bluuebunny/crossref_metadata_2025 huggingface dataset:
New diagnostic criteria and severity assessment of acute cholangitis in revised Tokyo guidelines
Authors: Kiriyama Seiki , Takada Tadahiro , Strasberg Steven M. , Solomkin Joseph S. , Mayumi Toshihiko , Pitt Henry A. , Gouma Dirk J. , Garden O. James , Büchler Markus W. , Yokoe Masamichi , Kimura Yasutoshi , Tsuyuguchi Toshio , Itoi Takao , Yoshida Masahiro , Miura Fumihiko , Yamashita Yuichi , Okamoto Kohji , Gabata Toshifumi , Hata Jiro , Higuchi Ryota , Windsor John A. , Bornman Philippus C. , Fan Sheung‐Tat , Singh Harijt , de Santibanes Eduardo , Gomi Harumi , Kusachi Shinya , Murata Atsuhiko , Chen Xiao‐Ping , Jagannath Palepu , Lee Sung Gyu , Padbury Robert , Chen Miin‐Fu
Published: July 2012

Background

The Tokyo Guidelines for the management of acute cholangitis and cholecystitis were published in 2007 (TG07) and have been widely cited in the world literature. Because of new information that has been published since 2007, we organized the Tokyo Guidelines Revision Committee to conduct a multicenter analysis to develop the updated Tokyo Guidelines (TG13).

Methods/materials

We retrospectively analyzed 1,432 biliary disease cases where acute cholangitis was suspected. The cases were collected from multiple tertiary care centers in Japan. The ‘gold standard’ for acute cholangitis in this study was that one of the three following conditions was present: (1) purulent bile was observed; (2) clinical remission following bile duct drainage; or (3) remission was achieved by antibacterial therapy alone, in patients in whom the only site of infection was the biliary tree. Comparisons were made for the validity of each diagnostic criterion among TG13, TG07 and Charcot's triad.

Results

The major changes in diagnostic criteria of TG07 were re‐arrangement of the diagnostic items and exclusion of abdominal pain from the diagnostic list. The sensitivity improved from 82.8 % (TG07) to 91.8 % (TG13). While the specificity was similar to TG07, the false positive rate in cases of acute cholecystitis was reduced from 15.5 to 5.9 %. The sensitivity of Charcot's triad was only 26.4 % but the specificity was 95.6 %. However, the false positive rate in cases of acute cholecystitis was 11.9 % and not negligible. As for severity grading, Grade II (moderate) acute cholangitis is defined as being associated with any two of the significant prognostic factors which were derived from evidence presented recently in the literature. The factors chosen allow severity assessment to be performed soon after diagnosis of acute cholangitis.

Conclusion

TG13 present a new standard for the diagnosis, severity grading, and management of acute cholangitis.
Parental Needs among Children with Birth Defects: Defining a Parent‐to‐Parent Support Network
Authors: Mathiesen A. M. , Frost C. J. , Dent K. M. , Feldkamp M. L.
Published: July 2012

The objective of this study was to explore how a parent‐to‐parent support network could impact parents of a child with a structural birth defect by specifically looking at parents’ continued needs, aspects influencing their participation in support networks, and their recommendations. Structural birth defects occur in approximately 3 % of all infants, representing a significant public health issue. For many reasons, parents are uniquely qualified to provide support to each other. Data were collected retrospectively through a qualitative approach of focus groups or one‐on‐one interviews. Thirty one parents of infants registered in the Utah Birth Defect Network participated in the study. Three themes emerged, “current sources and inconsistencies in parent‐to‐parent‐support,” “aspects that influence participation in parent‐to‐parent network,” and “recommendations for a parent‐to‐parent program.” Health care providers need to be aware of the services and inform parents about these options. A statewide parent‐to‐parent network integrated into all hospitals would be a valuable resource to facilitate sharing of issues related to caring for an infant or child with a birth defect.
Wealth Affirming Policies for Women of Color
Authors: Nembhard Jessica Gordon , Marsh Kris
Published: July 2012

There are a range of solutions that address asset building challenges for low-wealth women. Here we highlight some solutions that focus on basic needs (child care, child support) and creating economic stability with disposable income (income available after basic needs are met); solutions that address predatory lending and the housing crisis; and solutions that focus on joint ownership of assets and community-based asset building.
Locally bounded global solutions in a three-dimensional chemotaxis-Stokes system with nonlinear diffusion
Authors: Tao Youshan , Winkler Michael
Published: July 2012

This paper deals with a boundary-value problem in three-dimensional smoothly bounded domains for a coupled chemotaxis-Stokes system generalizing the prototype

\left\{\begin{matrix} n_{t} + u \cdot \mathrm{∇}n = \mathrm{\Delta }n^{m}−\mathrm{∇} \cdot (n\mathrm{∇}c), \\ c_{t} + u \cdot \mathrm{∇}c = \mathrm{\Delta }c−nc, \\ u_{t} + \mathrm{∇}P = \mathrm{\Delta }u + n\mathrm{∇}\phi , \\ \mathrm{∇} \cdot u = 0, \\ \end{matrix}\right.

which describes the motion of oxygen-driven swimming bacteria in an incompressible fluid.

It is proved that global weak solutions exist whenever

m > \frac{8}{7}

and the initial data

(n_{0},c_{0},u_{0})

are sufficiently regular satisfying

n_{0} > 0

and

c_{0} > 0

. This extends a recent result by Di Francesco, Lorz and Markowich [M. Di Francesco, A. Lorz, P.A. Markowich, Chemotaxis–fluid coupled model for swimming bacteria with nonlinear diffusion: Global existence and asymptotic behavior, Discrete Contin. Dyn. Syst. Ser. A 28 (2010) 1437–1453] which asserts global existence of weak solutions under the constraint

m \in [\frac{7 + \sqrt{217}}{12},2]

.

Ce papier considère un problème aux limites dans des domaines tridimensionnels réguliers et bornés, plus précisément, un système couplé de chemotaxie-Stokes qui généralise le prototype

\left\{\begin{matrix} n_{t} + u \cdot \mathrm{∇}n = \mathrm{\Delta }n^{m}−\mathrm{∇} \cdot (n\mathrm{∇}c), \\ c_{t} + u \cdot \mathrm{∇}c = \mathrm{\Delta }c−nc, \\ u_{t} + \mathrm{∇}P = \mathrm{\Delta }u + n\mathrm{∇}\phi , \\ \mathrm{∇} \cdot u = 0 \\ \end{matrix}\right.

et qui décrit le mouvement des bactéries nageuses conduites par lʼoxygène dans un fluide incompressible.

On montre que les solutions faibles globales existent quand

m > \frac{8}{7}

et la donnée initiale

(n_{0},c_{0},u_{0})

est suffisamment régulière et vérifie

n_{0} > 0

et

c_{0} > 0

. Cela étend le résultat récent de Di Francesco, Lorz et Markowich [M. Di Francesco, A. Lorz, P.A. Markowich, Chemotaxis–fluid coupled model for swimming bacteria with nonlinear diffusion: Global existence and asymptotic behavior, Discrete Contin. Dyn. Syst. Ser. A 28 (2010) 1437–1453] qui affirme lʼexistence globale de solutions faibles sous la contrainte

m \in [\frac{7 + \sqrt{217}}{12},2]

.
CEA‐producing urothelial cell carcinoma with metastasis presenting as a rectal adenocarcinoma
Authors: Yang Ming‐Hsin , Sun Guang‐Huan , Yu Dah‐Shyong , Chang Sun‐Yran , Ma Cheng‐Ping , Cha Tai‐Lung
Published: July 2012

This is a case study of a 61‐year‐old male who presented with difficult defecation for 1 month. A circumferential submucosal rectal tumor was noted on a digital rectal examination and colonoscopy. Laboratory examination revealed high serum levels of carcinoembryonic antigen (CEA; 43.75 ng/mL) and carbohydrate antigen 19‐9 (CA19‐9; 11,790 U/mL). In addition, tumor biopsies revealed a poorly differentiated adenocarcinoma of the rectum with intact mucosa. The patient had history of advanced stage‐T2 urothelial cell carcinoma of bladder, which had been downstaged to T0 by neoadjuvant chemotherapy followed by radical cystectomy 1 year prior. After investigating the initial bladder tumor specimens, a small portion of the tumor with high CEA expression comparable to the submucosal rectal tumor was found. The size of the tumor was reduced and the levels of the tumor markers decreased after administering FOLFIRI chemotherapy targeted at the adenocarcinoma. Although neoadjuvant chemotherapy may have a selective pressure to eliminate most urothelial cell carcinoma, physicians should be aware that it can lead to rectal metastasis via CEA‐producing components.
Charity in the Dutch Republic: an introduction
Authors: VAN VOSS LEX HEERMA , VAN LEEUWEN MARCO H. D.
Published: July 2012

This article surveys the literature on charity in the Dutch Republic, while also presenting the principles of our social science history approach to understanding charity in past societies. We specify a threefold theory on giving in the past, looking at characteristics of donors, characteristics of charitable causes, and at the giving structure at large. We discuss the research design we employ to test this theory on Dutch charity in the sixteenth, seventeenth and eighteenth centuries in the Giving in the Golden Age, or GIGA, project.
Collections for the poor: monetary charitable donations in Dutch towns, c. 1600–1800
Authors: TEEUWEN DANIËLLE
Published: July 2012

In many localities in the Dutch Republic, charitable collections were the single largest source of income for relief institutions for the outdoor poor. This article takes into account both the role of the authorities organising collections and the role of the city-dwellers making charitable donations. It is demonstrated that people from almost all layers of urban society contributed to the collections. By means of thorough planning and exerting social pressure, religious and secular administrators of poor relief tried to maximise Dutch generosity. They presented making charitable donations as a duty of the rich as well as of the less well-off. In the Dutch Republic, not only the elites, but also the middling groups of society, who approximately constituted almost half of the urban population, were of vital importance in financing poor relief.
New Insights into the Atomic-Scale Structures and Behavior of Steels
Authors: Marquis E. A. , Choi P.-Pa , Danoix F. , Kruska K. , Lozano-Perez S. , Ponge D. , Raabe D. , Williams C. A.
Published: July 2012

Atom probe tomography (APT) has significantly contributed to our understanding and development of structural materials through the detailed analysis of solute behavior, cluster formation, precipitate evolution, and interfacial and grain boundary chemistry. Whether one is concerned with light alloys, Ni-based superalloys, or steels, the design objectives are similar: developing alloys with optimum properties (strength, toughness, ductility, fatigue resistance, creep strength) through controlled precipitation, grain structure, solute state, and combination of phases. Performance in service, through microstructural stability and resistance to degradation, is also a major design criterion for the development of novel materials.
Fluorescence Microscopy Light Sources
Authors: Aswani Kavita , Jinadasa Tushare , Brown Claire M.
Published: July 2012

Fluorescence microscopy techniques are now prevalent throughout the life sciences and many of the physical sciences. These techniques are often dependent on white light sources that have evolved from the more traditional mercury arc lamp to metal halide sources to the more recent light emitting diodes (LEDs). The newer light sources show more uniform power across the visible light spectrum, allowing for the use of fluorophores and fluorescent proteins outside of the peak wavelengths associated with the more traditional light sources.
Microscopy Reveals the Chirping of a Jurassic Katydid!
Authors: Carmichael Stephen W.
Published: July 2012

Perhaps you've never wondered what sounds permeated the nighttime in a Jurassic forest, but there is now a partial answer. With the good fortune to obtain a well-preserved fossil specimen, Jun-Jie Gu, Fernando Montealegre-Z, Daniel Robert, Michael Engel, Ge-Xia Qiao, and Dong Ren were able to reconstruct the sounds that would have been made by a katydid of that geologic time.
NetNotes
Authors: Phillips Thomas E.
Published: July 2012

Selected postings to the Microscopy Listserver from March 1, 2012 to April 30, 2012. Complete listings and subscription information can be obtained at http://www.microscopy.com. Postings may have been edited to conserve space or for clarity.
Years to Remember
Authors: Lyman Charles
Published: July 2012

This year marks the 70th anniversary of the organizational meeting that led to what is now the Microscopy Society of America. From its beginnings as a group of electron microscope builders and users, the Society has grown to embrace the science and application of all microscopy and microanalysis techniques used in the physical and life sciences. The Society's publishing activities evolved from the innovative annual meeting proceedings with two-page papers 45 years ago to today's popular journal, proceedings, and trade magazine published for MSA by Cambridge University Press. Below are a few important milestones* for the Society.
Got the Results, Now What Do You Do?
Authors: Heese Michaela
Published: July 2012

Members of the Civil Air Navigation Services Organisation have committed themselves to measure and improve safety culture within their organizations by 2013 ( CANSO, 2010 ). This paper attempts to offer support to air navigation service providers that have already implemented a standardized safety culture survey approach, in the process of transforming their safety culture based on existing survey results. First, an overview of the state of the art with respect to safety culture is presented. Then the application of the CANSO safety culture model from theory into practice is demonstrated based on four selected case studies. Finally, a summary of practical examples for driving safety culture change is provided, and critical success factors supporting the safety culture transformation process are discussed.
Nanoparticle assembly for sensitive DNA detection using SERRS
Authors: McKeating Kristy S. , Dougan Jennifer A. , Faulds Karen
Published: July 2012

SERRS (surface-enhanced resonance Raman scattering) is a vibrational technique, whereby a relatively weak Raman scattering effect is enhanced through the use of a visible chromophore and a roughened metal surface. The direct analysis of DNA by SERRS requires the modification of a nucleic acid sequence to incorporate a chromophore, and adsorption of the modified sequence on to a roughened metal surface. Aggregated metallic nanoparticles are commonly used in the analysis of dye-labelled DNA by SERRS, allowing for detection levels that rival those gained from standard fluorescence-based techniques. In the present paper, we report on how SERRS can be exploited for the analysis of clinically relevant DNA samples. We also report on the ability of nanoparticles to aggregate as the result of a biologically significant event, as opposed to the use of an external charge-modifying agent. The self-assembly of metallic nanoparticles is shown to be a promising new technique in the move towards extremely sensitive methods of DNA analysis by SERRS.
Brain-penetrant microtubule-stabilizing compounds as potential therapeutic agents for tauopathies
Authors: Brunden Kurt R. , Ballatore Carlo , Lee Virginia M.-Y. , Smith Amos B. , Trojanowski John Q.
Published: July 2012

Neurons within the brains of those with AD (Alzheimer's disease) and related neurodegenerative disorders, collectively termed ‘tauopathies’, contain fibrillar inclusions composed of hyperphosphorylated tau protein. Tau is normally enriched in axons, where it binds and stabilizes MTs (microtubules). Tau hyperphosphorylation and aggregation probably result in reduced MT binding that could affect axonal transport and neuronal function. A possible therapeutic strategy to overcome a loss of tau function in tauopathies is administration of MT-stabilizing agents, such as those used in the treatment of cancer. However, these drugs elicit severe side effects, and most existing MT-stabilizing compounds have poor BBB (blood–brain barrier) permeability, which renders them unsuitable for tauopathy treatment. We identified EpoD (epothilone D) as a brain-penetrant MT-stabilizing agent with preferred pharmacokinetic and pharmacodynamic properties. EpoD was evaluated for its ability to compensate for tau loss-of-function in an established Tg (transgenic) mouse model, using both preventative and interventional dosing paradigms. EpoD at doses much lower than previously used in human cancer patients caused improved axonal MT density and decreased axonal dystrophy in the tau Tg mice, leading to an alleviation of cognitive deficits. Moreover, EpoD reduced the extent of tau pathology in aged tau Tg mice. Importantly, no adverse side effects were observed in the EpoD-treated mice. These results suggest that EpoD might be a viable drug candidate for the treatment of AD and related tauopathies.
Potential neuroprotective strategies against tauopathy
Authors: Wheeler Jeanna M. , Guthrie Chris R. , Kraemer Brian C.
Published: July 2012

Tauopathies are neurodegenerative diseases, including AD (Alzheimer's disease) and FTLD-T (tau-positive frontotemporal lobar degeneration), with shared pathology presenting as accumulation of detergent-insoluble hyperphosphorylated tau deposits in the central nervous system. The currently available treatments for AD address only some of the symptoms, and do not significantly alter the progression of the disease, namely the development of protein aggregates and loss of functional neurons. The development of effective treatments for various tauopathies will require the identification of common mechanisms of tau neurotoxicity, and pathways that can be modulated to protect against neurodegeneration. Model organisms, such as Caenorhabditis elegans, provide methods for identifying novel genes and pathways that are involved in tau pathology and may be exploited for treatment of various tauopathies. In the present paper, we summarize data regarding characterization of MSUT2 (mammalian suppressor of tau pathology 2), a protein identified in a C. elegans tauopathy model and subsequently shown to modify tau toxicity in mammalian cell culture via the effects on autophagy pathways. MSUT2 represents a potential drug target for prevention of tau-related neurodegeneration.
Extracellular small RNAs: what, where, why?
Authors: Hoy Anna M. , Buck Amy H.
Published: July 2012

miRNAs (microRNAs) are a class of small RNA that regulate gene expression by binding to mRNAs and modulating the precise amount of proteins that get expressed in a cell at a given time. This form of gene regulation plays an important role in developmental systems and is critical for the proper function of numerous biological pathways. Although miRNAs exert their functions inside the cell, these and other classes of RNA are found in body fluids in a cell-free form that is resistant to degradation by RNases. A broad range of cell types have also been shown to secrete miRNAs in association with components of the RISC (RNA-induced silencing complex) and/or encapsulation within vesicles, which can be taken up by other cells. In the present paper, we provide an overview of the properties of extracellular miRNAs in relation to their capacity as biomarkers, stability against degradation and mediators of cell–cell communication.
Long non-coding RNAs and human disease
Authors: Harries Lorna W.
Published: July 2012

The central dogma of molecular biology states that DNA is transcribed into RNA, which in turn is translated into proteins. We now know, however, that as much as 50% of the transcriptome has no protein-coding potential, but rather represents an important class of regulatory molecules responsible for the fine-tuning of gene expression. Although the role of small regulatory RNAs [microRNAs and siRNAs (small interfering RNA)] is well defined, another much less characterized category of non-coding transcripts exists, namely lncRNAs (long non-coding RNAs). Pervasively expressed by eukaryotic genomes, lncRNAs can be kilobases long and regulate their targets by influencing the epigenetic control, chromatin status, mRNA processing or translation capacity of their targets. In the present review, I outline the potential mechanisms of action of lncRNAs, the cellular processes that have been associated with them, and also explore some of the emerging evidence for their involvement in common human disease.
The mystery of mitochondrial RNases
Authors: Bruni Francesco , Gramegna Pasqua , Lightowlers Robert N. , Chrzanowska-Lightowlers Zofia M.A.
Published: July 2012

The central dogma states that DNA is transcribed to generate RNA and that the mRNA components are then translated to generate proteins; a simple statement that completely belies the complexities of gene expression. Post-transcriptional regulation alone has many points of control, including changes in the stability, translatability or susceptibility to degradation of RNA species, where both cis- and trans-acting elements will play a role in the outcome. The present review concentrates on just one aspect of this complicated process, which ultimately regulates the protein production in cells, or more specifically what governs RNA catabolism in a particular subcompartment of human cells: the mitochondrion.
Intronic microRNAs: a crossroad in gene regulation
Authors: Gromak Natalia
Published: July 2012

Most human genes transcribed by RNA Pol II (polymerase II) contain short exons separated by long tracts of non-coding intronic sequences. In addition to their role in generating proteomic diversity through the process of alternative splicing, intronic sequences host many ncRNAs (non-coding RNAs), involved in various gene regulation processes. miRNAs (microRNAs) are short ncRNAs that mediate either mRNA transcript translational repression and/or degradation. Between 50 and 80% of miRNAs are encoded within introns of host mRNA genes. This observation suggests that there is co-regulation between the miRNA biogenesis and pre-mRNA splicing processes. The present review summarizes current advances in this field and discusses possible roles for intronic co-transcriptional cleavage events in the regulation of human gene expression.
Functional self-assembling polypeptide bionanomaterials
Authors: Doles Tibor , Božič Sabina , Gradišar Helena , Jerala Roman
Published: July 2012

Bionanotechnology seeks to modify and design new biopolymers and their applications and uses biological systems as cell factories for the production of nanomaterials. Molecular self-assembly as the main organizing principle of biological systems is also the driving force for the assembly of artificial bionanomaterials. Protein domains and peptides are particularly attractive as building blocks because of their ability to form complex three-dimensional assemblies from a combination of at least two oligomerization domains that have the oligomerization state of at least two and three respectively. In the present paper, we review the application of polypeptide-based material for the formation of material with nanometre-scale pores that can be used for the separation. Use of antiparallel coiled-coil dimerization domains introduces the possibility of modulation of pore size and chemical properties. Assembly or disassembly of bionanomaterials can be regulated by an external signal as demonstrated by the coumermycin-induced dimerization of the gyrase B domain which triggers the formation of polypeptide assembly.
Role of splice variants in the metastatic progression of prostate cancer
Authors: Hagen Rachel M. , Ladomery Michael R.
Published: July 2012

AS (alternative splicing) and its role in disease, especially cancer, has come to forefront in research over the last few years. Alterations in the ratio of splice variants have been widely observed in cancer. Splice variants of cancer-associated genes have functions that can alter cellular phenotype, ultimately altering metastatic potential. As metastases are the cause of approximately 90% of all human cancer deaths, it is crucial to understand how AS is dysregulated in metastatic disease. We highlight some recent studies into the relationship between altered AS of key genes and the initiation of prostate cancer metastasis.
SAFB1- and SAFB2-mediated transcriptional repression: relevance to cancer
Authors: Hong Elaine A. , Gautrey Hannah L. , Elliott David J. , Tyson-Capper Alison J.
Published: July 2012

SAFB1 (scaffold attachment factor B1) and a second family member SAFB2, are multifunctional proteins implicated in a variety of cellular processes including cell growth, apoptosis and stress response. Their potential function as tumour suppressors has been proposed based on well-described roles in tran-scriptional repression. The present review summarizes the current knowledge of SAFB1 and SAFB2 proteins in transcriptional repression with relevance to cancer.
How does Tra2β protein regulate tissue-specific RNA splicing?
Authors: Elliott David J. , Best Andrew , Dalgliesh Caroline , Ehrmann Ingrid , Grellscheid Sushma
Published: July 2012

The splicing regulator protein Tra2β is conserved between humans and insects and is essential for mouse development. Recent identification of physiological RNA targets has started to uncover molecular targets and mechanisms of action of Tra2β. At a transcriptome-wide level, Tra2β protein binds a matrix of AGAA-rich sequences mapping frequently to exons. Particular tissue-specific alternatively spliced exons contain high concentrations of high scoring Tra2β-binding sites and bind Tra2β strongly in vitro. These top exons were also activated for splicing inclusion in cellulo by co-expression of Tra2β protein and were significantly down-regulated after genetic depletion of Tra2β. Tra2β itself seems to be fairly evenly expressed across several different mouse tissues. In the present paper, we review the properties of Tra2β and its regulated target exons, and mechanisms through which this fairly evenly expressed alternative splicing regulator might drive tissue-specific splicing patterns.
Form and function of eukaryotic unstable non-coding RNAs
Authors: Houseley Jonathan
Published: July 2012

Unstable non-coding RNAs are produced from thousands of loci in all studied eukaryotes (and also prokaryotes), but remain of largely unknown function. The present review summarizes the mechanisms of eukaryotic non-coding RNA degradation and highlights recent findings regarding function. The focus is primarily on budding yeast where the bulk of this research has been performed, but includes results from higher eukaryotes where available.
MicroRNA expression profiling of human islets from individuals with and without Type 2 diabetes: promises and pitfalls
Authors: Locke Jonathan M. , Harries Lorna W.
Published: July 2012

Recent studies in mouse, involving the β-cell-specific deletion of Dicer1, have highlighted the crucial role of miRNAs (microRNAs) in regulating insulin secretion and consequently Type 2 diabetes. Identifying the individual miRNAs involved in human islet dysfunction may be of diagnostic and therapeutic interest. miRNA expression profiling of human islets isolated from donors with and without Type 2 diabetes may represent one of the first steps in the discovery of these specific miRNAs. The present review discusses some of the potential pitfalls and promises of such an approach.
Terminal loop-mediated control of microRNA biogenesis
Authors: Choudhury Nila Roy , Michlewski Gracjan
Published: July 2012

Regulation of miRNA (microRNA) biogenesis shapes the profiles of miRNAs in the living cell, contributing to cell identity and function. Importantly, aberrant miRNA levels have been linked to a variety of human pathological states. In recent years, a number of proteins have been shown to regulate the miRNA biogenesis at the level of Drosha and Dicer cleavage. A large proportion of these factors regulate miRNA production through binding to the TL (terminal loop) regions of miRNA progenitors. In the present paper, we review the current knowledge about pri-miRNA (primary miRNA) and pre-miRNA (precursor miRNA) TL involvement in the regulation of miRNA biogenesis.
The increasing functional repertoire of U1 snRNA
Authors: West Steven
Published: July 2012

Splicing is a key process for mRNA maturation, particularly in higher eukaryotes where most protein-coding transcripts contain multiple introns. It is achieved by the concerted action of five snRNAs (small nuclear RNAs) and hundreds of accessory proteins that form the spliceosome. Although snRNAs are present in equal amounts in the spliceosome, there is an overall excess of U1 in human cells. This finding led to the opinion that U1 might be involved in processes other than splicing. Research has shown that this is indeed the case and some examples found from studies in human cell systems are described briefly in the present review.
The control of histone gene expression
Authors: Rattray Alexander M.J. , Müller Berndt
Published: July 2012

Histone proteins are essential for the packaging of DNA into chromosomes. Histone gene expression is cell-cycle-regulated and coupled to DNA replication. Control of histone gene expression occurs at the transcriptional and post-transcriptional level and ensures that a fine balance between histone abundance and DNA replication is maintained for the correct packaging of newly replicated DNA into chromosomes. In the present paper, we review histone gene expression, highlighting the control mechanisms and key molecules involved in this process.
Degradation of tau protein by autophagy and proteasomal pathways
Authors: Wang Yipeng , Mandelkow Eckhard
Published: July 2012

Tau aggregates are present in several neurodegenerative diseases and correlate with the severity of memory deficit in AD (Alzheimer's disease). However, the triggers of tau aggregation and tau-induced neurodegeneration are still elusive. The impairment of protein-degradation systems might play a role in such processes, as these pathways normally keep tau levels at a low level which may prevent aggregation. Some proteases can process tau and thus contribute to tau aggregation by generating amyloidogenic fragments, but the complete clearance of tau mainly relies on the UPS (ubiquitin–proteasome system) and the ALS (autophagy–lysosome system). In the present paper, we focus on the regulation of the degradation of tau by the UPS and ALS and its relation to tau aggregation. We anticipate that stimulation of these two protein-degradation systems might be a potential therapeutic strategy for AD and other tauopathies.
Deadenylation of cytoplasmic mRNA by the mammalian Ccr4–Not complex
Authors: Doidge Rachel , Mittal Saloni , Aslam Akhmed , Winkler G. Sebastiaan
Published: July 2012

The Ccr4–Not complex is one of the major deadenylase factors present in eukaryotic cells. This multi-subunit protein complex is composed of at least seven stably associated subunits in mammalian cells including two enzymatic deadenylase subunits: one DEDD (Asp-Glu-Asp-Asp)-type deadenylase (either CNOT7/human Caf1/Caf1a or CNOT8/human Pop2/Caf1b/Calif) and one EEP (endonuclease–exonuclease–phosphatase)-type enzyme (either CNOT6/human Ccr4/Ccr4a or CNOT6L/human Ccr4-like/Ccr4b). Here, the role of the human Ccr4–Not complex in cytoplasmic deadenylation of mRNA is discussed, including the mechanism of its recruitment to mRNA and the role of the BTG/Tob proteins.
Adaptation to stress in yeast: to translate or not?
Authors: Simpson Clare E. , Ashe Mark P.
Published: July 2012

For most eukaryotic organisms, including Saccharomyces cerevisiae, the rapid inhibition of protein synthesis forms part of a response to stress. In order to balance the changing conditions, precise stress-specific alterations to the cell's proteome are required. Therefore, in the background of a global down-regulation in protein synthesis, specific proteins are induced. Given the level of plasticity required to enable stress-specific alterations of this kind, it is surprising that the mechanisms of translational regulation are not more diverse. In the present review, we summarize the impact of stress on translation initiation, highlighting both the similarities and distinctions between various stress responses. Finally, we speculate as to how yeast cells generate stress-responsive programmes of protein production when regulation is focused on the same steps in the translation pathway.
Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer's disease
Authors: O'Neill Cora , Kiely Aoife P. , Coakley Meghan F. , Manning Sean , Long-Smith Caitriona M.
Published: July 2012

The quality control of protein homoeostasis deteriorates with aging, causing the accumulation of misfolded proteins and neurodegeneration. Thus, in AD (Alzheimer's disease), soluble oligomers, protofibrils and fibrils of the Aβ (amyloid β-peptide) and tau protein accumulate in specific brain regions. This is associated with the progressive destruction of synaptic circuits controlling memory and higher mental function. The primary signalling mechanisms that (i) become defective in AD to alter the normal proteostasis of Aβ and tau, and (ii) initiate a pathophysiological response to cause cognitive decline, are unclear. The IIS [insulin/IGF-1 (insulin-like growth factor 1)-like signalling] pathway is mechanistically linked to longevity, protein homoeostasis, learning and memory, and is emerging to be central to both (i) and (ii). This pathway is aberrantly overactivated in AD brain at the level of increased activation of the serine/threonine kinase Akt and the phosphorylation of its downstream targets, including mTOR (mammalian target of rapamycin). Feedback inhibition of normal insulin/IGF activation of the pathway also occurs in AD due to inactivation of IRS-1 (insulin receptor substrate 1) and decreased IRS-1/2 levels. Pathogenic forms of Aβ may induce aberrant sustained activation of the PI3K (phosphoinositide 3-kinase)/Akt signal in AD, also causing non-responsive insulin and IGF-1 receptor, and altered tau phosphorylation, conformation and function. Reducing IIS activity in animal models by decreasing IGF-1R levels or inhibiting mTOR activity alters Aβ and tau protein homoeostasis towards less toxic protein conformations, improves cognitive function and extends healthy lifespan. Thus normalizing IIS dysfunction may be therapeutically relevant in abrogating Aβ and tau proteotoxicity, synaptic dysfunction and cognitive decline in AD.
Pleiotropy of microRNA-192 in the kidney
Authors: Jenkins Robert H. , Martin John , Phillips Aled O. , Bowen Timothy , Fraser Donald J.
Published: July 2012

Diverse aetiologies result in significant deviation from homoeostasis in the kidney, leading to CKD (chronic kidney disease). CKD progresses to end-stage renal disease principally as a result of renal fibrosis, although the molecular mechanisms underlying this fibrotic process are still poorly understood. miRNAs (microRNAs) are a recently discovered family of endogenous short single-stranded RNAs that regulate global gene expression at the post-transcriptional level. The recent findings from our laboratory and others discussed in the present review outline pleiotropic roles for miR-192 in renal homoeostasis and in the fibrotic kidney. We describe miR-192-driven anti-and pro-fibrotic effects via the repression of ZEB1 and ZEB2 (zinc finger E-box-binding homeobox proteins 1 and 2), resulting in changes in extracellular matrix deposition and cell differentiation.
Analysis of urinary microRNAs in chronic kidney disease
Authors: Beltrami Cristina , Clayton Aled , Phillips Aled O. , Fraser Donald J. , Bowen Timothy
Published: July 2012

Kidney biopsy is the gold-standard diagnostic test for intrinsic renal disease, but requires hospital admission and carries a 3% risk of major complications. Current non-invasive prognostic indicators such as urine protein quantification have limited predictive value. Better diagnostic and prognostic tests for chronic kidney disease patients are a major focus for industry and academia, with efforts to date directed largely at urinary proteomic approaches. microRNAs constitute a recently identified class of endogenous short non-coding single-stranded RNA oligonucleotides that regulate gene expression post-transcriptionally. Quantification of urinary microRNAs offers an alternative approach to the identification of chronic kidney disease biomarkers.
Tau alternative splicing in familial and sporadic tauopathies
Authors: Niblock Michael , Gallo Jean-Marc
Published: July 2012

Six tau isoforms differing in their affinity for microtubules are produced by alternative splicing from the MAPT (microtubule-associated protein tau) gene in adult human brain. Several MAPT mutations causing the familial tauopathy, FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17), affect alternative splicing of exon 10, encoding a microtubule-binding motif. Advanced RNA analysis methods have suggested that levels of exon 10-containing MAPT mRNA are elevated in Alzheimer's disease. Furthermore, the MAPT H1 haplotype, associated with Alzheimer's disease, promotes exon 10 inclusion in MAPT mRNA. Thus an accurate regulation of tau alternative splicing is critical for the maintenance of neuronal viability, and its alteration might be a contributing factor to Alzheimer's disease. Tau alternative splicing could represent a target for therapeutic intervention to delay the progression of pathology in familial as well as sporadic tauopathies.
What is the pathological significance of tau oligomers?
Authors: Cowan Catherine M. , Quraishe Shmma , Mudher Amritpal
Published: July 2012

Insoluble aggregates of the microtubule-associated protein tau characterize a number of neurodegenerative diseases collectively termed tauopathies. These aggregates comprise abnormally hyperphosphorylated and misfolded tau proteins. Research in this field has traditionally focused on understanding how hyperphosphorylated and aggregated tau mediates dysfunction and toxicity in tauopathies. Recent findings from both Drosophila and rodent models of tauopathy suggest that large insoluble aggregates such as tau filaments and tangles may not be the key toxic species in these diseases. Thus some investigators have shifted their focus to study pre-filament tau species such as tau oligomers and hyperphosphorylated tau monomers. Interestingly, tau oligomers can exist in a variety of states including hyperphosphorylated and unphosphorylated forms, which can be both soluble and insoluble. It remains to be determined which of these oligomeric states of tau are causally involved in neurodegeneration and which signal the beginning of the formation of inert/protective filaments. It will be important to better understand this so that tau-based therapeutic interventions can target the most toxic tau species.
Twice is better: highlights of the second meeting focused on tau biology and pathology
Authors: Skoulakis Efthimios M.C. , Mudher Amritpal
Published: July 2012

It is an exciting time for tau researchers as it is now generally accepted that abnormal tau species are required to mediate the toxic effects of amyloid β-peptide oligomers in Alzheimer's disease. Tau may play multiple roles in neurophysiology and there may be further pathologically relevant tau alterations, besides hyperphosphorylation and aggregation. The recent Biology and Pathology of Tau and its Role in Tauopathies II meeting explored these various aspects of tau, and presentations at the meeting, described in the following articles in this issue of Biochemical Society Transactions, are outlined in the present paper.
Aufbau einer Sicherheitskultur – Eine Führungsaufgabe
Authors: Balhorn Jutta
Published: July 2012

Fehler in der Behandlung werden häufig den Akteuren zugeordnet. Die derzeitig gelebte Fehlerkultur macht es nicht möglich, damit offen und konstruktiv umzugehen. Mehrere Untersuchungen machen deutlich, dass die Ursache für Fehlhandlungen jedoch in der Organisation und dem Management zu suchen sind. Durch die Einführung eines Qualitätsmanagementsystems kann eine Sicherheitskultur aufgebaut werden, in der das Risiko von Fehlhandlungen minimiert wird und diese zu Vorbeugemaßnahmen genutzt werden.
Normen und Richtlinien – Hilfsmittel zur Erhöhung der Sicherheit von Patienten und Anwendern
Authors: Ludewig Thomas
Published: July 2012

In den vorhandenen Publikationen im Bereich der Nephrologie wird oft nur am Rande auf die Aspekte Qualität und Sicherheit in der Behandlungsroutine eingegangen. Die Behandlungsroutine birgt einige Restrisiken, die nicht durch Dialysegeräte oder andere Medizinprodukte abgedeckt werden. Medizinprodukte wie etwa Dialysegeräte, Einmalartikel oder Wasseraufbereitungsanlagen haben heute einen hohen Sicherheitsstandard. In den Gebrauchsanweisungen dieser Produkte sind jedoch umfangreiche Warnhinweise enthalten, in denen die Verantwortung der Anwender hinsichtlich der Sicherheit beschrieben wird. Darüber hinaus gibt es noch eine ganze Reihe von Maßnahmen, die zu treffen sind, um eine sichere Behandlung zu gewährleisten. Anhand der Anwendung der neuen IEC 62653 zusammen mit der ISO 9001 wird beschrieben, wie man Restrisiken und Fehler in der täglichen Routine im Sinne der Patienten- und Anwendersicherheit, aber auch im Hinblick auf die Rechtssicherheit für die Einrichtung, systematisch minimieren kann. Darüber hinaus bietet die ISO 9001 die Möglichkeit eines „lernenden Systems“ – also eines Systems, das durch systematische Kontrolle ständig verbessert wird. Die kombinierte Anwendung der beiden Standards ist in der Praxis eine optimale Grundlage, um die maximale Sicherheit zu erreichen.
Changing the game of outsourcing – the Microsoft OneFinance case
Authors: Vitasek Kate , Manrodt Karl , Krishna Srinivas
Published: July 2012

This case concerns Microsoft's attempt to completely restructure its major global finance processes and operations through what the authors call a Vested Outsourcing agreement. In February 2007, Microsoft signed an outsourcing agreement with Accenture, with an original contract term of 7 years at a value of US$185 million. This was extended 2 years later, to 2018, with expanded scope, and a total contract value of $330 million. Called the OneFinance initiative, the effort outsourced nearly all back office finance transactions spread across 95 countries to service provider Accenture under a new kind of outsourcing model. Under the agreement the parties operate under incentives to improve performance and deliver increased value year-over-year, while sharing in the risks and rewards of doing so. The case focuses on the rationale for this distinctive approach to outsourcing and transformational change, and provides details of the definitions of work, measurements, pricing models and governance structures adopted. The fine-grained account of the OneFinance outsourcing arrangements provides an opportunity to identify the distinctive principles and practices adopted by the parties. Readers can compare and contrast the case with other outsourcing deals and assess the challenges in choosing the supplier and the approach. The case also invites an assessment of the risks being incurred, the inherent implementation and operational challenges and how they might be met. The case also raises questions about what levels of success might be achieved, and what conditions would need to be present for success. Finally, the case raises the issue of whether, and if so how, this distinctive ‘vested’ approach could be adopted elsewhere.
Extracting core shape from x-ray images at the National Ignition Facility
Authors: Glenn S. M. , Benedetti L. R. , Bradley D. K. , Hammel B. A. , Izumi N. , Khan S. F. , Kyrala G. A. , Ma T. , Milovich J. L. , Pak A. E. , Smalyuk V. A. , Tommasini R. , Town R. P.
Published: July 2012

Measuring the shape of implosions is critical to inertial confinement fusion experiments at the National Ignition Facility. We have developed techniques that have proven successful for extracting shape information from images of x-ray self-emission recorded by a variety of diagnostic instruments for both DT-filled targets and low-yield surrogates. These key results help determine optimal laser and target parameters leading to ignition. We have compensated for instrumental response and have employed a variety of image processing methods to remove artifacts from the images while retaining salient features. The implosion shape has been characterized by decomposing intensity contours into Fourier and Legendre modes for different lines of sight. We also describe procedures we have developed for estimating uncertainties in these measurements.
Tensor hypercontraction density fitting. I. Quartic scaling second- and third-order Møller-Plesset perturbation theory
Authors: Hohenstein Edward G. , Parrish Robert M. , Martínez Todd J.
Published: July 2012

Many approximations have been developed to help deal with the O(N4) growth of the electron repulsion integral (ERI) tensor, where N is the number of one-electron basis functions used to represent the electronic wavefunction. Of these, the density fitting (DF) approximation is currently the most widely used despite the fact that it is often incapable of altering the underlying scaling of computational effort with respect to molecular size. We present a method for exploiting sparsity in three-center overlap integrals through tensor decomposition to obtain a low-rank approximation to density fitting (tensor hypercontraction density fitting or THC-DF). This new approximation reduces the 4th-order ERI tensor to a product of five matrices, simultaneously reducing the storage requirement as well as increasing the flexibility to regroup terms and reduce scaling behavior. As an example, we demonstrate such a scaling reduction for second- and third-order perturbation theory (MP2 and MP3), showing that both can be carried out in O(N4) operations. This should be compared to the usual scaling behavior of O(N5) and O(N6) for MP2 and MP3, respectively. The THC-DF technique can also be applied to other methods in electronic structure theory, such as coupled-cluster and configuration interaction, promising significant gains in computational efficiency and storage reduction.
The generalised Zakharov–Shabat system and the gauge group action
Authors: Grahovski Georgi G.
Published: July 2012

The generalized Zakharov–Shabat systems with complex-valued non-regular Cartan elements and the systems studied by Caudrey, Beals, and Coifman (CBC) systems and their gauge equivalent are studied. This study includes: the properties of fundamental analytical solutions for the gauge equivalent to CBC systems and the minimal set of scattering data; the description of the class of nonlinear evolutionary equations, solvable by the inverse scattering method, and the recursion operator, related to such systems; the hierarchies of Hamiltonian structures. The results are illustrated in the example of the multi-component nonlinear Schrödinger equations and the corresponding gauge-equivalent multi-component Heisenberg ferromagnetic type models, related to \documentclass[12pt]{minimal}\begin{document}$so(5,{\mathbb C})$\end{document}so(5,C) algebra.