Immensely enjoying all the treats of New Zealand! Wrapping up my first week here, and wifi is harder to come by than I had imagined! I'm sitting in pub in Wellington with exceptionally good Internet, so I'm taking the opportunity to share a few photos with you.
Beautiful! You're making me want to gooooo!
I love this!! I am so jealous!


text:
Alan II Krętobrody (ur. ok. 900, zm. 952), książę Bretanii, hrabia Vannes, Poher i Nantes, syn Mathuedoiego, hrabiego Poher, i jego nieznanej z imienia żony, córki króla Bretanii Alana I Wielkiego.

Życiorys
Po śmierci Alana Wielkiego, kiedy Bretanię opanowali wikingowie, Alan wraz z ojcem uciekli na dwór króla Anglii Edwarda Starszego. Po 29 latach bezkrólewia Alan II powrócił do Bretanii w 936 roku. Wylądował w Dol i został tam powitany przez mnicha Jana de Landévennec. Wsparcia Alanowi udzielił następca Edwarda Starszego, Athelstan. Do 937 r. Alan opanował większość Bretanii, spychając wikingów nad Loarę. W 938 r. został okrzyknięty księciem Bretanii. 1 sierpnia 939 r. umocnił swoje panowanie, pokonując wikingów pod Trans. Alan ogłosił dzień swego zwycięstwa świętem narodowym.

Alan był bliskim sojusznikiem króla Ludwika IV Zamorskiego, który razem z nim przebywał na wygnaniu w Anglii. Alan zrzekł się praw do Cotentin, Avranchin i Mayenne, w zamian za co Ludwik orzekł, że Bretania nigdy nie była częścią jego królestwa. Alan był również sprzymierzeńcem Tybalda I, hrabiego Blois.

Książę zmarł i został pochowany w swojej stolicy, Nantes, w bazylice Notre Dame. Jego następcą został jego małoletni syn Drogo. Alan miał również dwóch nieślubnych synów – Hoela i Guerecha, późniejszych książąt Bretanii.

Przypisy

Władcy Bretanii
Zmarli w 952

redpajama_set_name: RedPajamaWikipedia


text:
Q: How to write strictly conforming interrupt service routines (on AVR) The C Standard mandates that a signal handler may access only objects of type sig_atomic_t (besides lock-free atomics). Accesses to objects of other types produce UB. An interrupt service routine resembles a signal handler, so this restriction must be obeyed when writing ISRs.
avr-libc's signal.h is broken in that it does not declare type sig_atomic_t, though it does declare a variable of that name, of type volatile signed char.  Presumably, that was meant to be a typedef.
But if you want an ISR to access, say, a systick counter of type uint32_t then that would produce UB.
Are there any special precautions / exceptions from the standard that avr-gcc imposes, so that it would be possible to write a strictly conforming ISR?

A:
How to write strictly conforming interrupt service routines (on AVR)

As you tagged the question avr-gcc, I'll assume GCC1 in the remainder. It's not possible to do it in a performing way due to 2 reasons:

*

*There is no way to write an ISR in a conforming way. avr-gcc uses attributes to implement this.

*avr-gcc implements neither atomic types nor atomic builtins (where the latter are compiler specific of course, so you can ignore them for conforming discussion).  Even if avr-gcc implemented atomic types, using libatomic would be considered inappropriate due to its resource consumption by most AVR folks. And even the simple atomic accesses that could be performed by the compiler without resorting to lib code are not implemented. Take for example:
int var;
_Atomic int aaa;

int get_var_atomic (void)
{
    int v;
    __atomic_load (&var, &v, __ATOMIC_SEQ_CST);
    return v;
}

int get_var_atomic_n (void)
{
     return __atomic_load_n (&var, __ATOMIC_SEQ_CST);
}

int get_aaa (void)
{
    return aaa;
}

All three functions will forward to __atomic_load_2, which does not exists (as of avr-gcc v13), and respective insns don't exist, either. Or more precisely: there are generic versions in libatomic, but bachend avr has libatomic disabled.
So the closest you can do is to use these primitives to implement atomic magic, and also to provide these functions.  By its very nature, these functions cannot be inlined. So the only reasonable approach is to implement this in the compiler backend itself, which is somewhere in ./gcc/config/avr/avr.md2,3.

1 Hence avr-gcc or avr-g++ and AVR-LibC.  Dunno how the situation is for other compiler brands like IAR.
2 You can use the vanilla non-atomic loads and stores code emitters, but you'll have to get an 8-bit tmp reg Rx so you can
in Rx, SREG
cli
<vanilla-code>
out SREG, Rx

for the simple cases. __tmp_reg__ can't be used here for obvious reasons.
3 I just got ranted for globally switching off IRQs.  So if you want to avoid that, you'll have to go the libatomic way and allocate semaphores. No need so say that this is extremely expensive compared to the usual approaches.

redpajama_set_name: RedPajamaStackExchange


With this applet you can monitor the speed of your network devices.
Afterwards add the applet to the gnome-panel. Right click on the panel, choose "Add to panel" and select the applet.
Filezilla is an ftp-client with many features - supporting FTP, FTPS, FTPES and SFTP.
With gparted you are able to resize, move and format partitions - many file systems are supported.
Streamtuner is a stream directory browser. With Streamtuner you can listen to SHOUTcast streams etc.
K9copy is a DVD backup tool, which is able to shrink the content of a DVD9 to fit on a DVD5.
Audacity is a software to edit audio files.
You will be asked a few questions about install paths etc. - simply hit enter for every question - with the exception of the question if you want the installer to run vmware-config.pl after the installation.
Now download this patch. After that open a terminal and switch to the folder where you downloaded the patch. Unpack the patch and copy the included .tar-files to the VMware module-sources directory.
Answer all the questions with "yes" and accept the license agreement (if you agree with it). After that you'll be asked a few questions about install paths etc. - simply hit enter for every question. At the end you have to enter your serial number.
The VMware Server is now available in the gnome applications menu.
Please inform me if there is a problem with it but this is such a perfect introduction to linux world that I'd like to advertise it!!!!!!!


text:
(-) Remove <label class='research-domain' title='Computer Science and Informatics'>PE6 (4)</label> filter PE6 (4)
(-) Remove Finland (3) filter Finland (3)
(-) Remove Sweden (10) filter Sweden (10)
Project acronym ANGIOFAT
Project New mechanisms of angiogenesis modulators in switching between white and brown adipose tissues
Researcher (PI) Yihai Cao
Host Institution (HI) KAROLINSKA INSTITUTET
Summary Understanding the molecular mechanisms underlying adipose blood vessel growth or regression opens new fundamentally insight into novel therapeutic options for the treatment of obesity and its related metabolic diseases such as type 2 diabetes and cancer. Unlike any other tissues in the body, the adipose tissue constantly experiences expansion and shrinkage throughout the adult life. Adipocytes in the white adipose tissue have the ability to switch into metabolically highly active brown-like adipocytes. Brown adipose tissue (BAT) contains significantly higher numbers of microvessels than white adipose tissue (WAT) in order to adopt the high rates of metabolism. Thus, an angiogenic phenotype has to be switched on during the transition from WAT into BAT. We have found that acclimation of mice in cold could induce transition from inguinal and epidedymal WAT into BAT by upregulation of angiogenic factor expression and down-regulations of angiogenesis inhibitors (Xue et al, Cell Metabolism, 2009). The transition from WAT into BAT is dependent on vascular endothelial growth factor (VEGF) that primarily targets on vascular endothelial cells via a tissue hypoxia-independent mechanism. VEGF blockade significantly alters adipose tissue metabolism. In another genetic model, we show similar findings that angiogenesis is crucial to mediate the transition from WAT into BAT (Xue et al, PNAS, 2008). Here we propose that the vascular tone determines the metabolic switch between WAT and BAT. Characterization of these novel angiogenic pathways may reveal new mechanisms underlying development of obesity- and metabolism-related disease complications and may define novel therapeutic targets. Thus, the benefit of this research proposal is enormous and is aimed to treat the most common and highly risk human health conditions in the modern time.
Understanding the molecular mechanisms underlying adipose blood vessel growth or regression opens new fundamentally insight into novel therapeutic options for the treatment of obesity and its related metabolic diseases such as type 2 diabetes and cancer. Unlike any other tissues in the body, the adipose tissue constantly experiences expansion and shrinkage throughout the adult life. Adipocytes in the white adipose tissue have the ability to switch into metabolically highly active brown-like adipocytes. Brown adipose tissue (BAT) contains significantly higher numbers of microvessels than white adipose tissue (WAT) in order to adopt the high rates of metabolism. Thus, an angiogenic phenotype has to be switched on during the transition from WAT into BAT. We have found that acclimation of mice in cold could induce transition from inguinal and epidedymal WAT into BAT by upregulation of angiogenic factor expression and down-regulations of angiogenesis inhibitors (Xue et al, Cell Metabolism, 2009). The transition from WAT into BAT is dependent on vascular endothelial growth factor (VEGF) that primarily targets on vascular endothelial cells via a tissue hypoxia-independent mechanism. VEGF blockade significantly alters adipose tissue metabolism. In another genetic model, we show similar findings that angiogenesis is crucial to mediate the transition from WAT into BAT (Xue et al, PNAS, 2008). Here we propose that the vascular tone determines the metabolic switch between WAT and BAT. Characterization of these novel angiogenic pathways may reveal new mechanisms underlying development of obesity- and metabolism-related disease complications and may define novel therapeutic targets. Thus, the benefit of this research proposal is enormous and is aimed to treat the most common and highly risk human health conditions in the modern time.
Project acronym CORALWARM
Project Corals and global warming: The Mediterranean versus the Red Sea
Researcher (PI) Zvy Dubinsky
Host Institution (HI) BAR ILAN UNIVERSITY
Summary CoralWarm will generate for the first time projections of temperate and subtropical coral survival by integrating sublethal temperature increase effects on metabolic and skeletal processes in Mediterranean and Red Sea key species. CoralWarm unique approach is from the nano- to the macro-scale, correlating molecular events to environmental processes. This will show new pathways to future investigations on cellular mechanisms linking environmental factors to final phenotype, potentially improving prediction powers and paleoclimatological interpretation. Biological and chemical expertise will merge, producing new interdisciplinary approaches for ecophysiology and biomineralization. Field transplantations will be combined with controlled experiments under IPCC scenarios. Corals will be grown in aquaria, exposing the Mediterranean species native to cooler waters to higher temperatures, and the Red Sea ones to gradually increasing above ambient warming seawater. Virtually all state-of-the-art methods will be used, by uniquely combining the investigators expertise. Expected results include responses of algal symbionts photosynthesis, host, symbiont and holobiont respiration, biomineralization rates and patterns, including colony architecture, and reproduction to temperature and pH gradients and combinations. Integration of molecular aspects of potential replacement of symbiont clades, changes in skeletal crystallography, with biochemical and physiological aspects of temperature response, will lead to a novel mechanistic model predicting changes in coral ecology and survival prospect. High-temperature tolerant clades and species will be revealed, allowing future bioremediation actions and establishment of coral refuges, saving corals and coral reefs for future generations.
CoralWarm will generate for the first time projections of temperate and subtropical coral survival by integrating sublethal temperature increase effects on metabolic and skeletal processes in Mediterranean and Red Sea key species. CoralWarm unique approach is from the nano- to the macro-scale, correlating molecular events to environmental processes. This will show new pathways to future investigations on cellular mechanisms linking environmental factors to final phenotype, potentially improving prediction powers and paleoclimatological interpretation. Biological and chemical expertise will merge, producing new interdisciplinary approaches for ecophysiology and biomineralization. Field transplantations will be combined with controlled experiments under IPCC scenarios. Corals will be grown in aquaria, exposing the Mediterranean species native to cooler waters to higher temperatures, and the Red Sea ones to gradually increasing above ambient warming seawater. Virtually all state-of-the-art methods will be used, by uniquely combining the investigators expertise. Expected results include responses of algal symbionts photosynthesis, host, symbiont and holobiont respiration, biomineralization rates and patterns, including colony architecture, and reproduction to temperature and pH gradients and combinations. Integration of molecular aspects of potential replacement of symbiont clades, changes in skeletal crystallography, with biochemical and physiological aspects of temperature response, will lead to a novel mechanistic model predicting changes in coral ecology and survival prospect. High-temperature tolerant clades and species will be revealed, allowing future bioremediation actions and establishment of coral refuges, saving corals and coral reefs for future generations.
Project acronym DEPICT
Project Design principles and controllability of protein circuits
Researcher (PI) Uri Alon
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Summary Cells use circuits of interacting proteins to respond to their environment. In the past decades, molecular biology has provided detailed knowledge on the proteins in these circuits and their interactions. To fully understand circuit function requires, in addition to molecular knowledge, new concepts that explain how multiple components work together to perform systems level functions. Our lab has been a leader in defining such concepts, based on combined experimental and theoretical study of well characterized circuits in bacteria and human cells. In this proposal we aim to find novel principles on how circuits resist fluctuations and errors, and how they can be controlled by drugs: (1) Why do key regulatory systems use bifunctional enzymes that catalyze antagonistic reactions (e.g. both kinase and phosphatase)? We will test the role of bifunctional enzymes in making circuits robust to variations in protein levels. (2) Why are some genes regulated by a repressor and others by an activator? We will test this in the context of reduction of errors in transcription control. (3) Are there principles that describe how drugs combine to affect protein dynamics in human cells? We will use a novel dynamic proteomics approach developed in our lab to explore how protein dynamics can be controlled by drug combinations. This research will define principles that unite our understanding of seemingly distinct biological systems, and explain their particular design in terms of systems-level functions. This understanding will help form the basis for a future medicine that rationally controls the state of the cell based on a detailed blueprint of their circuit design, and quantitative principles for the effects of drugs on this circuitry.
Cells use circuits of interacting proteins to respond to their environment. In the past decades, molecular biology has provided detailed knowledge on the proteins in these circuits and their interactions. To fully understand circuit function requires, in addition to molecular knowledge, new concepts that explain how multiple components work together to perform systems level functions. Our lab has been a leader in defining such concepts, based on combined experimental and theoretical study of well characterized circuits in bacteria and human cells. In this proposal we aim to find novel principles on how circuits resist fluctuations and errors, and how they can be controlled by drugs: (1) Why do key regulatory systems use bifunctional enzymes that catalyze antagonistic reactions (e.g. both kinase and phosphatase)? We will test the role of bifunctional enzymes in making circuits robust to variations in protein levels. (2) Why are some genes regulated by a repressor and others by an activator? We will test this in the context of reduction of errors in transcription control. (3) Are there principles that describe how drugs combine to affect protein dynamics in human cells? We will use a novel dynamic proteomics approach developed in our lab to explore how protein dynamics can be controlled by drug combinations. This research will define principles that unite our understanding of seemingly distinct biological systems, and explain their particular design in terms of systems-level functions. This understanding will help form the basis for a future medicine that rationally controls the state of the cell based on a detailed blueprint of their circuit design, and quantitative principles for the effects of drugs on this circuitry.
Project acronym DIADRUG
Project Insulin resistance and diabetic nephropathy - development of novel in vivo models for drug discovery
Researcher (PI) Sanna Lehtonen
Host Institution (HI) HELSINGIN YLIOPISTO
Summary Up to one third of diabetic patients develop nephropathy, a serious complication of diabetes. Microalbuminuria is the earliest sign of the complication, which may ultimately develop to end-stage renal disease requiring dialysis or a kidney transplant. Insulin resistance and metabolic syndrome are associated with an increased risk for diabetic nephropathy. Interestingly, glomerular epithelial cells or podocytes have recently been shown to be insulin responsive. Further, nephrin, a key structural component of podocytes, is essential for insulin action in these cells. Our novel findings show that adaptor protein CD2AP, an interaction partner of nephrin, associates with regulators of insulin signaling and glucose transport in glomeruli. The results suggest that nephrin and CD2AP are involved, by association with these proteins, in the regulation of insulin signaling and glucose transport in podocytes. We hypothesize that podocytes can develop insulin resistance and that disturbances in insulin response affect podocyte function and contribute to the development of diabetic nephropathy. The aim of this project is to clarify the mechanisms leading to development of insulin resistance in podocytes and to study the association between insulin resistance and the development of diabetic nephropathy. For this we will develop transgenic zebrafish and mouse models by overexpressing/knocking down insulin signaling-associated proteins specifically in podocytes. Further, we aim to identify novel drug leads to treat insulin resistance and diabetic nephropathy by performing high-throughput small molecule library screens on the developed transgenic fish models. The ultimate goal is to find a treatment to combat the early stages of diabetic nephropathy in humans.
Up to one third of diabetic patients develop nephropathy, a serious complication of diabetes. Microalbuminuria is the earliest sign of the complication, which may ultimately develop to end-stage renal disease requiring dialysis or a kidney transplant. Insulin resistance and metabolic syndrome are associated with an increased risk for diabetic nephropathy. Interestingly, glomerular epithelial cells or podocytes have recently been shown to be insulin responsive. Further, nephrin, a key structural component of podocytes, is essential for insulin action in these cells. Our novel findings show that adaptor protein CD2AP, an interaction partner of nephrin, associates with regulators of insulin signaling and glucose transport in glomeruli. The results suggest that nephrin and CD2AP are involved, by association with these proteins, in the regulation of insulin signaling and glucose transport in podocytes. We hypothesize that podocytes can develop insulin resistance and that disturbances in insulin response affect podocyte function and contribute to the development of diabetic nephropathy. The aim of this project is to clarify the mechanisms leading to development of insulin resistance in podocytes and to study the association between insulin resistance and the development of diabetic nephropathy. For this we will develop transgenic zebrafish and mouse models by overexpressing/knocking down insulin signaling-associated proteins specifically in podocytes. Further, we aim to identify novel drug leads to treat insulin resistance and diabetic nephropathy by performing high-throughput small molecule library screens on the developed transgenic fish models. The ultimate goal is to find a treatment to combat the early stages of diabetic nephropathy in humans.
Project acronym FROMCHILDTOPARENT
Project From the Child's Genes to Parental Environment and Back to the Child: Gene-environment Correlations in Early Social Development
Researcher (PI) Ariel Knafo
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Summary The role of children's behavior and temperament is increasingly acknowledged in family research. Gene-environment Correlation (rGE) processes may account for some child effects, as parents react to children s behavior which is in part genetically influenced (evocative rGE). In addition, passive rGE, in which parenting and children s behavior are correlated through overlapping genetic influences on family members behavior may account in part for the parenting-child behavior relationships. The proposed project will be the first one to directly address these issues with DNA information on family members and quality observational data on parent and child behaviors, following children through early development. Two separate longitudinal studies will investigate the paths from children s genes to their behavior, to the way parents react and modify their parenting towards the child, affecting child development: Study 1 will follow first-time parents from pregnancy through children s early childhood, decoupling parent effect and child effects. Study 2 will follow dizygotic twins and their parents through middle childhood, capitalizing on genetic differences between twins reared by the same parents. We will test the hypothesis that parents' characteristics, such as parenting style and parental attitudes, are associated with children's genetic tendencies. Both parenting and child behaviors will be monitored consecutively, to investigate the co-development of parents and children in an evocative rGE process. Child and parent candidate genes relevant to social behavior, notably those from the dompaminergic and serotonergic systems, will be linked to parents behaviors. Pilot results show children s genes predict parenting, and an important task for the study will be to identify mediators of this effect, such as children s temperament. We will lay the ground for further research into the complexity of gene-environment correlations as children and parents co-develop.
The role of children's behavior and temperament is increasingly acknowledged in family research. Gene-environment Correlation (rGE) processes may account for some child effects, as parents react to children s behavior which is in part genetically influenced (evocative rGE). In addition, passive rGE, in which parenting and children s behavior are correlated through overlapping genetic influences on family members behavior may account in part for the parenting-child behavior relationships. The proposed project will be the first one to directly address these issues with DNA information on family members and quality observational data on parent and child behaviors, following children through early development. Two separate longitudinal studies will investigate the paths from children s genes to their behavior, to the way parents react and modify their parenting towards the child, affecting child development: Study 1 will follow first-time parents from pregnancy through children s early childhood, decoupling parent effect and child effects. Study 2 will follow dizygotic twins and their parents through middle childhood, capitalizing on genetic differences between twins reared by the same parents. We will test the hypothesis that parents' characteristics, such as parenting style and parental attitudes, are associated with children's genetic tendencies. Both parenting and child behaviors will be monitored consecutively, to investigate the co-development of parents and children in an evocative rGE process. Child and parent candidate genes relevant to social behavior, notably those from the dompaminergic and serotonergic systems, will be linked to parents behaviors. Pilot results show children s genes predict parenting, and an important task for the study will be to identify mediators of this effect, such as children s temperament. We will lay the ground for further research into the complexity of gene-environment correlations as children and parents co-develop.
Project acronym FUTUREGENES
Project Gene transfer techniques in the treatment of cardiovascular diseases and malignant glioma
Researcher (PI) Seppo Yla-Herttuala
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Summary Background: Poor angiogenesis and collateral vessel formation lead to coronary heart disease, claudication, infarctions and amputations while malignant glioma is one of the most aggressive proangiogenic tumors leading to death in a few months. For these diseases either stimulation or blocking, respectively, of angiogenesis may provide novel treatment options. Advancing State-of-the-Art: Our hypothesis is that in ischemia it will be possible to support natural growth of blood vessels with Therapeutic angiogenesis and lymphangiogenesis by using local gene transfer of the new members of vascular endothelial growth factor (VEGF) family and their receptors. New co-receptors, designer mutants and PCR suffling products of VEGFs will be used. New vector technology will be used to achieve long-lasting effects of VEGFs. We aim to develop novel site-specifically integrating, targeted, regulated vectors to precisely express the new VEGFs, their soluble decoy receptors and single-chain therapeutic antibodies (scFv) for pro- and anti-angiogenic purposes. As novel approaches, we have developed metabolically biotinylated lenti- and adenoviruses suitable for targeting and Epigenetherapy where siRNA/miRNAs and short nuclear RNAs regulate endogenous gene expression at the VEGF promoter level via modification of histone code. scFv library for endothelial cells and lentivirus-siRNA library directed to all human and mouse kinases will be screened to identify new mediators of angiogenesis in order to develop next generation pro- and antiangiogenic therapies. Based on our strong track record in Clinical applications, the best new pro- and antiangiogenic approaches will be taken to phase I clinical studies in myocardial ischemia and malignant glioma. Significance: This work should lead to significant advances and new therapies for severe ischemia and malignant glioma. Epigenetherapy and new site-specifically integrating, regulated vectors should be widely applicable in medicine.
Background: Poor angiogenesis and collateral vessel formation lead to coronary heart disease, claudication, infarctions and amputations while malignant glioma is one of the most aggressive proangiogenic tumors leading to death in a few months. For these diseases either stimulation or blocking, respectively, of angiogenesis may provide novel treatment options. Advancing State-of-the-Art: Our hypothesis is that in ischemia it will be possible to support natural growth of blood vessels with Therapeutic angiogenesis and lymphangiogenesis by using local gene transfer of the new members of vascular endothelial growth factor (VEGF) family and their receptors. New co-receptors, designer mutants and PCR suffling products of VEGFs will be used. New vector technology will be used to achieve long-lasting effects of VEGFs. We aim to develop novel site-specifically integrating, targeted, regulated vectors to precisely express the new VEGFs, their soluble decoy receptors and single-chain therapeutic antibodies (scFv) for pro- and anti-angiogenic purposes. As novel approaches, we have developed metabolically biotinylated lenti- and adenoviruses suitable for targeting and Epigenetherapy where siRNA/miRNAs and short nuclear RNAs regulate endogenous gene expression at the VEGF promoter level via modification of histone code. scFv library for endothelial cells and lentivirus-siRNA library directed to all human and mouse kinases will be screened to identify new mediators of angiogenesis in order to develop next generation pro- and antiangiogenic therapies. Based on our strong track record in Clinical applications, the best new pro- and antiangiogenic approaches will be taken to phase I clinical studies in myocardial ischemia and malignant glioma. Significance: This work should lead to significant advances and new therapies for severe ischemia and malignant glioma. Epigenetherapy and new site-specifically integrating, regulated vectors should be widely applicable in medicine.
Project acronym GAME-DYNAMICS
Project Game Theory: Dynamic Approaches
Researcher (PI) Sergiu Hart
Summary The general framework is that of game theory, with multiple participants ( players ) that interact repeatedly over time. The players may be people, corporations, nations, computers even genes. While many of the standard concepts of game theory are static by their very nature (for example, strategic equilibria and cooperative solutions), it is of utmost importance theoretically as well as in applications to study dynamic processes, and relate them to appropriate static solutions. This is a fundamental issue. On the one hand, the significance of a solution depends in particular on how easy it is to reach it. On the other hand, natural dynamics, that is, processes that to a certain degree reflect observed behaviors and actual institutions, are important to study and understand in their own right. We propose to work on three main areas. First, adaptive dynamics: the goal is to characterize those classes of dynamics for which convergence to Nash or correlated equilibria can be obtained, and those for which it cannot, and to find and study natural dynamics that are related to actual behavior and yield useful insights. Second, evolutionary dynamics: the goal is to investigate evolutionary and similar dynamics, with a particular emphasis on understanding the role that large populations may play, and on characterizing which equilibria are evolutionarily stable and which are not. Third, bargaining and cooperation: the goal is to develop a general research program that studies natural bargaining procedures that lead to cooperation and are based directly on the strategic form; some particular aims are to establish connections between the bargaining institutions and the resulting cooperative solutions, and to analyze relevant economic models.
The general framework is that of game theory, with multiple participants ( players ) that interact repeatedly over time. The players may be people, corporations, nations, computers even genes. While many of the standard concepts of game theory are static by their very nature (for example, strategic equilibria and cooperative solutions), it is of utmost importance theoretically as well as in applications to study dynamic processes, and relate them to appropriate static solutions. This is a fundamental issue. On the one hand, the significance of a solution depends in particular on how easy it is to reach it. On the other hand, natural dynamics, that is, processes that to a certain degree reflect observed behaviors and actual institutions, are important to study and understand in their own right. We propose to work on three main areas. First, adaptive dynamics: the goal is to characterize those classes of dynamics for which convergence to Nash or correlated equilibria can be obtained, and those for which it cannot, and to find and study natural dynamics that are related to actual behavior and yield useful insights. Second, evolutionary dynamics: the goal is to investigate evolutionary and similar dynamics, with a particular emphasis on understanding the role that large populations may play, and on characterizing which equilibria are evolutionarily stable and which are not. Third, bargaining and cooperation: the goal is to develop a general research program that studies natural bargaining procedures that lead to cooperation and are based directly on the strategic form; some particular aims are to establish connections between the bargaining institutions and the resulting cooperative solutions, and to analyze relevant economic models.
Project acronym ID-CAB
Project Individual differences in Collective Animal Behaviour
Researcher (PI) David Sumpter
Host Institution (HI) UPPSALA UNIVERSITET
Summary One of the key challenges in scientific research is to link together our understanding of different levels of biological organisation. This challenge is fundamental to the scientific endeavour: from understand how genes interact to drive the cell, to how cells interact to form organisms, up to how organisms interact to form groups and societies. My own and the research of others has addressed this question in the context of the collective behaviour of animals. Mathematical models of complex systems have been used to successfully predict experimental outcome. Most previous studies are however limited in one important aspect: individuals are treated as identical units. The aim of the proposed research proposed is to investigate features which produce differences within the units. The model systems of our study will be sticklebacks, homing pigeons and house sparrows. Individuals can differ from each other on a range of time scales, from information acquired within the last few minutes, through socially learnt information, to genetically inherited differences. Through a series of experiments on each of the study species, the development of mathematical models which incorporate between individual differences, and novel forms of data analysis, we will begin to understand the role played by individual differences within groups. We will look at the rules of motion for fish and birds; the role of personality in decision-making and how short term information differences improve decision-making accuracy. Achieving the project objectives will greatly enhance our understanding of the relationship between individual animals and the groups they live in, as well as impacting on our understanding of individual differences in other areas of biology.
One of the key challenges in scientific research is to link together our understanding of different levels of biological organisation. This challenge is fundamental to the scientific endeavour: from understand how genes interact to drive the cell, to how cells interact to form organisms, up to how organisms interact to form groups and societies. My own and the research of others has addressed this question in the context of the collective behaviour of animals. Mathematical models of complex systems have been used to successfully predict experimental outcome. Most previous studies are however limited in one important aspect: individuals are treated as identical units. The aim of the proposed research proposed is to investigate features which produce differences within the units. The model systems of our study will be sticklebacks, homing pigeons and house sparrows. Individuals can differ from each other on a range of time scales, from information acquired within the last few minutes, through socially learnt information, to genetically inherited differences. Through a series of experiments on each of the study species, the development of mathematical models which incorporate between individual differences, and novel forms of data analysis, we will begin to understand the role played by individual differences within groups. We will look at the rules of motion for fish and birds; the role of personality in decision-making and how short term information differences improve decision-making accuracy. Achieving the project objectives will greatly enhance our understanding of the relationship between individual animals and the groups they live in, as well as impacting on our understanding of individual differences in other areas of biology.
Project acronym IMMUNOSWITCH
Project Switch recombination: a model system for DNA editing and repair in human lymphocytes with relevance for primary immunodeficiency and cancer formation
Researcher (PI) Qiang Pan Hammarström
Summary The aim of this project is to try to understand the complex molecular mechanisms involved in DNA editing, repair and recombination during immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). We have developed a series of PCR-based assays to study in vivo generated CSR junctions and the pattern of mutations introduced in the immunoglobulin variable region genes in human B cells, allowing us to characterize CSR and SHM in patients with immunodeficiency due to defect(s) in DNA repair/recombination. Novel in vitro CSR assays, based on GFP expression, allowing quantitative measurement of substrate recombination, are also being developed. In addition, we have initiated an evolutionary analysis of the function and structure of activation-induced deaminase, an essential molecule involved both in CSR and SHM, aiming to identify CSR specific-cofactor(s). Combining these approaches, we will be able to define the DNA repair pathways involved in CSR and SHM. The suggested project requires access to patients with various defects in the DNA repair pathways. Many of these diseases are exceedingly rare. However, through worldwide collaboration, we have obtained samples from a majority of the diagnosed patients. We are also refining the existing screening methods and developing novel methods, that will allow identification of additional patients both with recognized and new diseases caused by mutations in DNA repair pathways. Finally, we hope to be able to address the question whether illegitimate CSR events are associated with predisposition to lymphomagenesis in patients with immunodeficiency/DNA repair defect(s), by analyzing the CSR induced chromosomal breaks and translocations in these patients. A large-scale sequencing project is also planned to characterize the CSRnome in B-cell lymphoma samples.
The aim of this project is to try to understand the complex molecular mechanisms involved in DNA editing, repair and recombination during immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). We have developed a series of PCR-based assays to study in vivo generated CSR junctions and the pattern of mutations introduced in the immunoglobulin variable region genes in human B cells, allowing us to characterize CSR and SHM in patients with immunodeficiency due to defect(s) in DNA repair/recombination. Novel in vitro CSR assays, based on GFP expression, allowing quantitative measurement of substrate recombination, are also being developed. In addition, we have initiated an evolutionary analysis of the function and structure of activation-induced deaminase, an essential molecule involved both in CSR and SHM, aiming to identify CSR specific-cofactor(s). Combining these approaches, we will be able to define the DNA repair pathways involved in CSR and SHM. The suggested project requires access to patients with various defects in the DNA repair pathways. Many of these diseases are exceedingly rare. However, through worldwide collaboration, we have obtained samples from a majority of the diagnosed patients. We are also refining the existing screening methods and developing novel methods, that will allow identification of additional patients both with recognized and new diseases caused by mutations in DNA repair pathways. Finally, we hope to be able to address the question whether illegitimate CSR events are associated with predisposition to lymphomagenesis in patients with immunodeficiency/DNA repair defect(s), by analyzing the CSR induced chromosomal breaks and translocations in these patients. A large-scale sequencing project is also planned to characterize the CSRnome in B-cell lymphoma samples.
Project acronym INTGEN
Project Intergenerational correlations of schooling, income and health: an investigation of the underlying mechanisms
Researcher (PI) Carl Mikael Lindahl
Summary The objective of this project is to use rich Swedish registry data to learn about mechanisms behind intergenerational correlations. Typically, considerably effort has been spent on estimating correlations between outcome variables, such as education and income, for parents and children. However, the estimated correlations are driven by the causal effect of the parental variable of interest as well as unobservable factors such as other family background related variables and a part that is due to genetic transmission between parent and child. Disentangling these parts is very difficult and only recently has researchers made serious attempts to disentangling these different parts. However, findings vary widely across methods and this literature is still in its infancy. Among questions we ask are: How much of the association between outcome variables for the child and a parent is due to a causal effect from the parental variable, and how much is transmitted through unobservable family factors and genetic transmission? What are the intergenerational transmission and channels for life expectancy and health? What is the importance of genes-environmental interaction? Has the importance of genes, environment and its interactions for the intergenerational associations changed during the growth of the Scandinavian welfare state? How many generations does it take for ancestors placement in the income distribution to not longer matter for life success? These questions are directly relevant for policy, and relate to classical social science issues such as inequality of opportunity and level-of-living in general. The innovativeness of this project is based on using the uniqueness of Swedish registry data (ideal to answer these questions), with which one can match biological and adoptive parents, children and siblings, and hence can identify whether children are reared by their biological or adoptive parents, for the population of Swedes.
The objective of this project is to use rich Swedish registry data to learn about mechanisms behind intergenerational correlations. Typically, considerably effort has been spent on estimating correlations between outcome variables, such as education and income, for parents and children. However, the estimated correlations are driven by the causal effect of the parental variable of interest as well as unobservable factors such as other family background related variables and a part that is due to genetic transmission between parent and child. Disentangling these parts is very difficult and only recently has researchers made serious attempts to disentangling these different parts. However, findings vary widely across methods and this literature is still in its infancy. Among questions we ask are: How much of the association between outcome variables for the child and a parent is due to a causal effect from the parental variable, and how much is transmitted through unobservable family factors and genetic transmission? What are the intergenerational transmission and channels for life expectancy and health? What is the importance of genes-environmental interaction? Has the importance of genes, environment and its interactions for the intergenerational associations changed during the growth of the Scandinavian welfare state? How many generations does it take for ancestors placement in the income distribution to not longer matter for life success? These questions are directly relevant for policy, and relate to classical social science issues such as inequality of opportunity and level-of-living in general. The innovativeness of this project is based on using the uniqueness of Swedish registry data (ideal to answer these questions), with which one can match biological and adoptive parents, children and siblings, and hence can identify whether children are reared by their biological or adoptive parents, for the population of Swedes.
Project acronym LAST
Project Large Scale Privacy-Preserving Technology in the Digital World - Infrastructure and Applications
Researcher (PI) Yehuda Lindell
Summary Data mining provides large benefits to the commercial, government and homeland security sectors, but the aggregation and storage of huge amounts of data about citizens inevitably leads to erosion of privacy. To achieve the benefits that data mining has to offer, while at the same time enhancing privacy, we need technological solutions that simultaneously enable data mining while preserving privacy. The current state of the art has focused on providing privacy-preserving solutions for very specific problems, and has thus taken a local perspective. Although this is an important first step in the development of privacy-preserving solutions, it is time for a global perspective on the problem that aims for providing full integrated solutions. Our goal in this research is to study privacy and develop comprehensive solutions for enhancing it in the digital era. Our proposed research project includes foundational research on privacy, an infrastructure level for achieving anonymity over the Internet, key cryptographic tools for constructing privacy-preserving protocols, and development of large-scale applications that are built on top of all of the above. The novelty of our research is in our focus on fundamental issues towards comprehensive solutions that are aimed for large-scale data sources. The project s outcome will allow migration from local solutions for specific problems that are suited for small to medium scale data sources to comprehensive privacy-preserving database and data mining solutions for large scale data warehouses. Achieving this great challenge carries immense scientific, technological and societal rewards.
Data mining provides large benefits to the commercial, government and homeland security sectors, but the aggregation and storage of huge amounts of data about citizens inevitably leads to erosion of privacy. To achieve the benefits that data mining has to offer, while at the same time enhancing privacy, we need technological solutions that simultaneously enable data mining while preserving privacy. The current state of the art has focused on providing privacy-preserving solutions for very specific problems, and has thus taken a local perspective. Although this is an important first step in the development of privacy-preserving solutions, it is time for a global perspective on the problem that aims for providing full integrated solutions. Our goal in this research is to study privacy and develop comprehensive solutions for enhancing it in the digital era. Our proposed research project includes foundational research on privacy, an infrastructure level for achieving anonymity over the Internet, key cryptographic tools for constructing privacy-preserving protocols, and development of large-scale applications that are built on top of all of the above. The novelty of our research is in our focus on fundamental issues towards comprehensive solutions that are aimed for large-scale data sources. The project s outcome will allow migration from local solutions for specific problems that are suited for small to medium scale data sources to comprehensive privacy-preserving database and data mining solutions for large scale data warehouses. Achieving this great challenge carries immense scientific, technological and societal rewards.
Project acronym MATHFOR
Project Formalization of Constructive Mathematics
Researcher (PI) Thierry Coquand
Host Institution (HI) GOETEBORGS UNIVERSITET
Summary The general theme is to explore the connections between reasoning and computations in mathematics. There are two main research directions. The first research direction is a refomulation of Hilbert's program, using ideas from formal, or pointfree topology. We have shown, with multiple examples, that this allows a partial realization of this program in commutative algebra, and a new way to formulate constructive mathematics. The second research direction explores the computational content using type theory and the Curry-Howard correspondence between proofs and programs. Type theory allows us to represent constructive mathematics in a formal way, and provides key insight for the design of proof systems helping in the analysis of the logical structure of mathematical proofs. The interest of this program is well illustrated by the recent work of G. Gonthier on the formalization of the 4 color theorem.
The general theme is to explore the connections between reasoning and computations in mathematics. There are two main research directions. The first research direction is a refomulation of Hilbert's program, using ideas from formal, or pointfree topology. We have shown, with multiple examples, that this allows a partial realization of this program in commutative algebra, and a new way to formulate constructive mathematics. The second research direction explores the computational content using type theory and the Curry-Howard correspondence between proofs and programs. Type theory allows us to represent constructive mathematics in a formal way, and provides key insight for the design of proof systems helping in the analysis of the logical structure of mathematical proofs. The interest of this program is well illustrated by the recent work of G. Gonthier on the formalization of the 4 color theorem.
Project acronym NEXTGENMOLECOL
Project Next Generation Molecular Ecology
Researcher (PI) Hans Ellegren
Summary There is an immediate need to increase our understanding of the genetic basis for fitness differences in natural populations (Ellegren and Sheldon Nature 452:169-175, 2008). Fortunately, technological developments within genome research, notably the recent ability to retrieve massive amounts of DNA sequence data based on next generation sequencing , will make possible completely novel investigations of the link between genotypes and phenotypes in non-model organisms. With our background as major players in molecular ecology and evolutionary genomics of non-models for the last 15-20 years, we are excellently placed to take on a leading role in this process, developing a Next Generation Molecular Ecology . This research program will combine studies of candidate genes with large-scale gene expression analysis, several mapping approaches and comparative genomics to study the genetic basis of trait evolution in wild bird populations. First, we will search for and analyse loci involved with reproductive isolation and adaptive population divergence in a well-known system for speciation research the pied flycatcher and the collared flycatcher. A milestone of this program will be genome sequencing of the two flycatcher species. Second, we will track the genetic basis of behaviour using a unique breeding population of zebra finches and benefitting from the recently obtained genome sequence of this species. Third, we will identify the targets for adaptive evolution during avian evolution using comparative genomics. Overall, the program will be able to reveal the molecular genetic architecture behind phenotypic variation. The potential for scientific break-through in this interdisciplinary program should be significant.
There is an immediate need to increase our understanding of the genetic basis for fitness differences in natural populations (Ellegren and Sheldon Nature 452:169-175, 2008). Fortunately, technological developments within genome research, notably the recent ability to retrieve massive amounts of DNA sequence data based on next generation sequencing , will make possible completely novel investigations of the link between genotypes and phenotypes in non-model organisms. With our background as major players in molecular ecology and evolutionary genomics of non-models for the last 15-20 years, we are excellently placed to take on a leading role in this process, developing a Next Generation Molecular Ecology . This research program will combine studies of candidate genes with large-scale gene expression analysis, several mapping approaches and comparative genomics to study the genetic basis of trait evolution in wild bird populations. First, we will search for and analyse loci involved with reproductive isolation and adaptive population divergence in a well-known system for speciation research the pied flycatcher and the collared flycatcher. A milestone of this program will be genome sequencing of the two flycatcher species. Second, we will track the genetic basis of behaviour using a unique breeding population of zebra finches and benefitting from the recently obtained genome sequence of this species. Third, we will identify the targets for adaptive evolution during avian evolution using comparative genomics. Overall, the program will be able to reveal the molecular genetic architecture behind phenotypic variation. The potential for scientific break-through in this interdisciplinary program should be significant.
Project acronym PAC
Project Proofs and Computation
Researcher (PI) Eliyahu Ben Sasson
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Summary The project described in this proposal studies formal proofs and their interaction with computation. The study of propositional proofs is connected to a spectrum of problems in our field, starting with the meta-mathematical quest to explain our failure to understand computation and make progress on the basic questions haunting our field (such as P vs. NP), and ending with the industry-driven quest for better algorithms for solving instances of the satisfiability problem. In a seemingly different direction, the recent introduction of magical probabilistically checkable proofs (PCPs) has opened new horizons in computer science, ranging from a deeper understanding of approximation algorithms and their limits to the construction of super-efficient protocols for the verification of proofs and computations. We suggest to study proofs and computation with three main objectives. First, to construct better SAT solvers via a better understanding of propositional proof systems. Second, to expand the range of applications of PCPs and transform them from the purely theoretical objects that they currently are to practical and accessible formats for use in all settings where proofs are encountered. Third, to expand our theoretical understanding of the intrinsic limits of proofs, with an eye towards explaining why we are unable to make significant progress on central questions in computational complexity. We believe this project can bridge across different regions of computer science such as SAT solving and proof complexity, theory and practice, propositional proofs and probabilistically checkable ones. And its expected impact will start on the theoretical mathematical level that forms the foundation of computer science and percolate to more practical areas of our field.
The project described in this proposal studies formal proofs and their interaction with computation. The study of propositional proofs is connected to a spectrum of problems in our field, starting with the meta-mathematical quest to explain our failure to understand computation and make progress on the basic questions haunting our field (such as P vs. NP), and ending with the industry-driven quest for better algorithms for solving instances of the satisfiability problem. In a seemingly different direction, the recent introduction of magical probabilistically checkable proofs (PCPs) has opened new horizons in computer science, ranging from a deeper understanding of approximation algorithms and their limits to the construction of super-efficient protocols for the verification of proofs and computations. We suggest to study proofs and computation with three main objectives. First, to construct better SAT solvers via a better understanding of propositional proof systems. Second, to expand the range of applications of PCPs and transform them from the purely theoretical objects that they currently are to practical and accessible formats for use in all settings where proofs are encountered. Third, to expand our theoretical understanding of the intrinsic limits of proofs, with an eye towards explaining why we are unable to make significant progress on central questions in computational complexity. We believe this project can bridge across different regions of computer science such as SAT solving and proof complexity, theory and practice, propositional proofs and probabilistically checkable ones. And its expected impact will start on the theoretical mathematical level that forms the foundation of computer science and percolate to more practical areas of our field.
Project acronym PREVENTRA
Project Genes, environment and immunity in the pathogenesis of rheumatoid arthritis
Researcher (PI) Lars Göran Yngve Klareskog
Summary Aims and significance: The aims of this program are (1) To obtain new understanding of how environmental and life style factors interact with genes to induce immune reactions able to cause the different forms of arthritis that are defined as RA; (2) To use this understanding to develop prevention and targeted therapy for different forms of RA, and to enable efficient and eventually curative therapy. Background: We build on new understanding or RA etiology that has followed from studies on interactions between genes, environment and immunity in different subsets of RA. This has been provided for new detailed studies on specific and eventually disease-inducing autoimmunity in RA. Research program: We will use our infrastructure (longitudinal large cohorts, biobanks genetic information and our molecular immunology laboratory) to investigate (1) how genes and environment interact in causing different forms of RA; (2) how specific immune reactions against post-translationally modified (mainly citrullinated) autoantigens are triggered by environmental agents in specific genetic contexts in different individuals; (3) How these immune reactions target different organs (joints, lungs etc) and eventually cause arthritis in model systems; (4) how the combination of genes, environment and immunity may determine disease course and response to various therapies. Novelty and opportunities to take knowledge of autoimmune disease and RA to a new level: The recent advances in understanding interactions between genes, environment and immunity in RA, provides a striking new opportunity to understand basic features of autoimmunity and autoimmune disease, as well as potentials to prevent and treat RA very early. I believe that the presented program is well positioned to use this opportunity and contribute to a new paradigm for understanding and preventing RA.
Aims and significance: The aims of this program are (1) To obtain new understanding of how environmental and life style factors interact with genes to induce immune reactions able to cause the different forms of arthritis that are defined as RA; (2) To use this understanding to develop prevention and targeted therapy for different forms of RA, and to enable efficient and eventually curative therapy. Background: We build on new understanding or RA etiology that has followed from studies on interactions between genes, environment and immunity in different subsets of RA. This has been provided for new detailed studies on specific and eventually disease-inducing autoimmunity in RA. Research program: We will use our infrastructure (longitudinal large cohorts, biobanks genetic information and our molecular immunology laboratory) to investigate (1) how genes and environment interact in causing different forms of RA; (2) how specific immune reactions against post-translationally modified (mainly citrullinated) autoantigens are triggered by environmental agents in specific genetic contexts in different individuals; (3) How these immune reactions target different organs (joints, lungs etc) and eventually cause arthritis in model systems; (4) how the combination of genes, environment and immunity may determine disease course and response to various therapies. Novelty and opportunities to take knowledge of autoimmune disease and RA to a new level: The recent advances in understanding interactions between genes, environment and immunity in RA, provides a striking new opportunity to understand basic features of autoimmunity and autoimmune disease, as well as potentials to prevent and treat RA very early. I believe that the presented program is well positioned to use this opportunity and contribute to a new paradigm for understanding and preventing RA.
Project acronym SINGLE-CELL GENOMICS
Project Single-cell Gene Regulation in Differentiation and Pluripotency
Researcher (PI) Thore Rickard Hakan Sandberg
Summary We aim to study transcriptomes with single-cell resolution, a long-standing goal in biology, to answer fundamental questions about gene regulation. The main objective concerns gene regulation during in vivo differentiation and in pluripotent cells by studying single-cells from murine preimplantation embryos, a model system with natural single-cell resolution, important biology and medical potential. This would also allow us to explore general regulatory principles of gene expression programs of individual cells. This research program will be accomplished by novel deep sequencing technology of mRNAs (mRNA-Seq) to obtain quantitative, unbiased and genome-wide gene and isoform expression measurements. We are therefore developing new experimental and computational methods for genome-wide analyses of transcriptomes at single-cell resolution. The biological significances of the proposed research are unique insights into early embryonic development. Deep sequencing of transcriptomes will also reveal post-transcriptional gene regulation important for pluripotent cells and identified pluripotency-specific gene and isoform expressions will be important for future stem cell based therapies. The inherit single-cell nature of the model system together with its important biology makes it a model systems exceptionally well suited for a systems biology approach aiming to characterize gene regulation at single-cell resolution. The novel methodology has tremendous potential to enable complete mRNA characterization of individual cells. The deep sequencing approach with state-of-the-art computational analyses is both more quantitative than previous methods and it will give readouts on alternative isoforms generated by alternative promoters, splicing and polyadenylation.
We aim to study transcriptomes with single-cell resolution, a long-standing goal in biology, to answer fundamental questions about gene regulation. The main objective concerns gene regulation during in vivo differentiation and in pluripotent cells by studying single-cells from murine preimplantation embryos, a model system with natural single-cell resolution, important biology and medical potential. This would also allow us to explore general regulatory principles of gene expression programs of individual cells. This research program will be accomplished by novel deep sequencing technology of mRNAs (mRNA-Seq) to obtain quantitative, unbiased and genome-wide gene and isoform expression measurements. We are therefore developing new experimental and computational methods for genome-wide analyses of transcriptomes at single-cell resolution. The biological significances of the proposed research are unique insights into early embryonic development. Deep sequencing of transcriptomes will also reveal post-transcriptional gene regulation important for pluripotent cells and identified pluripotency-specific gene and isoform expressions will be important for future stem cell based therapies. The inherit single-cell nature of the model system together with its important biology makes it a model systems exceptionally well suited for a systems biology approach aiming to characterize gene regulation at single-cell resolution. The novel methodology has tremendous potential to enable complete mRNA characterization of individual cells. The deep sequencing approach with state-of-the-art computational analyses is both more quantitative than previous methods and it will give readouts on alternative isoforms generated by alternative promoters, splicing and polyadenylation.
Project acronym SIRAID
Project SIRT6 activation for countering age-related metabolic diseases
Researcher (PI) Haim Cohen
Summary The significant increase in the human lifespan during the last century confronts us with great medical challenges. To answer them, one must understand and control the mechanisms that determine the rate of ageing. The sirtuins, and in particular the mammalian member SIRT6, are a family of NAD+ dependent deacetylases that were implicated in ageing and the regulation of metabolism. Much evidence correlates SIRT6 with the regulation of ageing, primarily the manifestation of ageing related pathologies in SIRT6 deficient mice, and the induction of SIRT6 by calorie-restricted diet that delays ageing and reduces its related diseases. Nonetheless, the role of SIRT6 in ageing and the mechanisms by which it might act are still elusive. To explore it at the molecular mechanistic level, SIRAID aims to i) study the role of SIRT6 in glucose and fat metabolism under high fat diet; ii) to determine whether SIRT6 is involved in regulating life span, and to characterise how SIRT6 is activated by calorie restriction; and iii) to perform large scale SILAC-based proteomics screening for SIRT6 substrates. These results will then be used for the development of small activator molecules of SIRT6 that may be used therapeutically for age related metabolic diseases. Taken together, we suggest a multifaceted approach that will allow us to explore the role of SIRT6 in ageing and metabolism, and to translate this knowledge to counter and prevent the medical problems associated with human longevity.
The significant increase in the human lifespan during the last century confronts us with great medical challenges. To answer them, one must understand and control the mechanisms that determine the rate of ageing. The sirtuins, and in particular the mammalian member SIRT6, are a family of NAD+ dependent deacetylases that were implicated in ageing and the regulation of metabolism. Much evidence correlates SIRT6 with the regulation of ageing, primarily the manifestation of ageing related pathologies in SIRT6 deficient mice, and the induction of SIRT6 by calorie-restricted diet that delays ageing and reduces its related diseases. Nonetheless, the role of SIRT6 in ageing and the mechanisms by which it might act are still elusive. To explore it at the molecular mechanistic level, SIRAID aims to i) study the role of SIRT6 in glucose and fat metabolism under high fat diet; ii) to determine whether SIRT6 is involved in regulating life span, and to characterise how SIRT6 is activated by calorie restriction; and iii) to perform large scale SILAC-based proteomics screening for SIRT6 substrates. These results will then be used for the development of small activator molecules of SIRT6 that may be used therapeutically for age related metabolic diseases. Taken together, we suggest a multifaceted approach that will allow us to explore the role of SIRT6 in ageing and metabolism, and to translate this knowledge to counter and prevent the medical problems associated with human longevity.
Project acronym SPECTRUM
Project Projections of Jerusalem in Europe: A Monumental Network
Researcher (PI) Bianca Kühnel
Summary This project concerns the monumental, multimedia, interactive re-creations of Jerusalem in Europe. These monuments represent the loca sancta through architectures in spatial and topographical relationships that reproduce the real ones, sculptural groups that re-enact the respective event in a painted décor, with artifacts completing the ambience. The project proposes to document, comprehensively study and conceptualize these sites. Their exact number is not known since a comprehensive study has never yet been attempted, but they can probably be numbered in many hundreds. This project will open up a totally new research area with considerable impact already at the initial documentation and survey stages, by bringing together both fresh data and interpretations. But the project proposes to go beyond and generate many new insights by a comparative study of the sites and a conceptualization of the phenomenon (with the aid of notions such as icon, map, network, interactive multimedia, space and place). The study will lead to the integration of these three-dimensional complexes in the ongoing discourse of image, and to the theoretical discourse pertaining to the relationships between original and copy, narrative and iconic. It will contribute essential new insights to the study of pilgrimage, the definition and process of the formation of sacred spaces, to devotionalism as a special type of piety and to the study of memory and mnemonic practices. Research will include field and textual documentation, cross referencing and grouping of related monuments, leading to crystallization of several clusters of monuments, representative at Pan-European and historical levels. Research will be accompanied by a conclusion-reaching process through discussions in small groups, exchange of working papers, as well as symposia and conferences with external participation. The results will be published throughout the stages of work, as well as in a book at the end of the research period.
This project concerns the monumental, multimedia, interactive re-creations of Jerusalem in Europe. These monuments represent the loca sancta through architectures in spatial and topographical relationships that reproduce the real ones, sculptural groups that re-enact the respective event in a painted décor, with artifacts completing the ambience. The project proposes to document, comprehensively study and conceptualize these sites. Their exact number is not known since a comprehensive study has never yet been attempted, but they can probably be numbered in many hundreds. This project will open up a totally new research area with considerable impact already at the initial documentation and survey stages, by bringing together both fresh data and interpretations. But the project proposes to go beyond and generate many new insights by a comparative study of the sites and a conceptualization of the phenomenon (with the aid of notions such as icon, map, network, interactive multimedia, space and place). The study will lead to the integration of these three-dimensional complexes in the ongoing discourse of image, and to the theoretical discourse pertaining to the relationships between original and copy, narrative and iconic. It will contribute essential new insights to the study of pilgrimage, the definition and process of the formation of sacred spaces, to devotionalism as a special type of piety and to the study of memory and mnemonic practices. Research will include field and textual documentation, cross referencing and grouping of related monuments, leading to crystallization of several clusters of monuments, representative at Pan-European and historical levels. Research will be accompanied by a conclusion-reaching process through discussions in small groups, exchange of working papers, as well as symposia and conferences with external participation. The results will be published throughout the stages of work, as well as in a book at the end of the research period.
Project acronym STATECAP
Project State Capacity, Development, Conflict, and Climate Change
Researcher (PI) Torsten Erik Persson
Host Institution (HI) STOCKHOLMS UNIVERSITET
Summary The proposed research concerns two sets of issues. The first concerns the role of state building in the development process, and the role played by violent conflict whether internal or external to the state. In this research, we will build a sequence of theoretical models, taking a stepping stone in a basic framework where new infrastructure that expands the state s capacity to raise revenue and to support private markets is viewed as outcome of investments under uncertainty. Our objective in model building is to provide guidance for the collection of historical and contemporary data and for econometric testing, which will both be central to the project. The overall goal of this project is to bring the analysis of state capacity into the mainstream of economics, and thereby shed light on the complex interactions between state building, conflict and development. The second set of issues ultimately concerns the economics of climate change. A first subproject aims at estimating the historical effects of weather on infant mortality in Africa, using a variety of data sources: individual data based on retrospective DHS surveys, finely-gridded weather data based on so-called re-analyis with large-scale climate models, and spatial data on harvest times based on satellite data on plant growth. Exploiting the random component of historical weather fluctuation allows us to estimate causal effects on health outcomes via mechanisms like malnutrition and malaria. This initial research will serve as a pilot study, to develop a methodology for studying the weather impacts on any outcome of interest anywhere in the world. Eventually such estimates will serve to estimate the future costs of climate change.
The proposed research concerns two sets of issues. The first concerns the role of state building in the development process, and the role played by violent conflict whether internal or external to the state. In this research, we will build a sequence of theoretical models, taking a stepping stone in a basic framework where new infrastructure that expands the state s capacity to raise revenue and to support private markets is viewed as outcome of investments under uncertainty. Our objective in model building is to provide guidance for the collection of historical and contemporary data and for econometric testing, which will both be central to the project. The overall goal of this project is to bring the analysis of state capacity into the mainstream of economics, and thereby shed light on the complex interactions between state building, conflict and development. The second set of issues ultimately concerns the economics of climate change. A first subproject aims at estimating the historical effects of weather on infant mortality in Africa, using a variety of data sources: individual data based on retrospective DHS surveys, finely-gridded weather data based on so-called re-analyis with large-scale climate models, and spatial data on harvest times based on satellite data on plant growth. Exploiting the random component of historical weather fluctuation allows us to estimate causal effects on health outcomes via mechanisms like malnutrition and malaria. This initial research will serve as a pilot study, to develop a methodology for studying the weather impacts on any outcome of interest anywhere in the world. Eventually such estimates will serve to estimate the future costs of climate change.
Project acronym STRONGPCP
Project Strong Probabilistically Checkable Proofs
Researcher (PI) Irit Dveer Dinur
Summary Probabilistically Checkable Proofs (PCPs) encapsulate the striking idea that verification of proofs becomes nearly trivial if one is willing to use randomness. The PCP theorem, proven in the early 90's, is a cornerstone of modern computational complexity theory. It completely revises our notion of a proof, leading to an amazingly robust behavior: A PCP proof is guaranteed to have an abundance of errors if attempting to prove a falsity. This stands in sharp contrast to our classical notion of a proof whose correctness can collapse due to one wrong step. An important drive in the development of PCP theory is the revolutionary effect it had on the field of approximation. Feige et. al. [JACM, 1996] discovered that the PCP theorem is *equivalent* to the inapproximability of several classical optimization problems. Thus, PCP theory has resulted in a leap in our understanding of approximability and opened the gate to a flood of results. To date, virtually all inapproximability results are based on the PCP theorem, and while there is an impressive body of work on hardness-of-approximation, much work still lies ahead. The central goal of this proposal is to obtain stronger PCPs than currently known, leading towards optimal inapproximability results and novel notions of robustness in computation and in proofs. This study will build upon (i) new directions opened up by my novel proof of the PCP theorem [JACM, 2007]; and on (ii) state-of-the-art PCP machinery involving techniques from algebra, functional and harmonic analysis, probability, combinatorics, and coding theory. The broader impact of this study spans a better understanding of limits for approximation algorithms saving time and resources for algorithm designers; and new understanding of robustness in a variety of mathematical contexts, arising from the many connections between PCPs and stability questions in combinatorics, functional analysis, metric embeddings, probability, and more.
Probabilistically Checkable Proofs (PCPs) encapsulate the striking idea that verification of proofs becomes nearly trivial if one is willing to use randomness. The PCP theorem, proven in the early 90's, is a cornerstone of modern computational complexity theory. It completely revises our notion of a proof, leading to an amazingly robust behavior: A PCP proof is guaranteed to have an abundance of errors if attempting to prove a falsity. This stands in sharp contrast to our classical notion of a proof whose correctness can collapse due to one wrong step. An important drive in the development of PCP theory is the revolutionary effect it had on the field of approximation. Feige et. al. [JACM, 1996] discovered that the PCP theorem is *equivalent* to the inapproximability of several classical optimization problems. Thus, PCP theory has resulted in a leap in our understanding of approximability and opened the gate to a flood of results. To date, virtually all inapproximability results are based on the PCP theorem, and while there is an impressive body of work on hardness-of-approximation, much work still lies ahead. The central goal of this proposal is to obtain stronger PCPs than currently known, leading towards optimal inapproximability results and novel notions of robustness in computation and in proofs. This study will build upon (i) new directions opened up by my novel proof of the PCP theorem [JACM, 2007]; and on (ii) state-of-the-art PCP machinery involving techniques from algebra, functional and harmonic analysis, probability, combinatorics, and coding theory. The broader impact of this study spans a better understanding of limits for approximation algorithms saving time and resources for algorithm designers; and new understanding of robustness in a variety of mathematical contexts, arising from the many connections between PCPs and stability questions in combinatorics, functional analysis, metric embeddings, probability, and more.
Project acronym TARGETING_CANCER
Project Eradication of tumors by targeting dsRNA selectively to cancer cells and recruitment of the innate immune system
Researcher (PI) Alexander Levitzki
Summary We have recently shown that EGFR over-expressing tumors can be eradicated by an EGFR homing chemical vector, carrying dsRNA. The vector is PolyInosine/Cytosine (PolyIC) bound to Polyethleneimine-Polyethyleneglycol-EGF (PEI-PEG-EGF, PPE). We have shown that even tumors in which up to 50% of cells do not express EGFR are eradicated, due to the strong tumor-localized bystander effects, which involve the innate immune system. Using this EGFR homing vector we have been able to eradicate EGFR overexpressing tumors by either local or systemic application. Since the success of this strategy seems to be due to the strong bystander effects induced by the internalized PolyIC it is likely that heterogeneous tumors, in which only a portion of the cells harbor the targeted receptor, will be eradicated too, as shown in our preliminary studies (PloS Med, 2006). This strategy actually targets the innate immune system to the tumor. We propose to establish tumors in which decreasing portions of cells over-express EGFR and determine the lowest number of EGFR over-expressing cells that can yield tumor eradication by the lowest dose of PolyIC/PPE. The principle behind the success of the Trojan horse approach is that the targeting moiety, EGF, is tethered to the other components of the vector in such a way that it retains its native EGFR binding properties and its ability to internalize with the receptor. The composition of the vector is such that the ligand EGF can be replaced by any other ligand, if the appropriate coupling conditions are used, retaining the ability of the ligand to bind to the target protein and internalize with it. We propose to replace EGF by a number of other ligands, such PSMA binding ligand (targeting prostate cancer) and Her-2 affibodies. Although only a fraction of women who over-express Her-2 respond to Herceptin, it is likely that they will respond to PolyIC/PP-Her-2 affibody.
We have recently shown that EGFR over-expressing tumors can be eradicated by an EGFR homing chemical vector, carrying dsRNA. The vector is PolyInosine/Cytosine (PolyIC) bound to Polyethleneimine-Polyethyleneglycol-EGF (PEI-PEG-EGF, PPE). We have shown that even tumors in which up to 50% of cells do not express EGFR are eradicated, due to the strong tumor-localized bystander effects, which involve the innate immune system. Using this EGFR homing vector we have been able to eradicate EGFR overexpressing tumors by either local or systemic application. Since the success of this strategy seems to be due to the strong bystander effects induced by the internalized PolyIC it is likely that heterogeneous tumors, in which only a portion of the cells harbor the targeted receptor, will be eradicated too, as shown in our preliminary studies (PloS Med, 2006). This strategy actually targets the innate immune system to the tumor. We propose to establish tumors in which decreasing portions of cells over-express EGFR and determine the lowest number of EGFR over-expressing cells that can yield tumor eradication by the lowest dose of PolyIC/PPE. The principle behind the success of the Trojan horse approach is that the targeting moiety, EGF, is tethered to the other components of the vector in such a way that it retains its native EGFR binding properties and its ability to internalize with the receptor. The composition of the vector is such that the ligand EGF can be replaced by any other ligand, if the appropriate coupling conditions are used, retaining the ability of the ligand to bind to the target protein and internalize with it. We propose to replace EGF by a number of other ligands, such PSMA binding ligand (targeting prostate cancer) and Her-2 affibodies. Although only a fraction of women who over-express Her-2 respond to Herceptin, it is likely that they will respond to PolyIC/PP-Her-2 affibody.
Project acronym TLIM
Project Talent and Learning in Imperfect Markets
Researcher (PI) Marko Juhani Terviö
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Summary The overall effectiveness at which the underlying talent resources in an economy are utilized is an important determinant of long-run economic growth and well-being. Recent work has shown that the processes through which talent is discovered and revealed in the economy are likely to suffer from market imperfections that are analogous to problems that have been for long been understood in the context of private provision of job training and education, resulting in not just reduced economic efficiency but also contributing to income inequality. The first basic question is what is the role of talent rents in explaining income inequality? In a static world where all information about talent is known, such talent rents would merely be compensation to a scarce factor of production. However, when the discovery of talent is subject to market imperfections then income differences that ostensibly look like talent rents are partly due to inefficient information rents. This raises the second and novel question, about whether and to what extent observed income differences are due to inefficient rents to information about talent that masquerade as talent rents. I also plan to investigate how technological change has impacted the distribution of talent rents via its effect on the discovery/revelation process of talent. The larger goal of the project is to help understand the economy-wide implications of institutions and policies that govern the discovery and allocation of talent in the economy. Better understanding could also point the way towards improved policy interventions.
The overall effectiveness at which the underlying talent resources in an economy are utilized is an important determinant of long-run economic growth and well-being. Recent work has shown that the processes through which talent is discovered and revealed in the economy are likely to suffer from market imperfections that are analogous to problems that have been for long been understood in the context of private provision of job training and education, resulting in not just reduced economic efficiency but also contributing to income inequality. The first basic question is what is the role of talent rents in explaining income inequality? In a static world where all information about talent is known, such talent rents would merely be compensation to a scarce factor of production. However, when the discovery of talent is subject to market imperfections then income differences that ostensibly look like talent rents are partly due to inefficient information rents. This raises the second and novel question, about whether and to what extent observed income differences are due to inefficient rents to information about talent that masquerade as talent rents. I also plan to investigate how technological change has impacted the distribution of talent rents via its effect on the discovery/revelation process of talent. The larger goal of the project is to help understand the economy-wide implications of institutions and policies that govern the discovery and allocation of talent in the economy. Better understanding could also point the way towards improved policy interventions.
Project acronym TMIHCV
Project Microfabrication-Based Rational Design of Transcriptional-Metabolic Intervention for the Treatment of Hepatitis C Virus (HCV) Infection
Researcher (PI) Yaakov Nahmias
Summary Hepatitis C Virus (HCV) infection affects over 3% of the world population and is the leading cause of chronic liver disease worldwide. Current treatments are effective in only 50% of the cases and associated with significant side effects. Therefore, there is a pressing need for the development of alternative treatments. Recently, our group and others demonstrated that the HCV lifecycle is critically dependent on host lipid metabolism. In this context, we demonstrated that the grapefruit flavonoid naringenin blocks HCV production through PPAR± and LXR±, transcriptional regulators of hepatic lipid metabolism. While these results are promising, our ability to rationally control metabolic pathways in infected cells is limited due to an incomplete understanding of the regulation of hepatic metabolism by its underlying transcriptional network. This project aims to develop a comprehensive model of hepatic metabolism by integrating metabolic fluxes with transcriptional regulation enabling the rational design of transcriptional-interventions which will minimize HCV replication and release. Our approach is to develop two microfabricated platforms that will enable high-throughput data acquisition and a human-relevant screening. One component is the Transcriptional Activity Array (TAA), a microdevice for the high-throughput temporal acquisition of transcriptional activity data. The second is the Portal Circulation Platform (PCP) which integrates intestinal absorption module with a liver metabolism compartment enabling the high-throughput human-relevant screening of treatments as a substitute to animal experiments. This work will lead to the development of novel drug combinations for the treatment of HCV infection and impact the treatment of diabetes, obesity, and dyslipidemia.
Hepatitis C Virus (HCV) infection affects over 3% of the world population and is the leading cause of chronic liver disease worldwide. Current treatments are effective in only 50% of the cases and associated with significant side effects. Therefore, there is a pressing need for the development of alternative treatments. Recently, our group and others demonstrated that the HCV lifecycle is critically dependent on host lipid metabolism. In this context, we demonstrated that the grapefruit flavonoid naringenin blocks HCV production through PPAR± and LXR±, transcriptional regulators of hepatic lipid metabolism. While these results are promising, our ability to rationally control metabolic pathways in infected cells is limited due to an incomplete understanding of the regulation of hepatic metabolism by its underlying transcriptional network. This project aims to develop a comprehensive model of hepatic metabolism by integrating metabolic fluxes with transcriptional regulation enabling the rational design of transcriptional-interventions which will minimize HCV replication and release. Our approach is to develop two microfabricated platforms that will enable high-throughput data acquisition and a human-relevant screening. One component is the Transcriptional Activity Array (TAA), a microdevice for the high-throughput temporal acquisition of transcriptional activity data. The second is the Portal Circulation Platform (PCP) which integrates intestinal absorption module with a liver metabolism compartment enabling the high-throughput human-relevant screening of treatments as a substitute to animal experiments. This work will lead to the development of novel drug combinations for the treatment of HCV infection and impact the treatment of diabetes, obesity, and dyslipidemia.
Project acronym TREATPD
Project Cell and gene therapy based approaches for treatment of Parkinson's disease: from models to clinics
Researcher (PI) Deniz Kirik
Host Institution (HI) LUNDS UNIVERSITET
Summary Parkinson s disease is one of the common causes of disability in the aging population, representing a major health problem for the affected individuals and a socioeconomic burden to the society. In the present proposal, the applicant puts forward an ambitious but feasible program to tackle a number of significant issues that remain unsolved in the field. He combines his strong track record in animal models of Parkinson s disease and novel cell and gene therapy-based therapeutic strategies with powerful bio-imaging techniques in order to make bold steps towards translation of new and better treatments to patients suffering from this illness. He does so in a manner that combines, on one hand, the strength of clearly-defined hypotheses and well-established tools for results towards clinical translation, with high-risk high-reward projects that hold the potential to yield ground-breaking discoveries in implementation of novel imaging techniques, on the other.
Parkinson s disease is one of the common causes of disability in the aging population, representing a major health problem for the affected individuals and a socioeconomic burden to the society. In the present proposal, the applicant puts forward an ambitious but feasible program to tackle a number of significant issues that remain unsolved in the field. He combines his strong track record in animal models of Parkinson s disease and novel cell and gene therapy-based therapeutic strategies with powerful bio-imaging techniques in order to make bold steps towards translation of new and better treatments to patients suffering from this illness. He does so in a manner that combines, on one hand, the strength of clearly-defined hypotheses and well-established tools for results towards clinical translation, with high-risk high-reward projects that hold the potential to yield ground-breaking discoveries in implementation of novel imaging techniques, on the other.

redpajama_set_name: RedPajamaCommonCrawl