julilili42/papers huggingface dataset:
In Vivo Analysis of Disease-Associated Point Mutations Unveils Profound Differences in mRNA Splicing of Peripherin-2 in Rod and Cone Photoreceptors
2016-01-21

Point mutations in peripherin-2 (PRPH2) are associated with severe retinal degenerative disorders affecting rod and/or cone photoreceptors. Various disease-causing mutations have been identified, but the exact contribution of a given mutation to the clinical phenotype remains unclear. Exonic point mutations are usually assumed to alter single amino acids, thereby influencing specific protein characteristics; however, they can also affect mRNA splicing. To examine the effects of distinct PRPH2 point mutations on mRNA splicing and protein expression in vivo, we designed PRPH2 minigenes containing the three coding exons and relevant intronic regions of human PRPH2. Minigenes carrying wild type PRPH2 or PRPH2 exon 2 mutations associated with rod or cone disorders were expressed in murine photoreceptors using recombinant adeno-associated virus (rAAV) vectors. We detect three PRPH2 splice isoforms in rods and cones: correctly spliced, intron 1 retention, and unspliced. In addition, we show that only the correctly spliced isoform results in detectable protein expression. Surprisingly, compared to rods, differential splicing leads to lower expression of correctly spliced and higher expression of unspliced PRPH2 in cones. These results were confirmed in qRT-PCR experiments from FAC-sorted murine rods and cones. Strikingly, three out of five cone disease-causing PRPH2 mutations profoundly enhanced correct splicing of PRPH2, which correlated with strong upregulation of mutant PRPH2 protein expression in cones. By contrast, four out of six PRPH2 mutants associated with rod disorders gave rise to a reduced PRPH2 protein expression via different mechanisms. These mechanisms include aberrant mRNA splicing, protein mislocalization, and protein degradation. Our data suggest that upregulation of PRPH2 levels in combination with defects in the PRPH2 function caused by the mutation might be an important mechanism leading to cone degeneration. By contrast, the pathology of rod-specific PRPH2 mutations is rather characterized by PRPH2 downregulation and impaired protein localization.
Interplay between Solution Processing and Electronic Structure in Metal-Free Organic Magnets Based on a TEMPO Pentacene Derivative
2016-01-21

We have used X-ray photoelectron spectroscopy (XPS) to describe the electronic structure of two newly synthesized derivatives of the 6,13-bis(triisopropylsilylethynyl) pentacene (TIPS-PEN) carrying the 2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) radical as a substituent. XPS results underline the existing interplay between electronic structure and preparation methods. Our observations suggest a strong influence of the film processing on the shakeup satellite intensities of the N 1s core level spectra. Preparation methods, by tuning the different degree of intermolecular screening, may be use as a tool to influence the properties and the behavior of these materials as thin films, including their local magnetic-exchange coupling.
Surgical accuracy in high tibial osteotomy: coronal equivalence of computer navigation and gap measurement
2016-01-22

Abstract Purpose Medial opening wedge high tibial osteotomy (MOW HTO) is now a successful operation with a range of indications, requiring an individualised approach to the choice of intended correction. This manuscript introduces the concept of surgical accuracy as the absolute deviation of the achieved correction from the intended correction, where small values represent greater accuracy. Surgical accuracy is compared in a randomised controlled trial (RCT) between gap measurement and computer navigation groups. Methods This was a prospective RCT conducted over 3 years of 120 consecutive patients with varus malalignment and medial compartment osteoarthritis, who underwent MOW HTO. All procedures were planned with digital software. Patients were randomly assigned into gap measurement or computer navigation groups. Coronal plane alignment was judged using the mechanical tibiofemoral angle (mTFA), before and after surgery. Absolute (positive) values were calculated for surgical accuracy in each individual case. Results There was no significant difference in the mean intended correction between groups. The achieved mTFA revealed a small under‐correction in both groups. This was attributed to a failure to account for saw blade thickness (gap measurement) and over‐compensation for weight bearing (computer navigation). Surgical accuracy was 1.7° ± 1.2° (gap measurement) compared to 2.1° ± 1.4° (computer navigation) without statistical significance. The difference in tibial slope increases of 2.7° ± 3.9° (gap measurement) and 2.1° ± 3.9° (computer navigation) had statistical significance ( P &lt; 0.001) but magnitude (0.6°) without clinical relevance. Conclusion Surgical accuracy as described here is a new way to judge achieved alignment following knee osteotomy for individual cases. This work is clinically relevant because coronal surgical accuracy was not superior in either group. Therefore, the increased expense and surgical time associated with navigated MOW HTO is not supported, because meticulously conducted gap measurement yields equivalent surgical accuracy. Level of evidence I.
Strategies for Transferring Mixtures of Organic Contaminants from Aquatic Environments into Bioassays
2016-01-23

Mixtures of organic contaminants are ubiquitous in the environment. Depending on their persistence and physicochemical properties, individual chemicals that make up the mixture partition and distribute within the environment and might then jointly elicit toxicological effects. For the assessment and monitoring of such mixtures, a variety of cell-based in vitro and low-complexity in vivo bioassays based on algae, daphnids or fish embryos are available. A very important and sometimes unrecognized challenge is how to combine sampling, extraction and dosing to transfer the mixtures from the environment into bioassays, while conserving (or re-establishing) their chemical composition at adjustable levels for concentration-effect assessment. This article outlines various strategies for quantifiable transfer from environmental samples including water, sediment, and biota into bioassays using total extraction or polymer-based passive sampling combined with either solvent spiking or passive dosing.
Inner ear morphology of the cioclovina early modern European calvaria from Romania
2016-01-25

ABSTRACT Objectives The morphology of the human bony labyrinth is thought to preserve a strong phylogenetic signal and to be minimally, if at all, affected by postnatal processes. The form of the semicircular canals is considered a derived feature of Neanderthals and different from the modern human anatomy. Among other hominins, European Middle Pleistocene humans have been found to be most similar to Neanderthals. Early modern humans have been proposed to show a pattern that is distinct, but most similar to that of Holocene people. Here we examine the inner ear structures of the Cioclovina calvaria, one of the earliest reliably dated and relatively complete modern human crania from Europe, in the context of recent and fossil human variation. Materials and Methods Bony labyrinths were virtually extracted from CT scans of recent Europeans and Cioclovina. Using univariate and multivariate methods, measurements of the semicircular canals were compared with published measurements of other fossil specimens. Results Our results show that Cioclovina's inner ear morphology falls within the range of modern variation, with affinities to both Late Pleistocene modern humans and recent Europeans. Using discriminant functions, the sex of the Cioclovina specimen is estimated as male. Discussion Results agree with previous work showing that Cioclovina exhibits fully modern cranial morphology. Am J Phys Anthropol 160:62–70, 2016. © 2016 Wiley Periodicals, Inc.
HCN1 Channels Enhance Rod System Responsivity in the Retina under Conditions of Light Exposure
2016-01-25

This work corroborates the hypothesis that, in the absence of HCN1-mediated feedback, the amplitude of rod signals remains at high levels for a prolonged period of time, leading to saturation of the retinal pathways. Our results demonstrate the importance of HCN1 channels for regular vision.
Psychosocial Intervention Is Associated with Altered Emotion Processing: An Event-Related Potential Study in At-Risk Adolescents
2016-01-25

Emotion processing is vital for healthy adolescent development, and impaired emotional responses are associated with a number of psychiatric disorders. However, it is unclear whether observed differences between psychiatric populations and healthy controls reflect modifiable variations in functioning (and thus could be sensitive to changes resulting from intervention) or stable, non-modifiable, individual differences. The current study therefore investigated whether the Late Positive Potential (LPP; a neural index of emotion processing) can be used as a marker of therapeutic change following psycho-social intervention. At-risk male adolescents who had received less than four months intervention (minimal-intervention, N = 32) or more than nine months intervention (extended-intervention, N = 32) passively viewed emotional images whilst neural activity was recorded using electroencephalography. Significant differences in emotion processing, indicated by the LPP, were found between the two groups: the LPP did not differ according to valence in the minimal-intervention group, whereas the extended-intervention participants showed emotion processing in line with low risk populations (enhanced LPP for unpleasant images versus other images). Further, an inverse relationship between emotional reactivity (measured via the LPP) and antisocial behaviour was observed in minimal-intervention participants only. The data therefore provide preliminary cross-sectional evidence that abnormal neural responses to emotional information may be normalised following psychosocial intervention. Importantly, this study uniquely suggests that, in future randomised control trials, the LPP may be a useful biomarker to measure development and therapeutic change.
Experimental explorations of a discrimination learning approach to language processing
2016-01-26

This dissertation investigates the potential of a discrimination learning approach to language processes across three different experimental tasks (word naming, compound reading in natural discourse and primed picture naming) and three different measures of language processing (reaction times, eye movements and event-related potentials). The work presented here demonstrates that discrimination learning offers a competitive approach to language processing as compared to traditional psycholinguistic models and analysis techniques.
Designing string-of-beads vaccines with optimal spacers
2016-01-26

String-of-beads polypeptides allow convenient delivery of epitope-based vaccines. The success of a polypeptide relies on efficient processing: constituent epitopes need to be recovered while avoiding neo-epitopes from epitope junctions. Spacers between epitopes are employed to ensure this, but spacer selection is non-trivial.We present a framework to determine optimally the length and sequence of a spacer through multi-objective optimization for human leukocyte antigen class I restricted polypeptides. The method yields string-of-bead vaccines with flexible spacer lengths that increase the predicted epitope recovery rate fivefold while reducing the immunogenicity from neo-epitopes by 44% compared to designs without spacers.
EEG-based prediction of cognitive workload induced by arithmetic: a step towards online adaptation in numerical learning
2016-01-26

Numeracy is a key competency for living in our modern knowledge society. Therefore, it is essential to support numerical learning from basic to more advanced competency levels. From educational psychology it is known that learning is most effective when the respective content is neither too easy nor too demanding in relation to learners’ prerequisites. However, so far it is difficult to assess individual’s cognitive workload independently from performance to adapt learning environments accordingly. In the present study, we aim at identifying learners’ cognitive workload induced by addition tasks of varying difficulty using electroencephalography (EEG). To this end, a classifier using specific features in the EEG-signal is trained to differentiate between different levels of task difficulty significantly above chance level and with high consistency over all participants. Importantly, our model even allows for the prediction of cognitive demands induced by the addition tasks in a cross-participant approach. Closer inspection of the crucial EEG features indicates that oscillations in the theta and alpha band recorded from parietal electrodes are most reflective of current task difficulty. In summary, we are able to differentiate cognitive workload of participants independently from performance based on data of only a small number of electrodes. This suggests that a reduced EEG-setup combined with cross-participant classification may be a feasible approach to assess learners’ cognitive workload.
The Medically Complex Living Kidney Donor: Glucose Metabolism as Principal Cause of Donor Declination
2016-01-26

Glucose metabolism is key in donor risk assessment and precludes kidney donation if abnormal. The high prevalence emphasizes the need for prevention. Prediabetes defines a cohort at risk and response to lifestyle intervention allows for individual risk stratification, thereby potentially increasing the number of persons eligible for kidney donation. Unification of evaluation criteria, as well as prospective long-term follow-up is required to account for increasingly complex living kidney donors.
Neurodegeneration Triggers Peripheral Immune Cell Recruitment into the Forebrain
2016-01-27

Brain-intrinsic degenerative cascades have been proposed to be an initial factor driving lesion formation in multiple sclerosis (MS). Here, we identify neurodegeneration as a potent trigger for peripheral immune cell recruitment into the mouse forebrain. Female C57BL/6 mice were fed cuprizone for 3 weeks, followed by a period of 2 weeks on normal chow to induce the formation of lesion foci in the forebrain. Subsequent immunization with myelin oligodendrocyte glycoprotein 35–55 peptide, which induces myelin autoreactive T cells in the periphery, resulted in massive immune cell recruitment into the affected forebrain. Additional adoptive transfer experiments together with flow cytometry analysis underline the importance of brain-derived signals for immune cell recruitment. This study clearly illustrates the significance of brain-intrinsic degenerative cascades for immune cell recruitment and MS lesion formation. Additional studies have to address the signaling cascades and mechanistic processes that form the top-down communication between the affected brain area, neurovascular unit, and peripheral immune cells. SIGNIFICANCE STATEMENT We identify neurodegeneration as a potent trigger for peripheral immune cell recruitment into the forebrain. Thus, immune cell recruitment might be a second step during the formation of new inflammatory lesions in multiple sclerosis. A better understanding of factors regulating neurodegeneration-induced immune cell recruitment will pave the way for the development of novel therapeutic treatment strategies.
DNA Methylation of ADME Genes
2016-01-27

The epigenetic regulation of expression of genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs contributes to interindividual variability in drug response. Epigenetic mechanisms include DNA methylation, histone modifications, and miRNAs. This review systematically outlines the influence of DNA methylation on ADME gene expression and highlights the consequences for interindividual variability in drug response or drug‐induced toxicity and the implications for personalized medicine.
It's in the eyes: Planning precise manual actions before execution
2016-01-27

It is well-known that our eyes typically fixate those objects in a scene, with which interactions are about to unfold. During manual interactions, our eyes usually anticipate the next subgoal and thus serve top-down, goal-driven information extraction requirements, probably driven by a schema-based task representation. On the other hand, motor control research concerning object manipulations has extensively demonstrated how grasping choices are often influenced by deeper considerations about the final goal of manual interactions. Here we show that also these deeper considerations are reflected in early eye fixation behavior, significantly before the hand makes contact with the object. In this study, subjects were asked to either pretend to drink out of the presented object or to hand it over to the experimenter. The objects were presented upright or upside down, thus affording a thumb-up (prone) or a thumb-down (supine) grasp. Eye fixation data show a clear anticipatory preference for the region where the index finger is going to be placed. Indeed, fixations highly correlate with the final index finger position, thus subserving the planning of the actual manual action. Moreover, eye fixations reveal several orders of manual planning: Fixation distributions do not only depend on the object orientation but also on the interaction task. These results suggest a fully embodied, bidirectional sensorimotor coupling of eye-hand coordination: The eyes help in planning and determining the actual manual object interaction, considering where to grasp the presented object in the light of the orientation and type of the presented object and the actual manual task to be accomplished with the object.
Dynamo generated magnetic configurations in accretion discs and the nature of quasi-periodic oscillations in accreting binary systems
2016-01-27

Magnetic fields are important for accretion disc structure. Magnetic fields\\nin a disc system may be transported with the accreted matter. They can be\\nassociated with either the central body and/or jet, and be fossil or dynamo\\nexcited in situ. We consider dynamo excitation of magnetic fields in accretion\\ndiscs of accreting binary systems in an attempt to clarify possible\\nconfigurations of dynamo generated magnetic fields. We first model the entire\\ndisc with realistic radial extent and thickness using an alpha-quenching\\nnon-linearity. We then study the simultaneous effect of feedback from the\\nLorentz force from the dynamo-generated field. We perform numerical simulations\\nin the framework of a relatively simple mean-field model which allows the\\ngeneration of global magnetic configurations. We explore a range of\\npossibilities for the dynamo number, and find quadrupolar-type solutions with\\nirregular temporal oscillations that might be compared to observed rapid\\nluminosity fluctuations. The dipolar symmetry models with have\\nlobes of strong toroidal field adjacent to the rotation axis that could be\\nrelevant to jet launching phenomena. We have explored and extended the\\nsolutions known for thin accretion discs.\\n
Methylation profiling of choroid plexus tumors reveals 3 clinically distinct subgroups
2016-01-28

Methylation profiling of choroid plexus tumors reveals 3 distinct subgroups (ie, pediatric low-risk choroid plexus tumors [cluster 1], adult low-risk choroid plexus tumors [cluster 2], and pediatric high-risk choroid plexus tumors [cluster 3]) and may provide useful prognostic information in addition to histopathology.
The Largest Metalloid Group 14 Cluster, Ge18[Si(SiMe3)3]6: An Intermediate on the Way to Elemental Germanium
2016-01-28

Abstract The oxidation of [Ge 9 (Hyp) 3 ] − (Hyp=Si(SiMe 3 ) 3 ) with an Fe II salt leads to Ge 18 (Hyp) 6 ( 1 ), the largest Group 14 metalloid cluster that has been structurally characterized to date. The arrangement of the 18 germanium atoms in 1 shows similarities to that found in the solid‐state structure Ge(cF136). Furthermore, 1 can be described as a macropolyhedral cluster of two Ge 9 units. Quantum‐chemical calculations further hint at a strained arrangement so that 1 can be considered as a first trapped intermediate on the way from Ge 9 units to elemental germanium with the clathrate‐II structure (Ge(cF136)).
Detecting Staphylococcus aureus Virulence and Resistance Genes: a Comparison of Whole-Genome Sequencing and DNA Microarray Technology
2016-01-28

ABSTRACT Staphylococcus aureus is a major bacterial pathogen causing a variety of diseases ranging from wound infections to severe bacteremia or intoxications. Besides host factors, the course and severity of disease is also widely dependent on the genotype of the bacterium. Whole-genome sequencing (WGS), followed by bioinformatic sequence analysis, is currently the most extensive genotyping method available. To identify clinically relevant staphylococcal virulence and resistance genes in WGS data, we developed an in silico typing scheme for the software SeqSphere + (Ridom GmbH, Münster, Germany). The implemented target genes ( n = 182) correspond to those queried by the Identibac S. aureus Genotyping DNA microarray (Alere Technologies, Jena, Germany). The in silico scheme was evaluated by comparing the typing results of microarray and of WGS for 154 human S. aureus isolates. A total of 96.8% ( n = 27,119) of all typing results were equally identified with microarray and WGS (40.6% present and 56.2% absent). Discrepancies (3.2% in total) were caused by WGS errors (1.7%), microarray hybridization failures (1.3%), wrong prediction of ambiguous microarray results (0.1%), or unknown causes (0.1%). Superior to the microarray, WGS enabled the distinction of allelic variants, which may be essential for the prediction of bacterial virulence and resistance phenotypes. Multilocus sequence typing clonal complexes and staphylococcal cassette chromosome mec element types inferred from microarray hybridization patterns were equally determined by WGS. In conclusion, WGS may substitute array-based methods due to its universal methodology, open and expandable nature, and rapid parallel analysis capacity for different characteristics in once-generated sequences.
Exploring Low-Mass Dark Matter with CRESST
2016-01-28

The CRESST-II (Cryogenic Rare Event Search with Superconducting Thermometers) experiment, whose second phase has been successfully finished in summer 2015, aims at the direct detection of dark matter particles. The intrinsic radiopurity of CaWO4 crystals, the capability to reject recoil events from alpha-surface contamination, and the energy threshold were significantly improved compared to previous runs of the experiment. A moderate exposure of 29 kg-days acquired by one ∼ 250 g CaWO4 detector provides competitive limits on the spin-independent dark matter particle-nucleon cross section and probes a new region of parameter space for dark matter particle masses below 3 GeV/c2. The potential for low-mass dark matter particle search can be further exploited by a new detector design planned for CRESST-III. We describe the experimental strategy for the near future and give projections for the sensitivity.
Kants Theorie der Personalität als Selbstverhältnis in der „Tugendlehre“ und in der Kritik der reinen Vernunft
2016-01-28

Abstract: The main thesis of this article holds that the theory of personhood as a relation of the self to itself is a fundamental structure not only of Kant’s practical but also of his theoretical philosophy. The first section discusses Kant’s theory of duties to oneself as an obligation of