most groups had consistent home range location over the course of the study but for some, we observed gradual range shifts of up to 4 km. Neighboring groups displayed high home range overlap, which increased dramatically after the formation of new groups. On average, each group used only 28.6% of its 90% kernel home range exclusively, and in some areas up to six different groups had overlapping home ranges with little or no exclusive areas. We found a significant intra‐group positive relationship between the number of weaned individuals in a group and the home range size, but the fitted models only explained 17.5% and 13.7% of the variance in 50% and 90% kernel home range size estimates, respectively. This suggests that despite the increase in size, the study population is not yet experiencing marked effects of feeding competition. However, the increase in home range overlap resulting from the formation of new groups led to a sixfold increase in the frequency of inter‐group encounters, which exposes the population to elevated risks of fight‐related injuries and infanticide. Am. J. Primatol. 76:730–746, 2014. © 2014 Wiley Periodicals, Inc.
Overexpression of angiomotin in sinonasal inverted papilloma
Authors: Byun Jang Yul , Lee Sang Hag , Shin Jae Min , Baek Byoung Joon , Lee Jae Yong
Published: February 2014

Background

Although inverted papilloma (IP) is one of the most common sinonasal tumors, its etiology and factors associated with tumor progression have not been fully determined. Generally, tumorigenesis or tumor growth requires angiogenesis to feed tumor cells. Angiomotin is a recently discovered protein that regulates migration and tubule formation in endothelial cells. It has been reported that angiomotin affects angiostatin (circulating inhibitor of angiogenesis), resulting in promotion of angiogenesis. Thus, we evaluated the expression and distribution of angiomotin in sinonasal IP, compared to normal control tissue.

Methods

The study included 10 subjects with sinonasal IP and 5 normal controls. Ethmoid sinus mucosa obtained during reduction of blowout fractures was used as a normal control. Reverse transcriptase–polymerase chain reaction (RT‐PCR), real‐time PCR, immunohistochemistry, and Western blot analysis were used to assess the expression, intensity, and distribution of angiomotin in tissues.

Results

Positive bands for angiomotin were seen in all specimens by RT‐PCR. The expression level of angiomotin was significantly upregulated in IP tissues versus normal sinus mucosa by real‐time PCR. Immunohistochemistry revealed positive reactions on endothelial cells of capillaries and small vessels within the tumor and normal tissues, but the positivity was significantly stronger in IP. Western blot analysis showed that expression levels of angiomotin were increased in IP compared to normal sinus mucosa.

Conclusion

Angiomotin, a novel protein in angiogenesis, was overexpressed in IP. Although it is not an etiological or initiating factor in tumor development, it seems to be associated with progression and growth of IP via promoting angiogenesis.
Gain‐of‐function ADCY5 mutations in familial dyskinesia with facial myokymia
Authors: Chen Ying‐Zhang , Friedman Jennifer R. , Chen Dong‐Hui , Chan Guy C.‐K. , Bloss Cinnamon S. , Hisama Fuki M. , Topol Sarah E. , Carson Andrew R. , Pham Phillip H. , Bonkowski Emily S. , Scott Erick R. , Lee Janel K. , Zhang Guangfa , Oliveira Glenn , Xu Jian , Scott‐Van Zeeland Ashley A. , Chen Qi , Levy Samuel , Topol Eric J. , Storm Daniel , Swanson Phillip D. , Bird Thomas D. , Schork Nicholas J. , Raskind Wendy H. , Torkamani Ali
Published: February 2014

Objective

To identify the cause of childhood onset involuntary paroxysmal choreiform and dystonic movements in 2 unrelated sporadic cases and to investigate the functional effect of missense mutations in adenylyl cyclase 5 (ADCY5) in sporadic and inherited cases of autosomal dominant familial dyskinesia with facial myokymia (FDFM).

Methods

Whole exome sequencing was performed on 2 parent–child trios. The effect of mutations in ADCY5 was studied by measurement of cyclic adenosine monophosphate (cAMP) accumulation under stimulatory and inhibitory conditions.

Results

The same de novo mutation (c.1252C>T, p.R418W) in ADCY5 was found in both studied cases. An inherited missense mutation (c.2176G>A, p.A726T) in ADCY5 was previously reported in a family with FDFM. The significant phenotypic overlap with FDFM was recognized in both cases only after discovery of the molecular link. The inherited mutation in the FDFM family and the recurrent de novo mutation affect residues in different protein domains, the first cytoplasmic domain and the first membrane‐spanning domain, respectively. Functional studies revealed a statistically significant increase in β‐receptor agonist‐stimulated intracellular cAMP consistent with an increase in adenylyl cyclase activity for both mutants relative to wild‐type protein, indicative of a gain‐of‐function effect.

Interpretation

FDFM is likely caused by gain‐of‐function mutations in different domains of ADCY5—the first definitive link between adenylyl cyclase mutation and human disease. We have illustrated the power of hypothesis‐free exome sequencing in establishing diagnoses in rare disorders with complex and variable phenotype. Mutations in ADCY5 should be considered in patients with undiagnosed complex movement disorders even in the absence of a family history. Ann Neurol 2014;75:542–549
Strukturbasiertes Design von Hemmstoffen der Aspartylprotease Endothiapepsin mittels dynamischer kombinatorischer Chemie
Authors: Mondal Milon , Radeva Nedyalka , Köster Helene , Park Ahyoung , Potamitis Constantinos , Zervou Maria , Klebe Gerhard , Hirsch Anna K. H.
Published: February 2014

Strukturbasiertes Design (SBD) wird für den Entwurf und/oder die Optimierung neuer Hemmstoffe für biologische Targets verwendet. Während De‐novo‐SBD selten benutzt wird, befassen sich Berichte über SBD meistens mit der Optimierung eines anfänglichen Hits. Dynamische kombinatorische Chemie (DKC) hat sich bei der die Identifizierung biologisch aktiver Liganden bewährt, da sie es dem Target ermöglicht, die Synthese der stärksten Binder zu steuern. Aus einer Bibliothek möglicher Hemmstoffe (Acylhydrazone), aus je fünf Aldehyden und Hydraziden erzeugt, haben wir mithilfe von DKC den besten Binder identifiziert. Nach Zugabe der Aspartylprotease Endothiapepsin haben wir die an das Protein gebundenen Bibliotheksmitglieder mittels Sättigungstransferdifferenz(STD)‐NMR‐Spektroskopie charakterisiert. Cokristallstrukturen bestätigen den vorhergesagten Bindungsmodus der beiden stärksten Hemmstoffe und zeigen, dass die Kombination von De‐novo‐SBD und DKC eine effiziente Identifizierung und Optimierung von Hits ermöglicht.
Die Isolierung eines labilen homoleptischen Diazeniumkations
Authors: Baumann Wolfgang , Michalik Dirk , Reiß Fabian , Schulz Axel , Villinger Alexander
Published: February 2014

Unserem Interesse an der Stickstoffchemie folgend, beschreiben wir hier die Synthese, Struktur und Bindung des labilen disilylierten Diazens, seines GaCl3‐Addukts und des ungewöhnlichen trisilylierten Diazeniumions, [(Me3Si)2NN‐SiMe3]+, ein tiefblaues, äußerst labiles (TZers.>−30 °C) homoleptisches Kation des Typs [R3N2]+. Während die direkte Silylierung des Me3Si‐NN‐SiMe3 scheiterte, konnte das [(Me3Si)2NN‐SiMe3]+‐Ion in einer einfachen Zwei‐Elektronen‐Oxidation ausgehend von Quecksilber(II)‐dihydrazid und Ag[GaCl4] erzeugt werden. Darüber hinaus werden die bisher bekannten Strukturdaten von Me3Si‐NN‐SiMe3 aufgrund neuer Daten korrigiert.
Copper‐Catalyzed Cross‐Coupling of Boronic Esters with Aryl Iodides and Application to the Carboboration of Alkynes and Allenes
Authors: Zhou Yiqing , You Wei , Smith Kevin B. , Brown M. Kevin
Published: February 2014

Copper‐catalyzed Suzuki–Miyaura‐type cross‐coupling and carboboration processes are reported. The cross‐couplings function well with a variety of substituted aryl iodides and aryl boronic esters and allows for orthogonal reactivity compared to palladium‐catalyzed processes. The carboboration method includes both alkynes and allenes and provides access to highly substituted and stereodefined vinyl boronic esters. The alkyne carboboration method is highlighted in the simple one‐pot synthesis of Tamoxifen.
Chemically Orthogonal Three‐Patch Microparticles
Authors: Rahmani Sahar , Saha Sampa , Durmaz Hakan , Donini Alessandro , Misra Asish C , Yoon Jaewon , Lahann Joerg
Published: February 2014

Compared to two‐dimensional substrates, only a few methodologies exist for the spatially controlled decoration of three‐dimensional objects, such as microparticles. Combining electrohydrodynamic co‐jetting with synthetic polymer chemistry, we were able to create two‐ and three‐patch microparticles displaying chemically orthogonal anchor groups on three distinct surface patches of the same particle. This approach takes advantage of a combination of novel chemically orthogonal polylactide‐based polymers and their processing by electrohydrodynamic co‐jetting to yield unprecedented multifunctional microparticles. Several micropatterned particles were fabricated displaying orthogonal click functionalities. Specifically, we demonstrate novel two‐ and three‐patch particles. Multi‐patch particles are highly sought after for their potential to present multiple distinct ligands in a directional manner. This work clearly establishes a viable route towards orthogonal reaction strategies on multivalent micropatterned particles.
Structure‐Based Design of Inhibitors of the Aspartic Protease Endothiapepsin by Exploiting Dynamic Combinatorial Chemistry
Authors: Mondal Milon , Radeva Nedyalka , Köster Helene , Park Ahyoung , Potamitis Constantinos , Zervou Maria , Klebe Gerhard , Hirsch Anna K. H.
Published: February 2014

Structure‐based design (SBD) can be used for the design and/or optimization of new inhibitors for a biological target. Whereas de novo SBD is rarely used, most reports on SBD are dealing with the optimization of an initial hit. Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify bioactive ligands given that it enables the target to direct the synthesis of its strongest binder. We have designed a library of potential inhibitors (acylhydrazones) generated from five aldehydes and five hydrazides and used DCC to identify the best binder(s). After addition of the aspartic protease endothiapepsin, we characterized the protein‐bound library member(s) by saturation‐transfer difference NMR spectroscopy. Cocrystallization experiments validated the predicted binding mode of the two most potent inhibitors, thus demonstrating that the combination of de novo SBD and DCC constitutes an efficient starting point for hit identification and optimization.
Isolation of a Labile Homoleptic Diazenium Cation
Authors: Baumann Wolfgang , Michalik Dirk , Reiß Fabian , Schulz Axel , Villinger Alexander
Published: February 2014

Following our interest in nitrogen chemistry, we now describe the synthesis, structure, and bonding of labile disilylated diazene, its GaCl3 adduct, and the intriguing trisilylated diazenium ion [(Me3Si)2NN‐SiMe3]+, a dark blue and highly labile (Tdecomp>−30 °C) homoleptic cation of the type [R3N2]+. Although direct silylation of Me3Si‐NN‐SiMe3 failed, the [(Me3Si)2NN‐SiMe3]+ ion was generated in a straightforward two‐electron oxidation reaction from mercury(II) dihydrazide and Ag[GaCl4]. Moreover, previous structure data of Me3Si‐NN‐SiMe3 were revised on the basis of new data.
2,5‐Bis(2‐(diphenylphosphino)phenyl)‐1,3,4‐oxadiazole ligands and their Cu(I) complexes for Sonogashira coupling reaction
Authors: Lin Cai‐Xia , Zhu Jia‐Fang , Li Qing‐Shan , Ao Li‐Hua , Jin Yan‐Juan , Xu Feng‐Bo , Hu Fang‐Zhong , Yuan Yao‐Feng
Published: February 2014

Two diphosphane ligands – 2,5‐bis(2‐(diphenylphosphino)‐5‐R)phenyl)‐1,3,4‐oxadiazole (L1, R = H, L2, R = OMe) and their binuclear complexes, L1Cu and L2Cu, were prepared and characterized. The molecular structures of L1Cu and L2Cu, as perchlorate salts, were established by X‐ray crystallography, which showed them to be binuclear complexes with each Cu atom tetrahedrally coordinated by two P atoms and two N atoms. The ligands and their Cu(I) complexes catalyzed Sonogashira coupling reactions of iodobenzene with phenylacetylene in the presence of K2CO3 under Pd‐free conditions. Coupling reactions catalyzed by L1 or L2 with Cu(MeCN)4ClO4 in situ exhibited better yields than those by the corresponding Cu(I) complexes L1Cu or L2Cu. Detailed studies showed L1 or L2 with Cu(MeCN)4ClO4 to be suitable catalysts for the coupling reaction of terminal alkynes and aryl halides. The coupling reactions of aryl iodides with electron‐withdrawing groups showed better results. Copyright © 2014 John Wiley & Sons, Ltd.
Organic multiviologen electrochromic cells for a color electronic display application
Authors: Chen Pin‐Yi , Chen Cheng‐Sao , Yeh Tsung‐Her
Published: February 2014

The electrochromic (EC) and optical properties of three new viologen compounds containing 1,1′‐di‐n‐heptyl‐4,4′‐bipyridinum dibromide (DHBPDB; C24H38Br2N2), 1‐heptyl‐4‐(4‐pyridyl)pyridinium bromide (HPPB; C17H23BrN2), and 1,1′‐dis(p‐cyanophenyl)‐4,4′‐bipyridinium chloride (DCBPC; C12H8N2OBr2) for potential use in electrochromism applications were investigated. The repetitive stability of all of the EC cells could be improved through the addition of ferrocene as an electron donor (a counter redox material) to the electrolyte solution under several redox cycles. The experimental results demonstrate that the EC cell showed a reversible color change from clear (tintless) to three different colors with the application of electrochemical stimuli at specific potentials. The color of the EC cells turned red, green, or blue upon electrochemical reduction for DHBPDB, HPPB, and DCBPC in indium tin oxide sandwich‐type cells. Because of the different viologen molecules competing to capture electrons and affecting the EC efficiency and life of the multiviologen cells, they could be improved by the optimization of the working voltage in the multiviologen cells from the modification of an operative potential based on the cyclic voltammetry measurements. In this article, we propose a prototype device of multicolor electrochromic display, which provides potential application for multicolor electronic displays or EC paper. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40485.
A review of sawfishes (Pristidae) in the Arabian region: diversity, distribution, and functional extinction of large and historically abundant marine vertebrates
Authors: Moore Alec B. M.
Published: February 2014

Sawfishes (Pristidae) are large shark‐like batoids (rays) that are among the most threatened of all marine fishes. While there is a broad consensus of severe sawfish declines globally, detailed status assessments for most of their vast circumtropical distribution do not exist. This paper reviews sawfishes of waters adjacent to the Arabian Peninsula, focusing on the Gulf.

Until around the 1960s, sawfishes were abundant and widespread in the region, but since around the 1980s, they have been rarely recorded. Sawfishes can now be considered extinct as a functional component of coastal ecosystems, and may be close to being regionally extinct. This assessment is based on the overwhelming weight of evidence from diverse sources such as archaeological data, historical accounts, grey literature, personal communications and extensive fish surveys.

Based on 176 individual records, Pristis zijsron was the most frequently recorded species, occurring in all regional seas. Anoxypristis cuspidata records were limited to the coasts of Iran, Pakistan, and Masirah Island (Oman). The first substantiated Pristis pristis records from the Arabian Peninsula are provided, and two records not identifiable to species do not exclude the possibility that Pristis clavata occurs in the region.

Humans have used sawfishes as a food, oil, trade, and cultural resource for several thousands of years. Fins have been highly valued since at least the mid‐19th century.

Based on recent and historical records, known biology, and marine conservation programmes for other species or habitats, priority areas for sawfish research and recovery programmes are the central southern Gulf; significant mangrove areas in Iran and the UAE; the Musandam Peninsula; and Masirah Island (Oman).

Historical regional declines coincide with the widespread availability of nylon gillnets, to which sawfishes are disproportionately vulnerable. Any attempt at sawfish recovery must enforce strict controls on gillnetting, which could have significant benefits for other marine species of commercial and conservation interest.

Copyright © 2014 John Wiley & Sons, Ltd.
Synthesis of Some New 1,2,4‐Triazole Derivatives Starting from 3‐(4‐Chlorophenyl)‐5‐(4‐methoxybenzyl)‐4H‐1,2,4‐triazol with Anti‐Lipase and Anti‐Urease Activities
Authors: Bekircan Olcay , Menteşe Emre , Ülker Serdar , Kucuk Cagatay
Published: February 2014

In the present study, starting compound 4 was prepared by deamination of compound 2 in the presence of hypophosphorous acid and sodium nitrite. Treatment of compound 4 with ethyl bromoacetate produced ethyl[3‐(4‐chlorophenyl)‐5‐(4‐methoxybenzyl)‐4H‐1,2,4‐triazol‐4‐yl]acetate (5), which was converted to the hydrazide derivative (6) by treatment with hydrazine hydrate. The reaction of compound 6 with aromatic aldehydes resulted in the formation of arylidene hydrazides (7). Treatment of 6 with CS2 in the presence of potassium hydroxide (KOH), followed by cyclization with hydrazine hydrate, afforded 4‐amino‐5‐{[3‐(4‐chlorophenyl)‐5‐(4‐methoxybenzyl)‐4H‐1,2,4‐triazol‐4‐yl]methyl}‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thione (9). The condensation of 9 with appropriate aldehydes gave Schiff bases (10), which were converted into Mannich bases (11) in the presence of formaldehyde. All the synthesized compounds were screened for their anti‐lipase and anti‐urease activities. Compounds 7b, 7d, 11b, 11c, and 11d showed moderate‐to‐good lipase inhibitory effects compared to orlistat. Compounds 7b and 7d exhibited better anti‐lipase activity. Furthermore, among the compounds tested, 11a and 11d were found to show high inhibitory effect against urease with IC50 values of 12.39 ± 0.35 and 16.12 ± 1.06 µg/mL, respectively. Compound 11c showed moderate inhibitory activity. The Mannich base containing compound 11 may be a source of good leads for the synthesis of lipase and urease dual inhibitors.
Enhanced production of 2,3‐butanediol by overexpressing acetolactate synthase and acetoin reductase in Klebsiella pneumoniae
Authors: Guo Xue‐Wu , Zhang Yun‐Hui , Cao Chun‐Hong , Shen Tong , Wu Ming‐Yue , Chen Ye‐Fu , Zhang Cui‐Ying , Xiao Dong‐Guang
Published: February 2014

Mutants with overexpression of α‐acetolactate synthase (ALS), α‐acetolactate decarboxylase, and acetoin reductase (AR), either individually or in combination, were constructed to improve 2,3‐butanediol (2,3‐BD) production in Klebsiella pneumoniae. The recombinant strains were characterized in terms of the enzyme activity, 2,3‐BD yield, and expression levels. The recombinant K. pneumoniae strain (KG‐rs) that overexpressed both ALS and AR showed an improved 2,3‐BD yield. When cultured in the media with five different carbon sources (glucose, galactose, fructose, sucrose, and lactose), the mutant exhibited higher 2,3‐BD productivity and production than the parental strain in all the tested carbon sources except for lactose. The 2,3‐BD production of KG‐rs in a batch fermentation with glucose as the carbon source was 12% higher than that of the parental strain.
Fungal secretomes enhance sugar beet pulp hydrolysis
Authors: Kracher Daniel , Oros Damir , Yao Wanying , Preims Marita , Rezic Iva , Haltrich Dietmar , Rezic Tonci , Ludwig Roland
Published: February 2014

The recalcitrance of lignocellulose makes enzymatic hydrolysis of plant biomass for the production of second generation biofuels a major challenge. This work investigates an efficient and economic approach for the enzymatic hydrolysis of sugar beet pulp (SBP), which is a difficult to degrade, hemicellulose‐rich by‐product of the table sugar industry. Three fungal strains were grown on different substrates and the production of various extracellular hydrolytic and oxidative enzymes involved in pectin, hemicellulose, and cellulose breakdown were monitored. In a second step, the ability of the culture supernatants to hydrolyze thermally pretreated SBP was tested in batch experiments. The supernatant of Sclerotium rolfsii, a soil‐borne facultative plant pathogen, was found to have the highest hydrolytic activity on SBP and was selected for further hydrolyzation experiments. A low enzyme load of 0.2 mg g–1 protein from the culture supernatant was sufficient to hydrolyze a large fraction of the pectin and hemicelluloses present in SBP. The addition of Trichoderma reesei cellulase (1–17.5 mg g–1 SBP) resulted in almost complete hydrolyzation of cellulose. It was found that the combination of pectinolytic, hemicellulolytic, and cellulolytic activities works synergistically on the complex SBP composite, and a combination of these hydrolytic enzymes is required to achieve a high degree of enzymatic SBP hydrolysis with a low enzyme load.
Structure of two crystal forms of sheep β‐lactoglobulin with EF‐loop in closed conformation
Authors: Loch Joanna I. , Molenda Marta , Kopeć Magdalena , Świątek Sylwia , Lewiński Krzysztof
Published: February 2014

Ovine β‐lactoglobulin has been isolated from whey fraction of sheep milk and crystallized. The high‐resolution structures of two crystal forms (triclinic and trigonal) obtained at pH 7.0 have been determined revealing that ovine protein, similarly to its bovine analog, is dimeric. Access to the binding site located in the eight‐stranded antiparallel β‐barrel in both structures is blocked by the EF loop that has been found in closed conformation. Similarly to bovine lactoglobulin (BLG), conformation of the EF loop is stabilized by hydrogen bond between Glu89 and Ser116 indicating that Tanford transition might occur with the same mechanism. The substitution at six positions in relation to the most abundant isoform B of BLG also affects the distribution of electrostatic potentials and the total charge. © 2014 Wiley Periodicals, Inc. Biopolymers 101: 886–894, 2014.
Stabilization of collagen through bioconversion: An insight in protein–protein interaction
Authors: Usharani Nagarajan , Jayakumar Gladstone Christopher , Kanth Swarna Vinodh , Rao Jonnalagadda Raghava
Published: February 2014

Collagen is a natural protein, which is used as a vital biomaterial in tissue engineering. The major concern about native collagen is lack of its thermal stability and weak resistance to proteolytic degradation. In this scenario, the crosslinking compounds used for stabilization of collagen are mostly of chemical nature and exhibit toxicity. The enzyme mediated crosslinking of collagen provides a novel alternative, nontoxic method for stabilization. In this study, aldehyde forming enzyme (AFE) is used in the bioconversion of hydroxylmethyl groups of collagen to formyl groups that results in the formation of peptidyl aldehyde. The resulted peptidyl aldehyde interacts with bipolar ions of basic amino acid residues of collagen. Further interaction leads to the formation of conjugated double bonds (aldol condensation involving the aldehyde group of peptidyl aldehyde) within the collagen. The enzyme modified collagen matrices have shown an increase in the denaturation temperature, when compared with native collagen. Enzyme modified collagen membranes exhibit resistance toward collagenolytic activity. Moreover, they exhibited a nontoxic nature. The catalytic activity of AFE on collagen as a substrate establishes an efficient modification, which enhances the structural stability of collagen. This finds new avenues in the context of protein–protein stabilization and discovers paramount application in tissue engineering. © 2014 Wiley Periodicals, Inc. Biopolymers 101: 903–911, 2014.
Systematic review and meta-analysis of cytokeratin 19-based one-step nucleic acid amplification versus histopathology for sentinel lymph node assessment in breast cancer
Authors: Tiernan J P , Verghese E T , Nair A , Pathak S , Kim B , White J , Thygesen H , Horgan K , Hanby A M
Published: February 2014

Background

One-step nucleic acid amplification (OSNA) is a new rapid assay for detecting breast cancer metastases during surgery, saving a second procedure for patients requiring an axillary clearance. Many centres in the UK and abroad have adopted OSNA in place of routine histopathology, despite no published meta-analysis. The aim of this systematic review and meta-analysis was to determine whether intraoperative OSNA for lymph node assessment is comparable to routine histopathology in the detection of clinically relevant metastases.

Methods

PubMed, Embase, Web of Knowledge and regional databases were searched for relevant studies published before December 2012. Included studies compared OSNA and standard histology using fresh lymph nodes that were assessed in a clearly defined systematic manner in accordance with the index study.

Results

Twelve eligible studies were identified that included 5057 lymph nodes from 2192 patients. Although meta-analysis using a random-effects model showed a similar overall proportion of macrometastases detected (429 of 3234 versus 432 of 3234; odds ratio 0·99, 95 per cent confidence interval 0·86 to 1·15), analysis of concordance showed that the pooled positive predictive value for detecting macrometastases was 0·79. This suggests that up to 21 per cent of patients found to have macrometastases using OSNA would have an axillary clearance when histology would have classified the deposits as non-macrometastases. Furthermore, analysis of data from the index publication showed that the range of cytokeratin 19 titres for tumours of a given volume is too wide to predict tumour size.

Conclusion

OSNA has an unacceptably low positive predictive value, leading to axillary clearances that would not be recommended if standard histology had been used to assess the sentinel node.
Arm lymphoedema after axillary surgery in women with invasive breast cancer
Authors: Sackey H , Magnuson A , Sandelin K , Liljegren G , Bergkvist L , Fülep Z , Celebioglu F , Frisell J
Published: February 2014

Background

The primary aim was to compare arm lymphoedema after sentinel lymph node biopsy (SLNB) alone versus axillary lymph node dissection (ALND) in women with node-negative and node-positive breast cancer. The secondary aim was to examine the potential association between self-reported and objectively measured arm lymphoedema.

Methods

Women who had surgery during 1999–2004 for invasive breast cancer in four centres in Sweden were included. The study groups were defined by the axillary procedure performed and the presence of axillary metastases: SLNB alone, ALND without axillary metastases, and ALND with axillary metastases. Before surgery, and 1, 2 and 3 years after operation, arm volume was measured and a questionnaire regarding symptoms of arm lymphoedema was completed. A mixed model was used to determine the adjusted mean difference in arm volume between the study groups, and generalized estimating equations were employed to determine differences in self-reported arm lymphoedema.

Results

One hundred and forty women had SLNB alone, 125 had node-negative ALND and 155 node-positive ALND. Women who underwent SLNB had no increase in postoperative arm volume over time, whereas both ALND groups showed a significant increase. The risk of self-reported arm lymphoedema 1, 2 and 3 years after surgery was significantly lower in the SLNB group compared with that in both ALND groups. Three years after surgery there was a significant association between increased arm volume and self-reported symptoms of arm lymphoedema.

Conclusion

SLNB is associated with a minimal risk of increased arm volume and few symptoms of arm lymphoedema, significantly less than after ALND, regardless of lymph node status.
Biochemistry students' ideas about shape and charge in enzyme–substrate interactions
Authors: Linenberger Kimberly J. , Bretz Stacey Lowery
Published: February 2014

Biochemistry is a visual discipline that requires students to develop an understanding of numerous representations. However, there is very little known about what students actually understand about the representations that are used to communicate ideas in biochemistry. This study investigated biochemistry students' understanding of multiple representations of enzyme–substrate interactions through both student interviews (N = 25) and responses by a national sample (N = 707) to the Enzyme–Substrate Interactions Concept Inventory. This manuscript reports the findings regarding one category of misconceptions measured by the concept inventory, namely, students' understandings of shape and charge in the context of enzyme–substrate interactions. Students interpret molecular representations depicting such interactions by determining the complementarity between enzyme and substrate by focusing upon charge and hydrogen bonding, but with a disregard for stereochemistry. © 2014 by The International Union of Biochemistry and Molecular Biology, 42(3):XXXXX–XXXXX, 2014.