julilili42/papers huggingface dataset:
Interaction of cCMP with the cGK, cAK and MAPK Kinases in Murine Tissues
2015-05-15

cAMP and cGMP are well established second messengers that are essential for numerous (patho)physiological processes. These purine cyclic nucleotides activate cAK and cGK, respectively. Recently, the existence of cCMP was described, and a possible function for this cyclic nucleotide was investigated. It was postulated that cCMP plays a role as a second messenger. However, the functions regulated by cCMP are mostly unknown. To elucidate probable functions, cCMP-binding and -activated proteins were identified using different methods. We investigated the effect of cCMP on purified cyclic nucleotide-dependent protein kinases and lung and jejunum tissues of wild type (WT), cGKI-knockout (cGKI KO) and cGKII-knockout (cGKII KO) mice. The catalytic activity of protein kinases was measured by a (γ-32P) ATP kinase assay. Cyclic nucleotide-dependent protein kinases (cAK, cGKI and cGKII) in WT tissue lysates were stimulated by cCMP. In contrast, there was no stimulation of phosphorylation in KO tissue lysates. Competitive binding assays identified cAK, cGKI, and cGKII as cCMP-binding proteins. An interaction between cCMP/MAPK and a protein-protein complex of MAPK/cGK were detected via cCMP affinity chromatography and co-immunoprecipitation, respectively. These complexes were abolished or reduced in jejunum tissues from cGKI KO or cGKII KO mice. In contrast, these complexes were observed in the lung tissues from WT, cGKI KO and cGKII KO mice. Moreover, cCMP was also able to stimulate the phosphorylation of MAPK. These results suggest that MAPK signaling is regulated by cGMP-dependent protein kinases upon activation by cCMP. Based on these results, we propose that additional cCMP-dependent protein kinases that are capable of modulating MAPK signaling could exist. Hence, cCMP could potentially act as a second messenger in the cAK/cGK and MAPK signaling pathways and play an important role in physiological processes of the jejunum and lung.
The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury
2015-05-16

Regeneration of injured central nervous system axons is highly restricted, causing neurological impairment. To date, although the lack of intrinsic regenerative potential is well described, a key regulatory molecular mechanism for the enhancement of both axonal regrowth and functional recovery after central nervous system injury remains elusive. While ubiquitin ligases coordinate neuronal morphogenesis and connectivity during development as well as after axonal injury, their role specifically in axonal regeneration is unknown. Following a bioinformatics network analysis combining ubiquitin ligases with previously defined axonal regenerative proteins, we found a triad composed of the ubiquitin ligases MDM4, MDM2 and the transcription factor p53 (encoded by TP53) as a putative central signalling complex restricting the regeneration program. Indeed, conditional deletion of MDM4 or pharmacological inhibition of MDM2/p53 interaction in the eye and spinal cord promote axonal regeneration and sprouting of the optic nerve after crush and of supraspinal tracts after spinal cord injury. The double conditional deletion of MDM4-p53 as well as MDM2 inhibition in p53-deficient mice blocks this regenerative phenotype, showing its dependence upon p53. Genome-wide gene expression analysis from ex vivo fluorescence-activated cell sorting in MDM4-deficient retinal ganglion cells identifies the downstream target IGF1R, whose activity and expression was found to be required for the regeneration elicited by MDM4 deletion. Importantly, we demonstrate that pharmacological enhancement of the MDM2/p53-IGF1R axis enhances axonal sprouting as well as functional recovery after spinal cord injury. Thus, our results show MDM4-MDM2/p53-IGF1R as an original regulatory mechanism for CNS regeneration and offer novel targets to enhance neurological recovery.media-1vid110.1093/brain/awv125_video_abstractawv125_video_abstract.
Cardiovascular Imaging
2015-05-16

Today's noninvasive imaging of the cardiovascular system has revolutionized the approach to various diseases and has substantially affected prognostic information. Cardiovascular magnetic resonance (MR) and computed tomographic (CT) imaging are at center stage of these approaches, although 5 decades ago, these technologies were unheard of. Both modalities had their inception in the 1970s with a primary focus on noncardiovascular applications. The technical development of the various decades, however, substantially pushed the envelope for cardiovascular MR and CT applications. Within the past 10-15 years, MR and CT technologies have pushed each other in cardiac applications; and without the "rival" modality, neither one would likely not have reached its potential today. This view on the history of MR and CT in the field of cardiovascular applications provides insight into the story of success of applications that once have been ideas only but are at prime time today.
Response to Comment on Heni et al. Central Insulin Administration Improves Whole-Body Insulin Sensitivity via Hypothalamus and Parasympathetic Outputs in Men. Diabetes 2014;63:4083–4088
2015-05-16

We wish to thank Dhindsa et al. (1) for their thoughtful comments on our article published in Diabetes (2). In our study, intranasal application of insulin to the human brain improved peripheral insulin sensitivity in lean but not obese men (assessed as glucose infusion rate during hyperinsulinemic-euglycemic clamp). This improvement was significantly correlated to hypothalamic insulin responsiveness as well as to parasympathetic outflows. Dhindsa et al. (1) provide the interesting hypothesis that obese humans could be resistant to “brain outputs” that regulate peripheral insulin sensitivity. Indeed, such a mechanism might contribute to the resistance of our obese participants to the ...
American Indians and German Peculiarities
2015-05-16

Kindred by choice? A revealing encounter challenged my initial scepticism. Six of us had gathered for lunch. Hanging on the wall was a picture of Pierre Brice as Winnetou, drawn by a grandson of the host. On previous occasions I had paid little attention to the image, but now, having read Penny’s work, I was drawn to it. Each of us at that lunch recognized Karl May’s hero, and in our youth all of us had read books by May and had seen films based on those books. My lunch companions were also aware of other individuals such as Liselotte Welskopf-Henrich, whom Penny presents as a point of access to North American Indian culture. None of us, however, had heard of the powwows held by German hobbyists ( Hobby-Indianern ). Penny’s book begins with an account of one such event, held in 2006 near Cottbus and attended by nearly 1,000 people. Hundreds of tepees had been erected. Tourists in everyday dress were not permitted, a rule that guards dressed as ‘Cheyenne Dog Soldiers’ enforced. Penny’s interpretation of the event, which I recounted, surprised the Karl May connoisseurs at lunch: that for over two centuries, German culture had been marked by ‘a striking sense of affinity for American Indians . . . which stems directly from German polycentrism, notions of tribalism, a devotion to resistance, a longing for freedom, and a melancholy sense of shared fate’ (p. xi).
Genetic suppression of plant development and chloroplast biogenesis via the Snowy Cotyledon 3 and Phytochrome B pathways
2015-05-17

Plant development is regulated by external and internal factors such as light and chloroplast development. A revertant of the Arabidopsis thaliana (L.) Heyhn. chloroplast biogenesis mutant snowy cotyledon 3 (sco3–1) was isolated partially recovering the impaired chloroplast phenotype. The mutation was identified in the Phytochrome B (PhyB) gene and is a result of an amino acid change within the PAS repeat domain required for light-induced nuclear localisation. An independent phyB-9 mutation was crossed into sco3–1 mutants, resulting in the same partial reversion of sco3–1. Further analysis demonstrated that SCO3 and PhyB influence the greening process of seedlings and rosette leaves, embryogenesis, rosette formation and flowering. Interestingly, the functions of these proteins are interwoven in various ways, suggesting a complex genetic interaction. Whole-transcriptome profiling of sco3–1phyB-9 indicated that a completely distinct set of genes was differentially regulated in the double mutant compared with the single sco3–1 or phyB-9 mutants. Thus, we hypothesise that PhyB and SCO3 genetically suppress each other in plant and chloroplast development.
The Stability of Extreme Response Style and Acquiescence Over 8 Years
2015-05-18

This study investigated the stability of extreme response style (ERS) and acquiescence response style (ARS) over a period of 8 years. ERS and ARS were measured with item sets drawn randomly from a large pool of items used in an ongoing German panel study. Latent-trait-state-occasion and latent-state models were applied to test the relationship between time-specific (state) response style behaviors and time-invariant trait components of response styles. The results show that across different random item samples, on average between 49% and 59% of the variance in the state response style factors was explained by the trait response style factors. This indicates that the systematic differences respondents show in their preferences for certain response categories are remarkably stable over a period of 8 years. The stability of ERS and ARS implies that it is important to consider response styles in the analysis of self-report data from polytomous rating scales, especially in longitudinal studies aimed at investigating stability in substantive traits. Furthermore, the stability of response styles raises the question in how far they might be considered trait-like latent variables themselves that could be of substantive interest.
Core Competencies for Medical Teachers (KLM) – A Position Paper of the GMA Committee on Personal and Organizational Development in Teaching
2015-05-18

Recent developments in medical education have created increasing challenges for medical teachers which is why the majority of German medical schools already offer educational and instructional skills trainings for their teaching staff. However, to date no framework for educational core competencies for medical teachers exists that might serve as guidance for the qualification of the teaching faculty. Against the background of the discussion about competency based medical education and based upon the international literature, the GMA Committee for Faculty and Organizational Development in Teaching developed a model of core teaching competencies for medical teachers. This framework is designed not only to provide guidance with regard to individual qualification profiles but also to support further advancement of the content, training formats and evaluation of faculty development initiatives and thus, to establish uniform quality criteria for such initiatives in German-speaking medical schools. The model comprises a framework of six competency fields, subdivided into competency components and learning objectives. Additional examples of their use in medical teaching scenarios illustrate and clarify each specific teaching competency. The model has been designed for routine application in medical schools and is thought to be complemented consecutively by additional competencies for teachers with special duties and responsibilities in a future step.
Knowing one’s food – making food a public issue
2015-05-18

There is a lively debate on consumers’ responsibility and the role of social institutions (e.g. market, state, common goods) in bringing about sustainable development. Subject to the institutional setting chosen, the claim for knowing one’s food acquires a different meaning, e.g. better information for consumers that help to take different purchase decisions (certification) or participating in the food process itself (community-supported agriculture). Regardless of contestation on appropriate institutional settings to bring about sustainable food production and consumption, all approaches seem to agree (in one way or another) on the relevance of public debate on both issues. By referring to the social philosophers Michael Sandel and Alan Gewirth, the paper advances two claims. First, it is necessary to lead a substantial public debate on the aims and the social organisation of food production and consumption. Second, public debate can be guided by principles that have a universal moral claim and are still open for different ways of life. The paper starts with an overview of debates on different food regimes. It will be argued for a substantial public debate as well as moral principles that might guide these debates. Making food an issue of public debate would also answer the question why knowing our food is important.
Bioeconomy and the future of food – ethical questions
2015-05-18

There is farming for food, biofuels, biomaterials, chemicals and biorefinery. All this, and more, is being lumped together under the new term 'bioeconomy' or 'bio-based economy'. In 2012, the European Commission launched a new strategy 'Innovating for sustainable growth: a bioeconomy for Europe'. It involves a radical change in biomass production, consumption and recycling, also opening up new and diversified markets in food and bio-based products. Bioeconomy takes place in the name of sustainable development. However, there are great discrepancies between adequate conditions of a bio-based economy and the current situation. On the one hand, we are dreaming of a 100% sustainable world in which fossil resources are not needed anymore, while everybody values nature and its services, resulting in a very efficient commerce with energy and natural resources. On the other hand, there are conflicting economic, political and societal interests. Concerning biomass production, there are many trade-offs and problems: (1) monocropping; (2) the competition of land use; (3) changing cultivation methods; (4) environmental problems; and (5) societal acceptance. The majority of the bioeconomic literature implies that genetic modifications are safe, healthy and socially acceptable, despite the problems and the already known negative consequences. Another problem is that the demand for biomass, e.g. for fuels in Germany, exceeds possible domestic production by far. Most of the globally traded biomass is produced under questionable conditions with respect to ethical and societal aspects. Hence the approach of bioeconomy is in need of a detailed critical ethical analysis. Our conceptual and ethical analysis of bioeconomy strategies will address the following issues: the meaning of sustainability in bioeconomy is opaque and the problems are rarely addressed. Sustainability in the sense of efficiency, sufficiency and resilience is not really dealt with. Bioeconomy does not yet address issues of insecurity, especially regarding long-time consequences on food production, food sovereignty, environmental conservation, human health, and loss of biodiversity. This is due, among others, to the employment of a business-asusual model of high-input, high-tech agriculture and to not reflecting on recent ethical debates on the values of biodiversity beyond monetary terms. Re-thinking a bioeconomy in these respects will remain a major theme with regard to a sustainable future of food.
A fully automatic reference deconvolution strategy to increase the accuracy of in vivo lipid signal quantification
2015-05-18

Purpose Lipid signals measured by 1 H MR spectroscopy cannot be adequately quantified by common fitting routines like VARPRO or AMARES, if lipid spectra are distorted by irregular spatial and temporal inhomogeneities of the static magnetic field during readout. A fully automatic reference deconvolution algorithm is presented that eliminates these distortions before application of fitting routines. Methods The measured signal of the dominant methyl resonance is isolated with aid of a spectral estimator (estimation of parameters via rotational invariance techniques) and used as reference signal for estimation of distortions. A Wiener filter is applied to deconvolve those distortions in the lipid spectrum. Performance of the algorithm is assessed for different bandwidths and shapes of distortions, using artificially distorted as well as measured data. Results Application of the fully automatic reference deconvolution algorithm on simulated spectra yields a distinct increase in quantification accuracy. Deconvolved in vivo spectra of subcutaneous fat indicate reduced spectral overlap after application of the proposed strategy. Conclusion The proposed method is helpful for in vivo magnetic resonance spectroscopy of adipose tissue to correct for effects of field inhomogeneities within the voxel and for inevitable eddy current effects. Quantification accuracy is improved by eliminating distortions before application of fitting routines. Magn Reson Med 75:1391–1401, 2016. © 2015 Wiley Periodicals, Inc.
c-JunN-terminal kinase inhibitors: a patent review (2010 – 2014)
2015-05-19

Although some selective pan-JNK inhibitors with reasonable in vivo profiles are now available, little is known about the isoform selectivity required for each particular indication and the development of isoform-selective JNK inhibitors still represents a challenge in JNK drug discovery. Moreover, isoform-selective tool compounds are a prerequisite to a comprehensive understanding of the biology of each JNK isoform. Potential approaches towards such compounds include the design of type-II and type-I(1)/2 binders, which are absent in the current JNK inhibitor portfolios, as well as the design of novel allosteric inhibitors. Furthermore, covalent inhibition, which already led to the first high-quality probe for JNKs, might be further exploited for gaining selectivity and in vivo efficacy. With regard to a potential therapeutic application, the recently proposed concept of covalent reversible inhibitors is expected to be attractive.
Applying DEKOIS 2.0 in structure-based virtual screening to probe the impact of preparation procedures and score normalization
2015-05-19

Abstract Background Structure-based virtual screening techniques can help to identify new lead structures and complement other screening approaches in drug discovery. Prior to docking, the data (protein crystal structures and ligands) should be prepared with great attention to molecular and chemical details. Results Using a subset of 18 diverse targets from the recently introduced DEKOIS 2.0 benchmark set library, we found differences in the virtual screening performance of two popular docking tools (GOLD and Glide) when employing two different commercial packages (e.g. MOE and Maestro) for preparing input data. We systematically investigated the possible factors that can be responsible for the found differences in selected sets. For the Angiotensin-I-converting enzyme dataset, preparation of the bioactive molecules clearly exerted the highest influence on VS performance compared to preparation of the decoys or the target structure. The major contributing factors were different protonation states, molecular flexibility, and differences in the input conformation (particularly for cyclic moieties) of bioactives. In addition, score normalization strategies eliminated the biased docking scores shown by GOLD (ChemPLP) for the larger bioactives and produced a better performance. Generalizing these normalization strategies on the 18 DEKOIS 2.0 sets, improved the performances for the majority of GOLD (ChemPLP) docking, while it showed detrimental performances for the majority of Glide (SP) docking. Conclusions In conclusion, we exemplify herein possible issues particularly during the preparation stage of molecular data and demonstrate to which extent these issues can cause perturbations in the virtual screening performance. We provide insights into what problems can occur and should be avoided, when generating benchmarks to characterize the virtual screening performance. Particularly, careful selection of an appropriate molecular preparation setup for the bioactive set and the use of score normalization for docking with GOLD (ChemPLP) appear to have a great importance for the screening performance. For virtual screening campaigns, we recommend to invest time and effort into including alternative preparation workflows into the generation of the master library, even at the cost of including multiple representations of each molecule.
Using human induced pluripotent stem cells to model cerebellar disease: Hope and hype
2015-05-19

The cerebellum forms a highly ordered and indispensible component of motor function within the adult neuraxis, consisting of several distinct cellular subtypes. Cerebellar disease, through a variety of genetic and acquired causes, results in the loss of function of defined subclasses of neurons, and remains a significant and untreatable health care burden. The scarcity of therapies in this arena can partially be explained by unresolved disease mechanisms due to inaccessibility of human cerebellar neurons in a relevant experimental context where initiating disease mechanisms could be functionally elucidated, or drug screens conducted. In this review we discuss the potential promise of human induced pluripotent stem cells (hiPSCs) for regenerative neurology, with a particular emphasis on in vitro modelling of cerebellar degeneration. We discuss progress made thus far using hiPSC-based models of neurodegeneration, noting the relatively slower pace of discovery made in modelling cerebellar dysfunction. We conclude by speculating how strategies attempting cerebellar differentiation from hiPSCs can be refined to allow the generation of accurate disease models. This in turn will permit a greater understanding of cerebellar pathophysiology to inform mechanistically rationalised therapies, which are desperately needed in this field.
Minimalist Model Systems Reveal Similarities and Differences between Membrane Interaction Modes of MCL1 and BAK
2015-05-19

Proteins belonging to the BCL2 family are key modulators of apoptosis that establish a complex network of interactions among themselves and with other cellular factors to regulate cell fate. It is well established that mitochondrial membranes are the main locus of action of all BCL2 family proteins, but it is difficult to obtain a precise view of how BCL2 family members operate at the native mitochondrial membrane environment during apoptosis. Here, we used minimalist model systems and multiple fluorescence-based techniques to examine selected membrane activities of MCL1 and BAK under apoptotic-like conditions. We show that three distinct apoptosis-related factors (i.e. the BCL2 homology 3 ligand cBID, the mitochondrion-specific lipid cardiolipin, and membrane geometrical curvature) all promote membrane association of BCL2-like structural folds belonging to both MCL1 and BAK. However, at the same time, the two proteins exhibited distinguishing features in their membrane association modes under apoptotic-like conditions. In addition, scanning fluorescence cross-correlation spectroscopy and FRET measurements revealed that the BCL2-like structural fold of MCL1, but not that of BAK, forms stable heterodimeric complexes with cBID in a manner adjustable by membrane cardiolipin content and curvature degree. Our results add significantly to a growing body of evidence indicating that the mitochondrial membrane environment plays a complex and active role in the mode of action of BCL2 family proteins.