Hormones, growth factors, and cytokines coordinate metabolism between tissues and within tissues. The transforming growth factor superfamily signaling pathway encompasses members of the TGFβ, activin, bone morphogenetic protein, Nodal, and growth and differentiation factor subfamilies, in addition to numerous other ligands, receptors, coreceptors, downstream signaling effectors, and regulating molecules. The elaborate multifunctional effects of this superfamily are highly cell-type and context-dependent (1, 2). Many of these ligands are involved in organ specification, patterning, proliferation, and differentiation, including important roles in the pancreas (3, 4). Studies of transgenic and knockout mice highlight the importance of this signaling pathway in islet development (5), and more recent work has also implicated the TGFβ superfamily in adult β-cell function and maturity (6, 7). In this issue of Endocrinology, Boerner and colleagues (8) report a novel role for Nodal, a secreted TGFβ superfamily member known for its roles in early embryogenesis and its mitogenic signaling through Smad2/3 and Smad4. Detailed studies on the role of Nodal in adult β-cells had not been reported. Boerner et al (8) identified Nodel in adult islets and used complementary techniques, including flow cytometry, to demonstrate that Nodal stimulates human pancreatic β-cell proliferation. This contrasts with studies employing pancreatic cell lines wherein Nodal was reported to induce apoptosis and inhibit proliferation (9, 10) and highlights the need to perform proliferation studies in nontransformed cells. This novel role of Nodal adds to the numerous roles that this family appears to have on adult pancreatic cells. Here, we will review developments in the field of TGFβ signaling in islets and emphasize that delineating clear roles of this signaling pathway has been quite challenging. Genetically engineered mouse models have provided insight, as well as confusion, on the roles of TGFβ family members (Table 1). Life-long global knockouts can provide information on gene function in the whole organism over its entire lifetime. Distinguishing effects of TGFβ family members on adult β-cell physiology from effects on development is not possible without conditional loss-of-function or gain-of-function models, but these are relatively few in number (11–13). Despite these caveats, a picture of multiple effects of TGFβ signaling on adult β-cell homeostasis has begun to emerge. A recurring phenotype manifested in adult mice carrying mutations in various TGFβ superfamily genes includes decreased β-cell mass, impaired glucose tolerance, and in some cases diabetes. Table 1 provides a glimpse of the plethora of effects of this superfamily, and its downstream signaling molecules, on pancreatic islets. Deletion of the negative downstream effector of TGFβ signaling Smad7 (14) in Pdx1-expressing cells decreased hormone-positive cells in late development (5). On the other hand, conditional overexpression of Smad7 in adult Pdx1-expressing cells altered the β-cell gene signature and reduced pancreatic insulin production and release, leading to diabetes (11). Furthermore, Smad7 appears to be crucial for beta-cell proliferation after partial pancreatectomy (50). Thus, the same TGFβ effector can have opposing roles depending on the temporal context. Moreover, the TGFβ signaling effectors can have opposing roles, given that Smad3 appears to be a negative regulator of insulin secretion and glucose tolerance (13). Taken together, many lines of evidence clearly suggest a role of this signaling pathway in regulating β-cell mass and function. More inducible knockout mouse studies are needed to clarify the specific cell targets and mechanisms of actions of this family on pancreatic cells. Pancreatic Actions of the TGFβ Superfamily Abbreviations: ALK, activin receptor-like kinase, ActR, activin receptor; BMP, bone morphogenetic protein; GDF, growth and differentiation factor. Pancreatic Actions of the TGFβ Superfamily Abbreviations: ALK, activin receptor-like kinase, ActR, activin receptor; BMP, bone morphogenetic protein; GDF, growth and differentiation factor. The effects of the TGFβ superfamily ligands on adult pancreatic β-cells can be directly tested in vitro, bypassing the complexities of the in vivo environment. For example, acute activin A treatment increased glucose-stimulated insulin secretion from human (15) and rat (16) islets, whereas prolonged treatment decreased glucose-stimulated insulin secretion from mouse islets, an effect reversed by the endogenous antagonist follistatin (17). β-Cell proliferation was increased by activin A treatment in adult rat islets (18) and a mouse β-cell line (17). Interestingly, there appears to be a species difference in the islet expression and action of activin A, follistatin, and TGFβ1 (19). Although TGFβ1 acutely stimulates glucose-stimulated insulin release from rat islets (19), prolonged treatment of human islet cells with TGFβ1 had a negative impact on the expression of genes important for β-cell function, likely via the Smad3 pathway (13). Interestingly, Boerner et al (8) did not report evidence of β-cell dedifferentiation, although β-cell function remains to be rigorously investigated in this model. The range of (and sometimes opposing) effects of the same factors observed on pancreatic cells illustrates the complexity and context-dependence of this signaling pathway. Although studies using animals with genetic manipulations are crucial, results from human islets are vital to uncover any species differences and for future clinical translation. One of the most important contributions of the Boerner study was the use of islets from human donors (8). Studies with human islets, or at least >1-year-old mice (which are equally refractory to β-cell proliferation), are crucial for clinical translation of the limited basic knowledge around primary β-cell proliferation mechanisms (20). The ultimate goal of this research is to provide the basis for a diabetes cure. Diabetes results from the immune-mediated destruction (type 1 diabetes) or functional failure (type 2 diabetes) of pancreatic insulin-producing β-cells (21). There are theoretically numerous approaches to treating or reversing diabetes using cell-based therapy, including in vivo regeneration via induction of replication of remaining β-cells, transdifferentiation of other adult cell types (in vivo and in vitro) and differentiation of embryonic (or induced) pluripotent stem cells into functional β-cells (22). Significant preclinical obstacles remain for each of these approaches. At this point, islet transplantation from cadaveric donors remains the only viable alternative to insulin therapy for treating type 1 diabetes (23). Nevertheless, the lack of islet donor tissue prevents widespread patient access to this therapy. Hence, the expansion of primary human islets is of great interest to the diabetes research community. Various studies have shown efficient induction of young rodent β-cell proliferation, yet the same approaches have either not been tested or failed to produce significant results on adult human β-cells (20, 24). Failure to induce proliferation in human islets could be in part a species difference and the fact that the human islet donor age is generally much higher in relative comparison with the young adolescent mice being used for studies (25). As has been elegantly shown, β-cell proliferation in mice and humans ceases to nearly zero after 1 and 30 years of age, respectively (26, 27). Hence, any study showing that a ligand can overcome this resistance of adult human β-cells to reenter the cell cycle, and stimulate proliferation even modestly, is an important contribution to the field. Boerner et al (8) found an ∼1.5-fold increase in human β-cell proliferation with Nodal treatment without affecting viability. Because it is estimated that only 1% of type 1 diabetes patients can be treated with the current scarce availability of donor islets (28) and the fact that a single patient requires at least 103 islet equivalents (from ∼2 pancreas donors) per kilogram of body weight (29), the expansion of islets from a single human donor pancreas would require at least an ∼200-fold increase for a widespread application of human islet transplantation. Therefore, more extensive research in human β-cell expansion is needed. Boerner et al (8) echoed statements by many in the field when they proposed in their paper that the ultimate therapeutic approach may require simultaneously harnessing multiple local signaling pathways. Indeed, genomic advances have revealed that islets produce hundreds of soluble ligands and express hundreds of receptors for ligands produced locally and in other tissues (30). It is clear that using high-throughput approaches will be required to make breakthroughs in this area. Pancreatic β-cell proliferation is exceedingly hard to measure in samples from humans and older adult rodents, given the rarity of events and the potential for false-positives with semiautomated counting. This means that there must be exceptional rigor. Bulk measurements of DNA synthesis are clearly unacceptable in heterogeneous human islet cell cultures where β-cells usually make up a minority of endocrine cells, to mention nothing of the fibroblast-like cells that dominate these cultures after a few days. Imaging must be of sufficient X, Y, and Z resolution such that highly proliferative fibroblasts, which overlay virtually all human islet cultures, are not mistaken for proliferating β-cells. In this regard, the use of flow cytometry by Boerner et al (8) to detect human β-cell proliferation is an important technical proof-of-concept. Clearly, the bar for measuring β-cell proliferation needs to continue to get higher to prevent costly false-positives in the field. Even considering the technical limitations, only a handful of studies have shown significant in vitro stimulation of human β-cell proliferation. These include cocktails of 1) hepatocyte growth factor, fibroblast growth factor 4, nicotinamide and fibrin gel (∼2-fold) (31), the L-type calcium channel agonist Bay K8644 (∼1.5-fold) (32), a diarylamide compound WS6 (∼5-fold) (33), and glycogen synthase kinase-3 inhibitors (∼2-fold) (34). It remains unclear whether any ligand alone will be able to safely increase human β-cell proliferation to therapeutic levels in vivo. It is not clear at this point whether TGFβ superfamily ligands are useful therapeutic targets for manipulating β-cell mass or function in vivo, because they may have off-target systemic effects. Most of the TGFβ family ligands share the same receptors, downstream effectors and antagonists (1) and are expressed ubiquitously in various tissues, including pancreatic islets (8, 12, 17, 19, 30, 35). Thus, the local concentration and length of exposure of the ligands as well as the combination of receptors, effectors and antagonists locally expressed will ultimately provide the final concerted effect on the β-cell, both in vivo and in vitro. Nodal and other TGFβ family members may be more promising factors for in vitro differentiation, expansion, and maturation of pancreatic β-cells. However, for human in vitro β-cell expansion to become clinically relevant, much more potent mitogens and/or combinations of factors working synergistically to retain β-cell maturity, viability, and function need to be evaluated. It will take the collaborative efforts between disciplines from basic β-cell biologists to physicians and engineers (36) to accomplish such an endeavor. Disclosure Summary: The authors have nothing to disclose.
Recently, smart devices for various services have been developed using converged telecommunications, and the markets for near field communication mobile services is expected to grow rapidly. In particular, the realization of mobile NFC payment services is expected to go commercial, and it is widely attracting attention both on a domestic and global level. However, this realization would increase privacy infringement, as personal information is extensively used in the NFC technology. One example of such privacy infringement would be the case of the Google wallet service. In this paper, we propose an zero-knowledge proof scheme and ring signature based on NTRU for protecting user information in NFC mobile payment systems without directly using private financial information of the user.
Consider a practical scenario: an untrusted gate-way is required to verify all the incoming information en-crypted via an encryption scheme, while the sender does not want to reveal any information about the plaintext and the privileged user to the gateway. That is, the gateway distributes the information to a predefined group of users and only the privileged user can open the message. To solve this problem, we need an access control mechanism to allow certain specification of the access control policies while protecting the users' privacy. With this scenario in mind, we propose the notion of verifiable and anonymous encryption where a verification function is added to the ciphertext, which captures the security requirements of the confidentiality of the plaintext and the anonymity of the privileged user. We present two specific constructions of our framework under the setting of asymmetric bilinear pairings in this paper. Our first scheme is proven confidential and anonymous under a weaker security model in the random oracle model, and our second one is built on the basis of a zero knowledge proof of knowledge under a strong security game.
Bit commitment is a fundamental cryptographic task that guarantees a secure commitment between two mutually mistrustful parties and is a building block for many cryptographic primitives, including coin tossing, zero-knowledge proofs, oblivious transfer and secure two-party computation. Unconditionally secure bit commitment was thought to be impossible until recent theoretical protocols that combine quantum mechanics and relativity were shown to elude previous impossibility proofs. Here we implement such a bit commitment protocol. In the experiment, the committer performs quantum measurements using two quantum key distribution systems and the results are transmitted via free-space optical communication to two agents separated with more than 20 km. The security of the protocol relies on the properties of quantum information and relativity theory. We show that, in each run of the experiment, a bit is successfully committed with less than 5.68*10^-2 cheating probability. Our result demonstrates unconditionally secure bit commitment and the experimental feasibility of relativistic quantum communication.
Kai-Min Chung, Daniel Dadush, Feng-Hao Liu, Chris Peikert
The smoothing parameter $η_ε(\mathcal{L})$ of a Euclidean lattice $\mathcal{L}$, introduced by Micciancio and Regev (FOCS'04; SICOMP'07), is (informally) the smallest amount of Gaussian noise that "smooths out" the discrete structure of $\mathcal{L}$ (up to error $ε$). It plays a central role in the best known worst-case/average-case reductions for lattice problems, a wealth of lattice-based cryptographic constructions, and (implicitly) the tightest known transference theorems for fundamental lattice quantities. In this work we initiate a study of the complexity of approximating the smoothing parameter to within a factor $γ$, denoted $γ$-${\rm GapSPP}$. We show that (for $ε= 1/{\rm poly}(n)$): $(2+o(1))$-${\rm GapSPP} \in {\rm AM}$, via a Gaussian analogue of the classic Goldreich-Goldwasser protocol (STOC'98); $(1+o(1))$-${\rm GapSPP} \in {\rm coAM}$, via a careful application of the Goldwasser-Sipser (STOC'86) set size lower bound protocol to thin spherical shells; $(2+o(1))$-${\rm GapSPP} \in {\rm SZK} \subseteq {\rm AM} \cap {\rm coAM}$ (where ${\rm SZK}$ is the class of problems having statistical zero-knowledge proofs), by constructing a suitable instance-dependent commitment scheme (for a slightly worse $o(1)$-term); $(1+o(1))$-${\rm GapSPP}$ can be solved in deterministic $2^{O(n)} {\rm polylog}(1/ε)$ time and $2^{O(n)}$ space. As an application, we demonstrate a tighter worst-case to average-case reduction for basing cryptography on the worst-case hardness of the ${\rm GapSPP}$ problem, with $\tilde{O}(\sqrt{n})$ smaller approximation factor than the ${\rm GapSVP}$ problem. Central to our results are two novel, and nearly tight, characterizations of the magnitude of discrete Gaussian sums.
This thesis proposes several protocols for achieving secure com- putation under concurrent and physical attacks. Secure computation allows many parties to compute a joint function of their inputs, while keeping the privacy of their input preserved. It is required that the pri- vacy one party's input is preserved even if other parties participating in the protocol collude or deviate from the protocol. In this thesis we focus on concurrent and physical attacks, where adversarial parties try to break the privacy of honest parties by ex- ploiting the network connection or physical weaknesses of the honest parties' machine. In the rst part of the thesis we discuss how to construct proto- cols that are Universally Composable (UC for short) based on physical setup assumptions. We explore the use of Physically Uncloneable Func- tions (PUFs) as setup assumption for achieving UC-secure computa- tions. PUF are physical noisy source of randomness. The use of PUFs in the UC-framework has been proposed already in [14]. However, this work assumes that all PUFs in the system are trusted. This means that, each party has to trust the PUFs generated by the other parties. In this thesis we focus on reducing the trust involved in the use of such PUFs and we introduce the Malicious PUFs model in which only PUFs generated by honest parties are assumed to be trusted. Thus the secu- rity of each party relies on its own PUF only and holds regardless of the goodness of the PUFs generated/used by the adversary. We are able to show that, under this more realistic assumption, one can achieve UC- secure computation, under computational assumptions. Moreover, we show how to achieve unconditional UC-secure commitments with (ma- licious) PUFs and with stateless tamper-proof hardware tokens. We discuss our contribution on this matter in Part I. These results are contained in papers [80] and [28]. In the second part of the thesis we focus on the concurrent setting, and we investigate on protocols achieving round optimality and black- box access to a cryptographic primitive. We study two fundamental functionalities: commitment scheme and zero knowledge, and we focus on some of the round-optimal constructions and lower bounds con- cerning both functionalities. We nd that such constructions present subtle issues. Hence, we provide new protocols that actually achieve the security guarantee promised by previous results. Concerning physical attacks, we consider adversaries able to re- set the machine of the honest party. In a reset attack a machine is forced to run a protocol several times using the same randomness. In this thesis we provide the rst construction of a witness indistinguish- able argument system that is simultaneous resettable and argument of knowledge. We discuss about this contribution in Part III, which is the content of the paper. [edited by Author]
Open access
Cryptography and Data Security
Physical Unclonable Functions (PUFs) and Hardware Security
Single-prover interactive proofs can recognize PSPACE; if certain complexity assumptions are made, they can do so in zero-knowledge. Generalizing to multiple non-communicating provers extends this class to NEXP, and at the same time removes the complexity assumption needed for zero-knowledge. \n \nHowever, it was recently discovered that the non-communication condition might be insufficient to guarantee soundness. The provers can form joint randomness through non-local computation without communicating. This could break protocols that rely on the statistical independence of the provers. \n \nIn this work, we analyze multi-prover interactive proofs under the constraint of statistical isolation which prohibits non-local computation. We show that there exists perfect zero-knowledge proofs for NEXP under statistical isolation.
최근 스마트 기기는 결제, 할인쿠폰 등 각종 기능을 제공하는 수단으로 진화되면서 통신과 금융이 융합된 모바일 NFC 서비스의 시장이 급성장할 것으로 전망되고 있다. 특히 모바일 NFC 결제 서비스 시장의 활성화가 예상됨에 따라 모바일 NFC 결제 서비스는 국내 외적으로 널리 주목받고 있다. 하지만 이에 따른 NFC 기술 활용 증가로 개인정보 이용이 늘면서 침해요소 또한 증가하고 있다. 최근 한국인터넷진흥원에서 발표한 "NFC 개인정보보호 대책 최종보고서"에 따르면 개인정보 암호화를 부분적으로 미지원하거나 불필요한 개인정보의 과도한 수집 및 저장 등이 문제점으로 제기되었으며 Google사의 Google Wallet 서비스의 개인정보 유출 사고 또한 이러한 문제점을 뒷받침하는 근거가 되고 있다. 본 논문에서는 기존에 서비스되고 있는 NFC 모바일 결제 서비스 상에서 결제정보의 이동 경로 별 결제 기술의 위협을 분석하고 OTA(Over the Air) 상에서 안전한 정보교환을 위한 NTRU 기반 상호인증 기법과 사용자와 은행 간의 결제 단계에서 결제정보를 직접적으로 사용하지 않고 결제자를 증명할 수 있는 NTRU기반 영지식 증명 기법에 대해 제안한다. Recently, smart devices for various services have been developed using converged telecommunications, and the markets for near field communication (NFC) mobile services is expected to grow rapidly. In particular, the realization of mobile NFC payment services is expected to go commercial, and it is widely attracting attention both on a domestic and global level. However, this realization would increase privacy infringement, as personal information is extensively used in the NFC technology. One example of such privacy infringement would be the case of the Google wallet service. In this paper, we propose an mutual authentication scheme based on NTRU for secure channel in OTA and an zero-knowledge proof scheme NTRU based on for protecting user information in NFC mobile payment systems without directly using private financial information of the user.
Jannik Dreier, Guillaume Dumas, Hugo Jonker, Pascal Lafourcade
An electronic auction protocol will only be used by those who trust that it operates correctly. Therefore, e-auction protocols must be verifiable: seller, buyer and losing bidders must all be able to determine that the result was correct. We pose that the importance of verifiability for e-auctions necessitates a formal analysis. Consequently, in the first part of the talk, we identify notions of verifiability for each stakeholder. We formalize these and then use the developed framework to study the verifiability of several examples. We provide an analysis of the protocol by Sako in the applied pi-calculus with help of ProVerif, finding it to be correct. Additionally we identify issues with the protocols due to Curtis et al. and Brandt. In the second part, we will analyze the protocol by Brandt in more detail. We show first that this protocol – when using malleable interactive zero-knowledge proofs – is vulnerable to attacks by dishonest bidders. Such bidders can manipulate the publicly available data in a way that allows the seller to deduce all participants’ bids. Additionally we discuss attacks on non-repudiation, fairness and the privacy of individual bidders exploiting authentication problems.
Henry‐York Steiner, Claire Halpin, Joseph M. Jez, John Kough · 8 authors
Plant breeding has a long history of developing varieties with desirable traits in response to the needs of both growers and consumers. Although the bases for most of these traits are not known genetically or biochemically, conventional breeding combines these multiple traits to create new hybrids and stable varieties that are safe and not generally subject to safety assessment. With the advent of genetic engineering, a tool for incorporating additional traits has become available to plant breeders. The safe application of genetic engineering to food and feed crops is widely acknowledged as a useful tool in addressing global agricultural challenges, including population growth and climate change. As used here, the term genetically engineered (GE) stack refers to a plant in which two or more transgenic events (i.e. single-locus insertions) that have been separately assessed for safety have been combined by conventional breeding (Table I). In recent years, increasing numbers of GE stacks have been planted, the first of which offered combinations of insect and herbicide tolerance genes to combat a wider range of pests and weeds than covered by the single events (Que et al., 2010; James, 2011). Two main questions arise when considering the food and feed safety of GE stacks: (1) does incorporation of more than one event increase genomic instability, and (2) can potential interactions between the products of the combined events impact safety? A related paper considered the stacking of events in light of the plasticity of plant genomes and concluded that enhanced genetic instability from a transgene or from common sequences in two or more transgenes is remote (Weber et al., 2012). This paper addresses the second question of potential interactions between events and their products combined in a stack, reviews the basic principles of plant breeding and its history of safe use, and extends these principles to the feed and food safety of events combined through the same processes used in conventional breeding of non-GE plants. Potential environmental impacts are outside the scope of food and feed safety. The new varieties developed through modern biotechnology are identified by a number of terms, including genetically modified (GM), GE, transgenic, biotech, recombinant, and plants with novel traits. The term GE is used here as defined by Weber et al. (2012). For these reasons, the term GE is preferred over the term GM. There are many methods encompassed by the general term conventional breeding, including wide crosses and selection, mutagenesis, and somaclonal variation. When the parental species are not closely related, the cross may be facilitated by embryo rescue, somatic hybridization, or x-ray-induced translocations. The term interaction, as used in this paper, refers to an effect, such as a new or modified metabolic activity, resulting from a combination of transgenes. An example of an interaction is protein-protein binding resulting in a novel effect only seen with a specific combination of proteins, for instance, protein cofactors or subunits for the same enzymatic complex or subcellular metabolic binding reaction. Examples can also include a direct metabolic interaction that would inhibit or activate components in a metabolic pathway shared by the proteins newly combined in the GE stack or components of independent metabolic pathways that indirectly interact by way of a common metabolite. Thus, interactions within GE stacks generally refer to the metabolic or physiochemical interplay between the products of transgenes or between the product of one transgene and the second gene, rather than between the two genes themselves. Conventional breeding has a long history of safe use despite the presence of antinutritional factors, toxins, and allergens in crops. There is no evidence that a random genomic change in a crop has resulted in a novel food or feed safety issue (Weber et al., 2012). Historically, humans have selected desirable traits that arise from the crop’s genomic plasticity and interactions between genes. As breeding became more advanced, new methods were applied to select and combine desired traits, which also modify the genome as a consequence. Plants produce a multitude of metabolites that provide various functions. These include signaling activities in response to environmental stress or attack from plant pathogens and pests. Some metabolites have beneficial effects, while others are toxic when fed at high levels to sensitive animal species (Ames et al., 1990). Although particular metabolites tend to be specific to some plant families, there are metabolites of concern in a number of common food and feed crops, including apple (Malus domestica), apricot (Prunus armeniaca), Brassica spp., celery (Apium graveolens), cucumber (Cucumis sativus), lima bean (Phaseolus lunatus), potato (Solanum tuberosum), cherry (Prunus avium or Prunus cerasus), and sorghum (Sorghum bicolor; Beier, 1990; D’Mello et al., 1991; Stewart, 2009). Examples of such metabolites include alkaloids, lectins, glucosinolates, furanocoumarins, cyanoglucosides, nicotines, and phytoestrogens. Some of these can impart bitter taste, and conventional breeding has repeatedly reduced their levels to acceptable concentrations (Drewnowski and Gomez-Carneros, 2000). There are few documented cases in which breeding led to an unacceptable level of a metabolite. Following reports of bitter taste, the potato var Lenape, which was developed from a cross of potato to a wild Solanum species, was found to contain doubled levels of glycoalkaloids (Anonymous, 1970). The only other documented incident of unacceptable metabolite levels associated with plant breeding is that of a disease-resistant celery containing elevated levels of furanocoumarins, which may have contributed to dermatitis among grocery store personnel (Berkley et al., 1986; Seligman et al., 1987). The environment can also play a role in impacting furanocoumarin levels; a later report of dermatitis among celery harvesters in southern Israel was attributed to delayed harvest, and hence more mature plants being handled, due to the Gulf War (Finkelstein et al., 1994). Similarly, reports of toxic squash (Rymal et al., 1984) and zucchini (Herrington, 1983) appear to have been limited to individual plants within otherwise widely grown varieties, suggesting the higher toxin levels were due to environmental conditions or mutations. Despite these few instances, these crops remain safe for food or feed use. Although breeders recombine tens of thousands of genes with virtually infinite potential interactions, to our knowledge, there has never been a report of a completely novel toxin or allergen appearing in a genus as a result of conventional breeding. The development of an interspecific somatic hybrid of potato (S. tuberosum and Solanum brevidens) containing demissidine (Laurila et al., 1996) has often been cited as proof that novel toxins can arise during breeding. In fact, Jadhav et al. (1981) documented the presence of demissidine in potato more than a decade before it was found in the hybrid. To guard against unexpected increases in levels of known toxins, breeders have instituted screens for these compounds in new varieties before they are released. Examples include cotton (Gossypium hirsutum), potato, lima bean, and canola (Brassica napus), because they contain known compounds that can impact food or feed safety. However, breeders cannot and do not screen for de novo compounds. Hundreds of thousands of varieties have been bred without the emergence of any novel allergens or toxins, indicating that the likelihood of such events is virtually zero (Stevens, 1974). Improved crop varieties produced by conventional breeding are the cornerstone of food production in the world today. Thus, the ways in which risks are managed during conventional breeding of non-GE crops, which includes testing for any known concerns, sets the framework for the food and feed safety assessment of GE stacks. As is the case for any other new variety or hybrid, GE stacks are only considered for market introduction if the combined traits have met the intended thresholds for efficacy and stability. Newly developed GE events undergo rigorous safety assessments by the developer and by regulatory agencies prior to their commercial release. These assessments evaluate the impact of both intended and potential unintended effects on food, feed, and other aspects of crop safety. Assessment criteria and objectives are based on national priorities and on international standards, such as those of the Joint Food Standards Program of the Food and Agriculture Organization of the United Nations and the World Health Organization (FAO/WHO, 1996, 2000), as well as Codex Alimentarius Commission recommendations for conducting food safety assessments of GE crops (Codex Alimentarius Commission, 2009). Codex principles and guidance are widely followed for single events. The key components of GE crop safety assessments include (1) descriptive information on the transgenes and inserted recombinant DNA; (2) detailed characterization of the DNA insert relative to the native genome, in planta concentration and stability of the products of the transgene(s), analysis of plant phenotype, and descriptive information such as efficacy, mechanism or mode of action of the new trait(s), and crop management considerations; (3) evaluation of the safety of the products of the transgene(s) in the context of common commercial crop practices and uses; and (4) comparative safety assessment for suitability as food and/or feed. Such analyses might include a determination of expression levels of known allergens and toxins, and overall composition, including nutrients, antinutrients, and selected metabolites for that crop (FAO/WHO, 1996, 2000; Cellini et al., 2004; Codex Alimentarius Commission, 2009; Thomas et al., 2009). Assessments of nutrient composition and agronomic characteristics, as well as an assessment of potential allergenicity and toxicity, are widely recognized as significant components of GE crop safety assessments (FAO/WHO, 1996, 2000; Metcalfe et al., 1996; Kuiper et al., 2001; Cellini et al., 2004; Delaney et al., 2008; Codex Alimentarius Commission, 2009; Thomas et al., 2009). Differences between the GE crop and appropriate comparators are evaluated in terms of biological relevance, magnitude of difference, exposure, and impact on food or feed safety to determine the need for further investigation. The comparators may include a closely related non-GE variety and other commercial GE and non-GE varieties. The International Life Sciences Institute’s Crop Composition Database (http://www.cropcomposition.org; International Life Sciences Institute, 2006) may also serve as a reference for comparison for some crops (Ridley et al., 2004). These holistic analyses also take into account interactions of the transgenes with endogenous genes and their products. Agriculturally important plants express approximately 25,000 to 50,000 genes at any given time. The safety assessment evaluates the GE crop phenotype, which includes interactions between the event and the host genome that may impact safety. Once the safety assessment is completed, conventional breeding is used to incorporate the event into different genetic backgrounds, without undergoing additional assessment. The developer of the resulting food and feed products is, however, responsible for the safety of those products and for meeting all relevant statutory and regulatory requirements, as is the case for all foods and feeds. Even within a single genus having species that differ in ploidy level, the number of genes within a plant can vary. For example, some 400 genes are not common in the historically important maize (Zea mays) inbreds B73 and Mo17; each of these genes is found in B73 but not in Mo17 or vice versa (Springer et al., 2009; Lai et al., 2010). Similarly, of the approximately 46,000 of genes in soybean (Glycine max), 856 genes were present in some but not all of the soybean genotypes tested (Lam et al., 2010). Of the two potato genotypes with sequenced genomes, 275 genes are found in only one or the other et al., 2011). Thus, different non-GE genotypes in novel combinations in novel interactions, but no safety have been this of novel interactions is to be by the stacking of transgenes. Despite the genetic in crop most regulatory agencies do not new non-GE varieties developed by conventional breeding there is a known safety concern or associated with the new variety of and Food and of the Food on Organization and Health Food This is based on the that conventional breeding is as As defined conventional breeding traits from genetic interactions of genes and their products are in breeding to produce new crop varieties. In plant breeders through crosses that combine different different et al., in some different genes et al., 2011). However, the are from and among have the that might be in et al., et al., et al., and et al., these that thousands of interactions are when genomes are combined by breeding. these interactions have led to which has been selected by plant breeders to desirable traits et al., 2010). these interactions of genes have a long history of food and feed the bases of these interactions are the information to a specific interactions between endogenous genes in conventional breeding do not to direct As information and methods to complex become it may be to such when GE events by breeding, it is to interactions between the events within the GE stack in a and can be developed for those specific with the historically used in conventional breeding to new traits into crop such as wide hybridization, genetic engineering a direct of a DNA that a specific into a the methods by which individual events are combined to produce a GE stack are to those used to combine multiple traits in new conventional crop varieties and two GE does not any in the genome is by two non-GE (Weber et al., the safety assessments for the individual events are to the GE The only safety question that the individual event assessments do not is that of interactions between the products of the combined transgenes. Two questions on the potential of interactions between the events in a particular GE (1) does a potential interaction between the products in each single event in the GE stack, and (2) would the potential interaction result in a food and feed safety In other are there of engineered and any interactions between these that might create A safety assessment of a crop produced by conventional breeding of parental into a GE stack can incorporate a that addresses interactions of the transgene products are and if they might food and feed safety. A for this is in which the overall development of a for potential interactions, with the and of the crop of the single and the prior food and feed safety assessments on the products. The question in the assessment is it or that the transgene expression products of the single events interact in the The only of interaction different in a GE stack from that seen in conventional breeding of non-GE plants is a metabolic or physiochemical interaction from the combination of the transgene products. other interactions are to those in bred non-GE plants. A for the safety assessment of a food and feed crop with a GE stack produced by conventional breeding of two or more events. if it is that novel interactions in the GE stack, can the interaction impact the safety of the GE This is a if there is no for a potential interaction, or if a potential interaction that does not the prior safety assessments on the individual events are for the GE a can be developed for an interaction that may food or feed further questions on the and of the A number of relevant be considered to a the presence and of interactions to a potential safety Although the of questions on the transgenes in the GE stack, these questions be to food and feed safety. Examples of questions that can be to a are in these questions on direct product interactions, expression and metabolic products of the transgenes. The same to genes expression of other such as transgenic and to the of endogenous genes. these of transgenes may expression of of other the and of by each transgene would be documented before each single event is used in be from the of the specific effects of each many products of conventional breeding of non-GE plants on known to have been from in or from et al., 2010). To the that conventional breeding has plants with associated with or in factors, there is no that metabolite have resulted in any novel to food or feed safety. In or there has not been the of novel toxins related to these metabolic of the specific of transgenes being assessment of the combined information from the single events can or a for The need for further safety assessment of the potential interaction is evaluated on a Examples of the can be used to at safety assessment are An interaction between the products of transgenes is not the single events combined in a GE stack proteins that are not known to interact or that on different metabolic pathways with no known or common metabolite between GE stacks that combine insect and herbicide tolerance are an In these crops, insect is by one or more genes toxin proteins from that are not native to but have a general history of safe use in the food as in conventional and and in GE crops. The proteins no known metabolic in plants and are in the or to tolerance is by a that an of a or that a that the of the herbicide For a herbicide tolerance stack, is there a that an interaction between these events The GE stack does not create a new The herbicide tolerance may or may not serve a metabolic in the and insect As herbicide tolerance may be engineered to be and in the or both and the protein herbicide tolerance be found in the same of the two transgenic traits the of interaction in the GE however, these proteins are not related, are not in the same metabolic and no common there is no biological pathway in which these products would or indirectly there is no or for the interaction of these proteins or their products in the GE stack that the need for a new safety evaluation The same to the stacking of transgenic with other transgenes in crops with events that have a safety assessment. the transgenes are not in the same or their products are not to the same there would be no new food or feed safety if the transgenic event the of endogenous there is no for a food or feed safety on an of the of some event combinations may have the potential to produce products that at For example, if individual events produce within metabolic pathways or produce that can for the same in a GE stack, a potential for interaction to the number of interactions, there are only a of direct interactions between metabolic and metabolic which are as through a a potential interaction does not that food or feed safety would be a of metabolites in plant pathways have been to have a role other than as in plant et al., 2000). An example a potential interaction within a pathway that does not impact food or feed safety can be found in the A in is the for and James, The product of the is used for Plant are of two subunits and two The two subunits are by different genes. In a GE stack, one event would an engineered of of higher levels of and the second event would an engineered of also of higher levels of In both single the level of is due to an level of from the would be in these traits to for an effect on In this example, the two genes would be for their direct genes expression and the proteins are in the same metabolic pathway and the same enzymatic interaction between the transgenes in these events is for the intended effect of further in a GE In this the GE stack does not a new pathway or metabolites only and effects are there is no potential impact on food or feed safety. is to a safety issue from a GE example which are produced plant metabolites in plant can be into and become toxic by by a and they in the plant response to from pests and pathogens et al., The is in the the is in the or In some the and its are in but to the of and no toxin is present in However, from insect and of enzymatic of the in the a toxic to the In this event the level of a particular that is present in the plant at resulting in a variety with to pests and Although event the level of this particular the is if found within the range of levels in this would no food or feed safety during the safety assessment of event which is also in a variety with a with enhanced that is to a The of this transgene into a host plant with levels of the particular of this no because the inserted the for toxin The safety assessment of each individual event would be to include an analysis of the safety of the event various environmental the of that enzymatic of the in the to produce a toxic would have been evaluated during the safety assessment of the individual events. However, for the of the combination of these two it is that this be more closely in the event than been with the individual events In such an additional assessment of the GE stack would be In over a of plant breeding, there are no known de novo effects from the breeding which has conventional plant breeding with a history of safety for food and feed. effects have have been can be between endogenous genes in a conventional breeding and transgenes by conventional breeding The between the endogenous genes combined conventional breeding and transgenes combined through conventional breeding is the of the transgenes and their products. This the development of food and feed safety. A safety assessment for a food or feed crop produced by conventional breeding of GE events first the likelihood of interactions if they do they might safety. the events are to no additional assessment be to a safety determination for the GE stack, because each individual event has independent safety When interactions are to the effects can be based on and safety assessment of the individual parental events. When there is a biological to an interaction, the of the interactions be evaluated to determine if there be an impact on food or feed safety. there is no impact of the interaction on food or feed no additional testing be to the GE if the identified interaction be to impact food or feed the GE stack would a food and feed on the specific interaction The need for such a further assessment and the used be on a on the specific interaction identified and into account the Codex Alimentarius principles for safety assessment (Codex Alimentarius Commission, 2009). International Life Sciences International Food and Plant and and and for and during the The also International Life Sciences and for their in this to also the of and in the of this The and would also to the for in the and for many and de de and of Standards Commission on of of of of Food and of and of of of Agriculture and and Plant Food and of and and genetically engineered genetically modified
Alcohol is the drug of choice among youth, with 12% of 8th-graders, 22% of 10th-graders, and 29% of 12th-graders reporting heavy episodic drinking. Although prevalence rates are at historic lows, alcohol use continues to be widespread among adolescents, and pediatricians must screen for underage and family alcohol use in health assessment visits.After completing this article, readers should be able to:National surveys make it clear that the use of alcohol among adolescents is both widespread and harmful. By the 12th grade, close to three-quarters of adolescents in high school report ever having an alcoholic drink, and more than one-quarter report having their first drink before age 13 years. Data from Monitoring the Future, an annual survey of youth in the United States, show that 71% of high school seniors reported some experience with alcohol in the past; 41% reported use in the last 30 days and, of great concern, 3% reported daily use. More than one-half (58%) of 10th-graders and more than one-third (36%) of 8th-graders report having consumed alcohol at some point in their lives, and more than one-third of 10th-graders (37%) and one of six 8th-graders (16%) report having been drunk in the past. (1) The good news is that the use of alcohol by teens, as well as the use of many of the illicit drugs, has declined over the past decade. The bad news is that, although these declines are encouraging, alcohol remains the drug of choice among youth.The pattern of alcohol use that is exhibited by many adolescents is one of drinking too much and at too early an age, thereby creating problems for themselves, for people around them, and for society as a whole. Underage drinking is a leading public health problem in this country. Underage drinkers consume, on average, four to five drinks per occasion approximately six times per month. By comparison, older adult drinkers, ages 26 and older, consume, on average, two to three drinks per occasion approximately nine times per month. A particularly worrisome trend is the high prevalence of heavy episodic or binge drinking in adolescents, which is defined often as five or more drinks in a row in a single episode. Monitoring the Future data show that 12% of 8th-graders, 22% of 10th-graders, and 29% of 12th-graders report engaging in heavy episodic drinking.Studies find that drinking alcohol often starts at very young ages. Moreover, studies indicate that the younger children and adolescents are when they begin to drink, the more likely they are to engage in behaviors that can harm themselves and others. Those who start to drink before age 13 years, for example, are nine times more likely to binge drink frequently as high school students than those who begin drinking later. Data from recent surveys show that approximately 10% of 9- to 10-year-olds have already started drinking; nearly one third of youth begin drinking before age 13, and more than one in four 14-year-olds report drinking within the past year. (2)(3)A number of studies show that the early onset of alcohol use, as well as the escalation of drinking in adolescence, are risk factors for the development of alcohol-related problems in adulthood. Initiating alcohol use earlier in adolescence or in childhood is a marker for later problems, including heavier use of alcohol and other drugs. Individuals who report initiation of alcohol use before age 15 years were four times more likely to meet criteria for alcohol dependence and two times more likely to meet criteria for alcohol abuse as those individuals who began drinking after age 21 years. (4)The consequences of underage drinking include a range of physical, academic, and social problems. Perhaps most frightening is the fact that alcohol is the leading contributor to morbidity and mortality in youth. Alcohol use is the leading contributor to death due to injuries, the primary cause of death in individuals younger than 21 years of age. Annually, 5,000 youth die of alcohol-related injuries that involve underage drinking. This includes injuries sustained in motor vehicle crashes (∼1,900), homicides (∼1,600), and suicides (∼300), as well as unintentional injuries not related to motor vehicle crashes. Among studies of adolescent trauma victims, alcohol is reported in 32% to 45% of hospital admissions. The association between alcohol use and violent behavior is well documented. Numerous studies of adolescents report that alcohol use is linked to both violent behavior and to violence-related injuries. (5)(6)Other harmful behaviors and negative consequences frequently related to excessive drinking among adolescents are high-risk sexual behaviors (unplanned and unprotected intercourse); sexual misconduct, including rape; and assaults. Having multiple sexual partners, failing to use condoms, and performing other high-risk sexual behaviors have been associated with alcohol use in adolescents. Furthermore, alcohol use by the offender, victim, or both has been linked to sexual assault, including date rape.As youth move from adolescence to young adulthood, they encounter dramatic physical, emotional, and lifestyle changes. Developmental transitions, such as puberty and increasing independence, have been associated with alcohol use. Because drinking is so widespread among adolescents, simply being an adolescent may be a key risk factor for initiation of alcohol use, as well as for drinking dangerously.Data from imaging studies show that the brain continues developing well into the twenties, during which time it continues to establish important communication connections and further refines its function. Many believe that this lengthy developmental period may help to explain some of the behaviors characteristic of adolescence, such as the propensity to seek out new and potentially dangerous situations. For some adolescents, thrill-seeking includes experimenting with alcohol use. Developmental changes also may offer a possible physiologic explanation for why teens act so impulsively, often not recognizing that their actions—such as drinking—have consequences.How adolescents view alcohol and its effects also influences their drinking behavior, including whether they begin to drink and how much. An adolescent who expects drinking to be a pleasurable experience is more likely to drink than one who does not. Beliefs about alcohol are established very early in life, even before entering elementary school. Before age 9 years, children generally view alcohol negatively and see drinking as bad and associated with adverse effects. By approximately age 13 years, however, their expectancies shift, becoming more positive. Accordingly, adolescents who drink the most also place the greatest emphasis on the positive and arousing effects of alcohol.Differences between the adult brain and the brain of the maturing adolescent may explain why many young drinkers are able to consume much larger amounts of alcohol than adults before experiencing the negative consequences of drinking, such as drowsiness, lack of coordination, and withdrawal or hangover effects. This unusual tolerance may help to explain the high rates of binge drinking among many adolescents and young adults. At the same time, adolescents appear to be particularly sensitive to the positive effects of drinking, such as feeling more at ease in social situations, and young people may drink more than adults because of these positive social experiences.Children who begin to drink at a very early age (before age 12 years) often share similar personality characteristics that may make them more likely to start drinking. Young people who are disruptive, hyperactive, and aggressive—often referred to as having conduct problems or being antisocial—as well as those who are depressed, withdrawn, or anxious, may be at greatest risk for alcohol problems. Other behavior problems associated with alcohol use include rebelliousness, difficulty avoiding harm or harmful situations, and a host of other traits seen in young people who act out without regard for rules or the feelings of others (ie, disinhibition).Some of the behavioral and physiologic factors that converge to increase or decrease a person’s risk for alcohol problems, including tolerance to alcohol’s effects, may be linked directly to genetic factors. For example, being a child of an alcoholic or having several alcoholic family members places a person at greater risk for alcohol problems. Children of alcoholics (COAs) are between 4 and 10 times more likely to become alcoholics themselves than are children who have no close relatives with alcoholism. (7) COAs also are more likely to begin drinking at a young age and to progress to drinking problems more quickly.Research shows that COAs may have subtle brain differences that could be markers for developing later alcohol problems. For example, by the use of newer brain-imaging techniques, scientists have found that COAs have a distinctive feature in one brainwave pattern (called a P300 response) that could be a marker for later alcoholism risk. (8) Some studies suggest that these brain differences may be particularly evident in people who also have certain behavioral traits, such as signs of conduct disorder, antisocial personality disorder, sensation-seeking, or poor impulse control. (9)Drinking and alcohol-related problem behavior reflect a complex interplay between inherited and social-environmental factors, the implications of which are only beginning to be explored in adolescents. And although even more is understood about the role and contribution of genetics, this knowledge still does not tell the entire story.Social and environmental factors, such as the influence of parents and peers, also play a role in alcohol use. For example, parents who drink more and who view drinking favorably may have children who drink more. Other influences, such as the impact of the media, have been examined and are felt to play an important role. Today, alcohol is widely available and aggressively promoted through television, radio, billboards, and the Internet.Although the severe health problems associated with harmful alcohol use are not as common in adolescents as they are in adults, studies show that adolescents who drink heavily may put themselves at risk for a range of health problems.Chronic heavy drinking during adolescence and into young adulthood appears to be associated with detrimental effects on brain development, brain functioning, and neuropsychological performance. Recent evidence suggests that heavy drinking during adolescence is associated with poorer neurocognitive functioning during the young adult years and is associated particularly with impairment of attention and visuospatial skills. (10)Brain imaging and studies of event-related potentials have demonstrated subtle but significant abnormalities in brain structure and function. In a recent study, researchers used magnetic resonance imaging to determine the effects of heavy drinking on the changing brain structure of teens and young adults with alcohol use disorders. Hippocampal volumes were smaller in youths with alcohol use disorders than in matched controls and correlated with the onset of alcohol use disorder and with the duration of alcohol use disorder. (11) The earlier an individual developed an alcohol use disorder and the longer the duration of the alcohol use disorder, the smaller was the volume of his or her hippocampus. (12) Other studies have looked at the effect of alcohol on the structure of white matter and have demonstrated that white matter integrity was reduced in the corpus callosum of youths with alcohol use disorders.Research studies indicate that a number of factors seem to influence how and to what extent alcohol affects the brain, including:Elevated liver enzymes, indicating some degree of liver damage, have been found in some adolescents who drink Young drinkers who are or liver enzymes, even with only of both and puberty is a period associated with including in the and in increase of other and factors, which are for alcohol during this period of and development (ie, before or during may the for development of and are the in the in of At the same time, they experience high rates of mortality and morbidity because of their behavior, including the use of many including adolescence is a time of risk and for many young people in some of that alcohol use. 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Bid validity proof and verification is an efficiency bottleneck and privacy drawback in homomorphic e‐auction. The existing bid validity proof technique is inefficient and only achieves honest‐verifier zero knowledge (ZK). In this study, an efficient proof and verification technique is proposed to guarantee bid validity in homomorphic e‐auction. The new proof technique is mainly based on hash function operations and only needs a very small number of costly public key cryptographic operations. Moreover, it can handle untrusted verifiers and achieve perfect ZK. As a result, efficiency and privacy of homomorphic e‐auction applications are significantly improved. To the best of authors’ knowledge, it proof technique is the first to handle untrusted verifiers in e‐auction applications.
In this decade, establishing structure-function relationships in human brain has become one of the most influential concepts in modern cognitive neuroscience since interactions among cerebral components are fundamental to explain cortical activities ([1]; [2]; [3]). \nIn literature such relationships have been defined in terms of structural, functional and effective connectivity. This distinction, mainly focused on the theoretic concept, is also related to the different measurement instruments and analytical tools used for acquiring and processing the data. The structural connectivity refers to a pattern of anatomical links among brain regions. Its analysis aims to characterize the architecture of complex networks underlying the cerebral functional organization. Magnetic Resonance Imaging and especially Diffusion Tensor Imaging can be used to convey information concerning the physical connection between neuronal populations. Functional/effective connectivity aims at identifying the presence and the strength of connections in terms of statistically significant dependency. The former is defined as the temporal correlation between neurophysiological events occurring in distributed neuronal groups and areas. The latter describes the causal influence that one neural system exerts over another either directly or indirectly in terms of temporal precedence and physical control ([4];[5]). Functional and effective connectivity can be estimated exploiting both Functional Magnetic Resonance Imaging (fMRI) and electrophysiological signals, such as Electroencephalography (EEG) and Magnetoencephalography (MEG), with different advantages and drawbacks, respectively. fMRI provides high spatial resolution (mm) but poor temporal precision (s) while EEG/MEG has more limited spatial resolution (cm) and higher temporal precision (ms). Because functional and effective connectivity are largely estimated over time, EEG and MEG are more suitable for calculating such connectivity. In literature several methods have been developed to characterize brain connectivity in terms of network topology, connections strength and causality, following two main approaches: the data-driven, where topology, causality and strength are all inferred from data, and the neural model-based, where the model topology is postulated from a priori knowledge and only the connections strength is estimated from the data. \n-\tData driven approach. The data driven approach includes linear, non-linear and information-based techniques. The linear ones provide a battery of indices derived by multivariate autoregressive models (MVAR) based on Granger causality principles ([6]) or MVAR frequency response ([7]). Such are Ordinary Coherence, Partial Coherence, Directed Transfer Function (DTF) and Partial Directed Coherence (PDC). These indexes measure the strength of the linear coupling between two signals; in addition DTF and PDC provide information about causal influence ([8]). \no\tAmong the non-linear techniques, phase synchronization has been shown to be very effcient in detecting interactions between oscillators. The phase locking values approach assumes that two dynamic systems may have their phases synchronized even if their amplitude are zero correlates ([9]). \no\tThe most representative information-based technique is the cross mutual information that measures the mutual dependence between two signals by quantifying the amount of information gained about one signal from measuring the other, as a function of delay between these two signals ([10]). \n-\tNeural model based approach. Representative methods are the Structural Equations Modelling (SEM) and the Dynamic Causal Modelling (DCM) ([11]; [12]). They are multivariate technique used to test hypothesis regarding the influences among interacting variables, but different concepts underlies these two methods. SEM approach assumes that neuronal dynamics are very fast in relation to signals uctuations and, hence, is based on a static neuronal model. This case, the neuronal activity has reached steady-state and changes in connectivity are led directly by changes in the covariance structure of the observed time series ([13]). On the other hand, in DCM the observed time series are modelled as a deterministic dynamical system in which external inputs causes changes in neural activity and therefore in connectivity values ([14]). \nMost approaches, like those based on Granger causality principles, have been examined in literature to quantify their ability in revealing cerebral connections ([15];[16]; [11]) but their simulation studies do not provide a comprehensive analysis because they use in silico data generated by self-referential linear methods which do not reproduce the complexity of brain. To overcome this issue, an innovative simulation approach has been developed in this work, based on a nonlinear neural mass model ([17]) totally independent of SEM and MVAR linear equation and able to address the complexity of neural networks. This no-self referential approach was exploited to generate in silico network data to be used as a benchmark, to quantitatively compare obtained results with true connections. The main objective of this work was to understand limits and advantages of MVAR indexes and SEM by exploiting the simulation study. Thus, it mainly serves as a proof-of-concept for connectivity measures under ideal conditions. Our purpose was to derive from simulation results some practical procedures in order to classify different brain states to support both cognitive research and clinical activity. First, research activity was focused to address connectivity on simulated data obtained on three regions networks characterized by different strength connections and based on different levels of non linearity. Second, a dataset, made available by Department of Medicine, University of Padova was used to explore application of these methods to real data by applying the simulation study suggestions. \nThis thesis consists of three main section. \nThe ffrst one includes Chapter 1-2-3 describing in detailed the considered connectivity measures, such are those based on Multivariate Autoregressive models and the Structural Equation Modelling, and the simulation study. The second part depicts in silico results and the application to EEG data. Finally, comments are reported in Discussion and Conclusions. \nChapter 1 explains how the connecting parameters of MVAR and SEM models are identified on EEG data and describes procedures commonly exploited to analyse connectivity. Chapter 2 reports an overview about the principal models used to generate in silico data, namely the neural mass models, and described the neural mass model exploited in this work. Finally, it characterizes network models adopted to simulate data and lists the procedure followed to generate in silico datasets. Chapter 3 summarizes the computations implemented to have more insights on our data by analysing the output of each methods. It describes the procedure used to evaluate the statistical signiffcance of each index results, such are the F-test for Granger causality index and the null distribution threshold using surrogate data for MVAR frequency indexes. Chapter 4 illustrates the results obtained with the simulation study. First, we reported the complete analysis for a representative subset of experiments, then for all datasets we showed topology and strength estimates. Chapter 6 delineates the procedure followed to study the connectivity in case of hepatic encephalopathy. Chapter 7 covers the Discussion and Conclusions. The Appendix is a parallel work aimed to understand the meaning of connectivity indexes computed via Structural Equation Modelling. By exploiting the neural mass model used to simulate cortical data, the objective is to quantify which measure its estimates represent. We demonstrated that Granger causality is a good estimator with high values both of sensitivity and specificity, while frequency indexes, DTF and PDC, are too much affected by the threshold choice and their interpretation in terms of absolute strength connection is not clear. As regard SEM, we proved the difficulty of its approach to describe just simple situations. Even if SEM is based on linear regression as well as MVAR models, it differently assumes there is no connection with past information, as if brain connectivity could describe time series relationships by the instant we observe it. Hence, it is not sufficiently robust to characterize neuronal dynamic activity. \n
High throughput DNA sequencing technologies have revolutionized the field of genomics.It is now possible to generate huge amounts of sequencing data at significantly lower costs and greater speed.In this study, we have utilized Illumina deep sequencing to analyze the fitness landscape of the four-helix bundle protein ROP.All possible single point mutants of the 63 amino acid protein ROP were constructed.From the library of single point mutants of ROP, variants were enriched 1,000 fold for activity by a growth selection for six rounds, which works based on ROP's role in plasmid copy number regulation.The enrichment was monitored by a cell-based screen using a GFP reporter.As a proof of principle experiment, point mutant libraries at positions 14, 30 and 43 were individually subjected to growth selection, and colony sequencing of random variants from sixth round were mostly actives as expected based on prior knowledge of these positions.Colony sequencing of rounds zero (naives) and six from the actual library enrichment yielded promising results.Illumina deep sequencing was performed on rounds zero, three, six and eight.Paired-end reads were generated with each sequence containing short barcodes at each end to reveal the round and orientation.From the data analysis, relative enrichment for variants from different rounds lets us delve into the fitness landscape of ROP.iii Dedication To my mom, dad and family
The main aim of cryptography is to provide the frameworks and solutions for information security. The fundamental weapons to protect information are interactions and private randomness. Since the breakthrough result, zero-knowledge proof system, by Goldwasser, Micali, and Rackoff in mid 80s, the cryptography community has endeavored to propose the new notions of information security and the relative solutions which more closely reflect the modern computing environment. Concurrent security first introduced by Dwork, Naor, and Sahai was suggested to capture the information security in the modern internet environment. That is, the adversary may interact with a honest parties in many concurrent executions of a protocol where the messages are scheduled in any adversarial way.Resettable security was first introduced by Canetti, Goldreich, Goldwasser, and Micali, which models the security issues in which parties have a limited source of private randomness. In other words, an adversary might interact with honest parties in many executions of a protocol while the honest parties are only allowed to use the polynomially bounded number of (hard-wired) randomness.An important question is: "How much efficient protocol can we construct to achieve the above security in terms of round complexity?" Unfortunately, it has been showed that the best possible round complexity for such protocols is poly-logarithmic in the security parameter based on black-box simulation without help of external set-up assumptions. Thus, the question is now to minimize the round complexity of protocols with a minimal set-up assumption.In this thesis, we positively answer the above question with help of set-up assumptions. Specifically, we consider two set-up assumptions, the Bare Public Key (BPK) model and the Cross-Domain (CD) model. The BPK model was first introduced by Canetti, Goldreich, Goldwasser, and Micali. In the BPK model, each party is required to register their public keys before the start of interacting with each other. The CD model is a newly proposed model in this work. In the CD model, we have domains which models key certification authorities in the real world and each party belongs to one of the domains.In the BPK model, we show a constructions of constant-round simultaneously resettable zero-knowledge argument of knowledge with a standard cryptographic assumptions. As a main building block for this result, we show a construction of constant-round simultaneously resettable witness-indistinguishable argument of knowledge.In the CD model, we show a construction of constant-round concurrently secure multi-party computation protocol with the fixed number of domains. On the other hand, we prove that if the number of domains is not fixed, such a constant-round protocol does not exist.
As a tool for cross-disciplinary collaboration, energy and emissions calculations were central as common reference point throughout the whole process studied here. Considering only the design phase, it is clear that particularly the energy account was useful in defining both the necessary amount of work and the methods of the collaborative work. One of the merits was its ability to force each participant onto neutral ground based on shared information and work requirements. The energy account served as a boundary object (Star 2010) in this way as it provided “something” around which to collaborate across disciplinary boundaries and something that could translate different disciplinary specialities into a mutually comparable success criterion: the primary energy factor. The primary energy factor was both the what and the why of this collaboration, simultaneously a process of creation and a guiding force. The effort that went into creating the energy account and collaboration in workshops, which were employed as a sort of management tool, were argued by some informants to have made the process ‘heavy on the nose’. This was largely due to design aspects and the signal effect, which was important for PH Kjørbo as a pilot project. As this was a pilot project, it has received a certain degree of special attention from all involved institutions. The participants describe the special requirements connected to this building as \n• trust in the concept,\n• broad participation in the project’s definition process,\n• trust between partners, and\n• high level decision making at the different partners’ companies to cater to an acceptable risk allocation for all parts.\nAccording to the respondents, the design process benefited much from the oversight of a dedicated process manager, a role that was served by one of the project’s senior architects. In fact, many respondents noted the exact point in time when the process manager exited the project was also the point when the project encountered problems. \nThe participants agree that “closeness” (in terms of frequent communication both face-to-face and by other means) between the central and defining actors in the project team was a key to success. Failures accrued once the distance between actors increased due to their involvement in other projects. According to respondents, one important role for a process manager in the later stages could have been as a liaison between project management levels (contractor) and subcontractors. Some problems that appeared in this phase involved the sheer disbelief shared by the subcontractors when they first became acquainted with the calculations, the functional demands, and the specifications that had resulted from the design process - a process they knew little about. This constituted a failure on behalf of the PH collaboration to translate the concept to the hired hands, which complicated the execution phase. \nContract frameworks were also mentioned as a contributing source of errors as turnkey contract frameworks dis-incentivised subcontractors from making order changes also after they were clearly deemed necessary by consulting engineers. This is not an unusual mode of contracting in the construction business from a traditional viewpoint and could perhaps prove to work better in the future as the concept matures along with the market. A greater level of detailing in the design phase is one way to address this. However, in light of the experiences gathered at PH Kjørbo, the question is whether a more collaborative framework could have been applied to allow subcontractors to identify and share in ZEB Project report 25-2015 Page 6 of 32 the risk taking with the main contractors and/or project owner - or, in fact, to take part in the social learning that occurs as actors make the project ‘their own’. One way to incentivise junior contractors to join in more time-consuming, perhaps less profitable, contract arrangements could be to highlight the skill and knowledge development benefits available for participants in such projects. This would, however, require some proof of concept to be sufficiently translated into a clear added value for\nsuppliers. At this juncture, the newly constructed Powerhouse is one such proof. In replicating elements of the Kjørbo project, it is likely that resources can be saved on design and parts of the pre-project phase. However, to avoid the amount of order changes seen in the execution of PH Kjørbo (especially for different projects), more resources must be spent on learning for junior contractors. \nFinally, the symbolic value that was characteristic of Powerhouse Kjørbo contributed to both its ability to be realised and concrete benefits for actors involved in the time after completion. Many have drawn parallels between PH Kjørbo and Tesla, implying that PH Kjørbo is for the building industry what that electric car is for the automotive industry. As many of the respondents emphasised, the building is a statement that says “it’s possible.” The goal had never been accomplished, let alone attempted, before, and success hinged on the project participants’ belief in that final statement. A radically different approach combined with an ambitious goal made that belief possible, and it was reinforced by the interdisciplinary work that was the basis of the project. This extra effort was a necessity in this project, but it might not be in the next. Some of it can most likely be implemented in other projects. However, as this report also demonstrates, picking pieces out of the success story PH Kjørbo may not yield equally impressive results because there is a connection between the pieces that is important for the whole building to succeed.\n1.2 Summary of part 2: Taking a zero emission office building in use\nThe second part of this report examined the early use phase of PH Kjørbo, which was undertaken by local actors with the tenant as well as the project team. Although it is clear that the planning and design phase and the technological solutions played important roles in the success of PH Kjørbo, the way in which the running-in period was handled contributed some crucial finishing touches to the users’ overall very positive experience with PH Kjørbo. Notwithstanding the technical calibrations themselves (which are outside the purview of this inquiry), the way user expectations were met by specific consideration of practical and cognitive aspects of the use of the building created a good use experience and not just an energy-saving machine. Great care was taken to prevent technical shortcomings from interfering with work and causing frustrations, even when it has compromised energy targets temporarily. A positive use experience was considered “elementary”, an attitude that, at least in theory, denied allowing money to become an issue in this pulling contest between energy efficiency and user experience. Challenges experienced in the running-in period overall were experienced by the tenant as lower or not above what was considered normal based on experience with previous moving processes. In PH Kjørbo the ventilation system was allowed to let temperatures drift more than in a normal building.\nHowever, this system also proved that indoor temperatures experienced as normal do not necessarily require them to stay consistently at “22.2 degrees” - in fact, a drift in temperature between 20-25 degrees was found to be perfectly acceptable by the occupants. Temperatures in the lower end of this range were considered cold by some but were manageable by providing information and handling practical and cognitive expectations - or, simply speaking, a sweater kept handy. Indoor temperatures in the top range or above, should they occur at all in the Nordic climate, are equally badly handled in most Norwegian buildings, according to the informants. Again, handling users’ expectations with care in this phase proved helpful in improving user acceptance. This same characteristic of the running-in period at PH Kjørbo was found when examining the acoustic issues posed by the extensive use of exposed concrete. Negative experiences were reported largely by ZEB Project report 25-2015 Page 7 of 32 users who were used to extremely silent conditions. Addressing the reasons for the design choices openly (thermal mass) allowed users to settle into their new surroundings. As one of the respondents noted, when viewing the experience of this particular building as a whole, the somewhat increased noise levels caused by scarce sound roofing due to a minimal ventilation system meant that the ventilation noise normally endured in other buildings was totally eliminated, but the indoor climate was still described as extremely good. The result was a sum of experiences that evidently surpassed any conventional building.\nPH Kjørbo shows that treating the user as a form of “sensor” and devoting resources to the “processing” of information from such “sensors” in the running-in period provides substantial insight into the user experience that is crucial for improving the use experience. At Kjørbo, user experiences were collected through the office link system by the office manager, who then bore witness for the users in the user forums that guided the work of the running-in team. This provided a unique data source for detecting the comfort threshold. When complaints started to come in, they could be addressed quickly - either through informing about the reasons or through actual technical fixes. According to our informants, at the time of the interviews, as issues were picked up, negotiated and solved, complaints began to disappear.
In this thesis, we construct an implementation of succinct non-interactive zero knowledge argument system. A non-interactive zero knowledge argument system is a protocol for a party (usually known as Prover) to provide a proof of knowledge to the solution of a statement to other parties (usually known as Verifier). The argument system will be able to provide such proof without leaking any other information regarding the solution. The non-interactivity allows such argument system to be done without requiring interaction between the parties involved. The statement that is proven in this work is the circuit satisfiability problem. The circuit satisfiability problem is a problem of deciding whether there exists an input that can make the final output of a circuit to be true. The argument system is based on Lipmaa's work \\cite{eprint2013:Lipmaa:NIZKSPECC} which uses span programs and linear error-correcting codes in its construction. We also try to give a very general explanation on zero knowledge argument system along the way in order to provide a simple concept to people encountering the notion for the first time. The argument system we attempt to construct is the non-adaptive version of the argument system. This version is useful for verifiable computation as pointed out by \\cite{Pinnochio2013:Parno} apart from its zero knowledge behavior. We begin by giving an overview on non-interactive zero knowledge, followed by span programs. We then proceed to describe on how to represent the circuit satisfiability problem using the mentioned tool. We present our implementation afterwards, listing out the libraries and implementation details that matters. We conclude by providing a speed measurement and possible future improvements of this work.
Cloud computing is a model for enabling convenient, on-demand network access to a shared pool of configurable computing resources (e.g., network, servers, storage, applications and services) that can be rapidly provisioned and released with minimal management effort or service provider interaction. During the last a few years, data security and integrity in cloud computing has emerged as a significantly important research area that has attracted increasing attention from both industry and academia. The virtual environment of cloud computing allows users to access computing power that exceeds what is contained within their own physical worlds. To enter this virtual environment, cloud users must transfer data throughout the cloud. Typically, cloud users know neither the exact location of their data nor the other sources of the data collectively stored with theirs. Consequently, several data security and integrity concerns have arisen, including key management, access control, searchable encryption techniques, remote integrity checks and proof of ownership in the cloud.\nThe first aspect of the work presented in this thesis is tree-based key management in cloud computing. Data encryption before outsourcing to the cloud is a common way to protect data privacy. Thus, key management is a challenging issue in cloud computing. It is the ability to correctly assign, monitor and secure keys which defines the level of operational security provided by any encryption implementation. The fundamental idea of this work is to design a secure and flexible key management mechanism for the outsourced data in cloud computing. In this thesis, an innovative tree-based key management scheme is proposed. The outsourced database remains private and secure, while some selected data and key nodes are shared with other parties in the cloud. Flexibility of key management is achieved and the security is proved in the standard model.\nThe second aspect of the work presented in this thesis is fine-grained access control. In order to secure the outsourced data in the cloud, designing efficient and secure access control is a challenging issue. Unlike traditional access control in which the data users and storage servers are in the same trust domain, access control techniques are very different in cloud computing, as the cloud servers are not trusted by most cloud users. The key idea of this work is to attribute sets-based access control. This thesis points out that any access policy can be defined as a logical expression formula over different attribute sets. Logical expression indicates what kind of user is allowed to access the data. A fine-grained and efficient access control is proposed, based on logical expression.\nThe third aspect of the work presented in this thesis is efficient searchable encryption techniques in cloud computing. Because the data is usually encrypted before being outsourced to the cloud, searching the encrypted data in cloud computing has recently gained attention and led to the development of efficient searchable encryption techniques. The fundamental idea of this work is to reduce the search cost on encrypted data. In this thesis, a practical keyword searching mechanism is proposed. The solution is very simple. It enables efficient multi-user keyword searches and hides the private information in the search queries. The security is proved in the standard model.\nThe fourth aspect of the work presented in this thesis is public remote data integrity checks. As the clients store important data in remote cloud storage without a local copy, it is important to check the remote data integrity. Design of efficient remote integrity check protocols without downloading the data is a challenging issue in cloud computing. The key idea of this work is a public remote integrity check based on zero-knowledge proof. In this thesis, an innovative public remote integrity check scheme (PRIC) is proposed. No information of either the verified data or the homomorphic tags is leaked. In addition, the experiment result shows that PRIC is efficient, especially when the data size is large or the integrity check is frequent. The security of PRIC is proved in the random oracle model.\nThe last aspect of the work presented in this thesis is proof of multiparty ownership for encrypted data in the cloud. There are many applications of ownership sharing by different users and the design of the proof protocols of joint ownership is a challenging issue. Meanwhile, the design of proof-of-ownership mechanisms for encrypted data is even more difficult. This is because encryption of the same file by different users with random keys results in different ciphertexts, and the cloud server cannot store the same hash root value for ownership verification. In this thesis, a proof of multiparty ownership solution (PMOW) with encrypted data is proposed. Every user can prove that he/she holds the plaintext of the encrypted file when the server stores one ciphertext only. In addition, a PMOW system is constructed. The security of PMOW is proved in the ideal cipher model.\nThe major contribution of this thesis is innovative and improved approaches to secure data in cloud computing. Using these approaches developed, a trustworthy cloud environment can be achieved.