bluuebunny/crossref_metadata_2025 huggingface dataset:
Probing the druggability of protein–protein interactions: targeting the Notch1 receptor ankyrin domain using a fragment-based approach
Authors: Abdel-Rahman Noha , Martinez-Arias Alfonso , Blundell Tom L.
Published: May 2012

In order to achieve greater selectivity in drug discovery, researchers in both academia and industry are targeting cell regulatory systems. This often involves targeting the protein–protein interactions of regulatory multiprotein assemblies. Protein–protein interfaces are widely recognized to be challenging targets as they tend to be large and relatively flat, and therefore usually do not have the concave binding sites that characterize the so-called ‘druggable genome’. One such prototypic multiprotein target is the Notch transcription complex, where an extensive network of protein–protein interactions stabilize the ternary complex comprising the ankyrin domain, CSL (CBF1/suppressor of Hairless/Lag-1) and MAML (Mastermind-like). Enhanced Notch activity is implicated in the development of T-ALL (T-cell acute lymphoblastic leukaemia) and selective inhibitors of Notch would be useful cancer medicines. In the present paper, we describe a fragment-based approach to explore the druggability of the ankyrin domain. Using biophysical methods and X-ray crystal structure analyses, we demonstrate that molecules can bind to the surface of the ankyrin domain at the interface region with CSL and MAML. We show that they probably represent starting points for designing larger compounds that can inhibit important protein–protein interactions that stabilize the Notch complex. Given the relatively featureless topography of the ankyrin domain, this unexpected development should encourage others to explore the druggability of such challenging multiprotein systems using fragment-based approaches.
Glycosylation of mouse and human immune cells: insights emerging from N-glycomics analyses
Authors: Antonopoulos Aristotelis , North Simon J. , Haslam Stuart M. , Dell Anne
Published: May 2012

N-glycans are key players mediating cell–cell communication in the immune system, interacting with glycan-binding proteins. In the present article, we discuss key themes that are emerging from the structural analysis of complex-type N-linked glycans from human and murine immune cell lines, employing high-sensitivity MALDI (matrix-assisted laser desorption ionization)–TOF (time-of-flight) MS technology. Particular focus is given to terminal epitopes, the abundance of multiply branched N-glycans and how glycosylation can affect human health in diseases such as congenital neutropenia and glycogen storage disease.
Combining modelling and mutagenesis studies of synaptic vesicle protein 2A to identify a series of residues involved in racetam binding
Authors: Shi Jiye , Anderson Dina , Lynch Berkley A. , Castaigne Jean-Gabriel , Foerch Patrik , Lebon Florence
Published: May 2012

LEV (levetiracetam), an antiepileptic drug which possesses a unique profile in animal models of seizure and epilepsy, has as its unique binding site in brain, SV2A (synaptic vesicle protein 2A). Previous studies have used a chimaeric and site-specific mutagenesis approach to identify three residues in the putative tenth transmembrane helix of SV2A that, when mutated, alter binding of LEV and related racetam derivatives to SV2A. In the present paper, we report a combined modelling and mutagenesis study that successfully identifies another 11 residues in SV2A that appear to be involved in ligand binding. Sequence analysis and modelling of SV2A suggested residues equivalent to critical functional residues of other MFS (major facilitator superfamily) transporters. Alanine scanning of these and other SV2A residues resulted in the identification of residues affecting racetam binding, including Ile273 which differentiated between racetam analogues, when mutated to alanine. Integrating mutagenesis results with docking analysis led to the construction of a mutant in which six SV2A residues were replaced with corresponding SV2B residues. This mutant showed racetam ligand-binding affinity intermediate to the affinities observed for SV2A and SV2B.
Collation and data-mining of literature bioactivity data for drug discovery
Authors: Bellis Louisa J. , Akhtar Ruth , Al-Lazikani Bissan , Atkinson Francis , Bento A. Patricia , Chambers Jon , Davies Mark , Gaulton Anna , Hersey Anne , Ikeda Kazuyoshi , Krüger Felix A. , Light Yvonne , McGlinchey Shaun , Santos Rita , Stauch Benjamin , Overington John P.
Published: May 2012

The challenge of translating the huge amount of genomic and biochemical data into new drugs is a costly and challenging task. Historically, there has been comparatively little focus on linking the biochemical and chemical worlds. To address this need, we have developed ChEMBL, an online resource of small-molecule SAR (structure–activity relationship) data, which can be used to support chemical biology, lead discovery and target selection in drug discovery. The database contains the abstracted structures, properties and biological activities for over 700000 distinct compounds and in excess of more than 3 million bioactivity records abstracted from over 40000 publications. Additional public domain resources can be readily integrated into the same data model (e.g. PubChem BioAssay data). The compounds in ChEMBL are largely extracted from the primary medicinal chemistry literature, and are therefore usually ‘drug-like’ or ‘lead-like’ small molecules with full experimental context. The data cover a significant fraction of the discovery of modern drugs, and are useful in a wide range of drug design and discovery tasks. In addition to the compound data, ChEMBL also contains information for over 8000 protein, cell line and whole-organism ‘targets’, with over 4000 of those being proteins linked to their underlying genes. The database is searchable both chemically, using an interactive compound sketch tool, protein sequences, family hierarchies, SMILES strings, compound research codes and key words, and biologically, using a variety of gene identifiers, protein sequence similarity and protein families. The information retrieved can then be readily filtered and downloaded into various formats. ChEMBL can be accessed online at https://www.ebi.ac.uk/chembldb.
Phylogeny of whey acidic protein (WAP) four-disulfide core proteins and their role in lower vertebrates and invertebrates
Authors: Smith Valerie J.
Published: May 2012

Proteins containing WAP (whey acidic protein) domains with a characteristic WFDC (WAP four-disulfide core) occur not only in mammals (including marsupials and monotremes) but also in birds, reptiles, amphibians and fish. In addition, they are present in numerous invertebrates, from cnidarians to urochordates. Many of those from non-mammalian groups are poorly understood with respect to function or phylogeny. Those well characterized so far are waprins from snakes, perlwapins from bivalves and crustins from decapod crustaceans. Waprins are venom proteins with a single WAP domain at the C-terminus. They display antimicrobial, rather than proteinase inhibitory, activities. Perlwapins, in contrast, possess three WAP domains at the C-terminus and are expressed in the shell nacre of abalones. They participate in shell formation by inhibiting the growth of calcium crystals in the shell. The crustin group is the largest of all WFDC-containing proteins in invertebrates with the vast majority being highly expressed in the haemocytes. Most have a single WAP domain at the C-terminus. The presence and type of the domains between the signal sequence and the C-terminus WAP domain separate the different crustin types. Most of the Type I and II crustins are antimicrobial towards Gram-positive bacteria, whereas the Type III crustins tend to display protease inhibition. Expression studies show that at least some crustins have other important biological effects, as levels change with physiological stress, wound repair, tissue regeneration or ecdysis. Thus WAP domains are widely distributed and highly conserved, serving in diverse physiological processes (proteinase inhibition, bacterial killing or inhibition of calcium transport).
WAP domain proteins as modulators of mucosal immunity
Authors: Wilkinson Thomas S. , Roghanian Ali , Simpson Alexander John , Sallenave Jean-Michel
Published: May 2012

WAP (whey acidic protein) is an important whey protein present in milk of mammals. This protein has characteristic domains, rich in cysteine residues, called 4-DSC (four-disulfide core domain). Other proteins, mainly present at mucosal surfaces, have been shown to also possess these characteristic WAP-4-DSC domains. The present review will focus on two WAP-4-DSC containing proteins, namely SLPI (secretory leucocyte protease inhibitor) and trappin-2/elafin. Although first described as antiproteases able to inhibit in particular host neutrophil proteases [NE (neutrophil elastase), cathepsin-G and proteinase-3] and as such, able to limit maladaptive tissue damage during inflammation, it has become apparent that these molecules have a variety of other functions (direct antimicrobial activity, bacterial opsonization, induction of adaptive immune responses, promotion of tissue repair, etc.). After providing information about the ‘classical’ antiproteasic role of these molecules, we will discuss the evidence pertaining to their pleiotropic functions in inflammation and immunity.
War and peace between WAP and HIV: role of SLPI, trappin-2, elafin and ps20 in susceptibility to HIV infection
Authors: Drannik Anna G. , Henrick Bethany M. , Rosenthal Kenneth L.
Published: May 2012

Despite tremendous advances in our understanding of HIV/AIDS since the first cases were reported 30 years ago, we are still a long way from understanding critical steps of HIV acquisition, pathogenesis and correlates of protection. Our new understanding of the importance of the mucosa as a target for HIV infection, as well as our recent observations showing that altered expression and responses of innate pattern recognition receptors are significantly associated with pathogenesis and resistance to HIV infection, indicate that correlates of immunity to HIV are more likely to be associated with mucosal and innate responses. Most of the heterosexual encounters do not result in productive HIV infection, suggesting that the female genital tract is protected against HIV by innate defence molecules, such as antiproteases, secreted mucosally. The present review highlights the role and significance of the serine protease inhibitors SLPI (secretory leucocyte protease inhibitor), trappin-2, elafin and ps20 (prostate stromal protein 20 kDa) in HIV susceptibility and infection. Interestingly, in contrast with SLPI, trappin-2 and elafin, ps20 has been shown to enhance HIV infectivity. Thus understanding the balance and interaction of these factors in mucosal fluids may significantly influence HIV infection.
mRNA stability and control of cell proliferation
Authors: Mazzoni Cristina , Falcone Claudio
Published: May 2012

Most of the studies on cell proliferation examine the control of gene expression by specific transcription factors that act on transcriptional initiation. In the last few years, it became evident that mRNA stability/turnover provides an important mechanism for post-transcriptional control of gene expression. In eukaryotes, mRNAs are mainly degraded after deadenylation by decapping and exosome pathways. Mechanisms of mRNA surveillance comprise deadenylation-independent pathways such as NMD (nonsense-mediated decay), when mRNAs harbour a PTC (premature termination codon), NSD (non-stop decay, when mRNAs lack a termination codon, and NGD (no-go decay), when mRNA translation elongation stalls. Many proteins involved in these processes are conserved from bacteria to yeast and humans. Recent papers showed the involvement of proteins deputed to decapping in controlling cell proliferation, virus replication and cell death. In this paper, we will review the newest findings in this field.
Yeast chronological lifespan and proteotoxic stress: is autophagy good or bad?
Authors: Sampaio-Marques Belém , Felgueiras Carolina , Silva Alexandra , Rodrigues Fernando , Ludovico Paula
Published: May 2012

Autophagy, a highly conserved proteolytic mechanism of quality control, is essential for the maintenance of metabolic and cellular homoeostasis and for an efficient cellular response to stress. Autophagy declines with aging and is believed to contribute to different aspects of the aging phenotype. The nutrient-sensing pathways PKA (protein kinase A), Sch9 and TOR (target of rapamycin), involved in the regulation of yeast lifespan, also converge on a common targeted process: autophagy. The molecular mechanisms underlying the regulation of autophagy and aging by these signalling pathways in yeast, with special attention to the TOR pathway, are discussed in the present paper. The question of whether or not autophagy could contribute to yeast cell death occurring during CLS (chronological lifespan) is discussed in the light of our findings obtained after autophagy activation promoted by proteotoxic stress. Autophagy progressively increases in cells expressing the aggregation-prone protein α-synuclein and seems to participate in the early cell death and shortening of CLS under these conditions, highlighting that autophagic activity should be maintained below physiological levels to exert its promising anti-aging effects.
Nma111p, the pro-apoptotic HtrA-like nuclear serine protease in Saccharomyces cerevisiae: a short survey
Authors: Fahrenkrog Birthe
Published: May 2012

The baker's yeast, Saccharomyces cerevisiae, is also capable of undergoing programmed cell death or apoptosis, for example in response to viral infection as well as during chronological and replicative aging. Intrinsically, programmed cell death in yeast can be induced by, for example, H2O2, acetic acid or the mating-type pheromone. A number of evolutionarily conserved apoptosis-regulatory proteins have been identified in yeast, one of which is the HtrA (high-temperature requirement A)-like serine protease Nma111p (Nma is nuclear mediator of apoptosis). Nma111p is a nuclear serine protease of the HtrA family, which targets Bir1p, the only known inhibitor-of-apoptosis protein in yeast. Nma111p mediates apoptosis in a serine-protease-dependent manner and exhibits its activity exclusively in the nucleus. How the activity of Nma111p is regulated has remained largely elusive, but some evidence points to a control by phosphorylation. Current knowledge of Nma111p's function in apoptosis will be discussed in the present review.
Proteases and caspase-like activity in the yeast Saccharomyces cerevisiae
Authors: Wilkinson Derek , Ramsdale Mark
Published: May 2012

A variety of proteases have been implicated in yeast PCD (programmed cell death) including the metacaspase Mca1 and the separase Esp1, the HtrA-like serine protease Nma111, the cathepsin-like serine carboxypeptideases and a range of vacuolar proteases. Proteasomal activity is also shown to have an important role in determining cell fate, with both pro- and anti-apoptotic roles. Caspase 3-, 6- and 8-like activities are detected upon stimulation of yeast PCD, but not all of this activity is associated with Mca1, implicating other proteases with caspase-like activity in the yeast cell death response. Global proteolytic events that accompany PCD are discussed alongside a consideration of the conservation of the death-related degradome (both at the level of substrate choice and cleavage site). The importance of both gain-of-function changes in the degradome as well as loss-of-function changes are highlighted. Better understanding of both death-related proteases and their substrates may facilitate the design of future antifungal drugs or the manipulation of industrial yeasts for commercial exploitation.
Occurrence of widely used organic UV filters in lake and river sediments
Authors: Kaiser Dominic , Wappelhorst Olaf , Oetken Matthias , Oehlmann Jörg
Published: May 2012

Environmental contextPersonal care products containing organic chemicals to filter the sun’s UV rays are produced and used on a broad scale worldwide. Consequently, these organic UV filters are now widespread in the environment. We investigate the occurrence of seven common organic UV filters in river and lake sediments thereby providing valuable data for the future environmental risk assessment of these chemicals to the benthic community of freshwater ecosystems.
AbstractPersonal care products (PCPs) are produced and used in huge amounts. These formulations are permanently introduced into the aquatic environment during regular use, mainly through municipal sewage treatment plants. Although there is increasing concern about PCP residues in the aquatic environment, little is known about the extent and level of contamination. The occurrence and concentrations of the seven most frequently used ultraviolet (UV) filters in river and lake sediments have been investigated over a 6-month period by gas chromatography–mass spectrometry: benzophenone-3 (BP-3), 3-benzyliden camphor (3-BC), butyl-methoxydibenzoylmethane (B-MDM), ethylhexyl dimethyl p-aminobenzoic acid (ED-PABA), ethylhexyl-methoxycinnamate (EHMC), 3′-(4′-methylbenzyliden)camphor (4-MBC) and octocrylene (OCR). B-MDM, EHMC and OCR were identified as major contaminants. They were present in every sediment sample with maximum concentrations of 62.2, 6.8 and 642 µg kg–1. 3-BC and ED-PABA could not be detected in any sediment sample. The temporal distribution profile and concentrations of UV filters differed between lakes and rivers. Whereas concentrations of all UV filters in river sediments were low and constant over time, lake sediments exhibited high UV-filter levels during summer and concentrations dropped in autumn. These findings support risk assessment activities and contribute to a better understanding of the magnitude of contamination with organic UV-filter substances in aquatic ecosystems.
Restaging Time: Photography, Performance and Anachronism in Shadi Ghadirian's Qajar Series
Authors: Heer Melissa
Published: May 2012

This paper looks at a group of photographs entitled Qajar Series (1998) by artist Shadi Ghadirian. Ghadirian recreates sets to look like those used in photographic portraits taken during the late nineteenth and early twentieth century of the Qajar dynasty period and dresses her female sitters in costumes reminiscent of clothes from the era. The artist also integrates contemporary objects that do not fit within the historical setting created for the camera. This essay examines how the artist uses performance to stage this anachronism and think critically about temporal discourses and their links to the categories of modernity and tradition.
The ethnic and non-ethnic politics of everyday life in Bulgaria's southern borderland
Authors: Dawson James
Published: May 2012

Ethnicity is found in real-world contexts where non-ethnic forms of identification are available. This conclusion is drawn from an empirical study carried out in the multiethnic town of Kurdzhali in Southern Bulgaria, where members of the Bulgarian majority live alongside the Turkish minority. Drawing on the “everyday nationhood” agenda that aims to provide a methodological toolkit for the study of ethnicity/nationhood without overpredicting its importance, the study involved the collection of survey, interview, and ethnographic data. Against the expectations of some experienced scholars of the Central and Eastern Europe region, ethnic identity was found to be more salient for the majority Bulgarians than for the minority Turks. However, the ethnographic data revealed the importance of a rural–urban cleavage that was not predicted by the research design. On the basis of this finding, I argue that the “everyday nationhood” approach could be improved by including a complementary focus on non-ethnic attachments that have been emphasized by scholarship or journalism relevant to the given context. Rather than assuming the centrality of ethnicity, such an “everyday identifications” approach would start from the assumption that ethnic narratives of identity always have to compete with non-ethnic ones.
YOU'RE NOT THERE TO MAKE THE WORLD ANY CLEANER
Authors: Abrantes Manuel
Published: May 2012

Based on a review of contributions from labour sociology, gender studies and neighbouring areas, this article starts by describing the recent manners in which domestic work emerged as a topic of interest. Then, key difficulties underlying the subject in hand are discussed. It is argued that analysis should comprehend the link between the position of in-house services at the lower end of work value hierarchies and the political dynamics of knowledge societies, which requires attention to the role of mentality and ideology in mediating everyday interaction. Ethnic change, the singularity of private households as workplaces and the ambiguous bond between skill and emotional labour are central issues. Some particular perspectives of labour studies are bound to offer an improved lens in generating answers as to where the distribution of fatigue and indignity is actually being decided – and challenged.
Developing research‐informed practitioners – an organisational perspective
Authors: McDonnell Liz , Stratton Peter , Butler Sheila , Cape Nick
Published: May 2012

Background: Two current trends are making it increasingly important for counsellors and psychotherapists to be more engaged with research. Evidence of effectiveness is being increasingly demanded by those who fund our therapies and also by our clients. Meanwhile therapy research is offering practicable ways for therapists to improve their practice. Therapy organisations have an opportunity, perhaps even a duty, to meet the research needs of their members. Methods: This paper reports on a survey conducted by the UK Council for Psychotherapy (UKCP) to help it plan the activities of its Research Faculty. Findings: Key findings from the survey were that the most common ways of UKCP practitioners engaging with research were through reading, discussions with colleagues and doing research. Engaging with research collaboratively with other therapists, having more time, and access to user‐friendly web‐based research resources and updates, were the factors most commonly cited as supporting practitioner engagement with research. Conversely, lack of time, difficulties accessing resources and materials and feeling not competent were the major barriers to practitioner engagement with research. Discussion: Implications for therapists, for training, and for therapy organisations are considered.
Adaptor protein 2–mediated endocytosis of the β-secretase BACE1 is dispensable for amyloid precursor protein processing
Authors: Prabhu Yogikala , Burgos Patricia V. , Schindler Christina , Farías Ginny G. , Magadán Javier G. , Bonifacino Juan S.
Published: May 2012

The β-site amyloid precursor protein (APP)–cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease that catalyzes the proteolytic processing of APP and other plasma membrane protein precursors. BACE1 cycles between the trans-Golgi network (TGN), the plasma membrane, and endosomes by virtue of signals contained within its cytosolic C-terminal domain. One of these signals is the DXXLL-motif sequence DISLL, which controls transport between the TGN and endosomes via interaction with GGA proteins. Here we show that the DISLL sequence is embedded within a longer [DE]XXXL[LI]-motif sequence, DDISLL, which mediates internalization from the plasma membrane by interaction with the clathrin-associated, heterotetrameric adaptor protein 2 (AP-2) complex. Mutation of this signal or knockdown of either AP-2 or clathrin decreases endosomal localization and increases plasma membrane localization of BACE1. Remarkably, internalization-defective BACE1 is able to cleave an APP mutant that itself cannot be delivered to endosomes. The drug brefeldin A reversibly prevents BACE1-catalyzed APP cleavage, ruling out that this reaction occurs in the endoplasmic reticulum (ER) or ER–Golgi intermediate compartment. Taken together, these observations support the notion that BACE1 is capable of cleaving APP in late compartments of the secretory pathway.
Comparison of fisheries yield and oceanographic features at the southern boundaries of the western and eastern Subarctic Pacific Ocean
Authors: Kim Suam , Kang Sukyung , Zhang Chang-Ik , Seo Hyunju , Kang Minho , Kim Jung J.
Published: May 2012

Kim, S., Kang, S., Zhang, C-I., Seo, H., Kang, M., and Kim, J. J. 2012. Comparison of fisheries yield and oceanographic features at the southern boundaries of the western and eastern Subarctic Pacific Ocean. – ICES Journal of Marine Science, 69: . The ecological characteristics of fish communities were compared at the southern boundaries of the eastern and western Subarctic Pacific, based on oceanography, fishery information, and ecological features. Sea surface temperature (SST) was higher in the western North Pacific (NP) than in the eastern NP, and changes in SST showed regional and temporal alternating patterns. Cool and warm SST regimes were observed in the western NP during the early 1980s and the early 2000s, respectively, compared with warm and cool regimes in the eastern NP. Increasing SSTs were more conspicuous in the western than in the eastern NP. Catches from commercial fisheries were higher in the western NP than in the eastern NP. Small pelagic fish were dominant in the western NP, whereas demersal behaviour was common for fish populations in the eastern NP. Changes in species composition also showed contrasting characteristics between the two regions. In the western NP during the early 1980s, landings were dominated (35.8%) by sardine. After two decades, however, landings consisted of a more diverse species group. In the eastern NP, five species appeared in similar percentages (∼10% each) during the early 1980s, but hake alone made up 36.3% of the landings in the early 2000s.
Gynaecomastia
Authors: Hussain Panna
Published: May 2012

Gynae means ‘woman’ and mastos means ‘breast’ in Greek. Gynaecomastia is essentially the presence of excessive breast tissue in a male that gives the appearance of having actual breasts. Gynaecomastia affects men of all ages but is more commonly found in teenage boys and older men. It can affect either one or both breasts. It is an important area of men's health as gynaecomastia can cause physical embarrassment and psychological distress to the individual and can be a marker of serious underlying disease. This article reviews the assessment and management of patients presenting with gynaecomastia in primary care.
Bell's Palsy: An Overview
Authors: Jones Becky
Published: May 2012

A GP will see on average one case of Bell's palsy per year. Bell's palsy, or idiopathic facial nerve palsy as is more correctly termed, is thought to account for around 60–75% of cases of acute facial nerve palsy. These palsies can produce profound cosmetic deformities, which lead to understandable patient distress. A knowledge of the common presentations, pitfalls, treatments and when to involve secondary care, along with effective and empathic communication, is essential for any GP to successfully manage such patients.
Effects of Pharyngeal Cooling on Brain Temperature in Primates and Humans
Authors: Takeda Yoshimasa , Hashimoto Hiroshi , Fumoto Koji , Danura Tetsuya , Naito Hiromichi , Morimoto Naoki , Katayama Hiroshi , Fushimi Soichiro , Matsukawa Akihiro , Ohtsuka Aiji , Morita Kiyoshi
Published: May 2012

Background

Pharyngeal cooling decreases brain temperature by cooling carotid arteries. This study was designed to evaluate the principle of pharyngeal cooling in monkeys and humans.

Methods

Monkeys (n = 10) were resuscitated following 12 min of cardiac arrest. Pharyngeal cooling (n = 5), in which cold saline (5°C) was perfused into the cuff at the rate of 500 ml/min, was initiated simultaneously with the onset of resuscitation for 30 min. Patients (n = 3) who were in an intensive care unit were subjected to 30 min of pharyngeal cooling under propofol anesthesia.

Results

In the animal study, core brain temperature was significantly decreased compared with that in the control group by 1.9°C (SD = 0.8, P < 0.001) and 3.1°C (SD = 1.0, P < 0.001) at 10 min and 30 min after the onset of cooling, respectively. The cooling effect was more evident in an animal with low postresuscitation blood pressure. Total dose of epinephrine, number of direct current shocks, and recovery of blood pressure were not different between the two groups. The pharyngeal epithelium was microscopically intact on day 5. In the clinical study, insertion of the cuff and start of perfusion did not affect heart rate or blood pressure. Tympanic temperature was decreased by 0.6 ± 0.1°C/30 min without affecting bladder temperature. The pharynx was macroscopically intact for 3 days.

Conclusions

Pharyngeal cooling rapidly and selectively decreased brain temperature in primates and tympanic temperature in humans and did not have adverse effects on return of spontaneous circulation, even when initiated during cardiac arrest in primates.
BK polyomavirus with archetypal and rearranged non-coding control regions is present in cerebrospinal fluids from patients with neurological complications
Authors: Bárcena-Panero Ana , Echevarría Juan E. , Van Ghelue Marijke , Fedele Giovanni , Royuela Enrique , Gerits Nancy , Moens Ugo
Published: May 2012

BK polyomavirus (BKPyV) has recently been postulated as an emerging opportunistic pathogen of the human central nervous system (CNS), but it is not known whether specific strains are associated with the neurotropic character of BKPyV. The presence of BKPyV large T-antigen DNA was examined in 2406 cerebrospinal fluid (CSF) samples from neurological patients with suspected JC polyomavirus infection. Twenty patients had a large T-antigen DNA-positive specimen. The non-coding control region (NCCR) of the BKPyV strains amplified from CSF from these 20 patients, strains circulating in renal and bone marrow transplant recipients and from healthy pregnant women was sequenced. The archetypal conformation was the most prevalent in all groups and 14 of the neurological patients harboured archetypal strains, while the remaining six patients possessed BKPyV with rearranged NCCR similar to previously reported variants from non-neurological patients. Transfection studies in Vero cells revealed that five of six early and four of six late rearranged promoters of these CSF isolates showed significantly higher activity than the corresponding archetypal promoter. From seven of the neurological patients with BKPyV DNA-positive CSF, paired serum samples were available. Five of them were negative for BKPyV DNA, while serum from the remaining two patients harboured BKPyV strains with archetypal NCCR that differed from those present in their CSF. Our results suggest that NCCR rearrangements are not a hallmark for BKPyV neurotropism and the dissemination of a rearranged NCCR from the blood may not be the origin of BKPyV CNS infection.
Enhanced Morbidity of Pectoralis Major Myocutaneous Flap Used for Salvage after Previously Failed Oncological Treatment and Unsuccessful Reconstructive Head and Neck Surgery
Authors: Ribeiro Salles Vanni Christiana Maria , de Matos Leandro Luongo , Faro Junior Mário Paulo , Ledo Kanda Jossi , Cernea Cláudio Roberto , Garcia Brandão Lenine , Pinto Fábio Roberto
Published: May 2012

Introduction. The reconstruction of complex cervicofacial defects arising from surgical treatment for cancer is a real challenge for head and neck surgeons, especially in salvage reconstruction surgery and/or failed previous reconstruction. The pectoralis major myocutaneous flap (PMMF) has been widely used in these specific situations due to its reliability and low rate of failure or complications.Objectives. Identify factors that determine complications and influence the final outcome of the reconstructions with PMMF in salvage cancer surgery or in salvage reconstruction.Methods. A cross-sectional study design was used to evaluate a sample including 17 surgical patients treated over a period of ten years that met the inclusion criteria.Results. Reconstruction was successful in 13 cases (76.5%), with two cases of partial flap loss and no case of total loss. Complications occurred in 13 cases (76.5%) and were specifically related to the flap in nine instances (52.9%). An association was identified between the development of major complications and reconstruction of the hypopharynx () as well as in patients submitted to surgery in association with radiation therapy as a previous cancer treatment (). The former condition is also associated with major reconstruction failure (). An even lower incidence of major complications was noted in patients under the age of 53 ().Conclusion. Older patients, with hypopharyngeal defects and submitted to previous surgery plus radiation therapy, presented a higher risk of complications and reconstruction failure with PMMF.
Source Apportionment of PM10by Positive Matrix Factorization in Urban Area of Mumbai, India
Authors: Gupta Indrani , Salunkhe Abhaysinh , Kumar Rakesh
Published: May 2012

Particulate Matter (PM10) has been one of the main air pollutants exceeding the ambient standards in most of the major cities in India. During last few years, receptor models such as Chemical Mass Balance, Positive Matrix Factorization (PMF), PCA–APCS and UNMIX have been used to provide solutions to the source identification and contributions which are accepted for developing effective and efficient air quality management plans. Each site poses different complexities while resolving PM10contributions. This paper reports the variability of four sites within Mumbai city using PMF. Industrial area of Mahul showed sources such as residual oil combustion and paved road dust (27%), traffic (20%), coal fired boiler (17%), nitrate (15%). Residential area of Khar showed sources such as residual oil combustion and construction (25%), motor vehicles (23%), marine aerosol and nitrate (19%), paved road dust (18%) compared to construction and natural dust (27%), motor vehicles and smelting work (25%), nitrate (16%) and biomass burning and paved road dust (15%) in Dharavi, a low income slum residential area. The major contributors of PM10at Colaba were marine aerosol, wood burning and ammonium sulphate (24%), motor vehicles and smelting work (22%), Natural soil (19%), nitrate and oil burning (18%).
Effect of ADH II Deficiency on the Intracellular Redox Homeostasis inZymomonas mobilis
Authors: Galinina Nina , Lasa Zane , Strazdina Inese , Rutkis Reinis , Kalnenieks Uldis
Published: May 2012

Mutant strain of the facultatively anaerobic, ethanol-producing bacteriumZymomonas mobilis, deficient in the Fe-containing alcohol dehydrogenase isoenzyme (ADH II), showed impaired homeostasis of the intracellular NAD(P)H during transition from anaerobic to aerobic conditions, and also in steady-state continuous cultures at various oxygen supplies. At the same time, ADH II deficiency in aerobically grown cells was accompanied by a threefold increase of catalase activity and by about 50% increase of hydrogen peroxide excretion. It is concluded that ADH II under aerobic conditions functions to maintain intracellular redox homeostasis and to protect the cells from endogenous hydrogen peroxide.
The Specific Characteristics in Children with Obstructive Sleep Apnea and Cor Pulmonale
Authors: Lee Pi-Chang , Hwang Betau , Soong Wen-Jue , Meng C. C. Laura
Published: May 2012

Background.The prevalence of obstructive sleep apnea (OSA) in the pediatric population is currently estimated at 1-2% of all children. The purpose of this study was to investigate the clinical and hemodynamic characteristics in pediatric patients with cor pulmonale and OSA.Methods.Thirty children with the diagnosis of OSA were included. These patients consisted of 26 male and 4 female children with a mean age of 7 ± 4 years old. Five of those children were found to be associated with cor pulmonale, and 25 had OSA but without cor pulmonale.Results.The arousal index was much higher in children with OSA and cor pulmonale. The children with OSA and cor pulmonale had much lower mean and minimal oxygen saturation and a higher incidence of bradycardia events. All 5 patients with OSA and cor pulmonale underwent an adenotonsillectomy, and the pulmonary arterial pressure dropped significantly after the surgery.Conclusion.This study demonstrated that the OSA pediatric patients with cor pulmonale had the different clinical manifestations and hemodynamic characteristics from those without cor pulmonale. The adenotonsillectomy had excellent results in both the OSA pediatric patients with and without cor pulmonale.
Applying Econometrics to the Carbon Dioxide “Control Knob”
Authors: Curtin Timothy
Published: May 2012

This paper tests various propositions underlying claims that observed global temperature change is mostly attributable to anthropogenic noncondensing greenhouse gases, and that although water vapour is recognized to be a dominant contributor to the overall greenhouse gas (GHG) effect, that effect is merely a “feedback” from rising temperatures initially resultingonlyfrom “non-condensing” GHGs and not at all from variations in preexisting naturally caused atmospheric water vapour (i.e., [H2O]). However, this paper shows that “initial radiative forcing” is not exclusively attributable to forcings from noncondensing GHG, both because atmospheric water vapour existed before there were any significant increases in GHG concentrations or temperatures and also because there is no evidence that such increases have produced measurably higher [H2O]. The paper distinguishes between forcing and feedback impacts of water vapour and contends that it is theprimaryforcing agent, at much more than 50% of the total GHG gas effect. That means that controlling atmospheric carbon dioxide is unlikely to be an effective “control knob” as claimed by Lacis et al. (2010).
The Relationship between Coenzyme Q10, Oxidative Stress, and Antioxidant Enzymes Activities and Coronary Artery Disease
Authors: Lee Bor-Jen , Lin Yi-Chin , Huang Yi-Chia , Ko Ya-Wen , Hsia Simon , Lin Ping-Ting
Published: May 2012

A higher oxidative stress may contribute to the pathogenesis of coronary artery disease (CAD). The purpose of this study was to investigate the relationship between coenzyme Q10 concentration and lipid peroxidation, antioxidant enzymes activities and the risk of CAD. Patients who were identified by cardiac catheterization as having at least 50% stenosis of one major coronary artery were assigned to the case group (n=51). The control group (n=102) comprised healthy individuals with normal blood biochemical values. The plasma coenzyme Q10, malondialdehyde (MDA) and antioxidant enzymes activities (catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx)) were measured. Subjects with CAD had significant lower plasma coenzyme Q10, CAT and GPx activities and higher MDA and SOD levels compared to those of the control group. The plasma coenzyme Q10 was positively correlated with CAT and GPx activities and negatively correlated with MDA and SOD. However, the correlations were not significant after adjusting for the potential confounders of CAD with the exception of SOD. A higher level of plasma coenzyme Q10 (≥0.52 μmol/L) was significantly associated with reducing the risk of CAD. Our results support the potential cardioprotective impact of coenzyme Q10.
Synthesis of New Bitopic Tetra(pyrazolyl)-Ligands with Neopentane and O-Xylene Backbones
Authors: Potapov Andrei S. , Nudnova Evgenia A. , Ogorodnikov Vladimir D. , Petrenko Tatiana V. , Khlebnikov Andrei I.
Published: May 2012

Several new bitopic pyrazole-containing ligands were prepared from the corresponding pyrazoles and tetrahalogen or tetratosyloxy derivatives of o-xylene and neopentane in a superbasic medium (KOH-DMSO).
Low Body Mass Index Can Identify Majority of Osteoporotic Inflammatory Bowel Disease Patients Missed by Current Guidelines
Authors: Atreja Ashish , Aggarwal Ashish , Licata Angelo A. , Lashner Bret A.
Published: May 2012

Background. Patients with inflammatory bowel disease (IBD) are at high risk of developing osteoporosis. Our objective was to determine the usefulness of IBD guidelines in identifying patients at risk for developing osteoporosis.Methods. We utilized institutional repository to identify patients seen in IBD center and extracted data on demographics, disease history, conventional, and nonconventional risk factors for osteoporosis and Dual Energy X-ray Absorptiometry (DXA) findings.Results. 59% of patients (1004/1703) in our IBD cohort had at least one risk factor for osteoporosis screening. DXA was documented in 263 patients with indication of screening (provider adherence, 26.2%), and of these, 196 patients had DXA completed (“at-risk” group). Ninety-five patients not meeting guidelines-based risk factors also had DXA completed (“not at-risk” group). 139 (70.9%) patients in “at-risk” group had low BMD, while 51 (53.7%) of “not-at-risk” patients had low BMD. Majority of the patients with osteoporosis (83.3%) missed by the current guidelines had low BMI. Multivariate logistic regression analysis showed that low BMI was the strongest risk factor for osteoporosis (OR 3.07; 95% CI, 1.47–6.42;P=0.003).Conclusions. Provider adherence to current guidelines is suboptimal. Low BMI can identify majority of the patients with osteoporosis that are missed by current guidelines.
An Optimized Real-Time PCR to Avoid Species-/Tissue-Associated Inhibition for H5N1 Detection in Ferret and Monkey Tissues
Authors: Zhan LingJun , Bao LinLin , Li FengDi , Lv Qi , Xu LiLi , Qin Chuan
Published: May 2012

The real-time PCR diagnostics for avian influenza virus H5N1 in tissue specimens are often suboptimal, since naturally occurring PCR inhibitors present in samples, or unanticipated match of primer to unsequenced species’ genome. With the principal aim of optimizing the SYBR Green real-time PCR method for detecting H5N1 in ferret and monkey (Chinese rhesus macaque) tissue specimens, we screened various H5N1 gene-specific primer pairs and tested their ability to sensitively and specifically detect H5N1 transcripts in the infected animal tissues, then we assessed RNA yield and quality by comparing Ct values obtained from the standard Trizol method, and four commonly used RNA isolation kits with small modifications, including Roche High Pure, Ambion RNAqueous, BioMIGA EZgene, and Qiagen RNeasy. The results indicated that a single primer pair exhibited high specificity and sensitivity for H5N1 transcripts in ferret and monkey tissues. Each of the four kits and Trizol reagent produced high-quality RNA and removed all or nearly all PCR inhibitors. No statistically significant differences were found between the Ct values from the isolation methods. So the optimized SYBR Green real-time PCR could avoid species- or tissue-associated PCR inhibition in detecting H5N1 in ferret and monkey tissues, including lung and small intestine.
Trypanosoma cruzi: Seroprevalence Detection in Suburban Population of Santiago de Querétaro (Mexico)
Authors: López-Céspedes Ángeles , Villagrán Elena , Briceño Álvarez Kervin , de Diego José Antonio , Hernández-Montiel Hebert Luís , Saldaña Carlos , Sānchez-Moreno Manuel , Marín Clotilde
Published: May 2012

Objectives. To evaluate the potential of iron-oxide dismutase excreted (SODeCRU) byT. cruzias the antigen fraction in the serodiagnosis of Chagas disease and compile new epidemiological data on the seroprevalence of this disease in the suburban population of the city of Santiago de Querétaro (Mexico).Design and Methods. 258 human sera were analyzed by the techniques of ELISA and Western blot and using the homogenate and the SODeCRU.Results. A total of 31 sera were positive against ELISA/SODeCRU (12.4%), while 30 sera proved positive by WB/SODeCRU (11.6%). The comparison between the technique of ELISA and WB showed a sensitivity of 93%, and a specificity of 99%. The positive predictive value was 93% and the negative predictive value was 99%, with a Kappa (κ) value of 1.Conclusions. These preliminary data reveal the degree of infection of nonrural areas of Mexico and demonstrated that SODeCRU is an antigen useful to diagnose Chagas disease.
Lymph Node Harvest in Dukes' A Cancer Pathologist May Need to Consider Fat Dissolving Technique: An Observational Study
Authors: Saklani A. P. , Udy T. , Chandrasekaran T. V. , Davies M. , Beynon J.
Published: May 2012

Background. National institute of clinical excellence (NICE) recommends that a median of 12 lymph nodes be examined in patients operated on with curative intent- to- treat colorectal cancer (CRC). Patients with lymph node harvest less than this may be considered under staged and may receive adjuvant chemotherapy. The aim of our study was to ascertain median number of lymph nodes examined in early colorectal cancers.Method. Patients undergoing colorectal resection between June 2007 and May 2008 were identified and pathological staging obtained using pathology database.Results. 146 patients underwent standardised laparoscopic or open resection of colorectal cancers during this period. Overall median number of lymph nodes harvested/patient was 14 (3–40). When analysed by stage, median number of lymph nodes harvested in Dukes' A, B, and C cancers was 10, 14, and 15, respectively. 11/18 (61%) patients with Dukes’ A carcinoma had lymph node harvest of less than 12 compared with 15/55 (27%) patients with Dukes’ B.Conclusion. Lymph node harvest in Dukes' A cancers using standard techniques tends to be low. Pathologists may have to consider special techniques in harvesting lymph nodes for early colorectal cancers.
Rainfall Mechanisms for the Dominant Rainfall Mode over Zimbabwe Relative to ENSO and/or IODZM
Authors: Manatsa Desmond , Mukwada Geoffrey
Published: May 2012

Zimbabwe’s homogeneous precipitation regions are investigated by means of principal component analysis (PCA) with regard to the underlying processes related to ENSO and/or Indian Ocean Dipole zonal mode (IODZM). Station standardized precipitation index rather than direct rainfall values represent the data matrix used in the PCA. The results indicate that the country’s rainfall is highly homogeneous and is dominantly described by the first principal mode (PC1). This leading PC can be used to represent the major rainfall patterns affecting the country, both spatially and temporarily. The current practice of subdividing the country into the two seasonal rainfall forecast zones becomes irrelevant. Partial correlation analysis shows that PC1 is linked more to the IODZM than to the traditional ENSO which predominantly demonstrates insignificant association with PC1. The pure IODZM composite is linked to the most intense rainfall suppression mechanisms, while the pure El Niño composite is linked to rainfall enhancing mechanisms.
Evaluation of the Ecochemical Status of the Danube in Serbia in Terms of Water Quality Parameters
Authors: Takić Ljiljana , Mladenović-Ranisavljević Ivana , Vuković Milovan , Mladenović Ilija
Published: May 2012

The Danube is an international river passing partly through Serbia. The protection of the environment and sustainable use of water resources is a primary task that implies constant monitoring of the quality status and evaluation of ecochemical status of the water in the Danube basin. The investigation includes calculation of all-inclusive water quality by the Serbian water quality index (SWQI) method and an evaluation of eco-chemical status of the Danube water in terms of water quality parameters from the entry to the exit point along its course through Serbia in the year of 2009. The results show that the overall quality of the Danube water on the territory of Serbia corresponds to the descriptive indicator of “very good” water. According to theCouncil Directive 75/440/EEC, the evaluation of the ecostatus, with slight deviation of individual parameters at Pančevo, corresponds to A1 category of the surface water quality intended for the abstraction of drinking water supplies in member states.