julilili42/papers huggingface dataset:
Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk
2015-09-10

Abstract Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1680–91. ©2015 AACR.
CD44 sensitivity of platelet activation, membrane scrambling and adhesion under high arterial shear rates
2015-09-10

Summary CD44 is required for signalling of macrophage migration inhibitory factor (MIF), an anti-apoptotic pro-inflammatory cytokine. MIF is expressed and released from blood platelets, key players in the orchestration of occlusive vascular disease. Nothing is known about a role of CD44 in the regulation of platelet function. The present study thus explored whether CD44 modifies degranulation (P-selectin exposure), integrin activation, caspase activity, phosphatidylserine exposure on the platelet surface, platelet volume, Orai1 protein abundance and cytosolic Ca2+-activity ([Ca2+]i). Platelets from mice lacking CD44 (cd44-/- ) were compared to platelets from corresponding wild-type mice (cd44+/+ ). In resting platelets, P-selectin abundance, αllbβ3 inte-grin activation, caspase-3 activity and phosphatidylserine exposure were negligible in both genotypes and Orai1 protein abundance, [Ca2+]i, and volume were similar in cd44-/- and cd44+/+ platelets. Platelet degranulation and αllbβ3 integrin activation were significantly increased by thrombin (0.02 U/ml), collagen related peptide (CRP, 2 μg/ml and Ca2+-store depletion with thapsigargin (1 μM), effects more pronounced in cd44-/- than in cd44+/+ platelets. Thrombin (0.02 U/ml) increased platelet [Ca2+]i, caspase-3 activity, phosphatidylserine exposure and Orai1 surface abundance, effects again significantly stronger in cd44-/- than in cd44+/+ platelets. Thrombin further decreased forward scatter in cd44-/- and cd44+/+ platelets, an effect which tended to be again more pronounced in cd44-/- than in cd44+/+ platelets. Platelet adhesion and in vitro thrombus formation under high arterial shear rates (1,700 s-1) were significantly augmented in cd44-/- mice. In conclusion, genetic deficiency of CD44 augments activation, apoptosis and prothrombotic potential of platelets.
No parkinsonism in SCA2 and SCA3 despite severe neurodegeneration of the dopaminergic substantia nigra
2015-09-11

See Klockgether (doi:10.1093/awv253) for a scientific commentary on this article.The spinocerebellar ataxias types 2 (SCA2) and 3 (SCA3) are autosomal dominantly inherited cerebellar ataxias which are caused by CAG trinucleotide repeat expansions in the coding regions of the disease-specific genes. Although previous post-mortem studies repeatedly revealed a consistent neurodegeneration of the dopaminergic substantia nigra in patients with SCA2 and with SCA3, parkinsonian motor features evolve only rarely. As the pathophysiological mechanism how SCA2 and SCA3 patients do not exhibit parkinsonism is still enigmatic, we performed a positron emission tomography and a post-mortem study of two independent cohorts of SCA2 and SCA3 patients with and without parkinsonian features. Positron emission tomography revealed a significant reduction of dopamine transporter levels in the striatum as well as largely unaffected postsynaptic striatal D2 receptors. In spite of this remarkable pathology in the motor mesostriatal pathway, only 4 of 19 SCA2 and SCA3 patients suffered from parkinsonism. The post-mortem investigation revealed, in addition to an extensive neuronal loss in the dopaminergic substantia nigra of all patients with spinocerebellar ataxia, a consistent affection of the thalamic ventral anterior and ventral lateral nuclei, the pallidum and the cholinergic pedunculopontine nucleus. With the exception of a single patient with SCA3 who suffered from parkinsonian motor features during his lifetime, the subthalamic nucleus underwent severe neuronal loss, which was clearly more severe in its motor territory than in its limbic or associative territories. Our observation that lesions of the motor territory of the subthalamic nucleus were consistently associated with the prevention of parkinsonism in our SCA2 and SCA3 patients matches the clinical experience that selective targeting of the motor territory of the subthalamic nucleus by focal lesions or deep brain stimulation can ameliorate parkinsonian motor features and is likely to counteract the manifestation of parkinsonism in SCA2 and SCA3 despite a severe neurodegeneration of the dopaminergic substantia nigra.
A systematic screening to identifyde novomutations causing sporadic early-onset Parkinson's disease
2015-09-11

Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that de novo mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent-child trios where the proband presents with typical PD to unequivocally identify de novo mutations. This approach allows us to test all genes in the genome in an unbiased manner. We have identified and confirmed 20 coding de novo mutations in 21 trios. We have used publicly available population genetic data to compare variant frequencies and our independent in-house dataset of exome sequencing in PD (with over 1200 cases) to identify additional variants in the same genes. Of the genes identified to carry de novo mutations, PTEN, VAPB and ASNA1 are supported by various sources of data to be involved in PD. We show that these genes are reported to be within a protein-protein interaction network with PD genes and that they contain additional rare, case-specific, mutations in our independent cohort of PD cases. Our results support the involvement of these three genes in PD and suggest that testing for de novo mutations in sporadic disease may aid in the identification of novel disease-causing genes.
Age-Associated Differences in MiRNA Signatures Are Restricted to CD45RO Negative T Cells and Are Associated with Changes in the Cellular Composition, Activation and Cellular Ageing
2015-09-11

MicroRNAs (miRNAs) have emerged as important players in the regulation of T-cell functionality. However, comprehensive insight into the extent of age-related miRNA changes in T cells is lacking. We established miRNA expression patterns of CD45RO- naïve and CD45RO+ memory T-cell subsets isolated from peripheral blood cells from young and elderly individuals. Unsupervised clustering of the miRNA expression data revealed an age-related clustering in the CD45RO- T cells, while CD45RO+ T cells clustered based on expression of CD4 and CD8. Seventeen miRNAs showed an at least 2-fold up- or downregulation in CD45RO- T cells obtained from young as compared to old donors. Validation on the same and independent samples revealed a statistically significant age-related upregulation of miR-21, miR-223 and miR-15a. In a T-cell subset analysis focusing on known age-related phenotypic changes, we showed significantly higher miR-21 and miR-223 levels in CD8+CD45RO-CCR7- TEMRA compared to CD45RO-CCR7+ TNAIVE-cells. Moreover, miR-21 but not miR-223 levels were significantly increased in CD45RO-CD31- post-thymic TNAIVE cells as compared to thymic CD45RO-CD31+ TNAIVE cells. Upon activation of CD45RO- TNAIVE cells we observed a significant induction of miR-21 especially in CD4+ T cells, while miR-223 levels significantly decreased only in CD4+ T cells. Besides composition and activation-induced changes, we showed a borderline significant increase in miR-21 levels upon an increasing number of population doublings in CD4+ T-cell clones. Together, our results show that ageing related changes in miRNA expression are dominant in the CD45RO- T-cell compartment. The differential expression patterns can be explained by age related changes in T-cell composition, i.e. accumulation of CD8+ TEMRA and CD4+ post-thymic expanded CD31- T cells and by cellular ageing, as demonstrated in a longitudinal clonal culture model.
Magnetic properties derived from a loess section at the northern piedmont of Tianshan Mountains, Xinjiang, China, and their paleoenvironmental significance
2015-09-11

Loess deposits in the arid Central Asia contain valuable information on the evolution of local aridification and dust sources in the Northern Hemisphere. Xinjiang is located in the eastern part of Central Asia and previous researches have revealed the complex enhancement of magnetic susceptibility in loess-paleosol sequences. However, systematic magnetic archives of loess deposit in this arid Asian interior are still far from adequate. In this study, magnetic parameters combined with nonmagnetic properties (granulometry and chromaticity) were analysed on a loess section in Shawan (SW), northwestern China. The section shares a similar magnetic composition with those in the Chinese Loess Plateau (CLP) as well as other sites in Xinjiang. Ferrimagnetic components (magnetite and maghemite) dominate the magnetic signal while the contribution of antiferromagnetic phases (like hematite and goethite) and paramagnetic portions are relatively low. There is no specific correlation between magnetic concentration and pedogenic intensity in the SW section. In general, magnetic enhancement was largely influenced by the paleowind intensity. However, a positive correlation between magnetic susceptibility and pedogenesis is observed in the upper part (0-3.5 m depths), which is characterized by a moderate wind intensity. Moreover, pedogenesis might be responsible for the enhancement of fine magnetic particles in paleosols. Magnetic properties are controlled by coarse magnetic particles in the pseudo-single domain state, but a coarse stable single domain phase was found in certain paleosol samples. The input of detrital fractions from a nearby dust source probably controlled the magnetic properties while a superparamagnetic fraction, which has been deemed as a product of pedogenesis in the CLP, is limited in the SW section. Caution is needed to employ magnetic susceptibility directly for paleoclimatic assessment because of its uncertainty in the Xinjiang loess. However, the chi(ARM)/SIRM ratio enhanced in paleosols and has more potential as an alternative index for the weakly pedogenic degree in this area.
Laparoscopic pelvic mesh placement with closure of pelvic floor entrance to prevent small intestine radiation trauma – A retrospective cohort analysis
2015-09-12

Laparoscopic mesh placement represents a safe and efficient procedure in patients requiring high-dose pelvic radiation, presenting with unacceptable small intestine volume in the radiation field. As an alternate to native tissue, the vicryl mesh is a safe, effective substitute for small bowel exclusion from external-beam radiation therapy.
Seasonal hunting of mammoth in the Ach-Valley of the Swabian Jura
2015-09-12

SUMMARY: This poster discusses the seasonality of mammoth hunting in the Ach Valley of the Swabian Jura during the Early Upper Palaeolithic. The aging of the infantile mammoth remains of two cave sites, the Geissenklosterle and the Hohle Fels, are discussed. Some of the infant mammoth bones bear cut marks suggesting an anthropogenic origin. In all three main occupation layers of the Geissenklosterle (AH I: Gravettian, AH II: Upper Aurignacian, AH III: Lower Aurignacian) as well as in the Gravettian layers of the Hohle Fels infantile mammoth remains were found, indicating that mammoth hunting took place repeatedly in spring and early summer.
The production of Upper Palaeolithic mammoth bone artifacts from southwestern Germany
2015-09-12

SUMMARY: This analysis discusses mammoth (Mammuthus primigenius) remains from the Aurignacian layers at the Geissenklosterle and from the Gravettian layers at the caves of Geissenklosterle, Hohle Fels and Brillenhohle. All the caves are situated in the Ach Valley between Blaubeuren and Schelklingen in the Swabian Jura. The role of mammoth is often underestimated at central European sites, simply because its remains are less abundant here than at Upper Palaeolithic sites in eastern Europe and Russia. But the selection of specific elements of mammoth shows the importance of this species as a raw material for the manufacture of tools. Mammoth ribs and ivory are the predominant elements of mammoth at these sites. The great length of mammoth ribs and tusks was an important advantage in the production of projectile points. This contribution emphasizes the importance of including bone tools into archaeozoological analyses, as opposed to examining them simply as artefacts.
Magnetoencephalography Reveals a Widespread Increase in Network Connectivity in Idiopathic/Genetic Generalized Epilepsy
2015-09-14

Idiopathic/genetic generalized epilepsy (IGE/GGE) is characterized by seizures, which start and rapidly engage widely distributed networks, and result in symptoms such as absences, generalized myoclonic and primary generalized tonic-clonic seizures. Although routine magnetic resonance imaging is apparently normal, many studies have reported structural alterations in IGE/GGE patients using diffusion tensor imaging and voxel-based morphometry. Changes have also been reported in functional networks during generalized spike wave discharges. However, network function in the resting-state without epileptiforme discharges has been less well studied. We hypothesize that resting-state networks are more representative of the underlying pathophysiology and abnormal network synchrony. We studied functional network connectivity derived from whole-brain magnetoencephalography recordings in thirteen IGE/GGE and nineteen healthy controls. Using graph theoretical network analysis, we found a widespread increase in connectivity in patients compared to controls. These changes were most pronounced in the motor network, the mesio-frontal and temporal cortex. We did not, however, find any significant difference between the normalized clustering coefficients, indicating preserved gross network architecture. Our findings suggest that increased resting state connectivity could be an important factor for seizure spread and/or generation in IGE/GGE, and could serve as a biomarker for the disease.
Psychosocial adjustment to ALS: a longitudinal study
2015-09-14

For the current study the Lazarian stress-coping theory and the appendant model of psychosocial adjustment to chronic illness and disabilities (Pakenham, 1999) has shaped the foundation for identifying determinants of adjustment to ALS. We aimed to investigate the evolution of psychosocial adjustment to ALS and to determine its long-term predictors. A longitudinal study design with four measurement time points was therefore, used to assess patients' quality of life, depression, and stress-coping model related aspects, such as illness characteristics, social support, cognitive appraisals, and coping strategies during a period of 2 years. Regression analyses revealed that 55% of the variance of severity of depressive symptoms and 47% of the variance in quality of life at T2 was accounted for by all the T1 predictor variables taken together. On the level of individual contributions, protective buffering, and appraisal of own coping potential accounted for a significant percentage in the variance in severity of depressive symptoms, whereas problem management coping strategies explained variance in quality of life scores. Illness characteristics at T2 did not explain any variance of both adjustment outcomes. Overall, the pattern of the longitudinal results indicated stable depressive symptoms and quality of life indices reflecting a successful adjustment to the disease across four measurement time points during a period of about two years. Empirical evidence is provided for the predictive value of social support, cognitive appraisals, and coping strategies, but not illness parameters such as severity and duration for adaptation to ALS. The current study contributes to a better conceptualization of adjustment, allowing us to provide evidence-based support beyond medical and physical intervention for people with ALS.
Noninvasive measurement of intracranial pressure via the pulsatility index on transcranial doppler sonography: Is improvement possible?
2015-09-14

ABSTRACT Purpose We hypothesized that using hemodynamic variables could improve the prediction of intracranial pressure (ICP) from the middle cerebral artery pulsatility index (PI) measured with transcranial Doppler sonography. Methods In this prospective study, 39 patients with traumatic brain injury were routinely examined with transcranial Doppler sonography, and the middle cerebral artery PI was calculated. A multivariate model including hematocrit, mean arterial blood pressure, heart rate, and arterial CO 2 pressure (P a CO 2 ) was evaluated. Results Thirty‐nine comatose patients (16 women and 23 men; age range 18–73 years; median 44 years) were included, and 234 data pairs (consisting of ICP and corresponding PI values) were analyzed. ICP ranged from −3 mmHg to +52 mmHg, and PI from 0.6 to 2.85. We found a significant but weak correlation between PI and the square root of ICP ( R 2 between 0.29 and 0.34, p &lt; 0.0001). A slightly stronger correlation was detected when hemodynamic variables were incorporated ( R 2 between 0.37 and 0.43). Of these variables, mean arterial blood pressure had the most significant influence. Conclusions In this study, PI was not a sufficiently strong predictor of ICP to be used in clinical practice. Its reliability did not improve even when hemodynamic variables were considered. Therefore, we recommend abandoning the use of PI for the noninvasive measurement of ICP in clinical practice. © 2015 Wiley Periodicals, Inc. J Clin Ultrasound 44 :40–45, 2016
IκBζ, an atypical member of the inhibitor of nuclear factor kappa B family, is induced by γ-irradiation in glioma cells, regulating cytokine secretion and associated with poor prognosis
2015-09-14

The inhibitor of nuclear factor kappa B zeta (IκBζ) is an atypical member of the IκB protein family. Its function in regulating the activity of the transcription factor nuclear factor kappa B (NFκB) as well as its involvement in cancer-associated processes is poorly understood. In glioma patients, enhanced expression of IκBζ in tumor specimen is associated with poor prognosis. Here we report that IκBζ is upregulated in a glioma cell line resistant towards NFκB-dependent non-apoptotic cell death. Upon γ-irradiation of glioma cells, IκBζ expression is enhanced, and subsequently serves as a transcriptional activator of the tumor promoting cytokines interleukin (IL-6), IL-8 and chemokine (C-X-C motif) ligand 1 (CXCL1) that are known to be involved in glioma associated inflammatory processes. In contrast, shRNA-mediated knockdown of IκBζ reduces the expression of the aforementioned cytokines. We propose a previously unappreciated role of IκBζ in the inflammatory micromilieu as well as progression in glioma.
Templating Effects of α-Sexithiophene in Donor–Acceptor Organic Thin Films
2015-09-14

Small-molecule organic photovoltaic cells often employ a planar heterojunction (PHJ) geometry where the electron donor and acceptor materials are stacked one on top of the other. The thin-film growth scenario of such PHJs can be very different from the one of a single compound on a bare substrate. We have investigated the growth of PHJs, consisting of two different donor-acceptor pairs, namely, <em>α</em>-sexithiophene (6T)/C<sub>60</sub> and 6T/diindenoperylene (DIP) using real-time in situ X-ray scattering. For both donor-acceptor material combinations, we observe that the coherent in-plane crystalline size of the second material strongly correlates with the one of the bottom one, and hence a strong templating effect of the 6T on the material deposited subsequently, indicating a strong interaction between the two materials in the PHJ. Furthermore, a change in the structure of the 6T film during the deposition of the second material was observed, which shows that the deposition of an additional material on top of a templating layer can partially change the crystal structure of the templating film itself.
Relativistic effects in three-nucleon forces for nuclear matter and finite nuclei
2015-09-14

In order to simulate the relativistic effects of the Dirac Brueckner Hartree Fock approach for finite nuclei the part of the Urbana 3 nucleon (3N) force is considered, which represents the enhancement of the small components of the Dirac spinors for the nucleons in the nuclear medium. This 3N force is included in a Brueckner Hartree Fock calculation with rearrangement terms using a realistic model for the NN interaction. The strength of the 3N force is adjusted to reproduce the empirical saturation point of nuclear matter and then used in corresponding studies of the closed shell nuclei O and Ca. Special attention is paid to a consistent treatment of the spectrum of particle states in the NN propagator of the Bethe-Goldstone equation.