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Project acronym BIOCCORA
Project Full biomechanical characterization of the coronary atherosclerotic plaque: biomechanics meets imaging
Researcher (PI) Jolanda Wentzel
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Summary Myocardial infarction is responsible for nearly 40% of the mortality in the western world and is mainly triggered by rupture of vulnerable atherosclerotic plaques in the coronary arteries. Biomechanical parameters play a major role in the generation and rupture of vulnerable plaques. I was the first to show the relationship between shear stress – one of the biomechanical parameters - and plaque formation in human coronary arteries in vivo. This accomplishment was achieved by the development of a new 3D reconstruction technique for (human) coronary arteries in vivo. This reconstruction technique allowed assessment of shear stress by computational fluid dynamics and thereby opened new avenues for serial studies on the role of biomechanical parameters in cardiovascular disease. However, these reconstructions lack information on the vessel wall composition, which is essential for stress computations in the vessel wall. Recent developments in intravascular image technologies allow visualization of one or more of the different plaque components. Therefore, advances in image fusion are required to merge the different plaque components into one single 3D vulnerable plaque reconstruction. I will go beyond the state-of-the art in image based modeling by developing novel technology to 3D reconstruct coronary lumen and vessel wall, including plaque composition and assess biomechanical tissue properties allowing for full biomechanical characterization (shear stress and wall stress) of the coronary plaque. The developed technology will be applied to study 1) vulnerable plaque progression, destabilization and rupture, to improve identification of risk on myocardial infarction and 2) predicting treatment outcome of stent implantation by simulating stent deployment, thereby opening a whole new direction in cardiovascular research.
Myocardial infarction is responsible for nearly 40% of the mortality in the western world and is mainly triggered by rupture of vulnerable atherosclerotic plaques in the coronary arteries. Biomechanical parameters play a major role in the generation and rupture of vulnerable plaques. I was the first to show the relationship between shear stress – one of the biomechanical parameters - and plaque formation in human coronary arteries in vivo. This accomplishment was achieved by the development of a new 3D reconstruction technique for (human) coronary arteries in vivo. This reconstruction technique allowed assessment of shear stress by computational fluid dynamics and thereby opened new avenues for serial studies on the role of biomechanical parameters in cardiovascular disease. However, these reconstructions lack information on the vessel wall composition, which is essential for stress computations in the vessel wall. Recent developments in intravascular image technologies allow visualization of one or more of the different plaque components. Therefore, advances in image fusion are required to merge the different plaque components into one single 3D vulnerable plaque reconstruction. I will go beyond the state-of-the art in image based modeling by developing novel technology to 3D reconstruct coronary lumen and vessel wall, including plaque composition and assess biomechanical tissue properties allowing for full biomechanical characterization (shear stress and wall stress) of the coronary plaque. The developed technology will be applied to study 1) vulnerable plaque progression, destabilization and rupture, to improve identification of risk on myocardial infarction and 2) predicting treatment outcome of stent implantation by simulating stent deployment, thereby opening a whole new direction in cardiovascular research.
Project acronym BIOMECHTOOLS
Project Biomechanical diagnostic, pre-planning and outcome tools to improve musculoskeletal surgery
Researcher (PI) Nicolaas Verdonschot
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Summary The aetiology of many musculoskeletal (MS) diseases is related to biomechanical factors. However, the tools to assess the biomechanical condition of patients used by clinicians and researchers are often crude and subjective leading to non-optimal patient analyses and care. In this project innovations related to imaging, sensor technology and biomechanical modelling are utilized to generate versatile, accurate and objective methods to quantify the (pathological) MS condition of the lower extremity of patients in a unique manner. The project will produce advanced diagnostic, pre-planning and outcome tools which allow clinicians and researchers for detailed biomechanical analysis about abnormal tissue deformations, pathological loading of the joints, abnormal stresses in the hard and soft tissues, and aberrant joint kinematics. The key objectives of this proposal are: 1) Develop and validate image-based 3-D volumetric elastographic diagnostic methods that can quantify normal and pathological conditions under dynamic loading and which can be linked to biomechanical modelling tools. 2) Create an ultrasound (US)-based system to assess internal joint kinematics which can be used as a diagnostic tool for clinicians and researchers and is a validation tool for biomechanical modelling. 3) Generate and validate an ambulant functional (force and kinematic) diagnostic system which is easy to use and which can be used to provide input data for biomechanical models. 4) Create and validate a new modelling approach that integrates muscle-models with finite element models at a highly personalized level. 5) Generate biomechanical models which have personalized mechanical properties of the hard and soft tissues. 6) Demonstrate the applicability of the personalized diagnostic and pre-planning platform by application to healthy individuals and patient subjects. Support from the ERC will open new research fields related to biomechanical patient assessment and modeling of MS pathologies.
The aetiology of many musculoskeletal (MS) diseases is related to biomechanical factors. However, the tools to assess the biomechanical condition of patients used by clinicians and researchers are often crude and subjective leading to non-optimal patient analyses and care. In this project innovations related to imaging, sensor technology and biomechanical modelling are utilized to generate versatile, accurate and objective methods to quantify the (pathological) MS condition of the lower extremity of patients in a unique manner. The project will produce advanced diagnostic, pre-planning and outcome tools which allow clinicians and researchers for detailed biomechanical analysis about abnormal tissue deformations, pathological loading of the joints, abnormal stresses in the hard and soft tissues, and aberrant joint kinematics. The key objectives of this proposal are: 1) Develop and validate image-based 3-D volumetric elastographic diagnostic methods that can quantify normal and pathological conditions under dynamic loading and which can be linked to biomechanical modelling tools. 2) Create an ultrasound (US)-based system to assess internal joint kinematics which can be used as a diagnostic tool for clinicians and researchers and is a validation tool for biomechanical modelling. 3) Generate and validate an ambulant functional (force and kinematic) diagnostic system which is easy to use and which can be used to provide input data for biomechanical models. 4) Create and validate a new modelling approach that integrates muscle-models with finite element models at a highly personalized level. 5) Generate biomechanical models which have personalized mechanical properties of the hard and soft tissues. 6) Demonstrate the applicability of the personalized diagnostic and pre-planning platform by application to healthy individuals and patient subjects. Support from the ERC will open new research fields related to biomechanical patient assessment and modeling of MS pathologies.
Project acronym ENVIRONAGE
Project Unravelling environmental exposures in the core axis of ageing
Researcher (PI) Tim Nawrot
Host Institution (HI) UNIVERSITEIT HASSELT
Summary "AGEing is a complex phenotype responsive to a plethora of ENVIRONmental inputs (ENVIRONAGE). Age related conditions in adults often find their origin in risk factors operative in early life. The molecular mechanisms behind these phenomena remain largely unknown. Mitochondria are involved in a variety of critical cell functions, including oxidative energy production and programmed cell death. Recently, I established in a study of 175 newborns, a strong association between mitochondrial DNA content and in utero exposure to particulate air pollution. Telomere length is highly heritable and erosion leads to an increasingly vulnerable structural integrity of the chromosomes. It is considered a marker of overall biological age compared with chronological age. In this regard, I demonstrated the heritability of telomere length and the influence of smoking on telomere erosion. These results support the ENVIRONAGE hypothesis, i.e. that environmental inputs influence biomolecular markers of ageing including mitochondrial function, telomere length along with DNA repair and epigenetics as the 'core axis of ageing'. The aim is to establish prospective epidemiological evidence for molecular mechanisms or early biomarkers, which may underlie the origins or reflect the risk of age-related diseases and to understand its association with other processes and the influence of environmental factors. To this end, I will establish a birth cohort and a cohort in middle-aged and elderly. I measure environmental pollutants, in interaction with parameters that I consider to have an important role in the ageing process (mitochondrial function, telomere length, epigenetics and DNA repair capacity). ENVIRONAGE integrates environmental influences and molecular mechanisms on ageing. The common molecular epidemiological strategies in newborns, middle-aged and elderly to unravel the environmental influence on ageing are groundbreaking."
"AGEing is a complex phenotype responsive to a plethora of ENVIRONmental inputs (ENVIRONAGE). Age related conditions in adults often find their origin in risk factors operative in early life. The molecular mechanisms behind these phenomena remain largely unknown. Mitochondria are involved in a variety of critical cell functions, including oxidative energy production and programmed cell death. Recently, I established in a study of 175 newborns, a strong association between mitochondrial DNA content and in utero exposure to particulate air pollution. Telomere length is highly heritable and erosion leads to an increasingly vulnerable structural integrity of the chromosomes. It is considered a marker of overall biological age compared with chronological age. In this regard, I demonstrated the heritability of telomere length and the influence of smoking on telomere erosion. These results support the ENVIRONAGE hypothesis, i.e. that environmental inputs influence biomolecular markers of ageing including mitochondrial function, telomere length along with DNA repair and epigenetics as the 'core axis of ageing'. The aim is to establish prospective epidemiological evidence for molecular mechanisms or early biomarkers, which may underlie the origins or reflect the risk of age-related diseases and to understand its association with other processes and the influence of environmental factors. To this end, I will establish a birth cohort and a cohort in middle-aged and elderly. I measure environmental pollutants, in interaction with parameters that I consider to have an important role in the ageing process (mitochondrial function, telomere length, epigenetics and DNA repair capacity). ENVIRONAGE integrates environmental influences and molecular mechanisms on ageing. The common molecular epidemiological strategies in newborns, middle-aged and elderly to unravel the environmental influence on ageing are groundbreaking."
Project acronym FWGDekker
Project Novel tools to read and write the epigenetic code in inflammation
Researcher (PI) Frans Jacobus Dekker
Summary Chronic inflammatory diseases, such as, for example, asthma, afflict millions of people worldwide. Nevertheless, the molecular mechanisms that drive inflammation remain poorly understood. Enzymes play a crucial regulatory role in inflammation and represent potential drug targets. Nevertheless, the activities of these enzymes are poorly studied due to a lack of convenient tools for modulation and detection. The importance of this issue is demonstrated by my previous work on small molecule probes for protein palmitoylation. It becomes increasingly clear that the slow advance in the development of chemistry-based methods to study enzyme activity in its physiological context delays drug discovery. To address this problem further, I will develop novel detection methods and small molecule inhibitors to study inflammatory signal transduction pathways. Protein acetylations at lysine residues have a broad regulatory scope. Acetylations of histones form a major part of the histone code for epigenetic regulation of gene-transcription. In addition, reversible acetylations of non-histone proteins proved to be crucial for regulation of nuclear factor kB (NF kB) mediated gene transcription. I aim to study the role of acetylations of histones and other proteins in NF kB mediated gene transcription. Firstly, I will develop a novel bioorthogonal ligation strategy for chemical labeling of protein acetylation in cells (aim 1) by employing the oxidative Heck reaction. Secondly, I will be the first to systematically investigate changes in protein acetylation in response to activation of the NF kB pathway using a proteomics strategy (aim 2). Thirdly, I will develop small molecule inhibitors of acetyltransferases and study their impact on acetylations that regulate the NF kB signaling pathway (aim 3). Ultimately, these newly developed detection methods and small molecule inhibitors open up opportunities for drug discovery aimed at epigenetic regulation of NF kB mediated inflammation.
Chronic inflammatory diseases, such as, for example, asthma, afflict millions of people worldwide. Nevertheless, the molecular mechanisms that drive inflammation remain poorly understood. Enzymes play a crucial regulatory role in inflammation and represent potential drug targets. Nevertheless, the activities of these enzymes are poorly studied due to a lack of convenient tools for modulation and detection. The importance of this issue is demonstrated by my previous work on small molecule probes for protein palmitoylation. It becomes increasingly clear that the slow advance in the development of chemistry-based methods to study enzyme activity in its physiological context delays drug discovery. To address this problem further, I will develop novel detection methods and small molecule inhibitors to study inflammatory signal transduction pathways. Protein acetylations at lysine residues have a broad regulatory scope. Acetylations of histones form a major part of the histone code for epigenetic regulation of gene-transcription. In addition, reversible acetylations of non-histone proteins proved to be crucial for regulation of nuclear factor kB (NF kB) mediated gene transcription. I aim to study the role of acetylations of histones and other proteins in NF kB mediated gene transcription. Firstly, I will develop a novel bioorthogonal ligation strategy for chemical labeling of protein acetylation in cells (aim 1) by employing the oxidative Heck reaction. Secondly, I will be the first to systematically investigate changes in protein acetylation in response to activation of the NF kB pathway using a proteomics strategy (aim 2). Thirdly, I will develop small molecule inhibitors of acetyltransferases and study their impact on acetylations that regulate the NF kB signaling pathway (aim 3). Ultimately, these newly developed detection methods and small molecule inhibitors open up opportunities for drug discovery aimed at epigenetic regulation of NF kB mediated inflammation.
Project acronym GENOMICMEDICINE
Project Towards evidence-based genomic medicine: filling the evidence gaps through modelling studies
Researcher (PI) Anna Caecilia Josephina Wilhelmina Janssens
Host Institution (HI) STICHTING VUMC
Summary At increasingly high rate, genome-wide association and whole genome sequencing studies unravel genetic variants implicated in common diseases such as coronary heart disease, cancer, dementia and type 2 diabetes. One of the major promises is that these advances will lead to more personalized medicine, in which preventive and therapeutic interventions are targeted to individuals based on their genetic profiles. There is increasing interest in the early adoption of novel applications and many commercial applications are already marketed without supporting empirical evidence. Already now, regulatory agencies like the US Food and Drug Administration face substantial gaps in empirical evidence, which hamper proper recommendations. The increasing interest in genomic medicine, the evidence gaps and the scarcity of research budgets are strong incentives to search for novel strategies that make the process of translation research more efficient and effective. This project aims to investigate modelling approaches that can be used to predict the expected outcomes of empirical studies on the basis of published epidemiological and intervention studies. This approach can be used to 1) identify genomic applications that are promising and warrant further empirical research, and 2) fill in evidence gaps by identifying applications that are not expected to improve health or health care. When they are valid, precise and simple, modelling studies can optimize the process of translational research so that time and money are allocated to the most promising applications. In this project, I will 1) characterize empirical studies in translational research in terms of the main outcome measures used and their key determinants; 2) develop simulation models that predict outcome measures; 3) investigate how accuracy and precision of the estimates vary with varying model complexity; and 4). investigate the generalizability of the modelling approaches.
At increasingly high rate, genome-wide association and whole genome sequencing studies unravel genetic variants implicated in common diseases such as coronary heart disease, cancer, dementia and type 2 diabetes. One of the major promises is that these advances will lead to more personalized medicine, in which preventive and therapeutic interventions are targeted to individuals based on their genetic profiles. There is increasing interest in the early adoption of novel applications and many commercial applications are already marketed without supporting empirical evidence. Already now, regulatory agencies like the US Food and Drug Administration face substantial gaps in empirical evidence, which hamper proper recommendations. The increasing interest in genomic medicine, the evidence gaps and the scarcity of research budgets are strong incentives to search for novel strategies that make the process of translation research more efficient and effective. This project aims to investigate modelling approaches that can be used to predict the expected outcomes of empirical studies on the basis of published epidemiological and intervention studies. This approach can be used to 1) identify genomic applications that are promising and warrant further empirical research, and 2) fill in evidence gaps by identifying applications that are not expected to improve health or health care. When they are valid, precise and simple, modelling studies can optimize the process of translational research so that time and money are allocated to the most promising applications. In this project, I will 1) characterize empirical studies in translational research in terms of the main outcome measures used and their key determinants; 2) develop simulation models that predict outcome measures; 3) investigate how accuracy and precision of the estimates vary with varying model complexity; and 4). investigate the generalizability of the modelling approaches.
Project acronym INTERACT
Project Counteracting psychosis by optimizing interaction
Researcher (PI) Inez Yvonne Ronald Germeys
Summary Psychotic disorders are amongst the most severe mental disorders. However, current treatments have failed to reduce disability or change the prospects for recovery for patients with a psychotic disorder. In this project, I will investigate an entirely novel therapy, targeting the core vulnerability profile of altered person-environment interactions underlying psychosis, specifically increased stress-reactivity and reduced motivated and goal-directed behaviour. My colleagues and I have developed a digital apparatus, the 'PsyMate', allowing real-time interventions for patients with severe mental illness. In this project, the PsyMate will be used to (1)reduce psychotic and emotional reactivity to stress with "detachment and acceptance" exercises in real life situations, and (2)improve motivated and goal-directed behaviour with real-time behavioural activation therapy. In a randomized controlled trial, I will investigate whether this self-management therapy, conducted outside the office in the patient's real life, is capable of reducing psychotic reactivity to stress and of improving motivated behaviour in participants with an at-risk mental state for psychosis. In order to understand the impact of this intervention in terms of brain plasticity and prediction of response, I will use an experimental medicine approach to investigate the neural effects of the intervention. I will focus particularly on prefrontal dopamine-reactivity as the brain mechanism mediating altered person-environment interactions. In the current study, I will examine prefrontal dopamine reactivity towards positive as well as stressful negative events as the biological process mediating underlying motivated behaviour and environmental reactivity. Furthermore, I will investigate whether a self-management therapy specifically focused at aberrant person-environment interactions alters brain plasticity at the level of prefrontal dopaminergic neurotransmission in persons at risk for psychosis.
Psychotic disorders are amongst the most severe mental disorders. However, current treatments have failed to reduce disability or change the prospects for recovery for patients with a psychotic disorder. In this project, I will investigate an entirely novel therapy, targeting the core vulnerability profile of altered person-environment interactions underlying psychosis, specifically increased stress-reactivity and reduced motivated and goal-directed behaviour. My colleagues and I have developed a digital apparatus, the 'PsyMate', allowing real-time interventions for patients with severe mental illness. In this project, the PsyMate will be used to (1)reduce psychotic and emotional reactivity to stress with "detachment and acceptance" exercises in real life situations, and (2)improve motivated and goal-directed behaviour with real-time behavioural activation therapy. In a randomized controlled trial, I will investigate whether this self-management therapy, conducted outside the office in the patient's real life, is capable of reducing psychotic reactivity to stress and of improving motivated behaviour in participants with an at-risk mental state for psychosis. In order to understand the impact of this intervention in terms of brain plasticity and prediction of response, I will use an experimental medicine approach to investigate the neural effects of the intervention. I will focus particularly on prefrontal dopamine-reactivity as the brain mechanism mediating altered person-environment interactions. In the current study, I will examine prefrontal dopamine reactivity towards positive as well as stressful negative events as the biological process mediating underlying motivated behaviour and environmental reactivity. Furthermore, I will investigate whether a self-management therapy specifically focused at aberrant person-environment interactions alters brain plasticity at the level of prefrontal dopaminergic neurotransmission in persons at risk for psychosis.
Project acronym INTERRUPTB
Project "Estimating the effective reproductive rate of M. tuberculosis from changes in molecular clustering rates, to measure the impact of public health interventions on TB transmission"
Researcher (PI) Bouke Catherine De Jong
Host Institution (HI) PRINS LEOPOLD INSTITUUT VOOR TROPISCHE GENEESKUNDE
Summary "Excessive delays in treatment onset limit current tuberculosis (TB) control programs, presenting a major obstacle to the control of the TB epidemic. Increasing case detection, both quantitatively and temporally, is considered a priority, benefiting the patient (reduced morbidity and mortality) and the society (shortened period of infectiousness). These improvements in patient care have a common goal: to reduce transmission and eventually contain the spread of TB within the population. However, assessing reduced transmission of TB proofs to be difficult, as to date molecular tools have not been integrated in mathematical models or in field trials of public health interventions. Therefore, I aim to develop a model that incorporates bacterial genotyping to follow TB transmission within the human host population, hypothesizing that an effective Enhanced-Case-Finding (ECF) method can interrupt TB transmission. Integration of routine epidemiological and genotyping data with bioinformatics and mathematical modelling provides a novel and powerful approach to understand the key determinants of the TB epidemic, such as the Effective Reproductive Number, and predict the dynamics of TB transmission. I have the unique opportunity to position the present proposal as an added-value study that builds on 3-year Cluster Randomized Trial of ECF that I designed, which is about to be launched in The Gambia in 2012. By applying molecular genotyping methods to bacterial isolates collected from both the ECF intervention- and control arm, I will develop a method to measure and model the impact of ECF on the transmission of TB. This will be the first study of its kind in integrating molecular genotyping data in a TB transmission model as applied to a population level interventional study. The identification of significant transmission parameters will be important both for basic TB research and also for health experts that design and evaluate Public Health TB interventions in the future."
"Excessive delays in treatment onset limit current tuberculosis (TB) control programs, presenting a major obstacle to the control of the TB epidemic. Increasing case detection, both quantitatively and temporally, is considered a priority, benefiting the patient (reduced morbidity and mortality) and the society (shortened period of infectiousness). These improvements in patient care have a common goal: to reduce transmission and eventually contain the spread of TB within the population. However, assessing reduced transmission of TB proofs to be difficult, as to date molecular tools have not been integrated in mathematical models or in field trials of public health interventions. Therefore, I aim to develop a model that incorporates bacterial genotyping to follow TB transmission within the human host population, hypothesizing that an effective Enhanced-Case-Finding (ECF) method can interrupt TB transmission. Integration of routine epidemiological and genotyping data with bioinformatics and mathematical modelling provides a novel and powerful approach to understand the key determinants of the TB epidemic, such as the Effective Reproductive Number, and predict the dynamics of TB transmission. I have the unique opportunity to position the present proposal as an added-value study that builds on 3-year Cluster Randomized Trial of ECF that I designed, which is about to be launched in The Gambia in 2012. By applying molecular genotyping methods to bacterial isolates collected from both the ECF intervention- and control arm, I will develop a method to measure and model the impact of ECF on the transmission of TB. This will be the first study of its kind in integrating molecular genotyping data in a TB transmission model as applied to a population level interventional study. The identification of significant transmission parameters will be important both for basic TB research and also for health experts that design and evaluate Public Health TB interventions in the future."
Project acronym MASS-CARE
Project Molecular Self Screening for Cervical Cancer Prevention
Researcher (PI) Christophorus Meijer
Summary Cervical carcinoma is a preventable cancer caused by a persistent infection with high-risk types of human papillomavirus (hrHPV). Several western countries have implemented nation-wide screening programs based on the detection of abnormal cells in cervical smears (cytology) for cervical cancer prevention. Although these programs have markedly reduced incidence in developed countries, even the most sophisticated cytology-based screening programs miss significant numbers of high-grade cervical lesions and fail to further reduce cervical cancer incidence. Besides loss to follow-up of women with abnormal cytology, the major causes underlying failure are: - Low sensitivity of the primary cytology based screening test, which is subjective, often not or poorly quality assessed (QA) and has low sensitivity for precancerous lesions - Incomplete coverage of women invited to participate in the screening program Remarkably, in developed countries with a successful nation-wide cervical screening programme 55% of all carcinomas are diagnosed in women who do not participate. Moreover, the lack of QA cytology in medium and low resource countries is one of the main reasons why incidence and mortality stay high in these countries. In recognition of these shortcomings the MASS-CARE project envisions a novel, objective, full molecular self-screening approach that enables molecular screening and triage for referral to the gynaecologist using self-collected cervico-vaginal samples as an alternative tool for cervical cancer screening. In particular, we aim to discover molecular triage markers specific for the stratification of women with hrHPV positive self-samples. The research team headed by professor Meijer has a strong track record of cutting edge translational research, has state-of-the art molecular tools in place and is equipped with unique biobanks of clinical cohorts of thousands of hrHPV positive women that are needed to successfully execute this ambitious project.
Cervical carcinoma is a preventable cancer caused by a persistent infection with high-risk types of human papillomavirus (hrHPV). Several western countries have implemented nation-wide screening programs based on the detection of abnormal cells in cervical smears (cytology) for cervical cancer prevention. Although these programs have markedly reduced incidence in developed countries, even the most sophisticated cytology-based screening programs miss significant numbers of high-grade cervical lesions and fail to further reduce cervical cancer incidence. Besides loss to follow-up of women with abnormal cytology, the major causes underlying failure are: - Low sensitivity of the primary cytology based screening test, which is subjective, often not or poorly quality assessed (QA) and has low sensitivity for precancerous lesions - Incomplete coverage of women invited to participate in the screening program Remarkably, in developed countries with a successful nation-wide cervical screening programme 55% of all carcinomas are diagnosed in women who do not participate. Moreover, the lack of QA cytology in medium and low resource countries is one of the main reasons why incidence and mortality stay high in these countries. In recognition of these shortcomings the MASS-CARE project envisions a novel, objective, full molecular self-screening approach that enables molecular screening and triage for referral to the gynaecologist using self-collected cervico-vaginal samples as an alternative tool for cervical cancer screening. In particular, we aim to discover molecular triage markers specific for the stratification of women with hrHPV positive self-samples. The research team headed by professor Meijer has a strong track record of cutting edge translational research, has state-of-the art molecular tools in place and is equipped with unique biobanks of clinical cohorts of thousands of hrHPV positive women that are needed to successfully execute this ambitious project.
Project acronym MECHANOSENSATION
Project What is the molecular mechanism of mechanosensation? Mechanosensitive channel of large conductance, MscL, as a model
Researcher (PI) Armagan Kocer
Summary "Equipped with his five senses, man explores the universe around him and calls the adventure science" E.P. Hubble It is amazing how much we have learned about the working of our universe by using our five senses and how little we still know about the working of these senses themselves! Even though the molecular mechanism of sight, taste, and smell is known, we still don't know how the mechanical sensations of touch and hearing function at the molecular level. Mechanosensitive (MS) ion channels, present in membranes, are the molecules that sense membrane tension in all species ranging from bacteria to man. They stay functional even in artificial membranes, indicating that mechanosensation occurs at the protein-lipid interface. In an effort to understand the mechanism of force sensation, the major limitation has been the inability to 'observe' the molecular changes occurring in MS channels from the onset of the force. The aim of this proposal is to understand how channel proteins sense mechanical force at the molecular level. A bacterial channel, MscL, will be used as a model for its natural function to couple tension in the membrane to protein conformational changes. Here, on the basis of my recent findings, I propose to build on synthetic biology approaches to develop unique tools to specifically address the MS channel, allowing controlling its activity extrinsically and reversibly. In combination with the spectroscopic techniques, I want to elucidate the mechanism of mechanosensation in MscL by measuring structural changes in the protein and its interaction with the surrounding lipids, starting from the onset of the force. The research will clarify not only the long-standing question of how MscL senses tension, but it will also shed light on the common property of mechanosensitivity among nature's sensors in higher organisms; transient receptor-potential (TRP) channels, which are involved in hearing, touching and other sensory actions.
"Equipped with his five senses, man explores the universe around him and calls the adventure science" E.P. Hubble It is amazing how much we have learned about the working of our universe by using our five senses and how little we still know about the working of these senses themselves! Even though the molecular mechanism of sight, taste, and smell is known, we still don't know how the mechanical sensations of touch and hearing function at the molecular level. Mechanosensitive (MS) ion channels, present in membranes, are the molecules that sense membrane tension in all species ranging from bacteria to man. They stay functional even in artificial membranes, indicating that mechanosensation occurs at the protein-lipid interface. In an effort to understand the mechanism of force sensation, the major limitation has been the inability to 'observe' the molecular changes occurring in MS channels from the onset of the force. The aim of this proposal is to understand how channel proteins sense mechanical force at the molecular level. A bacterial channel, MscL, will be used as a model for its natural function to couple tension in the membrane to protein conformational changes. Here, on the basis of my recent findings, I propose to build on synthetic biology approaches to develop unique tools to specifically address the MS channel, allowing controlling its activity extrinsically and reversibly. In combination with the spectroscopic techniques, I want to elucidate the mechanism of mechanosensation in MscL by measuring structural changes in the protein and its interaction with the surrounding lipids, starting from the onset of the force. The research will clarify not only the long-standing question of how MscL senses tension, but it will also shed light on the common property of mechanosensitivity among nature's sensors in higher organisms; transient receptor-potential (TRP) channels, which are involved in hearing, touching and other sensory actions.
Project acronym Nutri-CARE
Project Nutri-CARE: Nutrient restriction during Critical illness: from induction of Autophagy to Repression of aberrant Epigenetic alterations
Researcher (PI) Greta Herman A Van Den Berghe
Summary Modern intensive care medicine enables survival from previously lethal conditions. Risk of death is mostly attributable to lack of recovery from organ failure. Although intensive care has been practiced for over 6 decades, the understanding of why certain patients recover and others don't remains very limited. Furthermore, organs and tissues from patients who do not swiftly recover, do not show overt signs of cell death but instead accumulate damaged organelles and protein aggregates and reprogram towards other cell lineages. Accumulation of cell damage can be compared with what occurs during ageing, but much more pronounced and within a much shorter time. Even when patients survive, many continue to suffer from severe morbidity, referred to as the legacy of critical illness. This indicates that acute life-threatening illnesses, and/or the intensive care management, induce "carry-over" effects with long-term consequences with important humane and financial implications. We recently showed that nutrient restriction early during critical illness is an intervention that affects these processes. Nutrient restriction unexpectedly accelerated recovery from organ failure and enhanced rehabilitation far beyond the time window of the intervention. These data radically contradict the traditional dogma that early anabolism is required for recovery from critical illnesses. Also, they raise the hypothesis that pathways which are activated by fasting play a key role. This project is designed to understand the underlying molecular and cellular mechanisms of the damage-induced "reprogramming" and the benefit of nutrient restriction, which is essential in order to develop novel preventive and therapeutic interventions. We hypothesize that activated autophagy and repressed deleterious epigenetic alterations play a major role. The results of these studies are expected to pave the way towards novel effective interventions to prevent/treat the debilitating legacy of critical illness.
Modern intensive care medicine enables survival from previously lethal conditions. Risk of death is mostly attributable to lack of recovery from organ failure. Although intensive care has been practiced for over 6 decades, the understanding of why certain patients recover and others don't remains very limited. Furthermore, organs and tissues from patients who do not swiftly recover, do not show overt signs of cell death but instead accumulate damaged organelles and protein aggregates and reprogram towards other cell lineages. Accumulation of cell damage can be compared with what occurs during ageing, but much more pronounced and within a much shorter time. Even when patients survive, many continue to suffer from severe morbidity, referred to as the legacy of critical illness. This indicates that acute life-threatening illnesses, and/or the intensive care management, induce "carry-over" effects with long-term consequences with important humane and financial implications. We recently showed that nutrient restriction early during critical illness is an intervention that affects these processes. Nutrient restriction unexpectedly accelerated recovery from organ failure and enhanced rehabilitation far beyond the time window of the intervention. These data radically contradict the traditional dogma that early anabolism is required for recovery from critical illnesses. Also, they raise the hypothesis that pathways which are activated by fasting play a key role. This project is designed to understand the underlying molecular and cellular mechanisms of the damage-induced "reprogramming" and the benefit of nutrient restriction, which is essential in order to develop novel preventive and therapeutic interventions. We hypothesize that activated autophagy and repressed deleterious epigenetic alterations play a major role. The results of these studies are expected to pave the way towards novel effective interventions to prevent/treat the debilitating legacy of critical illness.
Project acronym STEMCARDIOVASC
Project Human Pluripotent Stem Cells: the new heart patient?
Researcher (PI) Christine Lindsay Mummery
Host Institution (HI) ACADEMISCH ZIEKENHUIS LEIDEN
Summary "The ability to generate pluripotent stem cells (iPSC) by reprogramming somatic tissues is arguably the greatest breakthrough in biomedical science of the last decade. The most inaccessible cells of the body can now be derived repeatedly from any individual. This could have a huge impact on understanding disease and the development of new therapeutic drugs but it will require a new level of sophistication in bioassays to create disease models and monitor disease phenotypes. The project I propose here will take up this challenge for the cardiovascular system, creating new human models of heart failure and vascular disease that presently do not exist. My group is uniquely positioned in Europe to realize these ambitions through more than a decade of research on cardiac and vascular cells from human embryonic stem cells and more recently hiPSC; its present location in Leiden University Medical Centre is optimal for fostering clinical links. My group is one of few worldwide that uses conventional homologous recombination in human PSCs. My aims here are (1) develop protocols for differentiating all cells of the heart (2) engineer synthetic and native human myocardium that models healthy tissue and common disease states and (3) generate sets of isogenic diseased hPSC to model pathogenesis. This will be realized by deriving lineage marked "rainbow coloured" reporter hPSC lines, introducing selected (immature) cardiovascular cells into engineered constructs and subjecting them to mechanical/biochemical stress factors like cyclic contraction and fluid flow that would normally induce maturation and disease. The constructs will support simultaneous measurement of functional tissue parameters and include hiPSC from relevant diseases, genetically or pharmacologically rescued and isogenic hESC with the corresponding gene mutations. These new "sick human heart" and " diseased vessel" models and novel bioassays will significantly advance technology to have major impact on the field."
"The ability to generate pluripotent stem cells (iPSC) by reprogramming somatic tissues is arguably the greatest breakthrough in biomedical science of the last decade. The most inaccessible cells of the body can now be derived repeatedly from any individual. This could have a huge impact on understanding disease and the development of new therapeutic drugs but it will require a new level of sophistication in bioassays to create disease models and monitor disease phenotypes. The project I propose here will take up this challenge for the cardiovascular system, creating new human models of heart failure and vascular disease that presently do not exist. My group is uniquely positioned in Europe to realize these ambitions through more than a decade of research on cardiac and vascular cells from human embryonic stem cells and more recently hiPSC; its present location in Leiden University Medical Centre is optimal for fostering clinical links. My group is one of few worldwide that uses conventional homologous recombination in human PSCs. My aims here are (1) develop protocols for differentiating all cells of the heart (2) engineer synthetic and native human myocardium that models healthy tissue and common disease states and (3) generate sets of isogenic diseased hPSC to model pathogenesis. This will be realized by deriving lineage marked "rainbow coloured" reporter hPSC lines, introducing selected (immature) cardiovascular cells into engineered constructs and subjecting them to mechanical/biochemical stress factors like cyclic contraction and fluid flow that would normally induce maturation and disease. The constructs will support simultaneous measurement of functional tissue parameters and include hiPSC from relevant diseases, genetically or pharmacologically rescued and isogenic hESC with the corresponding gene mutations. These new "sick human heart" and " diseased vessel" models and novel bioassays will significantly advance technology to have major impact on the field."
Project acronym SURVIVE
Project Integrating cancer detection and SURgery Via molecular Imaging
Researcher (PI) Cornelis Jan Hadde Van De Velde
Summary The ambitious aim of this ERC-advanced grant proposal is to develop strategies that will connect cancer detection and surgery via tumor-specific molecular imaging techniques. This will lead to personalized patient-, or even tumor-specific treatment strategies. In addition, it will provide a tool for the selection of patients that, following preoperative (neoadjuvant) treatment, would benefit from additional (minimally invasive) surgery and identify patients who may be treated non-operatively. Fine-tuning the relation between tumor diagnosis, neoadjuvant treatment, preoperative planning and minimally invasive image-guided surgery will likely improve radical oncologic surgery while reducing surgical morbidity in cancer patients. The mechanistic aim of the proposal is to develop an integrated multimodal imaging strategy that will more accurately connect tumor biology with surgical resection approaches via the use of tumor-specific molecular imaging agents. The cornerstone of this approach is the unique clinical translation of tumor-targeted imaging agents that are both radioactive (diagnostic imaging) and fluorescently (surgical guidance) labeled. It is expected that the proposed multimodal imaging agents will allow for a significant improvement of both imaging and surgery strategies.
The ambitious aim of this ERC-advanced grant proposal is to develop strategies that will connect cancer detection and surgery via tumor-specific molecular imaging techniques. This will lead to personalized patient-, or even tumor-specific treatment strategies. In addition, it will provide a tool for the selection of patients that, following preoperative (neoadjuvant) treatment, would benefit from additional (minimally invasive) surgery and identify patients who may be treated non-operatively. Fine-tuning the relation between tumor diagnosis, neoadjuvant treatment, preoperative planning and minimally invasive image-guided surgery will likely improve radical oncologic surgery while reducing surgical morbidity in cancer patients. The mechanistic aim of the proposal is to develop an integrated multimodal imaging strategy that will more accurately connect tumor biology with surgical resection approaches via the use of tumor-specific molecular imaging agents. The cornerstone of this approach is the unique clinical translation of tumor-targeted imaging agents that are both radioactive (diagnostic imaging) and fluorescently (surgical guidance) labeled. It is expected that the proposed multimodal imaging agents will allow for a significant improvement of both imaging and surgery strategies.
Project acronym TRIPLE-BC
Project Identification and functional validation of drugable targets/pathways for triple negative breast cancer
Researcher (PI) Johannes Albert Foekens
Summary Patients suffering from triple-negative breast cancer (TNBC) have a poor prognosis as these tumors frequently confer resistance against chemotherapeutic agents and lack drug targets such as estrogen receptor, progesterone receptor, and epidermal growth factor receptor 2. Insufficient knowledge on the biology of this specific breast tumor type and its heterogeneity hinder the identification of potential novel drug targets. Lethality enhancer screening is an ideal approach to identify new drug targets in tumors with specific genetic aberrations. We plan to adapt this concept of synthetic lethality by anticipating that while TNBC cells confer resistance to available anticancer drugs, specific knock down of particular genes by RNA-interference (RNAi) may result in a synergistic cell killing. Another important aspect of our approach is that we will concentrate in our screens on the top 500 candidate genes shown to be crucial in TNBC for cellular processes. The genes will be prioritized by Bayesian network analysis on prior knowledge on clinical TNBC from our own extensive genomics and proteomics studies, the literature, next generation sequencing efforts, and databases listing drugability of targets. We will employ RNAi-based knock down of drugable targets in 22 cell lines to reveal genes essential for drug resistance in TNBC. In addition to 2D cultures, screens will also be applied to 3D cultures, which are thought to better reflect the in vivo situation. The most effective combinations for each TNBC subtype will further be functionally investigated in vitro and in vivo to unravel the molecular nature of the synthetic lethality. Finally, translational studies will be performed to establish the potential clinical relevance of the identified targets/pathways in large numbers of human TNBC and non-TNBC tumors on tissue microarrays. It is expected that the newly designed (combination) therapies result in a decline in TNBC mortality and reduction of healthcare costs.
Patients suffering from triple-negative breast cancer (TNBC) have a poor prognosis as these tumors frequently confer resistance against chemotherapeutic agents and lack drug targets such as estrogen receptor, progesterone receptor, and epidermal growth factor receptor 2. Insufficient knowledge on the biology of this specific breast tumor type and its heterogeneity hinder the identification of potential novel drug targets. Lethality enhancer screening is an ideal approach to identify new drug targets in tumors with specific genetic aberrations. We plan to adapt this concept of synthetic lethality by anticipating that while TNBC cells confer resistance to available anticancer drugs, specific knock down of particular genes by RNA-interference (RNAi) may result in a synergistic cell killing. Another important aspect of our approach is that we will concentrate in our screens on the top 500 candidate genes shown to be crucial in TNBC for cellular processes. The genes will be prioritized by Bayesian network analysis on prior knowledge on clinical TNBC from our own extensive genomics and proteomics studies, the literature, next generation sequencing efforts, and databases listing drugability of targets. We will employ RNAi-based knock down of drugable targets in 22 cell lines to reveal genes essential for drug resistance in TNBC. In addition to 2D cultures, screens will also be applied to 3D cultures, which are thought to better reflect the in vivo situation. The most effective combinations for each TNBC subtype will further be functionally investigated in vitro and in vivo to unravel the molecular nature of the synthetic lethality. Finally, translational studies will be performed to establish the potential clinical relevance of the identified targets/pathways in large numbers of human TNBC and non-TNBC tumors on tissue microarrays. It is expected that the newly designed (combination) therapies result in a decline in TNBC mortality and reduction of healthcare costs.


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I found inspiring textures from nature too in my excursion to Door County. Sunlight reflecting off of water, the ripple of little waves; and I had never noticed the painterly quality of smoke and flame on its surroundings. It's back to work now with my new inspiration; it will take years to turn these into textile patterns!
You are currently reading Sturgeon Bay at Woven-Words.


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Porsche's Taycan is a sensational six-figure electric sports car
Posted on September 6, 2019 September 6, 2019 by Loknath Das
Porsche has finally unveiled its first all-electric car. After four years of concepts, name changes, spy shots, teases, and drips of information about the four-door EV, the German automaker revealed the production version of the Taycan electric sports car on Wednesday during an event that took place simultaneously on three continents.
Originally dubbed "Mission E" when it was announced as a concept car in 2015, the Taycan will begin its production life as two variants: the Taycan Turbo and the Taycan Turbo S, which run a staggering $150,900 and $185,000, respectively. Both are all-wheel drive machines, and both go from 0 to 60 miles per hour in three seconds or less. (Both are also likely to spark arguments about the use of the word "turbo" in the name, even though trying to stop semantic drain is a useless endeavor.)
More variants of the Taycan, like less powerful rear-wheel drive versions or the Cross Turismo crossover that Porsche has shown off in concept form, will follow the two Turbos. Porsche didn't share an EPA-estimated range for its first EV, though these higher-end versions are expected to travel somewhere near 300 miles on a full charge. (The automaker did cite a European estimate of 450 kilometers, which would equal about 280 miles.)
Both initial versions of the Taycan will use a dual-electric-motor setup to put out the equivalent of 616 horsepower. The Taycan Turbo will make 670 horsepower in the special get-off-the-line-quickly "launch control" mode, while the Turbo S can put down 750 horsepower in that mode. The result is that the Taycan Turbo can go from 0 to 60 miles per hour in three seconds flat, while the Turbo S will make that same run in 2.6 seconds.
The two Taycan Turbos draw their energy from a 93kWh battery pack that weighs in at 1,389 pounds. In all, both cars weigh just a touch over 5,100 pounds, which is just a few pounds lighter than the current version of Tesla's Model X SUV, and a few hundred pounds heavier than the Tesla Model S sedan.
All told, that means the first Porsche Taycans will cost more than Tesla's offerings, but they will just about keep pace with the Silicon Valley automaker's top-tier cars. (It will also leave its German counterparts' EVs in the dust in both categories.) The Taycan keeps pace with a top speed of 161 mph, as compared to Tesla Model S and X performance 163 mph top speed (thanks to a recent over-the-air software update). Porsche is also touting the Taycan's ability to repeatedly launch off the line without overheating the battery pack, something that most modern EVs aren't really built for.
One thing Porsche is counting on to move Taycans (beyond the brand name itself), is the thing Porsche has touted most during the four-year tease of its first EV: the fact that the car's massive battery packs can charge rapidly. Thanks to the 800-volt technology that Porsche is using in the Taycan, both variants can be charged from 5 percent to 80 percent in just under 23 minutes when hooked up to chargers that can charge at 270kW. (Porsche has promised to build charging stations capable of 350kW charging at its dealerships, and parent company Volkswagen has begun building out a network of chargers in North America that can handle up to 350kW charging.)
These details help fill out the picture Porsche's been painting of the Taycan, which is: it's an EV that will offer supercar performance without forcing buyers to make sacrifices on practicality. Last month, the German automaker showed off the first photos of the inside of its first EV, revealing a typically Porsche interior, though one with more screens and touch-sensitive panels than usual. The Taycan will also be the first car with a built-in Apple Music app. Buyers of similarly specced performance cars usually have to sacrifice some comfort, but Porsche is promising deep-pocketed Taycan buyers will get a future-facing (but still premium) version of the cabin experience the company's luxury sports cars are known for.
Porsche has said it wants to offer versions of the Taycan that cost under $100,000. But even if or when that happens, the car is never going to be a mass-market sensation. Instead, it's meant to be the most aspirational electric car in parent company Volkswagen's impending (and imposing) stable of electric cars. Wednesday's event didn't answer every question that potential buyers or outright Porsche fans might have about the company's first electric car. But it did answer just how aspirational Porsche wants the Taycan to be.
["source=theverge"]
Posted in Sports Cars Tagged a, electric, Is, Porsche's, sensational, six-figure, sports, Taycan
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text:
Compensation en droit civil français#La fongibilité
Fongibilité asymétrique

Voir aussi
Fongible

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text:
Paddle Battle
By Eric Howling
Also available from our distributor Lerner Publisher Services
Series: Lorimer Sports Stories
Set against a backdrop of the threat of wildfires on the west coast, this book looks at the effect changes at home can have on a young athlete's performance and the emotional support a team can provide. Thirteen-year-old kayaker Finn has been angry and resentful since his mother left the family. In a highly charged emotional state, Finn's performance is not only suffering, but he is also taking things out on his teammates. Like the wildfires that threaten Finn's Okanagan training camp, this book shows how new beginnings arise after a destructive event.
What if your biggest opponent is yourself?
Finn Hunter has high hopes of making the national kayaking team one day. And he might just make it too, since he made the regional team last year. But this year, since his mom left home, things have been different. Finn is angry, and his paddling and relationship with his teammates are suffering as a result. Can Finn pull it together to achieve his dreams?
ERIC HOWLING is an advertising creative director and the author of twelve books, including Head Hunter, Red Zone Rivals, Hoop Magic, Kayak Combat, Drive, Run and Gun and Long Bomb in the Lorimer Sports Stories series. His books have been shortlisted for the Hackmatack Children's Choice Book Award, named Resource Links Year's Best and picked as a CCBC Best Books selection. Eric lives in Calgary, Alberta.
"The author explores what this young teen goes through when faced with the breakdown of his parents' marriage. From feeling angry and blaming himself to finding support through his peers, Finn's character arc is well rounded. The realities of climate change and wildfires and their impacts on the younger generation are also seamlessly woven into the story."
ERIC HOWLING is an advertising creative director and the author of ten books, including Head Hunter, Red Zone Rivals, Hoop Magic, Kayak Combat, Drive, Run and Gun and Long Bomb in the Lorimer Sports Stories series. His books have been shortlisted for the Hackmatack Children's Choice Book Award, named Resource Links Year's Best and picked as a CCBC Best Books selection. Eric lives in Calgary, Alberta.
Format: 7.75in x 5in
Publication Date: 1st January 2022
Binding: Electronic book text
BIC Code: YFB, YFM, YFN, YFR, YXF, YXL, YXS, YXZG
BISAC Code: 4.0.2.0.2.0.0, JUV013060, JUV029010, JUV032060, JUV039050, JUV039060
Lexile Reading Level: HL580L


Spanish Studies Abroad is committed to helping make your dreams of studying in another country a reality. Toward that end, we're open to discussing the possibility of payment plans. If you would like to explore this option, please contact your Admissions Advisor by calling (413) 256-0011 and let them know you're interested in a payment plan.
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Remit payments by check made payable to The Center for Cross-Cultural Study, 446 Main Street, Amherst MA 01002, or by credit card.
Payments must be received by the due dates specified in your payment plan.
If the account becomes delinquent on any listed payment, the entire amount will become payable immediately.
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Agreement to and acceptance of the payment plan schedule and terms outlined above.


Two years ago the world realized what ICO was: a method of early project financing through the emission and sale of digital tokens. The thought still misleads some people that it was Vitalik Buterin who created ICO and conducted the very first one. Let's make it clear: the pioneer was the Mastercoin project, which collected $500,000 in BTC in 2012 (It could have been $18 mln by now). However, this project is no more, and since that, no one was interested in such crowdfunding method up to 2015.
In 2014-2015 Ethereum went "to the moon" and consequently, ICO gained popularity and saw development. SEC, as well as other regulators, didn't realize what was going on. The volumes were still tiny in comparison to the venture markets: $1-2 bln against $150 bln. And then 2017 came.
The capitalization of the market grew, as well as the appetites of the projects. Tezos, EOS, Bancor, SONM and many others tried to copy the success of Ethereum. This period even has a household name — "summer 2017." It was the time when the number of ICO-projects was high, and the percentage of their success was the highest. Everybody measured the speed of the "closing" of the round, not the sums collected. Every day the news from media proclaimed a new bunch of successful X-projects was closing ICO for N millions in a couple of hours. At the same time, the "shovel sellers" came out of nowhere. The rise of the ICO market promoted several industries at once. Crypto lawyers, crypto media, crypto marketers entered the sphere as well as an army of experts and advisors on investments, market-making, trading, etc.
Of course, 90% of these companies and people did not have proper experience and expertise to work in the investment environment. Such a factor is mainly the reason for the failure of almost 90% of the projects. It also boosted the loss of investors' faith which was growing since the fall of 2017. They faithfully invested in these "Ethereum killers" until the sharp drop of Bitcoin price took place in 2018, and then the entire cryptocurrency cap followed.
The second important factor which killed the ICO phenomenon and shook the market severely was the tokens' liquidity, or it's better to say the "lack of liquidity." For the same money they took from investors, these tokens were listed on the crypto exchanges. Imagine a similar situation with a classic IPO — a company lists a stock on the exchange, but then no one trades it. And that's what happened to the most ICO projects and tokens. Some managed to give the investors profit before the global market collapsed, but not more than 10% of them.
The late summer of 2017 was marked by the regulators' appearance, with the U.S. SEC playing the leading role, and Singapore, China, and Korea are in the spotlights as well. With no experience and valuable insights, the vast majority of projects, investors, and exchanges felt into the panic. The position of the SEC made it clear that the tokens of ICO-projects were divided into two classes: security and utility. In fact, there could be more than five different types of tokens, but the SEC didn't consider any other options. They carefully studied DAO, the notorious case of Vitalik Buterin, meanwhile making the ICO word quite abusive. Thus, since September we already observed TDE, TGE, STO, and others. An interesting format was DAICO, where investors kept control over their investments. However, this method was not widely spread due to the complexity.
Since autumn 2017 up to winter 2018, the time has come for the utility tokens. It was obvious that the traditional models of funding failed: the investors didn't want to know anything about the "new blockchains." Everyone was interested in ROI — the return on investment indicator, and the project team. All the advantages of cryptocurrency and blockchain technology were lost and forgotten. The ones who didn't make it during the "summer 2017", tried to catch at least something.
A vast number of crypto road shows emerged — these were the international conferences, which promised investors for everyone. ICO projects stopped making money, investors counted the losses, but the time has come for the PR-agencies, investment consultants and conference organizers. The end of 2017 and the beginning of 2018 were the best days for ICO promotions, such as ICO Bench or ICOdrops. Still, the market was falling, and investors' interest declined as well.
The grip of regulatory shackles, the final drop in liquidity, and the first scandals with ICO-fraudsters & bankrupt projects kept pulling the ICO market down. EOS and Telegram collected about $6 bln, but it did not save the general situation — these projects were unicorns, as venture capitalists used to say. So far neither the first nor the second has shown significant results.
The regulatory initiatives, as well as successful ICO of Telegram (technically, not an ICO, but two venture rounds), set a new trend among those who remained on the market and continued to struggle for results. STO is the trend — the emission of the same digital tokens on the same platforms (in 90% of cases it is ERC-20). The difference is that the token is registered as security. Several jurisdictions, such as the U.S., Switzerland, Liechtenstein, and others already adopted this opportunity. However, the costs for such a procedure are almost on the IPO level — but the funds collected are not worth it. Back in summer 2017, it was common to spend 500,000 dollars to collect $5 mln. The spring of 2018 raised the plank of costs up to $2-2.5 mln.
In the summer of 2018, Bitcoin stuck in a flat with the stagnation and uncertainty ruling the minds on the investment market. Liquidity did not change; the funds, which invested in the ICOs kept counting the losses. There were no new major projects on the horizon. Few exceptions like Quarkchain or Dragonchain barely managed to make a profit. The vast majority of projects simply ran out of money. Naturally, the staff dismissals and budget cuts followed, as well as the first criminal cases. The market entered a self-cleaning stage, and only true technology advocates and professionals remained.
The fall of 2018 presented a record low fall of capitalization, and the market froze. The rumors about the end of the ICO emerged here and there. However, a lot of STO and tokenization projects gained momentum, with the following of new asset class called the stablecoins.
A new chapter in ICO development started: the tokenization of real assets with the advantages of blockchain technology, combined with progressive legal practices. Despite the decrease in the investors' interest in simple projects, companies that tokenize assets such as real estate, land, and even water sources, show significant results.
What to expect from ICO in 2019?
In the fall of 2018, there were rumors about a so-called "Rothschild ICO" — the IMMO project. The future for the projects of such kind is not clear yet, as the concept of tokenization must be adopted and tested by the qualified investors and their "legacy money." There is also an essential type of "new wave" projects such as investment platform like Roobee, legally allowing investors to participate in an ICO or even an IPO with the use of cryptocurrency. Many people call STO to be the potential trend of 2019, but please remember that this trend strongly depends on the general investment attitude and market capitalization.
Obviously, we won't see another "summer 2017", but at the same time, the market would have more stable projects with serious legal attitude and experienced and professional teams. The ICO phenomenon will go on, one way or another. Still, like all new things, it has to go through the market and regulatory prizm.


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Computer programming & software development
Software Studies: A Lexicon
A cultural field guide to software: artists, computer scientists, designers, cultural theorists, programmers, and others define a new field of study and practice. This collection of short expository, critical, and speculative texts offers a field guide to the cultural, political, social, and aesthetic impact of software. Computing and digital media are essential to the way we work and live, and much has been said about their influence. But the very material of software has often been left invisible. In Software Studies, computer scientists, artists, designers, cultural theorists, programmers, and others from a range of disciplines each take on a key topic in the understanding of software and the work that surrounds it. These include algorithms; logical structures; ways of thinking and doing that leak out of the domain of logic and into everyday life; the value and aesthetic judgments built into computing; programming's own subcultures; and the tightly formulated building blocks that work to make, name, multiply, control, and interweave reality. The growing importance of software requires a new kind of cultural theory that can understand the politics of pixels or the poetry of a loop and engage in the microanalysis of everyday digital objects. The contributors to Software Studies are both literate in computing and involved in some way in the production of software and active in making and theorizing culture. Software Studies offers not only studies of software but proposes an agenda for a discipline that sees software as an object of study from new perspectives. Contributors Alison Adam, Wilfried Hou Je Bek, Morten Breinbjerg, Ted Byfield, Wendy Hui Kyong Chun, Geoff Cox, Florian Cramer, Cecile Crutzen, Marco Deseriis, Ron Eglash, Matthew Fuller, Andrew Goffey, Steve Goodman, Olga Goriunova, Graham Harwood, Friedrich Kittler, Erna Kotkamp, Joasia Krysa, Adrian Mackenzie, Lev Manovich, Michael Mateas, Nick Montfort, Michael Murtaugh, Jussi Parikka, Soren Pold, Derek Robinson, Warren Sack, Grzesiek Sedek, Alexei Shulgin, Matti Tedre, Adrian Ward, Richard Wright, Simon Yuill
Format(s): Hardback - ISBN: 9780262062749
Listed in: Software Engineering
Balancing Agility and Discipline: A Guide for the Perplexed
By Barry W. Boehm
Real-Time Agility: The Harmony/ESW Method for Real-Time and Embedded Systems Development
By Bruce Powel Douglass
High Integrity Software: The SPARK Approach to Safety and Security
By John Barnes
A Handbook of Software and Systems Engineering: Empirical Observations, Laws and Theories
By Albert Endres
Facts and Fallacies of Software Engineering
By Robert L. Glass


text:
Females in Combat
Shortchanging Vets
Aid Sought for Homeless Female Vets
Caroline Contreras says a rape at Fort Dix, N.J., 20 years ago derailed her military career and sent her on an inexorable path of addiction and homelessness.
But what the 48-year-old veteran says she remembers most painfully is how her government let her down when she finally sought help.
Last year, Contreras showed up at the U.S. Veterans Administration facility in West Haven homeless and ready to sober up and deal with the trauma of the sexual assault by fellow servicemen.
She completed the VA's substance abuse treatment program, restored her self-worth after working with a therapist and shed her destructive coping skills. When she was ready to leave the program to rebuild her life, the VA had no place to send her.
Women-only shelter beds in the state were full. Transitional housing wasn't available. The best the VA could offer her was a bus ticket to a shelter in Massachusetts.
"It brought me back to the way I felt when I was raped," Contreras said. "I was insignificant. I wasn't worthy. No matter what I did, I couldn't get the respect of a male veteran."
Every day, female veterans who are homeless in the state confront barriers in a VA system where services and housing options for women lag in comparison to their male counterparts.
Veteran advocates say the VA needs to address the national disparity as 200,000 female veterans return home from Iraq and Afghanistan, many with combat-related stress and military sexual trauma -- risk factors for homelessness.
"Folks are surprised when you tell them about homeless female veterans. You typically don't think of women as veterans, nevermind homeless veterans, but it's a real problem that is starting to get attention," said Natalie Matthews, director of policy and information at CT Coalition to End Homelessness.
There are an estimated 8,000 homeless female veterans nationwide. Veterans advocates say women account for about 4 percent of the total homeless veteran population, meaning about 200 of the estimated 5,000 homeless vets in Connecticut are women.
Of the 550 transitional housing programs for male veterans in the country, only 300 can accept women, said Pete Dougherty, the director of homeless veterans programs at the U.S. Department of Veterans Affairs.
The VA recognizes the problem and is making available more grants outside the VA system to develop more transitional and supportive housing programs for homeless women veterans, Dougherty said.
"We need more programs for women veterans and the VA has identified women as a priority for funding," Dougherty said.
Federal lawmakers have awoken to the problem.
Several bills introduced in Congress include development of affordable housing for female veterans and linking the VA with the Department of Defense to identify returning soldiers who are at risk for homelessness.
But even as the wheels of government begin to slowly turn, homeless women veterans in Connecticut continue to struggle to find accommodations.
Joy Kiss, who runs Home For the Brave in Bridgeport, turns away women veterans looking for a room in the all male, 33-bed transitional home.
"There is no place to refer them to in Connecticut. I know there is housing in Massachusetts," said Kiss, who has plans to open some type of supportive housing for women in Bridgeport.
At Columbus House in New Haven, a community-based transitional housing unit for 12 men and eight women, the turnover rate for beds is slow.
Residents stay on average a year, getting the skills and counseling they need while waiting for a housing voucher to move into their own apartments.
"There are waiting lists for transitional housing because things move at a snail's place as people wait to move on to permanent housing," said Alison Cunningham, the director of Columbus House.
"A woman is going to have a harder time whether she is a veteran or not, and I anticipate this is going to get worse before it gets better," she said.
At the state veterans home in Rocky Hill, where male veterans live in dormitory-style barracks, there is room for about only 20 women in a separate, secure wing. The home cannot take in women with children, said Linda Schwartz, the state commissioner of veterans affairs.
"During my military service, we weren't allowed to have children and be in the military. Now 70 percent of women veterans have children and we need to address the issue," said Schwartz, who served in Vietnam as a combat nurse.
Schwartz said the state has paid to house women veterans with children who sought help at the home. She is looking to convert vacant homes on the Rocky Hill campus into transitional housing.
"It's only going to grow," Schwartz said. "People don't realize that when people come home from war or out of the military, it's a big adjustment and some don't hit the ground running."
Establishing Support The plunge to homeless becomes harder to stop when the individual's support system collapses.
For Gladys Twarkins, an Air Force veteran of the Iraq War, it was triggered by the loss of her East Hartford home to a real estate scam and an injury during an air raid in southern Iraq. She slept in her car when she returned to Connecticut in 2005. Now she sleeps on her ex-husband's couch.
Shortly after she returned from Iraq, she told a clinician at the Newington VA that it was getting too cold to sleep in her car and that she needed a room temporarily.
"I asked her if she could get me in [the veterans home in Rocky Hill]; she gave me an application," said Twarkins, 53. She never filled out the application.
Air Force veteran Nissa LaPoint says a sexual assault at the Westover Air Reserve Base in Massachusetts disconnected her from her support system and she became homeless.
In 2006, LaPoint, 33, was sleeping in her car at a rest stop on I-395 when she called then-Congressman Rob Simmons for help. The blankets she had wrapped around her were frozen to the window. Simmons, a decorated Vietnam veteran, sent an aide to her rescue. She eventually found housing with the help of John March, a state service officer for the American Legion.
"I got off active duty and they pretty much sent me on my way," LaPoint said. "When I joined, the recruiter told me the Air Force was a better way of life. I took that opportunity. He also told me the VA would always have a place to stay, a roof over my head."
For Johanna Montalvo, who joined the National Guard in Puerto Rico, her descent was touched off by drugs and the death of her father. She lives at the Friendship Center shelter in New Britain in rooms segregated from homeless men. She wants to move to a shelter or transitional housing closer to the VA in West Haven, where she attends counseling sessions.
"There are a lot of us out there and the VA doesn't know what's going on," said Montalvo, 35. "We could be out in the streets, in crack houses, corners of prostitution, and we'll find female veterans."
Kate Kelly, who works with women veterans for the Connecticut VA, said it took her six months to secure a housing voucher for a female veteran with three children living in a shelter.
Yet she doesn't think women veterans are being shortchanged.
"They have the same opportunities as women in the general population. The reality is that it is going to be tough either way if you are male or female veteran," Kelly said.
Finding Success Ultimately, Contreras did not board the bus to a shelter in Massachusetts. She ended upinsteadat the Beth-El Center, a shelter in New Milford, where she stayed until she received a housing voucher.
Today, she lives in an apartment in West Haven and returns to Beth-El every week to work as a residential counselor. She's become an advocate for women veterans, speaking out against the lack of housing in the state. She's spoken to groups in Washington, D.C., and community events in the state. Her goal is to see transitional housing for women veterans built in the state.
"It's an awful feeling when you've made up your mind to rebuild your life and you have nowhere to go," Contreras said.
Site by PTSD Support Services, Woodland Park CO: |


text:
<?php

namespace backend\controllers;

use Yii;
use yii\filters\AccessControl;
use common\components\AccessRule;
use common\models\Post;
use common\models\User;

/**
 * Class CultureProgramController 艺术传承控制器
 * @package backend\controllers
 */
class CultureProgramController extends \yii\web\Controller
{

    public function behaviors()
    {
        return [
            'access' => [
                'class' => AccessControl::className(),
                // We will override the default rule config with the new AccessRule class
                'ruleConfig' => [
                    'class' => AccessRule::className(),
                ],
                'rules' => [
                    [
                        'allow' => true,
                        'roles' => [
                            User::ROLE_ADMIN
                        ],
                    ]
                ],
            ]
        ];
    }

    public function actionIndex(){
        return $this->render("index");
    }

    public function actionPosts(){
        return $this->render("posts");
    }

    public function actionCreate(){
        $model=new Post();

        return $this->render('cOU',[
            'model' => $model,
        ]);
    }

    public function actionUpdate($id){

        //这样获取会将isNewRecord设置为false
        $model = $this->findModel($id);

        return $this->render('cOU',[
            'model' => $model,
        ]);
    }

    public function actionPostsCreate(){
        $model=new Post();

        return $this->render('postsCOU',[
            'model' => $model,
        ]);
    }

    public function actionPostsUpdate($id){

        //这样获取会将isNewRecord设置为false
        $model = $this->findModel($id);

        return $this->render('postsCOU',[
            'model' => $model,
        ]);
    }

    /**
     * Finds the Notice model based on its primary key value.
     * If the model is not found, a 404 HTTP exception will be thrown.
     * @param integer $id
     * @return Notice the loaded model
     * @throws NotFoundHttpException if the model cannot be found
     */
    protected function findModel($id)
    {
        if (($model = Post::findOne($id)) !== null) {
            return $model;
        } else {
            throw new NotFoundHttpException('The requested page does not exist.');
        }
    }

}

redpajama_set_name: RedPajamaGithub


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On behalf of my committee, I just wanted to send along a note of thanks to you, Ron & John for providing us with an awesome night of music. Everyone had a blast and we've received many comments on how great you three were.
Again, many many thanks and I'm sure we will do business together again.
Would recommend to any bride looking for a variety of music to be played at their reception!


texts to send a hurting friend - Teens Finding Hope, Inc.
I know things have been tough.
I'm just a text away.
I hope you realize how awesome you are.
Today is a new day. Let's seize it.
Quote for the day: One small crack doesn't mean you're broken.
It means you didn't fall apart.
Push through this. It'll be worth it.
If you need anything, I'm here.
I can't imagine my life without you!
You know what I love about you?
What a great day to overcome!
Your struggle is real, and so is your hope.
Another day to breathe. Another day to heal.
Good morning, beautiful. Get ready for a great day.
Together, friend, we can do this.
Note: You are awesome just the way you are.
weren't a way to get over them.
Don't worry your pretty, little mind.


text:
a Fix It Upper Mystery starring Jewel
with special guest Cock Johnson, Private Detective
Cock needed help on this one. That's why he tracked down Jewel. The fictional building contractor/mystery solving character she played in a number of made for Hallmark Channel movies, as opposed to the real life singer/songwriter of such hits like Intuition and You Were Meant For Me.
Not that there's any goddamn difference. This pop-dead world's too far gone to destroy any more time trying to kid ourselves.
In those Hallmark movies, Jewel is just acting like Jewel.
Cock put on a nice shirt, cursing ontologically because he'd intended to wash his pants before she got here. His pants cursing the predictability of another broken promise. An anniversary attended by old paperbacks and the 12th day of Cock swearing like hell that he was going to do laundry again.
The kind of tragedy that almost gets to third base with Opera.
Another sad TidePod alone, stood up again.
Hamper knows how much those pants really wanted a goddamn bath.
"This is going to be one hell of a crossover!" Cock said to the car radio, driving like mad(ame bovary) all the way to the airport. It was already 6:58 and some parking meter change. Her flight was scheduled to arrive at 7:02.
"You'd better stop, STOP, using me up!" the car radio said back.
Matchbox Twenty.
Bic Lighter Twenty Seven.
Magnifying Glass Lighting Her Cigarette 2002.
Cock found Jewel waiting at baggage claim. Her suitcase looked weird.
"Do you like it?" Jewel asked. "It's from my Songlines Jewelry collection. We make luggage now too."
"It looks like a cat." Cock said, while in his head he was thinking:
Jewel makes jewelry?
That's like a guy named Frank making Frankenstiens.
Or a sentimentalist named Heartbreaker making sledge hammers and hearts.
"It is a cat." Jewel said. "It's my cat. Isn't she adorable?! She's eco-friendly too. Most suitcases are made out of whale teeth and plastic. Cat's don't come with that kind of ecological baggage. That's why when I travel, I carry Fluffles instead of a suitcase."
"Where do you put your clothes?" Cock asked "Or your poetry journal? Or your toothbrush and your soul?"
"I shove them in Fluffles." Jewel said, while giving her suitcase a little scratch behind the ear. "Everything except my building contracting skills." tapping the side of her head, finger first, "I keep those up here. Now what's this mystery you've told me almost nothing about?"
"I'll tell you when we get there." Cock said, "It'll be more dramatic that way."
Cock was right. They walked out of the airport, where he threw the cat in the trunk, and a math-related number of minutes later they were standing outside the Mercury Cafe, where the streets were paved with drama instead of ordinary pavement or gold. Only then did Cock tell Jewel everything.
"Wow, that sounds dramatic as hell." Jewel told Cock, "So there's what? Something wrong with the building? I'm a contractor. I can fix that."
Coincidence, or was she misquoting Coldplay? I guess we'll never know.
"I don't know." Cock said, lighting a cigarette like a tired pilot avoiding the sky because he didn't smoke anymore. "Wrong might be the wrong word, because everything seems to be walking around feeling wrong these days because everything else is walking around feeling so goddamn right. Let's say it's different."
"It's different?"
"Yes. The building's been, different."
"How's it different?" Jewel asked, as she pulled a tape measure out of her pocket and started measuring the sidewalk for clues.
"The long-time owner sold the place a few months ago. The suspicious activity moved in immediately after that. It started with the menu. This place used to serve stuff with interesting names like Roman's Holiday and the October Tiger. Sunday Night Spaghetti and Susan Jane's Chicken Fried Tofu. And then one day I walked in here, and all of that was gone. Nobody's seen a Roman Holiday in months. The restaurant side of the place has de-evolved into an overpriced Taco Bell, serving stuff with unimaginative names like enchiladas and nachos and quesadilla."
"I like nachos.' Jewel said.
"We all like nachos, Jewel." Cock said. "That's not the fucking point."
The side door of the Merc smashed open and a disgruntled Jake E. Lee exited the building, barking like hell at the concrete beneath his feet.
"Fucking Oligarchs!" Jake said. "You could spend All of your money in there."
He was either quoting one of the bloodhound tattoo guys from Hostel or he was being deadly serious. Cock assumed he was doing both.
"What's wrong with him?" Jewel asked.
"Jake runs a monthly Wednesday afternoon open mic for disgruntled musicians who used to play for Ozzy."
"Not any more I don't." Jake E Lee said. "The new owners of this creepy place wanna start charging me five hundred bucks a night. Either I pay up, or I can't host my reading series here. I can't afford that, so I'm gone."
"Why don't you just pay the extortion fee using some of the royalties you earn from writing the Bark at the Moon album?" Jewel suggested.
"Not everybody gets properly credited for writing their own songs, Jewel!" Jake said. "I'd stay out of there if I was you. It's not the Merc anymore. It might look like the Merc, but it's acting like a completely different building. It's Invasion Of The Building Snatchers in there. I think the goddamn thing's possessed."
From inside the building they could hear the sounds of a microphone being tested. The monthly Fbomb was about to begin.
"We've got to go inside, Jake E Lee." Cock said. "It's the only way we're going to get to the bottom of this to-be-continued-next-month's 2 part mystery. Also, I wrote something to read tonight. I'm dedicating it to Chis Martin and Dakota Johnson. It's called 50 Shade of Yellow.
To Be Continued!
Written for the October 2021 FBomb.
TagsColdplay, Jake E Lee, JewelLeave a comment
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Karine Vanasse is a Canadian Actress and Film Producer. Karine Vanasse Biography - Facts, Boyfriends, Age, Height, Wiki, Family & More.
Karine Vanasse is a Canadian Actress and Film Producer. She works in film and television industry. She is very talented and popular actress in Canada.
She was born on November 24, 1983 in Drummondville, Canada. Karine Vanasse age is 34 years old. Karine nationality is Canadian and caste is Christian, Currently her residence is in Drummondville, Quebec, Canada. There is no information about her education background. She is Christian and follows Christianity religion, her Star Sign is Sagittarius.
She belongs to a Christian family. Her father name is Conrad Vanasse (Council worker) and mother name is Renée Gamache. She has 2 brothers and 1 sister, brothers names are Vincent Vanasse and Alexis Vanasse, sister name is Élodie Vanasse. Karine Vanasse is married with Maxime Rémillard in 2006 and the couple get divorced in the year of 2014. After that, she start relationship with Samian canadian rapper and (Broke up in 2016). Currently she is single and not dating anyone. Let's read Becky G, Shiwani Saini, Maryse, Akam (WWE) Wiki & Biography.
She is talented Canadian Actress. Her journey began when she was a teenager. She started working in TV series '2 frères' in (1999). In TV series her acting role was as Lucie Chaput. Same year, she also started film acting career via South Korean film 'Set Me Free'. In film acted as Hanna. Since then, she appeared in many films and TV series in her career. In 2009, She did a movie 'Polytechnique' as a Valérie, for which she won the 'Genie Award for Best Actress'. Karine Vanasse net worth is $ 2 Million and salary information is not available, but seeing her performance in her field, we can assume that she earns good salary.
Karine Vanasse Height 5 feet 6 inches (168 cm) and Body Weight 121 Pounds (55-Kg). Her Body Measurements are 32-24-35 Inches. Karine Bra Size 32B, Waist Size 24 Inches and Hip Size 35 Inches. She has Brown color hair and Brown colored eyes. Body Type is slim.
She is quite active on social media. Karine has a huge followers on social media networking sites like Instagram, Facebook as well as Twitter. Karine Vanasse instagram 174k followers, Facebook page 13,253 followers and Twitter 90.4K followers.
These were latest information of Karine Vanasse Biography - Facts, Boyfriends, Family & More. Please share this biography with your friends and keep visit on celebsinfofeed.blogspot.com for celebrities exclusive updates.


This superb 2 bedroom condominium is located in the recently finished (2015) Baan Plai Haad on Wongamat Beach!. Baan Plai Haad is a 5 star condominium with 5 star facilities, and is located in probably Pattaya's best location, Wongamat Beach.
The interior of this condo has been meticulously designed by its owner from top to bottom with only the best high end furnishings, fixtures and appliances.


text:
1. WHO ARE YOUR MUSICAL INFLUENCES?
The Beatles, The Corrs, Alexz Johnson, Aerosmith, Bittersweet, and many more.
2. WHAT WRITERS ARE YOU INSPIRED BY?
T.V: Jane Espenson, Joss Whedon, Jed Whedon, Maurissa Tancheron, Steven Moffat, Mark Gatiss, J.J Abrams, Eric Kripke, Ben Edlund, Greg Berlanti, Marc Guggenheim, Shonda Rhimes, Rachel Bloom, Jason Katims, Rob Thomas, Miranda Hart, Damon Lindelof, Jenji Kohan, Tom Bidwell, Julie Plec, Kevin Williamson, Andrew Dabb, Jeremy Carver, Marti Noxon and many more.
Film: Nora Ephron, Aline Brosh McKenna, Karen McCullah, Kirsten Smith, Jennifer Lee, Fran Walsh, and many more.
Books: J.K. Rowling, Jane Austen, J.R.R. Tolkien, Eoin Colfer, John Green, Jostein Gaarder, Meg Cabot, Oscar Wilde, and many more.
3. WHERE CAN WE FIND WRITING SAMPLES FROM YOU?
Ask me here.
4. WHAT FESTIVALS/CONTESTS HAVE YOU BEEN SELECTED IN?
A complete list can be found here.
5. WHERE CAN WE LISTEN TO YOUR MUSIC?
Currently only "Mix it Up" is available online. On iTunes, Amazon, Spotify and a number of other online retailers and streaming services.
6. WHAT ADVICE WOULD YOU GIVE TO OTHER INDIE ARTISTS/ASPIRING WRITERS?
Firstly, don't conform to what society expects from you. I grew up in India and I get stereotyped a lot. People expect me to write Indian characters in my scripts. Or to write Hindi music or "fusion" music. But that's not me! I was always influenced by music from the U.K. and the U.S., as well as TV and films from the U.K. and the U.S. People don't expect to hear the kind of music I make coming from me, and I think that is a huge problem because people already have preconceived notions about someone before they even take the time to find out more about them. I think I've been very true to myself this whole time and not conformed to society's expectations of what an "Indian artist" should be. I think everyone should just be true to themselves and make the kind of music they want to make.
And secondly, get out there as much as possible. Write, sing, draw - whatever your craft is, do it. And once you've worked on it - get it out there. Submit your stuff to festivals, radio stations, websites...whatever it is, get out there. Get your voice heard.
7. WHERE CAN WE FIND YOU ON SOCIAL MEDIA?
Check out my social media links here
© 2020 Minoti Vaishnav


Would someone please post the song information (Name of movIe/Music Director/Lyricist) of this song sung by Asha Bhosle?
Please upload the song, maybe we can help in finding the details.
Thanks a lot Nabee sahab.
Nabee Saheb, Thank you for this nice song of Amanat.
An absolutely rare song. Ever since I downloaded it I have heard it many times, it does not cease to amaze.
As with Geeta ji, whose popular songs were always associated with Guru Dutt stable, Ashaji has also been, wrongly in my humble opinion, associated far too much with the OPN stable.
This song proves that there exists a world of Ashaji's songs outside the OPN school of compositions.
It gives me an idea to start a thread. May not be a bad idea.
Thanks once again, Nabeeji, you made my day.


text:
Q: cURL request in Swagger? I am new to Swagger. I want to ask a question. I have a docker on the server with a neural network that processes the photo! To send a photo to the docker for processing, I use the string "curl http: // localhost: 5000 / predict -X POST -F" image=@1201.jpg" to the terminal I tried to send this command along with the photo through the postman, and everything worked, but I want to try to do it through Swagger. This is possible ??? I wrote a form for downloading phtographs, but I cannot send a command (curl http: // localhost: 5000 / predict -X POST -F "image=@1201.jpg" ) Can you help?

 version: 1.0.0
# host: api.example.com
# basePath: /v1
# schemes:
#   - http
# host: 192.168.0.1:5000
# basePath: /predikt
paths:
   /upload:
     post:
       responses:
        '200':
          description: OK
       summary: Uploads a file.
       consumes:
         - multipart/form-data
       parameters:
        - in: formData
          name: upfile
          type: file
          required: true
          description: The file to upload.
        - in: formData
          name: note
          type: string
          required: false
          description: Description of file contents.

redpajama_set_name: RedPajamaStackExchange