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Project acronym ACTOMYO
Project Mechanisms of actomyosin-based contractility during cytokinesis
Researcher (PI) Ana Costa Xavier de Carvalho
Host Institution (HI) INSTITUTO DE BIOLOGIA MOLECULAR E CELULAR-IBMC
Summary Cytokinesis completes cell division by partitioning the contents of the mother cell to the two daughter cells. This process is accomplished through the assembly and constriction of a contractile ring, a complex actomyosin network that remains poorly understood on the molecular level. Research in cytokinesis has overwhelmingly focused on signaling mechanisms that dictate when and where the contractile ring is assembled. By contrast, the research I propose here addresses fundamental questions about the structural and functional properties of the contractile ring itself. We will use the nematode C. elegans to exploit the power of quantitative live imaging assays in an experimentally tractable metazoan organism. The early C. elegans embryo is uniquely suited to the study of the contractile ring, as cells dividing perpendicularly to the imaging plane provide a full end-on view of the contractile ring throughout constriction. This greatly facilitates accurate measurements of constriction kinetics, ring width and thickness, and levels as well as dynamics of fluorescently-tagged contractile ring components. Combining image-based assays with powerful molecular replacement technology for structure-function studies, we will 1) determine the contribution of branched and non-branched actin filament populations to contractile ring formation; 2) explore its ultra-structural organization in collaboration with a world expert in electron microcopy; 3) investigate how the contractile ring network is dynamically remodeled during constriction with the help of a novel laser microsurgery assay that has uncovered a remarkably robust ring repair mechanism; and 4) use a targeted RNAi screen and phenotype profiling to identify new components of actomyosin contractile networks. The results from this interdisciplinary project will significantly enhance our mechanistic understanding of cytokinesis and other cellular processes that involve actomyosin-based contractility.
Cytokinesis completes cell division by partitioning the contents of the mother cell to the two daughter cells. This process is accomplished through the assembly and constriction of a contractile ring, a complex actomyosin network that remains poorly understood on the molecular level. Research in cytokinesis has overwhelmingly focused on signaling mechanisms that dictate when and where the contractile ring is assembled. By contrast, the research I propose here addresses fundamental questions about the structural and functional properties of the contractile ring itself. We will use the nematode C. elegans to exploit the power of quantitative live imaging assays in an experimentally tractable metazoan organism. The early C. elegans embryo is uniquely suited to the study of the contractile ring, as cells dividing perpendicularly to the imaging plane provide a full end-on view of the contractile ring throughout constriction. This greatly facilitates accurate measurements of constriction kinetics, ring width and thickness, and levels as well as dynamics of fluorescently-tagged contractile ring components. Combining image-based assays with powerful molecular replacement technology for structure-function studies, we will 1) determine the contribution of branched and non-branched actin filament populations to contractile ring formation; 2) explore its ultra-structural organization in collaboration with a world expert in electron microcopy; 3) investigate how the contractile ring network is dynamically remodeled during constriction with the help of a novel laser microsurgery assay that has uncovered a remarkably robust ring repair mechanism; and 4) use a targeted RNAi screen and phenotype profiling to identify new components of actomyosin contractile networks. The results from this interdisciplinary project will significantly enhance our mechanistic understanding of cytokinesis and other cellular processes that involve actomyosin-based contractility.
Project acronym AXIAL.EC
Project PRINCIPLES OF AXIAL POLARITY-DRIVEN VASCULAR PATTERNING
Researcher (PI) Claudio Franco
Host Institution (HI) INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES
Summary The formation of a functional patterned vascular network is essential for development, tissue growth and organ physiology. Several human vascular disorders arise from the mis-patterning of blood vessels, such as arteriovenous malformations, aneurysms and diabetic retinopathy. Although blood flow is recognised as a stimulus for vascular patterning, very little is known about the molecular mechanisms that regulate endothelial cell behaviour in response to flow and promote vascular patterning. Recently, we uncovered that endothelial cells migrate extensively in the immature vascular network, and that endothelial cells polarise against the blood flow direction. Here, we put forward the hypothesis that vascular patterning is dependent on the polarisation and migration of endothelial cells against the flow direction, in a continuous flux of cells going from low-shear stress to high-shear stress regions. We will establish new reporter mouse lines to observe and manipulate endothelial polarity in vivo in order to investigate how polarisation and coordination of endothelial cells movements are orchestrated to generate vascular patterning. We will manipulate cell polarity using mouse models to understand the importance of cell polarisation in vascular patterning. Also, using a unique zebrafish line allowing analysis of endothelial cell polarity, we will perform a screen to identify novel regulators of vascular patterning. Finally, we will explore the hypothesis that defective flow-dependent endothelial polarisation underlies arteriovenous malformations using two genetic models. This integrative approach, based on high-resolution imaging and unique experimental models, will provide a unifying model defining the cellular and molecular principles involved in vascular patterning. Given the physiological relevance of vascular patterning in health and disease, this research plan will set the basis for the development of novel clinical therapies targeting vascular disorders.
The formation of a functional patterned vascular network is essential for development, tissue growth and organ physiology. Several human vascular disorders arise from the mis-patterning of blood vessels, such as arteriovenous malformations, aneurysms and diabetic retinopathy. Although blood flow is recognised as a stimulus for vascular patterning, very little is known about the molecular mechanisms that regulate endothelial cell behaviour in response to flow and promote vascular patterning. Recently, we uncovered that endothelial cells migrate extensively in the immature vascular network, and that endothelial cells polarise against the blood flow direction. Here, we put forward the hypothesis that vascular patterning is dependent on the polarisation and migration of endothelial cells against the flow direction, in a continuous flux of cells going from low-shear stress to high-shear stress regions. We will establish new reporter mouse lines to observe and manipulate endothelial polarity in vivo in order to investigate how polarisation and coordination of endothelial cells movements are orchestrated to generate vascular patterning. We will manipulate cell polarity using mouse models to understand the importance of cell polarisation in vascular patterning. Also, using a unique zebrafish line allowing analysis of endothelial cell polarity, we will perform a screen to identify novel regulators of vascular patterning. Finally, we will explore the hypothesis that defective flow-dependent endothelial polarisation underlies arteriovenous malformations using two genetic models. This integrative approach, based on high-resolution imaging and unique experimental models, will provide a unifying model defining the cellular and molecular principles involved in vascular patterning. Given the physiological relevance of vascular patterning in health and disease, this research plan will set the basis for the development of novel clinical therapies targeting vascular disorders.
Project acronym BODY-OWNERSHIP
Project Neural mechanisms of body ownership and the projection of ownership onto artificial bodies
Researcher (PI) H. Henrik Ehrsson
Host Institution (HI) KAROLINSKA INSTITUTET
Summary How do we recognize that our limbs are part of our own body, and why do we feel that one's self is located inside the body? These fundamental questions have been discussed in theology, philosophy and psychology for millennia. The aim of my ground-breaking research programme is to identify the neuronal mechanisms that produce the sense of ownership of the body, and the processes responsible for the feeling that the self is located inside the physical body. To solve these questions I will adopt an inter-disciplinary approach using state-of-the-art methods from the fields of imaging neuroscience, experimental psychology, computer science and robotics. My first hypothesis is that the mechanism for body ownership is the integration of information from different sensory modalities (vision, touch and muscle sense) in multi-sensory brain areas (ventral premotor and intraparietal cortex). My second hypothesis is that the sense of where you are located in the environment is mediated by allocentric spatial representations in medial temporal lobes. To test this, I will use perceptual illusions and virtual-reality techniques that allow me to manipulate body ownership and the perceived location of the self, in conjunction with non-invasive recordings of brain activity in healthy humans. Functional magnetic resonance imaging and electroencephalography will be used to identify the neuronal correlates of ownership and 'in-body experiences', while transcranial magnetic stimulation will be used to examine the causal relationship between neural activity and ownership. It is no overstatement to say that my pioneering work could define a new sub-field in cognitive neuroscience dealing with how the brain represents the self. These basic scientific discoveries will be used in new frontier applications. For example, the development of a prosthetic limb that feels just like a real limb, and a method of controlling humanoid robots by the illusion of 'becoming the robot'.
How do we recognize that our limbs are part of our own body, and why do we feel that one's self is located inside the body? These fundamental questions have been discussed in theology, philosophy and psychology for millennia. The aim of my ground-breaking research programme is to identify the neuronal mechanisms that produce the sense of ownership of the body, and the processes responsible for the feeling that the self is located inside the physical body. To solve these questions I will adopt an inter-disciplinary approach using state-of-the-art methods from the fields of imaging neuroscience, experimental psychology, computer science and robotics. My first hypothesis is that the mechanism for body ownership is the integration of information from different sensory modalities (vision, touch and muscle sense) in multi-sensory brain areas (ventral premotor and intraparietal cortex). My second hypothesis is that the sense of where you are located in the environment is mediated by allocentric spatial representations in medial temporal lobes. To test this, I will use perceptual illusions and virtual-reality techniques that allow me to manipulate body ownership and the perceived location of the self, in conjunction with non-invasive recordings of brain activity in healthy humans. Functional magnetic resonance imaging and electroencephalography will be used to identify the neuronal correlates of ownership and 'in-body experiences', while transcranial magnetic stimulation will be used to examine the causal relationship between neural activity and ownership. It is no overstatement to say that my pioneering work could define a new sub-field in cognitive neuroscience dealing with how the brain represents the self. These basic scientific discoveries will be used in new frontier applications. For example, the development of a prosthetic limb that feels just like a real limb, and a method of controlling humanoid robots by the illusion of 'becoming the robot'.
Project acronym BRAINGAIN
Project NOVEL STRATEGIES FOR BRAIN REGENERATION
Researcher (PI) Andras Simon
Summary In contrast to mammals, newts possess exceptional capacities among vertebrates to rebuild complex structures, such as the brain. Our goal is to bridge the gap in the regenerative outcomes between newts and mammals. My group has made significant contributions towards this goal. We created a novel experimental system, which recapitulates central features of Parkinson's disease in newts, and provides a unique model for understanding regeneration in the adult midbrain. We showed an unexpected but key feature of the newt brain that it is akin to the mammalian brain in terms of the extent of homeostatic cell turn over, but distinct in terms of its injury response, showing the regenerative capacity of the adult vertebrate brain by activating neurogenesis in normally quiescent regions. Further we established a critical role for the neurotransmitter dopamine in controlling quiescence in the midbrain, thereby preventing neurogenesis during homeostasis and terminating neurogenesis once the correct number of neurons has been produced during regeneration. Here we aim to identify key molecular pathways that regulate adult neurogenesis, to define lineage relationships between neuronal stem and progenitor cells, and to identify essential differences between newts and mammals. We will combine pharmacological modulation of neurotransmitter signaling with extensive cellular fate mapping approaches, and molecular manipulations. Ultimately we will test hypotheses derived from newt studies with mammalian systems including newt/mouse cross species complementation approaches. We expect that our findings will provide new regenerative strategies, and reveal fundamental aspects of cell fate determination, tissue growth, and tissue maintenance in normal and pathological conditions.
In contrast to mammals, newts possess exceptional capacities among vertebrates to rebuild complex structures, such as the brain. Our goal is to bridge the gap in the regenerative outcomes between newts and mammals. My group has made significant contributions towards this goal. We created a novel experimental system, which recapitulates central features of Parkinson's disease in newts, and provides a unique model for understanding regeneration in the adult midbrain. We showed an unexpected but key feature of the newt brain that it is akin to the mammalian brain in terms of the extent of homeostatic cell turn over, but distinct in terms of its injury response, showing the regenerative capacity of the adult vertebrate brain by activating neurogenesis in normally quiescent regions. Further we established a critical role for the neurotransmitter dopamine in controlling quiescence in the midbrain, thereby preventing neurogenesis during homeostasis and terminating neurogenesis once the correct number of neurons has been produced during regeneration. Here we aim to identify key molecular pathways that regulate adult neurogenesis, to define lineage relationships between neuronal stem and progenitor cells, and to identify essential differences between newts and mammals. We will combine pharmacological modulation of neurotransmitter signaling with extensive cellular fate mapping approaches, and molecular manipulations. Ultimately we will test hypotheses derived from newt studies with mammalian systems including newt/mouse cross species complementation approaches. We expect that our findings will provide new regenerative strategies, and reveal fundamental aspects of cell fate determination, tissue growth, and tissue maintenance in normal and pathological conditions.
Project acronym CENTRIOLSTRUCTNUMBER
Project Control of Centriole Structure And Number
Researcher (PI) Monica Bettencourt Carvalho Dias
Host Institution (HI) FUNDACAO CALOUSTE GULBENKIAN
Summary Centrioles are essential for the formation of several microtubule organizing structures including cilia, flagella and centrosomes. These structures are involved in a variety of functions, from cell motility to division. Centrosome defects are seen in many cancers, while abnormalities in cilia and flagella can lead to a variety of human diseases, such as polycystic kidney disease. The molecular mechanisms regulating centriole biogenesis have only recently started to be unravelled, opening new ways to answer a wide range of questions that have fascinated biologists for more than a century. In this grant we are asking two fundamental questions that are central to human disease: how is centriole structure and number established and regulated in the eukaryotic cell? To address these questions we propose to identify new molecular players, and to test the role of these and known players in the context of specific mechanistic hypothesis, using in vitro and in vivo models. We propose to develop novel assays for centriole structure and regulation in order to address mechanistic problems not accessible with today s assays. In our search for novel components we will use a multidisciplinary approach combining bioinformatics with high throughput screening. The use of in vitro systems will permit the quantitative dissection of molecular mechanisms, while the study of those mechanisms in Drosophila will allow us to understand them at the whole organism level. Furthermore, this analysis, together with studies in human tissue culture cells, will allow us to understand the consequences of misregulation of these fundamental centriole properties for human disease, such as ciliopathies and cancer. My group is already collaborating with medical doctors in the study of centriole aberrations in human disease (cancer and ciliopathies), which will be invaluable to bringing the results of this study to the translational level.
Centrioles are essential for the formation of several microtubule organizing structures including cilia, flagella and centrosomes. These structures are involved in a variety of functions, from cell motility to division. Centrosome defects are seen in many cancers, while abnormalities in cilia and flagella can lead to a variety of human diseases, such as polycystic kidney disease. The molecular mechanisms regulating centriole biogenesis have only recently started to be unravelled, opening new ways to answer a wide range of questions that have fascinated biologists for more than a century. In this grant we are asking two fundamental questions that are central to human disease: how is centriole structure and number established and regulated in the eukaryotic cell? To address these questions we propose to identify new molecular players, and to test the role of these and known players in the context of specific mechanistic hypothesis, using in vitro and in vivo models. We propose to develop novel assays for centriole structure and regulation in order to address mechanistic problems not accessible with today s assays. In our search for novel components we will use a multidisciplinary approach combining bioinformatics with high throughput screening. The use of in vitro systems will permit the quantitative dissection of molecular mechanisms, while the study of those mechanisms in Drosophila will allow us to understand them at the whole organism level. Furthermore, this analysis, together with studies in human tissue culture cells, will allow us to understand the consequences of misregulation of these fundamental centriole properties for human disease, such as ciliopathies and cancer. My group is already collaborating with medical doctors in the study of centriole aberrations in human disease (cancer and ciliopathies), which will be invaluable to bringing the results of this study to the translational level.
Project acronym ChromoCellDev
Project Chromosome Architecture and the Fidelity of Mitosis during Development
Researcher (PI) Raquel Aguiar Cardoso de Oliveira
Summary Genome stability relies on accurate partition of the genome during nuclear division. Proper mitosis, in turn, depends on changes in chromosome organization, such as chromosome condensation and sister chromatid cohesion. Despite the importance of these structural changes, chromatin itself has been long assumed to play a rather passive role during mitosis and chromosomes are usually compared to a "corpse at a funeral: they provide the reason for the proceedings but do not take an active part in them." (Mazia, 1961). Recent evidence, however, suggests that chromosomes play a more active role in the process of their own segregation. The present proposal tests the "active chromosome" hypothesis by investigating how chromosome morphology influences the fidelity of mitosis. I will use innovative methods for acute protein inactivation, developed during my postdoctoral studies, to evaluate the role of two key protein complexes involved in mitotic chromosome architecture - Condensins and Cohesins. Using a multidisciplinary approach, combining acute protein inactivation, 3D-live cell imaging and quantitative methods, I propose to investigate the role of mitotic chromosomes in the fidelity of mitosis at three different levels. The first one will use novel approaches to uncover the process of mitotic chromosome assembly, which is still largely unknown. The second will explore how mitotic chromosomes take an active part in mitosis by examining how chromosome condensation and cohesion influence chromosome movement and the signalling of the surveillance mechanisms that control nuclear division. Lastly we will evaluate how mitotic errors arising from abnormal chromosome structure impact on development. We aim to evaluate, at the cellular and organism level, how the cell perceives such errors and how (indeed if) they tolerate mitotic abnormalities. By conceptually challenging the passive chromosome view this project has the potential to redefine the role of chromatin during mitosis.
Genome stability relies on accurate partition of the genome during nuclear division. Proper mitosis, in turn, depends on changes in chromosome organization, such as chromosome condensation and sister chromatid cohesion. Despite the importance of these structural changes, chromatin itself has been long assumed to play a rather passive role during mitosis and chromosomes are usually compared to a "corpse at a funeral: they provide the reason for the proceedings but do not take an active part in them." (Mazia, 1961). Recent evidence, however, suggests that chromosomes play a more active role in the process of their own segregation. The present proposal tests the "active chromosome" hypothesis by investigating how chromosome morphology influences the fidelity of mitosis. I will use innovative methods for acute protein inactivation, developed during my postdoctoral studies, to evaluate the role of two key protein complexes involved in mitotic chromosome architecture - Condensins and Cohesins. Using a multidisciplinary approach, combining acute protein inactivation, 3D-live cell imaging and quantitative methods, I propose to investigate the role of mitotic chromosomes in the fidelity of mitosis at three different levels. The first one will use novel approaches to uncover the process of mitotic chromosome assembly, which is still largely unknown. The second will explore how mitotic chromosomes take an active part in mitosis by examining how chromosome condensation and cohesion influence chromosome movement and the signalling of the surveillance mechanisms that control nuclear division. Lastly we will evaluate how mitotic errors arising from abnormal chromosome structure impact on development. We aim to evaluate, at the cellular and organism level, how the cell perceives such errors and how (indeed if) they tolerate mitotic abnormalities. By conceptually challenging the passive chromosome view this project has the potential to redefine the role of chromatin during mitosis.
Project acronym COMPENZYMEEVOLUTION
Project Harnessing Proto-Enzymes for Novel Catalytic Functions
Researcher (PI) Shina Caroline Lynn Kamerlin
Host Institution (HI) UPPSALA UNIVERSITET
Summary Enzymes are Nature's catalysts, reducing the timescales of the chemical reactions that drive life from millions of years to seconds. There is also great scope for enzymes as biocatalysts outside the cell, from therapeutic and synthetic applications, to bioremediation and even for the generation of novel biofuels. Recent years have seen several impressive breakthroughs in the design of artificial enzymes, particularly through experimental studies that iteratively introduce random mutations to refine existing systems until a property of interest is observed (directed evolution), as well as examples of de novo enzyme design using combined in silico / in vitro approaches. However, the tremendous catalytic proficiencies of naturally occurring enzymes are, as yet, unmatched by any man made system, in no small part due the vastness of the sequence space that needs navigating and the almost surgical precision by which enzymatic catalysis is regulated. The proposed work aims to combine state of the art computational approaches capable of consistently reproducing the catalytic activities of both wild-type and mutant enzymes with novel screening approaches for predicting mutation hotspots, in order to redesign selected showcase systems. Specifically, we aim to (1) map catalytic promiscuity in the alkaline phosphatase superfamily, using the existing multifunctionality of these enzymes as a training set for the introduction of novel functionality, and (2) computationally design enantioselective enzymes, a problem which is of particular importance to the pharmaceutical industry due to the role of chirality in drug efficacy. The resulting theoretical constructs will be subjected to rigorous testing by our collaborators, providing a feedback loop for further design effort and methodology development. In this way, we plan to push existing theoretical tools to the limit in order to bridge the gap that exists between the catalytic proficiencies of biological and man-made catalysts.
Enzymes are Nature's catalysts, reducing the timescales of the chemical reactions that drive life from millions of years to seconds. There is also great scope for enzymes as biocatalysts outside the cell, from therapeutic and synthetic applications, to bioremediation and even for the generation of novel biofuels. Recent years have seen several impressive breakthroughs in the design of artificial enzymes, particularly through experimental studies that iteratively introduce random mutations to refine existing systems until a property of interest is observed (directed evolution), as well as examples of de novo enzyme design using combined in silico / in vitro approaches. However, the tremendous catalytic proficiencies of naturally occurring enzymes are, as yet, unmatched by any man made system, in no small part due the vastness of the sequence space that needs navigating and the almost surgical precision by which enzymatic catalysis is regulated. The proposed work aims to combine state of the art computational approaches capable of consistently reproducing the catalytic activities of both wild-type and mutant enzymes with novel screening approaches for predicting mutation hotspots, in order to redesign selected showcase systems. Specifically, we aim to (1) map catalytic promiscuity in the alkaline phosphatase superfamily, using the existing multifunctionality of these enzymes as a training set for the introduction of novel functionality, and (2) computationally design enantioselective enzymes, a problem which is of particular importance to the pharmaceutical industry due to the role of chirality in drug efficacy. The resulting theoretical constructs will be subjected to rigorous testing by our collaborators, providing a feedback loop for further design effort and methodology development. In this way, we plan to push existing theoretical tools to the limit in order to bridge the gap that exists between the catalytic proficiencies of biological and man-made catalysts.
Project acronym ComplexSwimmers
Project Biocompatible and Interactive Artificial Micro- and Nanoswimmers and Their Applications
Researcher (PI) Giovanni Volpe
Host Institution (HI) GOETEBORGS UNIVERSITET
Summary Microswimmers, i.e., biological and artificial microscopic objects capable of self-propulsion, have been attracting a growing interest from the biological and physical communities. From the fundamental side, their study can shed light on the far-from-equilibrium physics underlying the adaptive and collective behavior of biological entities such as chemotactic bacteria and eukaryotic cells. From the more applied side, they provide tantalizing options to perform tasks not easily achievable with other available techniques, such as the targeted localization, pick-up and delivery of microscopic and nanoscopic cargoes, e.g., in drug delivery, bioremediation and chemical sensing. However, there are still several open challenges that need to be tackled in order to achieve the full scientific and technological potential of microswimmers in real-life settings. The main challenges are: (1) to identify a biocompatible propulstion mechanism and energy supply capable of lasting for the whole particle life-cycle; (2) to understand their behavior in complex and crowded environments; (3) to learn how to engineer emergent behaviors; and (4) to scale down their dimensions towards the nanoscale. This project aims at tackling these challenges by developing biocompatible microswimmers capable of elaborate behaviors, by engineering their performance when interacting with other particles and with a complex environment, and by developing working nanoswimmers. To achieve these goals, we have laid out a roadmap that will lead us to push the frontiers of the current understanding of active matter both at the mesoscopic and at the nanoscopic scale, and will permit us to develop some technologically disruptive techniques, namely, targeted delivery of cargoes within complex environments, which is of interest for drug delivery and bioremediation, and efficient sorting of chiral nanoparticles, which is of interest for biomedical and pharmaceutical applications.
Microswimmers, i.e., biological and artificial microscopic objects capable of self-propulsion, have been attracting a growing interest from the biological and physical communities. From the fundamental side, their study can shed light on the far-from-equilibrium physics underlying the adaptive and collective behavior of biological entities such as chemotactic bacteria and eukaryotic cells. From the more applied side, they provide tantalizing options to perform tasks not easily achievable with other available techniques, such as the targeted localization, pick-up and delivery of microscopic and nanoscopic cargoes, e.g., in drug delivery, bioremediation and chemical sensing. However, there are still several open challenges that need to be tackled in order to achieve the full scientific and technological potential of microswimmers in real-life settings. The main challenges are: (1) to identify a biocompatible propulstion mechanism and energy supply capable of lasting for the whole particle life-cycle; (2) to understand their behavior in complex and crowded environments; (3) to learn how to engineer emergent behaviors; and (4) to scale down their dimensions towards the nanoscale. This project aims at tackling these challenges by developing biocompatible microswimmers capable of elaborate behaviors, by engineering their performance when interacting with other particles and with a complex environment, and by developing working nanoswimmers. To achieve these goals, we have laid out a roadmap that will lead us to push the frontiers of the current understanding of active matter both at the mesoscopic and at the nanoscopic scale, and will permit us to develop some technologically disruptive techniques, namely, targeted delivery of cargoes within complex environments, which is of interest for drug delivery and bioremediation, and efficient sorting of chiral nanoparticles, which is of interest for biomedical and pharmaceutical applications.
Project acronym DIRECT-fMRI
Project Sensing activity-induced cell swellings and ensuing neurotransmitter releases for in-vivo functional imaging sans hemodynamics
Researcher (PI) Noam Shemesh
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Summary Functional-Magnetic Resonance Imaging (fMRI) has transformed our understanding of brain function due to its ability to noninvasively tag 'active' brain regions. Nevertheless, fMRI only detects neural activity indirectly, by relying on slow hemodynamic couplings whose relationships with underlying neural activity are not fully known. We have recently pioneered two unique MR approaches: Non-Uniform Oscillating-Gradient Spin-Echo (NOGSE) MRI and Relaxation Enhanced MR Spectroscopy (RE MRS). NOGSE-MRI is an exquisite microstructural probe, sensing cell sizes (l) with an unprecedented l^6 sensitivity (compared to l^2 in conventional approaches); RE MRS is a new spectral technique capable of recording metabolic signals with extraordinary fidelity at ultrahigh fields. This proposal aims to harness these novel concepts for mapping neural activity directly, without relying on hemodynamics. The specific objectives of this proposal are: (1) Mapping neural activity via sensing cell swellings upon activity (μfMRI): we hypothesize that NOGSE can robustly sense subtle changes in cellular microstructure upon neural firings and hence convey neural activity directly. (2) Probing the nature of elicited activity via detection of neurotransmitter release: we posit that RE MRS is sufficiently sensitive to robustly detect changes in Glutamate and GABA signals upon activation. (3) Network mapping in optogenetically-stimulated, behaving mice: we propose to couple our novel approaches with optogenetics to resolve neural correlates of behavior in awake, behaving mice. Simulations for μfMRI predict >4% signal changes upon subtle cell swellings; further, our in vivo RE MRS experiments have detected metabolites with SNR>50 in only 6 seconds. Hence, these two complementary –and importantly, hemodynamics-independent– approaches will represent a true paradigm shift: from indirect detection of neurovasculature couplings towards direct and noninvasive mapping of neural activity in vivo.
Functional-Magnetic Resonance Imaging (fMRI) has transformed our understanding of brain function due to its ability to noninvasively tag 'active' brain regions. Nevertheless, fMRI only detects neural activity indirectly, by relying on slow hemodynamic couplings whose relationships with underlying neural activity are not fully known. We have recently pioneered two unique MR approaches: Non-Uniform Oscillating-Gradient Spin-Echo (NOGSE) MRI and Relaxation Enhanced MR Spectroscopy (RE MRS). NOGSE-MRI is an exquisite microstructural probe, sensing cell sizes (l) with an unprecedented l^6 sensitivity (compared to l^2 in conventional approaches); RE MRS is a new spectral technique capable of recording metabolic signals with extraordinary fidelity at ultrahigh fields. This proposal aims to harness these novel concepts for mapping neural activity directly, without relying on hemodynamics. The specific objectives of this proposal are: (1) Mapping neural activity via sensing cell swellings upon activity (μfMRI): we hypothesize that NOGSE can robustly sense subtle changes in cellular microstructure upon neural firings and hence convey neural activity directly. (2) Probing the nature of elicited activity via detection of neurotransmitter release: we posit that RE MRS is sufficiently sensitive to robustly detect changes in Glutamate and GABA signals upon activation. (3) Network mapping in optogenetically-stimulated, behaving mice: we propose to couple our novel approaches with optogenetics to resolve neural correlates of behavior in awake, behaving mice. Simulations for μfMRI predict >4% signal changes upon subtle cell swellings; further, our in vivo RE MRS experiments have detected metabolites with SNR>50 in only 6 seconds. Hence, these two complementary –and importantly, hemodynamics-independent– approaches will represent a true paradigm shift: from indirect detection of neurovasculature couplings towards direct and noninvasive mapping of neural activity in vivo.
Project acronym DYNEINOME
Project Cytoplasmic Dynein: Mechanisms of Regulation and Novel Interactors
Researcher (PI) Reto Gassmann
Summary "The megadalton cytoplasmic dynein complex, whose motor subunit is encoded by a single gene, provides the major microtubule minus end-directed motility in cells and is essential for a wide range of processes, ranging from the transport of proteins, RNA, and membrane vesicles to nuclear migration and cell division. To achieve this stunning functional diversity, cytoplasmic dynein is subject to tight regulation by co-factors that modulate localization, interaction with cargo, and motor activity. At present, our knowledge of the underlying mechanisms remains limited. An overarching goal of this proposal is to gain an understanding of how interactions with diverse adaptor proteins regulate dynein function in space and time. We choose the nematode C. elegans as our model system, because it will enable us to study the biology of dynein regulation in the broad context of a metazoan organism. The nematode's versatile genetic tools, its biochemical tractability, and the powerful molecular replacement technologies available, this makes for a uniquely attractive experimental system to address the mechanisms employed by dynein regulators through a combination of biochemical, proteomic, and cell biological assays. Specifically, we propose to use a biochemical reconstitution approach to obtain a detailed molecular picture of how dynein is targeted to the mitotic kinetochore; we will perform a forward genetic and proteomic screen to expand the so-far limited inventory of metazoan dynein interactors, whose functional characterization will shed light on known dynein-dependent processes and lead to novel unanticipated lines of research into dynein regulation; we will dissect the function and regulation of the most important dynein co-factor, the multi-subunit dynactin complex; and finally we will strive to establish a novel C. elegans model for human neurodegenerative disease, based on pathogenic point mutations in a dynactin subunit."
"The megadalton cytoplasmic dynein complex, whose motor subunit is encoded by a single gene, provides the major microtubule minus end-directed motility in cells and is essential for a wide range of processes, ranging from the transport of proteins, RNA, and membrane vesicles to nuclear migration and cell division. To achieve this stunning functional diversity, cytoplasmic dynein is subject to tight regulation by co-factors that modulate localization, interaction with cargo, and motor activity. At present, our knowledge of the underlying mechanisms remains limited. An overarching goal of this proposal is to gain an understanding of how interactions with diverse adaptor proteins regulate dynein function in space and time. We choose the nematode C. elegans as our model system, because it will enable us to study the biology of dynein regulation in the broad context of a metazoan organism. The nematode's versatile genetic tools, its biochemical tractability, and the powerful molecular replacement technologies available, this makes for a uniquely attractive experimental system to address the mechanisms employed by dynein regulators through a combination of biochemical, proteomic, and cell biological assays. Specifically, we propose to use a biochemical reconstitution approach to obtain a detailed molecular picture of how dynein is targeted to the mitotic kinetochore; we will perform a forward genetic and proteomic screen to expand the so-far limited inventory of metazoan dynein interactors, whose functional characterization will shed light on known dynein-dependent processes and lead to novel unanticipated lines of research into dynein regulation; we will dissect the function and regulation of the most important dynein co-factor, the multi-subunit dynactin complex; and finally we will strive to establish a novel C. elegans model for human neurodegenerative disease, based on pathogenic point mutations in a dynactin subunit."


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(e) Net debt equals the sum of deposits held and borrowing, minus the sum of cash and deposits, advances paid and investments, loans and placements.


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A basic law is either a codified constitution, or in countries with uncodified constitutions, a law given to have constitution powers and effect. The term basic law is used in some places as an alternative to "constitution", implying it is a temporary but necessary measure without formal enactment of constitution. The name is generally used to imply an interim or transitory nature, or to avoid claiming to be "the highest law", often for religious reasons. In West Germany the term "Basic Law" (Grundgesetz) was used to indicate that the Basic Law was provisional until the ultimate reunification of Germany. But in 1990 no new constitution was adopted and instead the Basic Law was adopted throughout the entire German territory. Basic law is entrenched in that it overrides ordinary 'statute law' passed by the legislature.

The Special Administrative Regions of the People's Republic of China, namely Hong Kong and Macau, have basic laws as their constitutional documents. The basic laws are the highest authority, respectively, in the territories, while the rights of amendment and interpretation rest with the Standing Committee of the National People's Congress of the People's Republic of China.

List of basic laws

 Basic Law for the Federal Republic of Germany
 Hong Kong Basic Law
 Basic Law, Fundamental Law or Constitution of Hungary
 Basic Laws of Israel
 Macao Basic Law
 Basic Statute of Oman
 Basic Law of Saudi Arabia
 Basic Laws of Sweden
 Bangsamoro Organic Law (sometimes called the Bangsamoro Basic Law)

See also
 Constitution
 Rule according to higher law
 Fundamental Law

Constitutional law

redpajama_set_name: RedPajamaWikipedia


text:
Kofi Annan, former United Nations Secretary General, passes away
News Nation Bureau | Edited By : Guihiamliu Riamei | Updated on: 18 Aug 2018, 05:40:51 PM
Kofi Annan, former United Nations Secretary General and Nobel Peace Prize laureate, passed away on Saturday morning after a short illness at the age of 80, official sources said.
"It is with immense sadness that the Annan family and the Kofi Annan Foundation announce that Kofi Annan, former Secretary General of the United Nations and Nobel Peace Laureate, passed away peacefully on Saturday 18th August after a short illness," the foundation said in a statement.
Annan was the first African to take up the role of the world's top diplomat, who served as the seventh Secretary General of the United Nations from January 1997 to December 2006. Annan was awarded the Nobel Peace Prize for his commitment to Human Rights.
It is with immense sadness that the Annan family and the Kofi Annan Foundation announce that Kofi Annan, former Secretary General of the United Nations and Nobel Peace Laureate, passed away peacefully on Saturday 18th August after a short illness... pic.twitter.com/42nGOxmcPZ
— Kofi Annan (@KofiAnnan) August 18, 2018
Congress MP Shashi Tharoor, who served as Under-Secretary General of the United Nations during Kofi Annan's leadership, condoled the demise of the former UN chief saying he lost an elder brother.
Kofi Annan was a proud son of Africa, a great admirer of India, a voice of the developing world, a paragon of internationalism & an exemplar of humanity. The @UN was fortunate to have been led by him at a pivotal moment in world history. He remains one of its greatest SecGens. https://t.co/CxPxtYNZIo
— Shashi Tharoor (@ShashiTharoor) August 18, 2018
Ghana's President Nana Akufo-Addo on Saturday declared a week of mourning to pay homage to Kofi Annan. Describing Annan as a 'consummate' diplomat, Akufo-Addo said in a statement that Ghana was 'deeply saddened' by news of his death in Switzerland on Saturday after a short illness.
For all the Latest World News, Download News Nation Android and iOS Mobile Apps.
Kofi Annan Former UN Chief Kofi Annan Kofi Annan Dead

redpajama_set_name: RedPajamaCommonCrawl


text:
Petsburgh USA is an American television program about pets, that premiered in 1998 on Animal Planet.

It was hosted by Brianne Leary and was filmed at a soundstage in the Disney-MGM Studios at the Walt Disney World Resort in Lake Buena Vista, Florida. The first season taped 65 episodes. A second season, taped in 1999, also consisted of 65 episodes.

References

External links

Animal Planet original programming
1998 American television series debuts


If your scanner is not working, odds are that your scanner lamp is burned out and needs to be replaced. In order to replace the scanner lamp, the scanner tray and glass must be removed from the printer.
Note: The scanner lamp is very fragile and must be handled with care.
Carefully wedge the flathead 3/32" screwdriver on the outer groove of the control panel faceplate.
Follow the perimeter of the groove with the flathead 3/32" screwdriver making sure to gently pry and lift upward until the control panel faceplate comes off.
Take your time prying off the control panel faceplate. If too much pressure is applied, the control panel faceplate can break.
Once the control panel faceplate is off, look for the Lock/Unlock tab located underneath the off button.
To unlock and release the control panel, insert the flathead 3/32" screwdriver into the tab and carefully push down. The control panel will then separate from the printer's base by sliding it downward a little.
Underneath the control panel will be a flat grey ribbon cable. This cable is attached at the base of the green control board with the other end of the cable located on the back side of the printer's base.
Carefully disconnect both ends of the flat grey ribbon cable to release the control panel in its entirety.
Only pull from the connector portion of the cable, as pulling on the wires may damage them.
Lift open the scanner lid and locate a black tab located at the center of the scanner bed.
Remove all four silver screws from the corners of the scanner glass cover with a T10 Torx Screwdriver.
Organization is everything. Remember to have your iFixit Magnetic Work Mat next to you. It will help keep screws organized and in place.
Remove the scanner head from the scanner tray by lifting the scanner head up and pulling the black tab from the gray drive belt.
Turn the scanner upside down and place it on a level surface.
Remove the small silver screw in the scanner head's control panel.
Remove the control panel from the scanner head.
Remove the black face plate from the scanner head. Push on the two black tabs located on opposite sides of the scanner head. One of them is located in the groove the control panel normally rests in.
Carefully twist white scanner lamp support out of its carriage and replace it with a new one.
Note: Scanner lamps are fragile and should be handled with care.


text:
Learn how the stages of ITIL® fit together and demonstrate your understanding
ITIL® Managing Across the Lifecycle leads to the ITIL® Expert certification, which proves that the holder has achieved a full understanding of the ITIL® service lifecycle.
Our ITIL® MALC course lasts 5 days, during which you'll be learning through instructor-led training and class exercises how the processes and practices of ITIL® can be combined into one service management approach.
ITIL® Expert Level
Learn about core concepts and terminologies used in ITIL® Service Lifecycle
Manage the interactions between different phases of the service lifecycle to enhance the service quality
Deliver effective services across the service lifecycle
Get to know about how different phases interact with each other so that the process runs smoothly
Identify the need for implementing and maintaining the core concepts used in service lifecycle
You must have at least 17 ITIL credits.
The course is intended for anybody who wishes to work in a service management role and who have achieved at least 17 credits in the ITIL scheme. This includes but is not limited to CIOs, IT managers, supervisors and IT operations or development practitioners.
ITIL® MALC
The ITIL® MALC exam certifies that candidates have the skills to support service delivery by bridging the lifecycle stages. It is multiple choice and consists of 10 questions which are based on a case study. The duration is 120 minutes, and the pass mark is 35/50 or 70%. It is closed book. After passing the exam you will receive the ITIL® Expert qualification.
120 minutes' duration
*After completing 4 days of classroom training and successfully gaining 17 ITIL® credits, the fifth day of this course is a flexible exam preparation day to complete at your convenience in order to prepare you to take and pass your MALC exam online.
Understand how the life cycle stages can be integrated across the service lifecycle
Gain competency in managing services across the service lifecycle
Prepare for the ITIL® MALC exam
Key Concepts of the Service Lifecycle
Communication & Stakeholder Management
Integrating Service Management Processes across the Lifecycle
Managing Services across the Lifecycle
Challenges, Critical Success Factors and Risks of Service Lifecycle Stages
Governance, Roles, People, Competence and the Organization
Implementing and Improving Service Capability
ITIL® Service Lifecycle - Managing Across The Lifecycle 06/04/2020 https://www.itil.org.uk/training/itil-expert-level-courses/itil-managing-across-the-lifecycle-malc-training#event523244 Scheduled Worcester
5 Days 2020-04-06 2020-04-10
About Worcester
Worcester is a city in Worcestershire, England. It is 31 miles south-west of Birmingham and 27 miles north of Gloucester. The Fight of Worcester was the concluding battle of the English Civil War, where Oliver Cromwell's New Model Army conquered King Charles I's, Cavaliers. Worcester is well-known as the home of Royal Worcester Porcelain, Lea & Perrins, composer Edward Elgar, the University of Worcester and manufacturers of traditional sauce of Worcestershire.
The Roman settlement at the place passes unmentioned by Ptolemy's Geography, the Antonine Itinerary and the Register of Dignitaries but would have developed on the road opened between Viroconium(Wroxeter) and Glevum (Gloucester) in the ad 40s and 50s.
From the year 2003 to 2007 the Conservative party had a majority in the council, but they lost in a by-election to Labour due to which council had no overall control. The Conservatives remained with the most seats overall with 17 out of 35 seats in the 2008 election.
Worcester has one member in a Parliament whose name is Robin Walker which belongs to Conservative Party, who represents the Worcester constituency during the general election in 2010.
The County of Worcestershire's local government arrangement is formed of a non-metropolitan county council and six non-metropolitan district councils, with Worcester City Council being the district council for most of Worcester, with a small area of the St. Peters suburb falling within the neighbouring Council.
ITIL® Managing Across the Lifecycle Availability
Training Locations at which ITIL® Managing Across the Lifecycle is presently scheduled at:


text:
MMSD students rally for LGBT+ youth
May 27, 2021 by Jonah Chester and WORT News Department
WORT 89.9FM Madison · MMSD students rally for LGBT+ youth
Despite a steady downpour of rain, Madison Metropolitan School District faculty, students and administrators rallied outside the district's administration building downtown today. About two dozen people huddled under tents in the building's parking lot, while even more attended virtually via a livestream.
The demonstration to support LGBT+ students comes as transgender youths find themselves targeted by Republican legislators across the country.
Just yesterday, Wisconsin's lawmakers considered public testimony on a pair of bills barring trans students from participating in girls and women's sports. According to the Milwaukee Journal Sentinel, those bills could be before the Republican-controlled legislature for a vote next month.
Earlier this week, Madison's school board unanimously passed a resolution opposing the legislation. But Amira Pierotti, a leader of Memorial High School's Gender Equity Association, says that action should have come much sooner.
"We appreciate the school board's statement in support of trans students in sports, but our district leaders waited too long to respond to the anti-trans bill in the Wisconsin state legislature. We must be proactive in our support of our most vulnerable populations," Pierotti told the crowd.
So far this year, at least 35 bills barring trans youth's access to gender-affirming medical care have been introduced in state legislatures across the country. That's according to the Human Rights Campaign, which tracks legislation targeting LGBT communities.
During today's rally, Pierotti issued a series of demands on behalf of the district's LGBT+ advocacy groups.
Those include, among other things, more transparency in a pending lawsuit over the district's gender identity guidance, engaging in monthly meetings with LGBT+ students and providing resources and affirming support for the district's LGBT+ youth.
Said Pierotti: "LGBTQ+ identities, history and contributions to society are left out of the curriculum. LGBTQ+ youth are tired of educating their teachers."
Speaking at today's rally, MMSD Superintendent Carlton Jenkins affirmed his support for the demands.
"As I continue to think about what life is about, and why we're really here today, it boils down to a simple thing — human decency," he said. "And the level of violence that comes just because people are ignorant? We've got to do a better job of educating and advocating. As you educate, you advocate."
The rally, an annual event organized by students across the country, typically carries the title of the "Day of Silence." This year, Madison's organizers opted for a name change — and it's now the "Breaking the Silence" rally.
PHOTO: MMSD Superintendent Carlton Jenkins addresses students and faculty / Jonah Chester
Protesters rally against legislation barring…
State assembly passes bills barring trans students…
State lawmakers propose barring trans student…
Governor Evers floats new Pride proposals, priorities
Breaking News, WORT Local News Amira Pierotti, breaking the silence, Carlton Jenkins, Day of Silence, Gender Equity Association, LGBT, MMSD


text:
Q: RunAnalyticsReport returning incorrect rows I have a problem with the RightNow SOAP API, specifically requesting a RunAnalyticsReport, the code is below. The export works when I set the report to return a fixed period, e.g. 4 or 6 hours. When I set the report to require a start date (AlertClosedAfter in this case), it timed out. Then I re-ran it after disabling the start date requirement and it only returns the rows that are created after the time out, no matter if I set any filters or not (I'm pretty sure my filter is wrong, so if you can help me with that it would be perfect). So now every time I run it it only returns the rows since the time out. Do you guys have any ideas? Thanks in advance!
Here's the code:
<?xml version="1.0"?>
<SOAP-ENV:Envelope
xmlns:SOAP-ENV="http://schemas.xmlsoap.org/soap/envelope/"
xmlns:v1="urn:messages.ws.rightnow.com/v1_2"
xmlns:v11="urn:base.ws.rightnow.com/v1_2"
xmlns:ns2="urn:objects.ws.rightnow.com/v1_2"
xmlns:ns3="urn:generic.ws.rightnow.com/v1_2"
xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"
xmlns:ns4="http://docs.oasis-open.org/wss/2004/01/oasis-200401-wss-wssecurity-secext-1.0.xsd">
<SOAP-ENV:Header>
<v1:ClientInfoHeader>
<v1:AppID>Create</v1:AppID>
</v1:ClientInfoHeader>
<ns4:Security SOAP-ENV:mustUnderstand="1">
<UsernameToken xsi:type="ns4:UsernameToken">
<Username>username</Username>
<Password>password</Password>
</UsernameToken>
</ns4:Security>
</SOAP-ENV:Header>
<SOAP-ENV:Body>
<n0:GetResponse xmlns:n0="urn:messages.ws.rightnow.com/v1_2" xmlns:n2="urn:base.ws.rightnow.com/v1_2" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:n1=
"urn:objects.ws.rightnow.com/v1_2">
<n0:RNObjectsResult>
<n0 :RNObjects xsi:type="n1:AnalyticsReport">
<n2:ID id="103151"></n2:ID>
<n1:Filters xsi:type="n1:AnalyticsReportFilter">
<n1:Name>AlertsClosedAfter</n1:Name>
<n1:Operator>
<n2:ID id="6"></n2:ID>
<n2:Name>></n2:Name>
</n1:Operator>
<n1:Values>29/01/2015 13:40</n1:Values>
<n1:Attributes>
<n1:Editable>true</n1:Editable>
<n1:Required>false</n1:Required>
</n1:Attributes>
<n1:DataType>
<n2:ID id="4"></n2:ID>
<n2:Name>DATETIME</n2:Name>
</n1:DataType>
<n1:Prompt>AlertsClosedAfter</n1:Prompt>
</n1:Filters>
<n1:Filters xsi:type="n1:AnalyticsReportFilter">
<n1:Name>Lead Rejection Reason</n1:Name>
<n1:Operator>
<n2:ID id="1"></n2:ID>
<n2:Name>=</n2:Name>
</n1:Operator>
<n1:Values>~any~</n1:Values>
<n1:Attributes>
<n1:Editable>true</n1:Editable>
<n1:Required>false</n1:Required>
</n1:Attributes>
<n1:DataType>
<n2:ID id="1"></n2:ID>
<n2:Name>MENU</n2:Name>
</n1:DataType>
<n1:Prompt>Lead Rejection Reason</n1:Prompt>
</n1:Filters>
</n0:RNObjects>
</n0:RNObjectsResult>
</n0:GetResponse>
</SOAP-ENV:Body>
</SOAP-ENV:Envelope>

A: I believe the format for dates is:
<year-month-day>T<24 hour time>Z

For example:
2015-01-29T13:40:00Z

Change your AlertsClosedAfter filter value to something like that.

redpajama_set_name: RedPajamaStackExchange


Home » Your pet has bad breath?
The first cause of bad breath is plaque.
• Toothpaste with toothbrush or fingers (also available as a spray without brushing or rinsing for dogs that do not allow to be touched).
• Menthol liquid solution to be added to its water.
• Buffalo skin bones, pork ears.
• Hard rubber toys to massage the gums and clean the teeth.
The accumulation of plaque can cause bacterial infections, gingivitis and eventually can lead to teeth removal.
You will find all these products in the shop.


text:
First Kid (1996)
Some say that to be the leader of a country is one of the loneliest jobs in the world. But being the child of a world leader can be doubly so. Constantly surrounded by security officers, restricted in movements and having almost every waking moment carefully monitored makes normalcy an impossibility. No one knows this better than young Luke Davenport, the son of U.S. President Davenport. He vents his loneliness, frustration and feelings of isolation from family and friends by being a brat to his private Secret Service agent. When the agent snaps from the strain in front of the First Lady, a new agent is assigned to Luke. He turns out to be the enormous Sam Simms, a bit of a rogue who managed to rise through the ranks by sheer determination rather than strict adherence to Secret-Service protocol. At first, Luke tries all his old tricks upon Sam. But instead of getting angry, Sam seems to actually understand.
The movie First Kid, released in 1996, features 16 songs from artists like Chill Rob G, Lalah Hathaway, Sly and the Family Stone and Sounds of Blackness. What is your favorite song from First Kid?
Songs from First Kid
Chill Rob G
Anyone Can Be A Hero
Lalah Hathaway
I Want to Take You Higher
Eel Pie Blues
I Got You Babe
The Pressure
Sounds of Blackness
Girl U Want
Your Sweetness (Is My Weakness)
The Good Girls
II'll Never Stop Loving You
J'son
How How
12 Gauge Soul
Hungry Crocodiles
I Can Love You Like That
The Diamond Mine with Joey Rishey
We Got It Goin' On
Darrell Black
The Sha-Shees
First Kid Questions and Comments
Realm of Souls
Looking for Kitty
Whispering Jack: In Concert
Ainthu Ainthu Ainthu
Krippendorf's Tribe
Two Ninas
An Officer and a Gentleman


Please Call Us For Catering Events & Birthday Parties!
Welcome to Mama's Pie & Pasta! We are a family-run restaurant in Deerfield Beach. We are proud to have been serving authentic Italian cuisine and Pizza in South Florida for the last 35 years, and now we are in Deerfield Beach, come to visit us. At Mama's Pie & Pasta, our menu of traditional Italian cuisine along with several daily specials, are sure to please! More food choices on our online menu, order online for Delivery or Pick-up! We look forward to welcoming you at our restaurant. Located at West Hillsboro Blvd and North Milltary Trl, near Interstate 35. Few minuties driving from Century Plaza Shopping Center.


text:
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	<META NAME="CREATED" CONTENT="20090128;142000000000000">
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redpajama_set_name: RedPajamaGithub


text:
Home DC Universe DC to Commemorate the 1000th Issue of ACTION COMICS with Star-Studded Celebration in 2018
DC to Commemorate the 1000th Issue of ACTION COMICS with Star-Studded Celebration in 2018
During DC's kick off "Meet the Publishers" panel at New York Comic Con today, Publishers Dan DiDio and Jim Lee announced there will be a star-studded celebration to commemorate the 1000th issue of ACTION COMICS, the longest running and first-ever superhero comic to reach 1000! The Publishers also revealed a new commemorative logo for the celebration.
In March 2018, DC will publish several special titles to honor the milestone:
New hardcover book: Join us for an 80th anniversary celebration of the single most important comic in American history: ACTION COMICS #1 and the birth of Superman. Revisit classic stories from over the decades featuring the debuts of Superman, Supergirl, Brainiac, the Fortress of Solitude, the Human Target and so much more. Read Superman stories by generations of top writers and artists and enjoy sparkling essays from literary wizards who've won Pulitzers and become bestsellers, including Jules Feiffer. Plus, a historical essay by guest editor Paul Levitz, and all 1000 ACTION covers collected in a new poster. And as a bonus, an UNPUBLISHED 1940s Superman tale believed to be by Jerry Siegel and the Joe Shuster studio salvaged from the DC files fifty years ago and hidden away until now.
ACTION COMICS #1000, written by Pete Tomasi and Dan Jurgens, will be published as a special, oversized edition featuring an all-star talent line-up writing back-up stories, including a story co-written by Geoff Johns and Superman film director, Richard Donner.
About ACTION COMICS 1000
In 1938, two kids from Cleveland, Ohio – Joe Shushter and Jerry Siegel – created a character they thought would represent the best of humanity in a troubled time with few beacons of hope for the future. That character went on to become one of the brightest and most well-known creations in all of pop culture: Superman. And it all began in ACTION COMICS. DC is proud to celebrate the 1000th edition of this seminal title that created the entire superhero genre – bringing joy, hope and inspiration to Superman fans around the world for 80 years.
Action Comics DC Comics
Bluefin Announces Bandai Hobby, Tamashii Nations, Sen-Ti-Nel and TruForce NYCC Exclusives
Toy Fair 2016 – NECA's Aliens, Predators and Much Much More
Factory Entertainment's SDCC Exclusive George R. R. Martin Deluxe Talking Plush
June Matty sale reminder


By Sara Castellanos. Source: WSJ.
CAMBRIDGE, Mass. — Hologram-like images and virtual reality could revolutionize the way corporations solve problems within their supply chains, because data that would otherwise be obscured in databases and complex mathematical models would be easier to visualize, says a researcher at the Massachusetts Institute of Technology.
Dr. Matthias Winkenbach, an MIT researcher with a Ph.D. in economics, envisions a future where supply chain managers wearing augmented or virtual reality headsets could make quicker decisions, save money and maximize their productivity.
Augmented reality superimposes digital content including hologram-like images onto a user's view of the real world. Virtual reality is a computer-generated simulation of an environment. Dr. Winkenbach shared possible scenarios for both technologies.
For example, he said, a supply chain manager who would normally run a traffic simulation model in a computer could wear an augmented reality headset, tap on a hologram-like image of a truck in the field, and a dashboard display could show data ranging from items in the truck to customer addresses and real-time weather and traffic conditions.
Supply chain managers interested in analyzing performance problems with conveyer belts in warehouses overseas could wear a virtual reality headset and immerse themselves in the real-time environment to solve problems without spending time and money traveling to the physical location.
Those scenarios are still at least three to five years away, but augmented and virtual reality would be a "more rich way" for supply chain managers to visualize information and understand problems, he said.
"A few years down the road we believe you could take this functionality anywhere. You'd just need a decent internet connection and an AR headset to pull up any … supply chain and logistics data anywhere in the world for whoever wants it," said Dr. Winkenbach, director at MIT's Megacity Logistics Lab at the Center for Transportation and Logistics.
He spoke Tuesday at MIT's annual Crossroads Conference, along with other MIT scientists and professors, who gave presentations about additive manufacturing, blockchain and other technologies that could transform supply chain management.
To that end, he's embarking on building a Visual Analytics Lab on MIT's campus, where corporations and researchers could experiment with visualizing supply chain-related data using technologies including augmented and virtual reality.
The lab is expected to be open for research and experimentation to both corporations and researchers across MIT departments beginning late 2017.
Technologies that could allow supply chain managers to see and experience problems in the field without actually being there could be game-changing because global supply chains are expensive to run, said Tom Linton, chief procurement and supply chain officer for Flextronics International Ltd., which designs, manufactures and ships products for original equipment manufacturers.
It would be a paradigm shift for supply chain managers who would need to get comfortable with wearing headsets and interacting with visualization technologies, he said.
Dr. Winkenbach said augmented and virtual reality also need to gain more traction in the consumer sector before hardware and software that would allow supply chain managers to visualize data in 3-D gets advanced enough to be used inside corporations. Makers of hardware devices tend to improve the technology for commercial use when it catches on in the consumer sector, he said. For example, the iPhone excelled as a consumer product, and is now a business tool that's frequently used in the commercial sector. "Without it catching up on the consumer side, it's going to be hard … for it to be technologically robust and advanced enough to create value in a corporate environment," he said.
But plans for the 500-square-foot Visual Analytics Lab are underway, and Dr. Winkenbach is currently soliciting corporations to help fund the $2 million to $3 million lab.
Dr. Winkenbach plans to work with a team of MIT researchers with experience in data science, quantitative modeling, software development, machine learning, supply chain logistics and other areas to build out the technologies in the lab.
With corporate partnerships, these researchers would take massive amounts of corporate data such as customer data and product information, and develop software applications that could turn the data into 3-D representations.
Augmented reality is already entering enterprises, although most use cases are mostly limited to the factory floor.
For example, AGCO Corp., a manufacturer of agricultural equipment, is experimenting this year with computer-generated hologram-like images to help guide workers wearing augmented reality headsets through the process of welding 30-foot booms to chemical sprayers.
About 14.4 million U.S. workers will use "smart glasses," such as Google Glass and HoloLens, in 2025, up from 400,000 this year, according to Forrester Research Inc. Large companies will spend $3.6 billion on smart glasses in 2025, up from $6 million in 2016, according to Forrester. The global 3-D imaging market, which includes holograms, is expected to grow from $4.9 billion in 2015 to $16.6 billion by 2020, according to Markets and Markets, a research firm in India.


text:
Home Health & Medicine Nanobodies, produced by llamas, shows promise against Covid-19: Scientists
Nanobodies, produced by llamas, shows promise against Covid-19: Scientists
Antibody produced by llamas, a domesticated South American camelid, will be helpful to treat Covid-19 patients and also, that can be taken by patients as a nasal spray, instead of an injection.
Nanobodies, simple form of antibody, generated by llamas and camels can effectively target the SARS-CoV-2 virus that causes Covid-19, Scientists at the Rosalind Franklin Institute in the UK said.
Scientists could come to know that, short chains of the molecules, which can be produced in large quantities in the laboratory, significantly reduced signs of the Covid-19 disease when administered to infected animals.
The results have been published in the journal Nature Communication.
The research has "significant potential for both the prevention and treatment of Covid-19", said Public Health England.
Prof Naismith, who is one of the lead researchers and director of the Rosalind Franklin Institute in Oxfordshire, explained that coronavirus-infected rodents treated with the new nanobody nasal spray fully recovered within six days, reported BBC.
The treatment has, so far, been tested only in those lab animals, but Public Health England said it was among the "most effective SARS-CoV-2 neutralizing agents" it had ever tested.
"Nanobodies have a number of advantages over human antibodies. They are cheaper to produce and can be delivered directly to the airways through a nebuliser or nasal spray, so can be self-administered at home rather than needing an injection. This could have benefits in terms of ease of use by patients but it also gets the treatment directly to the site of infection in the respiratory tract," said lead author Professor Ray Owens, head of protein production at the Institute.
COVID Treatment
Nanobodies
Previous articleOdisha CM distributes Smart Health Card in Bolangir District
Next articleDharmendra Pradhan urges to bridge digital divide & reach the unreached to bring greater inclusion in education
Odisha Reports Nearly 5000 Covid-19 Cases In A Single Day
India Reports 175 New Cases Of Omicron Variant; Total Tally Rises To 1700
99.78% Oxygen Beds In Hospitals Are Still Vacant: CM Delhi


Relaxation for himself and his two bachelor brothers (George and Henry) was Edward of Wales' frankly stated purpose in fitting up a country place at Fort Belvedere, near London. Each of Their Royal Highnesses will have a suite. Parties are expected to be merry. Last week steps were taken to convince the British public that this Royal whoopee will be harmless.
1) No unmarried women will be entertained at Fort Belvedere.


For brighter, even looking skin with more refined pores.
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Michigan Hospital to Pay $74.4K to Settle Religious Discrimination Lawsuit
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A hospital in Michigan will pay more than $74,000 to settle a religious discrimination lawsuit filed by federal officials.
Memorial Healthcare, which operates a hospital in Owosso, Mich., will pay $74,418 and furnish other relief to settle a religious discrimination lawsuit filed by the U.S. Equal Employment Opportunity Commission (EEOC).
The EEOC alleged that Memorial violated federal law by refusing to hire a medical transcriptionist because of her religious beliefs against receiving flu shots and refusing to accommodate those beliefs.
According to the EEOC's suit, Memorial refused to accommodate the sincerely held religious requirement of the transcriptionist, whose Christian beliefs require her to forgo inoculations. The transcriptionist offered to wear a mask during flu season. This was an acceptable alternative under hospital policy for those with medical problems with the flu shot, but Memorial refused to extend it to her. It then rescinded her offer of employment.
Such actions violate Title VII of the Civil Rights Act of 1964, which requires employers to provide reasonable accommodations for religious observances and beliefs, absent undue hardship. The EEOC filed its suit (Civil Action No. 2:18-cv-10523) in U.S. District Court for the Eastern District of Michigan) after first attempting to reach a pre-litigation settlement through its conciliation process.
Under the consent decree settling the suit, Memorial confirms that it now permits those with religious objections to wear masks in lieu of having a flu vaccine. The hospital will also train managerial staff participating in the accommodation process on the religious accommodation policy. In addition, the transcriptionist will receive $34,418 in back pay, along with $20,000 in compensatory damages and $20,000 in punitive damages.
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Categories: Midwest NewsTopics: $74.4K lawsuit settlement, Memorial Healthcare, religious discrimination lawsuit, U.S. Equal Employment Opportunity Commission (EEOC)
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Boonedoggle says:
Shouldn't any hospital, knowingly employing workers who refuse to take the flu vaccine be required to adequately disclose this increased health risk to prospective patients?
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Growing up surrounded by Latinos, I never perceived how my culture didn't apply to everyone.
During third grade, I rushed to complete a personality project about a fellow classmate which was comprised of writing an essay on a randomly selected partner after gathering information through a simple interview. In retrospect, I see the questions were so easy, they seemed too trivial for even an online dating profile: they asked one's favorite color, favorite animal, and the all-too-elusive favorite food.
I was a good kid and asked most questions, but I forgot to ask about my partner's favorite food. I didn't realize this until I sat down to type my essay and reviewed my notes—the day before my essay's due date.
In a logic that reflected how simple and self-resolving the world seems to a child, I smirked as I typed in what I figured to be everyone's favorite food, pozole. This is a traditional Mexican soup consisting of pork, chili, hominy and various seasonings; it is packed with flavor that demands to be experienced.
However, my partner was white. After reading my essay, he ran up to the teacher and complained he had no idea what pozole was. I didn't have time to pity the fact that he had not experienced life fully at the age of 7, because soon my essay solution had unraveled. I faced the consequences, but I was more troubled by how my partner didn't know what pozole was.
I grew up eating with this dish, and all my friends knew what it is.
This was the first time I truly perceived there were cultural and racial divisions. My partner didn't know what pozole was because he is white and didn't have immigrant parents, while most of my friends were Latinos who also took our heritage for granted, or as the standard. We were constantly mingling and united in daily life, from going to the Mexican supermarkets in East Los Angeles to growing up watching Spanish soap operas. While these may seem like generalizations, and many Latinos are much more Americanized or simply don't relate to these aspects of my life, these are experiences that resonate with many people I know.
Even though I am still surrounded by people from similar backgrounds, the mere consideration of college life raises concerns about whether I will be faced with the same dilemma I experienced in third grade; that of others not understanding parts of my life that are so common and frequent they fade into the background, afterthoughts that stubbornly resurface when I realize some do not understand them.
It dawns on me as I prepare for college that Latinos are the "other" in the statistics reported in guidebooks. Our numbers are usually lumped into together; we are an institutional asset tucked into the brochures to add diversity.
When surrounded by white people, I feel the need to make sure everyone knows I am a Latina; I feel I need to impose my culture upon them, just as theirs feels imposed upon me.
Not everyone will know what pozole is wherever it is I end up for college, but I won't cut corners in keeping in touch with my background and being vocal about who I am—unapologetically, a Latina.


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I'm all set up ready to check my new scope out.
Well I'm back in, bloody freezing, but happy.
Managed to bag 6 new Messier's for the list last night, M's 49,58,59,60,61 and 85. So 47 now imaged and 4 new visuals!
Well done Ron. Only two behind me now.
Still got a few in the Virgo galaxy group to get this month, hope it's clear Saturday night!!


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Cranston Fire knocked out electricity miles away; huge generators can die if Anza-area homes use AC
Colin Atagi Corinne S Kennedy
Palm Springs Desert Sun
Hundreds of San Jacinto Mountain residents, who are living with intermittent electrical service as a result of the still-burning Cranston Fire, turned out Tuesday night to a community meeting with fire and utility officials in the hopes of learning when full power might be restored.
A utility cooperative is using truck-size generators to power San Jacinto Mountain communities that lost electricity because of the Cranston Fire miles away, but no one can use air conditioning and hundreds of residents are only allotted about four hours of service per day.
About 1,500 customers have limited electricity in Aguanga, Garner Valley and Lake Riverside, according to the Anza Electric Cooperative. About 3,500 customers in Anza and Pinyon Pines have round-the-clock service, but that could change if there are mechanical issues with the generators, interruptions in fuel deliveries to the noisy machines or -- most importantly -- people use air conditioning even though temperatures are inching toward 100 degrees in the area.
"It's very limited generation we've got and we requested everyone curtail their load as much as possible," said Kevin Short, Anza Electric's general manager. "Until we get our full system restored, we can't consider this to be over."
He added, "If we lost any of those critical pieces, all bets are off."
Full power can't be restored until Anza Electric and SoCal Edison both make repairs to their damaged infrastructure.
SoCal Edison lost 126 utility poles, but "a large number of those" have already been replaced, spokesman Steven Conroy said.
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"If we make progress we've seen, we'll have our side of repairs completed Wednesday or Thursday," Conroy said.
A 7 p.m. town hall meeting took place Tuesday at Anza Community Hall, 56-630 Highway 371.
U.S. Rep. Raul Ruiz, who represents the affected region, was there and he thanked those in attendance for abiding by evacuation orders at the height of the blaze.
"Those who do not evacuate put themselves and the firefighters at risk," the Palm Desert Democrat said, adding that he was inspired by "the way the community came together."
Besides Ruiz, officials from CAL FIRE/Riverside County Fire Department, the California Department of Transportation and the Riverside County Sheriff's Department provided updates, as well.
CalTrans told residents its crews had cleared 300 damaged trees and that assessments would be conducted on Wednesday to determine resident safety, specifically in the event of significant rain, which increases the risk of flooding and landslides.
As for the power, Chris Abel with Southern California Edison, told those in attendance: "We have about 200 employees working up here for SoCal Edison."
He added that there are also twice as many contractors working, as well.
"We hope to have everyone energized very soon. We're working as hard as we can," Abel said.
Paradise Valley Cafe owner Neel Joshi said power at his restaurant has been out since July 25, when the Cranston Fire started, and he had been told it would be out for another 10 days.
The cafe had power for a few hours on Tuesday. Employees came in to clean out the kitchen and empty the fridge and freezer of spoiled food.
Joshi said he hopes the cafe will be able to open for a few hours Friday, and that staff would use Wednesday and Thursday to clean and prep.
"We'll do the best we can," he said. "What else can we do?"
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Despite the difficulties, Joshi was optimistic.
"It could be worse. We could have burned down," he said. "We got lucky."
Pinyon Pines residents rushed to the Coachella Valley to buy generators after the Cranston Fire cut electricity, and they have them on standby in case they lose power again.
Most have swamp coolers and they occasionally use their home electronics. Otherwise, they're adhering to Anza Electric's request not to use air conditioners.
"If people start turning on their air conditioners, it hurts all of us," said Jimmy Viglione, 76, who's been using social media to remind neighbors not to use air conditioners.
Anyone living in the mountains is self sufficient and the current situation hasn't really fazed many people, said Pinyon Pines resident Tom Mennig, 68.
"We're getting by. It's not the end of the world," he said.
Mennig purchased a 7,000-watt generator Thursday when it appeared electricity would be out indefinitely. It would've been enough to power his home for 24 hours.
Mennig said he's content with his swamp cooler and he's not in any rush to use electronics during the requested electricity conservation period.
"The TV doesn't have that big a draw," he said.
Viglione said the first couple days without electricity were "bananas," but power has since run smoothly outside of a couple hiccups, like a 30-minute outage Tuesday afternoon when Anza Electric switched generators.
He said the cooperative has been keeping residents informed and praised its efforts to keep power running.
Viglione said neighbors have been more concerned about not getting their mail. It's being stored at a U.S. Post Office in San Jacinto due to road closures in the area.
Neighbors have had to drive to Palm Desert to send mail and they've tried to help each other in the process.
"I'll let them know I'm going down the hill and ask if everyone needs anything," Viglione said.
Walter Magana, a supervisor at the San Jacinto Post Office, said the fire has prevented mail from getting to the mountain communities. Anyone who makes the special trip to San Jacinto to retrieve mail can pick up other people's letters and packages as long as they provide a note showing they have permission, Magana said.
People from all across the power outage area gathered at the Anza Community Hall, which had been giving out supplies since Wednesday.
Residents on Tuesday came by to catch up with friends and neighbors, eat a hot meal and charge their cell phones. They could also get ice, water, clothing, canned goods and household supplies for free.
Bill and Noel Donahue, who live in the unincorporated community of Sage, have spearheaded operations at the community hall.
Bill Donahue said the couple became involved in the community seven years ago and formed a nonprofit that operates out of the community hall and feeds 70 to 100 families a week "when there is power."
Since the fires broke out, he said they've seen about 1,500 people a day come through in need of supplies. One of the greatest needs is water. Residents of the communities around Anza all rely on wells, and when the power is out, they lose their ability to pump water.
"Once you lose your well, all the help is usually in Hemet or down in the desert," he said. "The need here is phenomenal."
Donahue estimated he and other volunteers had given out more than 10,000 cases of water in the past week.
"You don't think how important it is until you don't have it," he said. "But when you don't have water in these heat conditions, it's critical."
Many of the people in the community are also on fixed incomes, making it difficult for them to replace spoiled food.
Donahue said the community response has been incredible and generous and that people have donated time and supplies to others in need. He said the majority of donations have come from community members. One person even bought a refrigerated truck for him to use for the duration of the power outage, which he called a "lifesaver."
People with trucks have also been driving food, water and ice to shut-ins in the area.
"Every person in this community that was prepared and had a generator has been reaching back to help someone else," he said. "The response has been overwhelming."
He also said the Walmart in Temecula donated food, even before the Red Cross got to the community with supplies.
Donahue said living without electricity for an extended period of time was difficult but he had seen it bring out the best in people.
"The silver lining in this is it really broke down these factions," he said. "You start to see what is really important. The community is really coming together."
The Cranston Fire erupted July 25 off Highway 74, west of Mountain Center. It charred more than 13,000 acres and destroyed seven buildings before slowing down over the weekend.
As of 7:30 p.m. Tuesday, according to the U.S. Forest Service- San Bernardino National Forest, the Cranston Fire was 89 percent contained with 13,139 ares scorched, 296 people still evacuated and 90 structures still threatened.
Temecula resident Brandon McGlover, 32, is charged with starting the Cranston Fire, along with nine other fires in the Idyllwild, Anza and Sage areas. He pleaded not guilty to the charges on Friday.
The outage began last week after the fire damaged about two miles of Southern California Edison transmission lines near the blaze's point of origin.
Electricity initially went out to the entire area, but power was restored Saturday to Anza and Pinyon Pines, Short said.
Efforts to extinguish the fire are expected to cost at least $16 million, Cal Fire Capt. Fernando Herrera said Tuesday morning.
At least another $5 million was being spent to repair infrastructure along area highways, including guardrails, pavement and signs, according to Caltrans.
As of Tuesday, firefighters had contained 82 percent of the fire's perimeter.
Officials previously estimated full containment would be reached Aug. 9, but they didn't rule out containing the blaze earlier.
"There's always that possibility," Herrera said.
Desert Sun reporter Geraldine Estevez contributed.