julilili42/papers huggingface dataset:
E01 Analysis of mitochondrial genes as potential genetic modifiers of the age-at-onset in Huntington disease
2012-08-29

<h3>Background</h3> The major determinant of age-at-onset (AAO) in Huntington disease (HD) is the length of the causative polyglutamine expansion in the huntingtin protein, which is inversely correlated with the AAO and the course of the disease. However, both environmental and genetic factors are thought to modify the disease. Here, genetic factors are proposed to have an essential influence and especially polymorphism in genes associated with HD pathogenesis are thought to act as genetic modifiers. One characteristic feature in HD pathogenesis is mitochondrial dysfunction, which is marked by an impairment of mitochondrial integrity and trafficking leading to a disruption of mitochondrial function and an inhibition of energy supply in the cell. Amongst others, mutant huntingtin was shown to lead to oxidative stress, increased fragmentation of mitochondria and reduced ATP levels. A regulated expression of proteins, involved in mitochondrial fission and fusion (eg, Mfn1, Mfn2) antagonises the pathogenic effect, thus demonstrating to be interesting potential candidates for a modifying role in HD. <h3>Aim/method</h3> In order to identify genetic modifiers participating in mitochondrial function, we investigated several single nucleotide polymorphisms in mitochondrial fusion (Mfn1, Mfn2, Opa1) and fission (Fis1) genes for their frequency of ≥1%. Subsequently, we aim to analyse these polymorphic markers for a disease-modifying effect in more than 1400 European HD patients. Additionally, to establish a connection between mutant huntingtin and mitochondrial genes, we intend to examine a possible interaction between huntingtin and the fission protein Fis1 by co-immunoprecipitation experiments in cell culture. <h3>Conclusion</h3> The present study provides the opportunity to identify new genetic modifiers influencing the AAO and the pathogenic course of HD. These would further support the important pathophysiological role of mitochondrial dysfunction in HD and may offer new basis for further clarification of HD pathology.
E04 Autophagy-related gene Atg7 is a genetic modifier of AAO specific in the Italian population
2012-08-29

<h3>Background</h3> The only known cause of Huntington9s disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age-at-onset (AAO) of the disease. However, additional genetic factors apart from the expanded CAG repeat length can modify the course and the AAO in HD. Since autophagy, the major way for the degradation of mutant huntingtin, is thought to exert influence on the pathogenesis of HD, we hypothesised that autophagy-related (<i>Atg</i>) genes might contribute to the variation in the AAO. <h3>Aim/method</h3> In this regard, we analysed the association of the V471A polymorphism in the autophagy-related gene Atg7 gene in two large cohorts (1st study group: 952 patients; 2nd study group (EHDN REGISTRY): 1464 patients), composed of HD patients descending from different European countries. <h3>Results</h3> Although a polymorphism in the Atg7 gene that substitutes alanine for valine (V471A) showed a significant effect on the AAO in the first patient cohort mainly consisting of Italian and German HD patients, the significant effect of the Atg7 V471A polymorphism could not be confirmed in the second study group that was composed of European patients other than Italian and German patients. A more detailed analysis revealed a significant effect of the Atg7 V471A polymorphism on the AAO especially in the Italian population (327 patients) and was associated with a 4 years earlier disease onset. <h3>Conclusion</h3> Therefore, we identified a genetic modifier for HD in relationship to the autophagic pathway, but with a specific effect in a single population. This result affirms the influence of genetic modifiers on the course of HD, but also suggests population-specific modifying mechanisms in the HD pathogenesis.
C08 Motor, cognitive and emotional investigation in a novel rat model of Huntington's disease
2012-08-29

<h3>Background</h3> Huntington9s disease (HD) is one of the nine neurodegenerative disorders characterised by unstable Glutamine (CAG) repeats expansion in the causative gene. The hallmark feature in HD is progressive medium spiny neurons degeneration in the striatum. As a result, patients present progressive motor dysfunction, cognitive deficits and emotional disturbances. Early emotional and cognitive deficits precede motor dysfunction in HD patients. To date no disease modifying treatment for HD has been discovered. A BACHD rat model for HD which carries the human full length mutated huntingtin gene (mHtt, 97 polyglutamine) was recently established. Previous studies with HD murine models have focused mainly on motor deficits. <h3>Aim</h3> The present aim of this study was to investigate the emergence of motor, emotional and cognitive deficits in BACHD rats. <h3>Methods</h3> Motor deficits were assessed with Rotarod and Actimot; emotional disturbances were evaluated in a fear conditioning test, and cognitive deficits were investigated with a Cross-maze. <h3>Results</h3> Compared with wild type, transgenic rats showed (1) hypoactivity in a spontaneous locomotor activity test; (2) motor coordination imbalance in a rotarod test; (3) a lower freezing response in a fear conditioning test; and (4) difficulty in reversal learning in a strategy shifting task, indicative of a disruption in striatal-prefrontal pathway activity. <h3>Conclusion</h3> BACHD rats recapitulate HD-related motor, cognitive and emotional symptoms observed in patients and we propose that the model may lend itself for the assessment of novel drug treatments for this disorder.
ATXN2-CAG42 Sequesters PABPC1 into Insolubility and Induces FBXW8 in Cerebellum of Old Ataxic Knock-In Mice
2012-08-30

Spinocerebellar Ataxia Type 2 (SCA2) is caused by expansion of a polyglutamine encoding triplet repeat in the human ATXN2 gene beyond (CAG)(31). This is thought to mediate toxic gain-of-function by protein aggregation and to affect RNA processing, resulting in degenerative processes affecting preferentially cerebellar neurons. As a faithful animal model, we generated a knock-in mouse replacing the single CAG of murine Atxn2 with CAG42, a frequent patient genotype. This expansion size was inherited stably. The mice showed phenotypes with reduced weight and later motor incoordination. Although brain Atxn2 mRNA became elevated, soluble ATXN2 protein levels diminished over time, which might explain partial loss-of-function effects. Deficits in soluble ATXN2 protein correlated with the appearance of insoluble ATXN2, a progressive feature in cerebellum possibly reflecting toxic gains-of-function. Since in vitro ATXN2 overexpression was known to reduce levels of its protein interactor PABPC1, we studied expansion effects on PABPC1. In cortex, PABPC1 transcript and soluble and insoluble protein levels were increased. In the more vulnerable cerebellum, the progressive insolubility of PABPC1 was accompanied by decreased soluble protein levels, with PABPC1 mRNA showing no compensatory increase. The sequestration of PABPC1 into insolubility by ATXN2 function gains was validated in human cell culture. To understand consequences on mRNA processing, transcriptome profiles at medium and old age in three different tissues were studied and demonstrated a selective induction of Fbxw8 in the old cerebellum. Fbxw8 is encoded next to the Atxn2 locus and was shown in vitro to decrease the level of expanded insoluble ATXN2 protein. In conclusion, our data support the concept that expanded ATXN2 undergoes progressive insolubility and affects PABPC1 by a toxic gain-of-function mechanism with tissue-specific effects, which may be partially alleviated by the induction of FBXW8.
Dinuclear Coinage-Metal Complexes of Bis(NHC) Ligands: Structural Features and Dynamic Behavior of a Cu–Cu Complex
2012-08-30

Binuclear complexes of copper, silver, and gold bearing a 2,2′-bipyridine analogue, the pyridazine annelated bis(N-heterocyclic carbene) ligand (vegi) 1, were prepared and structurally characterized. They all feature the shortest metal–metal distances that have been measured so far in complexes with this structural motif bearing neutral bidentate ligands, indicative of d10–d10 interactions. While in the silver complex the linear coordination of each silver atom with two carbene ligands results in a planar complex, the ligand planes are twisted by 70° in the Cu complex 4 and by 31° in the gold complex 3. The copper complex shows a solvent-dependent equilibrium between the [Cu2L2]2+ complex and a [Cu2L3]2+ complex along with solvated CuPF6.
Hydration biomarkers in free-living adults with different levels of habitual fluid consumption
2012-08-31

Little is known about the impact of habitual fluid intake on physiology. Specifically, biomarkers of hydration status and body water regulation have not been adequately explored in adults who consume different fluid volumes in everyday conditions, without prolonged exercise or environmental exposure. The purpose of the present study was to compare adults with habitually different fluid intakes with respect to biomarkers implicated in the assessment of hydration status, the regulation of total body water and the risk of kidney pathologies. In the present cross-sectional study, seventy-one adults (thirty-two men, thirty-nine women, age 25–40 years) were classified according to daily fluid intake: thirty-nine low drinkers (LD; ≤ 1·2 litres/d) and thirty-two high drinkers (HD; 2–4 litres/d). During four consecutive days, urinary parameters (first morning urine (FMU) on day 1 and subsequent 24 h urine (24hU) collections), blood parameters, and food and beverage intake were assessed. ANOVA and non-parametric comparisons revealed significant differences between the LD and HD groups in 24hU volume (1·0 ( se 0·1) v . 2·4 ( se 0·1) litres), specific gravity (median 1·023 v . 1·010), osmolality (767 ( se 27) v . 371 ( se 33) mOsm/kg) and colour (3·1 ( se 0·2) v . 1·8 ( se 0·2)). Similarly, in the FMU, the LD group produced a smaller amount of more concentrated urine. Plasma cortisol, creatinine and arginine vasopressin concentrations were significantly higher among the LD. Plasma osmolality was similar between the groups, suggesting physiological adaptations to preserve plasma osmolality despite low fluid intake. The long-term impact of adaptations to preserve plasma osmolality must be examined, particularly in the context of renal health.
Sub-arborescent Lycophytes in coal-bearing strata from the Artinskian (Early Permian/Cisuralian) of the Santa Catarina coalfield (Paraná Basin, SC, Brazil)
2012-08-31

In the modern flora, lycophytes are restricted to a few herbaceous forms.The fossil record of this group is significantly larger, with numerous herbaceous, but also arborescent representatives, the latter mostly reported from late Paleozoic biomes.An association of compressed caulinar fragments of horizontally layered, sub-arborescent lycophytes (preserved as fossil casts) coming from a clastic level which overlies the Bonito coal seam in the Bonito I mine in the Santa Catarina coalfield (Santa Catarina state, Brazil) is analyzed in this paper.The material was identified as Brasilodendron pedroanum (Carruthers) Chaloner, Leistikow & Hill, a taxon that has been described from several outcrops in the coal-bearing interval of the Paraná Basin (Sakmarian/Artinskian).The present study supports the interpretation that sub-arborescent lycophyte plants showing the Brasilodendron leaf-cushion type were an important component of the coastal peat forming paleofloristic associations during the Early Permian (Cisuralian) in the Paraná Basin and were important contributors to the original biomass of coals.
ArabidopsisDefense againstBotrytis cinerea: Chronology and Regulation Deciphered by High-Resolution Temporal Transcriptomic Analysis
2012-09-01

Abstract Transcriptional reprogramming forms a major part of a plant's response to pathogen infection. Many individual components and pathways operating during plant defense have been identified, but our knowledge of how these different components interact is still rudimentary. We generated a high-resolution time series of gene expression profiles from a single Arabidopsis thaliana leaf during infection by the necrotrophic fungal pathogen Botrytis cinerea. Approximately one-third of the Arabidopsis genome is differentially expressed during the first 48 h after infection, with the majority of changes in gene expression occurring before significant lesion development. We used computational tools to obtain a detailed chronology of the defense response against B. cinerea, highlighting the times at which signaling and metabolic processes change, and identify transcription factor families operating at different times after infection. Motif enrichment and network inference predicted regulatory interactions, and testing of one such prediction identified a role for TGA3 in defense against necrotrophic pathogens. These data provide an unprecedented level of detail about transcriptional changes during a defense response and are suited to systems biology analyses to generate predictive models of the gene regulatory networks mediating the Arabidopsis response to B. cinerea.
Estimation of the acoustic range of bat echolocation for extended targets
2012-09-01

Extended natural structures of the bat environment such as trees, meadows, and water surfaces were ensonified in distances from 1 to 20 m and the echoes recorded using a mobile ultrasonic sonar system. By compensating the atmospheric attenuation, the attenuation of the reflected echo caused by diffraction, energy absorption of the target, and two-way-geometric spreading was calculated for each distance. For each target type the attenuation of the compensated echo sound pressure level was fitted over distance using a linear function which yields simple laws of reflection loss and geometric spreading. By adding to this function again variable atmospheric attenuation, the overall attenuation of a signal reflected from these targets can be estimated for various conditions. Given the dynamic range of a sonar system, the acoustic maximum detection distance can thus be estimated. The results show that the maximum range is dominantly limited by atmospheric attenuation. Energy loss in the reflecting surface is more variable than geometric spreading loss and accounts for most of the differences between the ensonified targets. Depending on atmospheric conditions, echolocation frequency, and the dynamic range of the sonar system, the maximum range for extended backgrounds such as a forest edge can be as short as 2.4 m.
Dealing with international crimes in post-war Bosnia: A look through the lens of the affected population
2012-09-01

Debates about serious human rights violations and international crimes committed in the past appear during times of political transition. New political elites are confronted with fundamental questions of how to seek truth, establish accountability for offenders, provide reparation to victims, promote reconciliation, deal with trauma and build trust. ‘Transitional’ or ‘post-conflict justice’ is most often managed by elites, national and international, while the views and expectations of the local populations are rarely taken into account. Population-based research can yield deep insights into strategies and mechanisms for dealing with the crimes of the past. This paper reports on the major findings of a study in Bosnia and on the factors that may contribute to trust and reconciliation in the country.
Hypoxia in the Eye: A Two-Sided Coin
2012-09-01

Tissue oxygenation in general and hypoxia in particular are important regulators of retinal physiology and pathophysiology. Reduced oxygen tension and hypoxia-inducible transcription factors along with some of their target genes are critically involved in retinal development, and especially in the generation of a normal retinal vasculature. Well-timed hypoxia is thus vital for the young eye to establish proper retinal function and vision. However, when hypoxia is ill-timed, reduced oxygen tension may be associated with the development of retinal pathologies, including retinopathy of prematurity, diabetic retinopathy, glaucoma, age-related macular degeneration, or high altitude retinopathy. Here, reduced oxygen tension activates a hypoxic response that culminates in an increased expression of vascular endothelial growth factor. This causes pathological neovascularization of the delicate neuronal retina, a process that may ultimately lead to loss of vision. In contrast, preconditioning by well-defined and controlled short-term hypoxia is not devastating for the retina but instead induces a molecular response that provides protection to neuronal cells. Detailed investigation of hypoxic mechanisms during development and adulthood may thus reveal factors, which may be targeted by therapeutic approaches to save and preserve vision in patients.
The significance of the nuclear farnesoid X receptor (FXR) in β cell function
2012-09-01

Bile acids (BAs) are important signaling molecules that are involved in the regulation of their own metabolism, lipid metabolism, energy expenditure and glucose homeostasis. The nuclear farnesoid X receptor (FXR) and the G-protein-coupled TGR-5 are the most prominent BA receptors. FXR is highly expressed in liver and activation of liver FXR profoundly affects glucose homeostasis. Strikingly, the effect of FXR activation on glucose metabolism seems to depend on the nutritional status of the organism, i.e., slimness or obesity. Recently, it became evident that FXR is present in pancreatic β cells and that activation of β cell FXR contributes to the regulation of glucose homeostasis. Interestingly, FXR activation increases glucose-induced insulin secretion by non-genomic effects on stimulus-secretion coupling. The first chapter of this review shortly introduces the role of liver FXR in glucose metabolism, the second part focuses on the impact of FXR in lean and obese animals, and the third chapter highlights the significance of FXR in β cells.
Exchange of Complementary and Alternative Medical Knowledge in Sport-Related Internet Fora
2012-09-01

This research note provides an explorative analysis of sport-related knowledge exchange about Complementary and Alternative Medicine (CAM) on the Internet. Data are taken from a qualitative content analysis of the largest German-speaking Internet sport portal. Knowledge exchange about CAM in these Internet fora is characterized by the following phenomena: Users expected CAM to improve their performance and discussed a great variety of treatments based on primarily anecdotal knowledge. In addition, two main types of users (helpers and help-seekers) dominated the exchanges. The main reasons for seeking alternative medical help on the Internet were cases of prolonged illness and dissatisfaction with biomedical care.
A Bayesian Model For The Estimation Of Latent Interaction And Quadratic Effects When Latent Variables Are Non-Normally Distributed
2012-09-01

Structural equation models with interaction and quadratic effects have become a standard tool for testing nonlinear hypotheses in the social sciences. Most of the current approaches assume normally distributed latent predictor variables. In this article, we present a Bayesian model for the estimation of latent nonlinear effects when the latent predictor variables are nonnormally distributed. The nonnormal predictor distribution is approximated by a finite mixture distribution. We conduct a simulation study that demonstrates the advantages of the proposed Bayesian model over contemporary approaches (Latent Moderated Structural Equations [LMS], Quasi-Maximum-Likelihood [QML], and the extended unconstrained approach) when the latent predictor variables follow a nonnormal distribution. The conventional approaches show biased estimates of the nonlinear effects; the proposed Bayesian model provides unbiased estimates. We present an empirical example from work and stress research and provide syntax for substantive researchers. Advantages and limitations of the new model are discussed.
Exploring prospects of novel drugs for tuberculosis
2012-09-01

Tuberculosis remains a disease with an enormous impact on public health worldwide. With the continuously increasing epidemic of drug-resistant tuberculosis, new drugs are desperately needed. However, even for the treatment of drug-sensitive tuberculosis, new drugs are required to shorten the treatment duration and thereby prevent development of drug resistance. Within the past ten years, major advances in tuberculosis drug research have been made, leading to a considerable number of antimycobacterial compounds which are now in the pipeline. Here we discuss a number of these novel promising tuberculosis drugs, as well as the discovery of two new potential drug targets for the development of novel effective drugs to curb the tuberculosis pandemic, ie, the coronin 1 and protein kinase G pathways. Protein kinase G is secreted by mycobacteria and is responsible for blocking lysosomal delivery within the macrophage. Coronin 1 is responsible for activating the phosphatase, calcineurin, and thereby preventing phagosome-lysosome fusion within the macrophage. Blocking these two pathways may lead to rapid killing of mycobacteria.
NOT QUITE ‘SUI GENERIS’ ENOUGH
2012-09-01

ABSTRACT The debate about the role of the EU in international politics is dominated by the characterisation of the EU as a normative power. In this article, I argue that there are fundamental tensions between the core values that the EU is supposed to embody and articulate in this context. In a first step, I introduce democracy and justice as two exemplary values associated with European integration and introduce the argument about the tensions between these values, which I largely take from the so-called English School of International Relations. This then serves as a basis for exploring these tensions in relation to two illustrative cases: EU-Turkey relations and the control of the external EU (or, to be more precise, Schengen) border. I conclude that the EU's often-invoked character as a ‘post-modern’ political system may well apply to its internal configuration, but much less so to its external relations. It thus cannot escape the normative tensions inherent to a territorially configured international society.
Skin symptoms in four ectodermal dysplasia syndromes including two case reports of Rapp-Hodgkin-Syndrome
2012-09-01

The skin, hair and nail changes in four distinct ectodermal dysplasia syndromes are compared and reviewed. These syndromes comprise Christ-Siemens-Touraine syndrome; ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome; ankyloblepharon-ectodermal defects-cleft lip/palate syndrome and Rapp-Hodgkin syndrome. A comprehensive overview of the dermatological signs and symptoms in these syndromes was generated from the database of the Ectodermal Dysplasia Network Germany, the clinical findings in the patients seen in our department and an extensive review of the literature. The findings included abnormalities of skin, sweating, hair and nails. These clinical findings are discussed in relation to the underlying molecular defects known to play a role in these four ectodermal dysplasia syndromes.