julilili42/papers huggingface dataset:
TOPPAS: A Graphical Workflow Editor for the Analysis of High-Throughput Proteomics Data
2012-05-15

Mass spectrometry coupled to high-performance liquid chromatography (HPLC-MS) is evolving more quickly than ever. A wide range of different instrument types and experimental setups are commonly used. Modern instruments acquire huge amounts of data, thus requiring tools for an efficient and automated data analysis. Most existing software for analyzing HPLC-MS data is monolithic and tailored toward a specific application. A more flexible alternative consists of pipeline-based tool kits allowing the construction of custom analysis workflows from small building blocks, e.g., the Trans Proteomics Pipeline (TPP) or The OpenMS Proteomics Pipeline (TOPP). One drawback, however, is the hurdle of setting up complex workflows using command line tools. We present TOPPAS, The OpenMS Proteomics Pipeline ASsistant, a graphical user interface (GUI) for rapid composition of HPLC-MS analysis workflows. Workflow construction reduces to simple drag-and-drop of analysis tools and adding connections in between. Integration of external tools into these workflows is possible as well. Once workflows have been developed, they can be deployed in other workflow management systems or batch processing systems in a fully automated fashion. The implementation is portable and has been tested under Windows, Mac OS X, and Linux. TOPPAS is open-source software and available free of charge at http://www.OpenMS.de/TOPPAS .
Principles of Justice as the Basis for Public Policy on Psychopharmacological Cognitive Enhancement
2012-05-15

ABSTRACT The paper provides a brief conceptual analysis of the debate on psycho-pharmacological cognitive enhancement from the point of view of public reason as it is construed in contemporary political philosophy. The author argues that the strong reasonable disagreement that marks authenticity, posthumanist and “playing God” arguments stems from their presuppositions in religious, ethical or metaphysical comprehensive doctrines, whereas the principles of justice could be the basis for an “overlapping consensus” in the context of regulating use of cognition enhancement drugs for non-therapeutic purposes. The analysis of requirements of justice points to a conclusion that discouraging the use of psycho-pharmacological cognitive enhancements would be the most legitimate public policy. The author offers a model of such a policy: with the imposition of taxes, fees and requirements of additional insurance, the use and indirect coercion to use would be less profitable and less wide-spread, while additional funds thus created could be allocated to meet basic medical needs.
Reply to Rossi et al.: Immunohistopathological findings in neuromyelitis optica concur with immunobiological observations in vitro
2012-05-15

Aquaporin-4 (AQP4) water-channel–specific IgG unifies a spectrum of autoimmune astrocytopathies exemplified by neuromyelitis optica (NMO): relapsing inflammatory myelopathy, optic neuritis, and disorders affecting AQP4-rich circumventricular organs. AQP4-IgG detection in serum distinguishes these disorders from other inflammatory demyelinating disorders. The points of our study (1) were to emphasize that (i) IgG-AQP4 interaction has multiple molecular sequelae that plausibly account for diverse pathology (edema, inflammation, demyelination, and necrosis) and (ii) some outcomes are AQP4 isoform (M1 or M23)-specific. Our study involves immunocytochemistry and freeze-fracture EM of cultured rodent astrocytes, HEK293 cells transfected with non-tagged human AQP4s, Xenopus oocytes expressing GFP-tagged human AQP4s, and NMO patient brain immunohistopathology. Because serum IgG is polyclonal, we used high-titered sera (or IgG) pooled from at least 50 patients with NMO (binding > 1,000 nmol AQP4/L) to broadly investigate potentially pathogenic, AQP4-specific outcomes of IgG-AQP4 interaction in live cells. The correspondents question our data’s validity (2), citing conflicting data they obtained by using various AQP4 isoform-transfected cell types, sera from six individual patients with NMO, and mouse neuropathology.
Carboxylesterase 1 Polymorphism Impairs Oseltamivir Bioactivation in Humans
2012-05-16

Bioactivation of the antiviral agent oseltamivir to active oseltamivir carboxylate is catalyzed by carboxylesterase 1 (CES1). After the screening of 860 healthy Finnish volunteers for the CES1 c.428G>A (p.Gly143Glu, rs121912777) polymorphism, a pharmacokinetic study with 75 mg oseltamivir was carried out in c.428G>A carriers and noncarriers. Heterozygous c.428GA carriers (n = 9) had 18% larger values of oseltamivir area under the plasma concentration-time curve from 0 h to infinity (AUC(0-∞)) (P = 0.025) and 23% smaller carboxylate-to-oseltamivir AUC(0-∞) ratio (P = 0.006) than noncarriers (n = 12). This shows that the CES1 c.428G>A polymorphism impairs oseltamivir bioactivation in humans.
The Antiquity of the Rhine River: Stratigraphic Coverage of the Dinotheriensande (Eppelsheim Formation) of the Mainz Basin (Germany)
2012-05-16

This study documents complex faunal mixing of classical Dinotheriensand fauna, covering at least six million years, during a time of low subsidence in the Mainz Basin and shifts back the origination of the Rhine River by some five million years. Our results have severe implications for biostratigraphy and palaeobiology of the Middle to Late Miocene. They suggest that turnover events may be obliterated and challenge the proposed 'supersaturated' biodiversity, caused by Middle Miocene superstites, of Vallesian ecosystems in Central Europe.
Light-Driven Calcium Signals in Mouse Cone Photoreceptors
2012-05-16

Calcium mediates various neuronal functions. The complexity of neuronal Ca 2+ signaling is well exemplified by retinal cone photoreceptors, which, with their distinct compartmentalization, offer unique possibilities for studying the diversity of Ca 2+ functions in a single cell. Measuring subcellular Ca 2+ signals in cones under physiological conditions is not only fundamental for understanding cone function, it also bears important insights into pathophysiological processes governing retinal neurodegeneration. However, due to the proximity of light-sensitive outer segments to other cellular compartments, optical measurements of light-evoked Ca 2+ responses in cones are challenging. We addressed this problem by generating a transgenic mouse ( HR2.1:TN-XL ) in which both short- and middle-wavelength-sensitive cones selectively express the genetically encoded ratiometric Ca 2+ biosensor TN-XL. We show that HR2.1:TN-XL allows recording of light-evoked Ca 2+ responses using two-photon imaging in individual cone photoreceptor terminals and to probe phototransduction and its diverse regulatory mechanisms with pharmacology at subcellular resolution. To further test this system, we asked whether the classical, nitric oxide (NO)-soluble guanylyl-cyclase (sGC)-cGMP pathway could modulate Ca 2+ in cone terminals. Surprisingly, NO reduced Ca 2+ resting levels in mouse cones, without evidence for direct sGC involvement. In conclusion, HR2.1:TN-XL mice offer unprecedented opportunities to elucidate light-driven Ca 2+ dynamics and their (dys)regulation in cone photoreceptors.
Focused didactic training for skills lab student tutors – which techniques are considered helpful?
2012-05-16

Objective: Peer-assisted learning is widely used in medical education. However, little is known about an appropriate didactic preparation for peer tutors. We herein describe the development of a focused didactic training for skills lab tutors in Internal Medicine and report on a retrospective survey about the student tutors’ acceptance and the perceived transferability of attended didactic training modules. Methods: The course consisted of five training modules: ‘How to present and explain effectively’: the student tutors had to give a short presentation with subsequent video analysis and feedback in order to learn methods of effective presentation. ‘How to explain precisely’: Precise explanation techniques were trained by exercises of exact description of geometric figures and group feedback. ‘How to explain on impulse’: Spontaneous teaching presentations were simulated and feedback was given. ‘Peyton’s 4 Step Approach’: Peyton‘s Method for explanation of practical skills was introduced and trained by the participants. ‘How to deal with critical incidents’: Possibilities to deal with critical teaching situations were worked out in group sessions. Twenty-three student tutors participated in the retrospective survey by filling out an electronic questionnaire, after at least 6 months of teaching experience. Results: The exercise ‘How to present and explain effectively’ received the student tutors’ highest rating for their improvement of didactic qualification and was seen to be most easily transferable into the skills lab environment. This module was rated as the most effective module by nearly half of the participants. It was followed by ‘Peyton’s 4 Step Approach’ , though it was also seen to be the most delicate method in regard to its transfer into the skills lab owing to time concerns. However, it was considered to be highly effective. The other modules received lesser votes by the tutors as the most helpful exercise in improving their didactic qualification for skills lab teaching. Conclusion: We herein present a pilot concept for a focused didactic training of peer tutors and present results of a retrospective survey among our skills lab tutors about the distinct training modules. This report might help other faculties to design didactic courses for skills lab student tutors.
Clinical Standardized fMRI Reveals Altered Language Lateralization in Patients with Brain Tumor
2012-05-17

Clinical language fMRI was feasible for patients with brain tumors and provided relevant presurgical information by localizing essential language areas and determining language dominance. A significant effect of the brain masses on language lateralization was observed, with a shift toward the contralesional, nondominant hemisphere. This may reflect compensatory mechanisms of the brain to maintain communicative abilities.
Exact results for the particle-number-projected BCS approach with isovector proton-neutron pairing
2012-05-17

The mean values of a many-body Hamiltonian including a proton-neutron pairing term and matrix elements of one-, two-, and four-body operators within a basis of particle-number-projected BCS states are analytically expressed in terms of a single function depending on the number of particles, . The function is calculated using a recursion in in which the shells and the BCS angles are kept the same for any iteration step. An illustrative example is numerically considered in a restricted single-particle space. Some specific features of the standard BCS, the projection after variation approach, and the variation after projection formalism are pointed out.
Akt Promotes Post-Irradiation Survival of Human Tumor Cells through Initiation, Progression, and Termination of DNA-PKcs–Dependent DNA Double-Strand Break Repair
2012-05-18

Abstract Akt phosphorylation has previously been described to be involved in mediating DNA damage repair through the nonhomologous end-joining (NHEJ) repair pathway. Yet the mechanism how Akt stimulates DNA-protein kinase catalytic subunit (DNA-PKcs)-dependent DNA double-strand break (DNA-DSB) repair has not been described so far. In the present study, we investigated the mechanism by which Akt can interact with DNA-PKcs and promote its function during the NHEJ repair process. The results obtained indicate a prominent role of Akt, especially Akt1 in the regulation of NHEJ mechanism for DNA-DSB repair. As shown by pull-down assay of DNA-PKcs, Akt1 through its C-terminal domain interacts with DNA-PKcs. After exposure of cells to ionizing radiation (IR), Akt1 and DNA-PKcs form a functional complex in a first initiating step of DNA-DSB repair. Thereafter, Akt plays a pivotal role in the recruitment of AKT1/DNA-PKcs complex to DNA duplex ends marked by Ku dimers. Moreover, in the formed complex, Akt1 promotes DNA-PKcs kinase activity, which is the necessary step for progression of DNA-DSB repair. Akt1-dependent DNA-PKcs kinase activity stimulates autophosphorylation of DNA-PKcs at S2056 that is needed for efficient DNA-DSB repair and the release of DNA-PKcs from the damage site. Thus, targeting of Akt results in radiosensitization of DNA-PKcs and Ku80 expressing, but not of cells deficient for, either of these proteins. The data showed indicate for the first time that Akt through an immediate complex formation with DNA-PKcs can stimulate the accumulation of DNA-PKcs at DNA-DSBs and promote DNA-PKcs activity for efficient NHEJ DNA-DSB repair. Mol Cancer Res; 10(7); 945–57. ©2012 AACR.
First‐trimester combined screening for trisomy 21 with different combinations of placental growth factor, free β‐human chorionic gonadotropin and pregnancy‐associated plasma protein‐A
2012-05-18

Abstract Objective To examine placental growth factor (PlGF) in euploid and trisomy 21 pregnancies at 11–13 weeks' gestation and to model the impact on first‐trimester combined screening. Methods PlGF was measured in 509 (409 euploid and 100 trisomic) fetal serum samples derived from prospective first‐trimester combined screening for trisomy 21 at 11–13 weeks' gestation. The serum samples were stored at −80°C, following the measurement of free β ‐human chorionic gonadotropin ( β ‐hCG) and pregnancy‐associated plasma protein‐A (PAPP‐A) levels, for median time spans of 0.9 and 4.1 years in the euploid and trisomy 21 pregnancies, respectively. The effect of additional PlGF measurement at the time of combined screening was investigated by simulating fetal nuchal translucency (NT) measurements and multiples of the median (MoM) values for PAPP‐A, free β ‐hCG and PlGF for 20 000 euploid and 20 000 trisomy 21 pregnancies. Patient‐specific combined risks were calculated based on maternal age and fetal NT in addition to free β ‐hCG, PAPP‐A and PlGF, PAPP‐A and PlGF or free β ‐hCG and PlGF, and detection and false‐positive rates were calculated. Results Median PlGF‐MoM was 1.0 (95% confidence interval (CI), 0.96–1.04) in euploid fetuses and significantly lower, at 0.73 (95% CI, 0.70–0.76), in trisomy‐21 fetuses ( P &lt; 0.0001). There was no significant dependency between PlGF‐MoM and either gestational age at the time of blood sampling ( r = 0.087, P = 0.392) or sample storage time ( r = 0.028, P = 0.785). Modeled detection and false‐positive rates for first‐trimester combined screening (based on maternal and gestational age, fetal NT and maternal serum biochemistry) without PlGF were 85% and 2.7% for a fixed risk cut‐off of 1:100. The addition of PlGF increased the detection rate to 87% and reduced the false‐positive rate to 2.6%. Screening by maternal age and fetal NT in combination with PlGF and PAPP‐A or in combination with PlGF and free β ‐hCG provided detection rates of 82% and 79%, with false‐positive rates of 2.7% and 3.0%, respectively. Conclusion In pregnancies with trisomy 21 PlGF is reduced. The impact on the overall screening performance for trisomy 21 is low and does not justify the measurement of PlGF solely for trisomy 21 screening. However, as PlGF is measured with the aim of assessing the risk for pre‐eclampsia, further improvement in screening for trisomy 21 can be considered as an added benefit.
iHAT: interactive Hierarchical Aggregation Table for Genetic Association Data
2012-05-18

In the search for single-nucleotide polymorphisms which influence the observable phenotype, genome wide association studies have become an important technique for the identification of associations between genotype and phenotype of a diverse set of sequence-based data. We present a methodology for the visual assessment of single-nucleotide polymorphisms using interactive hierarchical aggregation techniques combined with methods known from traditional sequence browsers and cluster heatmaps. Our tool, the interactive Hierarchical Aggregation Table (iHAT), facilitates the visualization of multiple sequence alignments, associated metadata, and hierarchical clusterings. Different color maps and aggregation strategies as well as filtering options support the user in finding correlations between sequences and metadata. Similar to other visualizations such as parallel coordinates or heatmaps, iHAT relies on the human pattern-recognition ability for spotting patterns that might indicate correlation or anticorrelation. We demonstrate iHAT using artificial and real-world datasets for DNA and protein association studies as well as expression Quantitative Trait Locus data.
An eQTL biological data visualization challenge and approaches from the visualization community
2012-05-18

In 2011, the IEEE VisWeek conferences inaugurated a symposium on Biological Data Visualization. Like other domain-oriented Vis symposia, this symposium's purpose was to explore the unique characteristics and requirements of visualization within the domain, and to enhance both the Visualization and Bio/Life-Sciences communities by pushing Biological data sets and domain understanding into the Visualization community, and well-informed Visualization solutions back to the Biological community. Amongst several other activities, the BioVis symposium created a data analysis and visualization contest. Unlike many contests in other venues, where the purpose is primarily to allow entrants to demonstrate tour-de-force programming skills on sample problems with known solutions, the BioVis contest was intended to whet the participants' appetites for a tremendously challenging biological domain, and simultaneously produce viable tools for a biological grand challenge domain with no extant solutions. For this purpose expression Quantitative Trait Locus (eQTL) data analysis was selected. In the BioVis 2011 contest, we provided contestants with a synthetic eQTL data set containing real biological variation, as well as a spiked-in gene expression interaction network influenced by single nucleotide polymorphism (SNP) DNA variation and a hypothetical disease model. Contestants were asked to elucidate the pattern of SNPs and interactions that predicted an individual's disease state. 9 teams competed in the contest using a mixture of methods, some analytical and others through visual exploratory methods. Independent panels of visualization and biological experts judged entries. Awards were given for each panel's favorite entry, and an overall best entry agreed upon by both panels. Three special mention awards were given for particularly innovative and useful aspects of those entries. And further recognition was given to entries that correctly answered a bonus question about how a proposed "gene therapy" change to a SNP might change an individual's disease status, which served as a calibration for each approaches' applicability to a typical domain question. In the future, BioVis will continue the data analysis and visualization contest, maintaining the philosophy of providing new challenging questions in open-ended and dramatically underserved Bio/Life Sciences domains.
Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma.
2012-05-20

8502^ Background: We previously reported results of the planned OS interim analysis for BRIM-3 (50% of the planned 196 deaths required for final analysis) at which time the independent Data Safety Monitoring Board recommended release of results due to compelling efficacy (hazard ratio [HR] for death, 0.37 [95% CI 0.26–0.55]); p&lt;0.0001 and PFS HR 0.26 [95% CI 0.20–0.33]; p&lt;0.0001) and that DTIC-treated patients be permitted to cross over to receive vem. Median follow-up for vem patients was 3.75 months, and longer follow-up would estimate median OS more reliably. Updated OS with median 6.2 months follow-up and 199 total deaths showed HR for death 0.44 (95% CI 0.33–0.59) favoring vem and median OS for vem not reached. We report here the results of an updated OS analysis performed in Nov 2011 with ~10 months median follow-up on vem. Methods: 675 patients with previously untreated, unresectable Stage IIIC or IV melanoma that tested positive for BRAF V600E mutation by the cobas 4800 BRAF V600 Mutation Test were randomized (1:1) from Jan to Dec 2010 to vem (960 mg po bid) or DTIC (1000 mg/m 2 IV q3w). Co-primary endpoints were OS and PFS. OS data for DTIC patients who crossed over to vem were censored at the time of crossover. Results: Median lengths of follow-up on vem and DTIC were 10.5 months (range 0.4–18.1) and 8.4 months (range &lt;0.1–18.3), respectively. There were 334 deaths. Median OS rates with vem and DTIC were 13.2 months (95% CI 12.0–15.0) and 9.6 months (95% CI 7.9–11.8), respectively. 12-month OS rates were 55% for vem and 43% for DTIC. HR for death was 0.62 (95% CI 0.49–0.77) in favor of vem. 81 DTIC patients crossed over to vem. 44 (13%) vem and 65 (19%) DTIC patients received ipilimumab post-progression. Conclusions: With longer follow-up, vem treatment continues to be associated with improved OS in the BRIM-3 study. An updated analysis, with estimated median follow-up of ~13 months and including response data, will be conducted in Apr 2012 and presented at the meeting.
Ligand-Binding Properties and Conformational Dynamics of Autolysin Repeat Domains in Staphylococcal Cell Wall Recognition
2012-05-20

ABSTRACT The bifunctional major autolysin Atl plays a key role in staphylococcal cell separation. Processing of Atl yields catalytically active amidase (AM) and glucosaminidase (GL) domains that are each fused to repeating units. The two repeats of AM (R1 and R2) target the enzyme to the septum, where it cleaves murein between dividing cells. We have determined the crystal structure of R2, which reveals that each repeat folds into two half-open β-barrel subunits. We further demonstrate that lipoteichoic acid serves as a receptor for the repeats and that this interaction depends on conserved surfaces in each subunit. Small-angle X-ray scattering of the mature amidase reveals the presence of flexible linkers separating the AM, R1, and R2 units. Different levels of flexibility for each linker provide mechanistic insights into the conformational dynamics of the full-length protein and the roles of its components in cell wall association and catalysis. Our analysis supports a model in which the repeats direct the catalytic AM domain to the septum, where it can optimally perform the final step of cell division.