Academic literature on the topic 'APP et fragments amyloïdes'

Mutations of presenilin 1 (PS1) causing Alzheimer's disease selectively increase the secretion of the amyloidogenic βA4(1-42), whereas knocking out the gene results in decreased production of both βA4(1-40) and (1-42) amyloid peptides (De Strooper et al. 1998). Therefore, PS1 function is closely linked to the γ-secretase processing of the amyloid precursor protein (APP). Given the ongoing controversy on the subcellular localization of PS1, it remains unclear at what level of the secretory and endocytic pathways PS1 exerts its activity on APP and on the APP carboxy-terminal fragments that are the direct substrates for γ-secretase. Therefore, we have reinvestigated the subcellular localization of endogenously expressed PS1 in neurons in vitro and in vivo using confocal microscopy and fine-tuned subcellular fractionation. We show that uncleaved PS1 holoprotein is recovered in the nuclear envelope fraction, whereas the cleaved PS fragments are found mainly in post-ER membranes including the intermediate compartment (IC). PS1 is concentrated in discrete sec23p- and p58/ERGIC-53–positive patches, suggesting its localization in subdomains involved in ER export. PS1 is not found to significant amounts beyond the cis-Golgi. Surprisingly, we found that APP carboxy-terminal fragments also coenrich in the pre-Golgi membrane fractions, consistent with the idea that these fragments are the real substrates for γ-secretase. Functional evidence that PS1 exerts its effects on γ-secretase processing of APP in the ER/IC was obtained using a series of APP trafficking mutants. These mutants were investigated in hippocampal neurons derived from transgenic mice expressing PS1wt or PS1 containing clinical mutations (PS1M146L and PS1L286V) at physiologically relevant levels. We demonstrate that the APP-London and PS1 mutations have additive effects on the increased secretion of βA4(1-42) relative to βA4(1-40), indicating that both mutations operate independently. Overall, our data clearly establish that PS1 controls γ42-secretase activity in pre-Golgi compartments. We discuss models that reconcile this conclusion with the effects of PS1 deficiency on the generation of βA4(1-40) peptide in the late biosynthetic and endocytic pathways.

A synthesis procedure and aggregation properties of a new homologous series of dicationic gemini surfactants with a dodecane spacer and two carbamate fragments (N,N′-dialkyl-N,N′-bis(2-(ethylcarbamoyloxy)ethyl)-N,N′-dimethyldodecan-1,6-diammonium dibromide, n-12-n(Et), where n = 10, 12, 14) were comprehensively described. The critical micelle concentrations of gemini surfactants were obtained using tensiometry, conductometry, spectrophotometry, and fluorimetry. The thermodynamic parameters of adsorption and micellization, i.e., maximum surface excess (Гmax), the surface area per surfactant molecule (Amin), degree of counterion binding (β), and Gibbs free energy of micellization (∆Gmic), were calculated. Functional activity of the surfactants, including the solubilizing capacity toward Orange OT and indomethacin, incorporation into the lipid bilayer, minimum inhibitory concentration, and minimum bactericidal and fungicidal concentrations, was determined. Synthesized gemini surfactants were further used for the modification of liposomes dual-loaded with α-tocopherol and donepezil hydrochloride for intranasal treatment of Alzheimer’s disease. The obtained liposomes have high stability (more than 5 months), a significant positive charge (approximately + 40 mV), and a high degree of encapsulation efficiency toward rhodamine B, α-tocopherol, and donepezil hydrochloride. Korsmeyer-Peppas, Higuchi, and first-order kinetic models were used to process the in vitro release curves of donepezil hydrochloride. Intranasal administration of liposomes loaded with α-tocopherol and donepezil hydrochloride for 21 days prevented memory impairment and decreased the number of Aβ plaques by 37.6%, 40.5%, and 72.6% in the entorhinal cortex, DG, and CA1 areas of the hippocampus of the brain of transgenic mice with Alzheimer’s disease model (APP/PS1) compared with untreated animals.

ABSTRACT A novel putative autotransporter protein (NMB1998) was identified in the available genomic sequence of meningococcal strain MC58 (ET-5; ST-32). The mspA gene is absent from the genomic sequences of meningococcal strain Z2491 (ET-IV; ST-4) and the gonococcal strain FA1090. An orthologue is present in the meningococcal strain FAM18 (ET-37; ST-11), but the sequence contains a premature stop codon, suggesting that the protein may not be expressed in this strain. MspA is predicted to be a 157-kDa protein with low cysteine content, and it exhibits 36 and 33% identity to the meningococcal autotransporter proteins immunoglobulin A1 (IgA1) protease and App, respectively. Search of the Pfam database predicts the presence of IgA1 protease and autotransporter β-barrel domains. MspA was cloned, and a recombinant protein of the expected size was expressed and after being affinity purified was used to raise rabbit polyclonal monospecific antiserum. Immunoblot studies showed that ca. 125- and 95-kDa fragments of MspA are secreted in meningococcal strain MC58, which are absent from the isogenic mutant. Secretion of MspA was shown to be modified in an AspA isogenic mutant. A strain survey showed that MspA is expressed by all ST-32 and ST-41/44 (lineage 3) strains, but none of the ST-8 (A4) strains examined. Sera from patients convalescing from meningococcal disease were shown to contain MspA-specific antibodies. In bactericidal assays, anti-MspA serum was shown to kill the homologous strain (MC58) and another ST-32 strain. Escherichia coli-expressing recombinant MspA was shown to adhere to both human bronchial epithelial cells and brain microvascular endothelial cells.

AbstractBackgroundIt has been shown that Aß is a normal component in urine (Ghiso et al, FEBS Lett, 1997) and may change with disease status (Takata et al, Neurosci Lett, 2008), however, research on amyloid in urine has been neglected for long time.MethodWe examined β amyloid proteins in urine from cognitive normal and dementia patients including Alzheimer’s disease (AD) and frontotemporal dementia (FTD) using Western blotting.ResultSeveral protein fragments were identified including the 12KD and 14KD bands recognized by the anti‐APP C‐termini antibody (Ab369), 14KD and 28KD bands by W0‐2 (Figure 1), and 28KD, 56KD and 68KD bands by Aducanumab (Figure 2) and anti‐APP N‐termini antibody (22C11). Further analysis with immunoprecipitation and mass spectrometry confirmed the presence of various APP fragments and Aß in urine. One type of peptide was found to have high affinity to Aß and APP fragments using microscale thermophoresis and circular dichroism spectroscopy. With the assistance from AIBL, we further invented a lateral flow immunoassay device with colloidal gold nanoparticles coated with anti‐APP/Aß antibodies. In the early clinical trials with aged people and children, 95% of dementia patients, 90% of MCI, 85% of SMC showed positivity while 90% of healthy children were negative. The second quality examination was performed in Oriental (Dongfeng) Hospital (Pudong, Shanghai) in Mar‐June 2022. The examination of detection limit, critical threshold, repeatability, tolerance to interferences (creatinine, protein, glucose, nitrites, pH) was performed and all passed. Furthermore, 43 of 49 cases showed positive (87.7%) while only 1 out of 30 controls was positive (3.3%). Since then, the device has been tested in a dozen of large hospitals and pathology laboratories in China, all provided positive feedback. The preliminary results from 175 AIBL participants showed overall 83.8% positivity to clinically diagnosed MCI (n = 37), while for those Aβ PET scan negative MCI (n = 17), positivity was 94.1% (Figure 3).ConclusionOur results indicates the high accuracy of this device, which has high potential to be used as an early screening tool for MCI and dementia. The longitudinal studies are currently undergoing in China (Xiangya Hospital) and in Australia (AIBL).

This study aimed to map and evaluate the evolution of habitat fragmentation between 2009 and 2018, using the Microregion of Ceres (Goiás) as a sample reference, using principles of Landscape Ecology. The methodology comprised the mapping of the fragments in the two years analyzed, using the OLI/Landsat 8 sensor, using scenes 222/70 and 222/71. The SPRING 5.2 software was used, where the supervised classification was performed, applying the semi-automatic process. The computational algorithm applied to classify the scenes was Maxver, which classifies pixel by pixel and groups the information of each one into homogeneous regions. After extracting the fragments of native vegetation, the methodology proposed by Juvanhol et al. (2011), in which the fragments were grouped into classes: Very Small (MP) ≤5 hectares; Small (P) ≥5.01 and ≤10 hectares; Medium (M) ≥10.01 and ≤100 hectares and Large (G) ≥100.01 hectares. For the analysis based on metrics in Landscape Ecology, the ArcGis 9.2 Patch Analyst extension was used. The results showed the expansion of vegetation cover areas in the study area, concentrated on tops of hills, APP and legal reserves. However, they pointed out intense fragmentation of native vegetation, which hinders the performance of fragments as habitats. It is considered that, from the contemporary problem of degradation of natural environments to the detriment of economic development, studies like this are necessary in order to identify existing environmental problems and propose strategies to minimize and mitigate ecological imbalances.

This report aims to inform on the progression of research into the genetic factors involved in the development of Alzheimer’s disease (AD). AD is a life-altering disease that affects millions of individuals from varying races and ethnic backgrounds1. According to the National Institute on Aging, a faculty of the U.S. Department of Health and Human Services, AD has been ranked as the third leading cause of death in the United States, only behind cancer and heart failure. It is predicted that by 2050, approximately one in 45 Americans will be afflicted with the disease5. Distinctive physical indications of the onset of AD include neuron loss, amyloid plaques and neurofibrillary tangles5. Onset is not frequent prior to 60 years of age but can be caused by one of two reasons. The first is a mutation in the amyloid precursor protein (APP) gene on chromosome 21. This gene is responsible for the regulation of the production of amyloid beta (Aβ) proteins, which are known to be abundant in the brains of AD patients. A mutation in the gene leads to an inappropriate regulation of this protein. The second, and more common cause is a result of an unidentified gene on chromosome 14 in AD patients2. It has been confirmed that there is involvement of chromosome 19 in late onset AD (LOAD) as well1. Most of the genes that are associated with the development of AD have yet to be identified, but the research is bringing society closer and closer to that goal everyday.Ce rapport vise à fournir de l’information sur la progression de la recherche au sujet des facteurs génétiques impliqués dans le développement de la maladie d'Alzheimer (MA). La MA est une maladie bouleversant la vie de la personne et qui affecte des millions d’individus de diverses races et ethnicité1. Selon l'Institut national sur le vieillissement, un corps professoral du département américain de la santé et des services sociaux, la MA a été classée comme la troisième cause de décès aux États-Unis, ne cédant le pas qu’au cancer et à l'insuffisance cardiaque. Il est prévu que d'ici l'an 2050, environ une personne sur 45 Américains sera affligée avec cette maladie5.Des indications visuelles distinctives de l'apparition de la MA comprennent la perte des neurones, les plaques amyloïdes et des enchevêtrements neurofibrillaires5. L'apparition précoce n’est pas fréquente avant 60 ans, mais peut être causée par l'une des deux raisons. La première raison est une mutation dans le gène de la protéine précurseur de l'amyloïde (PPA) sur le chromosome 21. Ce gène est responsable de la régulation de la production de protéines bêta-amyloïde (Aß), qui sont connues pour être abondant dans le cerveau des patients atteints de la MA. Une mutation dans le gène conduit à une régulation inappropriée de cette protéine. La seconde cause, et celle-là plus communes sont le résultat d'un gène inconnu sur le chromosome 142. Il a été confirmé qu'il y a aussi une participation du chromosome 19 dans l'apparition tardive de la MA (ATMA)1. La plupart des gènes qui sont associés avec le développement de la MA n’ont pas encore été identifiés, mais la recherche rapproche la société de cet objectif de plus en plus tous les jours.

Introduction Many social media tools and services are free to use. This fact often leads users to the mistaken presumption that the associated data generated whilst utilising these tools and services is without value. Users often focus on the social and presumed ephemeral nature of communication – imagining something that happens but then has no further record or value, akin to a telephone call – while corporations behind these tools tend to focus on the media side, the lasting value of these traces which can be combined, mined and analysed for new insight and revenue generation. This paper seeks to explore this social media contradiction in two ways. Firstly, a cursory examination of Google and Facebook will demonstrate how data mining and analysis are core practices for these corporate giants, central to their functioning, development and expansion. Yet the public rhetoric of these companies is not about the exchange of personal information for services, but rather the more utopian notions of organising the world’s information, or bringing everyone together through sharing. The second section of this paper examines some of the core ramifications of death in terms of social media, asking what happens when a user suddenly exists only as recorded media fragments, at least in digital terms. Death, at first glance, renders users (or post-users) without agency or, implicitly, value to companies which data-mine ongoing social practices. Yet the emergence of digital legacy management highlights the value of the data generated using social media, a value which persists even after death. The question of a digital estate thus illustrates the cumulative value of social media as media, even on an individual level. The ways Facebook and Google approach digital death are examined, demonstrating policies which enshrine the agency and rights of living users, but become far less coherent posthumously. Finally, along with digital legacy management, I will examine the potential for posthumous digital legacies which may, in some macabre ways, actually reanimate some aspects of a deceased user’s presence, such as the Lives On service which touts the slogan “when your heart stops beating, you'll keep tweeting”. Cumulatively, mapping digital legacy management by large online corporations, and the affordances of more focussed services dealing with digital death, illustrates the value of data generated by social media users, and the continued importance of the data even beyond the grave. Google While Google is universally synonymous with search, and is the world’s dominant search engine, it is less widely understood that one of the core elements keeping Google’s search results relevant is a complex operation mining user data. Different tools in Google’s array of services mine data in different ways (Zimmer, “Gaze”). Gmail, for example, uses algorithms to analyse an individual’s email in order to display the most relevant related advertising. This form of data mining is comparatively well known, with most Gmail users knowingly and willingly accepting more personalised advertising in order to use Google’s email service. However, the majority of people using Google’s search engine are unaware that search, too, is increasingly driven by the tracking, analysis and refining of results on the basis of user activity (Zimmer, “Externalities”). As Alexander Halavais (160–180) quite rightly argues, recent focus on the idea of social search – the deeper integration of social network information in gauging search results – is oxymoronic; all search, at least for Google, is driven by deep analysis of personal and aggregated social data. Indeed, the success of Google’s mining of user data has led to concerns that often invisible processes of customisation and personalisation will mean that the supposedly independent or objective algorithms producing Google’s search results will actually yield a different result for every person. As Siva Vaidhyanathan laments: “as users in a diverse array of countries train Google’s algorithms to respond to specialized queries with localised results, each place in the world will have a different list of what is important, true, or ‘relevant’ in response to any query” (138). Personalisation and customisation are not inherently problematic, and frequently do enhance the relevance of search results, but the main objection raised by critics is not Google’s data mining, but the lack of transparency in the way data are recorded, stored and utilised. Eli Pariser, for example, laments the development of a ubiquitous “filter bubble” wherein all search results are personalised and subjective but are hidden behind the rhetoric of computer-driven algorithmic objectivity (Pariser). While data mining informs and drives many of Google’s tools and services, the cumulative value of these captured fragments of information is best demonstrated by the new service Google Now. Google Now is a mobile app which delivers an ongoing stream of search results but without the need for user input. Google Now extrapolates the rhythms of a person’s life, their interests and their routines in order to algorithmically determine what information will be needed next, and automatically displays it on a user’s mobile device. Clearly Google Now is an extremely valuable and clever tool, and the more information a user shares, the better the ongoing customised results will be, demonstrating the direct exchange value of personal data: total personalisation requires total transparency. Each individual user will need to judge whether they wish to share with Google the considerable amount of personal information needed to make Google Now work. The pressing ethical question that remains is whether Google will ensure that users are sufficiently aware of the amount of data and personal privacy they are exchanging in order to utilise such a service. Facebook Facebook began as a closed network, open only to students at American universities, but has transformed over time to a much wider and more open network, with over a billion registered users. Facebook has continually reinvented their interface, protocols and design, often altering both privacy policies and users’ experience of privacy, and often meeting significant and vocal resistance in the process (boyd). The data mining performed by social networking service Facebook is also extensive, although primarily aimed at refining the way that targeted advertising appears on the platform. In 2007 Facebook partnered with various retail loyalty services and combined these records with Facebook’s user data. This information was used to power Facebook’s Beacon service, which added details of users’ retail history to their Facebook news feed (for example, “Tama just purchased a HTC One”). The impact of all of these seemingly unrelated purchases turning up in many people’s feeds suddenly revealed the complex surveillance, data mining and sharing of these data that was taking place (Doyle and Fraser). However, as Beacon was turned on, without consultation, for all Facebook users, there was a sizable backlash that meant that Facebook had to initially switch the service to opt-in, and then discontinue it altogether. While Beacon has been long since erased, it is notable that in early 2013 Facebook announced that they have strengthened partnerships with data mining and profiling companies, including Datalogix, Epsilon, Acxiom, and BlueKai, which harness customer information from a range of loyalty cards, to further refine the targeting ability offered to advertisers using Facebook (Hof). Facebook’s data mining, surveillance and integration across companies is thus still going on, but no longer directly visible to Facebook users, except in terms of the targeted advertisements which appear on the service. Facebook is also a platform, providing a scaffolding and gateway to many other tools and services. In order to use social games such as Zynga’s Farmville, Facebook users agree to allow Zynga to access their profile information, and use Facebook to authenticate their identity. Zynga has been unashamedly at the forefront of user analytics and data mining, attempting to algorithmically determine the best way to make virtual goods within their games attractive enough for users to pay for them with real money. Indeed, during a conference presentation, Zynga Vice President Ken Rudin stated outright that Zynga is “an analytics company masquerading as a games company” (Rudin). I would contend that this masquerade succeeds, as few Farmville players are likely to consider how their every choice and activity is being algorithmically scrutinised in order to determine what virtual goods they might actually buy. As an instance of what is widely being called ‘big data’, the data miing operations of Facebook, Zynga and similar services lead to a range of ethical questions (boyd and Crawford). While users may have ostensibly agreed to this data mining after clicking on Facebook’s Terms of Use agreement, the fact that almost no one reads these agreements when signing up for a service is the Internet’s worst kept secret. Similarly, the extension of these terms when Facebook operates as a platform for other applications is a far from transparent process. While examining the recording of user data leads to questions of privacy and surveillance, it is important to note that many users are often aware of the exchange to which they have agreed. Anders Albrechtslund deploys the term ‘social surveillance’ to usefully emphasise the knowing, playful and at times subversive approach some users take to the surveillance and data mining practices of online service providers. Similarly, E.J. Westlake notes that performances of self online are often not only knowing but deliberately false or misleading with the aim of exploiting the ways online activities are tracked. However, even users well aware of Facebook’s data mining on the site itself may be less informed about the social networking company’s mining of offsite activity. The introduction of ‘like’ buttons on many other Websites extends Facebook’s reach considerably. The various social plugins and ‘like’ buttons expand both active recording of user activity (where the like button is actually clicked) and passive data mining (since a cookie is installed or updated regardless of whether a button is actually pressed) (Gerlitz and Helmond). Indeed, because cookies – tiny packets of data exchanged and updated invisibly in browsers – assign each user a unique identifier, Facebook can either combine these data with an existing user’s profile or create profiles about non-users. If that person even joins Facebook, their account is connected with the existing, data-mined record of their Web activities (Roosendaal). As with Google, the significant issue here is not users knowingly sharing their data with Facebook, but the often complete lack of transparency in terms of the ways Facebook extracts and mines user data, both on Facebook itself and increasingly across applications using Facebook as a platform and across the Web through social plugins. Google after Death While data mining is clearly a core element in the operation of Facebook and Google, the ability to scrutinise the activities of users depends on those users being active; when someone dies, the question of the value and ownership of their digital assets becomes complicated, as does the way companies manage posthumous user information. For Google, the Gmail account of a deceased person becomes inactive; the stored email still takes up space on Google’s servers, but with no one using the account, no advertising is displayed and thus Google can earn no revenue from the account. However, the process of accessing the Gmail account of a deceased relative is an incredibly laborious one. In order to even begin the process, Google asks that someone physically mails a series of documents including a photocopy of a government-issued ID, the death certificate of the deceased person, evidence of an email the requester received from the deceased, along with other personal information. After Google have received and verified this information, they state that they might proceed to a second stage where further documents are required. Moreover, if at any stage Google decide that they cannot proceed in releasing a deceased relative’s Gmail account, they will not reveal their rationale. As their support documentation states: “because of our concerns for user privacy, if we determine that we cannot provide the Gmail content, we will not be able to share further details about the account or discuss our decision” (Google, “Accessing”). Thus, Google appears to enshrine the rights and privacy of individual users, even posthumously; the ownership or transfer of individual digital assets after death is neither a given, nor enshrined in Google’s policies. Yet, ironically, the economic value of that email to Google is likely zero, but the value of the email history of a loved one or business partner may be of substantial financial and emotional value, probably more so than when that person was alive. For those left behind, the value of email accounts as media, as a lasting record of social communication, is heightened. The question of how Google manages posthumous user data has been further complicated by the company’s March 2012 rationalisation of over seventy separate privacy policies for various tools and services they operate under the umbrella of a single privacy policy accessed using a single unified Google account. While this move was ostensibly to make privacy more understandable and transparent at Google, it had other impacts. For example, one of the side effects of a singular privacy policy and single Google identity is that deleting one of a recently deceased person’s services may inadvertently delete them all. Given that Google’s services include Gmail, YouTube and Picasa, this means that deleting an email account inadvertently erases all of the Google-hosted videos and photographs that individual posted during their lifetime. As Google warns, for example: “if you delete the Google Account to which your YouTube account is linked, you will delete both the Google Account AND your YouTube account, including all videos and account data” (Google, “What Happens”). A relative having gained access to a deceased person’s Gmail might sensibly delete the email account once the desired information is exported. However, it seems less likely that this executor would realise that in doing so all of the private and public videos that person had posted on YouTube would also permanently disappear. While material possessions can be carefully dispersed to specific individuals following the instructions in someone’s will, such affordances are not yet available for Google users. While it is entirely understandable that the ramification of policy changes are aimed at living users, as more and more online users pass away, the question of their digital assets becomes increasingly important. Google, for example, might allow a deceased person’s executor to elect which of their Google services should be kept online (perhaps their YouTube videos), which traces can be exported (perhaps their email), and which services can be deleted. At present, the lack of fine-grained controls over a user’s digital estate at Google makes this almost impossible. While it violates Google’s policies to transfer ownership of an account to another person, if someone does leave their passwords behind, this provides their loved ones with the best options in managing their digital legacy with Google. When someone dies and their online legacy is a collection of media fragments, the value of those media is far more apparent to the loved ones left behind rather than the companies housing those media. Facebook Memorialisation In response to users complaining that Facebook was suggesting they reconnect with deceased friends who had left Facebook profiles behind, in 2009 the company instituted an official policy of turning the Facebook profiles of departed users into memorial pages (Kelly). Technically, loved ones can choose between memorialisation and erasing an account altogether, but memorialisation is the default. This entails setting the account so that no one can log into it, and that no new friends (connections) can be made. Existing friends can access the page in line with the user’s final privacy settings, meaning that most friends will be able to post on the memorialised profile to remember that person in various ways (Facebook). Memorialised profiles (now Timelines, after Facebook’s redesign) thus become potential mourning spaces for existing connections. Since memorialised pages cannot make new connections, public memorial pages are increasingly popular on Facebook, frequently set up after a high-profile death, often involving young people, accidents or murder. Recent studies suggest that both of these Facebook spaces are allowing new online forms of mourning to emerge (Marwick and Ellison; Carroll and Landry; Kern, Forman, and Gil-Egui), although public pages have the downside of potentially inappropriate commentary and outright trolling (Phillips). Given Facebook has over a billion registered users, estimates already suggest that the platform houses 30 million profiles of deceased people, and this number will, of course, continue to grow (Kaleem). For Facebook, while posthumous users do not generate data themselves, the fact that they were part of a network means that their connections may interact with a memorialised account, or memorial page, and this activity, like all Facebook activities, allows the platform to display advertising and further track user interactions. However, at present Facebook’s options – to memorialise or delete accounts of deceased people – are fairly blunt. Once Facebook is aware that a user has died, no one is allowed to edit that person’s Facebook account or Timeline, so Facebook literally offers an all (memorialisation) or nothing (deletion) option. Given that Facebook is essentially a platform for performing identities, it seems a little short-sighted that executors cannot clean up or otherwise edit the final, lasting profile of a deceased Facebook user. As social networking services and social media become more ingrained in contemporary mourning practices, it may be that Facebook will allow more fine-grained control, positioning a digital executor also as a posthumous curator, making the final decision about what does and does not get kept in the memorialisation process. Since Facebook is continually mining user activity, the popularity of mourning as an activity on Facebook will likely mean that more attention is paid to the question of digital legacies. While the user themselves can no longer be social, the social practices of mourning, and the recording of a user as a media entity highlights the fact that social media can be about interactions which in significant ways include deceased users. Digital Legacy Services While the largest online corporations have fairly blunt tools for addressing digital death, there are a number of new tools and niche services emerging in this area which are attempting to offer nuanced control over digital legacies. Legacy Locker, for example, offers to store the passwords to all of a user’s online services and accounts, from Facebook to Paypal, and to store important documents and other digital material. Users designate beneficiaries who will receive this information after the account holder passes away, and this is confirmed by preselected “verifiers” who can attest to the account holder’s death. Death Switch similarly provides the ability to store and send information to users after the account holder dies, but tests whether someone is alive by sending verification emails; fail to respond to several prompts and Death Switch will determine a user has died, or is incapacitated, and executes the user’s final instructions. Perpetu goes a step further and offers the same tools as Legacy Locker but also automates existing options from social media services, allowing users to specify, for example, that their Facebook, Twitter or Gmail data should be downloaded and this archive should be sent to a designated recipient when the Perpetu user dies. These tools attempt to provide a more complex array of choices in terms of managing a user’s digital legacy, providing similar choices to those currently available when addressing material possessions in a formal will. At a broader level, the growing demand for these services attests to the ongoing value of online accounts and social media traces after a user’s death. Bequeathing passwords may not strictly follow the Terms of Use of the online services in question, but it is extremely hard to track or intervene when a user has the legitimate password, even if used by someone else. More to the point, this finely-grained legacy management allows far more flexibility in the utilisation and curation of digital assets posthumously. In the process of signing up for one of these services, or digital legacy management more broadly, the ongoing value and longevity of social media traces becomes more obvious to both the user planning their estate and those who ultimately have to manage it. The Social Media Afterlife The value of social media beyond the grave is also evident in the range of services which allow users to communicate in some fashion after they have passed away. Dead Social, for example, allows users to schedule posthumous social media activity, including the posting of tweets, sending of email, Facebook messages, or the release of online photos and videos. The service relies on a trusted executor confirming someone’s death, and after that releases these final messages effectively from beyond the grave. If I Die is a similar service, which also has an integrated Facebook application which ensures a user’s final message is directly displayed on their Timeline. In a bizarre promotional campaign around a service called If I Die First, the company is promising that the first user of the service to pass away will have their posthumous message delivered to a huge online audience, via popular blogs and mainstream press coverage. While this is not likely to appeal to everyone, the notion of a popular posthumous performance of self further complicates that question of what social media can mean after death. Illustrating the value of social media legacies in a quite different but equally powerful way, the Lives On service purports to algorithmically learn how a person uses Twitter while they are live, and then continue to tweet in their name after death. Internet critic Evgeny Morozov argues that Lives On is part of a Silicon Valley ideology of ‘solutionism’ which casts every facet of society as a problem in need of a digital solution (Morozov). In this instance, Lives On provides some semblance of a solution to the problem of death. While far from defeating death, the very fact that it might be possible to produce any meaningful approximation of a living person’s social media after they die is powerful testimony to the value of data mining and the importance of recognising that value. While Lives On is an experimental service in its infancy, it is worth wondering what sort of posthumous approximation might be built using the robust data profiles held by Facebook or Google. If Google Now can extrapolate what a user wants to see without any additional input, how hard would it be to retool this service to post what a user would have wanted after their death? Could there, in effect, be a Google After(life)? Conclusion Users of social media services have differing levels of awareness regarding the exchange they are agreeing to when signing up for services provided by Google or Facebook, and often value the social affordances without necessarily considering the ongoing media they are creating. Online corporations, by contrast, recognise and harness the informatic traces users generate through complex data mining and analysis. However, the death of a social media user provides a moment of rupture which highlights the significant value of the media traces a user leaves behind. More to the point, the value of these media becomes most evident to those left behind precisely because that individual can no longer be social. While beginning to address the issue of posthumous user data, Google and Facebook both have very blunt tools; Google might offer executors access while Facebook provides the option of locking a deceased user’s account as a memorial or removing it altogether. Neither of these responses do justice to the value that these media traces hold for the living, but emerging digital legacy management tools are increasingly providing a richer set of options for digital executors. While the differences between material and digital assets provoke an array of legal, spiritual and moral issues, digital traces nevertheless clearly hold significant and demonstrable value. For social media users, the death of someone they know is often the moment where the media side of social media – their lasting, infinitely replicable nature – becomes more important, more visible, and casts the value of the social media accounts of the living in a new light. For the larger online corporations and service providers, the inevitable increase in deceased users will likely provoke more fine-grained controls and responses to the question of digital legacies and posthumous profiles. It is likely, too, that the increase in online social practices of mourning will open new spaces and arenas for those same corporate giants to analyse and data-mine. References Albrechtslund, Anders. “Online Social Networking as Participatory Surveillance.” First Monday 13.3 (2008). 21 Apr. 2013 ‹http://firstmonday.org/article/view/2142/1949›. boyd, danah. “Facebook’s Privacy Trainwreck: Exposure, Invasion, and Social Convergence.” Convergence 14.1 (2008): 13–20. ———, and Kate Crawford. “Critical Questions for Big Data.” Information, Communication & Society 15.5 (2012): 662–679. Carroll, Brian, and Katie Landry. “Logging On and Letting Out: Using Online Social Networks to Grieve and to Mourn.” Bulletin of Science, Technology & Society 30.5 (2010): 341–349. Doyle, Warwick, and Matthew Fraser. “Facebook, Surveillance and Power.” Facebook and Philosophy: What’s on Your Mind? Ed. D.E. Wittkower. Chicago, IL: Open Court, 2010. 215–230. Facebook. “Deactivating, Deleting & Memorializing Accounts.” Facebook Help Center. 2013. 7 Mar. 2013 ‹http://www.facebook.com/help/359046244166395/›. Gerlitz, Carolin, and Anne Helmond. “The Like Economy: Social Buttons and the Data-intensive Web.” New Media & Society (2013). Google. “Accessing a Deceased Person’s Mail.” 25 Jan. 2013. 21 Apr. 2013 ‹https://support.google.com/mail/answer/14300?hl=en›. ———. “What Happens to YouTube If I Delete My Google Account or Google+?” 8 Jan. 2013. 21 Apr. 2013 ‹http://support.google.com/youtube/bin/answer.py?hl=en&answer=69961&rd=1›. Halavais, Alexander. Search Engine Society. Polity, 2008. Hof, Robert. “Facebook Makes It Easier to Target Ads Based on Your Shopping History.” Forbes 27 Feb. 2013. 1 Mar. 2013 ‹http://www.forbes.com/sites/roberthof/2013/02/27/facebook-makes-it-easier-to-target-ads-based-on-your-shopping-history/›. Kaleem, Jaweed. “Death on Facebook Now Common as ‘Dead Profiles’ Create Vast Virtual Cemetery.” Huffington Post. 7 Dec. 2012. 7 Mar. 2013 ‹http://www.huffingtonpost.com/2012/12/07/death-facebook-dead-profiles_n_2245397.html›. Kelly, Max. “Memories of Friends Departed Endure on Facebook.” The Facebook Blog. 27 Oct. 2009. 7 Mar. 2013 ‹http://www.facebook.com/blog/blog.php?post=163091042130›. Kern, Rebecca, Abbe E. Forman, and Gisela Gil-Egui. “R.I.P.: Remain in Perpetuity. Facebook Memorial Pages.” Telematics and Informatics 30.1 (2012): 2–10. Marwick, Alice, and Nicole B. Ellison. “‘There Isn’t Wifi in Heaven!’ Negotiating Visibility on Facebook Memorial Pages.” Journal of Broadcasting & Electronic Media 56.3 (2012): 378–400. Morozov, Evgeny. “The Perils of Perfection.” The New York Times 2 Mar. 2013. 4 Mar. 2013 ‹http://www.nytimes.com/2013/03/03/opinion/sunday/the-perils-of-perfection.html?pagewanted=all&_r=0›. Pariser, Eli. The Filter Bubble: What the Internet Is Hiding from You. London: Viking, 2011. Phillips, Whitney. “LOLing at Tragedy: Facebook Trolls, Memorial Pages and Resistance to Grief Online.” First Monday 16.12 (2011). 21 Apr. 2013 ‹http://firstmonday.org/ojs/index.php/fm/article/view/3168›. Roosendaal, Arnold. “We Are All Connected to Facebook … by Facebook!” European Data Protection: In Good Health? Ed. Serge Gutwirth et al. Dordrecht: Springer, 2012. 3–19. Rudin, Ken. “Actionable Analytics at Zynga: Leveraging Big Data to Make Online Games More Fun and Social.” San Diego, CA, 2010. Vaidhyanathan, Siva. The Googlization of Everything. 1st ed. Berkeley: University of California Press, 2011. Westlake, E.J. “Friend Me If You Facebook: Generation Y and Performative Surveillance.” TDR: The Drama Review 52.4 (2008): 21–40. Zimmer, Michael. “The Externalities of Search 2.0: The Emerging Privacy Threats When the Drive for the Perfect Search Engine Meets Web 2.0.” First Monday 13.3 (2008). 21 Apr. 2013 ‹http://firstmonday.org/ojs/index.php/fm/article/view/2136/1944›. ———. “The Gaze of the Perfect Search Engine: Google as an Infrastructure of Dataveillance.” Web Search. Eds. Amanda Spink & Michael Zimmer. Berlin: Springer, 2008. 77–99.

Introduction Many destinations promote culinary encounters. Foods and beverages, and especially how these will taste in situ, are being marketed as niche travel motivators and used in destination brand building across the globe. While initial usage of the term culinary tourism focused on experiencing exotic cultures of foreign destinations by sampling unfamiliar food and drinks, the term has expanded to embrace a range of leisure travel experiences where the aim is to locate and taste local specialities as part of a pleasurable, and hopefully notable, culinary encounter (Wolf). Long’s foundational work was central in developing the idea of culinary tourism as an active endeavor, suggesting that via consumption, individuals construct unique experiences. Ignatov and Smith’s literature review-inspired definition confirms the nature of activity as participatory, and adds consuming food production skills—from observing agriculture and local processors to visiting food markets and attending cooking schools—to culinary purchases. Despite importing almost all of its foodstuffs and beverages, including some of its water, Singapore is an acknowledged global leader in culinary tourism. Horng and Tsai note that culinary tourism conceptually implies that a transferal of “local or special knowledge and information that represent local culture and identities” (41) occurs via these experiences. This article adds the act of reading to these participatory activities and suggests that, because food writing forms an important component of Singapore’s suite of culinary tourism offerings, taste contributes to the cultural experience offered to both visitors and locals. While Singapore foodways have attracted significant scholarship (see, for instance, work by Bishop; Duruz; Huat & Rajah; Tarulevicz, Eating), Singapore food writing, like many artefacts of popular culture, has attracted less notice. Yet, this writing is an increasingly visible component of cultural production of, and about, Singapore, and performs a range of functions for locals, tourists and visitors before they arrive. Although many languages are spoken in Singapore, English is the national language (Alsagoff) and this study focuses on food writing in English. Background Tourism comprises a major part of Singapore’s economy, with recent figures detailing that food and beverage sales contribute over 10 per cent of this revenue, with spend on culinary tours and cookery classes, home wares such as tea-sets and cookbooks, food magazines and food memoirs additional to this (Singapore Government). This may be related to the fact that Singapore not only promotes food as a tourist attraction, but also actively promotes itself as an exceptional culinary destination. The Singapore Tourism Board (STB) includes food in its general information brochures and websites, and its print, television and cinema commercials (Huat and Rajah). It also mounts information-rich campaigns both abroad and inside Singapore. The 2007 ‘Singapore Seasons’ campaign, for instance, promoted Singaporean cuisine alongside films, design, books and other cultural products in London, New York and Beijing. Touring cities identified as key tourist markets in 2011, the ‘Singapore Takeout’ pop-up restaurant brought the taste of Singaporean foods into closer focus. Singaporean chefs worked with high profile locals in its kitchen in a custom-fabricated shipping container to create and demonstrate Singaporean dishes, attracting public and media interest. In country, the STB similarly actively promotes the tastes of Singaporean foods, hosting the annual World Gourmet Summit (Chaney and Ryan) and Pacific Food Expo, both attracting international culinary professionals to work alongside local leaders. The Singapore Food Festival each July is marketed to both locals and visitors. In these ways, the STB, as well as providing events for visitors, is actively urging Singaporeans to proud of their food culture and heritage, so that each Singaporean becomes a proactive ambassador of their cuisine. Singapore Food Writing Popular print guidebooks and online guides to Singapore pay significantly more attention to Singaporean food than they do for many other destinations. Sections on food in such publications discuss at relative length the taste of Singaporean food (always delicious) as well as how varied, authentic, hygienic and suited-to-all-budgets it is. These texts also recommend hawker stalls and food courts alongside cafés and restaurants (Henderson et al.), and a range of other culinary experiences such as city and farm food tours and cookery classes. This writing describes not only what can be seen or learned during these experiences, but also what foods can be sampled, and how these might taste. This focus on taste is reflected in the printed materials that greet the in-bound tourist at the airport. On a visit in October 2013, arrival banners featuring mouth-watering images of local specialities such as chicken rice and chilli crab marked the route from arrival to immigration and baggage collection. Even advertising for a bank was illustrated with photographs of luscious-looking fruits. The free maps and guidebooks available featured food-focused tours and restaurant locations, and there were also substantial free booklets dedicated solely to discussing local delicacies and their flavours, plus recommended locations to sample them. A website and free mobile app were available that contain practical information about dishes, ingredients, cookery methods, and places to eat, as well as historical and cultural information. These resources are also freely distributed to many hotels and popular tourist destinations. Alongside organising food walks, bus tours and cookery classes, the STB also recommends the work of a number of Singaporean food writers—principally prominent Singapore food bloggers, reviewers and a number of memoirists—as authentic guides to what are described as unique Singaporean flavours. The strategies at the heart of this promotion are linking advertising to useful information. At a number of food centres, for instance, STB information panels provide details about both specific dishes and Singapore’s food culture more generally (Henderson et al.). This focus is apparent at many tourist destinations, many of which are also popular local attractions. In historic Fort Canning Park, for instance, there is a recreation of Raffles’ experimental garden, established in 1822, where he grew the nutmeg, clove and other plants that were intended to form the foundation for spice plantations but were largely unsuccessful (Reisz). Today, information panels not only indicate the food plants’ names and how to grow them, but also their culinary and medicinal uses, recipes featuring them and the related food memories of famous Singaporeans. The Singapore Botanic Gardens similarly houses the Ginger Garden displaying several hundred species of ginger and information, and an Eco(-nomic/logical) Garden featuring many food plants and their stories. In Chinatown, panels mounted outside prominent heritage brands (often still quite small shops) add content to the shopping experience. A number of museums profile Singapore’s food culture in more depth. The National Museum of Singapore has a permanent Living History gallery that focuses on Singapore’s street food from the 1950s to 1970s. This display includes food-related artefacts, interactive aromatic displays of spices, films of dishes being made and eaten, and oral histories about food vendors, all supported by text panels and booklets. Here food is used to convey messages about the value of Singapore’s ethnic diversity and cross-cultural exchanges. Versions of some of these dishes can then be sampled in the museum café (Time Out Singapore). The Peranakan Museum—which profiles the unique hybrid culture of the descendants of the Chinese and South Indian traders who married local Malay women—shares this focus, with reconstructed kitchens and dining rooms, exhibits of cooking and eating utensils and displays on food’s ceremonial role in weddings and funerals all supported with significant textual information. The Chinatown Heritage Centre not only recreates food preparation areas as a vivid indicator of poor Chinese immigrants’ living conditions, but also houses The National Restaurant of Singapore, which translates this research directly into meals that recreate the heritage kopi tiam (traditional coffee shop) cuisine of Singapore in the 1930s, purposefully bringing taste into the service of education, as its descriptive menu states, “educationally delighting the palate” (Chinatown Heritage Centre). These museums recognise that shopping is a core tourist activity in Singapore (Chang; Yeung et al.). Their gift- and bookshops cater to the culinary tourist by featuring quality culinary products for sale (including, for instance, teapots and cups, teas, spices and traditional sweets, and other foods) many of which are accompanied by informative tags or brochures. At the centre of these curated, purchasable collections are a range written materials: culinary magazines, cookbooks, food histories and memoirs, as well as postcards and stationery printed with recipes. Food Magazines Locally produced food magazines cater to a range of readerships and serve to extend the culinary experience both in, and outside, Singapore. These include high-end gourmet, luxury lifestyle publications like venerable monthly Wine & Dine: The Art of Good Living, which, in in print for almost thirty years, targets an affluent readership (Wine & Dine). The magazine runs features on local dining, gourmet products and trends, as well as international epicurean locations and products. Beautifully illustrated recipes also feature, as the magazine declares, “we’ve recognised that sharing more recipes should be in the DNA of Wine & Dine’s editorial” (Wine & Dine). Appetite magazine, launched in 2006, targets the “new and emerging generation of gourmets—foodies with a discerning and cosmopolitan outlook, broad horizons and a insatiable appetite” (Edipresse Asia) and is reminiscent in much of its styling of New Zealand’s award-winning Cuisine magazine. Its focus is to present a fresh approach to both cooking at home and dining out, as readers are invited to “Whip up the perfect soufflé or feast with us at the finest restaurants in Singapore and around the region” (Edipresse Asia). Chefs from leading local restaurants are interviewed, and the voices of “fellow foodies and industry watchers” offer an “insider track” on food-related news: “what’s good and what’s new” (Edipresse Asia). In between these publications sits Epicure: Life’s Refinements, which features local dishes, chefs, and restaurants as well as an overseas travel section and a food memories column by a featured author. Locally available ingredients are also highlighted, such as abalone (Cheng) and an interesting range of mushrooms (Epicure). While there is a focus on an epicurean experience, this is presented slightly more casually than in Wine & Dine. Food & Travel focuses more on home cookery, but each issue also includes reviews of Singapore restaurants. The bimonthly bilingual (Chinese and English) Gourmet Living features recipes alongside a notable focus on food culture—with food history columns, restaurant reviews and profiles of celebrated chefs. An extensive range of imported international food magazines are also available, with those from nearby Malaysia and Indonesia regularly including articles on Singapore. Cookbooks These magazines all include reviews of cookery books including Singaporean examples – and some feature other food writing such as food histories, memoirs and blogs. These reviews draw attention to how many Singaporean cookbooks include a focus on food history alongside recipes. Cookery teacher Yee Soo Leong’s 1976 Singaporean Cooking was an early example of cookbook as heritage preservation. This 1976 book takes an unusual view of ‘Singaporean’ flavours. Beginning with sweet foods—Nonya/Singaporean and western cakes, biscuits, pies, pastries, bread, desserts and icings—it also focuses on both Singaporean and Western dishes. This text is also unusual as there are only 6 lines of direct authorial address in the author’s acknowledgements section. Expatriate food writer Wendy Hutton’s Singapore Food, first published in 1979, reprinted many times after and revised in 2007, has long been recognised as one of the most authoritative titles on Singapore’s food heritage. Providing an socio-historical map of Singapore’s culinary traditions, some one third of the first edition was devoted to information about Singaporean multi-cultural food history, including detailed profiles of a number of home cooks alongside its recipes. Published in 1980, Kenneth Mitchell’s A Taste of Singapore is clearly aimed at a foreign readership, noting the variety of foods available due to the racial origins of its inhabitants. The more modest, but equally educational in intent, Hawkers Flavour: A Guide to Hawkers Gourmet in Malaysia and Singapore (in its fourth printing in 1998) contains a detailed introductory essay outlining local food culture, favourite foods and drinks and times these might be served, festivals and festive foods, Indian, Indian Muslim, Chinese, Nyonya (Chinese-Malay), Malay and Halal foods and customs, followed with a selection of recipes from each. More contemporary examples of such information-rich cookbooks, such as those published in the frequently reprinted Periplus Mini Cookbook series, are sold at tourist attractions. Each of these modestly priced, 64-page, mouthwateringly illustrated booklets offer framing information, such as about a specific food culture as in the Nonya kitchen in Nonya Favourites (Boi), and explanatory glossaries of ingredients, as in Homestyle Malay Cooking (Jelani). Most recipes include a boxed paragraph detailing cookery or ingredient information that adds cultural nuance, as well as trying to describe tastes that the (obviously foreign) intended reader may not have encountered. Malaysian-born Violet Oon, who has been called the Julia Child of Singapore (Bergman), writes for both local and visiting readers. The FOOD Paper, published monthly for a decade from January 1987 was, she has stated, then “Singapore’s only monthly publication dedicated to the CSF—Certified Singapore Foodie” (Oon, Violet Oon Cooks 7). Under its auspices, Oon promoted her version of Singaporean cuisine to both locals and visitors, as well as running cookery classes and culinary events, hosting her own television cooking series on the Singapore Broadcasting Corporation, and touring internationally for the STB as a ‘Singapore Food Ambassador’ (Ahmad; Kraal). Taking this representation of flavor further, Oon has also produced a branded range of curry powders, spices, and biscuits, and set up a number of food outlets. Her first cookbook, World Peranakan Cookbook, was published in 1978. Her Singapore: 101 Meals of 1986 was commissioned by the STB, then known as the Singapore Tourist Promotion Board. Violet Oon Cooks, a compilation of recipes from The FOOD Paper, published in 1992, attracted a range of major international as well as Singaporean food sponsors, and her Timeless Recipes, published in 1997, similarly aimed to show how manufactured products could be incorporated into classic Singaporean dishes cooked at home. In 1998, Oon produced A Singapore Family Cookbook featuring 100 dishes. Many were from Nonya cuisine and her following books continued to focus on preserving heritage Singaporean recipes, as do a number of other nationally-cuisine focused collections such as Joyceline Tully and Christopher Tan’s Heritage Feasts: A Collection of Singapore Family Recipes. Sylvia Tan’s Singapore Heritage Food: Yesterday’s Recipes for Today’s Cooks, published in 2004, provides “a tentative account of Singapore’s food history” (5). It does this by mapping the various taste profiles of six thematically-arranged chronologically-overlapping sections, from the heritage of British colonialism, to the uptake of American and Russia foods in the Snackbar era of the 1960s and the use of convenience flavoring ingredients such as curry pastes, sauces, dried and frozen supermarket products from the 1970s. Other Volumes Other food-themed volumes focus on specific historical periods. Cecilia Leong-Salobir’s Food Culture in Colonial Asia: A Taste of Empire discusses the “unique hybrid” (1) cuisine of British expatriates in Singapore from 1858 to 1963. In 2009, the National Museum of Singapore produced the moving Wong Hong Suen’s Wartime Kitchen: Food and Eating in Singapore 1942–1950. This details the resilience and adaptability of both diners and cooks during the Japanese Occupation and in post-war Singapore, when shortages stimulated creativity. There is a centenary history of the Cold Storage company which shipped frozen foods all over south east Asia (Boon) and location-based studies such as Annette Tan’s Savour Chinatown: Stories Memories & Recipes. Tan interviewed hawkers, chefs and restaurant owners, working from this information to write both the book’s recipes and reflect on Chinatown’s culinary history. Food culture also features in (although it is not the main focus) more general book-length studies such as educational texts such as Chew Yen Fook’s The Magic of Singapore and Melanie Guile’s Culture in Singapore (2000). Works that navigate both spaces (of Singaporean culture more generally and its foodways) such Lily Kong’s Singapore Hawker Centres: People, Places, Food, provide an consistent narrative of food in Singapore, stressing its multicultural flavours that can be enjoyed from eateries ranging from hawker stalls to high-end restaurants that, interestingly, that agrees with that promulgated in the food writing discussed above. Food Memoirs and Blogs Many of these narratives include personal material, drawing on the author’s own food experiences and taste memories. This approach is fully developed in the food memoir, a growing sub-genre of Singapore food writing. While memoirs by expatriate Singaporeans such as Cheryl Lu-Lien Tan’s A Tiger in the Kitchen: A Memoir of Food and Family, produced by major publisher Hyperion in New York, has attracted considerable international attention, it presents a story of Singapore cuisine that agrees with such locally produced texts as television chef and food writer Terry Tan’s Stir-fried and Not Shaken: A Nostalgic Trip Down Singapore’s Memory Lane and the food memoir of the Singaporean chef credited with introducing fine Malay dining to Singapore, Aziza Ali’s Sambal Days, Kampong Cuisine, published in Singapore in 2013 with the support of the National Heritage Board. All these memoirs are currently available in Singapore in both bookshops and a number of museums and other attractions. While underscoring the historical and cultural value of these foods, all describe the unique flavours of Singaporean cuisine and its deliciousness. A number of prominent Singapore food bloggers are featured in general guidebooks and promoted by the STB as useful resources to dining out in Singapore. One of the most prominent of these is Leslie Tay, a medical doctor and “passionate foodie” (Knipp) whose awardwinning ieatŸishootŸipost is currently attracting some 90,000 unique visitors every month and has had over 20,000 million hits since its launch in 2006. An online diary of Tay’s visits to hundreds of Singaporean hawker stalls, it includes descriptions and photographs of meals consumed, creating accumulative oral culinary histories of these dishes and those who prepared them. These narratives have been reorganised and reshaped in Tay’s first book The End of Char Kway Teow and Other Hawker Mysteries, where each chapter tells the story of one particular dish, including recommended hawker stalls where it can be enjoyed. Ladyironchef.com is a popular food and travel site that began as a blog in 2007. An edited collection of reviews of eateries and travel information, many by the editor himself, the site features lists of, for example, the best cafes (LadyIronChef “Best Cafes”), eateries at the airport (LadyIronChef “Guide to Dining”), and hawker stalls (Lim). While attesting to the cultural value of these foods, many articles also discuss flavour, as in Lim’s musings on: ‘how good can chicken on rice taste? … The glistening grains of rice perfumed by fresh chicken stock and a whiff of ginger is so good you can even eat it on its own’. Conclusion Recent Singapore food publishing reflects this focus on taste. Tay’s publisher, Epigram, growing Singaporean food list includes the recently released Heritage Cookbooks Series. This highlights specialist Singaporean recipes and cookery techniques, with the stated aim of preserving tastes and foodways that continue to influence Singaporean food culture today. Volumes published to date on Peranakan, South Indian, Cantonese, Eurasian, and Teochew (from the Chaoshan region in the east of China’s Guangdong province) cuisines offer both cultural and practical guides to the quintessential dishes and flavours of each cuisine, featuring simple family dishes alongside more elaborate special occasion meals. In common with the food writing discussed above, the books in this series, although dealing with very different styles of cookery, contribute to an overall impression of the taste of Singapore food that is highly consistent and extremely persuasive. This food writing narrates that Singapore has a delicious as well as distinctive and interesting food culture that plays a significant role in Singaporean life both currently and historically. It also posits that this food culture is, at the same time, easily accessible and also worthy of detailed consideration and discussion. 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Acknowledgements Research to complete this article was supported by Central Queensland University, Australia, under its Outside Studies Program (OSPRO) and Learning and Teaching Education Research Centre (LTERC). An earlier version of part of this article was presented at the 2nd Australasian Regional Food Networks and Cultures Conference, in the Barossa Valley in South Australia, Australia, 11–14 November 2012. The delegates of that conference and expert reviewers of this article offered some excellent suggestions regarding strengthening this article and their advice was much appreciated. All errors are, of course, my own.

La maladie d'Alzheimer (MA) se caractérise par la présence de deux lésions : les dégénérescences neurofibrillaires (DNF) et les dépôts amyloïdes, ces derniers résultants de l'accumulation du peptide bêta-amyloïde. Ce peptide dérive du catabolisme de l'APP (Précurseur du Peptide Amyloïde). Les travaux réalisés au laboratoire montrent qu'il existe une relation entre le métabolisme de l'APP et la progression des DNF qui s'illustre par une perte du domaine intracellulaire et des fragments carboxy-terminaux de l'APP (AICD et APP-CTFs). La phosphorylation de ces derniers est également modifiée dans la MA. Notre objectif a donc été de déterminer quels étaient les facteurs susceptibles de diminuer les APP-CTFs et l'AICD. Nos travaux ont permis de montrer que la phosphorylation des APP-CTFs pouvait réguler leur clivage via l'activité γ-sécrétase, que la voie endosome/lysosome est impliquée dans la dégradation de l'AICD et ils décrivent une nouvelle voie de sécrétion pour l'APP et ses dérivés
Alzheimer's disease (AD) is characterized by two distinct pathologies: neurofibrillary tangles (NFT) and extracellular amyloid plaques composed of beta-amyloid peptide (Abeta). Abeta derive from the catabolism of the Amyloid Precursor Protein (APP). A relationship between APP metabolism and NFT is observed in AD. This relation is illustrated by a significant decrease of APP-CTFs and AIDD, which correlated with the progression of NFT. APP-CTFs phosphorylation is also modified in AD. The main objectives of this thesis were to identify the degradations pathways of APP-CTFs and AICD. Our results demonstrated that increase in the phosphorylation of APP-CTFs facilitates their processing by the gamma-secretase. Moreover, our data demonstrate for the first time that the endosome/lysosome pathway mediates the degradation of AICD and we describe a novel secretion pathway of APP catabolic derivatives

La maladie d'Alzheimer (MA) est une pathologie complexe et multifactorielle pour laquelle il n'existe actuellement aucun traitement. Plusieurs hypothèses ont été proposées pour expliquer l'apparition et la progression de cette maladie, dont la cascade amyloïde, qui prédomine dans le domaine de la recherche depuis 30 ans. La voie amyloïdogène nécessite l'endocytose de la protéine APP dans les endosomes précoces où elle subit deux clivages protéolytiques, d'abord par la β-sécrétase pour produire le fragment C99, puis par la γ-sécrétase pour produire le peptide Aβ. L'une des hypothèses actuelles est que les anomalies de l'endocytose et le dysfonctionnement du système endolysosomal dans les neurones constitueraient un des mécanismes neuropathologiques précoces de la MA, bien avant la cascade neurotoxique générée par Aβ et les dépôts amyloïdes. Nous défendons l'hypothèse que des modifications de l'organisation membranaire, notamment au cours du vieillissement ou dues à des déséquilibres lipidiques, pourraient exacerber ou favoriser ces dysfonctionnements. Pour cette étude, nous avons utilisé un modèle de neuroblastome humain surexprimant la protéine mutante APPswe. Nous avons tout d'abord vérifié la présence d'anomalies endolysosomales typiques de la MA (endosomes hypertrophiés, trafic vésiculaire bloqué), auxquelles nous avons également associé une faible production d'exosomes, conditions de stress chronique que nous avons corrélées à la mort neuronale. Incriminant dans un premier temps une production continue d'Aβ dans ces cellules, nous avons cherché à réduire son impact en inhibant l'activité γ-sécrétase. Cela n'a pas amélioré le stress, mais l'a au contraire aggravé, ce qui nous a conduit à considérer que c'est le fragment C99 de l'APP, c'est-à-dire le substrat de la production d'Aβ, qui est le produit amyloïde central de la cascade neurotoxique observée dans les cellules surexprimant l'APP. Les effets délétères du C99 doivent se produire avant ceux de l'Aβ, expliquant la précocité connue des altérations endolysosomales. S'accumulant à la suite de l'inhibition de la γ-sécrétase, le fragment C99 interagit davantage avec la protéine Rab5, spécifique de l'endosome précoce. La maturation de cette dernière est ainsi empêchée, bloquant le trafic vésiculaire du système endolysosomal. Comme les interactions entre C99 et Rab5 se produisent au niveau de la membrane des endosomes, nous avons modifié la composition lipidique de la bicouche et exploré les conséquences sur ces interactions. À cette fin, nous avons traité des cellules SH-SY5Y-APPswe par de l'acide docosahexaénoïque (DHA, C22:6 n-3), le principal acide gras polyinsaturé des membranes neuronales et connu pour ses propriétés neuroprotectrices contre le stress amyloïde et la MA. L'effet bénéfique attendu sur la survie neuronale a bien été observé, en parallèle au déblocage du trafic endolysosomal et à la production d'exosomes. Tous ces changements ont été corrélés à une dispersion entre C99 et Rab5 dans la membrane, suggérant que le traitement par le DHA a pu initier un remodelage membranaire. Ce remodelage peut conduire à une relocalisation des protéines, les endosomes pouvant alors échanger Rab5 contre Rab7 et évoluer en endosomes tardifs, levant ainsi le blocage initial. À notre connaissance, il s'agit de la première preuve que le DHA peut corriger un phénotype directement lié à la MA, mais sa capacité à remodeler la membrane neuronale a déjà été démontrée par notre équipe pour préserver la signalisation par le facteur neurotrophique CNTF dans le cerveau de souris âgées. Nous ignorons quels principes mécanistiques pourraient régir ces effets bénéfiques, certainement non spécifiques, mais nous supposons qu'en préservant l'organisation des membranes des neurones âgés ou soumis à un stress chronique, ils pourraient prévenir ou restaurer une partie des dommages subis, augmenter les chances de survie des neurones et ainsi ralentir le développement de la MA
Alzheimer's disease (AD) is a complex and multifactorial pathology for which there is no current treatment. Several hypotheses have been proposed to explain the onset and progression of this disease, including the amyloid cascade, which predominates the field of research for the past 30 years. The amyloidogenic pathway requires the endocytosis of the APP protein in early endosomes where it undergoes two proteolytic cleavages, first by β-secretase to produce the C99 fragment, and then by γ-secretase to produce the Aβ peptide. One of the current hypotheses is that abnormalities of endocytosis and dysfunction of the endolysosomal system in neurons would constitute one of the early neuropathological mechanisms of AD, well before the neurotoxic cascade generated by Aβ and amyloid deposits. We advocate the hypothesis that changes in membrane organization, particularly during aging or due to lipid imbalances, may exacerbate or promote these dysfunctions. For this study, we used a human neuroblastoma model overexpressing the mutant protein APPswe. We first verified the presence of typical AD endolysosomal abnormalities (enlarged endosomes, blocked vesicular trafficking), to which we also associated low exosome production, chronic stress conditions that we correlated with neuronal death. Initially incriminating continuously produced Aβ in these cells, we sought to reduce its impact by inhibiting γ-secretase activity. This did not ameliorate the stress, but instead aggravated it, leading us to consider that it is the C99 fragment of APP, i.e. the substrate of Aβ production, that is the central amyloid product in the neurotoxic cascade seen in APP-overexpressing cells. The deleterious effects of C99 must occur before those of Aβ, explaining the known precocity of endolysosomal alterations. Accumulating as a result of γ-secretase inhibition, the C99 fragment interacts further with the early endosome-specific Rab5 protein. Maturation of the latter is thus prevented, blocking vesicular trafficking of the endolysosomal system. As the interactions between C99 and Rab5 occur at the membrane level of endosomes, we have modified the lipid composition of the bilayer and explored the consequences on these interactions. For this purpose, we treated SH-SY5Y-APPswe cells with docosahexaenoic acid (DHA, C22:6 n-3), the major polyunsaturated fatty acid in neuronal membranes and known for its neuroprotective properties against Aβ toxicity and AD. The expected beneficial effect on neuronal survival was indeed observed, in parallel with the unblocking of endolysosomal trafficking and exosomal production. All these changes were correlated with a dispersion between C99 and Rab5 in the membrane, suggesting that DHA treatment may initiate membrane remodeling. This remodeling may lead to protein relocalization, whereby endosomes may exchange Rab5 for Rab7 to evolve into late endosomes, thereby overcoming the initial blockage. To our knowledge, this is the first evidence that DHA can correct a phenotype directly related to AD, but its ability to remodel the neuronal membrane was previously demonstrated by our team to preserve the neurotrophic CNTF signaling in the brain of aged mice. We do not know what mechanistic principles might govern these beneficial effects, which are certainly non-specific, but we assume that by preserving the organization of the membranes of aged or chronically stressed neurons, they may prevent or restore some of the damage suffered, increase the chances of neuronal survival and thus slow AD development

Depuis quelques années, les oligomères du peptide Aβ sont identifiés comme étant responsables du déclenchement de la pathologie alors que les dépôts amyloïdes sont des conséquences aggravantes de la pathologie. Cependant, les formes oligomériques d’Aβ impliquées dans la pathologie ainsi que l’origine de ces peptides sont toujours débattues. Notre objectif principal était d’identifier des signatures Aβ oligomériques cérébrales et vasculaires et de déterminer si nous pouvions interférer avec ces signatures pour modifier le décours de la pathologie. Nous avons réalisé des analyses biochimiques qualitative des formes d’Aβ dans des échantillons de cerveau et de vaisseaux issus de patients atteints de la MA et de souris transgéniques modèle de la MA. Nous avons montré qu’une même forme Aβ oligomérique (17-18 kDa) est impliquée dans le développement de la pathologie cognitive chez l’homme et chez la souris APP/PS1. Une signature Aβ oligomérique vasculaire spécifique a été observée dans les vaisseaux périphériques et plus particulièrement la veine porte hépatique des souris APP/PS1. De plus, un traitement pharmacologique ciblant l’expression des protéines de transport de l’Aβ a permis de restaurer les profils Aβ oligomériques contrôles dans le cerveau des souris APP/PS1 tout en « chargeant » la veine porte des mêmes souris en Aβ oligomérique. Ces résultats montrent que les signatures Aβ vasculaires et cérébrales sont intimement liées. De plus, nos travaux mettent l’accent sur une possible intervention thérapeutique agissant sur les formes Aβ cérébrales et vasculaires
Alzheimer's disease (AD) is a complex disorder of the central nervous system that affects an increasing number of people worldwide due to the overall aging of the human population. Vascular factors and mechanisms have emerged as an area of key importance. Accumulating evidence indicates that pre-fibrillar aggregates, specifically the low-molecular weight oligomers of Aβ peptide, are responsible for the synaptic dysfunction and neuronal loss that occur in AD pathology. But, these oligomeric forms implicated in the pathology are currently under debate. Our primary goal was to identify cerebral and vascular oligomeric signatures. Secondly, we try to interfere with these signatures in order to modify the evolution of AD. We realize qualitative analyses of cerebral and vascular oligomers Aβ by western-blot. Vascular and cerebral tissues were extracted from AD patients and from a transgenicmouse model of AD. We demonstrate that the same oligomer Aβ (17-18 kDa) is implicated in the cognitive impairment for patients and APP/PS1 mouse. A specific vascular signature of oligomer Aβ was detected in peripheral vessels and particularly in portal vein from liver of APP/PS1 mouse. Moreover, pharmacological treatment targeting clearance of soluble Aβ restored the control signature of oligomer Aβ in the brain of APP/PS1 mouse. This configurational change was associated with an increase of oligomer Aβ in portal vein from liver. These results show that cerebral and vascular oligomeric signatures were closely linked. Finally, our work emphasizes potential therapeutic strategies for AD by targeting cerebrals and vasculars oligomers Aβ

L’accumulation cérébrale progressive de peptides amyloïdes générés à partir du clivage du précurseur du peptide amyloïde (APP) par les sécrétases est un mécanisme central de la maladie d’Alzheimer. C’est pourquoi, améliorer la compréhension de la régulation et de l’homéostasie du métabolisme de l’APP est devenu primordial. Partant de ce constat, nous avons supposé qu’une partie de la réponse pourrait être apportée par la caractérisation de nouveaux acteurs du métabolisme de l’APP. De part leurs rôles cruciaux dans le cerveau (développement, plasticité et réparations) et dans le métabolisme de l’APP (α-sécrétases), les ADAMs sont des protéines d’intérêt dont certaines fonctions ou rôles restent à déterminer. Précédemment, par une approche transcriptomique ciblant la famille des ADAMs dans des cerveaux de patients et de contrôles, ADAM30 a été retrouvée sous-exprimée dans le cerveau des patients atteints de la pathologie. Dans deux modèles cellulaires nous avions constaté que la sous-expression d’ADAM30 entraînait une augmentation de tous les produits du métabolisme de l’APP comme chez les patients. Le résultat opposé a été obtenu lors de la sur-expression d’ADAM30 dans ces cellules. Pour tenter de répliquer ces résultats dans un modèle plus proche de la physiopathologie humaine, nous avons développé un modèle de souris triples transgéniques surexprimant l’APPSweInd et ADAM30 de manière conditionnelle. Dans ce modèle nous avons observé et mesuré une diminution des dépôts amyloïdes dans le cerveau des souris exprimant ADAM30. Dans un second temps puisqu’il avait été montré au laboratoire qu’ADAM30 ne module pas l’activité des sécrétases et ne clive pas directement l’APP, nous avons cherché à déterminer les substrats d’ADAM30 dans le cadre du métabolisme de l’APP. Par une approche systématique nous avons pu déterminer que la Cathepsine D (CTSD) et l’Insuline Receptor Substrat 4 (IRS4) sont deux substrats potentiels d’ADAM30. Dans nos modèles cellulaires et de souris, nous avons pu constater qu’ADAM30 est capable de cliver et d’activer la CTSD. L’activité de la CTSD semble nécessaire pour l’action d’ADAM30 sur le métabolisme de l’APP. Nous avons pu déterminer que l’action spécifique d’ADAM30 pour la CTSD est dépendante de la séquence d’adressage au lysosome située dans l’extrémité C-terminale de l’APP. Comme la CTSD est une protéine Lysosomale, ADAM30 pourrait favoriser spécifiquement l’activation de la CTSD augmentant ainsi la dégradation de l’APP au sein de la voie endosome/lysosome. Ce mécanisme limiterait l’entrée de l’APP dans son métabolisme et donc la production de peptides amyloïdes. Afin de mieux comprendre la spécificité d’action d’ADAM30 pour la CTSD et l’APP, nous avons commencé à travailler sur le rôle potentiel d’IRS4 et la relation entre la voie de signalisation de l’Insuline et le métabolisme de l’APP. Nos travaux nous ont donc permis de mettre en évidence un nouvel acteur du métabolisme de l’APP, ADAM30, intervenant dans la régulation et la dégradation de ce dernier et ainsi d’améliorer notre compréhension des mécanismes de régulations fins impliqués dans le processus physiopathologique de la maladie d’Alzheimer
Progressive intra-cerebral accumulation of amyloid peptides formed after sequential cleavage of the amyloid peptide precursor (APP) by secretases , is a central mecanism for Alzheimer’s disease. Therefore, a better understanding of APP regulation and homeostasy is now crucial. With this background, we postulate that the characterization of new actors in the APP metabolism could provide a more subtle understanding of this APP metabolism and trafficking. From their obvious implication in brain (development, plasticity and repair) and in APP metabolism (α-secretases), ADAMs (A Disintegrin And Metalloprotease) are an important protein proteins family which still have some undetermined function or role. Previously, a transcriptomic approach targeting ADAMs family bas been done at the laboratory on Alzheimer’s patient or control brains and found ADAM30 as under-expressed in Alzheimer’s patient brains. On cellular models, we confirmed that ADAM30 under-expression was associate with an increase in production/secretion of all the APP metabolim byproducts. Opposite results were found with ADAM30 over-expression. To replicate those results in another model closest to human pathophysiology, we have developed a triple transgenic mice model over-expressing APPSweInd and conditionally over-expressing ADAM30. In this model, we have observed and measured a decrease in amyloid deposits in mice brains over-expressing ADAM30. Secondly, because ADAM30 did not modulate secretase activities and did not cleave APP directly, we decided to determine ADAM30 substrats in the APP metabolism context. With a systematic approach, we have determined that Cathepsin D (CTSD) and Insulin Receptor Substrat 4 (IRS4) are two ADAM30 potential substrats. In our cellular models, we have found that ADAM30 is able to cleave and activate CTSD. This CTSD activity is required for ADAM30 action on APP metabolism. We have determined that ADAM30 specific action for CTSD is dependent on lysosome adressing sequence localised in APP C-terminal part. CTSD is a lysosomal protein and so ADAM30 would make CTSD specific activation easier. This mecanism would be able to increase APP degradation in endosome/lysosome pathway and reduce APP entry in its metabolism. To better understand ADAM30 specific action on CTSD and APP, we begin to investigate the potential role of IRS4 and the relation between insulin signaling pathway ans APP metabolism. Combined together, those data suggest that ADAM30 is a new APP metabolism actor, involved in an early APP regulation and degradation pathway dependent on lysosome activation. This study participate in a better understanding of the fine mecanism regulations involved in Alzheimer’s disease pathophysiological process