julilili42/papers huggingface dataset:
A large genome scan for rare CNVs in amyotrophic lateral sclerosis
2010-08-04

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.
Group III Metabotropic Glutamate Receptors Inhibit Startle-Mediating Giant Neurons in the Caudal Pontine Reticular Nucleus But Do Not Mediate Synaptic Depression/Short-Term Habituation of Startle
2010-08-04

Short-term habituation is a basic form of learning that is analyzed in different species and using different behavioral models. Previous studies on mechanisms of short-term habituation yielded evidence for a potential role of group III metabotropic glutamate receptors (mGluRIIIs). Here we tested the hypothesis that mGluRIII mediate short-term habituation of startle in rats, combining electrophysiological experiments in vitro with behavioral studies in vivo . We applied different mGluRIII agonists and antagonists on rat brainstem slices while recording from startle-mediating neurons in the caudal pontine reticular nucleus (PnC) and monitoring synaptic depression presumably underlying habituation. Furthermore, we injected the mGluRIII antagonist (RS)-α-phosphonophenylglycine (MPPG) and the agonist l -(+)-2-amino-4-phosphonobutyric acid ( l -AP4) into the PnC of rats in vivo and measured its effect on startle habituation. Our results show that activation of mGluRIIIs in the PnC strongly inhibits startle-mediating giant neurons in vitro . Accordingly, l -AP4 reduced startle responses in vivo . However, synaptic depression in the slice was not disrupted by mGluRIII antagonists or agonists. Correspondingly, the in vivo application of the mGluRIII antagonist MPPG failed to show any effect on short-term habituation of startle responses. We therefore conclude that mGluRs are expressed within the primary startle pathway and that they inhibit startle responses upon activation; however, this inhibition does not play any role in synaptic depression and short-term habituation of startle. This is in contrast to the role of mGluRIIIs in other forms of habituation and supports the notion that there are different mechanisms involved in habituation of sensory-evoked behaviors.
Thermal history of the central Gotthard and Aar massifs, European Alps: Evidence for steady state, long‐term exhumation
2010-08-05

Quantifying long‐term exhumation rates is a prerequisite for understanding the geodynamic evolution of orogens and their exogenic and endogenic driving forces. Here we reconstruct the exhumation history of the central Aar and Gotthard external crystalline massifs in the European Alps using apatite and zircon fission track and apatite (U‐Th)/He data. Age‐elevation relationships and time‐temperature paths derived from thermal history modeling are interpreted to reflect nearly constant exhumation of ∼0.5 km/Ma since ∼14 Ma. A slightly accelerated rate (∼0.7 km/Ma) occurred from 16 to 14 Ma and again from 10 to 7 Ma. Faster exhumation between 16 and 14 Ma is most likely linked to indentation of the Adriatic wedge and related thrusting along the Alpine sole thrust, which, in turn, caused uplift and exhumation in the external crystalline massifs. The data suggest nearly steady, moderate exhumation rates since ∼14 Ma, regardless of major exogenic and endogenic forces such as a change to wetter climate conditions around 5 Ma or orogen‐perpendicular extension initiated in Pliocene times. Recent uplift and denudation rates, interpreted to be the result of climate fluctuations and associated increase in erosional efficiency, are nearly twice this ∼0.5 km/Ma paleoexhumation rate.
Research in practice: More than skin deep –aging of subcutaneous fat tissue
2010-08-05

Summary Mitochondria, responsible for the generation of energy in our cells, contain their own genome, mitochondrial (mt)DNA. It is known that mutations of mtDNA accumulate during normal aging and that this can be accelerated by oxidative stress, i.e. induced by ultraviolet radiation. These mutations are functionally relevant and they play a causative role in normal aging as well as premature aging induced by ultraviolet radiation. While the focus of scientific research was more on epidermis and dermis within the last years, alterations of subcutaneous fat tissue were not investigated thus far. Cockayne syndrome (CS) A and B are two proteins known to repair oxidatively induced DNA damage via nucleotide excision repair (NER) in the nucleus. We could show that these two proteins enrich in mitochondria upon oxidative stress, directly interact with mtDNA and the two repair‐associated proteins mtSSBP‐1 and mtOGG‐1 and protect from deletions of mtDNA. If CSA or CSB are lacking, mtDNA mutations accumulate particularly in the cells of subcutaneous fat tissue which appears to mediate loss of adipocytes via apoptosis. Therefore, the two NER‐associated proteins CSA and CSB appear to play a direct role in protection from mutations which in turn are causative in aging‐associated loss of subcutaneous fat tissue.
Blunted IgE-mediated activation of mast cells in mice lacking the serum- and glucocorticoid-inducible kinase SGK3
2010-08-05

Previous studies have shown that pharmacological inhibition of the phosphoinositol-3 (PI3) kinase disrupts the activation of mast cells. Through phosphoinositide-dependent kinase PDK1, PI3 kinase activates the serum- and glucocorticoid-inducible kinase 3 (SGK3). The present study explored the role of SGK3 in mast cell function. Mast cells were isolated and cultured from bone marrow (BMMCs) of gene-targeted mice lacking SGK3 ( sgk3 −/− ) and their wild-type littermates ( sgk3 +/+ ). BMMC numbers in the ear conch were similar in both genotypes. Stimulation with IgE and cognate antigen triggered the release of intracellular Ca 2+ and entry of extracellular Ca 2+ . Influx of extracellular Ca 2+ but not Ca 2+ release from intracellular stores was significantly blunted in sgk3 −/− BMMCs compared with sgk3 +/+ BMMCs. Antigen stimulation further led to a rapid increase of a K + -selective conductance in sgk3 +/+ BMMCs, an effect again blunted in sgk3 −/− BMMCs. In contrast, the Ca 2+ ionophore ionomycin activated K + currents to a similar extent in sgk3 −/− and in sgk3 +/+ BMMCs. β-Hexosaminidase release, triggered by antigen stimulation, was also significantly decreased in sgk3 −/− BMMCs. IgE-dependent anaphylaxis measured as a sharp decrease in body temperature upon injection of DNP-HSA antigen was again significantly blunted in sgk3 −/− compared with sgk3 +/+ mice. Serum histamine levels measured 30 min after induction of an anaphylactic reaction were significantly lower in sgk3 −/− than in sgk3 +/+ mice. In conclusion, both in vitro and in vivo function of BMMCs are impaired in gene targeted mice lacking SGK3. Thus SGK3 is critical for proper mast cell function.
Cooperative scattering by cold atoms
2010-08-06

We have studied the interplay between disorder and cooperative scattering for the single scattering limit in the presence of a driving laser. Analytical results have been derived and we have observed cooperative scattering effects in a variety of experiments, ranging from thermal atoms in an optical dipole trap, atoms released from a dark MOT and atoms in a BEC, consistent with our theoretical predictions.
Critical current diffraction pattern of SIFS Josephson junctions with a step-like F-layer
2010-08-06

We present the latest generation of\\nsuperconductor-insulator-ferromagnet-superconductor Josephson tunnel junctions\\nwith a step-like thickness of the ferromagnetic (F) layer. The F-layer\\nthicknesses and in both halves were varied to obtain different\\ncombinations of positive and negative critical current densities and\\n . The measured dependences of the critical current on applied magnetic\\nfield can be well described by a model which takes into account different\\ncritical current densities (obtained from reference junctions) and different\\nnet magnetization of the multidomain ferromagnetic layer in both halves.\\n
Effects of aging on discriminating emotions from point-light walkers
2010-08-06

The visual system is able to recognize human motion simply from point lights attached to the major joints of an actor. Moreover, it has been shown that younger adults are able to recognize emotions from such dynamic point-light displays. Here, we investigated whether the ability to recognize emotions from point-light displays changes with age. There is accumulating evidence that older adults are less sensitive to emotional stimuli. For example, it has been shown that older adults are impaired in recognizing emotional expressions from static faces. In addition, it has been shown that older adults have difficulties perceiving visual motion, which might be helpful to recognize emotions from point-light displays. In the current study, ten older (mean = 70.4 years) and ten younger adults (mean = 26.1 years) were asked to identify three emotions (happy, sad, and angry) displayed by four types of point-light walkers: upright and inverted normal walkers, which contained both local motion and global form information; upright scrambled walkers which contained only local motion information; and upright random-position walkers which contained only global form information. Observers in both age groups were able to recognize emotions from all types of point-light walkers, but performance was best with upright-normal walkers, worst with scrambled walkers, and intermediate with random-position and inverted-normal walkers. Older subjects performed worse than younger subjects in the scrambled and random-position conditions, but no age difference was found in the upright- and inverted-normal conditions. These results suggest that both older and younger adults are able to recognize emotions from point-light walkers on the basis of local motion or global form information alone. However, performance is best when both form and motion information are presented simultaneously, an effect which is enhanced in older subjects.
Palmitoylation of the S0-S1 Linker Regulates Cell Surface Expression of Voltage- and Calcium-activated Potassium (BK) Channels
2010-08-07

S-palmitoylation is rapidly emerging as an important post-translational mechanism to regulate ion channels. We have previously demonstrated that large conductance calcium- and voltage-activated potassium (BK) channels are palmitoylated within an alternatively spliced (STREX) insert. However, these studies also revealed that additional site(s) for palmitoylation must exist outside of the STREX insert, although the identity or the functional significance of these palmitoylated cysteine residues are unknown. Here, we demonstrate that BK channels are palmitoylated at a cluster of evolutionary conserved cysteine residues (Cys-53, Cys-54, and Cys-56) within the intracellular linker between the S0 and S1 transmembrane domains. Mutation of Cys-53, Cys-54, and Cys-56 completely abolished palmitoylation of BK channels lacking the STREX insert (ZERO variant). Palmitoylation allows the S0-S1 linker to associate with the plasma membrane but has no effect on single channel conductance or the calcium/voltage sensitivity. Rather, S0-S1 linker palmitoylation is a critical determinant of cell surface expression of BK channels, as steady state surface expression levels are reduced by ∼55% in the C53:54:56A mutant. STREX variant channels that could not be palmitoylated in the S0-S1 linker also displayed significantly reduced cell surface expression even though STREX insert palmitoylation was unaffected. Thus our work reveals the functional independence of two distinct palmitoylation-dependent membrane interaction domains within the same channel protein and demonstrates the critical role of S0-S1 linker palmitoylation in the control of BK channel cell surface expression.
Vegetation development in the Middle Euphrates and Upper Jazirah (Syria/Turkey) during the Bronze Age
2010-08-08

Abstract Vegetation changes are reconstructed based on more than 51,000 charcoal fragments of more than 380 samples from nine Bronze Age sites in northern Syria and southern Turkey. In addition to fragment proportions, special attention was paid to the frequency of Pistacia relative to Quercus and Populus / Salix relative to Tamarix , fruit-tree ubiquity, and riverine diversity in order to gain an improved understanding of the human versus climatic impact on the vegetation. The results indicate that human impacts first took place within the riverine forest. This phase was followed by land clearing within the woodland steppe, especially in the northern portion of the study area. In the south near Emar, the woodland steppe probably disappeared by the Late Bronze Age. It is uncertain whether this was caused by aridification and/or human clearing. The northward shift of the Pistacia-woodland steppe is very likely a result of climatic drying that occurred throughout the entire period under investigation. Although increased deforestation is evident through time, the small proportions of imported wood indicate that local resources were still available.
Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation
2010-08-09

Estrogen receptor α (ERα) plays an important role in the onset and progression of breast cancer, whereas p53 functions as a major tumor suppressor. We previously reported that ERα binds to p53, resulting in inhibition of transcriptional regulation by p53. Here, we report on the molecular mechanisms by which ERα suppresses p53’s transactivation function. Sequential ChIP assays demonstrated that ERα represses p53-mediated transcriptional activation in human breast cancer cells by recruiting nuclear receptor corepressors (NCoR and SMRT) and histone deacetylase 1 (HDAC1). RNAi-mediated down-regulation of NCoR resulted in increased endogenous expression of the cyclin-dependent kinase (CDK)-inhibitor p21 Waf1/Cip1 ( CDKN1A ) gene, a prototypic transcriptional target of p53. While 17β-estradiol (E2) enhanced ERα binding to p53 and inhibited p21 transcription, antiestrogens decreased ERα recruitment and induced transcription. The effects of estrogen and antiestrogens on p21 transcription were diametrically opposite to their known effects on the conventional ERE-containing ERα target gene, pS2/TFF1. These results suggest that ERα uses dual strategies to promote abnormal cellular proliferation: enhancing the transcription of ERE-containing proproliferative genes and repressing the transcription of p53-responsive antiproliferative genes. Importantly, ERα binds to p53 and inhibits transcriptional activation by p53 in stem/progenitor cell-containing murine mammospheres, suggesting a potential role for the ER–p53 interaction in mammary tissue homeostasis and cancer formation. Furthermore, retrospective studies analyzing response to tamoxifen therapy in a subset of patients with ER-positive breast cancer expressing either wild-type or mutant p53 suggest that the presence of wild-type p53 is an important determinant of positive therapeutic response.
Genetic variation of theFADS1 FADS2gene cluster andn-6 PUFA composition in erythrocyte membranes in the European Prospective Investigation into Cancer and Nutrition-Potsdam study
2010-08-09

Delta-5 (D5D) and delta-6 (D6D) desaturases are key enzymes in PUFA metabolism. Several factors (e.g. hyperglycaemia, hypertension, blood lipids, statins and fatty acids in diet and biological tissues) may influence desaturase activity. The goals were to evaluate the associations between variation in genes encoding these desaturases ( FADS1 and FADS2 ) and blood concentrations of n -6 PUFA and estimated D5D and D6D activities (evaluated as product/precursor ratio), and to investigate whether other factors influencing the activity of desaturases modify these associations. A random sample of 2066 participants from the European Prospective Investigation into Cancer and Nutrition-Potsdam study ( n 27 548) was utilised in the analyses. Crude and adjusted associations between rs174546 genotypes (reflecting genetic variation in the FADS1 FADS2 gene cluster), n -6 PUFA in erythrocytes and estimated desaturase activities were evaluated using multiple linear regression. Potential effect modification was determined by performing stratified analyses and evaluating interaction terms. We found rs174546 genotypes to be related to linoleic ( r 2 0·060), γ-linolenic ( r 2 0·041), eicosadienoic ( r 2 0·034), arachidonic ( r 2 0·026), docosatetraenoic acids ( r 2 0·028), estimated D6D activity ( r 2 0·052) and particularly strongly to dihomo-γ-linolenic acid (DGLA, r 2 0·182) and D5D activity ( r 2 0·231). We did not observe effect modifications with regard to the estimated D5D activity, DGLA and arachidonic acid (AA) for most of the factors evaluated; however, the genetic effect on D5D activity and DGLA may be modified by the dietary n -6: n -3-ratio ( P -values for interaction: 0·008 and 0·002), and the genetic effect on DGLA and AA may be modified by lipid-lowering medication ( P -values for interaction: 0·0004 and 0·006). In conclusion, genetic variation in the FADS1 FADS2 gene cluster affects n -6 PUFA profiles in erythrocytes reflecting altered D5D activity.
Ectopic vesicular neurotransmitter release along sensory axons mediates neurovascular coupling via glial calcium signaling
2010-08-09

Neurotransmitter release generally is considered to occur at active zones of synapses, and ectopic release of neurotransmitters has been demonstrated in a few instances. However, the mechanism of ectopic neurotransmitter release is poorly understood. We took advantage of the intimate morphological and functional proximity of olfactory receptor axons and specialized glial cells, olfactory ensheathing cells (OECs), to study ectopic neurotransmitter release. Axonal stimulation evoked purinergic and glutamatergic Ca 2+ responses in OECs, indicating ATP and glutamate release. In axons expressing synapto-pHluorin, stimulation evoked an increase in synapto-pHluorin fluorescence, indicative of vesicle fusion. Transmitter release was dependent on Ca 2+ and could be inhibited by bafilomycin A1 and botulinum toxin A. Ca 2+ transients in OECs evoked by ATP, axonal stimulation, and laser photolysis of NP-EGTA resulted in constriction of adjacent blood vessels. Our results indicate that ATP and glutamate are released ectopically by vesicles along axons and mediate neurovascular coupling via glial Ca 2+ signaling.
Defining species in Tulasnella by correlating morphology and nrDNA ITS-5.8S sequence data of basidiomata from a tropical Andean forest
2010-08-09

The genus Tulasnella comprises important orchid mycobionts. Molecular phylogenetic studies on nrITS-5.8S sequences of Tulasnella species previously isolated from mycorrhizas of epiphytic orchids from a tropical Andean forest showed genomic variability among clones which was difficult to interpret as intra- or interspecific variations or to correlate with described Tulasnella species. To improve this situation, we collected basidiomata of Tulasnella in an Andean forest, studied part of the sequences of fungal ribosomal genes and correlated molecular data with the morphology of the specimens. Within five basidiomata displaying slight morphological variability, we found inter-specimen nrITS1-5.8S-ITS2 variability corresponding to proportional differences of less than 1% except for one clone with 5.1% divergence. Results indicate that the slightly variable basidiomata should be considered as one species, which is morphologically tentatively assigned to the Tulasnella pruinosa complex. However, comparison of nrITS1-5.8S-ITS2 sequences, including sequences of T. pruinosa from other origins, indicate that Tulasnella sp. is only distantly related to the T. pruinosa specimens included in the analyses. Sequences of all morphologically similar and taxonomically well-identified species are required to decide whether the basidiomata analyzed in the present study represent a new species. The new sequences are rather similar to sequences obtained previously from mycorrhizae of epiphytic orchids of the same area indicating mycorrhizal potential of this fungus. © 2010 German Mycological Society and Springer.
Simultaneous in situ measurements of x-ray reflectivity and optical spectroscopy during organic semiconductor thin film growth
2010-08-09

Simultaneous in situ real-time measurements of x-ray reflectivity and differential reflectance spectroscopy were conducted during deposition of perfluorinated copper-phthalocyanine thin films on SiO2/Si. We found a continuous spectral change coinciding with structural changes from submonolayer coverage, to standing βbilayer-phase and to β-phase for thicker films. This combined measurement enables us to study the relationship between structural and optical properties of organic semiconductor thin films.
Quantifying Tectonic and Geomorphic Interpretations of Thermochronometer Data with Inverse Problem Theory
2010-08-09

Abstract Thermochronometer data offer a powerful tool for quantifying a wide range of geologic processes, such as the deformation and erosion of mountain ranges, topographic evolution, and hydrocarbon maturation. With increasing interest to quantify a wider range of complicated geologic processes, more sophisticated techniques are needed. This paper is concerned with an inverse problem method for interpreting the thermochronometer data quantitatively. Two novel models are proposed to simulate the crustal thermal fields and paleo mountain topography as a function of tectonic and surface processes. One is a heat transport model that describes the change of temperature of rocks; while the other is surface process model which explains the change of mountain topography. New computational algorithms are presented for solving the inverse problem of the coupled system of these two models. The model successfully provides a new tool for reconstructing the kinematic and the topographic history of mountains.