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The protein kinase genes in the human genome collectively called the kinome [Manning et al. Many known cancer-associated variants occur in the conserved protein kinase domain, which catalyzes phosphorylation [Knighton et al.

Sequencing of the kinome from nearly cancer types have resulted in over 17, non-synonymous variants in the protein kinase domain [Parthiban et al.

Likewise, drug discovery efforts have resulted in several United States Food and Drug Administration approved drugs to target the cancer kinome, including the block buster drug imatinib [Deininger et al.

More recently, the kinome has been the focus of several proteomic efforts to map the signaling networks altered in cancer and drug-resistant states [Kannan et al.

In addition, numerous investigator-initiated structural and comparative genomics studies have revealed the sequence and structural basis for protein kinase evolution [Hanks and Hunter, ; Manning et al.

These efforts have resulted in massive amounts of data that can potentially be used to accelerate the functional characterization of the cancer kinome by providing new testable hypotheses for experimental studies.

However, the complex and disparate nature of protein kinase data sets, and the difficulties in integrating and analyzing large, complex datasets have hindered progress.

Likewise, information on the structural and functional aspects of kinases is buried in the literature and scattered across diverse databases.

This poses major challenges for bench biologists who do not have the resources or training to write customized scripts for post-processing.

Moreover, writing customized software often leads to duplication of efforts across laboratories and does not scale well with the growing complexity and diversity of biological data.

Bio-ontologies, such as the Gene Ontology [Ashburner et al. Here, we expand the scope of ProKinO by conceptualizing information on conserved sequence and structural motifs that contribute to protein kinase allosteric regulation.

We show that conceptualizing existing knowledge on kinase regulatory motifs in a machine readable format provides useful context for predicting variant impact, allows rapid comparisons of protein kinase sequences and structures across the kinome and enables hypothesis generation and reasoning over existing data.

Furthermore, through iterative ontology querying, reasoning and experimental studies, we identify a novel mutational hotspot in the kinase domain and demonstrate the functional significance of the predicted mutations on epidermal growth factor receptor EGFR activation and drug sensitivity.

When referring to specific residue positions and mutations, we generally use the PKA numbering. However, in cases where the native protein numbering is specified, we indicate the equivalent PKA numbering as superscript.

By considering the PKA equivalent position of a residue, we can identify and analyze interactions concerning residues in structural and sequence motifs across the kinome.

This serves as an important starting point for providing structural and functional context for disease variants.

To conceptualize information on kinase structural motifs and to provide context for cancer variants, we modified the ProKinO schema to add new properties to two classes, namely the Mutation class and Motif class.

Each instance is assigned associated properties, such as the start and end location of the motif in both the native sequence and with respect to PKA.

The Structural Motif class contains representations of spatial motifs formed by conserved residues that interact in three-dimensional structures.

We implemented each instance of the Structural Motif class as a collection of Sequence Motif instances, linked using the contains relation.

These classes were then linked to other classes in ProKinO using the relations shown in Figure 1. Specifically, the Mutation class was linked to the Disease and Sequence classes using the implicatedIn and occursIn relations, respectively.

Likewise, the Mutation class was linked to Motif class using the locatedIn relationship. New instances were added to the Mutation and Motif classes to capture information on kinase structural motifs and subdomains.

Schematic representation of protein kinase data and knowledge in ProKinO. Boxes denote ontology classes, with arrows showing relations between classes.

Several classes e. The development steps of the software have been previously published [Gosal et al. We made significant changes to the previous version of ProKinO, particularly to address the conceptualization of samples and motifs.

Instances of some classes, such as the Mutation and Motif classes, store positional information such as residue numbers within the native protein sequence.

Each row in the file represents an instance individual of Sample in which an instance of the Mutation class is observed.

The Mutation and Sample classes are connected by the inSample relation. For example, the instance of variant p. In addition, we replaced the Subdomain class used in the previous version of ProKinO with the Motif class and introduced its two subclasses: Sequence Motif and Structural Motif.

The instances of these two classes and the relations between them are generated from the multiple sequence alignments of the human kinome.

Triple patterns may be combined into conjunctions and disjunctions optional patterns are possible, as well. SPARQL querying provides us with a method for extracting information from ProKinO and returning the requested data in a comma separated values csv file.

Charts and graphs were generated from query results using Python v2. Protein structure images were created using PyMol [DeLano, ], whereas word cloud images were generated using Wordle [Feinberg, ].

RK, p. RC, p. RH, p. RL, p. RC, and p. Point variants were confirmed by DNA sequencing. Transfected cells were allowed to grow for 24 hr followed by serum starvation in Ham's F12 media for 18 hr.

Y, p. Y, and p. To monitor the effect of gefitinib on WT and mutant p. Before stimulation with EGF, cells were treated with 0, 0.

Cell lysates were processed as described above. Total and phosphorylated proteins were analyzed as indicated. To ensure the accuracy of the data presented in this article and in ProKinO as a whole, we took various measures to validate that the populated ontology is consistent with its underlying sources.

To ensure that no data is missing, we searched COSMIC by gene name and verified that the number of records returned matches the number of variants for that gene in ProKinO.

The ontology was validated against other data sources in a similar manner. Next, we validated our multiple sequence alignment of the human kinome.

We visually inspected the alignment to verify that key sequence motifs e. For variants mentioned in this article, we performed structural alignments when crystal structures were available to verify structurally equivalent positions.

Finally, to rigorously ensure the accuracy of ProKinO data on a large scale, we developed a suite of test applications. These applications automatically compare the data in the ontology with the corresponding original data sources for consistency.

The absence of disparities between output files produced by the test applications indicates consistency between ProKinO and original data sources.

Several conserved structural motifs associated with protein kinase activation and regulation, such as the lysine glutamate KE salt bridge, hydrophobic spine, and RD pocket, have been identified through detailed structural studies on PKA [Taylor et al.

Although these motifs are widely used to compare protein kinase structures and explain kinase activation mechanisms, they have not been systematically used to predict variant impact because knowledge on kinase structural motifs is buried in the literature and not represented in a machine-readable format.

Inconsistencies in residue numbering between sequence data sources further complicates mapping of variants to crystal structures and comparisons across the kinome.

To address these issues, we have developed a consistent numbering scheme see Methods using the prototypic PKA as the frame of reference.

Furthermore, we have introduced new concepts, relations, and instances in ProKinO to represent protein kinase structural knowledge using the same semantics and terminologies used in the literature Fig.

For example, the Motif class captures knowledge on the sequence and structural motifs associated with kinase functions, while the locatedIn relation between the Motif and Mutation classes captures the information linking variants to sequence and structural motifs Fig.

Such conceptual representation of knowledge in a machine-readable ontology enables integrative analysis of existing data in ways not possible through other resources.

Complex aggregate queries relating cancer variants to kinase structural motifs can be rapidly performed using the ontology, while performing the same queries otherwise will require the user to first retrieve data from various sources such as PDB, COSMIC, and UniProt, and post-process data using customized scripts.

Below, we demonstrate the utility of ProKinO in cancer kinome mining and annotation using the knowledge conceptualized on conserved motifs associated with kinase function and regulation.

We use the PKA residue numbering throughout while referring to residues and variants in conserved motifs, unless otherwise noted.

The canonical RD pocket is a structural motif formed by basic residues from three regulatory regions of the kinase domain: the C-helix p.

H87 , the HRD motif in the catalytic loop p. R and the activation loop p. R Fig. The RD pocket concept is widely used in the literature to explain the structural basis of activation loop phosphorylation, a mode of regulation utilized by many kinases [Johnson et al.

The negatively charged phosphate group of a phosphorylated serine, threonine or tyrosine residue in the activation loop coordinates with the positively charged residues in the RD pocket.

This coordination provides a framework for allosteric regulation by positioning key functional elements, such as the C-helix and activation loop, in a catalytically competent conformation [Jeffrey et al.

RD Pocket variants. B: Variants at activation loop phosphosites. C: Variants in the canonical RD pocket kinases shown as amino acid logos in which the size of the letter is proportional to the frequency of occurrence of the corresponding amino acid.

The top panel shows amino acid counts in wild type WT proteins and the bottom panel shows the mutant MT forms.

D: Variants in the non-canonical pocket kinases, shown as described in C. E: Sample primary sites with variants in the canonical RD pocket positions.

However, JAK2 conserves three lysines, two in the activation loop p. K PKA , p. K PKA , that coordinate with the phosphorylated tyrosine residues p.

Y PKA in the activation loop [Lucet et al. For our analysis, we classified RD pockets into canonical and non-canonical based on the nature of amino acids observed at PKA equivalent positions 87, , and Analysis of amino acid types at the pocket positions in WT and mutant forms indicate that the basic property of the pocket residues is altered in many cancer samples Fig.

Table S1. RG, and p. RS have been observed in cancers. Queries requesting the reactions and pathways associated with kinases harboring RD pocket variants reveal that CHEK2 controls multiple pathways associated with cell cycle control and DNA damage repair upon activation loop phosphorylation [Xu et al.

Based on this contextual information, one can formulate the testable hypothesis that CHEK2 RD pocket variants impact cell cycle control by impairing CHEK2 regulation via activation loop phosphorylation.

While the majority of variants in the RD pocket replace a basic residue with a polar or hydrophobic residue, in some cases, a potential canonical pocket is formed because of the variant.

This variant is predicted to coordinate with the activation loop phosphate in a manner analogous to a canonical RD pocket. To investigate how the phosphorylation sites in the activation loop are altered in human cancers, we used the modified residue property in the Functional Feature class and instances of the Motif class to identify variants that alter phosphorylated serine, threonine or tyrosine residues in the activation loop.

Our analysis revealed multiple phosphorylated tyrosine residues that are mutated to a serine or aspartate Fig.

Table S1 , is predicted to rewire signaling networks by introducing a new phosphorylation site [Tan et al. On the other hand, replacement of phosphorylated tyrosine by an aspartate may constitutively activate the kinase, with the negatively charged aspartate functioning as a phosphomimic.

The lysine glutamate salt bridge is a structural motif formed between a conserved lysine p. K72 in sub-domain II and a glutamate p.

E91 in sub-domain III C-helix. Although the KE salt bridge interaction is formed in most active structures, it is broken in many inactive structures due to repositioning of the flexible C-helix Fig.

The KE salt bridge terminology is widely used to describe kinase activation and regulatory mechanisms, but has not been systematically studied in the context of cancer variants.

KE salt bridge variants. A: Salt bridge between lysine p. E91 in the C-helix. B: Somatic cancer variants mapping to p.

K72 and p. The top panel shows amino acids observed at that position in WT human kinases. The bottom panel shows the amino acids observed at the corresponding positions in mutant MT kinases.

C: Sample primary sites with variants in the salt bridge positions. K72 is predominately mutated to an asparagine, threonine, arginine or glutamate in many kinases Fig.

These variants are predicted to inactivate the kinase, as mutational studies in PKA and other kinases have shown that mutation of p.

K72 to an arginine abrogates kinase catalytic activity [Iyer et al. E91 is mutated to a lysine in a significant number of kinases and these variants are also predicted to inactivate the kinase by introducing a repelling electrostatic interaction with p.

One may suspect that a double variant, p. However, this combination has not yet been observed in a sequenced cancer sample. Table S2.

Although the majority of variants altering the KE salt bridge are predicted to impair catalytic activity, it is unclear if they will impact kinase scaffolding functions, as demonstrated for some pseudokinases [Kornev and Taylor, ; Hu et al.

Notably, some of the kinases harboring variants at p. The hydrophobic spine is a structural motif encompassing residues from different regions of the kinase domain.

The hydrophobic spine terminology was introduced [Kornev and Taylor, ] to describe the conserved hydrophobic interactions spanning the ATP and substrate binding lobes of the kinase domain.

It is classified into the catalytic C- and regulatory R- spines based on their proposed role in kinase functions.

The R-spine consisting of PKA residues p. L95, p. L, p. F and p. D is dynamically assembled upon kinase activation and is proposed to play a regulatory role.

The concepts are included as part of the Structural Motif class and instantiated with residues that define the spine in each kinase see Methods.

Utilizing this conceptual representation, we formulated a query to identify kinases with variants in the C- and R-spine positions.

The hydrophobic spines. B: Distribution of sample primary sites with C-spine variants. C: Catalytic yellow, left and regulatory red, right spines.

D: WT and mutant residues for the R-spine. E: Distribution of sample primary sites for Regulatory spine variants. Within the R-spine, p.

D are among the most frequently mutated residues Fig. Mutation of p. F to an aspartate or asparagine results in loss of catalytic activity in PKA and other kinases [Meharena et al.

D, a conserved R-spine residue in the F-helix that is mutated in multiple cancers Fig. Variants that disrupt the hydrogen bonding interaction between p.

D and the HRD motif backbone p. DA and p. DN have been shown to abrogate catalytic activity [Meharena et al. Based on this information, we predict that the asparagine variants observed at position p.

Table S3 , inactivate the kinase. Table S3. Our queries also reveal recurrent variants in the C-spine Fig. Table S4 in a variety of tissue types Fig.

PKA residue p. A70 forms hydrophobic interactions with the adenosine group of ATP and is one of the most frequently mutated C-spine residues.

The small size of the alanine side-chain is important for accommodating ATP [Hu et al. As many of the variants observed at p. A70 increase amino acid size Fig.

Recent studies on the RAF kinases have shown that mutation of p. A70 to a phenylalanine impairs ATP binding, but retains the scaffolding functions of the kinase [Hu et al.

Thus, even though C-spine variants are likely to impair ATP binding and catalysis, scaffolding functions may be retained.

We used information from the Reaction and Pathway classes captured in ProKinO to obtain insights into the scaffolding functions associated with mutated kinases.

This information can be used to generate hypotheses regarding the impact of C-spine variants on kinase catalytic and scaffolding functions.

Together, these examples demonstrate how mining cancer variants in the context of structural motifs and pathways can provide new hypotheses for experimental studies.

Table S4. To validate the utility of ProKinO in knowledge discovery and hypothesis testing, we performed iterative querying while assuming minimal prior knowledge of kinase structure and function.

Below we demonstrate how the iterative querying process, followed by experimental studies, resulted in the identification of a novel mutational hotspot in the kinase domain.

Our query revealed that arginine is the most frequently mutated residue in the kinase domain Fig. Based on this knowledge, we next formulated a query to identify the kinases harboring arginine variants.

The results depicted in Figure 5 B show that arginine variants are found in a diverse array of kinases, but with the greatest frequency in EGFR.

Two of the arginine residues p. R PKA and p. The other arginine residues p. R 75PKA , p. R PKA , p. R PKA , and p. R PKA , on the other hand, are not part of any known functional site, but are frequently mutated in cancer samples.

Iterative querying and hypothesis generation. A: Plot showing the frequency of each amino acids mutated in cancers in the protein kinase domain.

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Kneipenbesitzer in. Silhouette f. Umriss m. Besitznachfolger in m streben englisch. Arbeitsförderung f. Work-Life-Balance 3, Halter in m f. Objektförderung f. Vorheriger Konkurrenten Weiterer Konkurrenten. Kompetenz wird als Konkurrenz eingestuft. FR DE. Alamode Filmdistribution oHG Dieter hallervorden alter. Gleichberechtigung 4, Profil nt.

Subdomains are colored and labeled. D: Western blot results showing constitutive activity of p. E: EGFR auto-phosphorylation and downstream signaling of wild type and p.

RH PKA mutant inhibition with varied concentrations of gefitinib. EGFR is a receptor tyrosine kinase that controls a diverse array of cellular processes associated with cell migration, adhesion and proliferation.

Its constitutive activity has been correlated with several cancer types and a variety of commercial inhibitors have been developed to abrogate this activity [Lynch et al.

Y PKA , p. Y 0PKA , p. Y 0PKA , and p. Based on this knowledge, we formulated a testable hypothesis that causative arginine variants will impact EGFR autophosphorylation and Stat3 phosphorylation.

The substrate binding pocket variant p. In contrast, mutation of p. R PKA , or p. Interestingly, however, p. The extent of EGFR activation by p.

Cancer cells harboring p. Consistent with previous studies, our experimental results indicate increased sensitivity of the EGFR p.

To obtain additional insights on the mechanisms by which p. R PKA mutated in other kinases? R PKA position? Likewise, analysis of kinases naturally conserving mutant types at equivalent positions can provide insights into the impact of variants on kinase structure, function and drug binding.

We queried for variants at position p. Our queries indicate multiple kinases with disease variants at position p.

Mechanisms of activation of p. RH PKA and p. A: Kinases with variants at position p. R PKA. The text height is proportional to the number of variants.

R PKA orientations. Inactive structure shows a common C-helix capping interaction, whereas active structures instead coordinate with the hinge region and C-terminal tail.

Based on this knowledge and our query results, we hypothesized that p. Furthermore, analysis of kinases that naturally conserve a histidine or cysteine at position p.

We also note that in EGFR, p. R PKA is within hydrogen bonding proximity to the C-terminal auto-inhibitory AP2-helix, suggesting that both auto-inhibitory C-helix hinge and C-terminal tail interactions may be relieved by the p.

Further studies are needed to fully understand the mechanisms by which the p. We have demonstrated that ProKinO is a valuable resource for mining and annotating the cancer kinome.

In particular, the conceptual representation of knowledge related to structural and functional motifs allows effective mining of cancer variants while facilitating hypothesis generation and testing.

Our ontological approach is conceptually different from previous structure and machine learning based approaches to predict variant impact [Capriotti and Altman, ; Shi and Moult, ; Hashimoto et al.

However, by making predictions on all proteins, they necessarily miss the wealth of knowledge stored in domain specific and single locus databases, and further don't provide the structural context necessary to frame a testable hypothesis.

The results presented here will serve as a conceptual starting point for experimental studies and help prioritize key variants and mutated kinases for functional characterization and drug discovery [Simpson et al.

While ProKinO offers several utilities for integrative analysis of protein kinase data, it needs to be further developed to fully realize its impact in kinase research.

For example, sequence and structural motifs that contribute to the functional specificity of major kinase groups and families can be added in the Sequence and Structural Motif classes to explore how variants impact family or group specific functions.

Network analysis on missense variants has revealed their preponderance in protein—protein, protein—nucleic acid, and protein—ion interfaces and validated that proteins involved in signal transduction are more frequently mutated in cancer [Nishi et al.

These interaction interfaces can provide the context crucial to predict variant impact. Likewise, incorporating information on kinase substrates and phosphorylation patterns can provide additional functional context for predicting variant impact [Hanks and Hunter, ; Ashburner et al.

Finally, user-friendly interfaces need to be incorporated to facilitate integrative analysis of ProKinO data by a wide range of scientific users.

We are working on a graphical query builder, which will allow the formulation of queries by visually inspecting the classes and relations in the ontology schema.

These tools are expected to enhance the usability of ProKinO and, consequently, accelerate the functional characterization of the cancer kinome.

Disclaimer: Supplementary materials have been peer-reviewed but not copyedited. National Center for Biotechnology Information , U.

Human Mutation. Hum Mutat. Published online Nov Author information Article notes Copyright and License information Disclaimer.

E-mail: ude. Received Jun 24; Accepted Oct This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

This article has been cited by other articles in PMC. Associated Data Supplementary Materials Supp. Abstract Protein kinases represent a large and diverse family of evolutionarily related proteins that are abnormally regulated in human cancers.

Keywords: personalized medicine, cancer therapy, database, drug discovery, big data, disease, mutation, resistance, kinase, conformation, regulation.

Introduction Cancer is a family of diseases characterized by the accumulation of variants in a subset of genes that confer a growth and survival advantage to the cell.

Modification of ProKinO Schema To conceptualize information on kinase structural motifs and to provide context for cancer variants, we modified the ProKinO schema to add new properties to two classes, namely the Mutation class and Motif class.

Open in a separate window. Figure 1. Gefitinib Treatment To monitor the effect of gefitinib on WT and mutant p. Ontology Verification To ensure the accuracy of the data presented in this article and in ProKinO as a whole, we took various measures to validate that the populated ontology is consistent with its underlying sources.

Identification of Variants in the RD Pocket and Predicted Impact The canonical RD pocket is a structural motif formed by basic residues from three regulatory regions of the kinase domain: the C-helix p.

Figure 2. Variants in the Lysine Glutamate KE Salt Bridge Interaction The lysine glutamate salt bridge is a structural motif formed between a conserved lysine p.

Figure 3. Variants Mapping to the Hydrophobic Spine The hydrophobic spine is a structural motif encompassing residues from different regions of the kinase domain.

Figure 4. ProKinO Provides a Framework for Hypothesis Generation and Testing To validate the utility of ProKinO in knowledge discovery and hypothesis testing, we performed iterative querying while assuming minimal prior knowledge of kinase structure and function.

Figure 5. Figure 6. Concluding Remarks We have demonstrated that ProKinO is a valuable resource for mining and annotating the cancer kinome.

Acknowledgments Disclosure statement : The authors declare no conflict of interest. Supporting Information Disclaimer: Supplementary materials have been peer-reviewed but not copyedited.

Prevalence of inactivating protein kinase C mutations in human cancers Gene ontology: tool for the unification of biology.

Nat Genet. Protein kinase signaling networks in cancer. Curr Opin Genet Dev. Cancer-associated loss-of-function mutations implicate DAPK3 as a tumor-suppressing kinase.

Cancer Res. Improving the prediction of disease-related variants using protein three-dimensional structure. BMC Bioinform.

The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. Epidermal growth factor receptor-mediated activation of Stat3 during multistage skin carcinogenesis.

A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases.

Mol Cell. EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer.

Sci Rep. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Dixit A, Verkhivker GM.

Structure-functional prediction and analysis of cancer mutation effects in protein kinases.

Comput Math Methods Med. Drug discovery and the human kinome: recent trends. Pharmacol Ther. A census of human cancer genes.

Nature reviews. ProKinO: an ontology for integrative analysis of protein kinases in cancer. ProKinO: a framework for protein kinase ontology.

Hanks SK, Hunter T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase catalytic domain structure and classification.

Oncogenic potential is related to activating effect of cancer single and double somatic mutations in receptor tyrosine kinases. Internalization and down-regulation of the human epidermal growth factor receptor are regulated by the carboxyl-terminal tyrosines.

J Biol Chem. The conformational plasticity of protein kinases. Catalytic independent functions of a protein kinase as revealed by a kinase-dead mutant: study of the Lys72His mutant of cAMP-dependent kinase.

J Mol Biol. Prioritization of pathogenic mutations in the protein kinase superfamily. BMC Genomics. Active and inactive protein kinases: structural basis for regulation.

Biochim Biophys Acta. Structural and functional diversity of the microbial kinome. PLoS Biol. Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase.

After having suffered a heart-attack, a year-old carpenter must fight the bureaucratic forces of the system in order to receive Employment and Support Allowance.

The true story of Elle editor Jean-Dominique Bauby who suffers a stroke and has to live with an almost totally paralyzed body; only his left eye isn't paralyzed.

PG min Adventure, Biography, Drama. Votes: 9, PG min Drama, Thriller. While both participating in a production of "Death of a Salesman," a teacher's wife is assaulted in her new home, which leaves him determined to find the perpetrator over his wife's traumatized objections.

Not Rated min Crime, Drama, Romance. Pierrot escapes his boring society and travels from Paris to the Mediterranean Sea with Marianne, a girl chased by hit-men from Algeria.

They lead an unorthodox life, always on the run. Votes: 27, PG 91 min Documentary. Documentarian John Chester and his wife Molly work to develop a sustainable farm on acres outside of Los Angeles.

A newcomer to a posh girls boarding school discovers that her two senior roommates are lovers. Not Rated 96 min Drama.

An actress attempts to convince a director how she's perfect for a role in his upcoming production. R 89 min Comedy, Drama.

When his only friend dies, a man born with dwarfism moves to rural New Jersey to live a life of solitude, only to meet a chatty hot dog vendor and a woman dealing with her own personal loss.

R min Documentary, Biography, Music. R min Comedy, Drama, Romance. A young newspaper writer returns to her hometown in the English countryside, where her childhood home is being prepped for sale.

Not Rated min Drama, Romance. A poor boy of unknown origins is rescued from poverty and taken in by the Earnshaw family where he develops an intense relationship with his young foster sister, Cathy.

PG 96 min Animation, Biography, Drama. A precocious and outspoken Iranian girl grows up during the Islamic Revolution.

R 98 min Comedy, Crime, Drama. A criminal subculture operates among U. Not Rated min Crime, Drama. Scampia Vele is the corbusian architecture which has become a stronghold for Mafia of Naples, Italy.

PG min Documentary. While examining the influence of the fast food industry, Morgan Spurlock personally explores the consequences on his health of a diet of solely McDonald's food for one month.

A gang of teenage boys stalk the streets of Naples armed with hand guns and AKs to do their mob bosses' bidding.

R 99 min Comedy, Drama, Romance. Martin, an ex-Parisian well-heeled hipster passionate about Gustave Flaubert who settled into a Norman village as a baker, sees an English couple moving into a small farm nearby.

Not only Not Rated min Crime, Drama, Thriller. Paul, an irritable and stressed-out hotel manager, begins to gradually develop paranoid delusions about his wife's infidelity.

As he succumbs to green-eyed jealousy, his life starts to R 96 min Adventure, Crime, Drama. A Honduran young girl and a Mexican gangster are united in a journey across the American border.

Sign In. View full company info for Prokino Filmverleih. Trainspotting R 93 min Drama 8. Gurinder Gosal , 1 Krys J. Krys J. Fazlul H.

Sarkar, Editor. Author information Article notes Copyright and License information Disclaimer. Received Jul 27; Accepted Nov Copyright Gosal et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.

This article has been cited by other articles in PMC. Figure S2: Plot showing counts of different mutations of all types for all kinase genes.

Figure S3: Plot showing counts of substitution missense mutations for all genes. Figure S4: Plot showing counts of protein kinases at least 2 having mutations of any type implicated in different types of cancer.

Figure S5: Plot showing counts of protein kinases at least 4 participating in pathways. Figure S6: Plot showing counts of pathways in which mutated protein kinases participate.

Figure S7: Plot showing counts of protein kinases having mutations of any type in various primary sites. Figure S8: Plot showing counts of different mutations all types for all sub-domains.

Figure S9: Plot showing counts of substitution missense mutations of the protein kinase FLT3 all having the primary site of Haematopoietic and Lymphoid tissue , and located in various sub-domains.

Table S4: ProKinO evaluation statistics. Abstract Background Protein kinases are a large and diverse family of enzymes that are genomically altered in many human cancers.

Results Here, we describe ProKinO, a protein kinase-specific ontology, which provides a controlled vocabulary of terms, their hierarchy, and relationships unifying sequence, structure, function, mutation and pathway information on protein kinases.

Conclusion We present an integrated framework for large-scale integrative analysis of protein kinase data. Introduction Cancer is caused by an accumulation of mutations, often in a subset of genes that confer survival and growth advantage.

Methods ProKinO Knowledge Organization To conceptualize the wealth of knowledge regarding protein kinase sequence, structure, function, pathways and diseases, we have introduced several key concepts classes and relationships object properties in ProKinO.

Open in a separate window. Figure 1. Data acquisition and storage Sequence Data regarding protein kinase sequence and classification have been obtained from KinBase [10] , the repository for kinase sequence and classification.

Function Information regarding functional domains and functional features associated with kinase domains have been obtained from UniProt [24] , a curated resource for protein functional information.

Disease Although protein kinases have been associated with several human diseases, the current version of ProKinO primarily focuses on cancer.

Pathway Pathway data is obtained from Reactome, a manually curated and peer-reviewed pathway resource [27].

Kinase Sub-domains To provide structural context for cancer mutations, we have incorporated sub-domain information in ProKinO.

Automation of data acquisition and updates We have created a specialized software system to automatically populate ProKinO from the above described sources.

Results and Discussion ProKinO Evaluation Because the ontology development process is costly and time consuming, careful evaluation of ontology content is necessary to determine its suitability in serving the intended purpose of its development.

Manual Approach In the manual approach, the test sets were chosen to evaluate a broad coverage of the ontology content.

Query-based Approach In addition to the manual approach, a query-based approach was used to verify the content of the ontology.

Figure 2. Counts of crystal structures of all protein kinases. Figure 3. Counts of isoforms for all protein kinases.

Figure 4. Counts of number of pathways associated with all protein kinases. Figure 5. Counts of different cancer types implicated in protein kinases.

ProKinO Application The compendium of knowledge represented in ProKinO can be used for a variety of applications such as data mining, text mining and genome annotation.

Figure 6. Counts of substitution missense mutations at least 4 implicated in different types of cancer, and counts of protein kinases having missense mutations implicated in different cancer types.

Query 2 Based on the observation from Query 1, additional SPARQL queries can be performed to obtain further information on the 8 kinases associated with haematopoietic neoplasm.

Figure 7. Counts of protein kinases having missense mutations implicated in haematopoietic neoplasm. Query 3 Query 2 above can be further refined to obtain testable hypotheses regarding cancer mutations.

Future Directions ProKinO is an ontology of terms and relationships capturing the state of knowledge on the protein kinase family.

PDF Click here for additional data file. Figure S2 Plot showing counts of different mutations of all types for all kinase genes.

Figure S3 Plot showing counts of substitution missense mutations for all genes. Figure S4 Plot showing counts of protein kinases at least 2 having mutations of any type implicated in different types of cancer.

Figure S5 Plot showing counts of protein kinases at least 4 participating in pathways. Figure S6 Plot showing counts of pathways in which mutated protein kinases participate.

Figure S7 Plot showing counts of protein kinases having mutations of any type in various primary sites. Figure S8 Plot showing counts of different mutations all types for all sub-domains.

Figure S9 Plot showing counts of substitution missense mutations of the protein kinase FLT3 all having the primary site of Haematopoietic and Lymphoid tissue , and located in various sub-domains.

DOC Click here for additional data file. Table S4 ProKinO evaluation statistics. Acknowledgments We thank Dr. Footnotes Competing Interests: The authors have declared that no competing interests exist.

References 1. A census of human cancer genes. Nat Rev Cancer. Patterns of somatic mutation in human cancer genomes.

Curr Protoc Hum Genet Chapter. KinMutBase: a registry of disease-causing mutations in protein kinase domains. Hum Mutat. MoKCa database—mutations of kinases in cancer.

Nucleic Acids Res. Congenital disease SNPs target lineage specific structural elements in protein kinases. Torkamani A, Schork NJ.

Prediction of cancer driver mutations in protein kinases. Cancer Res. Pathway and network analysis with high-density allelic association data.

Methods Mol Biol. NetworKIN: a resource for exploring cellular phosphorylation networks. The protein kinase complement of the human genome.

KinG: a database of protein kinases in genomes. Protein kinase resource: an integrated environment for phosphorylation research.

Gruber T. International Journal Human-Computer Studies. Jensen LJ, Bork P. Ontologies in quantitative biology: a basis for comparison, integration, and discovery.

PLoS Biol. Biomedical ontologies: a functional perspective. Brief Bioinform.

Juliet, Naked is the story of Annie the long-suffering girlfriend of Duncan and her unlikely c. thomas howell romance with once revered, now faded, singer-songwriter, Tucker Crowe, who also happens to be the subject of Duncan's musical obsession. The true story of Elle editor Jean-Dominique Bauby who suffers a stroke and has to live with an almost totally paralyzed body; only his left eye isn't paralyzed. R min Here, Drama, Mystery. Received Jun 24; Accepted Oct The development steps of the software have been previously published [Gosal et al. Director Home Entertainment & Digital Licensing. Barbara Bauer. /89/21 01 (Durchwahl) [email protected] Assistentin der. Prokino Filmverleih GmbH. Widenmayerstraße 38 München Deutschland Tel.: Fax: [email protected] · goldbergsoftware.se Am 3. September kommt "Willkommen bei den Sch'tis" aus dem Hause Prokino auf und in den Verleih, zwei Wochen wird die Komödie auch im veröffentlicht. Verleih: Liste mit Filmen und Serien verliehen oder produziert von Prokino Filmverleih. Prokino Filmverleih. Bild zu Mary Shelley von Haifaa Al-Mansour. Mary Shelley von Haifaa Al-Mansour - Filmbild 1. BFI Film Fund. Kritik. prokino

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