The C3BI have set up periodic seminars related to Bioinformatics, Biostatistics and Integrative Biology.
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There is a wide gap between the generation of large-scale biological data sets and more-detailed, structural and mechanistic studies. However, recent work that explicitly combine data from systems and structural biological approaches is having a profound effect on our ability to predict how mutations and small molecules affect atomic-level mechanisms, disrupt systems-level networks and ultimately lead to changes in organismal fitness. Our group aims to create a stronger bridge between these areas primarily using three types of data: genetic interactions, protein-protein interactions and post-translational modifications. Â Protein structural information helps to prioritize and functionally understand these large-scale datasets; conversely global, unbiasedly collected datasets helps inform the more mechanistic studies. Our efforts in this respect have been focused on three disease areas: cancer, infectious diseases and neuropsychiatric disorders. Our work has found remarkable similarities between these and other disease areas which are leading to novel therapeutic strategies.
Anna-Sapfo Malaspinas is assistant professor in the Department of computational biology of Université de Lausanne since 2017. Her work aims to characterize evolutionary processes (genetic drift, natural selection, migration and mutation), using genomics data from both modern and ancient samples. Her group develops analytical and computational methods to analyse and interpret time-sampled data and applies those methods to novel ancient DNA datasets. Her work allows quantification and timing of adaptive and migration events, in particular in the context of human colonization of the world.
Matrix factorization/completion methods provide an attractive framework to handle sparsely observed data, also called "scarce" data. A typical setting for scarce data are is clinical diagnosis in a real-world setting. Not all possible symptoms (phenotype/biomarker/etc.) will have been checked for every patient. Deciding which symptom to check based on the already available information is at the heart of the diagnostic process. If genetic information about the patient is also available, it can serve as side information (covariates) to predict symptoms (phenotypes) for this patient. While a classification/regression setting is appropriate for this problem, it will typically ignore the dependencies between different tasks (i.e., symptoms). We have recently focused on a problem sharing many similarities with the diagnostic task: the prediction of biological activity of chemical compounds against drug targets, where only 0.1% to 1% of all compound-target pairs are measured. Matrix factorization searches for latent representations of compounds and targets that allow an optimal reconstruction of the observed measurements. These methods can be further combined with linear regression models to create multitask prediction models. In our case, fingerprints of chemical compounds are used as "side information" to predict target activity. By contrast with classical Quantitative Structure-Activity Relationship (QSAR) models, matrix factorization with side information naturally accommodates the multitask character of compound-target activity prediction. This methodology can be further extended to a fully Bayesian setting to handle uncertainty optimally, and our reformulation allows scaling up this MCMC scheme to millions of compounds, thousands of targets, and tens of millions of measurements, as demonstrated on a large industrial data set from a pharmaceutical company. We also show applications of this methodology to the prioritization of candidate disease genes and to the modeling of longitudinal patient trajectories. We have implemented our method as an open source Python/C++ library, called Macau, which can be applied to many modeling tasks, well beyond our original pharmaceutical setting. https://github.com/jaak-s/macau/tree/master/python/macau.
Meiotic recombination is a fundamental genetic process that generates new combinations of alleles on which natural selection can act and ensures the proper alignment and segregation of chromosomes. Recombination events are initiated by double strand breaks deliberately inflicted on the genome during meiosis. As I will discuss, in vertebrates, there appear to be two main mechanisms by which the locations of these double strand breaks are specified: through binding of the gene PRDM9 or by localization to promoter-like features of the genome. I will present our recent work linking these two mechanisms to dramatic differences in the evolutionary dynamics of recombination hotspots, and draw out potential implications for hybridization between closely related species.
Conclusion:Refined multi-scale models increasingly permit realistic prediction of liver function as well as of toxic injury in acute and chronic damage states. Those models can integrate data from various sources, in vitro, different animal models or human data. The direct representation of liver micro-architecture in those models will open up the future perspective to feed these models with patient-specific data, hence generating a virtual twin of a patients' liver to guide personalized diagnosis and therapy planning.
The field of computational phylodynamics has witnessed a rich development of statistical inference tools with increasing levels of sophistication that can be applied to address a variety of questions about the evolution and epidemiology of viruses. The central premise of the field is that viruses generally evolve so rapidly that epidemic processes leave an imprint in their genomes. When focusing on deep phylogenies, a rich substitution history may confound time-measured evolutionary analyses, whereas for short-term outbreaks, it may be questioned whether the imprint provides the necessary resolution for insightful evolutionary reconstructions. Here, I will illustrate these aspects on different viral examples. The Hepatitis B virus represents an example of a deep evolutionary history that has been difficult to date accurately using sequences sampled over the last decades. Recently, ancient DNA work has resulted in the first HBV samples dating back thousands of years. Using molecular clock modeling that accommodates time-dependent evolutionary rates, I will show how recent rapid evolutionary rate estimates can be reconciled with the long-term evolutionary dynamics of the virus. The 2013-2016 West African Ebola epidemic marked the start of real-time genomic sequencing. Using this example, I will illustrate that short-term outbreak dynamics can be investigated using viral genome sequences, but integrating various sources of information with genomic data promises to deliver more precise insights in infectious diseases. Finally, using recent work on Lassa virus in West Africa, I will further highlight how in-field, real-time molecular epidemiology may impact outbreak responses.
RNA modifications are emerging players in the field of posttranscriptional regulation of gene expression, and are attracting a comparable degree of research interest to DNA and histone modifications in the field of epigenetics. The true potential of only a handful out of more than 100 RNA modifications is currently emerging as the consequence of a leap in detection technology, principally associated with high-throughput sequencing. In the seminar I will outline the major developments in this field with thorougful discussion of detection principles, advantages and drawbacks of new high-throughput approaches, with particular focus on 2′-O-methylations in rRNA and tRNA.
Given the functional interdependencies between the molecular components in a human cell, a disease is rarely a consequence of an abnormality in a single gene, but reflects the perturbations of the complex intracellular network. The emerging tools of network medicine offer a platform to explore systematically not only the molecular complexity of a particular disease, leading to the identification of disease modules and pathways, but also the molecular relationships between apparently distinct (patho) phenotypes. Advances in this direction are essential to identify new disease genes, to uncover the biological significance of disease-associated mutations identified by genome-wide association studies and full genome sequencing, and to identify drug targets and biomarkers for complex diseases.
Research in the Carlson lab focuses broadly on the molecular recognition between ligands and proteins, from the fundamental biophysics of ligand binding to applied inhibitor design. Understanding protein flexibility, allosteric control, and ligand binding all require dynamic information at the atomic level. The technique that we prefer is molecular dynamics (MD) simulations. Our most recent projects have focused on developing mixed-solvent MD (MixMD), a surface-mapping technique which samples protein motion in a solution of water and organic probe molecules. This technique identifies possible binding hotspots for ligands and protein-protein interactions. It requires many MD simulations, typically 10-20 independent simulations of 20-100ns, to properly sample the possible configurations. This series of MD simulations must be done for each possible probe types. It is a resource intensive method, but it has the promise of identifying previously unknown regulatory sites on proteins. This could significantly increase the number of drug targets available to treat a wide variety of medical disorders.
Molecular phenotypes inform us about genetic and environmental effects on cellular and tissue state. The elucidation of the genetic basis of gene expression and other cellular phenotypes is highly informative for the impact of genetic variants in the cell and the subsequent consequences in the organism. In this talk I will discuss recent advances in key areas of the analysis and integration of the genomics of gene expression, chromatin and cellular phenotypes in human populations and multiple tissues from various cohorts including the GTEx consortium and how this assists in the interpretation of regulatory networks and human disease variants. I will also discuss how these recent advances are informing us about the impact of regulatory variation in cancer.
The potential for genome-wide modeling of epistasis has recently surfaced given the possibility of sequencing densely sampled populations and the emerging families of statistical interaction models. Direct coupling analysis (DCA) has earlier been shown to yield valuable predictions for single protein structures, and has recently been extended to genome-wide analysis of bacteria, identifying novel interactions in the co-evolution between resistance, virulence and core genome elements. However, earlier computational DCA methods have not been scalable to enable model fitting simultaneously to 10000-100000 polymorphisms, representing the amount of core genomic variation observed in analyses of many bacterial species. Here we introduce a novel inference method (SuperDCA) which employs a new scoring principle, efficient parallelization, optimization and filtering on phylogenetic information to achieve scalability for up to 100000 polymorphisms. Using two large population samples of Streptococcus pneumoniae, we demonstrate the ability of SuperDCA to make additional significant biological findings about this major human pathogen. We also show that our method can uncover signals of selection that are not detectable by genome-wide association analysis, even though our analysis does not require phenotypic measurements. SuperDCA thus holds considerable potential in building understanding about numerous organisms at a systems biological level.
One of the major limitations in the study of complex molecular pathways is adaptation of the system to experimental perturbation. With 'complex' we mean pathways with a significant level of functional redundancy between components and nonlinear interactions. In this scenario, perturbation of one component may lead to an observable phenotype. However, it is impossible to interpret the difference between phenotype and wildtype in terms of the function the targeted component fulfills in the unperturbed system – although this is the predominant approach cell and systems biologists take to dissect molecular functions. Over the past decade my lab has made efforts to circumvent this problem by exploiting the basal fluctuations of molecular activities observed in live cell movies to establish causal functional relations between pathway components. Inspired by the accomplishments of econometrics, where predictive models are built entirely from passive observation of financial fluctuation time series, we have developed a computational framework to determine nonlinear interdependencies between pathway components. This presentation will introduce some of the mathematical, computational, and experimental concepts based on which we can now accurately delineate the functional hierarchy between signaling and mechanical processes that control cellular morphogenesis, which is a prime example of a complex molecular process.
Many important regulatory interactions are mediated by short linear motif sequences, which are often embedded in disordered protein regions. These interactions tend to be transient, and therefore pose special experimental challenges. In order to develop precise tools for the manipulation and study of such interactions, accurate structural models are needed. However, due to weak binding affinity and the considerable flexibility of the peptide, structural modeling of peptide-mediated interactions presents a considerable challenge. In my talk I will present an overview of our research on peptide-mediated interactions. I will describe Rosetta FlexPepDock, the suite of protocols that we have developed, and applied, for the structure-based characterization and manipulation of peptide-mediated interactions. FlexPepDock is guided by observations of peptide binding strategies revealed from solved complex crystal structures. Efficient but focused sampling strategies have opened the way to model these interactions at high, atom-level accuracy, starting from a receptor structure and the peptide sequence. Using these starting models, we were able to study binding affinity and specificity, and detect novel substrates for a range of peptide-binding receptors as well as peptide-modifying enzymes. Overall, successful modeling strategies have revealed principles of peptide-mediated interactions that can explain how these interactions are established, and provide a starting point for the extension and specification of the peptide-protein interaction repertoire.
Since the advent of genomics, the Genome Browser has proven an enduring and successful way of representing genomic information, using the paradigm of a linear map; and well-assembled and annotated genomes of experimental organisms have served as references for broader taxonomic groups. Ensembl, developed by EMBL-EBI, is one of the most widely used software platforms organising and serving data according tot his model. Â But large scale projects to sequence populations of major species, and to more fully sample the taxonomy, are already commonplace, and accelerating in their ambitions. The logical ay to represent many (related) genome sequences is a graph; but graph-based visualisations may be confusing to users, and the majority of experimental discovery still takes lace in a small number of species. Â In this talk, I will present how Ensembl is experimenting with new models to organise and display genomic data, more suited to a world where sequence is ubiquitous (with examples from vertebrates, vectors, pathogens and plants); and will explore not just technological, but also sociological and political aspects to developing a suitable data infrastructure for an era of genomic plenty.
Statistical methodology is key for quantitative proteomics, as it helps reduce bias and inefficiencies, Â distinguish the systematic variation from random artifacts, and maximize the reproducibility of the results. This talk will overview the statistical methodology implemented in MSstats, an open-source R package for statistical relative quantification of proteins and peptides. MSstats supports experiments with complex designs, such as comparisons of multiple groups or time course comparisons. It handles quantitative shotgun DDA (data-dependent acquisition) experiments, targeted SRM (selected reaction monitoring), and SWATH/DIA (data independent acquisition) experiments. It can be used in conjunction with label-free experimental workflows, or with workflows that utilize stable isotope reference proteins or peptides. MSstats contains functionalities for data processing, model-based statistical analysis (including testing proteins and peptides for differential abundance, or estimating protein abundance on a relative scale), and model-based calculation of a sample size for a future experiment. It also contains functionalities for systems suitability and statistical process control, and for quantification of figures of merit (such as limit of detection) of mass spectrometric assays. MSstats is available stand-alone or via graphical user interface as an external tool in the software framework Skyline. It can be interfaced with numerous spectral processing tools, such as MaxQuant.
DNA of the human genome is 2m long and is folded into chromosomes that fit in 10-micron cellular nucleus. How are these long polymers of DNA folded and organized in 3D inside the nucleus? How can proteins that are much smaller than chromosomes drive chromosome compaction, segregation or control functional interactions at much larger scales? Recently developed Chromosome Conformation Capture technique (Hi-C) provides comprehensive information about frequencies of spatial interactions between genomic loci. Inferring principles and mechanisms of 3D organization of chromosomes from these and imaging data is a challenging biophysical problem. Recently we proposed that chromosomes are organized by an active, motor-driven process of loop extrusion. Loop extrusion can be a universal mechanism responsible for formation of domains and facilitation on enhancer-promoter interaction during interphase , and chromosome compaction and segregation in metaphase . I will review recent experimental studies [3-5] that provide strong support to loop extrusion as a universal mechanism of chromosome folding.
Proteins are the workhorses of the cell and, over billions of years, they have evolved an amazing plethora of extremely diverse and versatile structures with equally diverse functions. Therefore, their evolution echoes the evolution of all forms of life. Evolutionary emergence of new proteins and transitions between existing ones are widely believed to be rare or even impossible. However, recent advances in comparative genomics have repeatedly called some 10%-30% of all genes without any detectable similarity to existing proteins. Even after careful scrutiny, some of those "orphan" genes contain protein coding reading frames with detectable transcription and translation. Thus some proteins seem to have emerged from previously non-coding 'dark genomic matter'. These 'de novo' proteins tend to be disordered, fast evolving, weakly expressed but also rapidly assuming novel and physiologically important functions. I will review mechanisms by which 'de novo' proteins might be created, under which circumstances they may become fixed and why they are elusive. I will present a couple of studies which mostly focus on metazoan genomes.
In this talk, I will describe several recently developed methods to study disease perturbations through the lens of network science. First I will present an investigation of the personalized gene expression responses when inducing hypertrophy and heart failure in 100+ strains of genetically distinct mice from the Hybrid Mouse Diversity Panel (HMDP). I will show that genes whose expression change significantly correlates with the severity of the disease are either up- or down-regulated across strains, and therefore missed by traditional population-wide analyses of differential gene expression. These uncovered personalised genes are enriched in human cardiac disease genes and form a dense co-regulated module strongly interacting with the cardiac hypertrophic signaling network in the human interactome, the set of molecular interactions in the cell. We validate our approach by showing that the knockdown of Hes1, predicted as a strong candidate, induces a dramatic reduction of hypertrophy by 80-90% in neonatal rat ventricular myocytes, demonstrating that individualized approaches are crucial to identify genes underlying complex diseases as well as to develop personalized therapies. Then, I will present a novel approach to identify the collective impact of miRNAs in disease. Instead of focusing on the magnitude of miRNA differential expression, here we address the secondary consequences for the interactome. We developed the Impact of Differential Expression Across Layers (IDEAL), a network-based algorithm to prioritize disease-relevant miRNAs based on the central role of their targets in the molecular interactome. This method was used in the context of asthmatic Th2 inflammation and identified five Th2-related miRNAs (mir27b, mir206, mir106b, mir203, and mir23b) whose antagonization led to a sharp reduction of the Th2 phenotype. This result offers novel approaches for therapeutic interventions. Finally, I will present evidence that one can accurately predict perturbation patterns from the topology of biological networks, even when lacking measurements on the kinetic parameters governing the dynamics of these interactions. Using 87 biochemical networks with experimentally measured kinetic parameters, we show that a knowledge of the network topology offers 65% to 80% accuracy in predicting the impact of perturbations. In other words, we can use the increasingly accurate topological models to approximate perturbation patterns, bypassing expensive kinetic constant measurement. These results open new avenues in modeling drug action, and in identifying drug targets relying on the human interactome only.
Biological function emerges from the complex interplay between molecules in our cells, comprising the human interactome. While interactions between proteins play a central role in the interactome, current maps are still missing the majority of these interactions. State-of-the-art network-based link prediction tools rely on the triadic closure principle, stating that proteins are likely to interact if they share many of their interaction partners, utilizing network paths of length l=2. We show that this principle is valid only for the small fraction of self-interacting proteins, while it fails completely for the rest of the network. Supported by both evolutionary and protein structural arguments, we identify missing protein interactions based on l=3 paths. Our top predictions validate as well experimentally as known protein-protein interactions, outperforming previous methods at least 2-3 fold. Our Length 3 Association Prediction (L3AP) approach provides a fundamental biological principle with a broad potential applicability, including also protein associations (i.e. co-complex membership) information, enabling us to better understand the emergence of biological function under both healthy and pathological conditions.
Ewan Birney: Co-director of the European Bioinformatic Institute and played a vital role in annotating the genome sequences of human, mouse, chicken and several other organisms. He was one of the founder of the Ensembl Genome Browser and the head of the Encode data analysis group. Ewan is a non-executive Director of Genomics England, and is a consultant and advisor to a number of companies, including Oxford Nanopore Technologies and GSK. Abstract: Molecular biology is now a leading example of a data intensive science, with both pragmatic and theoretical challenges being raised by data volumes and dimensionality of the data. These changes are present in both "large scale" consortia science and small scale science, and across now a broad range of applications – from human health, through to agriculture and ecosystems. All of molecular life science is feeling this effect. This shift in modality is creating a wealth of new opportunities and has some accompanying challenges. In particular there is a continued need for a robust information infrastructure for molecular biology. This ranges from the physical aspects of dealing with data volume through to the more statistically challenging aspects of interpreting it. A particular problem is finding causal relationships in the high level of correlative data. Drawing on recent experience I will explore both the "blue collar" challenges of data volume and the "white collar" challenges of interpretation. I will end with exploration of linear traits in cardiac biology using large scale cohorts.
Eugene Myers: Best known for contributing to the early development of the BLAST tool for sequence analysis. His 1990 paper (with Stephen Altschul and others) describing BLAST has received over 62,000+ citations making it amongst the most highly cited papers ever. Myers was also the Vice President of Informatics Research at Celera Genomics, where he was involved in the sequencing of the human genome, as well as the genomes of Drosophila and mouse. In 2012, Myers moved to Dresden to lead a new center for systems biology. Abstract: Our group has been actively pursuing the idea that with great microscopes and great informatics we will be able to truly digitize models of cells, tissues, and organisms through time with information about the genetic and proteomic states of each cell layered there on. The belief is that these atlases combined with optical observations of labeled entities will accelerate the life sciences by allowing us to visualize these systems from any vantage point and as a system, thus leading to many discoveries such as the nature of the genetic control of fly wing development. Since arriving in Dresden five years ago we have made significant progress on hard segmentation and tracking problems with the use of AI techniques developed in the computer vision community. We will present several examples of current projects that exemplify various such techniques and present the quality of results we obtain with them. Despite these improvements we still find ourselves at the limit of what can be determined because of the limited resolution and contrast of the imagery. Fortunately, advances in microscope componentry such as adaptive optics, spatial light modulators, and ultra high-speed cameras present opportunities for improving the underlying imagery. We will report on two microscope development projects in our lab, where the aim is to improve resolution by making multiple observations of a volume and from them computing a better reconstruction of the object under observation using deep neural networks. We think better microscopy through computation and dynamic onboard control of acquisitions is an emerging trend that we generally call computational optics.
Linking gene and function by integrated approaches: how to improve the poor annotation status of sequenced genomes Identifying the function of every gene in all sequenced organisms is the major challenge of the post-genomic era and an obligate step for any systems biology approach. This objective is far from reached. By various estimates, at least 30-50% of the genes of any given organism are of unknown function, incorrectly annotated, or have only a generic annotation such as "ATPase". Moreover, with ~8000 genomes sequenced and ~80,000 in the pipeline (http://www.genomeson.line.org), the numbers of unknown genes are increasing, and annotation errors are proliferating rapidly. For some gene families, 40% of the annotations are wrong. On the other side of the coin, there are still ~1,900 known enzyme activities for which no corresponding gene has been identified and these numbers are also increasing. This biochemical knowledge is yet to be captured in genome annotations. Using mainly a comparative genomic approach, we have linked gene and function for around 50 gene families related mainly to the fields of coenzyme metabolism, tRNA modification, protein modification and more recently metabolite repair. This approach integrates several types of data and uses filters, sieves, and associations to make predictions that can then be tested experimentally. An unknown gene's function may thus be predicted from those of its associates: the 'guilt by association' principle. Associations that can be derived from whole genome datasets include: gene clustering, gene fusion events, phylogenetic occurrence profiles or signatures and shared regulatory sites. Post-genomic experimental sources such as protein interaction networks, gene expression profiles and phenomics data can also be used to find associations. In practice it is often 'guilt by multiple association' as genes can be associated in several ways, and analyzing more than one of these improves the accuracy of predictions. If these types of comparative genomic approaches were systematically used to annotate genomes, the quality of annotations would greatly improve. Also the experimentalists need to be more involved in the annotation process, as without expert knowledge the curation effort is beyond what annotation resources such as Uniprot or NCBI can do alone.
Metagenomic assembly through the lens of validation: recent advances in assessing and improving the quality of genes and genomes assembled from metagenomes Metagenomic samples are snapshots of complex ecosystems at work. These samples often involve hundreds of known and unknown species, contain multiple strain variants, and vary greatly both within environments and across environments. Metagenomic assembly is a fundamental tool for elucidating microbial ecology behind these dynamic communities. Specifically, metagenome assembly allows us to reconstruct genes and genomes from metagenomes. Genes and genomes are on two ends of the assembly spectrum, the former often represents the minimal continuous region that is desired, and the later, the optimal result; one contig per replicon. Multiple metagenomic assembly strategies, pipelines, and assemblers have appeared in recent years; several of these have been substantially improved upon the original heuristics and algorithms employed nearly a decade ago designed to solve this challenging computational problem. However, due to the inherent complexity of the metagenome assembly problem, regardless of the assembly algorithm and sequencing method, metagenome assemblies contain errors. In this talk I will cover three main topics: 1) recent progress in de novo assembly of metagenomes, 2) reference-guided assembly of metagenomes with MetaCompass, and 3) de novo metagenomic assembly mis-assembly detection with VALET.
Between chaos and determinism: the evolution of stochastic gene expression While often depicted as finely tuned programs, biochemical processes in the cell are subject to random fluctuations because of the small number of molecules involved. While this phenomenon was long recognised, it was only recently assessed at a genomic scale. In particular, the advent of single cell transcriptomics technologies have provided us with a picture of the amount of each mRNA present in a cell giving us access to a cell-specific measure of gene expression. The comparison of multiple, isogenic cells allows us to measure the variance in gene expression (also called "noise"). Just as average gene expression, expression noise is also subject to natural selection. Housekeeping genes, for instance, have been reported to be less noisy. Conversely, genes involved in stress or immune response are more variable in their expression, an observation which was hypothesised to result from a bet-edging strategy. In order to quantify transcriptional noise, we used single-cell transcriptomes of mouse cells. I will discuss statistical biases in the current measures of noise and introduce a new statistic for its estimation. We compared gene-specific transcriptional noise with other genomic variables, including sequence conservation and 3D genome architecture. Our results demonstrate that the major factors explaining transcriptional noise are linked to gene network architecture, consistent with a multi-level selection model where selection acts at the pathway level to prevent noise propagation.
Most of the human morbidity and mortality due to malaria is caused by two plasmodium species: falciparum and vivax. Generation of whole genome sequencing data for malaria is now routine. It is generated by extracting the plasmodium DNA from human red blood cells. In countries with a high burden of malaria this can lead to samples with multiple clones, known as multiplicity of infection (MOI). We have developed two algorithms to help detect genetic relatedness, incorporating and leveraging MOI. These two algorithms implement hidden Markov models (HMMs) to identify relatednes, or identity-by-descnet (IBD), between clones within, and between, samples. Using these results we developed an algorithm to detect regions of high relatedness which we postulate as being due to selection pressures. The algorithms also give probability-based measures to distinguish local from imported infections. We demonstrate the algorithm on whole genome sequencing data from P. falciparum from Papua New Guinea and the MalariaGen Pf3K data. We can recapitulate all of the known selection signals as well as identifying some new ones.
Know Thy Ancestors to Know Thyself: Improving Our Understanding of the Human Genome Using Computational Paleogenomics The genomes of more than one hundred vertebrate genomes are now largely sequenced. How can one make use of this massive amount of evolutionary information to better understand the origin and function of portions of the human genome? In this talk, I will first discuss how the genomes of ancestral mammalian species can be reconstructed with surprisingly high accuracy from the genomes of extant species. I will then present how inferred ancestral sequences can be used to improve the detection of ancient evolutionary events such as transposable element and pseudogene insertions that have shaped mammalian genomes. Finally, I will then introduce algorithmic and machine learning approaches that make use of inferred ancestral DNA sequences to improve the accuracy of transcription factor binding site and micro-RNA target site prediction.
We are interested in understanding how gene expression is encoded in genomes, and how to leverage this knowledge to understand the basis of genetic diseases. To this end, we employ statistical modeling of 'omics data and work in close collaboration with experimentalists. I will provide an overview of recent studies from our lab, covering work on RNA metabolism in S. pombe  and on mRNA stability in S. cerevisiae , and discussing the implications of TT-seq, a novel protocol suited to study nascent transcriptomes in higher eukaryotes . I will also report on a recent pilot study where we established RNA-sequencing as a powerful companion tool to genome sequencing for pinpointing molecular causes of rare genetic disorders . The talk will end with a discussion on future directions in computational modeling of cis-regulatory elements.
Genetic sequencing data contain a fingerprint of past evolutionary and population dynamic processes. Phylogenetic methods infer evolutionary relationships — the phylogenetic tree — between individuals based on their genetic sequences. Phylodynamics aims to understand the population dynamic processes — such as epidemiological processes — giving rise to the phylogenetic tree. I will present the mathematical and computational aspects of our recently developed phylodynamic tools for understanding the evolution and epidemic spread of pathogens. In particular, I will highlight our insights into the evolution and epidemic spread of Ebola, Diphtheria, Tuberculosis, Influenza and HIV. I will end the talk touching upon phylodynamic applications beyond epidemiology, such as immunology, developmental biology, and macroevolution.
Protein flexibility through in silico approaches The function of a protein is directly dependent on its 3-dimensional structure. Visualization tools have oversimplified our views of protein structures. Often, they are considered as macromolecules with repetitive structures as rigid while the connecting loops as flexible or even disordered. in silico approaches are interesting tools to tackle this critical question of protein flexibility. Moreover, it allows applying other criteria than B-factors, to define flexibility . We have previously developed different structural alphabets (SAs) , . They are libraries of small protein fragments that are able to approximate every part of protein structures, making them more precise than classical secondary structures. During this talk, I will present: * How a more precise and complete description of protein backbone conformation can be obtained using SAs for the structural analysis? With examples from definition of ligand binding sites to superimposition of protein structures . * How SAs are also well suited to perform prediction of protein flexibility from the sequence ? * How have we also used them to analyse the dynamics of protein structures in a case of a transmembrane protein  * For integrins implicated in pathologies , . * Finally, I will present unpublished results based on a selected a representative set of Molecular Dynamic (MD) performed on 169 protein structures. We show how the SAs can underline specific change of local protein conformations during dynamics , especially using PBxplore tool . References 1. Craveur, P., Joseph, A.P., Esque, J., Narwani, T.J., Noël, F., Shinada, N., Goguet, M., Leonard, S., Poulain, P., Bertrand, O., Faure, G., Rebehmed, J., Ghozlane, A., Swapna, L.S., Bhaskara, R.M., Barnoud, J., Télétchéa, S., Jallu, V., Cerny, J., Schneider, B., Etchebest, C., Srinivasan, N., Gelly, J.-C., de Brevern A.G.: Protein flexibility in the light of structural alphabets., Frontiers in Molecular Biosciences – Structural Biology, 2:20. (2015) 2. de Brevern, A.G. , Etchebest, C., Hazout, S.: Bayesian probabilistic approach for predicting backbone structures in terms of protein blocks, Proteins, 41:271-287. (2000) 3. Bornot, A., Etchebest, C., de Brevern, A.G. : A new prediction strategy for long local protein structures using an original description, Proteins, 76:570-87. (2009) 4. Joseph, A.P., Agarwal, G., Mahajan, S., Gelly, J.-C., Swapna, L.S., Offmann, B., Cadet, F., Bornot, A., Tyagi M., Valadié, H., Schneider, B., Etchebest, C., Srinivasan, N., de, Brevern, A.G. : A short survey on Protein Blocks, Biophysical Reviews, 2:137-145. (2010) 5. de Brevern, A.G., Bornot, A., Craveur, P., Etchebest, C., Gelly, J.-C. : PredyFlexy: Flexibility and Local Structure prediction from sequence, Nucleic Acid Res, 40:W317-22. (2012) 6. de Brevern, A.G., Wong, H., Tournamille, C., Cartron, J.-P., Colin, Y., Le Van Kim, C., Etchebest, C. : A structural model of seven transmembrane helices receptor, Duffy Antigen / Receptor for Chemokines (DARC), Biochem Biophys Acta, 1724:288-306. (2005) 7. Jallu, V., Poulain, P., Fuchs, P.F., Kaplan, C., de Brevern, A.G.: Modeling and Molecular Dynamics of HPA-1a and -1b Polymorphisms: Effects on the Structure of the β3 Subunit of the αIIb/β3 Integrin, Plos One, 7:e47304. (2010) 8. Jallu, V., Poulain, P., Fuchs, P.F., Kaplan, C., de Brevern, A.G.: Modeling and molecular dynamics simulations of the V33 variant of the integrin subunit β3: structural comparison with the L33 (HPA-1a) and P33 (HPA-1b) variants, Biochimie, 105:84-90. (2014) 9. Narwani, T., Craveur, P., Shinada, N., Santuz, H., Rebehmed, J., Etchebest, C., de Brevern, A.G. Dynamics and deformability of α-, 310- and π-helices, submitted. 10.Barnoud, J., Santuz, H., Craveur, P., Joseph, A.P., Jallu, V., de Brevern, A.G., Poulain, P. PBxplore: a tool to analyze local protein
structure and deformability with Protein
Blocks, https://github.com/pierrepo/PBxplore, in preparation.
RNA viruses: characterizing hidden features revealed via comparative genomics RNA viruses have compact multifunctional genomes. During the course of infection, the genome or its derivatives must direct translation of virus proteins, genome replication and genome packaging. To realize these multiple roles, RNA virus genomes commonly have many overlapping coding and non-coding functional elements. Overlapping functional elements have often escaped detection because it can be difficult to disentangle the multiple roles of the constituent nucleotides via, for example, mutational analysis. On the other hand, RNA viruses evolve very rapidly and there are many sequenced isolates, thus providing potential for powerful comparative genomic analyses, even within single virus species. We have been using comparative genomics to systematically identify 'hidden' functional elements in RNA virus genomes. Computationally identified features can then be efficiently targeted for experimental analysis. We are particularly interested in characterizing unusual translation mechanisms – such as ribosomal frameshifting, stop codon readthrough, non-AUG initiation and IRES-mediated initiation – that are so frequently used by RNA viruses for gene expression. Recent work has focused on short overlapping genes identified in the arteriviruses, cardioviruses and potyviruses, and the atypical programmed ribosomal frameshifting and RNA polymerase slippage mechanisms used to express them. To further understand these mechanisms, we have also employed the emerging technique of Ribosome Profiling.
While re-using data from the wider community to validate specific hypotheses or to explore new questions is becoming increasing common, it is still more often than not challenging to efficiently find and access relevant data, and have these sufficiently documented to be safely re-used and integrated. While some journals have started publishing data (i.e their description and scope of use) discoverability, the question of the data publishing incentive and of sustainability are pressing. In this talk, I will review the data sharing and publishing issues in the context of scientific reproducibility and will take the example of neuroscience to demonstrate how data can be made "FAIR". I will point to current solutions for researchers to link their data with the scientific community and will discuss the remaining technical but also cultural challenges.
Phylodynamic models are widely used in infectious disease epidemiology to infer the dynamics and structure of pathogen populations. However, these models generally assume that individual hosts contact one another at random, ignoring the fact that many pathogens spread through highly structured contact networks. We present a new framework for phylodynamics on local contact networks based on pairwise epidemiological models that track the status of pairs of nodes in the network rather than just individuals. Shifting our focus from individuals to pairs leads naturally to coalescent models that describe how lineages move through networks and the rate at which lineages coalesce. These pairwise coalescent models not only consider how network structure directly shapes pathogen phylogenies, but also how the relationship between phylogenies and contact networks changes depending on epidemic dynamics and the fraction of infected hosts sampled. By considering pathogen phylogenies in a probabilistic framework, these coalescent models can also be used to estimate the statistical properties of contact networks directly from phylogenies using likelihood-based inference. We use this framework to explore how much information phylogenies retain about the underlying structure of contact networks and to infer the structure of a sexual contact network underlying a large HIV-1 sub-epidemic in Switzerland.
It has been said that in order to cure cancer, we must first cure research. First, we need to improve how researchers work and make breakthrough discoveries by tackling one of the most important parts of the research cycle, which is as important as research itself: scientific communication. The big step is to reinvent the scientific article – the main vehicle of scientific dissemination – that hasn't changed in format and scope since the birth of the scientific method.
Structural organisation of human replication timing domains Understanding how the DNA double helix is spatially and dynamically organized in the nucleus of eukaryotic cells and how this affects genome functions is one of the main challenges of cell biology. In this seminar, I will illustrate that when combining concepts and methodologies coming from physics with wavelet-based multi-scale signal processing, we are able to extract original information about the structure/function relationship in the nucleus. I will review some recent analyses of genome-wide epigenetic modification data, mean replication timing (MRT) profiles and chromosome conformation (HiC) data that have established some link between the spatio-temporal replication program, gene expression and chromatin structural domains. This provides an analysis framework for the understanding of the epigenetically regulated global chromatin reorganization that underlies the loss of pluripotency during cell differentiation in human. The proposed view reconciles the dichotomic picture of early transcriptionally active and late heterochromatin constant timing regions that replicate by multiple rather synchronous origins in separated nuclear compartments of open and closed chromatins, with the model proposed by our group where U-shaped MRT domains are bordered by ''master'' replication origins from which a replication wave initiates and propagates toward the domain centre via a cascade of origin firing. I will finally discuss a unified framework based on equilibrium globule models where early euchromatin regions behave as a simple 3D equilibrium globule while, specifically in differentiated cell lines, chromatin folding in heterochromatin regions is compatible with a transition to 2D equilibrium dynamics associated with the nuclear lamina. This transition corresponds to a progressive segregation from 3D dynamics at the nucleus centre of early replicating regions to 2D dynamics confined at the nuclear envelop of late replicating regions. These results shed a new light on replication foci formation and dynamics in human, depending on the cells' differentiation status.
Bayesian Markov models consistently outperform PWMs at regulatory motif prediction – Sensitive protein sequence searching for parallelized analysis of massive data sets The talk will cover two very different topics. First I will present Bayesian approach for motif discovery using Markov models in which conditional probabilities of order k − 1 act as priors for those of order k. This Bayesian Markov model (BaMM) training automatically adapts model complexity to the amount of available data. BaMMs improve on PWMs by ~40% in AUC on ~400 ENCODE ChIP-seq data sets and achieves similar improvements in detecting core promoter sequences, poly(A) sites, RNAP pause sites and binding sites for ~20 PAR-CLIPped RNA binding factors. BaMMs never performed worse than PWMs. These robust improvements argue in favour of generally replacing PWMs by BaMMs. Second, I will present our new method MMseqs2 (Many-against-Many sequence searching) for very fast batch protein sequence searches and clustering of huge protein sequence data sets. Protein sequence searching is the main time, cost and quality bottleneck for the analysis of metagenomic datasets. While previous search methods sacrificed sensitivity for speed gains, MMseqs2 is as sensitive as BLAST, more sensitive than PSI-BLAST, and 36 to 1300 times faster. I will explain the ideas that led to this massive improvement. MMseqs2 searching and clustering will considerably increase the fraction of annotatable metagenomic ORFs.
Computational strategies for the analysis of epigenetic landscape in cancer and their application to decipher rewiring of transcriptional regulatory networks in neuroblastoma.
We consider the well known problem of gene regulatory network inference from time series measurements (gene expression, protein concentration) under the angle of Machine Learning. We address two different instances of this problem.
Ces dernières années, beaucoup d'Infrastructures de Recherche dédiées aux sciences du vivant, ont été mises en place à l'échelle nationale et européenne, et produisent d'énormes quantités de données expérimentales hétérogènes à analyser. Leur analyse demande un grand nombre d'outils logiciels et souvent la comparaison avec des collections de données de références. De la même manière, les interfaces requises couvrent un spectre large : de la ligne de commande au portail web, en passant par des logiciels graphiques. L'objectif de l'Institut Français de Bioinformatique (IFB) est de fournir aux scientifiques et ingénieurs, utilisateurs comme développeurs, les capacités de stockage et de calculs requises dans une solution flexible, simple d'utilisation et facilement adaptable. Pour simplifier l'utilisation des logiciels bioinformatiques pertinents, nous les avons intégrés dans des machines virtuelles préconfigurées (les appliances), prêtes à l'emploi sur le cloud de l'IFB. Le modèle d'organisation envisagé vise un équilibre entre les mouvements de données, qui peuvent être très couteux et dans certains cas impossible pour les données confidentielles, et le déploiement automatique des appliances sur des clouds locaux, au plus près des dépôts de données mais nécessitant une infrastructure locale compatible. Pour répondre aux besoins les plus courants, nous avons installé une sélection de plusieurs logiciels scientifiques dans des appliances pour différents domaines des sciences du vivant. L'IFB référence les outils des machines virtuelles dans un catalogue, disponible en ligne, et contenant déjà vingt appliances pour différents sujets comme l'analyse de séquence, l'écologie et la dynamique de populations, la génomique avec le portail Galaxy et des outils comme Stacks pour le RAD-seq, la bio-imagerie, les statistiques avec la suite R, le portail R-studio et l'API web Shiny, etc.


As someone who lives in skirts and/or pants, it's a breath of fresh air to be wearing a dress - let alone a figure-hugging one! However, with Christmas and New Year parties looming around the corner, it is easy to see why I'm venturing out of my comfort zone a little more this time, but still sticking to the classic black, which makes up about 40% of my wardrobe (no joke). The last time I wrote about a little black dress was about 15 months ago, and this time I've found the perfect upgrade. The price is a little (haha, 'a little') steep, but I believe in investing in timeless, classic pieces, and I'm confident that this perfect laced Nicholas number will be a crowd favorite and wardrobe staple for years to come.


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Home » Destinations » Location of shipwreck with $22b of treasure discovered
Location of shipwreck with $22b of treasure discovered
2018-09-15 mediabest Destinations
A SPANISH galleon laden with gold that sank to the bottom of the Caribbean off the coast of Colombia more than 300 years ago was found three years ago with the help of an underwater autonomous vehicle operated by the Woods Hole Oceanographic Institution, the agency disclosed for the first time.
New details about the discovery of the San Jose were released on Monday with permission from the agencies involved in the search, including the Colombian government.
"We've been holding this under wraps out of respect for the Colombian government," said Rob Munier, WHOI's vice president for marine facilities and operations.
Details about the discovery of treasure, worth billions of dollars, have been released with permission from the agencies involved. Picture: Woods Hole Oceanographic Institution via APSource:AP
A mosaic of images taken by the REMUS 6000 shows the complete wreck site. Picture: Jeff Kaeli/Woods Hole Oceanographic InstitutionSource:Supplied
The exact location of the wreck of the San Jose, often called the "holy grail of shipwrecks," was long considered one of history's enduring maritime mysteries.
The 62-gun, three-masted galleon, went down on June 8, 1708, with 600 people on board as well as a treasure of gold, silver and emeralds during a battle with British ships in the War of Spanish Succession.
The treasure is worth as much as $22 billion by modern standards.
Ceramic jars and other items from the 300-year-old shipwreck. Picture: Woods Hole Oceanographic InstitutionSource:AP
The Massachusetts-based WHOI was invited to join the search because of its recognised expertise in deep water exploration.
The institute's autonomous underwater vehicle, REMUS 6000, helped find the wreckage of Air France 447 in 2011, which crashed in 2009 several hundred miles off the coast of Brazil. It was REMUS 6000 that in November 2015 took some side sonar images that found the San Jose in more than 600 metres of water.
REMUS 6000 off the Colombian Navy research ship, ARC Malpelo. Picture: Mike Purcell, Woods Hole Oceanographic InstitutionSource:Supplied
The vehicle descended to nine meters above the wreck to take several photographs, including some of the distinctive dolphin engravings on the San Jose's cannons, a key piece of visual evidence.
"The wreck was partially sediment-covered, but with the camera images from the lower altitude missions, we were able to see new details in the wreckage and the resolution was good enough to make out the decorative carving on the cannons," said WHOI engineer and expedition leader Mike Purcell.
WHOI researchers aboard the ARC Malpelo. Picture: Mike Purcell/Woods Hole Oceanographic InstitutionSource:Supplied
The explosion of the San Jose, depicted in a 1708 oil painting. Picture: Wikimedia CommonsSource:Supplied
"It was a pretty strong feeling of gratification to finally find it," said Munier, who was not at the site but learned in a phone call from Purcell. "It was a great moment."
The treasure has been the subject of legal battles between several nations as well as private companies.
Several weeks ago, UNESCO, the United Nations cultural agency, called on Colombia not to commercially exploit the wreck, whose exact location remains a state secret.
As for the treasure, that remains on the sea bed — for now.
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Robin Mesarosch (* 1. April 1991 in Herrenberg) ist ein deutscher Politiker der SPD und ehemaliger Poetry Slammer. Bei der Bundestagswahl 2021 wurde er über die Landesliste Baden-Württemberg in den Bundestag gewählt.

Leben

Mesarosch wuchs in Langenenslingen auf und bezeichnet sich bis heute als "Dorfkind". Er besuchte die Liebfrauenschule Sigmaringen und studierte zuerst Kommunikation an der HdM in Stuttgart, später Philosophie und Geschichte in Berlin. Zwischen 2009 und 2011 trat er nach eigener Aussage bei über 200 Poetry Slams in Deutschland, Österreich und der Schweiz auf und moderierte auch einige.

Politische Karriere
In die SPD trat Mesarosch mit 18 Jahren ein. Als seine Hauptmotivation nennt er den Kampf gegen soziale Ungerechtigkeit. So schreibt er auf seiner Homepage:
Er arbeitete als Referent und Mitarbeiter unter anderem für Martin Schulz, Andrea Nahles und Heiko Maas. 2021 bewarb er sich bei der Bundestagswahl um das Direktmandat im Wahlkreis Zollernalb-Sigmaringen und stand auf der Landesliste auf Platz 16. Im Kampf um das Direktmandat unterlag er als Zweitplatzierter dem CDU-Kandidaten Thomas Bareiß, erreichte jedoch über den Listenplatz einen Sitz im Bundestag.

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Bundestagsabgeordneter (Baden-Württemberg)
Politiker (21. Jahrhundert)
SPD-Mitglied
Deutscher
Geboren 1991
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Where Will a Crisis of Faith Lead You? Patterns of Evidence: The Exodus DVD Review and Giveaway
My family and I are big documentary enthusiasts. I especially enjoy films that delve into religious studies and historical exploration of the Bible. That's why I was thrilled to have the opportunity to grab a sneak peek of Patterns of Evidence: The Exodus before it's official DVD release date.
For those who may not be familiar with the Book of Exodus in the Bible. It tells the story of God's mission for Moses to lead his people, the Israelites, out of slavery and ultimately to freedom. Throughout history, there have been controversial debates on whether or not the story of Exodus really happened. Patterns of Evidence: The Exodus dives deeper into those controversies and tries to unlock the mystery and truth behind one of the Bible's most influential stories.
ABOUT PATTERNS OF EVIDENCE: THE EXODUS:
For more than 50 years, the vast majority of the world's most prominent archaeologists and historians have proclaimed that there is no hard evidence to support the Exodus story found in the Bible. In fact, they say that the archaeological record is completely opposed to the Bible's account. This view of extreme skepticism has spread from academia to the world. The case against the Exodus appears to be so strong that even some religious leaders are labeling this ancient account as historical fiction. Filmmaker Timothy Mahoney begins with the questions, "Is the Bible just a myth, or did the archaeologists get it wrong?" He decides to tackle this issue wit a deliberate scientific approach. After examining the details in the biblical text, he journeys across the globe to search for patterns of evidence firsthand. The result is the most in-depth archaeological investigation into the Exodus from Egypt ever captured on film. This scientific documentary's goal is to communicate the TRUTH of the Bible and help equip believers with defending their faith and the Bible."
It's no secret that scholars and historians have been debating the truth in Biblical stories for some time now. The Book of Exodus is no exception to this. Winning several awards, including Best Feature Documentary 2014 at the Big Bear International Film Festival and the Best Documentary at the Pan Pacific Film Festival, this documentary really examines and discusses historical findings to help find proof that the Exodus from Egypt actually did occur. Discussions include the Walls of Jericho, possible tombs of Joseph and his siblings, as well as the Ipuwer Papyrus, which holds an uncanny similarity to the accounts told in the Book of Exodus.
One of the main factors discussed in the documentary is the historical timeline of when the Exodus from Egypt actually happened. Some Archeologists and Egyptologists argue that Exodus didn't really occur, due to the discrepancies of evidence found during that time period. However, the real question to ponder is if Exodus actually took place during the time of Ramesses' rule, or much earlier than we originally thought. Due to misinterpretation of what is already written, could new evidence provide a breakthrough in the truth? The film really investigates this timeline based on the information put forth by professionals and what's already been discovered.
Patterns of Evidence: The Exodus had it's official theatrical debut back in January 2015. The film, narrated by Kevin Sorbo, includes rare interviews with leading archaeologists including Israel Finkelstein, Kent Weeks, and David Rohl, as well as guest appearances by Israel's Benjamin Netanyahu and Shimon Peres.
For those who enjoy extras, the DVD also includes several special features:
Cast Profiles with Seventeen Extra Interviews
From Film to Book
Additional Books and Resources
Host a Patterns of Evidence Movie Event
Although, I personally believe that the Exodus did happen, I really appreciate the film's use of non-bias opinions by a slew of professionals in the field. I enjoyed hearing the many different perspectives, and towards the end everything really fit into place. The film also offers outstanding visual effects throughout, while discussing the authenticity of the Exodus of Israelite slaves from Egypt to their homeland.
Patterns of Evidence: The Exodus is a truly informative documentary. The fact that Timothy Mahoney dedicated twelve years to search for the answers is incredible. I really walked away from this film with way more information than I could ever hoped for, and look forward to the possibility of seeing future Patterns of Evidence documentaries for other stories in the Bible. If you enjoy studying or learning about Biblical history, then this film is something you'll definitely want to experience for yourself.
The Patterns of Evidence: The Exodus DVD officially releases and will be available for purchase on August 4, 2015.
One Our Everyday Harvest reader will also have the opportunity to win a copy of this award winning DVD!
Only one entrant per mailing address, per giveaway. If you have won a prize from our sponsor Propeller / FlyBy Promotions in the last 30 days, you are not eligible to win. If you have won the same prize on another blog, you are not eligible to win it again. Winner is subject to eligibility verification.
Disclosure (in accordance with the FTC's 16 CFR, Part 255: "Guides Concerning the Use of Endorsements and Testimonials in Advertising"): Many thanks to Propeller Consulting, LLC for providing this prize for the giveaway. Choice of winners and opinions are 100% my own and NOT influenced by monetary compensation. I did receive a sample of the product in exchange for this review and post.
Tags: Christian, Faith, Giveaways, Movies, Reviews


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In a flashback, Hinata receives the Breeder Diary from her dog breeder father, who wants her to eliminate Aru. When Hinata demands Aru's diary, he challenges her to guess which hand he's hiding a coin in, with his diary as the forfeit. Despite using Yuki's diary, Hinata loses and has to release Yuki. Yuno, however, realizes that Aru is not a Future Diary owner, relying on bluff and observation instead. Unfazed, Aru proposes one more round of his game, with Yuki's diary on the line. By intending to tell Yuki that he lost, no matter what the outcome, Aru manages to neutralize Yuki's diary, since its predictions are based on Yuki's perception. With the game thus reduced to a 50/50 gamble, Aru manages to guess correctly. Mao attempts to destroy Yuki's diary, but Yuno injures her. Yuki, Yuno, Aru and Kousaka leave the park, while Hinata uses her diary to send the dog pack after them. Yuki decides to return to Hinata and try to reason with her, but Yuno reaches her first and threatens to kill her, as well as anyone who attempts to come between her and Yuki. To pacify Yuno, Yuki is forced to declare her his girlfriend. Hinata's father communicates with everyone via radio, explaining that he mistook Aru for a diary owner and warning Yuki about Keigo before being killed by him.


Holiday recipes. For more holiday sites look at Society/Holidays.
Listing food related holidays and events.
Offers a selection of sweet and savory dishes to cook.
Provides their own and submitted recipes for a variety of occasions including Cinco de Mayo, Kwanzaa and Mardi Gras.
Thanksgiving and Christmas recipes from almost every country of the world, mostly meatless.
Recipes for Hamantaschen, Kreplach, and other easy and gourmet menus served at Purim.
Holiday and seasonal recipes are featured year-round.
Holiday cooking and recipes. Menu plans are available also.


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Faith Speaking Understanding: Performing the Drama of Doctrine
by Kevin J. Vanhoozer
To assess this book properly, we must begin by referencing Vanhoozer's previous work The Drama of Doctrine. While there are points of contact between the works, Faith Speaking Understanding is neither a distillation nor popularization of Drama of Doctrine. The author suggests that it is better to view this volume picking up where the previous one left off and yet targeting a different audience. But while the book does not require the same background knowledge of theological arguments about doctrine and theology, it is not necessarily a lighter read.
In Part 1 Vanhoozer lays out his premise. First, Christian doctrine is not dry information that is mentally assented to but disconnected from daily life, but rather serves as directions in how to enact the Christ-life faithfully. Second, the role doctrine has in the life of the church can be best articulated through the use of theater and drama as an extended metaphor. Recognizing the uniqueness of the dramatic metaphor for addressing doctrine and church practice he makes a case for the fitness of dramatic concepts for capturing what should be the dynamic relationship between doctrine and practice in the church. Most importantly, theatrical language draws out what is often lacking in doctrinal education: the necessity of living out the faith, of "performing" what we believe. Church and humanity are caught up in a drama in which the Divine Dramatist invites audience participation. Fitting participation involves faithfully enacting "what is in Christ," a key phrase throughout the book. (He also addresses concerns with the use of the theatrical metaphor both here and in an appendix).
What follows in Part 2 might rightly be considered a dramatic theology in outline, bearing many of the marks of systematic theology in that the following chapters canvass the main theological loci, though in an admittedly distinct manner: theological anthropology, Trinity, Scripture, Christ and salvation, and church.
To begin, Vanhoozer presents the malaise that is the contemporary crisis of identity and authenticity and offers what could be called a theological anthropology of incarnational communicative action. It is communicative action that defines being and it is in Christ that both divine and human communicative action reach their apex. Christ is the authentic divine-human actor and we are most authentically human when we act as he did.
In what may be the most challenging section of the book for many readers, Vanhoozer roots the drama of redemption in the Trinity. That is, "God's mighty work in the history of redemption enacts the perfections of God's inner life" (p. 74). Both in eternity past in himself and in his action in the drama, God has been involved in self-communication. The interaction of the Father and Son in eternity past—sharing glory, life and love—corresponds to their relationship in time. Here Vanhoozer delves into the question of the divine decree, giving it a dialogical twist by discussing it first as covenant between Father and Son regarding the plan of redemption and their respective roles. This pactum salutis roots the substance of the drama of redemption in the divine relationships before the world began. From there he depicts the mission of the Father's sending of the Son as an instantiation in time of the eternal procession of the Son. This is the view of the drama "from above."
In the same chapter Vanhoozer also considers the drama "from below." The divine drama can be seen as a series of entrances and exits or moves between heaven and earth. Though brief, some of his comments on the relationship between heaven and earth here offer a much needed corrective to the simplistic ideas that often hold sway. But it is also here where Vanhoozer weighs in on the structure of the biblical drama and how one ought to divide it. He interacts with the proposals of N. T. Wright (5 acts: Creation, Fall, Israel, Jesus, Church), Samuel Wells (5 acts: Creation, Israel, Jesus, Church, Eschaton), Craig Bartholomew and Michael Goheen (6 acts: Creation, Fall, Israel, Jesus, Church, Eschaton). Perhaps not surprisingly, he chides them for never considering what constitutes a dramatic act. He proposes a five-act drama in which each act centers on a key action in the outworking of the divine decree. His acts, therefore, are: Creation, Election of Abraham/Israel, Sending of the Son, Sending of the Spirit, Return of the King; a noticeably more theological rather than strictly narratival organization. Both here and in the discussion of the pactum salutis one can begin to see the role that covenant plays in Vanhoozer's understanding of the plot of the drama. Before closing this key chapter, he sketches his conception of the plot of the drama in such a way as to weave together the themes of covenant, kingdom and courtroom.
These foundational matters set, he moves to consider how the Christian should act in light of the nature and direction of the drama. In short, the Christian's call is to put on Christ, to act out Christ. Here he addresses the question of whether this dramatic model encourages "faking it." He exploits acting theory to suggest that true acting involves inhabiting the role as totally as possible. Here, too, he addresses the ministry of Word and Spirit in forming the actors.
Two more chapters engage directly with the church and its dramatic role within and without. Church practices such as catechesis, confessions, and the creed are for the purpose of rehearsing doctrine and preparing for performance outside the church. Key elements of his practice are reconciliation, fidelity (especially in marriage), generosity, and hospitality. He also addresses the Lord's Supper at some length as a particularly dramatic moment in the church's performance of the Gospel. With reference to its acts in the world, Vanhoozer steers the church away from thinking it exists to effect redemption in the world toward a call to proclaim that redemption has come. The church does this through careful improvisation on the biblical and doctrinal themes rather than mere repetition. This improvisation is constrained principally by checking it against Christ.
Most readers will find something to quibble with either in the dramatic metaphor or in the theological content. At various points this reader wished that the book was either longer or shorter. Several issues could have benefitted from greater development and other pieces seemed repetitive. Since the emphasis is on "rehearsal" and "performing" one might have expected more reflection on the spiritual disciplines such as prayer and fasting.
It is a bit difficult to say if readers will find this work practical and helpful. While there is little doubt of the author's immense creativity and freshness of thought, sometimes this surplus of creativity threatens to undermine clarity and succinctness. Each reader will have to decide if the dramatic metaphor works at the broadest level, but it seems clear that dramatic language and concepts do offer new and poignant ways to speak about doctrine and the performance of the faith.
Stephen Jenks
Response to Richard Averbeck
by John H. Walton
Another Riddle without a Resolution? A Reply to Stephen Williams
by Hans Madueme
Stephen Williams raises a number of concerns with the book, Adam, the Fall, and Original Sin...
Can Antigone Work in a Secularist Society?
by Michael J. Ovey
Five Truths for Sufferers from the Book of Job
by Eric Ortlund
The book of Job is an obvious place to turn when a Christian suffers, but it is not easy to discern what God means to teach his people through this difficult book...
Adam in Evangelical Theology
by Brian J. Tabb
The Good Shepherd: A Thousand-Year Journey from Psalm 23 to the New Testament
Reviewed by Silviu Tatu
Ancient Israel's History: An Introduction to Issues and Sources
Reviewed by Matthieu Richelle
The Atonement in Lukan Theology
Reviewed by Benjamin R. Wilson
Acts: An Exegetical Commentary: Volume 2: 3:1–14:28
Reviewed by Sean A. Adams
Repentance at Qumran: The Penitential Framework of Religious Experience in the Dead Sea Scrolls
Reviewed by Brian J. Wright


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Why Can You Gamble In A Casino In Japan But Not Online?
Posted On 26.03.2021 26.03.2021 By German Lowren
Japan will start building its first land-based casino in 2021 in Yokohama after the country recently legalized gambling. However, don't celebrate too soon as online gambling sites will remain illegal in Japan. If travelling to Japan to gambe is too far try your luck online at Cookie Casino.
Hashiro Okonogi, the representative of the Liberal Democratic Party of Japan and chairman of the Gambling Commission, said the opening of the first Integrated Resorts casino complex in Japan does not influence Japan's view on online betting.
While speaking on national television, Oknogi answered questions from rival politicians on how to deal with the increase in gambling during the pandemic.
Okonogi said that online gambling operators are not allowed to operate in Japan, so during lockdowns, Japanese citizens will not be able to succumb to obsessive online gambling habits seen in other countries.
Okonogi said that the laws that were altered to allow the construction of casinos in Japan were independent of those restricting online gambling. He said that if online gambling is to be legalized in Japan, those specific laws need to be altered. Okonogi said that currently, online betting laws are not being reviewed.
How Much Will Japan's New Casino In Yokohama Cost?
Japan's new casino in Yokohama is expected to cost over $3.4 billion. The city council is willing to heavily invest in the project and has included the cost of the casino into their 2021 budget.
The proposed casino must include both a hotel and gaming facilities. The gaming facilities can make up a maximum of 3% of the resort's floor area. The casino must also have relaxation areas and aesthetic outdoor gardens. The Japanese officials want the casino to have a high-class atmosphere where adults can freely gather.
The Yokohama government believes that the casino can help Japan by increasing its annual visitors by 60 million by 2030 and believes the casino is capable of injecting $14.5 billion into the economy annually.
The Yokohama government has not selected a company to head the project. They are currently accepting pitches from all the most prominent casino operators in the world who are eager to tap into the newly opened Japanese market.
Some of the favourites to win the contract are Galaxy Entertainment Group Ltd, Genting Singapore Ltd, Melco Resorts and Entertainment Ltd, Sega Sammy Holdings Inc and Shotoku Corp. These companies operate casinos around the world, including in nearby Macau and Singapore.
The famed Las Vegas operators Las Vegas Sands Corp attempted to win the deal; however, the recently passed CEO Sheldon Adelson said he was withdrawing Sands' bid after being unable to reach an economically beneficial agreement with the Japanese government. He said he still believed that Japan was a great gambling market.
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© Canal+, Filmstiftung Nordrhein-Westfalen, France 3 Cinéma, Claudie Ossard Productions, MMC Independent, Union Générale Cinématographique (UGC), Tapioca Films, Sofica Sofinergie 5, Victoires Productions
Gare de l'Est - Rue d'Alsace
Amélie (2001)
This is the place where Amélie was filmed at Gare de l'Est - Rue d'Alsace in Paris, France. Start scrolling to find out more.
Amelie chases Nino who is desperately chasing another man.
29-25 Rue d'Alsace, 75010 Paris, France
48.8780975341797, 2.35836791992188
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Gare de l'Est, officially Paris-Est, is one of the six large SNCF termini in Paris. It was opened in 1849 by the Compagnie du Chemin de Fer de Paris à Strasbourg under the name Strasbourg platform. It was designed by architect François Duquesnay, it was renamed the "Gare de l'Est" in 1854. On 4 October 1883, the Gare de l'Est saw the first departure of the Orient Express for Istanbul.
car, road, stairs, train station
Audrey Tautou, Mathieu Kassovitz
At a tiny Parisian café, the adorable yet painfully shy Amélie accidentally discovers a gift for helping others. Soon Amelie is spending her days as a matchmaker, guardian angel, and all-around do-gooder. But when she bumps into a handsome stranger, will she find the courage to become the star of her very own love story?
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Wilford Woodruff Sees a Sign in the Winter Skies
The following is an account recorded by Wilford Woodruff while on his missionary journeys in Bangor, Maine in 1838 with James Townsend.
"On the evening of the 21st of February, as we came out of the schoolhouse [where he had preached that day], a light appeared in the northeastern horizon, and spread to the west and soon rolled over our heads. It had the appearance of fire, blood, and smoke, and at times resembled contending armies. The heavens were illuminated for the space of half an hour. It seemed at times as though the veil was about to rend in twain and the elements were contending with each other.
"We looked upon it as one of the signs in the heavens predicted by the prophets of old, as to appear in the last days. We were wading through deep snowdrifts most of the time while witnessing this remarkable scene."
Wilford Woodruff, Leaves from my Journal, p. 50
Is it possible that many signs of the times have already taken place, that we mistakenly still await?
Author The Fairest GemPosted on March 31, 2010 Categories Signs of the TimesTags Last Days, Visions, Wilford WoodruffLeave a comment on Wilford Woodruff Sees a Sign in the Winter Skies
A Remarkable Sign in the Heavens Seen by Wilford Woodruff
This event took place on the North Fox Island off the coast of Maine on 21 February 1838:
"On the evening of the 21st of February, as we came out of the schoolhouse, a light appeared in the northeastern horizon, and spread to the west and soon rolled over our heads. It had the appearance of fire, blood, and smoke, and at times resembled contending armies. The heavens were illuminated for the space of half an hour. It seemed at times as thought the veil was about to rend in twin and the elements were contending with each other.
We looked upon it as one of the signs in the heavens predicted by the prophets of old, as to appear in the last days. We were wading through deep snowdrifts most of the time while witnessing this remarkable scen."
Wilford Woodruff, Leaves From My Journal, p.50
Author The Fairest GemPosted on March 6, 2010 Categories Church HistoryTags Visions, Wilford WoodruffLeave a comment on A Remarkable Sign in the Heavens Seen by Wilford Woodruff
Miracles in Canada with Wilford Woodruff
"I felt impressed by the Spirit of God to take a mission to the Fox Islands, situated east of the Maine shore, a country I knew nothing about. I made my feelings known to the apostles, and they advised me to go.
We crossed Lake Ontario on the steamer Oneida, to Kingston, Upper Canada, and from there also by steamer along the canal to Jone's Falls, whence we walked to a place called Bastard, Leeds County. [near present-day Smith's Falls, Ontario]
Here we found a branch of the Church, presided over by John E. Page and James Blakesly. We accompanied them to their place of meeting, and attended a conference with them at which three hundred members of the Church were represented.
We ordained seven Elders, nine Priests, eleven Teachers and five Deacons.
We spoke to the people several times during this conference, and at its close we were called upon to administer to a woman who was possessed of the devil. At times she was dumb, and greatly afflicted with the evil spirits that dwelt in her. She believed in Jesus and in us as His servants, and wished us to administer to her. Four of us laid our hands upon her head and commanded the devil, in the name of Jesus Christ, to depart out of her. It was immediately done, and the woman arose with great joy, and gave thanks and praise unto God; for, according to her faith, she was made whole from that hour.
A child, also, that was sick, was healed by the laying on of hands, according to the word of God.
We walked thirty miles to visit another branch of the Saints at Leeds, where we met with John Gordon and John Snyder. Here we held a meeting and bore our testimony to the people.
A Sister Carns here came to us and requested to have the ordinance for the healing of the sick performed for two of her children who were afflicted. One was a suckling child, which was lying at the point of death. I took it in my arms and presented it before the Elders, who laid their hands upon it, and it was made whole immediately, and I handed it back to the mother entirely healed.
We afterwards laid hands upon the other, when it was also healed. It was done by the power of God, in the name of Jesus Christ, and the parents praised God for His goodness."
Wilford Woodruff, "Leaves From My Journal" pp. 33-34
Author The Fairest GemPosted on March 6, 2010 February 15, 2017 Categories Church History, Miracles, Missionary WorkTags Canada, Miracles, Missionary Work, Wilford WoodruffLeave a comment on Miracles in Canada with Wilford Woodruff
Wilford Woodruff's First Missionary Year
"This brings the year 1835 to a close – the first year of my mission, during which time I had traveled three thousand two hundred and forty eight miles, held one hundred and seventy meetings, baptized forty three persons, assisted Elder Parrish to baptize twenty more, confirmed 35, organized 3 branches, ordained two Teachers and one Deacon, procured 30 subscribers for the Messenger and Advocate, 173 signers to the petition to the governor of Missouri, had three mobs rise against me – but was not harmed, wrote eighteen letters, received ten, and finally closed the labors of the year 1835 by eating johnny-cake, butter, and honey at Brother A. O. Smoot's.
Author The Fairest GemPosted on March 6, 2010 Categories Church History, Missionary WorkTags Missionary Work, Wilford WoodruffLeave a comment on Wilford Woodruff's First Missionary Year


Moog Memorymoog synthesizer, Taurus II bass pedals, and DSC sequencer (Digital Sequential Controller) from page 39 of Keyboard magazine Feburary 1982.
1981 was around the time I first started reading Keyboard, so this 'family photo' is etched in my brain almost as deep as the real family photo that hung in my parent's kitchen directly opposite to where I ate three meals a day growing up.
It was actually a follow-up ad to Moog's January 1982 advertisement where the gear was covered up.
Ads for the Memorymoog continued to pop up in Keyboard magazine well into 1983-84 (see my 1983 Memorymoog ad post) with later Moog ads suggesting more and more that the Memorymoog was the equivalent of six Minimoogs, as well as the promotion of the Memorymoog Plus (adding MIDI and two sequencers). I'll post more of those ads in the near future.
Lots of Memorymoog information is available online, including Cary Robert's excellent Memorymoog Web site that contains a 1984 Moog liquidation flyer (What? - A Moog Source for $199?)! Vintage Synth Explorer and Wikipedia also contain useful info.
The Taurus II pedals were also promoted in ads as late as 1983, and you can find most of the basics online, including the Taurus page on Wikipedia and Vintage Synth Explorer.
I wasn't able to find much information on the Moog DSC, although the Audities Foundation has a page with some great close-up photos . Please post links if you have more information.
That must be a very early prototype MM because to the best of my knowledge it wasn't released to the public until Nov 1982 or so.


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Review: 'Welcome Home' by Joel McKerrow & The Mysterious Few
Review by Alia Gabres
Joel McKerrow and the Mysterious Few's latest album Welcome Home is a warm fire on a cold winter's night. The album masterfully balances harmonies and oral traditions while posing questions about life and the bitter sweet art of living. It would be remise to attempt to describe it as a spoken word album as this genre defying piece of art is unassuming in its casual defiance of genre specific norms.
As a leading member of the Melbourne spoken word community, Joel has been on a journey of creative discovery for many years. From traditional spoken word, to page poetry, to collaborative art making Joel continues to evolve his storytelling techniques to paint vivid illustrations that challenge and grow the artform.
Joel's current collaboration with his band members the Mysterious Few is a testament of what is possible when local musicians such as Josh Fuhrmeister (production, guitars, keys), Richelle Boer (vocals and guitars), Jhana Allan (Violin) and Leah Scholes (Percussion) join forces. This collaboration is a timely reminder that independent art making is still a viable and important creative platform.
Joel's opening title track 'Welcome Home' attempts to unpack the intimate relationship between creativity and the trials that come with it. Joel's gentle invitation to 'just create' alludes to all things that get lost along the path of art making when insecurities, society and politics get in the way.
The second track on the album 'We Tell Stories' is a marriage of resilience and hope that conjures up the ability to witness a new day.
My favourite line in the album is on the sixth track 'Awaken'. Joel opens the track with the line 'the best way to destroy a people is to take away their stories' then going on to remind us that 'our stories have fallen from our bags'. If you were ever in question of the necessity of this art form or wondered about its ability to 'aw
Making You Sound Delicious
An open letter to those wishing to provide recorded work for Audacious
Dear eager and brave applicants,
My name is Armand (Mandy) and I've been doing this stuff for a while now. Both poetry and audio engineering. I haven't been published as yet, nor have I won any awards for my writing, so I'm not here to tell you how to go about that side of the craft. I do however have a Diploma in Sound Production and have recorded, mixed and mastered a variety of audio work that encompasses podcasts, music, film & TV, and of course spoken word.
Some of you may have noticed that one of the most recent projects I was involved with happened to be the Melbourne Spoken Word audio compilation 'Audacious – Issue 1'.
When it comes to us audio engineers, there is a common myth that we are magicians of sound and can make any piece sparkle. I wish I could say this was true, but even we and our (usually) trusty technology have our limitations. A number of you wishing to provide your work to MSW may be a little fresh to the process of recording. Firstly, it's wonderful and exciting to see how many people out there want to give it a go. I say go for it, learn, embrace, conquer! However, do bear in mind, with the ease of access to in-built microphones on computers and devices, bargain bin recording home studios and free downloadable studio software – there comes the trade off of poor sound quality. Don't let that turn you off, if you are on a stringent budget. There are a few diamonds in the rough to be found. I'll get on to where to find them later.
Over the near 8 years that I've been involved in this, I have been provided a wealth of material. Some glorious snippets, some bat shit crazy stuff with talking dolls, deep creepy breathing and distorted glockenspiels played with drum sticks wrapped in condoms. And then there are those really taxing tracks containing all manner of: squelch, hiss, microphone feedback, jarring r
Submit to Audacious Issue Two
Following the successful release of our first issue of our 'audio-journal' spoken word album, Audacious, we have now opened submissions for the second issue of Audacious until midnight Monday, June 30. We are seeking submissions of audio recorded spoken word (in a .wav file) as well as submissions for photography or artwork for the front cover.
It is important to abide by the following guidelines when submitting and failure to do so, may result in us not considering your piece at all. It is also advised that you listen to the previous issue of Audacious and read two articles, one by myself, and one by Audacious' sound engineer, Armand Petit on tips for good quality recording.
Submissions are made by the Submittable platform here. Artwork is submitted via a separate Submittable Page here. We do not accept submissions via email or other means.
Pieces for Audacious are selected from both commissioned artists or poets asked by the editor to record work as well as submissions for the open submission process. There is no guarantee on the amount of pieces selected from the open submission process. Audio recordings must be submitted in .wav or wave format. We do not accept .mp3 files. This is to maintain the quality of the audio for editing and publishing purposes. We accept work from not just Melbourne or Australia. Everyone is eligible to submit but we do have a bias toward work from inside of Melbourne or those who perform in the live poetry scene in Melbourne, both from open mic and feature poets. Only one submission per artist or poet. We are a group of volunteers and do not have time to listen to four or five submissions from one poet. Submit us your best poem. Poems must be no longer than 5 minutes. Artwork and photography submitted must be the sole property of the author submitting. Authors must submit a bio. Please do not use the bio field in the submission form for a cover letter or any other notes. Bio should be short. Arou
Amal Ibrahim
From To the Ends of the 'Verse Open Mic @ Open Studio, March 17
Filmed and Edited by Freeman Trebilcock
Krish Prasad / The Militant Spoke
Krish Prasad, performing 'The Militant Spoke' at the Slamalamadingdong 'Be Right Back Party' on February 28, 2015.
Video filmed and edited by Freeman Trebilcock. Produced by Melbourne Spoken Word
In Tribute: Melbourne Poets Lost and Loved - Part 1
Words by Steve Smart
During a performance at Slamalamadingdong in Carlton last year, I performed a piece in tribute to a number of Melbourne poets who have passed away in the last 20 years or so. Afterwards Benjamin Solah suggested I curate a series of articles for MSW based this theme. So this is the beginning salvo in a war against forgetting!
I will say that I'm pretty nervous about this project. I've ummed and ahhed and put it off because in comparison I often still feel like a stupid kid. But I'm not a kid anymore, and as I grow older I feel more keenly the responsibility to help keep the words of others alive. This isn't about me, this is about us
I'm gonna throw a list of names at you and see which ones you recognise. My thanks to Pamela Sidney for publishing the original list, which I've added to. The list is in (hopefully) chronological order of passing but isn't a reflection of the order in which the articles will be written. That one will be a bit more random.
A.P. Johnson * John Anderson * Alan 'All-Ego/Word-Warrior' Gregory * John Forbes * Mal Morgan * David Branson * Adrian Rawlins * Glen Tomasetti, Sandon McLeod * Doris Leadbetter * Patrick Alexander * Odin Karlsson * Amanda Wilson * Jenny Boult * Shelton Lea, * Michael Duggan * Lisa Bellear * Ted Lord * Joyce Lee * Geoffrey Eggleston * Jonathan Dark * Dorothy Porter * Martin Downey * John West * Aileen Kelly * Cornelis Vleeskins * Leon Shann * Ken Taylor
This is not an exhaustive list by any means. I'm sure there are names missing. Nor is it an Australian dead poets list. In order to maintain focus and not spend the next 30 years of my life doing this (though I will anyway), I've kept it to Melbourne poets or poets who had a particularly strong connection to Melbourne.
Several of the poets on the list are my friends and mentors, and I don't feel I should discount them on that basis. I am in no way objective. This m


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Sonar Kella (), also Shonar Kella, is a 1971 mystery novel written by  by Bengali writer and filmmaker Satyajit Ray.  In 1974, Ray directed a film adaption of the book, also named Sonar Kella, starring Soumitra Chatterjee, Santosh Dutta, Siddartha Chatterjee and Kushal Chakraborty. The movie was released in the United States as The Golden Fortress. It is the first film adaptation of Ray's famous sleuth Feluda and was followed by Joi Baba Felunath.

Plot

The film begins with a school-boy Mukul Dhar (Kushal Chakraborty), who is said to be able to remember events of his previous life, and soon receives media attention. Dr. Hemanga Hajra (Sailen Mukherjee), a parapsychologist, offers his help, believing it might help him in his own research. Mukul always remains sombre and paints peacocks, forts, camels and battlescenes at midnight; he mentions that he lived in the Golden Fortress (Sonar Kella) and that their house had many gems. Dr. Hajra decides to take Mukul on a trip to Rajasthan, famous for forts, historical importance and desert landscape. Two seasoned fraudsters, Amiyanath Burman and Mandar Bose, plan to kidnap Mukul to capture the treasure. Their first attempt at the kidnapping fails when they pick up another boy, also named Mukul (Santanu Bagchi), from the same neighborhood. Alarmed by this, Mukul's father engages Pradosh Chandra Mitter a.k.a. Feluda (Soumitra Chatterjee), a private investigator, to protect his son. Feluda leaves for Rajasthan along with his cousin Tapesh a.k.a Topshe (Siddartha Chatterjee), following Dr. Hajra. On their way, they meet and befriend Lalmohan Ganguly, a.k.a. Jatayu (Santosh Dutta), a popular thriller writer.

Meanwhile, Burman and Bose kidnap Mukul and push Dr. Hajra off a cliff to his presumed death at the Nahargarh Fort in Jaipur. Burman impersonates as Dr. Hajra and Bose impersonates as a globe-trotter. Dr. Hajra actually survived the fall and begins to pursue them. Feluda arrives in Jodhpur Circuit House and meets Burman, assuming him to be Dr. Hajra. Feluda begins to suspect Bose based on his clothes and his accent. Feluda even suspects "Dr. Hajra's" conduct as he appears lackadaisical in his research. Mukul keeps saying he is followed by a "bad man". Burman successfully hypnotizes Mukul, who says that the Golden Fortress is in Jaisalmer. Dr. Hajra reaches to the same conclusion by learning about the history of the Fort of Jaisalmer from a police inspector. Feluda learns that the Jaisalmer Fort is made of yellow limestone, giving it a golden glow. Bose lies to Feluda by saying that Burman/Dr. Hajra has already left with Mukul for Barmer, in order to lure Feluda on the wrong track. Feluda suspects foul play but cannot be sure. By chance, his eye falls upon the card of Dr Hajra; an idea flashes in his mind and he rushes to check the register of the circuit house and finds that it is signed as 'Hazra' not 'Hajra'. He is now sure about the man impersonating as Dr Hajra, and  leaves for Jaisalmer by car. Bose strands Feluda, Topshe, and Jatayu on the highway. Feluda takes a camel caravan to the nearest train station, from which he takes the next train to Jaisalmer. At night, in the train, Bose attacks and attempts to stab Feluda to death, who anticipated the attack and nearly defeats him; eventually, Bose falls out of the train and most probably dies after seeing the real Dr. Hajra in a separate compartment of the same train and assuming him to be a ghost. The trio arrive in Jaisalmer along with Dr. Hajra. They rush to the fort, where they find Burman searching for the treasure where Mukul recalled his home of previous life was. Feluda confronts and captures Burman, telling him that there never was any treasure. They find that Mukul is cured of his obsession of previous life, and they return to Kolkata.

Characters
 Pradosh Chandra Mitter a.k.a. Feluda
 Tapesh Ranjan Mitter a.k.a. Topshe
 Lalmohan Ganguly a.k.a. Jatayu
 Sidhu Jyatha
 Mukul Dhar
 Mandar Bose
 Amiyanath Burman
 Dr. Hemanga Hajra
 Dibbhojuthi Paul
 Binay Mitra

Cast
 Soumitra Chatterjee as Feluda
 Siddartha Chatterjee as Topshe
 Santosh Dutta as Jatayu
 Kushal Chakraborty as Mukul Dhar
 Kamu Mukherjee as Mandar Bose
 Harindranath Chattopadhyay as Sidhu Jyatha
 Haradhan Banerjee as Binay Mitra
 Shailen Mukherjee as Dr. Hemanga Hajra
 Ajoy Banerjee as Amiyanath Burman a.k.a Bhavananda a.k.a The Fake Dr Hemanga Hazra.
 Bishnupada Rudrapaul as Dibbhojuthi Paul
 Santanu Bagchi as Mukul, another boy
 Bimal Chatterjee as the grandfather of the another Mukul
 Ashok Mukherjee as the Journalist

Crew
 Satyajit Ray - Director, Screenplay, Music Score (composer)
 Soumendu Roy - Cinematography
 Dulal Dutta - Editor
 Mangesh Deshai - Sound Mixing Engineer (Re recording)
 J.D Irani - Dubbing Sound Recordist
 Anil Talukdar - Guide Track Sound recordist
 Ashoke Bose - Production Designer
 Debayan Roy - Production Basic

Awards

 National Film Awards for Best Screenplay & Best Direction(1974)
 Best Film, Direction and Screenplay, Government of West Bengal, 1974
 Best Feature Film for Children and Young Adults, Tehran, 1975
 National Film Award for Best Cinematography (1974)
 National Film Award for Best Child Artist (1974)
 National Film Award for Best Feature Film in Bengali (1974)

See also
 Joi Baba Felunath (1979)

References

External links

 Sonar Kella (SatyajitRay.org)

Films directed by Satyajit Ray
Bengali-language Indian films
Indian detective films
1974 films
1971 novels
Feluda (series)
Novels by Satyajit Ray
Indian novels adapted into films
Films based on Indian novels
Novels set in India
Films set in India
Films set in Rajasthan
Indian children's films
Rajasthani culture
Films whose director won the Best Director National Film Award
Films whose cinematographer won the Best Cinematography National Film Award
Films shot in Rajasthan
Films with screenplays by Satyajit Ray
Films whose writer won the Best Original Screenplay National Film Award
Best Bengali Feature Film National Film Award winners
1970s Bengali-language films