bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteasomes
Authors: Dahlmann Burkhardt
Published: August 2015

The major enzyme system catalysing the degradation of intracellular proteins is the proteasome system. A central inner chamber of the cylinder-shaped 20 S proteasome contains the active site, formed by N-terminal threonine residues. The 20 S proteasomes are extremely inefficient in degrading folded protein substrates and therefore one or two multisubunit 19 S regulatory particles bind to one or both ends of the 20 S proteasome cylinder, forming 26 S and 30 S proteasomes respectively. These regulatory complexes are able to bind proteins marked as proteasome substrates by prior conjugation with polyubiquitin chains, and initiate their unfolding and translocation into the proteolytic chamber of the 20 S proteasome, where they are broken down into peptides of 3–25 amino acids. The polyubiquitin tag is removed from the substrate protein by the deubiquitinating activity of the 19 S regulator complex. Under conditions of an intensified immune response, many eukaryotic cells adapt by replacing standard 20 S proteasomes with immuno-proteasomes and/or generating the proteasome activator complex, PA28. Both of these adaptations change the protein-breakdown process for optimized generation of antigenic peptide epitopes that are presented by the class I MHCs. Hybrid proteasomes (19 S regulator–20 S proteasome–PA28) may have a special function during the immune response. The functions of other proteasome accessory complexes, such as PA200 and PI31 are still under investigation.
Transgenic manipulation of the ubiquitin–proteasome system
Authors: Gray Douglas A.
Published: August 2015

The transgenic approach has been used in model systems from yeast to mammals to address basic research questions, and to achieve agricultural, pharmaceutical or industrial objectives. In basic research, transgenic organisms have generated novel observations that could not have been obtained otherwise. This chapter concentrates on the use of transgenics in deciphering the operation of the UPS (ubiquitin–proteasome system) in the yeast, plant, nematode, fly, and mouse model systems, and will touch on ways in which transgenic manipulation of the UPS has been exploited for agricultural, pharmaceutical, and industrial applications.
The ubiquitin–proteasome system and cancer
Authors: Devoy Anny , Soane Tim , Welchman Rebecca , Mayer R. John
Published: August 2015

The ubiquitin proteasome system (UPS) has emerged from obscurity to be seen as a major player in all regulatory processes in the cell. The concentrations of key proteins in diverse regulatory pathways are controlled by post-translational ubiquitination and degradation by the 26 S proteasome. These regulatory cascades include growth-factor-controlled signal-transduction pathways and multiple points in the cell cycle. The cell cycle is orchestrated by a combination of cyclin-dependent kinases, kinase inhibitors and protein phosphorylation, together with the timely and specific degradation of cyclins and kinase inhibitors at critical points in the cell cycle by the UPS. These processes provide the irreversibility needed for movement of the cycle through gap 1 (G1), DNA synthesis (S), gap 2 (G2) and mitosis (M). The molecular events include cell-size control, DNA replication, DNA repair, chromosomal rearrangements and cell division. It is doubtful whether these events could be achieved without the temporally and spatially regulated combination of protein phosphorylation and ubiquitin-dependent degradation of key cell-cycle regulatory proteins. The oncogenic transformation of cells is a multistep process that can be triggered by mutation of genes for proteins involved in regulatory processes from the cell surface to the nucleus. Since the UPS has critical functions at all these levels of control, it is to be expected that UPS activities will be central to cell transformation and cancer progression.
How to characterize an antioxidant: an update
Authors: Halliwell Barry
Published: August 2015

The term antioxidant is widely used but rarely defined. One suggested definition is that an antioxidant is 'a substance that, when present at low concentrations compared with those of an oxidizable substrate, significantly delays or prevents oxidation of that substrate'. Many substances have been suggested to act as antioxidants in vivo, but few have been proved to do so. This chapter addresses the criteria necessary to evaluate a proposed antioxidant activity. Simple methods for assessing the possibility of physiologically feasible scavenging of important biological oxygen-derived species (superoxide, hydrogen peroxide, hydroxyl radical, hypochlorous acid, haem-associated ferryl species, radicals derived from activated phagocytes and peroxyl radicals, both lipid-soluble and water-soluble) are presented. Methods that may be used to gain evidence that a compound actually does function as an antioxidant in vivo are discussed.
Myeloperoxidase as a generator of drug free radicals
Authors: Uetrecht Jack P.
Published: August 2015

Reactive metabolites are believed to be responsible for many types of toxicity, including idiosyncratic drug reactions. Bone marrow is a frequent target of idiosyncratic reactions, and, since these reactions have characteristics that suggest involvement of the immune system, the formation of reactive metabolites by leucocytes could also play a role in the aetiology of idiosyncratic drug reactions. The major oxidation system in neutrophils and monocytes is a combination of NADPH oxidase and myeloperoxidase. This system oxidizes primary arylamines, such as sulphonamides, to reactive metabolites and these drugs are also associated with a high incidence of agranulocytosis, generalized idiosyncratic reactions and/ or drug-induced lupus. Clozapine is oxidized by this system to a relatively stable nitrenium ion; clozapine is also associated with a high incidence of agranulocytosis. Arylamines that have an oxygen or nitrogen in the para position, such as amodiaquine, vesnarinone and 5-aminosalicylic acid, are oxidized to quinone-like reactive intermediates. Aminopyrine is oxidized to a very reactive dication. Such reactive metabolites could also inhibit neutrophil function and mediate some of the therapeutic effects of these drugs: for example, the use of dapsone for dermatitis herpetiformis and the use of 5-aminosalicylic acid for inflammatory bowel disease.
Atherogenic and anti-atherogenic factors in the human diet
Authors: Addis P.B. , Carr T.P. , Hassel C.A. , Huang Z.Z. , Warner G.J.
Published: August 2015

New atherosclerosis causative factors and preventive modalities have been identified. Atherogenic factors include lipid oxidation products, such as cholesterol oxidation products, malonaldehyde and other aldehydes; trans-fatty acids; some saturated fatty acids (lauric, myristic and possibly palmitic acids); and myristic acid plus cholesterol. Lipid oxidation products are well suited to induce arterial damage, based on their known cytotoxic effects; evidence also indicates the possibility of plaque promotion and stimulation of thrombogenesis. Anti-atherogenic factors include antioxidants, fish oils and other polyunsaturates (if protected from oxidation), fibre and trace minerals such as copper, manganese, selenium and zinc. Iron is unique, being considered as both a potential promoter of atherosclerosis (component of ferritin, conceivably inducing lipid oxidation) and a possible anti-atherogenic component (of antioxidant enzyme catalase). It is apparent that an entire new series of research challenges has been uncovered.
Presenilin function: connections to Alzheimer's disease and signal transduction
Authors: Fraser Paul E. , Yu Gang , Lévesque Lyne , Nishimura Masaki , Yang Dun-Sheng , Mount Howard T.J. , Westaway David , St George-Hyslop Peter H.
Published: August 2015

Missense mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are associated with early-onset familial Alzheimer's disease which displays an accelerated deposition of amyloid plaques and neurofibrillary tangles. Presenilins are multi-spanning transmembrane proteins which localize primarily to the endoplasmic reticulum and the Golgi compartments. We have previously demonstrated that PS1 exists as a high-molecular-mass complex that is likely to contain several functional ligands. Potential binding proteins were screened by the yeast two-hybrid system using the cytoplasmically orientated PS1 loop domain which was shown to interact strongly with members of the armadillo family of proteins, including ϐ-catenin, p0071 and a novel neuron-specific plakophilin-related armadillo protein (NPRAP). Armadillo proteins can have dual functions that encompass the stabilization of cellular junctions/synapses and the mediation of signal transduction pathways. Our observations suggest that PS1 may contribute to both aspects of armadillo-related pathways involving neurite outgrowth and nuclear translocation of ϐ-catenin upon activation of the wingless (Wnt) pathway. Alzheimer's disease (AD)-related presenilin mutations exhibit a dominant gain of aberrant function resulting in the prevention of ϐ-catenin translocation following Wnt signalling. These findings indicate a functional role for PS1 in signalling and suggest that mistrafficking of selected presenilin ligands may be a potential mechanism in the genesis of AD.
New insights into heparan sulphate biosynthesis from the study of mutant mice
Authors: Merry Catherine L. R. , Gallagher John T.
Published: August 2015

Heparan sulphate (HS) is an essential co-receptor for a number of growth factors, morphogens and adhesion proteins. The biosynthetic modifications involved in the generation of a mature HS chain may determine the strength and outcome of HS–ligand interactions. These modifications are catalysed by a complex family of enzymes, some of which occur as multiple gene products. Various mutant mice have now been generated, which lack the function of isolated components of the HS biosynthetic pathway. In this discussion, we outline the key findings of these studies, and use them to put into context our own work concerning the structure of the HS generated by the Hs2st-/- mice.
Roles for asparagine endopeptidase in class II MHC-restricted antigen processing
Authors: Watts Colin , Mazzeo Daniela , West Michelle A. , Matthews Stephen P. , Keane Doreen , Hamilton Garth , Persson Linda V. , Lawson Jennifer M. , Manoury Bénédicte , Moss Catherine X.
Published: August 2015

The adaptive immune response depends on the creation of suitable peptides from foreign antigens for display on MHC molecules to T lymphocytes. Similarly, MHC-restricted display of peptides derived from self proteins results in the elimination of many potentially autoreactive T cells. Different proteolytic systems are used to generate the peptides that are displayed as T cell epitopes on class I compared with class II MHC molecules. In the case of class II MHC molecules, the proteases that reside within the endosome/lysosome system of antigen-presenting cells are responsible; surprisingly, however, there are relatively few data on which enzymes are involved. Recently we have asked whether proteolysis is required simply in a generic sense, or whether the action of particular enzymes is needed to generate specific class II MHC-associated T cell epitopes. Using the recently identified mammalian asparagine endopeptidase as an example, we review recent evidence that individual enzymes can make clear and non-redundant contributions to MHC-restricted peptide display.
Defining substrate specificity and catalytic mechanism in ascorbate peroxidase
Authors: Raven Emma L. , Lad Latesh , Sharp Katherine H. , Mewies Martin , Moody Peter C. E.
Published: August 2015

Haem peroxidases catalyse the H2O2-dependent oxidation of a variety of, usually organic, substrates. Mechanistically, these enzymes are very well characterized: they share a common catalytic cycle that involves formation of a two-electron oxidized intermediate (Compound I) followed by reduction of Compound I by substrate. The substrate specificity is more diverse, however. Most peroxidases oxidize small organic substrates, but there are prominent exceptions to this and the structural features that control substrate specificity remain poorly defined. APX (ascorbate peroxidase) catalyses the H2O2-dependent oxidation of l-ascorbate and has properties that place it at the interface between the class I (e.g. cytochrome c peroxidase) and classical class III (e.g. horseradish peroxidase) peroxidase enzymes. We present a unified analysis of the catalytic and substrate-binding properties of APX, including the crystal structure of the APX-ascorbate complex. Our results provide new rationalization of the unusual functional features of the related cytochrome c peroxidase enzyme, which has been a benchmark for peroxidase-mediated catalysis for more than 20 years.
Generation of bile pigments by haem oxygenase: a refined cellular strategy in response to stressful insults
Authors: Foresti Roberta , Green Colin J. , Motterlini Roberto
Published: August 2015

The family of haem oxygenase enzymes is unique in nature for its role in haem degradation. Haem is cleaved at the α-meso position by haem oxygenase with the support of electrons donated by cytochrome P450 reductase, the first products of this reaction being CO, iron and biliverdin. Biliverdin is then converted to bilirubin by biliverdin reductase. If haem is viewed as a substrate for an anabolic pathway, it becomes evident that haem oxygenases do not break down haem for elimination from the body, but rather use haem to generate crucial molecules that can modulate cellular functions. The facts that biliverdin and bilirubin are potent antioxidants and that CO is both a vasoactive and signalling molecule sustain this idea. The existence of a constitutive haem oxygenase (HO-2), mainly present in the vasculature and nervous system, and an inducible haem oxygenase (HO-1), which is highly expressed during stress conditions in all tissues, also suggests that cells have evolved a fine control of this enzymic pathway to ultimately regulate haem consumption and to ensure production of CO, biliverdin/bilirubin and iron during physiological and pathophysiological situations. This review will focus primarily on the biological actions of biliverdin and bilirubin derived from the haem oxygenase/biliverdin reductase systems and their potential roles in counteracting oxidative and nitrosative stress.
Chromatin-remodelling factors and the maintenance of transcriptional states through DNA replication
Authors: Aligianni Sofia , Varga-Weisz Patrick
Published: August 2015

At the replication fork, nucleosomes, transcription factors and RNA polymerases are stripped off the DNA, the DNA double strands are unzipped and DNA methylation marks may be erased. Therefore DNA replication is both a ‘curse’ and ‘bliss’ for the epigenome, as it disrupts its stability by causing chromatin perturbations, yet it offers an opportunity to initiate changes in chromatin architecture and gene expression patterns, especially during development. Thus the DNA replication site is a critical point for regulation. It has become apparent that there is a close functional relationship between those factors that regulate transcriptional competence and the DNA replication programme. In this review we discuss novel insights into how chromatin-remodelling factors at replication sites are involved in both the maintenance and regulation of transcriptional states.
Core promoter-selective RNA polymerase II transcription
Authors: Gross Petra , Oelgeschläger Thomas
Published: August 2015

The initiation of mRNA synthesis in eukaryotic cells is a complex and highly regulated process that requires the assembly of general transcription factors and RNAP II (RNA polymerase II; also abbreviated as Pol II) into a pre-initiation complex at the core promoter. The core promoter is defined as the minimal DNA region that is sufficient to direct low levels of activator-independent (basal) transcription by RNAP II in vitro. The core promoter typically extends approx. 40 bp up- and down-stream of the start site of transcription and can contain several distinct core promoter sequence elements. Core promoters in higher eukaryotes are highly diverse in structure, and each core promoter sequence element is only found in a subset of genes. So far, only TATA box and INR (initiator) element have been shown to be capable of directing accurate RNAP II transcription initiation independent of other core promoter elements. Computational analysis of metazoan genomes suggests that the prevalence of the TATA box has been overestimated in the past and that the majority of human genes are TATA-less. While TATA-mediated transcription initiation has been studied in great detail and is very well understood, very little is known about the factors and mechanisms involved in the function of the INR and other core promoter elements. Here we summarize our current understanding of the factors and mechanisms involved in core promoter-selective transcription and discuss possible pathways through which diversity in core promoter architecture might contribute to combinatorial gene regulation in metazoan cells.
Inositol lipids and TRPC channel activation
Authors: Putney James W.
Published: August 2015

The original hypothesis put forth by Bob Michell in his seminal 1975 review held that inositol lipid breakdown was involved in the activation of plasma membrane calcium channels or ‘gates’. Subsequently, it was demonstrated that while the interposition of inositol lipid breakdown upstream of calcium signalling was correct, it was predominantly the release of Ca2+ that was activated, through the formation of Ins(1,4,5)P3. Ca2+ entry across the plasma membrane involved a secondary mechanism signalled in an unknown manner by depletion of intracellular Ca2+ stores. In recent years, however, additional non-store-operated mechanisms for Ca2+ entry have emerged. In many instances, these pathways involve homologues of the Drosophila trp (transient receptor potential) gene. In mammalian systems there are seven members of the TRP superfamily, designated TRPC1–TRPC7, which appear to be reasonably close structural and functional homologues of Drosophila TRP. Although these channels can sometimes function as store-operated channels, in the majority of instances they function as channels more directly linked to phospholipase C activity. Three members of this family, TRPC3, 6 and 7, are activated by the phosphoinositide breakdown product, diacylglycerol. Two others, TRPC4 and 5, are also activated as a consequence of phospholipase C activity, although the precise substrate or product molecules involved are still unclear. Thus the TRPCs represent a family of ion channels that are directly activated by inositol lipid breakdown, confirming Bob Michell's original prediction 30 years ago.
Structural studies of phosphoinositide 3-kinase-dependent traffic to multivesicular bodies
Authors: Gill David J. , Teo Hsiangling , Sun Ji , Perisic Olga , Veprintsev Dmitry B. , Vallis Yvonne , Emr Scott D. , Williams Roger L.
Published: August 2015

Three large protein complexes known as ESCRT I, ESCRT II and ESCRT III drive the progression of ubiquitinated membrane cargo from early endosomes to lysosomes. Several steps in this process critically depend on PtdIns3P, the product of the class III phosphoinositide 3-kinase. Our work has provided insights into the architecture, membrane recruitment and functional interactions of the ESCRT machinery. The fan-shaped ESCRT I core and the trilobal ESCRT II core are essential to forming stable, rigid scaffolds that support additional, flexibly-linked domains, which serve as gripping tools for recognizing elements of the MVB (multivesicular body) pathway: cargo protein, membranes and other MVB proteins. With these additional (non-core) domains, ESCRT I grasps monoubiquitinated membrane proteins and the Vps36 subunit of the downstream ESCRT II complex. The GLUE (GRAM-like, ubiquitin-binding on Eap45) domain extending beyond the core of the ESCRT II complex recognizes PtdIns3P-containing membranes, monoubiquitinated cargo and ESCRT I. The structure of this GLUE domain demonstrates that it has a split PH (pleckstrin homology) domain fold, with a non-typical phosphoinositide-binding pocket. Mutations in the lipid-binding pocket of the ESCRT II GLUE domain cause a strong defect in vacuolar protein sorting in yeast.
The inositol polyphosphate 5-phosphatases: traffic controllers, waistline watchers and tumour suppressors?
Authors: Astle Megan V. , Horan Kristy A. , Ooms Lisa M. , Mitchell Christina A.
Published: August 2015

Phosphoinositide signals regulate cell proliferation, differentiation, cytoskeletal rearrangement and intracellular trafficking. Hydrolysis of PtdIns(4,5)P2 and PtdIns(3,4,5)P3, by inositol polyphosphate 5-phosphatases regulates synaptic vesicle recycling (synaptojanin-1), hematopoietic cell function [SHIP1(SH2-containing inositol polyphosphate 5-phosphatase-1)], renal cell function [OCRL (oculocerebrorenal syndrome of Lowe)] and insulin signalling (SHIP2). We present here a detailed review of the characteristics of the ten mammalian 5-phosphatases. Knockout mouse phenotypes and underexpression studies are associated with significant phenotypic changes, indicating non-redundant roles, despite, in many cases, overlapping substrate specificity and tissue expression. The extraordinary complexity in the control of phosphoinositide signalling continues to be revealed.
Reading and spelling skills inGerman third graders: Examining the role of student and context characteristics
Authors: von Suchodoletz Antje , Larsen Ross A. A. , Gunzenhauser Catherine , Fäsche Anika
Published: August 2015

Background

Educational processes and outcomes are influenced by a multitude of factors, including individual and contextual characteristics. Recently, studies have demonstrated that student and context characteristics may produce unique and cumulative effects on educational outcomes.

Aims

The study aimed to investigate (1) the relative contribution of student, classroom, and school characteristics to reading fluency and orthographic spelling, (2) the relative contribution of specific predictors to reading fluency and orthographic spelling within the sets of student, classroom, and school characteristics, and (3) whether the contribution of student, classroom, and school characteristics differs for reading fluency and orthographic spelling.

Sample

Participants were 789German third‐grade students from 56 classrooms in 34 schools.

Method

Students completed an intelligence test and a questionnaire assessing self‐control. Reading fluency and orthographic spelling performance were assessed using standardized achievement tests. Multilevel structural equation modelling was used to control for the hierarchical structure of educational data.

Results and conclusion

Variances in students' reading and spelling skills were in large part explained by student characteristics (>90%). Classroom and school characteristics yielded little variance. Student‐level intelligence and self‐control were significantly related to reading fluency. For orthographic spelling, student‐level intelligence and self‐control, class‐average intelligence, and, at the school level, the socio‐economic status of the school's neighbourhood were significant predictors. Future research needs to investigate relevant classroom and school factors that may directly and indirectly relate to academic outcomes.
Continuous Matching via Vector Field Flow
Authors: Corman Etienne , Ovsjanikov Maks , Chambolle Antonin
Published: August 2015

We present a new method for non‐rigid shape matching designed to enforce continuity of the resulting correspondence. Our method is based on the recently proposed functional map representation, which allows efficient manipulation and inference but often fails to provide a continuous point‐to‐point mapping. We address this problem by exploiting the connection between the operator representation of mappings and flows of vector fields. In particular, starting from an arbitrary continuous map between two surfaces we find an optimal flow that makes the final correspondence operator as close as possible to the initial functional map. Our method also helps to address the symmetric ambiguity problem inherent in many intrinsic correspondence methods when matching symmetric shapes. We provide practical and theoretical results showing that our method can be used to obtain an orientation preserving or reversing map starting from a functional map that represents the mixture of the two. We also show how this method can be used to improve the quality of maps produced by existing shape matching methods, and compare the resulting map's continuity with results obtained by other operator‐based techniques.
Use of endobronchial valve insertion to treat relapsing pneumothorax: a case report and literature review
Authors: Qi Fei , Tian Qing , Chen Liang'an , Li Chunyan , Zhang Shu , Liu Xingchen , Xiao Binbin
Published: August 2015

Backgorund and Aims: Unidirectional endobronchial valves have recently been shown to be beneficial as treatment for persistent air leaks. This report presents a first case of endobronchial valve implantation to treat relapsing pneumothorax in a Chinese patient, and also presents a review of the literature on the use of one‐way valve insertion for the treatment of persistent air leaks.

Methods: The patient did undergo a recent but failed chest tube intervention. By bronchoscopy and using Chartis® system measurements, the upper left lobe (including the left apical bronchus) was closed using a catheter.

Results: After the expected decrease in airflow following bronchial occlusion, increased air pressure and decreased spilled air were noted; it was concluded that the pneumothorax was located in the left upper lobe. A Zephyr® endobronchial valve was placed in the left upper apical bronchus. The health benefits of the procedure were noticed in the following days.

Conclusion: Our review suggests that the use of endobronchial valves could be used as an effective, minimally invasive, low‐risk intervention for patients with pneumothorax that cannot be treated surgically.
The diagnostic value of tumor markers in bronchoalveolar lavage fluid for the peripheral pulmonary carcinoma
Authors: Zhang Shi , Zhao Yun‐feng , Zhang Ming‐zhou , Wu Xue‐ling
Published: August 2015

Background

To investigate the value of Ubiquitin specific peptidase 8 (USP8), Chitinase 3‐like 1 (YKL40), Heat shock protein 90a (HSP90α), glutathione S‐transferase P1 (GSTP1), carcinoembryonic antigen (CEA), neuron specific enolase (NSE) and cytokeratin fragment antiogen 21‐1 (CYFRA21‐1) in bronchoalveolar lavage fluid (BALF) and serum for diagnosis in patients with peripheral lung cancer.

Methods

The concentration of these markers were measured in 50 patients with peripheral lung cancer and 50 patients with benign lung diseases by using enzyme‐linked immuno sorbent assay methods.

Results

There were significant differences between the peripheral lung cancer group and the benign lung disease group (P < 0.05) in the BALF of USP8, YKL40, HSP90α, CEA, NSE and CYFRA21‐1. There were significant differences between the peripheral lung cancer group and the benign lung disease group (P < 0.05) in the serum of HSP90α and CEA. There were no differences in others. There were no correlation between the concentration of all markers and age, histological type, TNM stage (I–IV). There was a weak correlation between the primary foci diameters and the concentration of YKL40 in BALF. (Pearson's correlation: 0.203, P = 0.048) The diagnostic efficiencies of USP8, YKL40, HSP90α were superior to CYFRA21‐1 and NSE, being lower CEA.

Conclusion: Detection of tumor markers in BALF was superior to serum specimens. The measurement of USP8, HSP90α and YKL40 in BALF had more clinical value for the diagnosis of peripheral pulmonary carcinoma.
The effect of CPAP therapy on insulin‐like growth factor and cognitive functions in obstructive sleep apnea patients
Authors: Kanbay Asiye , Demir Neslihan Cerrah , Tutar Nuri , Köstek Osman , Özer Şimşek Zuhal , Buyukoglan Hakan , Demir Ramazan , Parrino Liborio
Published: August 2015

Objectives

Cognitive impairment is common among patients with obstructive sleep apnea syndrome (OSAS). In this study, we aimed to investigate the effect of continuous positive airway pressure (CPAP) therapy on serum insulin‐like growth factor‐1 (IGF‐1) levels and cognitive functions in patients with OSAS.

Patient/Methods: Thirty‐three patients with newly diagnosed OSAS and 17 healthy‐control subjects enrolled in the study. All individuals completed the mini‐mental state examination (MMSE) to evaluate cognitive function. Blood samples were taken at the end of the polysomnography in the morning and the same procedures were repeated 3 months after starting CPAP treatment.

Results

In the OSAS group, the baseline MMSE score was 23.5 ± 3.6, and serum IGF‐1 level was 79.1 ± 36.1 ng/mL. Both values were significantly lower compared with the control group (mean MMSE score = 28.1 ± 1.4, P = 0.0001; mean serum IGF‐1 level = 147.1 ± 49.1 ng/mL, P < 0.0001). Three months after CPAP treatment, OSAS patients showed a significant improvement in MMSE scores (26.5 ± 2.8, P = 0.0001) and serum IGF‐1 level (129.1 ± 58.2, P = 0.0001). In contrast, baseline and third‐month measurements for IGF‐1 levels and MMSE scores were not significantly different in the control group.

Conclusions

The results indicate that effective CPAP therapy in OSAS patients leads to significant improvement in cognitive functions and IGF‐1 even in a short‐term follow‐up. Cognitive function assessment might be a part of evaluation in OSAS patients.
Island time and the interplay between ecology and evolution in species diversification
Authors: Gillespie Rosemary G.
Published: August 2015

Research on the dynamics of biodiversity has progressed tremendously over recent years, although in two separate directions – ecological, to determine change over space at a given time, and evolutionary, to understand change over time. Integration of these approaches has remained elusive. Archipelagoes with a known geological chronology provide an opportunity to study ecological interactions over evolutionary time. Here, I focus on the Hawaiian archipelago and summarize the development of ecological and evolutionary research; I emphasize spiders because they have attributes allowing analysis of ecological affinities in concert with diversification. Within this framework, I highlight recent insights from the island chronosequence, in particular the importance of (i) selection and genetic drift in generating diversity; (ii) fusion and fission in fostering diversification; and (iii) variability upon which selection can act. Insights into biodiversity dynamics at the nexus of ecology and evolution are now achievable by integrating new tools, in particular (i) ecological metrics (interaction networks, maximum entropy inference) across the chronosequence to uncover community dynamics and (ii) genomic tools to understand contemporaneous microevolutionary change. The work can inform applications of invasion and restoration ecology by elucidating the importance of changes in abundances, interaction strengths, and rates of evolutionary response in shaping biodiversity.
Corpus Callosum Diffusion and Language Lateralization in Patients with Brain Tumors: A DTI and fMRI Study
Authors: Tantillo Gabriella , Peck Kyung K. , Arevalo‐Perez Julio , Lyo John K. , Chou Joanne F. , Young Robert J. , Brennan Nicole Petrovich , Holodny Andrei I.
Published: August 2015

BACKGROUND AND PURPOSE

Examining how left‐hemisphere brain tumors might impact both the microstructure of the corpus callosum (CC) as measured by fractional anisotropy (FA) values in diffusion tensor imaging (DTI) as well as cortical language lateralization measured with functional MRI (fMRI).

METHODS

fMRI tasks (phonemic fluency and verb generation) were performed in order to detect activation in Broca's and Wernicke's area. Twenty patients with left‐hemisphere brain tumors were investigated. fMRI results were divided into left dominant (LD), right dominant (RD), or codominant (CD) for language function. DTI was performed to generate FA maps in the anterior and posterior CC. FA values were correlated with the degree of language dominance.

RESULTS

Patients who were LD or RD for language in Broca's area had lower FA in the anterior CC than those who were CD for language (median for CD = .72, LD = .66, RD = .65, P < .09). Lateralized versus CD group level analysis also showed that CD patients had higher FA in the anterior CC than patients who displayed strong lateralization in either hemisphere (median for CD = .72, lateralized = .65, P < .05).

CONCLUSION

Our preliminary observations indicate that the greater FA in CD patients may reflect a more directional microstructure for the CC in this region, suggesting a greater need for interhemispheric transfer of information. Because brain tumors can cause compensatory codominance, our findings may suggest a mechanism by which interhemispheric transfer is facilitated during plasticity in the presence of a tumor.
Obatoclax as a perpetrator in drug–drug interactions and its efficacy in multidrug resistance cell lines
Authors: Theile Dirk , Allendorf David , Köhler Bruno Christian , Jassowicz Adam , Weiss Johanna
Published: August 2015

Objectives

Obatoclax is a pan-Bcl-2 inhibitor with promising efficacy, especially when combined with other antineoplastic agents. Pharmacokinetic drug–drug interactions can occur systemically and at the level of the tumour cell. Thus, this study scrutinised the interaction potential of obatoclax in vitro.

Methods

Obatoclax was screened for P-gp inhibition by calcein assay, for breast cancer resistance protein (BCRP) inhibition by pheophorbide A assay and for inhibition of cytochrome P450 isoenzymes (CYPs) by commercial kits. Induction of mRNA of drug-metabolising enzymes and drug transporters was quantified in LS180 cells via real-time polymerase chain reaction and involvement of nuclear receptors was assessed by reporter gene assays. Proliferation assays were used to assess whether obatoclax retains its efficacy in cell lines overexpressing BCRP, P-glycoprotein (P-gp) or multidrug resistance-associated protein 2 (MRP2).

Key findings

Obatoclax induced the mRNA expression of several genes (e.g. CYP1A1, CYP1A2 and ABCG2 (five to seven-fold) through activation of the aryl hydrocarbon receptor in the nanomolar range. Obatoclax inhibits P-gp, BCRP and some CYPs at concentrations exceeding plasma levels. P-gp, MPR2 or BCRP overexpression did not influence the efficacy of obatoclax.

Conclusions

Obatoclax retains its efficacy in cells overexpressing P-gp, MRP2 or BCRP and might act as a perpetrator drug in interactions with drugs, for example being substrates of CYP1A2 or BCRP.
The formation of an inclusion complex between a metabolite of ginsenoside, compound K and γ-cyclodextrin and its dissolution characteristics
Authors: Igami Kentaro , Ozawa Masatoshi , Inoue Sae , Iohara Daisuke , Miyazaki Toshitsugu , Shinoda Masamitsu , Anraku Makoto , Hirayama Fumitoshi , Uekama Kaneto
Published: August 2015

Objectives

20S-protopanaxadiol 20-O-β-D-glucopyranoside (compound K), a metabolite of ginsenoside, is only sparingly soluble in water. The aim of this study was to improve the low solubility, slow dissolution rate and low oral bioavailability of compound K by forming an inclusion complex with γ-cyclodextrin (γ-CyD), and to compare the results with those of β-CyD complex.

Methods

The interactions of compound K with β and γ-CyDs were studied by the solubility method and proton nuclear magnetic resonance spectroscopy. Solid forms of compound K/CyD complexes with different molar ratios were prepared by the kneading method, and the resulting complex was characterized by powder X-ray diffractometry. The dissolution rate of the complexes was measured by the rotary disk method. In-vivo absorption studies in rats were carried out, and the serum level of compound K, after its oral administration, was measured by a liquid chromatography-tandem mass spectrometry system.

Key findings

γ-CyD markedly improved the low solubility of compound K at lower CyD concentrations (<0.03 M), whereas the solubility was decreased at higher concentrations (>0.06 m). The enhancement in solubility by γ-CyD at a lower concentration was much higher than the corresponding values for β-CyD. The apparent 1:1 stability constant (1.5 × 105  m−1) for the γ-CyD complex was 18-fold larger than that (8.2 × 103  m−1) of the β-CyD complex. The dissolution rate of the 1:1 compound K/γ-CyD complex was faster than that for the 1:3 (guest : host) complex. These results suggest that the dissolution rate of the 1:1 complex, in which the drug is partially included, was faster than that of the 1:3 complex, in which the drug was completely included, due to the higher solubility and amorphous property of the former complex compared with the properties of the latter complex. The fast dissolution of the γ-CyD complex was reflected in the maximum plasma level (Cmax) of the drug and the time (Tmax) to reach the maximum plasma level after its oral administration to rats.

Conclusions

The effect of γ-CyD on enhancing the solubility of compound K is much higher than that for the β-CyD complex, and the dissolution rate of the guest when it is partially included in the γ-CyD is faster the corresponding value when it is completely included in the cavity.
Extrapolation of enalapril efficacy from adults to children using pharmacokinetic/pharmacodynamic modelling
Authors: Kechagia Irene-Ariadne , Kalantzi Lida , Dokoumetzidis Aristides
Published: August 2015

Objectives

To extrapolate enalapril efficacy to children 0–6 years old, a pharmacokinetic/pharmacodynamic (PKPD) model was built using literature data, with blood pressure as the PD endpoint.

Methods

A PK model of enalapril was developed from literature paediatric data up to 16 years old. A PD model of enalapril was fitted to adult literature response vs time data with various doses. The final PKPD model was validated with literature paediatric efficacy observations (diastolic blood pressure (DBP) drop after 2 weeks of treatment) in children of age 6 years and higher. The model was used to predict enalapril efficacy for ages 0–6 years.

Key findings

A two-compartment PK model was chosen with weight, reflecting indirectly age as a covariate on clearance and central volume. An indirect link PD model was chosen to describe drug effect. External validation of the model's capability to predict efficacy in children was successful. Enalapril efficacy was extrapolated to ages 1–11 months and 1–6 years finding the mean DBP drop 11.2 and 11.79 mmHg, respectively.

Conclusions

Mathematical modelling was used to extrapolate enalapril efficacy to young children to support a paediatric investigation plan targeting a paediatric-use marketing authorization application.
Natural course of subjects with elevated liver tests and normal liver histology
Authors: Strasser Michael , Stadlmayr Andreas , Haufe Heike , Stickel Felix , Ferenci Peter , Patsch Wolfgang , Feldman Alexandra , Weghuber Daniel , Datz Christian , Aigner Elmar
Published: August 2015

Background & Aims

Liver biopsy (LB) is performed if non‐invasive work‐up of liver disease is inconclusive. The examination of liver tissue occasionally reveals normal histology. Long‐term follow‐up of such patients has not been performed.

Methods

We identified a total 70 subjects from our LB database with elevated liver tests and normal liver histology after a mean of 90.5 ± 52.3 (range 15–216) months and conducted reassessment of medical history, physical examination, laboratory testing, ultrasound, transient elastography and LB if indicated.

Results

At follow‐up examination, 15 (7 females (f)/8 males (m); 21.4%) subjects had normal liver tests and no further evidence of liver disease. A subset of 37 (29 f/8 m; 52.9%) subjects had persistently elevated liver tests without evidence indicating progressive liver disease but the cause thereof remained unexplained also at the follow‐up visit. Three (0 f/3 m; 4.3%) subjects had consumed excessive alcohol with indicators of alcoholic liver disease. Eleven subjects (4 f/7 m; 15.7%) had developed steatosis on ultrasound examination along with weight gain and/or biochemical features of the metabolic syndrome. In addition, three (2 f/1 m) patients developed autoimmune hepatitis, one female presented with primary biliary cirrhosis. One male was diagnosed with cholangiocellular carcinoma 3 months after the initial evaluation.

Conclusion

The clinical course of most patients was benign, but in approximately 20% of the subjects a liver disease developed. Particular attention should be given to autoimmune liver diseases in subjects with positive autoantibodies. In addition, lifestyle factors such as weight gain and alcohol consumption were associated with the manifestation of liver diseases.
Pacing Strategy, Muscle Fatigue, and Technique in 1500-m Speed-Skating and Cycling Time Trials
Authors: Stoter Inge K. , MacIntosh Brian R. , Fletcher Jared R. , Pootz Spencer , Zijdewind Inge , Hettinga Florentina J.
Published: August 2015

Purpose:

To evaluate pacing behavior and peripheral and central contributions to muscle fatigue in 1500-m speed-skating and cycling time trials when a faster or slower start is instructed.

Methods:

Nine speed skaters and 9 cyclists, all competing at regional or national level, performed two 1500-m time trials in their sport. Athletes were instructed to start faster than usual in 1 trial and slower in the other. Mean velocity was measured per 100 m. Blood lactate concentrations were measured. Maximal voluntary contraction (MVC), voluntary activation (VA), and potentiated twitch (PT) of the quadriceps muscles were measured to estimate central and peripheral contributions to muscle fatigue. In speed skating, knee, hip, and trunk angles were measured to evaluate technique.

Results:

Cyclists showed a more explosive start than speed skaters in the fast-start time trial (cyclists performed first 300 m in 24.70 ± 1.73 s, speed skaters in 26.18 ± 0.79 s). Both trials resulted in reduced MVC (12.0% ± 14.5%), VA (2.4% ± 5.0%), and PT (25.4% ± 15.2%). Blood lactate concentrations after the time trial and the decrease in PT were greater in the fast-start than in the slow-start trial. Speed skaters showed higher trunk angles in the fast-start than in the slow-start trial, while knee angles remained similar.

Conclusions:

Despite similar instructions, behavioral adaptations in pacing differed between the 2 sports, resulting in equal central and peripheral contributions to muscle fatigue in both sports. This provides evidence for the importance of neurophysiological aspects in the regulation of pacing. It also stresses the notion that optimal pacing needs to be studied sport specifically, and coaches should be aware of this.
De NovoCD5 Negative Blastic Mantle Cell Lymphoma Presented with Massive Bone Marrow Necrosis without Adenopathy or Organomegaly
Authors: Elyamany Ghaleb , Alzahrani Ali Matar , Al Mussaed Eman , Aljasem Hassan , Alotaibi Sultan , Elghezal Hatem
Published: August 2015

The recent World Health Organization (WHO) classification defines mantle cell lymphoma (MCL) as a distinct entity characterized by a unique immunophenotype and a molecular hallmark of chromosomal translocation t(11;14)(q13;q32). We report an unusual case of an advanced stage of CD5 negative MCL with a blastoid variant with a massive bone marrow (BM) necrosis as an initial presenting feature, with no adenopathy or hepatosplenomegaly. The pathologic features showed blastoid variant of MCL and flow cytometry showed that the tumor cells were CD5−, CD19+, CD20+, FMC-7+, CD23−, and lambda light chain restricted. Chromosomal analysis, using karyotype and fluorescent in situ hybridization (FISH), demonstrated karyotypic abnormalities in addition to the t(11;14). Our case study may be reported as a unique case of CD5− blastic MCL with unusual presentation and findings which made the diagnosis of MCL difficult.
Interaction betweenFlavivirusand Cytoskeleton during Virus Replication
Authors: Foo Kar Yue , Chee Hui-Yee
Published: August 2015

Flaviviruses are potentially human pathogens that cause major epidemics worldwide.Flavivirusinteracts with host cell factors to form a favourable virus replication site. Cell cytoskeletons have been observed to have close contact with flaviviruses, which expands the understanding of cytoskeleton functions during virus replication, although many detailed mechanisms are still unclear. The interactions between the virus and host cytoskeletons such as actin filaments, microtubules, and intermediate filaments have provided insight into molecular alterations during the virus infection, such as viral entry, in-cell transport, scaffold assembly, and egress. This review article focuses on the utilization of cytoskeleton byFlavivirusand the respective functions during virus replication.
Study on theΥ(1S)→BcMWeak Decays
Authors: Sun Junfeng , Chen Lili , Wang Na , Chang Qin , Huang Jinshu , Yang Yueling
Published: August 2015

Motivated by the prospects of the potentialΥ(1S)particle at high-luminosity heavy-flavor experiments, we studied theΥ(1S)→BcMweak decays, whereM=π,ρ,K(∗). The nonfactorizable contributions to hadronic matrix elements are taken into consideration with the QCDF approach. It is found that the CKM-favoredΥ(1S)→Bcρdecay has branching ratio ofO(10-10), which might be measured promisingly by the future experiments.
Self-Healing Hydrogels Based on Carboxymethyl Chitosan and Acryloyl-6-aminocaproic Acid
Authors: Duan Jiufang
Published: August 2015

Once cracks have formed within hydrogel materials, the integrity of the structure is signifcantly compromised, regardless of the application. Here, we demonstrate cross-linked CMCS hydrogels can be engineered to exhibit self-healing under mild conditions. CMCS hydrogels based on CMCS and acryloyl-6-aminocaproic acid (A6ACA) were synthesized by free radical aqueous copolymerization using ammonium persulfate as initiator. A series of hydrogels was synthesized varying the percentage of A6ACA. The hydrogels were characterized by Fourier transform infrared spectroscopy (FTIR) techniques and their morphologies were investigated by scanning electron microscope (SEM) images. When the proportion of A6ACA was increased, the compressive strength, stress, and strain of hydrogels were increased. The cross-linked hydrogel based on CMCS that can autonomously heal between cut surfaces after 1 h was formed under mild conditions. The increase of A6ACA content in the hydrogels will lead to increased mechanical properties and mechanical healing efficiencies for highly cross-linked polymeric networks. Hydrogen bond is the main reason for self-healing ability, and the covalent cross-linkss and noncovalent cross-links both bear loads in the hyrogel. Polymers with the ability to self-repair after sustaining damage could extend the lifetime of materials used in many applications.
An Affinity Propagation-Based DNA Motif Discovery Algorithm
Authors: Sun Chunxiao , Huo Hongwei , Yu Qiang , Guo Haitao , Sun Zhigang
Published: August 2015

The planted(l,d)motif search (PMS) is one of the fundamental problems in bioinformatics, which plays an important role in locating transcription factor binding sites (TFBSs) in DNA sequences. Nowadays, identifying weak motifs and reducing the effect of local optimum are still important but challenging tasks for motif discovery. To solve the tasks, we propose a new algorithm, APMotif, which first applies the Affinity Propagation (AP) clustering in DNA sequences to produce informative and good candidate motifs and then employs Expectation Maximization (EM) refinement to obtain the optimal motifs from the candidate motifs. Experimental results both on simulated data sets and real biological data sets show that APMotif usually outperforms four other widely used algorithms in terms of high prediction accuracy.