text:
(-) Remove Starting Grant (StG) (156) filter Starting Grant (StG) (156)
(-) Remove (LS) Life Sciences (167) filter (LS) Life Sciences (167)
(-) Remove LS1 (8) filter LS1 (8)
(-) Remove LS3 (11) filter LS3 (11)
(-) Remove LS7 (24) filter LS7 (24)
(-) Remove LS8 (12) filter LS8 (12)
(-) Remove LS9 (14) filter LS9 (14)
(-) Remove Belgium (53) filter Belgium (53)
(-) Remove Israel (103) filter Israel (103)
Displaying 1 - 10 of 156. Show 10 | 20 | 50 | 100 results per page.
Project acronym 20SComplexity
Project An integrative approach to uncover the multilevel regulation of 20S proteasome degradation
Researcher (PI) Michal Sharon
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS1, ERC-2014-STG
Summary For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route. To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation: Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome. Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function. Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach. Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.
For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route. To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation: Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome. Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function. Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach. Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.
Project acronym ABDESIGN
Project Computational design of novel protein function in antibodies
Researcher (PI) Sarel-Jacob Fleishman
Summary We propose to elucidate the structural design principles of naturally occurring antibody complementarity-determining regions (CDRs) and to computationally design novel antibody functions. Antibodies represent the most versatile known system for molecular recognition. Research has yielded many insights into antibody design principles and promising biotechnological and pharmaceutical applications. Still, our understanding of how CDRs encode specific loop conformations lags far behind our understanding of structure-function relationships in non-immunological scaffolds. Thus, design of antibodies from first principles has not been demonstrated. We propose a computational-experimental strategy to address this challenge. We will: (a) characterize the design principles and sequence elements that rigidify antibody CDRs. Natural antibody loops will be subjected to computational modeling, crystallography, and a combined in vitro evolution and deep-sequencing approach to isolate sequence features that rigidify loop backbones; (b) develop a novel computational-design strategy, which uses the >1000 solved structures of antibodies deposited in structure databases to realistically model CDRs and design them to recognize proteins that have not been co-crystallized with antibodies. For example, we will design novel antibodies targeting insulin, for which clinically useful diagnostics are needed. By accessing much larger sequence/structure spaces than are available to natural immune-system repertoires and experimental methods, computational antibody design could produce higher-specificity and higher-affinity binders, even to challenging targets; and (c) develop new strategies to program conformational change in CDRs, generating, e.g., the first allosteric antibodies. These will allow targeting, in principle, of any molecule, potentially revolutionizing how antibodies are generated for research and medicine, providing new insights on the design principles of protein functional sites.
We propose to elucidate the structural design principles of naturally occurring antibody complementarity-determining regions (CDRs) and to computationally design novel antibody functions. Antibodies represent the most versatile known system for molecular recognition. Research has yielded many insights into antibody design principles and promising biotechnological and pharmaceutical applications. Still, our understanding of how CDRs encode specific loop conformations lags far behind our understanding of structure-function relationships in non-immunological scaffolds. Thus, design of antibodies from first principles has not been demonstrated. We propose a computational-experimental strategy to address this challenge. We will: (a) characterize the design principles and sequence elements that rigidify antibody CDRs. Natural antibody loops will be subjected to computational modeling, crystallography, and a combined in vitro evolution and deep-sequencing approach to isolate sequence features that rigidify loop backbones; (b) develop a novel computational-design strategy, which uses the >1000 solved structures of antibodies deposited in structure databases to realistically model CDRs and design them to recognize proteins that have not been co-crystallized with antibodies. For example, we will design novel antibodies targeting insulin, for which clinically useful diagnostics are needed. By accessing much larger sequence/structure spaces than are available to natural immune-system repertoires and experimental methods, computational antibody design could produce higher-specificity and higher-affinity binders, even to challenging targets; and (c) develop new strategies to program conformational change in CDRs, generating, e.g., the first allosteric antibodies. These will allow targeting, in principle, of any molecule, potentially revolutionizing how antibodies are generated for research and medicine, providing new insights on the design principles of protein functional sites.
Project acronym AcetyLys
Project Unravelling the role of lysine acetylation in the regulation of glycolysis in cancer cells through the development of synthetic biology-based tools
Researcher (PI) Eyal Arbely
Host Institution (HI) BEN-GURION UNIVERSITY OF THE NEGEV
Summary Synthetic biology is an emerging discipline that offers powerful tools to control and manipulate fundamental processes in living matter. We propose to develop and apply such tools to modify the genetic code of cultured mammalian cells and bacteria with the aim to study the role of lysine acetylation in the regulation of metabolism and in cancer development. Thousands of lysine acetylation sites were recently discovered on non-histone proteins, suggesting that acetylation is a widespread and evolutionarily conserved post translational modification, similar in scope to phosphorylation and ubiquitination. Specifically, it has been found that most of the enzymes of metabolic processes—including glycolysis—are acetylated, implying that acetylation is key regulator of cellular metabolism in general and in glycolysis in particular. The regulation of metabolic pathways is of particular importance to cancer research, as misregulation of metabolic pathways, especially upregulation of glycolysis, is common to most transformed cells and is now considered a new hallmark of cancer. These data raise an immediate question: what is the role of acetylation in the regulation of glycolysis and in the metabolic reprogramming of cancer cells? While current methods rely on mutational analyses, we will genetically encode the incorporation of acetylated lysine and directly measure the functional role of each acetylation site in cancerous and non-cancerous cell lines. Using this methodology, we will study the structural and functional implications of all the acetylation sites in glycolytic enzymes. We will also decipher the mechanism by which acetylation is regulated by deacetylases and answer a long standing question – how 18 deacetylases recognise their substrates among thousands of acetylated proteins? The developed methodologies can be applied to a wide range of protein families known to be acetylated, thereby making this study relevant to diverse research fields.
Synthetic biology is an emerging discipline that offers powerful tools to control and manipulate fundamental processes in living matter. We propose to develop and apply such tools to modify the genetic code of cultured mammalian cells and bacteria with the aim to study the role of lysine acetylation in the regulation of metabolism and in cancer development. Thousands of lysine acetylation sites were recently discovered on non-histone proteins, suggesting that acetylation is a widespread and evolutionarily conserved post translational modification, similar in scope to phosphorylation and ubiquitination. Specifically, it has been found that most of the enzymes of metabolic processes—including glycolysis—are acetylated, implying that acetylation is key regulator of cellular metabolism in general and in glycolysis in particular. The regulation of metabolic pathways is of particular importance to cancer research, as misregulation of metabolic pathways, especially upregulation of glycolysis, is common to most transformed cells and is now considered a new hallmark of cancer. These data raise an immediate question: what is the role of acetylation in the regulation of glycolysis and in the metabolic reprogramming of cancer cells? While current methods rely on mutational analyses, we will genetically encode the incorporation of acetylated lysine and directly measure the functional role of each acetylation site in cancerous and non-cancerous cell lines. Using this methodology, we will study the structural and functional implications of all the acetylation sites in glycolytic enzymes. We will also decipher the mechanism by which acetylation is regulated by deacetylases and answer a long standing question – how 18 deacetylases recognise their substrates among thousands of acetylated proteins? The developed methodologies can be applied to a wide range of protein families known to be acetylated, thereby making this study relevant to diverse research fields.
Project acronym AIDA
Project Architectural design In Dialogue with dis-Ability Theoretical and methodological exploration of a multi-sensorial design approach in architecture
Researcher (PI) Ann Heylighen
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Summary This research project is based on the notion that, because of their specific interaction with space, people with particular dis-abilities are able to appreciate spatial qualities or detect misfits in the environment that most architects—or other designers—are not even aware of. This notion holds for sensory dis-abilities such as blindness or visual impairment, but also for mental dis-abilities like autism or Alzheimer's dementia. The experiences and subsequent insights of these dis-abled people, so it is argued, represent a considerable knowledge resource that would complement and enrich the professional expertise of architects and designers in general. This argument forms the basis for a methodological and theoretical exploration of a multi-sensorial design approach in architecture. On the one hand, a series of retrospective case studies will be conducted to identify and describe the motives and elements that trigger or stimulate architects' attention for the multi-sensorial spatial experiences of people with dis-abilities when designing spaces. On the other hand, the research project will investigate experimentally in real time to what extent design processes and products in architecture can be enriched by establishing a dialogue between the multi-sensorial 'knowing-in-action' of people with dis-abilities and the expertise of professional architects/designers. In this way, the research project aims to develop a more profound understanding of how the concept of Design for All can be realised in architectural practice. At least as important, however, is its contribution to innovation in architecture tout court. The research results are expected to give a powerful impulse to quality improvement of the built environment by stimulating and supporting the development of innovative design concepts.
This research project is based on the notion that, because of their specific interaction with space, people with particular dis-abilities are able to appreciate spatial qualities or detect misfits in the environment that most architects—or other designers—are not even aware of. This notion holds for sensory dis-abilities such as blindness or visual impairment, but also for mental dis-abilities like autism or Alzheimer's dementia. The experiences and subsequent insights of these dis-abled people, so it is argued, represent a considerable knowledge resource that would complement and enrich the professional expertise of architects and designers in general. This argument forms the basis for a methodological and theoretical exploration of a multi-sensorial design approach in architecture. On the one hand, a series of retrospective case studies will be conducted to identify and describe the motives and elements that trigger or stimulate architects' attention for the multi-sensorial spatial experiences of people with dis-abilities when designing spaces. On the other hand, the research project will investigate experimentally in real time to what extent design processes and products in architecture can be enriched by establishing a dialogue between the multi-sensorial 'knowing-in-action' of people with dis-abilities and the expertise of professional architects/designers. In this way, the research project aims to develop a more profound understanding of how the concept of Design for All can be realised in architectural practice. At least as important, however, is its contribution to innovation in architecture tout court. The research results are expected to give a powerful impulse to quality improvement of the built environment by stimulating and supporting the development of innovative design concepts.
Project acronym ARISE
Project The Ecology of Antibiotic Resistance
Researcher (PI) Roy Kishony
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), LS8, ERC-2011-StG_20101109
Summary Main goal. We aim to understand the puzzling coexistence of antibiotic-resistant and antibiotic-sensitive species in natural soil environments, using novel quantitative experimental techniques and mathematical analysis. The ecological insights gained will be translated into novel treatment strategies for combating antibiotic resistance. Background. Microbial soil ecosystems comprise communities of species interacting through copious secretion of antibiotics and other chemicals. Defence mechanisms, i.e. resistance to antibiotics, are ubiquitous in these wild communities. However, in sharp contrast to clinical settings, resistance does not take over the population. Our hypothesis is that the ecological setting provides natural mechanisms that keep antibiotic resistance in check. We are motivated by our recent finding that specific antibiotic combinations can generate selection against resistance and that soil microbial strains produce compounds that directly target antibiotic resistant mechanisms. Approaches. We will: (1) Isolate natural bacterial species from individual grains of soil, characterize their ability to produce and resist antibiotics and identify the spatial scale for correlations between resistance and production. (2) Systematically measure interactions between species and identify interaction patterns enriched in co-existing communities derived from the same grain of soil. (3) Introducing fluorescently-labelled resistant and sensitive strains into natural soil, we will measure the fitness cost and benefit of antibiotic resistance in situ and identify natural compounds that select against resistance. (4) Test whether such "selection-inverting" compounds can slow evolution of resistance to antibiotics in continuous culture experiments. Conclusions. These findings will provide insights into the ecological processes that keep antibiotic resistance in check, and will suggest novel antimicrobial treatment strategies.
Main goal. We aim to understand the puzzling coexistence of antibiotic-resistant and antibiotic-sensitive species in natural soil environments, using novel quantitative experimental techniques and mathematical analysis. The ecological insights gained will be translated into novel treatment strategies for combating antibiotic resistance. Background. Microbial soil ecosystems comprise communities of species interacting through copious secretion of antibiotics and other chemicals. Defence mechanisms, i.e. resistance to antibiotics, are ubiquitous in these wild communities. However, in sharp contrast to clinical settings, resistance does not take over the population. Our hypothesis is that the ecological setting provides natural mechanisms that keep antibiotic resistance in check. We are motivated by our recent finding that specific antibiotic combinations can generate selection against resistance and that soil microbial strains produce compounds that directly target antibiotic resistant mechanisms. Approaches. We will: (1) Isolate natural bacterial species from individual grains of soil, characterize their ability to produce and resist antibiotics and identify the spatial scale for correlations between resistance and production. (2) Systematically measure interactions between species and identify interaction patterns enriched in co-existing communities derived from the same grain of soil. (3) Introducing fluorescently-labelled resistant and sensitive strains into natural soil, we will measure the fitness cost and benefit of antibiotic resistance in situ and identify natural compounds that select against resistance. (4) Test whether such "selection-inverting" compounds can slow evolution of resistance to antibiotics in continuous culture experiments. Conclusions. These findings will provide insights into the ecological processes that keep antibiotic resistance in check, and will suggest novel antimicrobial treatment strategies.
Project acronym BACTERIAL SPORES
Project Investigating the Nature of Bacterial Spores
Researcher (PI) Sigal Ben-Yehuda
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Summary When triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.
When triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.
Project acronym BARCODE DIAGNOSTICS
Project Next-Generation Personalized Diagnostic Nanotechnologies for Predicting Response to Cancer Medicine
Researcher (PI) Avraham Dror Schroeder
Summary Cancer is the leading cause of death in the Western world and the second cause of death worldwide. Despite advances in medical research, 30% of cancer patients are prescribed a medication the tumor does not respond to, or, alternatively, drugs that induce adverse side effects patients' cannot tolerate. Nanotechnologies are becoming impactful therapeutic tools, granting tissue-targeting and cellular precision that cannot be attained using systems of larger scale. In this proposal, I plan to expand far beyond the state-of-the-art and develop a conceptually new approach in which diagnostic nanoparticles are designed to retrieve drug-sensitivity information from malignant tissue inside the body. The ultimate goal of this program is to be able to predict, ahead of time, which treatment will be best for each cancer patient – an emerging field called personalized medicine. This interdisciplinary research program will expand our understandings and capabilities in nanotechnology, cancer biology and medicine. To achieve this goal, I will engineer novel nanotechnologies that autonomously maneuver, target and diagnose the various cells that compose the tumor microenvironment and its disseminated metastasis. Each nanometric system will contain a miniscule amount of a biologically-active agent, and will serve as a nano lab for testing the activity of the agents inside the tumor cells. To distinguish between system to system, and to grant single-cell sensitivity in vivo, nanoparticles will be barcoded with unique DNA fragments. We will enable nanoparticle' deep tissue penetration into primary tumors and metastatic microenvironments using enzyme-loaded particles, and study how different agents, including small-molecule drugs, proteins and RNA, interact with the malignant and stromal cells that compose the cancerous microenvironments. Finally, we will demonstrate the ability of barcoded nanoparticles to predict adverse, life-threatening, side effects, in a personalized manner.
Cancer is the leading cause of death in the Western world and the second cause of death worldwide. Despite advances in medical research, 30% of cancer patients are prescribed a medication the tumor does not respond to, or, alternatively, drugs that induce adverse side effects patients' cannot tolerate. Nanotechnologies are becoming impactful therapeutic tools, granting tissue-targeting and cellular precision that cannot be attained using systems of larger scale. In this proposal, I plan to expand far beyond the state-of-the-art and develop a conceptually new approach in which diagnostic nanoparticles are designed to retrieve drug-sensitivity information from malignant tissue inside the body. The ultimate goal of this program is to be able to predict, ahead of time, which treatment will be best for each cancer patient – an emerging field called personalized medicine. This interdisciplinary research program will expand our understandings and capabilities in nanotechnology, cancer biology and medicine. To achieve this goal, I will engineer novel nanotechnologies that autonomously maneuver, target and diagnose the various cells that compose the tumor microenvironment and its disseminated metastasis. Each nanometric system will contain a miniscule amount of a biologically-active agent, and will serve as a nano lab for testing the activity of the agents inside the tumor cells. To distinguish between system to system, and to grant single-cell sensitivity in vivo, nanoparticles will be barcoded with unique DNA fragments. We will enable nanoparticle' deep tissue penetration into primary tumors and metastatic microenvironments using enzyme-loaded particles, and study how different agents, including small-molecule drugs, proteins and RNA, interact with the malignant and stromal cells that compose the cancerous microenvironments. Finally, we will demonstrate the ability of barcoded nanoparticles to predict adverse, life-threatening, side effects, in a personalized manner.
Project acronym BARINAFLD
Project Using Bariatric Surgery to Discover Weight-Loss Independent Mechanisms Leading to the Reversal of Fatty Liver Disease
Researcher (PI) Danny Ben-Zvi
Summary Non-Alcoholic Fatty Liver Disease (NAFLD), a disease characterized by accumulation of lipid droplets in the liver, is the major precursor for liver failure and liver cancer, and constitutes a global health challenge. An estimated 25% of the adult population suffers from NAFLD, but no FDA approved drugs are available to treat this condition. Obesity is a major NAFLD risk factor and weight-loss improves disease severity in obese patients. Bariatric surgeries are an effective treatment for obesity when lifestyle modifications fail and often lead to improvement in NAFLD and type 2 diabetes. The overreaching objective of this proposal is to combine bariatric surgery in mice and humans with advanced molecular and computational analyses to discover novel, weight-loss independent mechanisms that lead to NAFLD alleviation, and harness them to treat NAFLD. In preliminary studies, I discovered that bariatric surgery clears lipid droplets from the livers of obese db/db mice without inducing weight-loss. Using metabolic and computational analysis, I found that bariatric surgery shifts hepatic gene expression and blood metabolome of post-bariatric patients to a new trajectory, distinct from lean or sick patients. Data analysis revealed the transcription factor Egr1 and one-carbon and choline metabolism to be key drivers of weight-loss independent effects of bariatric surgery. I will use two NAFLD mouse models that do not lose weight after bariatric surgery to characterize livers of mice post-surgery. Human patients do lose weight following surgery, therefore I will use computational methods to elucidate weight-independent pathways induced by surgery, by comparing livers of lean patients to those of NAFLD patients before and shortly after bariatric surgery. Candidate pathways will be studied by metabolic flux analysis and manipulated genetically, with the ultimate goal of reaching systems-levels understanding of NAFLD and identifying surgery-mimetic therapies for this disease.
Non-Alcoholic Fatty Liver Disease (NAFLD), a disease characterized by accumulation of lipid droplets in the liver, is the major precursor for liver failure and liver cancer, and constitutes a global health challenge. An estimated 25% of the adult population suffers from NAFLD, but no FDA approved drugs are available to treat this condition. Obesity is a major NAFLD risk factor and weight-loss improves disease severity in obese patients. Bariatric surgeries are an effective treatment for obesity when lifestyle modifications fail and often lead to improvement in NAFLD and type 2 diabetes. The overreaching objective of this proposal is to combine bariatric surgery in mice and humans with advanced molecular and computational analyses to discover novel, weight-loss independent mechanisms that lead to NAFLD alleviation, and harness them to treat NAFLD. In preliminary studies, I discovered that bariatric surgery clears lipid droplets from the livers of obese db/db mice without inducing weight-loss. Using metabolic and computational analysis, I found that bariatric surgery shifts hepatic gene expression and blood metabolome of post-bariatric patients to a new trajectory, distinct from lean or sick patients. Data analysis revealed the transcription factor Egr1 and one-carbon and choline metabolism to be key drivers of weight-loss independent effects of bariatric surgery. I will use two NAFLD mouse models that do not lose weight after bariatric surgery to characterize livers of mice post-surgery. Human patients do lose weight following surgery, therefore I will use computational methods to elucidate weight-independent pathways induced by surgery, by comparing livers of lean patients to those of NAFLD patients before and shortly after bariatric surgery. Candidate pathways will be studied by metabolic flux analysis and manipulated genetically, with the ultimate goal of reaching systems-levels understanding of NAFLD and identifying surgery-mimetic therapies for this disease.
Project acronym BETATOBETA
Project The molecular basis of pancreatic beta cell replication
Researcher (PI) Yuval Dor
Summary A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size. A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size.
A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size. A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size.
Project acronym BisProt
Project Developing Multispecific Biological Agents that Target Tumor Neovasculature for Cancer Imaging and Therapy
Researcher (PI) Niv Papo
Summary The dysregulation of signaling pathways that mediate cell proliferation, survival and migration is an underlying cause of many cancers. In particular, dysregulation and over-expression of avb3 integrin, membrane-type-1 matrix metalloproteinase (MT1-MMP; also known as matrix metalloproteinase-14, MMP14) and vascular endothelial growth factor receptor-2 (VEGFR2) correlate with poor prognosis in many human tumors, making these proteins attractive targets for therapeutic intervention. Numerous papers have demonstrated the cross-talk between biological processes mediated by αvβ3 integrins, MT1-MMP, VEGFR2, and their ligands, particularly pathways responsible for angiogenesis. Dual-specific proteins that can target and inhibit the activity of the above multiple receptors therefore have superior potential to single-targeted agents due to differential expression of these disease markers in different patients and the ability of this expression to change over time. Most currently available bispecific protein therapeutics comprise antibodies (Abs) or antibody fragments. The new approach proposed here entails rational and combinatorial methods for engineering multispecificity into small peptides and natural protein ligands to function as non-immunoglobulin alternatives to antibodies. In this innovative approach to creating dual-specific proteins, an additional functionality is introduced into a small peptide or into a natural protein ligand to complement its existing biological properties. We predict that this approach will form a major part of a highly effective strategy for creating ligand-based multispecific receptor inhibitors and molecular tools for protein recognition. We envision that protein variants generated from these efforts will promote the next generation of therapeutics including, but not limited to, molecular imaging agents, targeted drug delivery agents, and selective tissue targeting probes.
The dysregulation of signaling pathways that mediate cell proliferation, survival and migration is an underlying cause of many cancers. In particular, dysregulation and over-expression of avb3 integrin, membrane-type-1 matrix metalloproteinase (MT1-MMP; also known as matrix metalloproteinase-14, MMP14) and vascular endothelial growth factor receptor-2 (VEGFR2) correlate with poor prognosis in many human tumors, making these proteins attractive targets for therapeutic intervention. Numerous papers have demonstrated the cross-talk between biological processes mediated by αvβ3 integrins, MT1-MMP, VEGFR2, and their ligands, particularly pathways responsible for angiogenesis. Dual-specific proteins that can target and inhibit the activity of the above multiple receptors therefore have superior potential to single-targeted agents due to differential expression of these disease markers in different patients and the ability of this expression to change over time. Most currently available bispecific protein therapeutics comprise antibodies (Abs) or antibody fragments. The new approach proposed here entails rational and combinatorial methods for engineering multispecificity into small peptides and natural protein ligands to function as non-immunoglobulin alternatives to antibodies. In this innovative approach to creating dual-specific proteins, an additional functionality is introduced into a small peptide or into a natural protein ligand to complement its existing biological properties. We predict that this approach will form a major part of a highly effective strategy for creating ligand-based multispecific receptor inhibitors and molecular tools for protein recognition. We envision that protein variants generated from these efforts will promote the next generation of therapeutics including, but not limited to, molecular imaging agents, targeted drug delivery agents, and selective tissue targeting probes.


beautiful areas to hike and bike. You will find small to large lakes, including lakes for High Sierra Hikers.
Many of the recreational areas offered are a short drive from most places in Nevada County. If you have not seen some of the areas we have here between the two counties, you are truly missing out. It is true that "beauty is in the eye of the beholder". There is no mistaking the beauty of some of the recreational areas that would be available to you.


text:
Q: Extract zipx format in ubuntu I compressed my folder using Windows7 and it compressed to zipx format. How can I extract it in ubuntu 12.04 because it encountered error while extracting. When I google for it I came across this 'http://www.westernwillow.com/cms/blog/franco/open-zipx-file-linux-ubuntu-or-mac-anything-other-windows-7' but it also gives me unsupprted error while installing. Is their any other perfect solution.

A: WinZip through Wine
In case we do not have access to a Windows or OSX box where WinZip is installed and running we can also install WinZip through Wine where it is rated Gold or Platinum. ZIPX is supported from version 12.1.
My own tests on Wine (Ubuntu 12.04) running WinZIP 15.5 and the most recent version 17.5 lets you compress, and extract ZIPX archives but of course Ubuntu permissions will not be preserved by doing so.
For some files (here tested with PNG images) we may still be able to extract them with the Ubuntu Archive Manager, but on most of the files extraction will fail.
In case we need to extract ZIPX files more than once we will have to buy the full version but just a single extraction (or compression) will work just fine when running the free 45 day evaluation version.

A: Try to install 7z
sudo apt-get install p7zip-full

And then extract file using,

*

*Extracts all files from archive to the current directory.
7z e archive.zipx

*If you want extract files with full paths,
7z x archive.zipx

See more options: https://sevenzip.osdn.jp/chm/cmdline/commands/extract.htm

A: The Unarchiver's open-source command-line tools are listed as supporting zipx, so one option is:
sudo apt-get install unar

Then, you unpack using:
unar FILENAME.zipx

(The Unarchiver is to MacOS as 7-Zip is to Windows, so they both support a massive swath of formats but there are also many formats where they don't overlap. For example, 7-Zip doesn't support Stuffit .sit and .sitx files and, because macOS supports them natively, The Unarchiver doesn't support .dmg files.)

A: You can not. ZIPX is Windows 7 only at the moment.

Since the ZIPX file format is rather newly introduced by WinZIP, there are few zip utilities supporting it (WinRAR doesn't support ZIPX yet, neither does 7Zip). Thus, if you happen to encounter a corrupt zipx file you cannot repair it since no zipx repair utilities are yet available, so the only option is to go back and repackage the files (if you still have them) and only after that re-create the zipx archive.

Source

redpajama_set_name: RedPajamaStackExchange


I moved to the United States 30 years ago and have been in the insurance business ever since. I was born and raised in Zambia, Africa. I speak five different languages, which include: English, Hindi Gujarati, Chilapalapa and Bemba. I love to learn about different cultures and meet people from all around the world. My primary focus is on helping people secure their financial, health, life and long term care solutions that suits their personal needs.


The Evanni Multi LG TV Stand w/Fireplace Option available at Riley's Rooms serving Tecumseh and Windsor, ON.
How does this sound? An urban sleek aesthetic with a touch of the great outdoors. ThatåÕs the beauty of this refreshingly different 59-inch TV stand. Its vintage white finish is blended with replicated gray wood grain with butcher block design for a dual serving of style. The stand's long, linear drawer pull in a gunmetal finish is cool and eye-catching. You'll love the functionality. A spacious drawer, open cubby and adjustable shelf easily accommodate media needs. Cutouts keep wires out of sight and provide ventilation. Sold separately, an electric fireplace or integrated audio unit can easily be installed on the right-facing side.
Click the button below to add the Evanni Multi LG TV Stand w/Fireplace Option to your wish list.


The saldo can be checked on each countries gift card page depending on in which country you have purchased the gift card. Press here to check saldo of it is bought in Finland, here if in Sweden and here if in Estonia. The saldo is checked by typing the 16-digit card number from the back of the card. You can also check balance from the gift card kiosk in your shopping centre.
The gift card is valid 12 months from the purchase date. You can also check the expiry date on the saldo pages, see the previous question for links.
I want to buy a gift card. Where can I do this?
You can buy it from the gift card kiosks located in the shopping centres. See the list of shopping centres here.You can pay with the most common bank cards at the kiosk.
Can the gift card be exchanged for cash?
I have lost my gift card. Can it be replaced?
Lost gift card cannot be replaced.
Is it possible to return a product I have bought with a gift card?
Customer returns follow the rules of each store; please ask it straight from the store.
Can I use the card in more than one transaction?
Yes. You can use it in several shops in several transactions.


Flat through the summit of Mount Moriah is today, it was not always so; extensive substructures still exist beneath the surface, and there is reason to believe that recourse was held to something of the kind from the earliest days. Moreover, the ground level has been raised many feet by the accumulated debris of ages. This model, showing the original contours of the hill in relation to the buildings round it, will help in realizing the problems of the Temple builders.


text:
Home Articles Articles Home Natural20's Random Thought Table - It's Good To Talk Thursday, 18 July 2019
Natural20's Random Thought Table - It's Good To Talk
Written by Brian Nisbet
Our bestest Natural20 tells us of the trials and tribulations of allowing your players the benefits of free communication. I say gag all of 'em!
It's Good to Talk
As I write this I'm travelling from Dublin to Cork, the 3G connection on my laptop fading in and out of coverage, webpages failing to load and emails trying desperately to reach my inbox. Most of the cities and towns in Ireland are bathed in radiowaves these days, so it's only when you flit between them that the fragility of our communications networks is really laid bare. I have a little bit of a thing about the ability to keep in touch, to be reached and to get all the latest news, so I felt it was a suitable topic for today.
In our modern world we've begun to take the ability to communicate with everyone, instantly, for granted. Players have a tendency to carry this assumption, like many others, into whatever game they're playing, or to attempt to recreate technological advantage with magic or the like. There's also the massive advantage to be gleaned from the ability to communicate both within the party and with whatever important NPCs there may be elsewhere, either to keep abreast of what's going on or to call in the cavalry when it all starts to go wrong.
However this gift is one easily given and oft regretted, by the GM at least. Be it a set of magical items, a spell (Mage: The Ascension players used to be very, very fond of their Mind links), brain implants, genetic mutations or a variety of other options once the party can talk to each other, securely, the GM has lost one of their biggest plot levers. Players are, as we know, a devious bunch, and given a chance to plan, consult with those both near and far and get their story straight, their normal plot-derailing powers can be magnified tenfold!
Before you start adding "never let the players talk to anyone" into your list of GMing commandments, do remember just how useful it can be for both sides of the shield. And that's before you consider that any gift given is only there to be taken away at some crucial stage. For a start, dropping plot in from afar is always going to be a handy trick, especially if it forces difficult decisions on your group - "We realise you're only a day's travel away from the target system, but if you don't get to Quadrant Seven now, millions will die!" And as with any communication, who says the information being passed is accurate or true? Most people implicitly trust things that are sent from home/base/the boss, often with good reason, but much fun can be had when those at home don't have the group's best interests at heart, or have decided to sacrifice them without consultation. Depending on the communications method there could easily be the issues of impersonation or Chinese whispers. Partial or garbled messages can also be a lot of fun, missing crucial information, or offering up interpretations other than the intended. Of course you have to be very careful to limit the party's ability to clarify things in that situation, but we'll deal with methods of controlling media in a moment.
Intra-party communications are a bit trickier. They are obviously a massive boon to the players, but they can make the GM's life a damn sight easier as well. Sometimes. In a lot of situations it's just easier to let the PCs, briefly, chat amongst themselves and assume this is taking place in character rather than out. It also solves a number of issues where players say something, by accident, meant only for the rest of the party. But these are fudges to get around behaviour that should either be discouraged or should attract a heavy in game penalty. In the vast majority of situations the benefit is to the group. As I mentioned above it can allow for all sorts of plotting and scheming that would otherwise be impossible, whether due to the proximity of unwanted listeners, physcial separation, the need to be very quiet or very loud background noise. The last two tend to be more of a benefit when there is either fighting or sneaking to be done. I don't have the space to ennumerate all the different plot issues silent (or near silent) intra-party communications can neuter, but off the top of my head, here's a few: interrogations, diplomatic negotiations, covert ops, sudden changes in situation, ambush planning, con jobs, seduction and prison breaks. But really, the list goes on. So, this naturally leads to the question, why would you ever let your players have this kind of advantage?
In some cases the system explicitly gives options. There are multiple cyberpunk games (you remember those, they're like steampunk games with slightly less silly goggles) where everyone and their mother has the ability to communicate sub-vocally via an implant in their throat or a chip in their heads. Now, as it is oft stated, there's no compulsion on the GM to give the players something, just because it's in the sourcebook, but that argument wears thin when you're talking about something that really is a staple of the genre. Future games assume faster and better communications and reality backs this up. The same compulsion doesn't exist with fantasy games (remember, the only form of instant communication in Lord of the Rings was fraught with danger for the user and by the late Third Age there was really only one person to talk to), but there can still be reasons to say yes. One of the big reasons to allow this trick applies to so much else; if the players can have it, so can the NPCs. This is less useful for the GM, obviously, but it gives justification for a number of things and may be worth the hassle. Obviously if you don't allow the power/ability/thingy, then you can't screw around with it, and the options here are legion.
For a start, anything that starts off as secure and silent should never remain so forever. If you have players who don't think they can be hacked, then they deserve everything they get. It may not be in character for all of them to think about it, but someone should. The frequency and accuracy of the hacking (and obviously the justification/method) are up to the GM, but it may be considered cruel to just immediately have the NPCs know everything. It may be that certain NPCs can hear them when they're near-by, or that only long distance communications can be hacked, but there are a wealth of options.
The other big category of ways to screw around with things is with misinformation. This is, to a certain extent, still hacking, but it's a different magnitude, largely because it assumes the messages can be heard as well. Removing certain words, delaying messages, even different emphasis can cause all sorts of fun problems. Blocking one end or the other of a conversation is a little more obvious, but who says the problem isn't naturally occuring (gotta watch out for that cosmic radiation). Perhaps dealing with the hacker (an almost demeaning title to use for a major villain, but such is life) is a campaign goal and will result in the medium being unusable for a while, and used cautiously ever afterwards?
Precise communication is one of the hallmarks of true sentience and most of us rely on it quite a bit in real life. Players will love their GM if they're allowed to communicate with themselves and others, but drama and the chance that things could go wrong is what keeps games moving, keeps players on their toes and, in the end, makes the experience all the more memorable. So yes, it is good to talk, but nothing in a roleplaying game comes without a price.
Comment by GUEST on 2012-04-27 06:28:13
Profile headliner for dantig website, . Dating sites fish.Best on line dantig. Sim naughty dantig games page 1, .Ati card driver update video, . Sex dantig in bonnie illinois.Top dantig singles and personals websites. Dating north waterboro, .Dating north salem, . Dating hindman.
9HrNSw jqgtwrmflhgy
E7l8NX , [url=http://yovttzyjpxpd.com/]yovttzyjpxpd[/url], [link=http://ornxixeqljtl.com/]ornxixeqljtl[/link], http://zuwnidesctag.com/
SocZNn dbkxrkldgcnx
MCeitl , [url=http://qdmmbndnoyem.com/]qdmmbndnoyem[/url], [link=http://lkokooirlssj.com/]lkokooirlssj[/link], http://oufjlzhvycik.com/
Rolex is the best known and most reputed names in the world of luxury watches today. It is a brand which produces quality of watches for the customer across the world for ages. fake watches for men
Your post captures the issue pelefctry!
Great common sense here. Wish I'd thoguht of that. http://lenfhec.com [url=http://lytqdqkqp.com]lytqdqkqp[/url] [link=http://lcvynstxi.com]lcvynstxi[/link]
Your family photo's aywlas are so warm and inviting... These especially make one wish for an invite!!Glad you could be all together and enjoying each other during the holidays!! http://uiofsf.com [url=http://imfdxejcg.com]imfdxejcg[/url] [link=http://btfqbqq.com]btfqbqq[/link]
This is an absolutely sunnnitg home on a pristine lake. Trully a Jewel a must do. The hospitality of the owners is a major part of the experience as they seek to anticipate your every move. The rooms are more than just comfortable , they are just the way you would like your guest room to be. Peaceful picturesque asking to be your host!!!! Thank you Rick and Kyn for being the best if hosts on your delightful home
Previous - Next >>

redpajama_set_name: RedPajamaCommonCrawl


Elegantly finished in Midnight Black, this 2012 Jaguar XF Portfolio is a sleek, 1-owner saloon. It is a low-mileage Portfolio edition that has been garage kept and meticulously cared for since new and has spent the majority of its life here in the Seattle area since being sold new for $62,550. This XF remains under its factory 3-year warranty through 2015.
XF Portfolios come standard with an extremely long list of standard features and this example is further equipped with the optional Premium Package and optional glossy burl walnut interior inlays. The Premium Package outfits the car with blind spot monitoring, auto high-beam control, auto-dimming exterior mirrors and a power rear sunshade for added comfort. Notable standard luxury amenities include a London Tan / Warm Charcoal colored leather interior, Bluetooth telephone integration, GPS navigation, heated & cooled power adjustable front seats, power adjustable lumbar support, satellite radio, iPod/USB integration, HD radio and keyless ignition. The car rolls on 19" "Caravella" wheels and also features front and rear parking sensors, bi-Xenon head lamps and a rear-view camera.
Power comes from a 5.0L V8 engine that develops 385hp/380lb-ft of torque. The engine is backed by a shiftable 6-speed automatic transmission that drives the rear wheels.
CarFax history report and one remote key included with purchase.
The XF sedans are among the most attractive on the road today and this Midnight Black example is a great chance to get into a very well-equipped and low-mileage one for more than $15,000 off MSRP.


I never thought that I owned my son. Implicit with having a child, and the inherent parental bonding, I, like most parents, would do anything to protect our children. That includes shielding them from pain, even when it might be necessary like the vaccination or tetanus shots. The notion that I don't own my son combined with a consciousness that he is his own individual has led me to make parental decisions that err on the side of his autonomy as a human being.
It was when he recently passed his driver's license test and took another step towards complete independence that I realized I never told my son Walker that I owned him. I can't remember ever telling Walker, "…because you are my son you must do XYZ." I never asserted ownership of him by virtue of being his father that he should modify his behavior or perform a task.
I was consciously struck by my avoidance to lay claim to my son when I thought about how I speak of and to him. Rarely will I introduce Walker, as "my son" to somebody and I have never told him he must do something because he is "my son." The absolute weakest excuse for compelling a child to modify his or her actions is because you own them in some weird parental sense.
Do I mark my child forever?
Walker quickly grew out of wanting to dress like daddy.
The collision of perspectives, child ownership versus stewardship, happened before Walker was born. The central question at that point was whether to have him circumcised. My two primary resources for the decision were the Bible and my gut. Apostle Paul said let people circumcise their hearts and not their bodies. My default instinct is to do to others as I would have them do to me. Walker didn't get circumcised.
A child is not a project. You don't get to stand back at the end of the day and gaze with satisfaction at what you have built. Some parents try to etch their initials on their child which is almost universally met with push back from the prodigy. The thought of exerting some sort of ownership over Walker gives me this nauseous feeling of trying to be a slave owner. Walker, or any other child, wasn't born to be anybody's slave. And he successfully reminds "his" parents of it every day when he doesn't put away the dishes or clean up after "his" projects.
There are numerous decisions parents must make when raising a child. Health care decisions that must necessarily cause pain are the toughest. I didn't have to think too long before deciding that Walker should have surgery to permanently repair a broken leg even though I knew it would prolong and probably enhance his pain. It was a decision based on making him whole again after the accident and not subtracting from him.
Just because I fed and changed him, doesn't mean I get to own him.
It's a similar dilemma when it comes to having 'your' child vaccinated. Just like having you baby boy circumcised, there are the issues of illness and death from the procedure or vaccination. I may be guilty of going-with-the-flow when it came to having our child vaccinated. Aside from the possibility of injury, I knew I wasn't taking anything away from him. I don't fault my parents for having me vaccinated or circumcised. But there are times when I wish I got to make the decisions that permanently altered my body forever.
Our goal has always been to help him develop into an independent adult. Our decisions have always been colored with the realization that we don't own him and he must eventually mature into his own man. This has actually helped when, as a parent, we have to deal with the inevitable challenges to authority or just plain teenage lethargy. But honestly, I stand in shock when parents profess ownership over their children. No amount of rational argument to the contrary will change the opinion of these parents who revel in being ruler of their subjects for at least 18 years.
The best we can hope for is to forge a strong partnership with our son or daughter to help them mature into productive and sustainable adults. If I tried to exert ownership over Walker our relationship would be exponentially more difficult. I don't own him and he doesn't own me. Parents co-exist with children in an odd symbiotic relation where in no case should a mark of ownership ever be placed upon the child.


On 24 October 2018, HOPE'87 General Assembly took place at the Royal Archives (Haus-, Hof- und Staatsarchiv) in Vienna's inner district.
The annual HOPE'87 General Assembly will be held on the 24 October 2018 from 3-4 PM at the Haus-, Hof- und Staatsarchiv, Minoritenplatz 1, 1010 Vienna.
It's been exactly one and a half years since the implementation of the following project in several communities in Burundi that aim to enhance access to education and essential child protection services for children and adolescents.
Read more about Let the Championship begin!


Raspberry Pi: An affordable treat for students?
Technology affordability and sustainability are key concerns for educational leaders. Schools need seriously low-cost and capable options to inspire the next generation of programmers, computer scientists and technologists. Enter the Raspberry Pi, a forthcoming $35.00 mini computer running Linux.
About the size of a credit card, the Raspberry Pi connects to a USB keyboard and monitor or TV via HDMI. Powered by a 700Mhz ARM processor and 256M of RAM, the device runs Debian Linux and sports high-definition video playback. Two USB ports and an Ethernet jack are included. A less expensive model, sans Ethernet and with half the RAM, will also be available for $25.00. Overall, the Raspberry Pi is somewhat similar in power to a first generation XBOX; rather impressive for a device costing less than the price of dinner and a movie.
There are a few trade-offs to achieving a low-cost balance of power and capability. Current models do not include a wireless card. Additionally, the first production run is lacking a case, although the foundation has indicated that future models will address this limitation.
A UK registered non-profit, the Raspberry Pi Foundation's social mission is to "see cheap, accessible, programmable computers everywhere." After several years of development, the foundation plans to begin selling the Raspberry Pi in the next few weeks. Read more about the project at: http://www.raspberrypi.org/.


text:
Cool ReadsHighlights
Chris Babu's "The Initation" available via Permuted Press – (Press release)
Last Day Deaf — June 2, 2018
Everyone is equal. But no one is safe.
In a ruined world, Manhattan is now New America, a walled-in society based on equality. But the perfect facade hides a dark truth.
A timid math geek, sixteen-year-old Drayden watches his life crumble when his beloved mother is exiled. The mystery of her banishment leads him to a sinister secret: New America is in trouble, and every one of its citizens is in jeopardy.
With time running out, he enters the Initiation. It's a test within the empty subway tunnels—a perilous journey of puzzles and deadly physical trials. Winners join the ruling Bureau and move to its safe haven. But failure means death. Can Drayden conquer the Initiation, or is salvation out of his grasp?
About Chris Babu
Chris Babu grew up in North Haven, CT, playing soccer and the violin in his free time. After devouring The Shining under the covers with a flashlight when he was eight, Chris was hooked on fiction. He's always had a thing for young adult books. But he's also a major science and math nerd—physics being his favorite—and he has a math degree from MIT.
For nineteen years, he worked as a bond trader on Wall Street, riding the subway to and from work every day. He traded mortgage-backed securities for Bank of America and then Deutsche Bank, where he eventually ran the MBS trading desk. Now Chris writes full-time, always with his trusted assistant Buddy, a 130-pound Great Dane, who can usually be found on his lap. They split their time between New York City and the east end of Long Island. Their omnipresence at home drives his wife Michelle and daughter Lily crazy. The Initiation is his first novel.
Tags: Chris BabuCool ReadsPermuted Press
Next post Mixtape#89, (02/06/2018)
Previous post Indie Free Festival #28 (June 9, Central Park, Athens) {cancelled}


text:
Quick Spin: Zamboni 522 Electric Ice Resurfacer
When Frank J. Zamboni opened one of the largest ice skating rinks in the country just outside Los Angeles in 1940, he realized he needed to streamline the ice resurfacing process.
When Frank J. Zamboni opened one of the largest ice skating rinks in the country just outside Los Angeles in 1940, he realized he needed to streamline the ice resurfacing process, which required a tractor with a blade to shave the ice and three to four additional staff to sweep the shavings, pour water and squeegee away the slush. Using surplus war parts from Jeeps and tractors, he perfected his design on a number of iterations — and in 1949 the Model A Zamboni Ice Resurfacer was born.
Fast forward more than 60 years and the company, which has become ubiquitous with hockey games and halftime shows, now offers more than 10 machines ranging in capacity, price and ability. We had the chance to take the all-electric Zamboni 552 ($160,000) model for a spin at the East West Ice Palace in Artesia, CA, and the drive was, as expected, extraordinary.
The Zamboni 552 boasts a massive 17.5 horsepower electric motor that gets it to 60 mph…never; an 80-volt lead-acid battery pack and a steel frame are the primary contributors to its 9,750 pound weight. At first glance this thing might not seem vehicularly impressive, but take into consideration that it works silently and without emissions, can collect 125 cubic feet of shaved ice while simultaneously carrying more than 250 gallons of water, has studded tires, four-wheel-drive and a snowflake on the steering wheel, and it all becomes clear: this is a purpose-built machine that functions brilliantly. Turn the key, release the parking brake, flip the switch to forward, and you realize how smooth and surprisingly agile this five-ton machine really is, in spite of its imposing size and a drag coefficient equal to a small iceberg. It's not only easy to drive but oddly pleasurable for something so visually and literally cumbersome.
Turn the key, release the parking brake, flip the switch to forward, and you realize how smooth and surprisingly agile this five-ton machine really is, in spite of its imposing size and a drag coefficient equal to a small iceberg.
But the goal is more about smoothness and efficiency than it is about acceleration and speed — this unique vehicle was truly born out of a specialized necessity. Plus, the Zamboni does something few other vehicles do: it's used to enhance the safety and excitement of a sport without actually being central to the sport itself. Nevertheless, the Zamboni evokes a positive feeling that pervades the field of spectators. We'd be hard pressed to find anyone who didn't find the Zamboni a unique source of simple joy.
Surely day in and day out driving the Zamboni 552 Electric Ice Resurfacer would get old at some point, but I smiled the whole time I was piloting it and even thought what a great retirement job this would be. No bumps, smooth as glass and completely silent? My inner 70-year-old is already chomping at the bit.
Learn More: Here
The Best Wireless Earbuds for 2023 (So Far)
You're Cleaning Your Coffee Maker the Wrong Way
The 50 Best Watches for Men, from Casual to Luxury
28 Great Vintage Cameras You Can Still Buy
The Best Whiskey Glasses for Bourbon or Scotch
The Way to Keep Coffee Fresh Is the Simplest
15 Incredible Dive Watches Under $1,000
This Bourbon Is the Natural Wine of Whiskey
The Top German Watchmaker on Great Casual Watches
This Tiny Knife Changed How I Think About Knives


Sam Waver has always idolised his big brother, Jason. Unlike Sam, Jason, seems to have life sorted - he's kind, popular, amazing at football, and girls are falling over themselves to date him.
But then one evening Jason calls his family together to tell them that he's been struggling with a secret for a long time. A secret which quickly threatens to tear them all apart. His parents don't want to know and Sam simply doesn't understand. Because what do you do when your brother says he's not your brother at all? That he thinks he's actually . . . your sister?


text:
Home/News/India/More than 2,210 rape cases remain pending in Indian-held J&K
IndiaNews
More than 2,210 rape cases remain pending in Indian-held J&K
1,584 rape case reported during past four months of 2018
World News May 29, 2018
JAMMU: An Indian newspaper, Statetimes has reported on May 29, 2018 THAT While a section of the Kashmir society became pro-active in Kathua rape and murder case, "unfortunately the voice for justice remained silent for over 2,210 rape victims across the State, highest of these in the Valley."
The Statetimes report said that as per official record, 2,210 rape cases lodged in different police stations across the State till April 2018 still remained unsolved and most of these are registered in the Kashmir Valley.
According to the report in Indian-held Kashmir Valley 1584 rape cases continue to remain in the process of investigations in police stations of 12 districts.
The report newspaper quoted sources as saying that "a strong voice was raised in the Valley for justice to Kathua victim but they unfortunately never stood for the hundreds of women including the girl child who faced the similar fate in Kashmir." The sources further said that in Jammu less than half of the cases, as compared to the Kashmir, are pending in the Court of Law.
The report added that "in Kashmir division, 1,584 cases are pending for the past four months of the current year, which include 125 in Srinagar, 252 in Budgam, 70 in Pulwama, 58 in Shopian, 148 in Kulgam, 167 in Anantnag, 41 in Ganderbal, 85 in Bandipora, 306 in Baramulla and 332 in Kupwara. On the contrary, in Jammu 507 cases are still pending, which include 106 in Jammu, 77 in Udhampur, 49 in Reasi, 20 in Kishtwar, 69 in Bhadarwah, 61 in Ramban, 12 in Rajouri, 43 in Poonch, 30 in Samba and 40 in Kathua. However, the Leh region has fewer number of pending rape cases, which include three in Kargil and six in Leh.
India Rape
VOSA News Bulletin 28th May 2018
UK Foreign Secretary Victim Of Prank Call By Two Russian Comedians As An "Armenian PM"
Unidentified Virus Outbreak Takes Eight Lives In China
176 Lives Lost; A Human Error ?
Thousands Of Thirsty Camels To Be Killed As Water Drought Strikes South Australia
Trump Raises China Tariffs, Urges US Companies to Leave China
Nankana Sahib in Pakistan Lit Up Ahead of Guru Nanak Dev's 550th Birth Anniversary
At Least 12 Dead in India Tour Boat Capsize


text:
Chris Strompolos
David Yip
Felix Silla
Gregory Harsh
Hal Barwood
Jim Tso
Julian Glover
Max McCoy
Michael Sheard
Paul Freeman
Rob MacGregor
The Raiders Guys
Interview with Hal Barwood
By Eddie Mishan
Considered by most fans to be the greatest Indiana Jones video game creators, Hal Barwood has brought us some of the most popular Indy games over the years. Hal's accomplishments throughout his video game career include, Indiana Jones and the Infernal machine and Indiana Jones and the Fate of Atlantis, considered by most fans to be the quintessential Indiana Jones gaming experience. We were very fortunate that Mr. Barwood agreed to take time out of his busy schedule to speak with us about his work throughout the years on the Indiana Jones video games as well as a look into what goes on behind the scenes in creating an Indiana Jones video game.
What was the first game you ever created?
I've been designing and making games since I was a kid, and that was a long time ago. Back then there were no computers available to the average Joe, and certainly not to the average kid, so everything was paper or mechanical. I guess my first real game was an electrical football machine, where throwing concealed switches selected plays & defenses, and visible switches were used to set formations. My school friends used to borrow the thing and play for hours.
Did you have a passion for video games or was this just a career that you enjoyed?
Yes, I have been excited by video games since the moment they came into existence. I once drove all the way from LA to Barstow in order to play Computer Space, for example. That excitement eventually turned into a career I have thoroughly enjoyed. Or, to be more precise, to use an analogy I learned while writing MacArthur – as the wildcat said to the polecat after mistakenly mating with it, I've enjoyed as much of it as I could stand.
When did you first start working at LucasArts? What was the experience like?
1990. The company was then called Lucasfilm Games. I was invited to join up, because management wanted to do a follow up adventure to The Last Crusade, but no one then employed wanted to tackle the project. Some of the folks there knew me and knew I was working on some computer games, so they thought, give me a try. In those days the company was small. Eight years later I had more members on my team building The Infernal Machine than were in the entire organization back then.
Have there ever been any Indy game storylines that were considered but never went into development? If so, what kinds of stories were considered and can you tell us about them?
Well yes, several. The first one I'm aware of was what I was originally hired to design and build. I've forgotten the actual title, but Chris Columbus had written a screenplay for a 4th Jones movie, and it had been rejected. Management thought it might work as a game, but I thought it was substandard. I guess everyone else did too, but I was the only real screenwriter in the company, and when I turned up my nose everyone breathed a sigh of relief. The narrative took Indy to Africa and had him pursuing Chinese artifacts there.
Much later, when I was starting what turned out to become The Infernal Machine, I wanted to do a game based on a story that George and Steve were rumored to have concocted. The next movie wasn't happening, so I was hopeful. Instead, I was told, "don't go there," because the story might still become the basis of a movie. Aside from mentioning that the subject was science fiction and the setting was America in the 1950's, I can't talk about it.
Indiana Jones and the Fate of Atlantis was your first Indiana Jones game, how did that project come about?
Following on from above... I was brought into Lucasfilm Games specifically to design & build a Jones game, following on the success of The Last Crusade. The story I was handed, in the form of a Chris Columbus screenplay, had already been rejected for a Jones movie, and it didn't seem very interesting as a game either. So Noah Falstein (who worked with me on the initial design) and I, desperate to come up with an alternative, hurried over to the Skywalker Ranch research library and started leafing through some cheap Mysteries-of-the-Pasttype books. And when we cracked the pages of the Time-Life volume, we found ourselves staring at a diagram of Atlantis laid out in three concentric circles. The shapes just looked like a game, and we seized upon the idea. Soon thereafter I learned about a precious metal alloy invented by the Atlanteans -- orichalcum -- and that provided the basis for competition with the Nazis.
Could you describe the kind of work you did during the production of Indiana Jones and the Fate of Atlantis?
I was a jack-of-all-trades. I fleshed out the design even as production got underway, wrote a screenplay, oversaw the art and SCUMM-coding teams, and even did a little art plus a lot of the coding myself.
Did George Lucas have any direct involvement in the production of Fate of Atlantis?
No, he didn't. He's pretty much always been an avuncular presence at the game company. A steadfast supporter, but always in the background.
Was there any research done for the game? That is, was there research on both the subject of Atlantis and the character of Indiana Jones?
The research was extensive, but as mentioned above, it consisted largely of reading through crazy books by strange authors who were true believers in the reality of Atlantis and thought they knew where to find it. Some placed it in the Americas, some off Spain, and others near the volcanic island of Santorini in the Mediterranean. Out of it all came the plot-driving notion of inventing a mythical book written by Plato that pinpoints the city's whereabouts. The most important parts of the story -- I made them up. We all have more fun that way.
As to research on Jones... well, I watched the movies again and again, and I read the Lucasfilm "bible" that annotated important dates and times in Indy's fictional life. Injecting Jones into a game requires extending his abilities and tendencies into the world of interactivity, but it's crucial to stay true to what everyone already knows about him.
Were there any major production problems that you were faced with during the creation Indiana Jones Fate of Atlantis?
There were two of note. First, Noah Falstein and I set up three paths (wits, team, and fists) to take the player through the game on his or her own terms, depending on preference for lonely puzzle-solving, companionable cooperation, or bare-knuckled action. This attractive feature took immense amounts of labor to implement, even after we limited the idea to the first two-thirds of the game. It added about six months to the production schedule and earned me a lot of scowls from management along the way.
Second, Fate was conceived during a carefree era when production was pretty free form and resources were brought on as needed without much ado. It was completed two years later when the company had experienced the first of many regime changes and was counting every penny. During the middle of it all I suddenly found myself squeezed for the animation and coding I desperately needed to finish. What started out as fun ended up as a grueling experience.
From start to finish, how long did it take to create Fate of Atlantis?
Just about 2 years. I began designing and writing in the spring of 1990, and we published in 1992.
Indiana Jones and the Fate of Atlantis is considered by a lot of fans to be the greatest Indiana Jones game in history. What do you attribute to the success of Fate of Atlantis?
I don't have a real good answer. I like it because it's dense, has a variety of game play mechanics, and tells a pretty good tall tale.
Has it ever been considered to remake Fate of Atlantis and make it a 3D game in the style of Emperor's Tomb? Would you want to do something like that?
No thanks. Enough is enough.
Back in the early 90's, LucasArts was working on a sequel to Fate of Atlantis called Indiana Jones and the Iron Phoenix. What can you tell us about the project and why it was dropped?
I had a hand in this one as a story consultant. It was my idea to find some artifact that would allow post-war Nazis hiding in Bolivia to resurrect Der Fuehrer from his ashes. Everyone got excited and started building the game. Fifteen months into production the company showed some of it at ECTS, the European trade show. There they were told that selling a game depicting post-war Nazi revival, no matter how negatively would be illegal in Germany. We should have known. Without sales there, one of our most important overseas territories, LucasArts couldn't hope to recoup their investment, so the game was canceled. Joe Pinney, the project leader, was crushed. Eventually, a toned-down version of the story was published by Dark Horse Comics.
Also, what can you tell us about the so-called canceled Indy game called, Indiana Jones and the Spear of Destiny?
Not sure, but my guess is, this is the game Aric Wilmunder, a fellow who was working on Iron Phoenix, wanted to do. It almost happened with a small studio in Canada, but we couldn't perfect the internal supervision / external work model at the time, and it fell apart.
Indiana Jones and his Desktop Adventures is a pure gem when it comes to Indy gaming. When did the idea of Desktop Adventures first arise?
I like storytelling, and I also like classical, rhythmic, replayable games, like Stratego or chess. It occurred to me that I might be able to split story and game elements into small chunks and find ways of algorithmically assembling them into replayable action adventures. So I did. I built a working prototype on a Mac in HyperCard, using the scripting language called HyperTalk. The prototype story had nothing to do with Jones. It took place in a post-apocalyptic future where only an elite few know how to repair and maintain the few vital machines that preserve some semblance of human civilization. It was called, Tools of the Tinker's Trade.
Could you tell us about the production of the game? Was the randomly created worlds an already established concept or did you have to start from scratch?
I'm hardly the first to figure out how to recombine game elements, but the Desktop Adventure idea was the first to concentrate on replayable storylines. And yup, I started from scratch (see above).
LucasArts sales people couldn't figure out how to sell the idea, even though Solitaire and Hearts and their ilk were already popular on PC desktops. So eventually I was forced to drop the Tinker's Trade concept and reach for marketplace security in the form of Dr. Jones. It didn't really work -- the game generated negative reviews (from people who expected cutting edge graphics and sound from Lucas, not desktop toys) and barely sold.
Personally, I much prefer the second version of the game, Yoda Stories. We improved the engine quite a bit to make predicting outcomes a little less trivial, and not only that, it sold really well. Too bad we didn't make some more of these things.
Indiana Jones and the Infernal Machine was revolutionary in that it was the first game to put Indiana Jones in a full 3D world. How did this project first come about?
I'm not a fan of first person shooters, but I certainly admired the 3D worlds that were being created for them as 3D got going. It has always seemed to me that Jones is by nature an action kind of guy, and I wanted to exploit that characteristic by turning him loose in a 3D environment, whip, gun, fists, exotic locales, and all.
What inspired the move from 2D to 3D when Infernal Machine was made? Was it ever considered to do Infernal Machine as a 2D game like Fate of Atlantis?
2D was never considered for The Infernal Machine. 3D was in the air, it was becoming popular; we all saw it as the natural evolution of our biz. I wanted Jones to take part in the new era. The premise of the game was, "Jones action in 3D." Once I got the company to commit to that, then I thought up the story.
It would seem as though putting Indiana Jones in a 3D game environment and still making it a true Indiana Jones adventure would be difficult. Was this ever an issue?
That's true; and The Infernal Machine isn't a "true adventure," which is not my favorite kind of game, to play or build, anyway. It's an action-adventure, a popular genre on consoles, but not as common on PCs. Changing the game genre was never an issue – in fact, doing so was crucial; no one wanted to do another puzzly adventure game like Fate of Atlantis. We had combat, we had stunts, and we also had puzzles. The puzzles seemed like an extension of exploration to most, though, simply how you would normally interact with a world of mysterious archeological ruins and magical artifacts.
What was your reason for bringing back Sophia Hapgood in Indiana Jones and the Infernal Machine?
I think she was an alluring, exciting, tricky character, very much Indy's match in spirit and resourcefulness. And I didn't think Indy would ever join up with a spy organization unless invited by someone he knew, no matter how intriguing the mystery that awaited. Of course he had long since learned not to trust her, but he was always attracted.
Some fans of the game would have preferred a more action based game rather than the platform jumping and puzzle solving. Was the puzzle aspect a new concept or was it something that had been done before?
I've never played an action game that didn't include stunts and a few puzzles, but we emphasized them, and partly because that's what Jones does: he gets his hands on ancient artifacts by means of his physical daring and puzzle-solving skills.
How do the supernatural elements in Fate of Atlantis and Infernal Machine compare to the supernatural elements in the Indiana Jones films?
Not that different in nature, but in expression, a lot. The Indy movies last, what, two hours? In that brief space of time the fictional world goes from ordinary to spooky, and then the lights come up and, whew, it's over. My Indy games were designed to take 15-20 hours to complete, and that raises a fundamental story problem. Delaying the arrival of supernatural elements until 15 hours of game play have been accomplished is a surefire way to bore Jones fans, so I elected to construct the story in rhythmic segments, each going from ordinary to weird, and in the case of The Infernal Machine, each culminating in an encounter with a supernatural boss monster.
We heard that you were involved in the production of Indiana Jones and the Emperor's Tomb early on. Can you tell us more about this and how you were involved?
My involvement was limited to a brief story review, without much effect, I'm afraid.
Have you ever considered doing another Indiana Jones game?
I loved working on Jones games. Jones doesn't exist in his own universe, but right here in the real world, at some historical remove. And that means each adventure is a brand new story, a wonderful opportunity to be creative. But my Jones period is over.
Would you ever like to do an adaptation of the Indiana Jones trilogy as a 3D game series and do you think it would work?
I think the license is getting tired. And I think the best way to keep it alive is to be as original as possible in the storytelling. I don't want to be involved with the trilogy.
If you had whatever technology you needed at your fingertips, had unlimited funding, and could do anything you wanted, what would be your dream Indiana Jones game?
The game that management warned me away from, the mysterious "don't go there" game.
Can you tell us about your new company, Finite Arts?
It's not really new. Finite Arts was, for nearly twenty years, my "personal service company" in Hollywood, my way of legally dodging taxes as a freelance screenwriter. Now that I've left LucasArts, I'm reviving it for a freelance whirl in game design and writing.
What do you consider your all time favorite video game?
That's like asking a composer about his favorite chord -- I love many, many games that I have played over the long years (and have often been irritated beyond measure by the very same games). To pick one out of the crowd is tough. The first one that I thought demonstrated creative charm was Rogue. It combined a vague narrative with minimalist x & y geometry good enough to make me feel like I was exploring a world. The title that encouraged me to actively pursue a career in games was the original Castle Wolfenstein. I thought it was fun, and it's many little conceptual errors flattered me into thinking I could do better. The more you learn, though, the harder your heart becomes, and in more recent times less stands out from the crowd, even though the average game is of much higher quality today than when I got started. I guess one of my favorites is the N64 Zelda action-adventure, Ocarina of Time. My favorite plat former is a toss-up between Tomb Raider II and Rayman 2. For sense of humor, I vote for Vice City. For sports, I'm an EA NHL Name-the-Year fan. And don't wince; I'm also partial to Spyro the Dragon.
From your point of view, what do you see happening in the future of games?
I'm lousy at predicting sunrise, let alone anything else. There is no 4D, so an important revolution, the transition from 2D to 3D, has already been accomplished. I look for more and more sophistication in visual expression over the next few years until it will hardly be possible to differentiate a game from a movie on our TV sets. The online phenomenon will continue to grow, but I believe massive-multiplayer-online-games are lifestyles rather than entertainment, and I think success will be confined to very few titles. On the other hand, I expect online contest games, in the mode of Counterstrike, to proliferate with the next generation of consoles. Longer term, I hope that natural language production combined with expert systems will completely revolutionize how we interact with computers themselves and the artificial characters inside computer games.
Do you have any advice or tips to someone looking to get into the video game industry?
Like the movie business, the book trade, Broadway musicals, like any of the so-called "arts" you care to name, the sad truth is, there's no rational way to get into the business of electronic games. It's not like becoming a lawyer, where you go to school, pass the bar, and voila, hold off the recruiters.
My advice is: look at the ingredients of games -- design, art, programming, production, marketing, sales, and so on; think what attracts you -- and then get good at it! Put your ideas into action by building some games. Learn Flash or Director, or pick up a level editor and start cranking out mods.
Thank you very much for your time Mr. Barwood!
Thanks. It's a very nice site you have. Let's hope someone continues the Indy gaming tradition with some punch and polish, so you guys will have some more grist for your well-tuned mill. - Hal
Interview conducted on: October 10th, 2004