bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of p53 Genotype on Gene Expression and DNA Adducts in ENU‐Exposed Mice
Authors: Kulkarni Rohan , Petibone Dayton M. , Chang Ching‐Wei , Chen James J. , Tolleson William H. , Melchior William B. , Churchwell Mona I. , Beland Frederick A. , Morris Suzanne M.
Published: March 2013

P53, the tumour suppressor protein, plays a crucial role in the maintenance of genomic stability and is regarded as the ‘guardian of the genome’. To study tissue differences in
p
53 loss‐of‐function mutations, we investigated the effect of
N
‐ethyl‐
N
‐nitrosourea (ENU), a highly potent mutagen, on gene expression at 4 and 24 h after exposure in the liver of
p53
+/+
,
p
53
+/−
and
p
53
−/−
mice. Quantitative PCR and a targeted array were used to analyse the expression of 84 genes known to be involved in the p53 pathway at each time point. In addition, the levels of O
6
‐ethyldeoxyguanosine, a major mutagenic DNA adduct, and the expression of
Mgmt
were determined at the 4‐ and 24‐h time points. Significant differences were found among the three genotypes for the expression of the functional gene groupings of apoptosis, cell cycle, cell growth and proliferation and DNA repair. Furthermore, the loss of O
6
‐ethyldeoxyguanosine from the DNA paralleled the expression of
Mgmt
in
p
53
+/+
and
p
53
+/−
mice. The data from this study will aid in understanding variation in the DNA damage response across tissues and the biological effects of loss of function in
p
53.
Application of Ecotoxicogenomics for Understanding Mode of Action of Chemicals and Species Extrapolation
Authors: Hajime Watanabe , Yasuhiko Kato , Taisen Iguchi
Published: March 2013

Chemicals released into the environment have a potential to affect various species; therefore, evaluation of the impacts of the chemicals on ecosystems is an urgent issue. However, strategies to evaluate impacts of chemicals on ecosystems have been very limited, because species in the environment are too diverse to establish common strategy for the evaluation. This difficulty can be overcome by applying genomic approaches because genomic information is conserved among various species. Recent advances in toxicogenomics, the integration of genomics into toxicology, can be applied to ecotoxicology, named ecotoxicogenomics. Application of ecotoxicogenomics to
Daphnia magna
, a small crustacean, proved that it can be used for classification of chemicals. Similar approaches can also be applied to other organisms such as algae. By taking into account gene annotations and other genomic information, these analyses can be helpful to extrapolate the effects of chemicals to other species.
Integrative Analysis of Microarray Data: A Path for Systems Toxicology
Authors: Rasche Axel , Yildirimman Reha , Herwig Ralf
Published: March 2013

Microarrays are the standard tool for a genome‐wide analysis of gene expression. Multiple studies exist that, for example, track changes of systems with respect to compound treatment or compare the treated versus the untreated states. Besides these single studies, integrative approaches that analyze many such studies in parallel have gained increasing attention because they constitute a crucial step for the identification of general biological processes to relevant the system under analysis and would, thus, lead to the identification of more stable and robust marker genes. For gene expression analysis, the Affymetrix arrays are a well‐established and widely used experimental system. In this chapter, we provide a basic understanding of this microarray technology and describe the design, pre‐processing, and analysis of the data. Standardized and automatic pre‐processing procedures are essential for the subsequent parallel analysis of many data sets. These procedures are greatly supported by storage and information systems collecting the essential information. As an example for an integrated analysis of a large number of toxicology data sets, we describe recent results on a meta‐analysis combining different chip platforms, different species, and treatments with different genotoxic and non‐genotoxic compounds. We show how general mechanisms, biological pathways, and endpoints of toxicity can be reconstructed by this approach.
Mitochondria‐Specific Mouse Gene Array and its Application in Toxicogenomics
Authors: Desai Varsha G.
Published: March 2013

In recent years, mitochondria have gained significant attention in toxicology because of their involvement in several drug‐induced toxicities and in the pathogenesis of a number of degenerative diseases. Thus far, numerous molecular and biochemical assays have been developed and utilized to understand the association between mitochondria and drug toxicities or disease processes. However, the knowledge gained by these assays is inadequate to obtain a comprehensive outlook of the mitochondrial activity during toxic exposures and the underlying pathologies. High‐throughput technologies, such as DNA microarray, have great potential in advancing genomic research in toxicology. This technology allows expression profiling of thousands of genes in a single experiment. Building on this technology, a mitochondria‐specific mouse oligonucleotide microarray (MitoChip) was developed, which is described in this review. This review also discusses results generated using the MitoChip in studies that were designed to elucidate the molecular mechanisms of altered mitochondrial function induced by anti‐HIV drugs (zidovudine and lamivudine) and a weight‐loss dietary supplement (usnic acid) in mice. The results from these studies clearly demonstrate that the MitoChip is a valuable genomic tool and can help unravel the underlying molecular basis of impaired mitochondrial function in drug‐induced toxicities.
Use of Proteomic and Metabolomic Techniques in Ecotoxicological Research
Authors: Sepúlveda Maria S. , Ralston‐Hooper Kimberly J. , Sanchez Brian C. , Hopf‐Jannasch Amber , Baker Stephanie D. , Diaz Naomi , Adamec Jiri
Published: March 2013

Over the last decade, the environmental sciences have witnessed an incredible movement towards the utilization of high through‐put molecular tools that are capable of detecting simultaneous changes of hundreds and even thousands of molecules and molecular components after exposure of organisms to different environmental stressors. These techniques have received lots of attention because they not only offer the potential to unravel novel mechanisms of physiological and toxic action, but they also are amenable for the discovery of biomarkers of exposure and effects. In this chapter we will review the state of knowledge of two of these holistic tools in ecotoxicological research: Proteomics and metabolomics. We will follow this review with a presentation of three of our own case studies utilizing proteomic and metabolomic tools: (i) Analysis of proteomic responses in fish exposed to different types of contaminants using GeneGo™; (ii) Comparison of proteomic and metabolomic responses in aquatic invertebrates exposed to herbicides; and (ii) Use of metabolomics to characterize egg quality in fish eating birds exposed to persistent organic pollutants. We will end with some ideas for future studies and research needs.
Metabolomics in Systems Toxicology: Towards Personalized Medicine
Authors: Schnackenberg Laura K. , Sun Jinchun , Beger Richard D.
Published: March 2013

Metabolomics along with systems biology technologies such as transcriptomics and proteomics has the capability of providing translational diagnostic, prognostic and mechanistic biomarkers of drug‐induced injury. Metabolomics has several advantages over the other omics platforms, such as ease of sample preparation, data acquisition and use of biofluids collected through minimally invasive procedures in pre‐clinical and clinical studies. The role of metabolomics in systems toxicology is reviewed and examples of metabolomics in pre‐clinical and clinical studies are provided. The role of metabolomics in personalized medicine is provided with special sections focusing on drug–drug and drug–nutrient interactions, metabolic fluxes and challenge tests.
Application of Metabonomic Approach in Target Organ Toxicity
Authors: Zira Athina , Theocharis Stamatios
Published: March 2013

The report and understanding of interactions among genes, proteins and metabolites is of crucial importance in the classification of mechanisms involved in chemical/drug‐induced toxicity. Consequently, the application of the “omics” technologies (genomics, proteomics and metabonomics), and mainly metabonomics, is imperative in toxicological studies. Metabonomics has been widely used in established models of target organ toxicity in order to monitor the effect of the toxic agents and possibly identify novel biomarkers of toxicity. In the present review, the applications of metabonomics in toxicological studies have been reported. Although limitations from the use of this technology in toxicology still exist, its combination with genomics and proteomics could provide valuable information for the underlying mechanisms of target organ toxicity.
Mechanistic Investigation of
EMD
335823s Hepatotoxicity Using Multiple Omics Profiling Technologies
Authors: Sposny Alexandra , Schmitt Christina S. , Hewitt Philip G.
Published: March 2013

We have used modern omics technologies (including Toxicogenomics, proteomics, metabonomics and profiling from FFPE tissues) to ascertain whether a systems biology approach would improve our understanding of the mechanism of toxicity of a compound.

Wistar rats were treated for up to 14 days with a non‐toxic dose (15 mg kg
−1
) or a high dose (350 mg kg
−1
) of a known hepatotoxic compound (EMD 335823), chosen to ensure significant hepatotoxicity (liver necrosis, fibrosis, and bile duct necrosis/hyperplasia).

Genomics, proteomics, and metabonomics identified animals with the most severe effects, in good agreement with pathological findings. Protein expression changes correlated well with gene expression changes, indicating that EMD 335823 regulated PPARα signaling. EMD 335823 is an aldose reductase inhibitor resulting in increased glucose metabolism and alterations in fatty acid metabolism. These disturbances result in lower energy resources, contributing to the pathogenesis of liver damage. Proteomics and metabonomics also showed clear separation of the most severely affected animals, although the limited numbers of molecules identified could not reveal the mechanism of toxicity alone.

The combination of omics technologies allowed a more detailed analysis and identification of potential mechanisms of action, improving the overall understanding of the compounds toxicity. Additionally, there are indications that a compound‐specific signature was visible earlier, when no histopathological changes occurred.
Unravelling Sex Differences in Drug‐Induced Liver Injury
Authors: Tong Weida , Shi Qiang , Salminen William , Chen Minjun , Fang Hong , Suzuki Ayako , Mendrick Donna L.
Published: March 2013

Liver toxicity accounts for 40% of failed drugs in clinical studies and approximately 21% of drugs that are removed from the market. It is suspected that drug‐induced liver injury (DILI) is more common in females, thus impacting women's health to a higher degree. However, it is unclear how common this potential sex‐based sensitivity may be and the mechanisms underlying the differences. High‐content and high‐throughput molecular technologies such as DNA microarrays have contributed significantly to the understanding of health and disease at the molecular level. In 2001, DNA microarray studies began to emerge to investigate sex‐associated liver gene expression profiles under physiological and pathological conditions. This review is an analysis of clinical reports published to date to determine the weight of evidence in support of sex‐biased sensitivity to DILI. Sex differences related to disease susceptibility/progression and adverse drug events are discussed at the molecular level with emphasis on genomic data in an attempt to place the evidence in a biological context.
Commonality and Stochasticity in Systems Toxicology
Authors: Hirabayashi Yoko , Inoue Tohru
Published: March 2013

“Systems toxicology” is “systems biology” applied to general toxicology, which is to elucidate a universal concept of biological interactions between living organisms and xenobiotics by global assays of transcriptomics, proteomics and other various applied omics studies, during various biological steps inin vivoresponses, in developmental, pubertal and senescent stages, and at the ontological or phylogenical level, in addition toin vitrocellular responses. The aim of the chapter is to focus on systems toxicology to incorporate a new biological concept that distinguishes commonality and stochasticity from those xenobiotic responses when one incorporates computational toxicological data from the gene chip microarray into systems toxicology. The multiplicity of biological reactions can be better understood when common gene expression profiles and stochastic gene expression profiles would be unsupervisedly analyzed computationally. Previous toxicological data have been analysed frequently with their average endpoints focused on the commonality. However, probabilistic stochasticity may be analysed as specific stochastic clusters that elucidate other aspects of biological diversity in future “systems toxicology”.
Systems Biology: Integrating ‘‐Omics'‐Oriented Approaches to Determine Foodborne Microbial Toxins
Authors: Singh Om V. , Nagaraj Nagathihalli S. , Gabani Prashant
Published: March 2013

The possible origins of microbial toxins vary widely, and detection of these toxins in different food matrices is a major challenge for food industries and regulatory agencies. New methodologies are needed to quickly and precisely detect traces of micro‐organisms and their toxic metabolites. In post‐genomics era, systems biology approaches, ranging from genomic sequencing to transcriptomics, proteomics and metabolomic profiling, may be an effective platform for developing tests to identify a variety of toxins in field applications; multiple functional ‘‐omics’ could be combined into a system‐wide approach for detecting toxins, which may also be useful in the study of microbial pathogenesis. Advances in systems biology are addressed in the current article, as well as possible uses of these high‐throughput platforms to ensure food and feed safety.
Epigenomic Analysis in Toxicology
Authors: Ushijima Toshikazu , Okochi‐Takada Eriko , Takeshima Hideyuki
Published: March 2013

Epigenetic modifications are essential for development, differentiation, and reprogramming. They are inherited upon somatic cell replication, and include DNA methylation and histone modifications. Abnormality of epigenetic modifications is deeply involved in human cancers, as known by global hypomethylation and regional hypermethylation. Recent findings on the high fraction of cells affected in normal‐appearing tissues indicated that epigenomic alterations are also involved in acquired disorders other than cancers. In spite of the deep involvement of epigenomic alterations in human diseases, only limited information is available for inducers of epigenetic changes, including aging, chronic inflammation, virus infection, disturbances in one carbon metabolism, and some chemicals. One of the reasons why a very limited number of chemicals are known as inducers of epigenetic alterations (epimutagens) is the lack of a sufficiently convenient and sensitive assay system. Toxicological considerations from the viewpoint of epigenomics are critically important, and epigenomic toxicology has just started.
Sequencing Technology Advances and Toxicology
Authors: Ratnasinghe Luke D.
Published: March 2013

Systems toxicology is going through a revolution with advancements in genomics methods. Microarray technology has been a significant driving force in toxicogenomics. Next generation sequencing methods promise to overtake use of microarrays in the toxicology tool kit by overcoming many of the limitations of microarrays. In next generation sequencing, every nucleic acid molecule is sequenced individually and counted. Millions of molecules can be sequenced simultaneously eliminating the need for traditional standards and reference samples. The promise of next generation sequencing is that genome of an entire organism or a cell can be sequenced rapidly and affordably. All the RNA transcripts in a cell can be sequenced, identified, counted, and categorized with almost absolute precision. Systems toxicology, which involves the iterative study of how chemicals influence gene expression and toxicological outcomes will be vastly improved with the adaptation of next generation sequencing.
Next‐Generation Sequencing: A Revolutionary Tool for Toxicogenomics
Authors: Su Zhenqiang , Ning Baitang , Fang Hong , Hong Huixiao , Perkins Roger , Tong Weida , Shi Leming
Published: March 2013

Over the past five years, DNA sequencing has been undergoing fundamental changes due to the rapid development of next‐generation sequencing (NGS) technologies. NGS technologies have been offering unprecedented opportunities for high‐throughput functional genomic research, and opening up new fields and novel applications in biology, life sciences, and biomedicine. The major advantages of NGS technologies over conventional Sanger sequencing include sequencing cost reduction from about 0.50 per kilobase to as little as 0.001 per kilobase, and massive parallelism that dramatically increases sequencing throughput. However, Sanger‐based approaches provide advantages in terms of read‐length and base call accuracy.

In this chapter, we first describe the fundamental principles of four currently commercialized NGS platforms from Roche/454, Illumina, Life Technologies, and Helicos BioSciences. Next we discuss the challenges in analyzing short reads from NGS, and outline major applications of these new technologies. Finally, we compare data between NGS and microarrays with a toxicogenomics study aiming at gene expression profiling.
In Silico
Tools for Molecular Modeling
Authors: Umashankar Vetrivel , Gurunathan Subramanian
Published: March 2013

Molecular modeling is the atomic‐level description of molecular systems. The development of molecular modeling programs and their application in pharmaceutical research has been formalized as a field of study known as computer‐assisted drug design (CADD) or computer‐assisted molecular design (CAMD). Molecular modeling methods are now routinely used to investigate the structure, dynamics and thermodynamics of biological, inorganic and polymeric systems. Although initially models were physically drawn or made using appropriate materials, the development of computer programs introduced CADD or CAMD. Stages of molecular modeling are covered in this chapter and a few
in silico
tools available are discussed. Molecular modeling has been of great use to many scientists by decreasing time taken for the otherwise tedious task of modeling and associated analysis such as potential drug candidate identification, docking, protein–protein interactions, etc.
Nanotoxicology
Authors: Ma Yinfa , Lin Weisheng
Published: March 2013

Nanotechnology has become one of the leading technologies in the past two decades due to its unique applications in many areas. However, the health effects of nanomaterials have caused people great concerns, mainly due to the small particle sizes and unique properties of the nanomaterials. The large specific surface areas of the nanomaterials make them very reactive in the cellular environment, and may impose very different biological effects than those of the bulk materials. Consequently, the levels of toxicity of nanomaterials are potentially higher than those of bulk materials. A large amount of research, bothin vitroandin vivo, has been conducted and the data have shown that several types of nanomaterials are highly toxic. This chapter mainly summarizes the work being done in the area of nanotoxicology and the proper ways to carry out nanotoxicology studies to assure that valid data can be obtained, including characterization of nanomaterials, proposed mechanisms of nanomaterials, types of biomarkers and analytical techniques that were used to assess the levels of nanotoxicity, and experimental design forin vitroandin vivonanotoxicology studies. In conclusion, this chapter serves as a short version of a handbook to assist nanotoxicology researchers in experimental designs, assessment, and data evaluations.
Toxicity of Selenium Compounds and Nano‐Selenium Particles
Authors: Zhang Jinsong , Spallholz Julian E.
Published: March 2013

Selenium is a necessary dietary constituent of at least 25 human selenoproteins and enzymes all containing selenocysteine. In excessive amounts, all selenium compounds become toxic in a dose‐dependent fashion to cellsin vitroand to the primary target tissue of chronic selenium toxicity, the liver. Elemental selenium of zero valence state has long been considered to be biologically inert. With bovine serum albumin or other dispersant agents such as polysaccharide, biologically active nano‐selenium particles (Nano‐Se) are formed from sodium selenite and glutathione. Different from the biologically inert black elemental selenium with coarse size, red Nano‐Se manifests toxicity which conforms to the concern of nanotoxicity. However, compared with selenium compounds such as sodium selenite, selenomethionine and Se‐methylselenocysteine, Nano‐Se is not compromised in increasing the activities of selenoenzymes including glutathione peroxidase and thioredoxin reductase at nutritional levels and phase 2 detoxification enzymes such as glutathioneS‐transferase at supranutritional levels, but exhibits much lower toxicities. Nano‐Se is thus a potential selenium source with a prominent characteristic of lower toxicity for supplementation.
Gout‐Related Health Care Utilization in US Emergency Departments, 2006 Through 2008
Authors: Garg Rohini , Sayles Harlan R. , Yu Fang , Michaud Kaleb , Singh Jasvinder , Saag Kenneth G. , Mikuls Ted R.
Published: March 2013

Objective

To characterize gout‐related emergency department (ED) utilization using a nationally representative sample and to examine factors associated with the frequency and charges of gout‐related ED visits.

Methods

Using the National Emergency Department Sample data from 2006–2008, the weighted national frequency of gout visits was calculated along with the median ED charge and total national ED‐related charges. Associations of several patient‐ and facility‐level factors were examined with the occurrence of gout visits using multivariable logistic regression and with ED‐related charges using multivariable linear regression.

Results

Gout was the primary indication for 168,410 ED visits in 2006, 171,743 visits in 2007, and 174,823 visits in 2008, accounting for ∼0.2% of all visits annually and generating ED charges of more than $128 million in 2006, $144 million in 2007, and $166 million in 2008. Age, male sex, household income <$39,000, private insurance, and hospital locations in nonmetropolitan areas and the southern US were associated with an increased propensity for ED utilization in gout. Higher ED‐related charges for gout were associated with female sex, age, a higher number of coded diagnoses, and a metropolitan residence.

Conclusion

Gout accounts for a substantial proportion of ED visits, leading to significant health care charges. Effective strategies to reduce gout burden in EDs could potentially benefit by targeting groups characterized by factors demonstrated to be related to a higher ED utilization in gout as identified by our study.
Evaluation of Test Characteristics for Outcome Measures Used in Raynaud's Phenomenon Clinical Trials
Authors: Gladue Heather , Maranian Paul , Paulus Harold E. , Khanna Dinesh
Published: March 2013

Objective

Randomized controlled trials (RCTs) in Raynaud's phenomenon (RP) have shown conflicting efficacy data. Also, there is no consensus on the outcome measures that should be used. Our objectives were to assess the reliability of individual core set measures used in 3 RCTs, evaluate the placebo response for individual core set measures, and determine if a composite of individual core set measures will decrease the placebo response, which may improve our ability to see treatment effects in future trials.

Methods

We analyzed core set measures from 249 patients in the placebo‐treated groups from 3 RCTs. Core set measures analyzed included the Raynaud's Condition Score (RCS); patient and physician assessment of RP; pain, numbness, and tingling during an RP attack; average number of attacks/day; and duration of attacks. Intraclass correlation coefficients (ICCs) were calculated during the run‐in period to the RCTs.

Results

ICCs of ≥0.70 were observed for the RCS, attack symptoms, and average attacks/day. A high placebo response rate was observed for all individual core measures except the duration of attacks. For the RCS, the placebo response ranged from 56% with ≥10% improvement to 19.5% with ≥60% improvement. In contrast, placebo response rates of 10–20% were observed when several core set measures were combined to develop a composite score.

Conclusion

Outcome measures used in RCTs of RP are associated with marked variability. A combination of outcome measures is associated with low placebo responses. Future studies are needed to assess if a composite score will be able to differentiate placebo from an effective agent.
Dravet syndrome patient‐derived neurons suggest a novel epilepsy mechanism
Authors: Liu Yu , Lopez‐Santiago Luis F. , Yuan Yukun , Jones Julie M. , Zhang Helen , O'Malley Heather A. , Patino Gustavo A. , O'Brien Janelle E. , Rusconi Raffaella , Gupta Ajay , Thompson Robert C. , Natowicz Marvin R. , Meisler Miriam H. , Isom Lori L. , Parent Jack M.
Published: March 2013

Objective

Neuronal channelopathies cause brain disorders, including epilepsy, migraine, and ataxia. Despite the development of mouse models, pathophysiological mechanisms for these disorders remain uncertain. One particularly devastating channelopathy is Dravet syndrome (DS), a severe childhood epilepsy typically caused by de novo dominant mutations in the SCN1A gene encoding the voltage‐gated sodium channel Nav1.1. Heterologous expression of mutant channels suggests loss of function, raising the quandary of how loss of sodium channels underlying action potentials produces hyperexcitability. Mouse model studies suggest that decreased Nav1.1 function in interneurons causes disinhibition. We aim to determine how mutant SCN1A affects human neurons using the induced pluripotent stem cell (iPSC) method to generate patient‐specific neurons.

Methods

Here we derive forebrain‐like pyramidal‐ and bipolar‐shaped neurons from 2 DS subjects and 3 human controls by iPSC reprogramming of fibroblasts. DS and control iPSC‐derived neurons are compared using whole‐cell patch clamp recordings. Sodium current density and intrinsic neuronal excitability are examined.

Results

Neural progenitors from DS and human control iPSCs display a forebrain identity and differentiate into bipolar‐ and pyramidal‐shaped neurons. DS patient‐derived neurons show increased sodium currents in both bipolar‐ and pyramidal‐shaped neurons. Consistent with increased sodium currents, both types of patient‐derived neurons show spontaneous bursting and other evidence of hyperexcitability. Sodium channel transcripts are not elevated, consistent with a post‐translational mechanism.

Interpretation

These data demonstrate that epilepsy patient–specific iPSC‐derived neurons are useful for modeling epileptic‐like hyperactivity. Our findings reveal a previously unrecognized cell‐autonomous epilepsy mechanism potentially underlying DS, and offer a platform for screening new antiepileptic therapies. Ann Neurol 2013;74:128–139
Inhibiting glycogen synthesis prevents lafora disease in a mouse model
Authors: Pederson Bartholomew A. , Turnbull Julie , Epp Jonathan R. , Weaver Staci A. , Zhao Xiaochu , Pencea Nela , Roach Peter J. , Frankland Paul W. , Ackerley Cameron A. , Minassian Berge A.
Published: March 2013

Lafora disease (LD) is a fatal progressive myoclonus epilepsy characterized neuropathologically by aggregates of abnormally structured glycogen and proteins (Lafora bodies [LBs]), and neurodegeneration. Whether LBs could be prevented by inhibiting glycogen synthesis and whether they are pathogenic remain uncertain. We genetically eliminated brain glycogen synthesis in LD mice. This resulted in long‐term prevention of LB formation, neurodegeneration, and seizure susceptibility. This study establishes that glycogen synthesis is requisite for LB formation and that LBs are pathogenic. It opens a therapeutic window for potential treatments in LD with known and future small molecule inhibitors of glycogen synthesis. Ann Neurol 2013;74:297–300
β‐synuclein aggregates and induces neurodegeneration in dopaminergic neurons
Authors: Taschenberger Grit , Toloe Johan , Tereshchenko Julia , Akerboom Jasper , Wales Pauline , Benz Roland , Becker Stefan , Outeiro Tiago F. , Looger Loren L. , Bähr Mathias , Zweckstetter Markus , Kügler Sebastian
Published: March 2013

Objective

Whereas the contribution of α‐synuclein to neurodegeneration in Parkinson disease is well accepted, the putative impact of its close homologue, β‐synuclein, is enigmatic. β‐Synuclein is widely expressed throughout the central nervous system, as is α‐synuclein, but the physiological functions of both proteins remain unknown. Recent findings have supported the view that β‐synuclein can act as an ameliorating regulator of α‐synuclein–induced neurotoxicity, having neuroprotective rather than neurodegenerative capabilities, and being nonaggregating due to the absence of most of the aggregation‐promoting NAC domain. However, a mutation of β‐synuclein linked to dementia with Lewy bodies rendered the protein neurotoxic in transgenic mice, and fibrillation of β‐synuclein has been demonstrated in vitro.

Methods

Neurotoxicity and aggregation properties of α‐, β‐, and γ‐synuclein were comparatively elucidated in the rat nigro‐striatal projection and in cultured neurons.

Results

Supporting the hypothesis that β‐synuclein can act as a neurodegeneration‐inducing factor, we demonstrated that wild‐type β‐synuclein is neurotoxic for cultured primary neurons. Furthermore, β‐synuclein formed proteinase K–resistant aggregates in dopaminergic neurons in vivo, leading to pronounced and progressive neurodegeneration in rats. Expression of β‐synuclein caused mitochondrial fragmentation, but this fragmentation did not render mitochondria nonfunctional in terms of ion handling and respiration even at late stages of neurodegeneration. A comparison of the neurodegenerative effects induced by α‐, β‐, and γ‐synuclein revealed that β‐synuclein was eventually as neurotoxic as α‐synuclein for nigral dopaminergic neurons, whereas γ‐synuclein proved to be nontoxic and had very low aggregation propensity.

Interpretation

Our results suggest that the role of β‐synuclein as a putative modulator of neuropathology in aggregopathies like Parkinson disease and dementia with Lewy bodies needs to be revisited. Ann Neurol 2013;74:109–118
Comparing positron emission tomography imaging and cerebrospinal fluid measurements of β‐amyloid
Authors: Landau Susan M. , Lu Ming , Joshi Abhinay D. , Pontecorvo Michael , Mintun Mark A. , Trojanowski John Q. , Shaw Leslie M. , Jagust William J. ,   for the Alzheimer's Disease Neuroimaging Initiative
Published: March 2013

Objective

We examined agreement and disagreement between 2 biomarkers of β‐amyloid (Aβ) deposition (amyloid positron emission tomography [PET] and cerebrospinal fluid [CSF] Aβ1–42) in normal aging and dementia in a large multicenter study.

Methods

Concurrently acquired florbetapir PET and CSF Aβ were measured in cognitively normal, mild cognitive impairment (MCI), and Alzheimer's disease participants (n = 374) from the Alzheimer's Disease Neuroimaging Initiative. We also compared Aβ measurements in a separate group with serial CSF measurements over 3.1 ± 0.8 years that preceded a single florbetapir session. Additional biomarker and cognitive data allowed us to further examine profiles of discordant cases.

Results

Florbetapir and CSF Aβ were inversely correlated across all diagnostic groups, and dichotomous measurements were in agreement in 86% of subjects. Among subjects showing the most disagreement, the 2 discordant groups had different profiles: the florbetapir+/CSF Aβ−group was larger (n = 13) and was made up of only normal and early MCI subjects, whereas the florbetapir−/CSF Aβ+group was smaller (n = 7) and had poorer cognitive function and higher CSF tau, but no ApoE4 carriers. In the longitudinal sample, we observed both stable longitudinal CSF Aβ trajectories and those actively transitioning from normal to abnormal, but the final CSF Aβ measurements were in good agreement with florbetapir cortical retention.

Interpretation

CSF and amyloid PET measurements of Aβ were consistent in the majority of subjects in the cross‐sectional and longitudinal populations. Based on our analysis of discordant subjects, the available evidence did not show that CSF Aβ regularly becomes abnormal prior to fibrillar Aβ accumulation early in the course of disease. Ann Neurol 2013;74:826–836
Developing medical students as teachers: An anatomy‐based student‐as‐teacher program with emphasis on core teaching competencies
Authors: Andrew Jay Erie , Starkman Sidney J. , Pawlina Wojciech , Lachman Nirusha
Published: March 2013

Teaching is an increasingly recognized responsibility of the resident physician. Residents, however, often assume teaching responsibilities without adequate preparation. Consequently, many medical schools have implemented student‐as‐teacher (SAT) programs that provide near‐peer teaching opportunities to senior medical students. Near‐peer teaching is widely regarded as an effective teaching modality; however, whether near‐peer teaching experiences in medical school prepare students for the teaching demands of residency is less understood. We explored whether the anatomy‐based SAT program through the Human Structure didactic block at Mayo Medical School addressed the core teaching competencies of a medical educator and prepared its participants for further teaching roles in their medical careers. A web‐based survey was sent to all teaching assistants in the anatomy‐based SAT program over the past five years (2007–2011). Survey questions were constructed based on previously published competencies in seven teaching domains – course development, course organization, teaching execution, student coaching, student assessment, teacher evaluation, and scholarship. Results of the survey indicate that participants in the anatomy‐based SAT program achieved core competencies of a medical educator and felt prepared for the teaching demands of residency. Anat Sci Educ 6: 385–392. © 2013 American Association of Anatomists.
75 Jahre BAUTECHNIK
Authors: Greiner‐Mai D.
Published: March 2013

Mit dem Januar‐Heft 1998 erreicht die Zeitschrift BAUTECHNIK, seit 1923 vom Verlag Ernst & Sohn publiziert, das 75. Jahr ihres Bestehens, Grund genug, ein wenig die Wurzeln zu beleuchten, Entwicklungen zu verfolgen, Gegenwärtiges zu konstatieren und Zukünftiges anzustoßen.
Neue Erkenntnisse aus Messungen an tiefen Baugruben am Potsdamer Platz in Berlin
Authors: Triantafyllidis Th.
Published: March 2013

Diese Arbeit stellt eine Zusammenfassung der bislang an einer Versuchsbaugrube am Potzdamer Platz durchgeführten Messungen, um das Verhalten des Bodens bei tiefen Baugruben zu erfassen wie auch das Wechselwirkungsverhalten der Baugrubenkonstruktion mit dem Boden während der diversen Bauphasen zu analysieren, dar. Es handelt sich dabei auch um den Einsatz von neueren Meßtechniken und Analysemethoden. In diesem Beitrag werden erste Interpretationen und Deutungen dieser Meßergebnisse auf der Basis bodenmechanischer Prinzipien dargelegt. Es stellte sich heraus, daß der Entwurf der Konstruktion nicht alle wichtigen Arbeitsphasen, die signifikante Verformungen der Verbauwände hervorrufen, erfassen kann. Dabei hat man festgestellt, daß die Einbringung von Sohlverankerungspfählen, um die Sohle der Trogbauweise sichern zu können, Verformungen der Verbauwände hervorruft, die in der gemessenen Größenordnung nicht erwartet waren. Signifikante Bodenbewegungen innerhalb und außerhalb der Baugrube haben stattgefunden, die um eine Größenordnung größer waren als diejenigen, die sich beim UW‐Aushub oder Lenzen der Baugrube einstellten. Erste Modellvorstellungen sind in der Arbeit entwickelt, die uns erlauben, solche Effekte zunächst einmal zu beschreiben und in einer zweiten Stufe ihre Auswirkungen abschätzen zu können.
Neuer Antennenträger der Senderanlage "Hohe Linie" bei Regensburg. Ein Bauvorhaben mit Modellcharakter
Authors: Flügel K.
Published: March 2013

Angesichts der in den letzten Jahren immer größer gewordenen Bedeutung von Satelliten für die Übertragung von Rundfunk‐ und Fernsehprogrammen verdient es besondere Beachtung, wenn eine öffentlich‐rechtliche Rundfunkanstalt sich noch einmal für den Bau eines Antennenträgers zur terrestrischen Abstrahlung dieser Dienste entscheidet. Beim Bau des neuen Antennenträgers an seiner Senderanlage "Hohe Linie" bei Regensburg hat der Bayerische Rundfunk bereits mit seinem Entschluß zur vorherigen Durchführung eines Ingenieur‐Ideenwettbewerbs einen ungewöhnlichen Schritt getan, um auf diese Art unter Beachtung der betrieblichen Anforderungen die für ihn wirtschaftlich günstigste Lösung zu finden; auch der bei diesem Wettbewerb ausgewählte und später realisierte Entwurf ‐ ein freistehender 100 m hoher Stahllbetonturm mit einem am Turmkopf eingespannten 51 m hohen Stahlrohraufsatz ‐ stellt eine nach Wissen des Autors bislang noch nicht ausgeführte Lösung für einen Antennenträger dieser Bauhöhe dar. Der vom Bayerischen Rundfunk gewählten Verfahrens‐ und Bauweise kann deswegen nach Auffassung des Autors Modellcharakter zugesprochen werden.
Systemtechnik contra DIN EN ISO 9000?
Authors: Fritz H. A.
Published: March 2013

Noch zehn Jahre nach Einführung der Normen zum Qualitätsmanagement, die als DIN EN ISO 9000ff branchenübergreifend sowohl im internationalen, europäischen und deutschen Geltungsbereich eingeführt wurden, gibt es gerade in der Baubranche unterschiedlichste Akzeptanz dieses Regelwerkes. Während Produzenten wie Bauunternehmen und Bauproduktenhersteller den Wert eines Qualitätsmanagement längst erkannt haben und nutzen, stehen Dienstleister wie Ingenieurbüros und öffentliche Auftraggeber dieser Entwicklung eher noch skeptisch gegenüber. Dieser Beitrag öffnet einen ingenieurgerechten Zugang zum zeitgemäßen Qualitätsmanagement und geht dabei insbesondere auf die Frage ein, inwieweit die oben zitierte Normenserie sich auf bekannte Inhalte der Systemtechnik abstützt und das Verständnis für Qualitätsmanagement durch die Hochschulausbildung der Bauingenieure gefördert werden kann.
"Der Träger aus der Tüte"
Authors: Heller H.
Published: March 2013

Für unterschiedliche Anwendungsbereiche im Hochbau oder auch im Ausbau sind immer wieder Tragwerke (Träger) für relative kleine Lasten und kleine Spannweiten gefragt. Dabei spielen bei vielen Bauaufgaben auch gestalterische Gesichtspunkte im Zusammenhang mit der Wahl der Tragwerke eine Rolle. Normale Rechteckprofile aus Holz oder Walzprofile aus Stahl bieten hier wenig Spielräume. Im folgenden wird ein neuartiges, vorzugsweise aus Holz hergestelltes Leichtbau‐Trägersystem mit nicht parallel laufenden Gurten vorgestellt.
Das neue Bremer Weserwehr Entwurf und Ausführung Teil 1: Topologie und Entwurf
Authors: Grabau J.
Published: March 2013

Nach 5‐jähriger Bauzeit wurde 1993 das neue Bremer Weserwehr in Betrieb genommen. Wegen der Lage innerhalb Bremens hat das Wehr wesentlichen Einfluß auf die Hochwassersicherheit im dicht besiedelten Innenstadtbereich. Das Wehr hält den normalen Tideeinfluß der Unterweser von der staugeregelten Mittelweser fern. Der mittlere Tidehub unterstromig des Wehres beträgt fast 4 m und sorgt damit für tägliche periodische Einwirkungen auf das Bauwerk, die an den meisten anderen Wehren an staugeregelten Flüssen nicht auftreten. Planung und Entwurf der Anlage wurden vom Wasser‐ und Schiffahrtsamt Bremen durchgeführt. Die Baudurchführung erfolgte im Rahmen von Bauverträgen zwischen verschiedenen Fachunternehmen und der Wasser‐ und Schiffahrtsverwaltung des Bundes (WSV), vertreten durch das Wasser‐ und Schiffahrtsamt Bremen, das nach Abnahme am 1. April 1993 den Betrieb der Anlage übernommen hat.
Zur Ermittlung verformungsabhängiger Windlasten bei leichten Flächentragwerken
Authors: Rosemeier G.‐E.
Published: March 2013

Bei leichten Flächentragwerken ist es bisher üblich, die Windlasten an unverformten Modellen im Windkanalversuch zu bestimmen und darauf die nachfolgende statische Berechnung aufzubauen. Bei bestimmten Systemen ist jedoch eine Wechselwirkung zwischen der Windlastund den stark deformierbaren Strukturen von Interesse (z. B. das Durchschlagverhalten gewichtsstabilisierter Hängedächer). Hierbei sind sowohl Bereiche abgerissener Strömungszonen (Totwasser) als auch anliegende Strömungszonen bei sich bewegenden Dachstrukturen zu berücksichtigen. Es wird ein computerorientiertes Rechenverfahren vorgelegt, das die Erfassung der Windlasten unter den vorgenannten Voraussetzungen gestattet. Das Systemverhalten der stark deformierbaren Dachkonstruktionen kann z. B. bei Durchschlagproblemen in einem verformungsabhängigen Lastfaktor erfaßt werden, der als Verhältnis einer Stabilitätsgrenze (kritische Windlast) der ursprünglichen Dachgeometrie zur maximal auftretenden Windlast definiert wird.
Reibung und Verbundspannungen zwischen Spundwand und Unterwasserbeton
Authors: Wolff F.
Published: March 2013

Die Kompensation des Auftriebs allein mit dem Eigengewicht von Unterwasserbetonsohlen (UWBS) ist nicht wirtschaftlich, so daß z. T. die Verbauspundwände als Zugglieder mit herangezogen werden können. Die Übertragung von Auftriebslasten vom UWB zur Spundwand kann über Reibung und/oder Verbundspannungen erfolgen. Es werden aus Laborversuchen Reibungsbeiwerte und Verbundspannungen angegeben.
Zukunftsorientierte Konzepte zur Beschreibung seismischer Einwirkungen für das Erdbebeningenieurwesen
Authors: Schwarz J. , Grünthal G.
Published: March 2013

Der Beitrag gibt einen Eindruck von aktuellen Möglichkeiten und künftig zu erwartenden Anforderungen an die Beschreibung seismischer Einwirkungen für das Ingenieurwesen. Verdeutlicht werden Entwicklungen und Veränderungen, die sich aus den methodischen Grundlagen und rechentechnischen Möglichkeiten der probabilistischen seismischen Gefährdungsanalyse ableiten lassen. Zukunftsorientierte Konzepte der Einwirkungsbeschreibung werden dadurch charakterisiert, daß die Standortspezifik um das Element der Gefährdungsspezifik zu ergänzen ist. Eine Kopplung beider Anforderungen läßt sich in Form von untergrundbezogenen Spektralbewegungsgrößen erzielen, die direkt aus Gefährdungsaussagen, dem Gefährdungshintergrund sowie der lokalen Untergrundsituation eines Standortes ermittelt werden. Der Beitrag unternimmt den Versuch, Maßstäbe für die Bewertung der Qualität der Ergebnisse auf der Einwirkungsseite zu definieren. Es sind dies die Berücksichtigung der regionalen Spezifik, der Gefährdungs‐ und Standortspezifik sowie die Einbeziehung der zyklischen Charakteristik der Bodenbewegung. Ausgehend von der Erfahrung aus aktuellen Erdbeben, daß zwischen der Größe der registrierten Bodenbewegung und dem tatsächlichen Bauwerksverhalten Widersprüche bestehen und erdbebengerecht ausgelegte Bauwerke auch starken seismischen Bodenbewegungen widerstehen können, werden neuartige Ansätze der Einwirkungsbeschreibung diskutiert, die eine Reduzierung der Größe der Lastparameter gestatten. Die anhand von Beispielen herausgearbeiteten Konsequenzen verdeutlichen, daß künftig eine auf Erfahrungen gestützte Auslegung an Bedeutung gewinnen wird, die bereits bei der Festlegung der Lastgrößen ansetzen muß.
Zum Wiederaufbau der Frauenkirche zu Dresden ‐ Tragsystem der Kuppel und deren Brandverhalten
Authors: Kordina K.
Published: March 2013

Das Brandverhalten der Kuppel der Frauenkirche zu Dresden ist nach Kenntnis des Verfassers noch nicht untersucht worden. Da es aber für die Beständigkeit und Dauerhaftigkeit von Bauwerken allgemein und der Frauenkirche insbesondere von wesentlicher Bedeutung ist, wird hierauf nachfolgend eingegangen.

Zum besseren Verständnis wird das Bauwerk zunächst beschrieben. Dann wird der Brand und der Einsturz von 1945, so wie er sich aus der Literatur ergibt, erläutert, um hieraus Erkenntnisse für den Wiederaufbau zu ziehen. Hiernach werden Vorstellungen über das Gesamt‐Brandverhalten des Bauwerkes aufgrund von überschlägigen Brandsimulations‐Berechnungen abgeleitet und erforderliche Abhilfemaßnahmen entwickelt.
Sicherheitskonzept für neue Normen ‐ ENV und DIN‐neu. Grundlagen und Hintergrundinformationen Teil 2: Statstik und Wahrscheinlichkeitstheorie, Teil 2.1: Grundlagen der Statistik und Wahrscheinlichkeitstheorie
Authors: Fischer L.
Published: March 2013

Die Statistik und die Wahrscheinlichkeitstheorie werden als Teilgebiet der Stochastik aufgefaßt. Eine moderne Darstellung der Datenverarbeitung muß sich in der Statistik wiederfinden, insbesondere im Datenmanagement: Datengewinnung, Datenerfassung, Datenanalyse, Datenpräsentation und Datensicherung/Datenschutz.

Der Begriff "Wahrscheinlichkeit" wird eingeführt und in bezug zum naturwissenschaftlichen Wahrscheinlichkeitsbegriff diskutiert. Aufbauend auf die mathematischen Operationen einer abstrakten Wahrscheinlichkeit werden wesentliche Sätze für die Zuverlässigkeitstheorie vorgestellt: bedingte Wahrscheinlichkeit, Unabhängigkeit von Ereignissen, Satz von der totalen Wahrscheinlichkeit und das Bayessche Theorem.
Endstücke von Planken und Wänden im Straßenraum ‐ Grenzen eines Schutzes ‐
Authors: Gülich H.‐A.
Published: March 2013

Es ist eine Frage der Bewegungsrichtung, ob an Endstücken (Terminals) von Schutzplanken und ‐wänden deren Schutzwirkung beginnt oder endet. Im übertragenen Sinn kann dort auch das Schutzprinzip selbst enden oder in Frage gestellt sein, wenn sich unter ungünstigen Bedingungen ein Endstück als gefährliches Hindernis erweist. Wie ein Rückblick auf ältere Versuchsergebnisse zeigt, werden Fragen der zweckmäßigen Gestaltung für Anfang und Ende von Schutzeinrichtungen seit Jahrzehnten gestellt. Weil jedoch eine allen Ansprüchen gerechte Lösung nicht zu verwirklichen ist, muß bei der Anwendung von Planken und Wänden jeweils an den Endstücken der unumgängliche Kompromiß zwischen Schutz und Risiko gesucht werden. Dabei zeigt sich zugleich die Notwendigkeit, auch bei Forderungen nach gesteigerter Verkehrssicherheit Augenmaß zu bewahren, denn bei der Ausstattung von Straßen ist (nach persönlicher Meinung des Berichters) nicht anders als bei Fahrzeugen ein Schutz vor sämtlichen Risiken des Straßenverkehrs weder vertretbar noch wünschenswert.
Entwicklung eines hybriden, objektorientierten Systems zur optimierten Baustelleneinrichtungsplanung (ESBE) (Teil 1)
Authors: Lennerts K.
Published: March 2013

Ziel des Forschungsprojekts war die objektorientierte Modellierung (Analyse, Entwurf) und die Prototypentwickung eines hybriden objektorientierten Systems (ESBE) zur Planung von dynamischen Baustelleneinrichtungen für Hochbaustellen, das in Interaktion mit dem Benutzer optimierte Baustellen‐Layouts generiert. Es wird die räumliche Zuordnung geeigneter Baustelleneinrichtungselemente ermittelt. Die Hauptkomponente von ESBE bildet ein hybrides System, bestehend aus bauspezifischen Facility‐Layout‐Planungslogarithmen und einer wissensbasierten Komponente. Zusammen mit den weiteren Komponenten, der Baustellendatenbank, der Benutzeroberfläche und der 3D‐Visualisierungskomponente wird das Gesamtsystem ESBE geformt.

(wird fortgesetzt)