julilili42/papers huggingface dataset:
Presence of disseminated tumor cells in bone marrow correlates with tumor stage and nodal involvement in cervical cancer patients
2013-08-07

Detection of disseminated tumor cells (DTCs) in the bone marrow (BM) of breast cancer patients is associated with poor outcome. The aim of our study was to evaluate the impact of BM status on survival in a large cohort of cervical cancer patients. Three hundred twenty‐five patients with cervical cancer were included into this prospective two‐center study (University Hospitals Tuebingen, Munich, Germany). BM was collected preoperatively. DTCs were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3. DTCs were detected in 22% of all BM aspirates. The number of CK‐positive cells ranged from 1 to 93 per 2 × 10 6 mononuclear cells. Eighteen percent of patients with T1 stage presented with DTCs in BM compared to 30% in T2 and 45% in T3/4 patients. Among nodal negative patients, 18% had tumor cells in BM compared to 32% of nodal positive patients. Positive DTC status was associated with tumor size ( p = 0.007) and nodal status ( p = 0.009) but not with grading ( p = 0.426). DTC status did not correlate with overall or disease‐free survival. In the univariate analysis, tumor stage, nodal status, resection status and grading correlated with OS and DFS. In the multivariate analysis, only tumor stage and nodal status were independent predictors of OS and tumor stage, nodal status and grading of DFS. Tumor cell dissemination into BM is thus a common phenomenon in cervical cancer and correlates with higher tumor load but lacks prognostic relevance. Alternative detection methods may be needed to establish prognostic potential.
Doubly Latent Multilevel Analyses of Classroom Climate: An Illustration
2013-08-08

Many classroom climate studies suffer from 2 critical problems: They (a) treat climate as a student-level (L1) variable in single-level analyses instead of a classroom-level (L2) construct in multilevel analyses; and (b) rely on manifest-variable models rather than on latent-variable models that control measurement error at L1 and L2, and sampling error in the aggregation of L1 ratings to form L2 constructs. On the basis of an analysis of 2,541 students in Grades 5 or 6 from 89 classrooms, the authors demonstrate doubly latent multilevel structural equation models that overcome both of these problems. The results show that L2 classroom climate (a higher-order factor representing classroom mastery goal orientation, challenge, and teacher caring) had positive effects on self-efficacy and achievement. The authors conclude with a discussion of related issues (e.g., the meaning of L2 constructs vs. L1 residuals, the dimensionality of climate constructs at L2) and guidelines for future research.
Cytokine response of primary human myotubes in an in vitro exercise model
2013-08-08

Muscle contraction during exercise is a major stimulus for the release of peptides and proteins (myokines) that are supposed to take part in the beneficial adaptation to exercise. We hypothesize that application of an in vitro exercise stimulus as electric pulse stimulation (EPS) to human myotubes enables the investigation of the molecular response to exercise in a clearly defined model. We applied EPS for 24 h to primary human myotubes and studied the whole genome-wide transcriptional response as well as the release of candidate myokines. We observed 183 differentially regulated transcripts with fold changes &gt;1.3. The transcriptional response resembles several properties of the in vivo situation in the skeletal muscle after endurance exercise, namely significant enrichment of pathways associated with interleukin and chemokine signaling, lipid metabolism, and antioxidant defense. Multiplex immunoassays verified the translation of the transcriptional response of several cytokines into high-secretion levels (IL-6, IL-8, CXCL1, LIF, CSF3, IL-1B, and TNF) and the increased secretion of further myokines such as angiopoietin-like 4. Notably, EPS did not induce the release of creatine kinase. Inhibitor studies and immunoblotting revealed the participation of ERK1/2-, JNK-, and NF-κB-dependent pathways in the upregulation of myokines. To conclude, our data highlight the importance of skeletal muscle cells as endocrine cells. This in vitro exercise model is not only suitable to identify exercise-regulated myokines, but it might be applied to primary human myotubes obtained from different muscle biopsy donors to study the molecular mechanisms of the individual response to exercise.
Reversal Mechanism of an Individual Ni Nanotube Simultaneously Studied by Torque and SQUID Magnetometry
2013-08-08

Using an optimally coupled nanometer-scale SQUID, we measure the magnetic flux originating from an individual ferromagnetic Ni nanotube attached to a Si cantilever. At the same time, we detect the nanotube's volume magnetization using torque magnetometry. We observe both the predicted reversible and irreversible reversal processes. A detailed comparison with micromagnetic simulations suggests that vortexlike states are formed in different segments of the individual nanotube. Such stray-field free states are interesting for memory applications and noninvasive sensing.
Bilateral Bi-Cephalic Tdcs with Two Active Electrodes of the Same Polarity Modulates Bilateral Cognitive Processes Differentially
2013-08-08

Transcranial direct current stimulation (tDCS) is an innovative method to explore the causal structure-function relationship of brain areas. We investigated the specificity of bilateral bi-cephalic tDCS with two active electrodes of the same polarity (e.g., cathodal on both hemispheres) applied to intraparietal cortices bilaterally using a combined between- and within-task approach. Regarding between-task specificity, we observed that bilateral bi-cephalic tDCS affected a numerical (mental addition) but not a control task (colour word Stroop), indicating a specific influence of tDCS on numerical but not on domain general cognitive processes associated with the bilateral IPS. In particular, the numerical effect of distractor distance was more pronounced under cathodal than under anodal stimulation. Moreover, with respect to within-task specificity we only found the numerical distractor distance effect in mental addition to be modulated by direct current stimulation, whereas the effect of target identity was not affected. This implies a differential influence of bilateral bi-cephalic tDCS on the recruitment of different processing components within the same task (number magnitude processing vs. recognition of familiarity). In sum, this first successful application of bilateral bi-cephalic tDCS with two active electrodes of the same polarity in numerical cognition research corroborates the specific proposition of the Triple Code Model that number magnitude information is represented bilaterally in the intraparietal cortices.
Highly Conserved Cysteines Are Involved in the Oligomerization of Occludin—Redox Dependency of the Second Extracellular Loop
2013-08-08

Our findings support the new concept that occludin acts as a hypoxiasensor and contributes toward regulating the TJ assembly redox dependently. This is of pathogenic relevance for tissue barrier injury with reducing conditions. The ECL2 disulfide might be a model for four TMD proteins in TJs with two conserved cysteines in an ECL.
Isolation of adult human spermatogonial progenitors using novel markers
2013-08-08

Abhishek Harichandan, Kavitha Sivasubramaniyan, Jorg Hennenlotter, Christian Schwentner, Arnulf Stenzl, Hans-Jorg Buhring1,* University Clinic of Tubingen, Department of Internal Medicine II, Division of Hematology, Immunology, Oncology, Rheumatology and Pulmonology, 72076 Tubingen, Germany University Clinic of Tubingen, Department of Urology, 72076 Tubingen, Germany Correspondence to: Hans-Jorg Buhring, Tel: +49-7071-2982730; Fax: +49-7071-292730; E-
Nucleoside Analogues with a 1,3‐DieneFe(CO)3 Substructure: Stereoselective Synthesis, Configurational Assignment, and Apoptosis‐Inducing Activity
2013-08-09

Abstract The synthesis and stereochemical assignment of two classes of iron‐containing nucleoside analogues, both of which contain a butadieneFe(CO) 3 substructure, is described. The first type of compounds are Fe(CO) 3 ‐complexed 3′‐alkenyl‐2′,3′‐dideoxy‐2′,3′‐dehydro nucleosides (2,5‐dihydrofuran derivatives), from which the second class of compounds is derived by formal replacement of the ring oxygen atom by a CH 2 group (carbocyclic nucleoside analogues). These compounds were prepared in a stereoselective manner through the metal‐assisted introduction of the nucleobase. Whilst the furanoid intermediates were prepared from carbohydrates (such as methyl‐glucopyranoside), the carbocyclic compounds were obtained by using an intramolecular Pauson–Khand reaction. Stereochemical assignments based on NMR and CD spectroscopy were confirmed by X‐ray structural analysis. Biological investigations revealed that several of the complexes exhibited pronounced apoptosis‐inducing properties (through an unusual caspase 3‐independent but ROS‐dependent pathway). Furthermore, some structure–activity relationships were identified, also as a precondition for the design and synthesis of fluorescent and biotin‐labeled conjugates.
Neandertals made the first specialized bone tools in Europe
2013-08-12

Modern humans replaced Neandertals ∼40,000 y ago. Close to the time of replacement, Neandertals show behaviors similar to those of the modern humans arriving into Europe, including the use of specialized bone tools, body ornaments, and small blades. It is highly debated whether these modern behaviors developed before or as a result of contact with modern humans. Here we report the identification of a type of specialized bone tool, lissoir , previously only associated with modern humans. The microwear preserved on one of these lissoir is consistent with the use of lissoir in modern times to obtain supple, lustrous, and more impermeable hides. These tools are from a Neandertal context proceeding the replacement period and are the oldest specialized bone tools in Europe. As such, they are either a demonstration of independent invention by Neandertals or an indication that modern humans started influencing European Neandertals much earlier than previously believed. Because these finds clearly predate the oldest known age for the use of similar objects in Europe by anatomically modern humans, they could also be evidence for cultural diffusion from Neandertals to modern humans.
The GPVI – Fc Fusion Protein Revacept Reduces Thrombus Formation and Improves Vascular Dysfunction in Atherosclerosis without Any Impact on Bleeding Times
2013-08-12

Repeated doses of Revacept led to a significant improvement of endothelial dysfunction and vascular morphology in atherosclerotic rabbits. Furthermore, no influence of Revacept on bleeding time alone or in combinations with various anti-platelet drugs was found in mice. Thus, the inhibition of collagen-mediated platelet interaction with the atherosclerotic endothelium by Revacept exerts beneficial effects on morphology and vascular function in vivo and seems to have a wide therapeutic window without influencing the bleeding time.
New constraints on the chronology, magnitude, and distribution of deformation within the central Andean orocline
2013-08-12

Abstract Constructing an accurate kinematic model for crustal thickening in the central Andes is hampered by the inability of 2‐D balanced cross sections to resolve the 3‐D displacement field within the poorly studied orocline core. This study presents new structural and thermochronometer data from the orocline axis in the central Andes that constrains the magnitude and timing of deformation through (1) a balanced cross section quantifying shortening perpendicular to strike, (2) field observations that constrain translational displacements parallel to strike, and (3) thermochronology that brackets the age of exhumation and deformation. Mapping results show that north directed, right‐lateral motion has been accommodated on at least one major strike‐slip fault in the Eastern Cordillera (EC). Shortening perpendicular to fault strike is ~179 km (41%) for the EC and inter‐Andean zone (IA) and ~86 km (39%) for the sub‐Andes (SA). Apatite fission track cooling ages indicate rapid EC/IA exhumation from 46 to 18 Ma and 15 to 0 Ma in the SA. Zircon and apatite (U‐Th)/He ages show that rapid exhumation began 10–5 Ma in the SA. These results are integrated with existing paleomagnetic and GPS rotation data in map view reconstructions to quantify the magnitude of translational faulting related to oroclinal bending. The reconstructions suggest that at least 85 km of north directed translational displacement has been accommodated within the orocline core. Orogen‐parallel displacement and vertical axis rotations have focused crustal thickening at the orocline core and facilitated development of a high‐elevation plateau, suggesting a genetic link between large‐scale oroclines and plateaus.
Two types of exercise‐induced neuroplasticity in congenital hemiparesis: a transcranial magnetic stimulation, functional MRI, and magnetoencephalography study
2013-08-13

Aim Early unilateral brain lesions can lead to a persistence of ipsilateral corticospinal projections from the contralesional hemisphere, which can enable the contralesional hemisphere to exert motor control over the paretic hand. In contrast to the primary motor representation (M1), the primary somatosensory representation (S1) of the paretic hand always remains in the lesioned hemisphere. Here, we report on differences in exercise‐induced neuroplasticity between individuals with such ipsilateral motor projections (ipsi) and individuals with early unilateral lesions but ‘healthy’ contralateral motor projections (contra). Method Sixteen children and young adults with congenital hemiparesis participated in the study (contralateral [Contra] group: n =7, four females, three males; age range 10–30y, median age 16y; ipsilateral [Ipsi] group: n =9, four females, five males; age range 11–31y, median age 12y; Manual Ability Classification System levels I to II in all individuals in both groups). The participants underwent a 12‐day intervention of constraint‐induced movement therapy ( CIMT ), consisting of individual training (2h/d) and group training (8h/d). Before and after CIMT , hand function was tested using the Wolf Motor Function Test ( WMFT ) and diverging neuroplastic effects were observed by transcranial magnetic stimulation ( TMS ), functional magnetic resonance imaging ( fMRI ), and magnetoencephalography ( MEG ). Statistical analysis of TMS data was performed using the non‐parametric Wilcoxon signed‐rank test for pair‐wise comparison; for fMRI standard statistical parametric and non‐parametric mapping ( SPM 5, SnPM3) procedures (first level/second level) were carried out. Statistical analyses of MEG data involved analyses of variance ( ANOVA ) and t ‐tests. Results While MEG demonstrated a significant increase in S1 activation in both groups ( p =0.012), TMS showed a decrease in M1 excitability in the Ipsi group ( p =0.036), but an increase in M1 excitability in the Contra group ( p =0.043). Similarly, fMRI showed a decrease in M1 activation in the Ipsi group, but an increase in activation in the M1–S1 region in the Contra group (for both groups p &lt;0.001 [SnPM3] within the search volume). Interpretation Different patterns of sensorimotor (re)organization in individuals with early unilateral lesions show, on a cortical level, different patterns of exercise‐induced neuroplasticity. The findings help to improve the understanding of the general principles of sensorimotor learning and will help to develop more specific therapies for different pathologies in congenital hemiparesis.
RACK1 scaffold proteins influence miRNA abundance in Arabidopsis
2013-08-13

Summary MicroRNAs (miRNAs) regulate plant development by post‐transcriptional regulation of target genes. In Arabidopsis thaliana , DCL1 processes precursors (pri‐miRNAs) to miRNA duplexes, which associate with AGO1. Additional proteins act in concert with DCL1 (e.g. HYL1 and SERRATE) or AGO1 to facilitate efficient and precise pri‐miRNA processing and miRNA loading, respectively. In this study, we show that the accumulation of plant microRNAs depends on RECEPTOR FOR ACTIVATED C KINASE 1 (RACK1), a scaffold protein that is found in all higher eukaryotes. miRNA levels are reduced in rack1 mutants, and our data suggest that RACK1 affects the microRNA pathway via several distinct mechanisms involving direct interactions with known microRNA factors: RACK1 ensures the accumulation and processing of some pri‐miRNAs, directly interacts with SERRATE and is part of an AGO1 complex. As a result, mutations in RACK1 lead to over‐accumulation of miRNA target mRNA s, which are important for ABA responses and phyllotaxy, for example. In conclusion, our study identified complex functioning of RACK1 proteins in the Arabidopsis miRNA pathway; these proteins are important for miRNA production and therefore plant development.
Fine-Mapping, Gene Expression and Splicing Analysis of the Disease Associated LRRK2 Locus
2013-08-13

Association studies have identified several signals at the LRRK2 locus for Parkinson's disease (PD), Crohn's disease (CD) and leprosy. However, little is known about the molecular mechanisms mediating these effects. To further characterize this locus, we fine-mapped the risk association in 5,802 PD and 5,556 controls using a dense genotyping array (ImmunoChip). Using samples from 134 post-mortem control adult human brains (UK Human Brain Expression Consortium), where up to ten brain regions were available per individual, we studied the regional variation, splicing and regulation of LRRK2. We found convincing evidence for a common variant PD association located outside of the LRRK2 protein coding region (rs117762348, A>G, P = 2.56×10(-8), case/control MAF 0.083/0.074, odds ratio 0.86 for the minor allele with 95% confidence interval [0.80-0.91]). We show that mRNA expression levels are highest in cortical regions and lowest in cerebellum. We find an exon quantitative trait locus (QTL) in brain samples that localizes to exons 32-33 and investigate the molecular basis of this eQTL using RNA-Seq data in n = 8 brain samples. The genotype underlying this eQTL is in strong linkage disequilibrium with the CD associated non-synonymous SNP rs3761863 (M2397T). We found two additional QTLs in liver and monocyte samples but none of these explained the common variant PD association at rs117762348. Our results characterize the LRRK2 locus, and highlight the importance and difficulties of fine-mapping and integration of multiple datasets to delineate pathogenic variants and thus develop an understanding of disease mechanisms.
Correction: Bilateral Bi-Cephalic Tdcs with Two Active Electrodes of the Same Polarity Modulates Bilateral Cognitive Processes Differentially
2013-08-13

Transcranial direct current stimulation (tDCS) is an innovative method to explore the causal structure-function relationship of brain areas.We investigated the specificity of bilateral bi-cephalic tDCS with two active electrodes of the same polarity (e.g., cathodal on both hemispheres) applied to intraparietal cortices bilaterally using a combined between-and within-task approach.Regarding between-task specificity, we observed that bilateral bi-cephalic tDCS affected a numerical (mental addition) but not a control task (colour word Stroop), indicating a specific influence of tDCS on numerical but not on domain general cognitive processes associated with the bilateral IPS.In particular, the numerical effect of distractor distance was more pronounced under cathodal than under anodal stimulation.Moreover, with respect to within-task specificity we only found the numerical distractor distance effect in mental addition to be modulated by direct current stimulation, whereas the effect of target identity was not affected.This implies a differential influence of bilateral bi-cephalic tDCS on the recruitment of different processing components within the same task (number magnitude processing vs. recognition of familiarity).In sum, this first successful application of bilateral bi-cephalic tDCS with two active electrodes of the same polarity in numerical cognition research corroborates the specific proposition of the Triple Code Model that number magnitude information is represented bilaterally in the intraparietal cortices.
Screening of a Large Cohort of Leber Congenital Amaurosis and Retinitis Pigmentosa Patients Identifies Novel LCA5 Mutations and New Genotype-Phenotype Correlations
2013-08-14

This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ∼2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.