We hypothesize that linguistic (dis-)organization in the schizophrenic brain plays a more central role in the pathogenesis of this disease than commonly supposed. Against the standard view, that schizophrenia is a disturbance of thought or selfhood, we argue that the origins of the relevant forms of thought and selfhood at least partially depend on language. The view that they do not is premised by a theoretical conception of language that we here identify as ‘Cartesian’ and contrast with a recent ‘un-Cartesian’ model. This linguistic model empirically argues for both (i) a one-to-one correlation between human-specific thought or meaning and forms of grammatical organization, and (ii) an integrative and co-dependent view of linguistic cognition and its sensory-motor dimensions. Core dimensions of meaning mediated by grammar on this model specifically concern forms of referential and propositional meaning. A breakdown of these is virtually definitional of core symptoms. Within this model the three main positive symptoms of schizophrenia fall into place as failures in language-mediated forms of meaning, manifest either as a disorder of speech perception , abnormal speech production running without feedback control , or production of abnormal linguistic content (Delusions). Our hypothesis makes testable predictions for the language profile of schizophrenia across symptoms; it simplifies the cognitive neuropsychology of schizophrenia while not being inconsistent with a pattern of neurocognitive deficits and their correlations with symptoms; and it predicts persistent findings on disturbances of language-related circuitry in the schizophrenic brain. If language is merely a tool, and this tool is detached or broken, we would then expect that thought could stay the same, and vice versa. Global aphasia, where core cognition can seem surprisingly normal may illustrate precisely such a predicament , or disordered speech (‘A conclusion is my French professor’), language loses its function of carrying and conveying such content. If having and conveying such content is an inherent aspect of language, such loss therefore is a disorder of language, though crucially not an aphasic one. Kunstsprachen) used as if they were normal ones. Moreover, his essential experimental methods were word association experiments carried out with his assistant C. G. Jung, who theorized that ‘words are really something like condensed actions, situations, and things. [They are] linguistic substitutes for reality’ . According to re-configuring the hominin mind rather than merely expressing one that pre-existed the arrival of linguistic communication. Supporting this perspective, Comparative studies of cognition and communication across species confirm an explanatory gap between linguistic and non-linguistic cognitive and communicative contents . Some phcognitive type that characterizes modern humans, putting a form of rational thought in place that we do not see in non-human species, including extinct human ones. The question that un-Cartesian linguistics addresses is how we obtain this cognitive type, which uniquely invented language and started communicating linguistically2. Its central claim, that the human-specific form of rational thought and language arose together, makes the prediction that they should also fall together. It follows that schizophrenia could be re-conceptualized as manifesting a breakdown of the linguistic frame of thought and hence that it can be illuminated in linguistic terms.The un-Cartesian linguistic framework goes further than recent foundational views that grant language a ‘supra-communicative’ function, over and above its function as a tool of interpersonal communication . On ClarThe hypothesis of this article is that schizophrenia is a breakdown of how language configures thought in the normal brain, viewed against an un-Cartesian background theory of what language is. Language circuitry in the brain is disturbed, resulting in forms of thought that cannot be shared anymore and lose objectivity, including thoughts about other minds, leading to a breakdown of normal social cognition and communication that depend on the linguistic frame of thought being intact.(1)match.Most fundamentally, language should illuminate cognitive change seen in symptoms, which should not only have linguistic interpretations, as already argued by (2)use linguistic theory as a way of formalizing and identifying anomalies in schizophrenia speech rather than as an explanatory framework. By contrast, the un-Cartesian linguistic framework generates the prediction that the linguistic anomalies we will find in such speech specifically concern the ways in which, according to this framework, grammar mediates referential, and propositional forms of meaning. A very specific prediction is that the more forms of reference are mediated grammatically, the more they should manifest anomalies/impairment .Studies of the language of schizophrenia after (3)The more language-dependent a neurocognitive variable is, the more it should be affected (see Section “Language and the Cognitive Neuropsychology of Schizophrenia”).(4)The neural correlates of core symptoms – and even of key cognitive variables including ‘theory of mind’ (ToM) – should be part of the language network.integrative system: therein lies its special status among all other neurocognitive variables. In any utterance we ever make, all of the cognitive functions come together in a coherent way: speech, thought, affect, perception, memory, attention, planning, etc. If language falls apart, ‘loosening of associations’ in I think/say to you that.’ Moreover, all such talk is about the world, the grammatical 3rd (or non-) Person .Language is an Figure 2):Depending, then, on which corner is disproportionally affected by the disease process , creating an imbalance in the normal language function, we can give a linguistic characterization of the three core positive symptoms according to current DSM-5 criteria in the following way .A disorder of speech perception leading to a conflation of thought and speech, as in •Formal Thought Disorder (FTD).A disorder of speech production leading to disordered speech without feedback control, as in varieties of •Delusions.A disorder of content formation leading to distorted meanings that cannot be true as in 3. Current support for the hypothesis and theory firstly comes from the independent un-Cartesian linguistic theory (cf. Section “How can Language Illuminate Psychosis?”), which argues empirically that a propositional and referential capacity in humans is based on language, depending on grammar  as its essential principle of organization. A breakdown of language thus viewed predicts the loss of a propositional and referential capacity. This loss is virtually descriptively equivalent to what we see in positive symptoms as described in Section “Linguistic Dimensions across Positive Symptoms.” These can thus not only be given linguistic characterizations, in which core linguistic variables identified in the linguistic theory figure, but these descriptions provide a mechanism for symptom formation. The connection between the neurocognition of schizophrenia  and symptoms now becomes immediate. In contrast, relating general or specific neurocognitive deficits (say in memory or executive function) to the ‘excesses’ of functions that the positive symptoms represent  has been a persistent problem (We currently test predictions (1)–(2) above problem , where l problem . It is aWe review four decades of findings on the language of schizophrenia in Section “The Language Profile of Schizophrenia against our Predictions.” The pattern of these findings, we suggest, is strongly consistent with our predictions. In Section “Language in the Schizophrenic Brain,” we briefly review the neural correlates of schizophrenia in the light of our hypothesis, and again suggest that findings on disorders in speech perception and comprehension areas as well as ToM areas are consistent with our account. Due to space limitations, we do not discuss negative symptoms in this paper.According to current DSM-5 criteria, a diagnosis of ‘schizophrenia’ requires the presence of at least one of the following three ‘positive’ symptoms :(1)Hallucinations(2)Delusions(3)Disorganized speechnone of these syndromes inherently relate to language4.A long-standing orthodoxy suggests that Box 1):In FTD, a connection with language is obvious: DSM-5 refers to it as ‘disorganized thinking,’ which is ‘typically inferred from the individual’s speech’ (p. 88). Such speech can be productive (no ‘poverty of speech’), and patients can be fully cooperative communicators. Yet however much speech is produced, the listener has difficulties identifying what is actually being ‘said’ (‘poverty of content’). In another classical profile, patients are clinically said to exhibit ‘loss of goal,’ ‘derailment,’ and ‘tangentiality’. One example of each, from Q. How do you like it in hospital?A. Well, er not quite the same as, er don’t know quite how to say it. It isn’t the same, being in hospital as, er working. Er the job isn’t quite the same, er very much the same but, of course, it isn’t exactly the same.Q. How are you?A. ’To relate to people about new-found talk about statistical ideology. Er, I find that it’s like starting in respect of ideology, ideals change, and ideals present ideology and new entertainments new, new attainments. And the more one talks about like, ideal totalitananism, or hotelatarianism, it’s like you want new ideas to be formulated, so that everyone can benefit in mankind, so we can all live in our ideal heaven. Presumably that’s what we still want, and with these ideas it can be brought about. I find the it’s like a rose garden.’In poverty of content, phrasal and even sentential structure can seem normal, but the thought carried by language is hard to pin down. Thus in the second example, an initial topic is not addressed, a new topic is vigorously set, but the speaker derails, and the discourse is carried forth more on the basis of lexical associations than propositional meaning. Overall, no point or message emerges.The intrusions of semantic  or phono‘My mother’s name was Bill. [pause] … and coo? St. Valentine’s Day is the official startin’ of the breedin’ season of the birds. All buzzards can coo. I like to see it pronounced buzzards rightly. They work hard.’In a production like ‘A conclusion was a French professor,’ uttered by one of the FTD patients in our study, the system of grammatically categorizing ideas seems to have broken down .independently of the abnormal linguistic patterns in which it consists and as which it is diagnosed. Specific linguistic processes and principles of organization – e.g., derivational morphology, phrases vs. sentences, referential phrases, proper names vs. common nouns, etc. – are involved in it, which have to come together in the right way to generate the clinical impressions of ‘emptiness’ and ‘disorganization’ that we see.Over time, talk, using words and  sentences, and hallucinations in this sense take an auditory verbal form (AVHs). AVHs therefore are inherently a linguistic experience and hence involve an anomaly of speech perception by definition. This speech further has contents that ‘are perceived as distinct from the individual’s own thoughts’ (ibid.), which is to say that they are perceived as the thoughts of what is, from the viewpoint of the voice hearer, a grammatical second (‘you’) or third (‘he’/’she’) person, while the voice hearer in turn is a second or third person from the viewpoint of the voices. This entails a loss of first-person ownership of the patient’s self-generated thoughts, which we earlier identified as the implicit subordination of every thought or utterances under the phrase ‘I think that.’ To illustrate, suppose an example of the thought in question is (1):Hallucinations are defined in DSM-5 as ‘perception-like experiences that occur without an external stimulus’ . Auditory ones are identified as the most common. These in turn prototypically take the form of voices, whether familiar or unfamiliar. These do not prototypically grunt, bark or whistle, but (1)I am weak.He thinks/says that’):Then there is a transition from this thought, to the thought that would in mental health be expressed by another person’s utterance of the form in (2), which is now what the voice is heard to say (‘(2)He is weak.deictic shift, specifically from the 1st to the 3rd (or else to the 2nd Person). While the words ‘I’ in (1) and the word ‘he’ in (2) refer to the exact same person, i.e., the voice hearer, the thought as expressed in the two utterances has crucially become a different one and the identification ‘he = I’ is not made by the voice hearer, even though he is perceiving what are effectively his own thoughts. In delusions the identification is made: ‘he’ becomes ‘I,’ leading, e.g., from ‘He is Jesus’ to ‘I am Jesus’. This seems to indicate a broader pattern of the loosening of deictic anchoring to which we return.We will call this a AVHs, but its linguistic profile involves specific grammatical distinctions and pronominal patterns, without which the phenomenon would not be what it is. In line with this, language plays a crucial role in reference to the patient , hence they really represent what are now termed referential delusions. Crucially, reference is nothing we can hear. As we argue in Section “How can Language Illuminate Psychosis?,” it is a linguistic category inherently. The most common auditory hallucinations, 5. For verbal hallucinations, moreover, audition is not actually essential, as is now widely documented (language is perceived (whether or not sound is), in the sense that the thoughts in question have a linguistic articulation, come with a content that is given by this articulation, and that such thoughts/voices often appear as acts of linguistic communication to the recipient .Again these initial observations suggest that not only is language a defining feature of cumented : many socumented , p. 90. meaningful commands (‘Go into the water’), which are often followed by them, turning into the thought ‘I go into the water,’ just as for a person who gives instructions to herself using self-talk . In this regard the voice hearer is confused as to whether the thought ‘he says I should do X’ really is the thought ‘I should do X.’ There is a Person confusion in addition to a shift, which in and of itself would not entail the phenomenology of AVHs. Perceiving speech of other people normally simply means that we recognize them as individuals like ourselves, who have their own bodies, 1st-personal narrative histories and beliefs about the world, and whose commands for actions are just that: things that someone else wants us to do. But voices do characteristically not develop a personal narrative or talk much about themselves in the 1st Person, nor about the world, using the 2nd or 3rd Persons near exclusively . In commands like ‘wash your hair’ endlessly repeated, heard speech content cannot be rationalized any more, as it normally can be, and voices cease to be rational speech agents. Nor is such speech appraised as normal speech would be. We may on occasion misattribute speech, but we would not hear the fridge or the bread talking to us. Nor would we wonder why we can hear our relatives talking to us, while we have to travel to them in order for them to do so  disturbance in speech perception, (ii) deictic shifting and Person confusion, (iii) content distortion, and (iv) grammatical narrowing, but also (v) the erasure of a normal boundary between thought and speech, providing another linguistic index for a disintegration of the self, for whose integrity it is essential that one’s 1st Personal thoughts are one’s own and private to oneself. It is a defining phenomenological feature of normal 1st Person thoughts that they are silent: we can voice them, if only by moving our lips, but if we don’t, we don’t hear them. If we utter them and they become overt, they become also different, being necessarily addressed to a grammatical 2nd Person (not ‘I think…’ but ‘I say to you…’). In AVHs, thoughts become perceived as speech when they should be silent 7.There is, then, a speech profile to voicesis typically taken to be, like an assertion: we can decide what we say or believe. The beliefs in question are further described as ‘fixed,’ and as held with incontrovertible certainty. These beliefs must be linguistically articulated internally, on the assumption, to which we return, that a belief like ‘I came to earth in a cosmic bubble’ cannot be formed without linguistic articulation. This already entails an anomaly in language, since delusions are beliefs that come with a quasi-perceptual force, which propositions expressed as sentences in language characteristically not only lack, but which truth does not require (things can be true even if this truth is not evident or forceful).Finally, delusions are defined in DSM-5 as beliefs rather than perceptions, which is what hallucinations are. Qua perceptions, the latter are not under voluntary control, while a belief, being rational, impossibly true . These, moreover, are often generated without much consideration or reasoning – they can simply ‘pop up’ and patients can typically not justify what they believe. Apart from such delusions, there are referential delusions such as the belief that gestures, utterances, and other environmental cues refer to the patient. Also included among delusions in DSM-5 are delusions expressing a loss of control over one’s mind or body, e.g., thought withdrawal (one’s thoughts have been removed by an outside force) and insertion , i.e., In line with the anomaly of their incontrovertible certainty, delusions are not contentful but contingently false, like a person’s claim that coffee grows on trees. Instead, they are propositions that are often bizarre and judged by others as being ipso facto has such content. The most immediate thing to say, therefore, is that in the expression of a delusion such as ‘I am Jesus,’ a predicate  and a subject (‘I’) are combined in a way that a monstrous propositional content arises. At the word level, ‘Jesus’ is presumably used correctly, but like in FTD, the mistake lies at the grammatical level, i.e., how words are related grammatically as subjects and predicates. In particular, while the speaker still uses the proper name ‘Jesus’ correctly to refer to Jesus (not Napoleon), he is not using ‘I’ properly to locate himself in deictic space, as a bearer of the property of being Jesus. Where ‘He is Jesus’ would be fine, a shift to the 1st Person has taken place, and ‘I am Jesus’ results. Similarly, where ‘The Mafia is trying to kill someone’ is surely true, and ‘the Mafia’ is used correctly, a shift to the first Person takes place here too, resulting in a falsehood ‘The Mafia is trying to kill me.’We take the prevailing view to be that none of these delusions are in some essential sense language-related. Yet as noted above, it is part of the essence of language that it carries a content of a particular kind: content, in particular, that can be true even if false, and can, unlike a perception, be negated and reasoned with. Language is not a system to which such content accrues somehow accidentally: content is not something that it ‘also has,’ and could also lack, while staying what it is. In virtue of having a certain grammatical structure – with a predicate attributed to a subject – a sentence only. The structure of meaning – the triangulation – has thus fundamentally shifted8. A dysfunction of the propositional function of language therefore is not restricted to FTD and AVHs but concerns delusions as well, with one difference: in severe thought disorder, the referential function of language is impaired at all levels; in delusions, the propositional capacity is sufficiently intact to nail down at least one referent – the Mafia, or Jesus – but it then derails at the grammatical level, where no propositional contents relating to the world are obtained. We do not think we learn anything about the world from such delusional statements, which do not trigger any criminal or religious investigation. Unlike all normal assertions, we take them to inform us about the  thought of the speaker unlike FTD, cannot be studied objectively and ‘directly.’ But the disorder that delusions represent is exactly as overt and objective as that of FTD: delusions are linguistically articulated thoughts, even if not pronounced, and pronounced they typically are. They are not known (and could not be known) to be held in some ‘private’ mental space, while never appearing in overt language. The essential difference between FTD and delusions is that in the latter case, contents can still be identified but are judged to not possibly be true, while in the former no contents may even be discernible. Either way, the problems concern meaning generated at a grammatical level.Against this account, see in the sentences expressing them. We would therefore have to stipulate the existence of exact non-linguistic ‘mental’ equivalents of these constituents and relations at the level of ‘non-linguistic thought’. But this extra step seems to reap no explanatory benefits and the same problem now arises: why are the mental equivalents of ‘I’ and ‘Jesus’ combined in such ‘non-linguistic thought’ as subject and predicate in a fashion that a proposition arises that cannot be true, yet is taken as true with quasi-perceptual force?grammatically of the wrong types9. Instead, typical examples of delusions involve the grammatical 1st Person combined with a 3rd person predicate, in a non-embedded sentence, often copular, typically in the present tense or with an atemporal meaning. If changing the grammar entails changing the status of a sentence as a delusion, grammar is essential to its status of a delusion, and propositional delusions have a linguistic identity not contingently, but necessarily.As in AVHs or FTD, the linguistic elements involved in delusional statements are again specific. Thus ‘Napoleon is Hitler’ is not a likely delusional statement that a clinician would expect to find; nor are ‘The Mafia is trying to kill Obama,’ ‘German towns are beautiful,’ ‘I will be Jesus,’ or ‘I think I am Jesus.’ These are fixes his 1st Person identity via a 3rd Person description, which is impossible in mental health, where no such description ever accounts for our 1st Person identity as selves: any descriptive properties we have (‘I am X’), we can in principle also lose (‘I found out that I was switched as a newborn and baptized a Y’). For the patient with schizophrenia, not being Jesus would be for him not to exist. When ‘I am Jesus’ expresses a delusion, therefore, the sentence is not used with its normal meaning: language changes. Again there is a Person shift involved.In the mouth of a normal speaker, moreover, the statement ‘I am Jesus’ means something different: it could be a joke or metaphor, or it could mean that the speaker is the Jesus figure in a play. The schizophrenia patient says none of these things, but rather is the prime function of language. Even referential gestures such as declarative pointing are closely correlated with language in human development  can be used to code for it. As argued in the un-Cartesian framework, reference elopment . In the thought control, too, involve confusions in the function of the system of grammatical Person. All thoughts generated have to be deictically anchored in one of the three grammatical persons: they are mine, yours, or a third party’s; or else they are viewed simply as facts . When this species-specific deictic frame is disturbed, we predict the Schneiderian first rank symptoms that DSM-5 subsumes under delusions, in line with Delusions of why should it do? What is it about language that makes it an essential neurocognitive variable involved? Can linguistics illuminate psychopathology apart from providing formal tools for analyzing anomalies in language production and perception that we see? We answer that a theory of psychosis qua ‘reality distortion’ requires specification of a principle – some unified system – from which a sense of ‘reality’ in human cognition derives. Such a sense – the basis of science and rationality – is in part human-specific. It does not come from perception, nor from logic alone, assuming that the latter already presupposes possession of a notion of truth, which in its human-specific form is arguably language-dependent . The unity of the person or self, moreover, which grammatical notion, defined through its contrast with the grammatical 2nd and 3rd Person. Explications of what selfhood or ‘first Person subjectivity’ are, standardly invoke reference to oneself in the grammatical 1st Person, and we know of no account of such self-reference that does not explicitly or implicitly invoke the 1st Person pronoun, a crucial and universal element of linguistic organization. Invocations in phenomenological psychiatry of such terms as ‘Ichstörung’ , yet the objects identified lack the properties ascribed to them (the Mafia does not try to kill me). These various distortions reveal health risks that uniquely arise for a mind endowed with a language capacity. Thought carried out in language is not stimulus-driven , and with every word goes a concept. Yet lexical concepts alone – HOUSE, MAN, GO, MOUSE, DOWN – give us no content (or thought) in the above sense. A principle of combination is needed. But there is no known principle of combination of a kind that can productively generate a potential infinity of thought with the relevant kind of contents, than grammar. Grammar is the system that makes words become nouns and verbs, gives them grammatical roles, turns them into subjects and referential expressions, or else predicates exhibiting generality. From the combination of subjects and predicates in this sense, propositions arise, which are what can be true or false. The function of grammar is thus not to add to our stock of concepts but to make them referential, moving from MAN to ‘the man,’ where the former cannot refer to an individual man but the latter can. Referentiality comes in a number of specific forms, thus we can refer generically or indefinitely to the world , definitely (‘the man entered’), rigidly (‘Tom’), deictically , or personally . Beyond the noun phrase, we obtain forms of reference to states, then events, then propositions, then facts. It is a crucial claim of un-Cartesian linguistics that all of these forms of reference co-vary with specific grammatical configurations .As noted, utterances not merely express thoughts but involve an implicit reference to our own 1st Person. All referential phrases within utterances require Person specifications that are fixed relatively to this 1st Person. Thus ‘he’ in ‘He sleeps’ encodes the 3rd Person Singular, in agreement with the inflection of the verb; its meaning is that the relation of the person referenced, who is the agent of the act of sleeping denoted, to the speech act participants, as and when the act takes place, is non-identity. Both the speech act and its 1st Person subject are thus implicitly referenced in Person distinctionsFigure 2) is that all the positive symptoms above can be characterized as disturbances in this single grammatically determined deictic frame, which predicts symptoms depending on which of its corners is disproportionately affected. If it is not clear who speaks, speech perception can more easily become abnormal as in AVHs. Where the perceptual saliency of these deictically loosened thoughts is not high, the loosening itself is enough to lead to confusing experiences in which one doesn’t know whether the thoughts are mine, yours, or simply truths. Some may appear up for public viewing (thought broadcast), or taken out of the speaker’s mind , who loses 1st Person control over them. In yet other cases, this same 1st Person finds itself thinking thoughts that are experienced as a 3rd Person’s (thought insertion). A ‘self-disturbance’ must be the result: for to understand the notion of self, we need all of the foregoing: concepts including a concept of thought, a capacity for reference, where acts of reference take place in a deictic frame marked by Person distinctions.Specification of Person is a ‘syntactic’ constraint on grammatical well formedness as well as propositionality in language: there is no truth in language without such deictic anchoring. Our proposal  into referential expressions that have content on an occasion of use. Based on this, highly specific testable predictions arise, such as:We have now given a linguistic characterization of the positive symptoms, and we have a linguistic model that derives a propositional and referential capacity and new form of selfhood from language, suggesting that grammar  is the essential principle of organization of human-specific thought. A breakdown of language viewed this way The more grammatically  mediated forms of reference become in language, the more reference will be impaired or anomalous. Splitting the forms of reference mentioned above into two halves, with generic and indefinite forms on one side, and definite, rigid, deictic, and personal ones on the other, the latter should be disproportionately affected. We do not know whether this is true, but note that:(i)sentential level, where alone truth values are encoded.Delusional statements tend to be specific, involving the 1st person pronoun, proper names such as Jesus, Superman, or the Mafia; and by definition, they arise at the (ii)Lexical knowledge as such , by contrast, should be least impaired of all, which coheres with evidence . As note(iii)Problems in encoding definite forms of reference are virtually a re-description of the symptom of ‘poverty of content,’ or ‘empty philosophizing’ used to characterize some forms of thought-disordered speech .(iv)15. As It is often noted that patients with schizophrenia ‘frequently fail to use pronominal reference correctly’ : pronoun(v)16.‘Referential failures’ are highlighted in unimpaired, whereas processes of ‘discourse planning’ are affected, as words and sentences are combined with one another. However, there is no ‘discourse planning’ when there is no capacity to use language in the normal, i.e., the propositional way, with sentences configured that are true or false. A ‘pragmatic’ capacity to communicate in language and to maintain a discourse plan presupposes a grammatical ability to configure propositional information: by definition, pragmatics begins where grammar leaves off. Is this propositional capacity maintained in schizophrenia? Not in any of the positive symptoms, by definition of these symptoms; nor does the problem lie in communication, when the problem instead is that thought is heard, or the content of thought is the problem. If so, discourse is disordered because a propositional capacity is lost, not vice versa. A patient who answers ‘Yes, iron is heavy’ to ‘Are your thoughts wearing heavily on you?’  and negative and disorganization symptoms exist , not processing aspects (production/comprehension) to which standard neuropsychological tests may primarily be sensitive.By the 1980s, neuropsychological deficits in the schizophrenia population were well established, involving both general intellectual impairment  and selems exist , this doms exist . In Dibbper se in this syndrome, a view he saw supported by the putative lack of a comprehension deficit in language. However, a comprehension deficit has by now often been reported , reported . Nonethereported . Howeverreported . Whateveipso facto arises, and no special capacity for representing mental state contents has to be postulated beyond grammar itself, which we need anyhow. A putative non-linguistic ToM module also does not as such entail any propositional capacity, and it fails to yield Person distinctions: ‘mentalizing’ is an unspecific term, and if it is propositional, this does not follow from anything in ToM. Crucially, second-order representations are propositions too: it can clearly be false that Bill believes that John is tall. Such representations are ipso facto part of language, which entails their propositionality for free.In sum, invoking impairments in neurocognitive variables primarily known from neurological patients has met with considerable obstacles in schizophrenia. Correlations of variables with these symptoms have proven difficult; the mechanism of symptom formation is unclear; and core variables like ToM are not likely language-independent. This invites factoring language into the cognitive neuropsychiatry of schizophrenia and to develop more fine-grained clinical tests of grammar-based meaning distinctions to re-assess the connection between language and cognition.Our account makes us expect the finding that neuroimaging the brain of persons with FTD in particular, have identified anomalies in classical language-related areas and circuitry . Sans-Saacross the schizophrenia spectrum show more bilateral and right-lateralized activity during speech processing, verbal fluency, and lexical discrimination tasks (linguistic sound processing is to some extent impaired throughout the disease.Many studies have reported aberrant patterns in fronto-temporal networks across schizophrenia in response to a range of tasks with linguistic demands . In addion tasks . Angrillbe a key neurocognitive variable to be targeted in understanding symptom formation, therapeutic intervention, and cognitive remediation.A linguistic model of positive symptoms may cast fresh light on their pathogenesis and underlying neuropsychology. ‘Thought’ is not a standard neurocognitive variable. This makes it hard to tackle delusional thought. If thought of the kind we see impaired in positive symptoms is language-mediated inherently, and a disintegration of basic functions of language in the configuration of reference is seen empirically in symptoms, then language could The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In his recent perspective in the New England Journal of Medicine, the head of the United States (US) Centers for Disease Control and Prevention (CDC), Thomas Frieden, and colleagues, were concerned that the arrival of the Ebola virus (EVD) in Lagos, Nigeria heralded a concerning escalation of the epidemic in West Africa . By 24th. Furthermore, they developed a robust and coherent Social Mobilization strategy that included multiple response teams spanning across several cities [The subsequent successful containment of the virus in Nigeria led to a flurry of declarations in the media that much could be learned from Nigeria’s approach -6. What l cities . These tl cities -9. Suspel cities . Finallyl cities ,7, stronl cities , but alsl cities , Short Ml cities , and tral cities ,6,9. To Pleasing, though it is, to see successful experiences from an emerging economy given broad exposure, we believe that to fully embrace the potential learning two important issues ought to be addressed.First, we must not assume automatically that the key features of the Nigerian response do not apply to more ‘advanced’ health systems like that of the US. Although the US boasts some of the world’s leading class hospitals, the healthcare delivery system here is also somewhat fragmented, with a primary care infrastructure that can be significantly strenthened . This muSecond, it should not take an epidemic of unprecedented proportion, such as this Ebola crisis, to acknowledge that learning can run from the so-called “Global South” to the “Global North”. So deeply entrenched are the expectations that technical expertise flows only one way, that our mental blinders do not allow us to contemplate anything else in reverse. Sadly, this mental model has marked the global health dialogue on the subject of Ebola. The World Health Organization, the CDC, Médecins Sans Frontières (MSF), and UNICEF, all worked alongside the Nigerian government during the Ebola outbreak ,9. What Since the outbreak began, there have been 24,247 reported Ebola cases and 9,961 reported deaths in nine countries  (WHO). NClearly, not enough has been done to support well-functioning health systems in many African countries, but the US too is no exception to this rule. As each of the three high-transmission countries now moves forward on the immediate priority of getting to zero cases, a simultaneous emphasis is being placed on early recovery with a specific attention on the re-activation of essential health services. Multiple priorities emerge – immunization, malaria control, integrated management of childhood illness, maternal health to name a few. The challenge is to integrate these priority interventions within a comprehensive, people centred approach to re-designing service delivery with people and not diseases. Further, efforts to strengthen preparedness for future outbreaks needs to be integrated with the delivery of services using a “one health system” approach. Might there also be lessons that emerge from this upcoming effort here for the world? We believe that harvesting insights from these experiences will be important for the global pool of knowledge, for all countries.Rare, novel infections like Ebola will continue to test our ability to respond to diseases. When the current crisis dies down, we might realise that strengthening health systems is actually a good plan for any disease or outbreak, not just for Ebola. At the same time we might also recognize that the fluid and rapidly evolving health systems in African countries may hold multiple ‘golden nuggets’ that can be utilized to strengthen systems in the US and elsewhere in the world. This requires a greater appreciation that examples of best practice can come from anywhere and flow anywhere, including from the “global south” to the “global north”.


Illicit drug use, and the associated health problems, is a frequent issue encountered by medical providers. Because of its salience as a piece of health care information, drug use history is often included in patient charts and presentations by house staff and medical students. However, if used and recorded inappropriately, drug use history can have significant long-lasting effects on the perception of patients in a system where they have little agency. It was my first day on my Obstetrics rotation, and I was flustered, running late and feeling damp from the blistering Fresno heat. I stepped through the hospital doors and wandered down a hallway replete with moans, yells and whimpers. I found the physician rounding room and glimpsed a white board divided into a grid, one line for each patient, rife with acronyms too arcane to decipher.The chief resident saw me agape and assigned me my first patient, Ms. Lisa ValleThe next morning I steeled myself for my first meeting with such a methamphetamine user. After reviewing Ms. Valle’s chart, I knocked, entered her room, and was taken aback. Here was a startlingly healthy woman. She had all of her teeth. She wasn’t emaciated. Disarmed, I stumbled through my questions—questions I’d prepared for a more hostile recipient. Lisa answered my questions calmly and asked important and pertinent questions about her baby’s health. As I went over her baby’s prognosis and the likely length of her hospital stay (not cheerful answers on either account) her demeanour paradoxically brightened a bit. She promised to think of more questions for me.I learned more about her over the following week, including her ‘substance abuse history.’ She’d tried meth once years ago, a poor decision borne from late-night alcohol-fuelled peer pressure. When I first started my presentations in front of the entire team, I emulated my resident, pronouncing my patient’s drug history in my opening line. But eventually her methamphetamine use sank down through my presentation, until finally I didn’t mention it at all. It was a remote history written on the board, and even this seemed unjust.Lisa’s drug history was a profound piece of health information for me. It was a perplexing thing; the word ‘methamphetamine’ scared me, but also set my mind whirring. If methamphetamines directly caused her condition, my cognitive response to her drug history could have been vital. But the relevance of remote, one-time drug use was more murky. The billboard’s emaciated, toothless spectre arose with little benefit to Lisa’s care.After 2 weeks, Lisa’s condition had not changed. Each morning, at the end of her case discussion, a small pause ensued, as if to insulate such a hopeless patient from those more hopeful ones who came after. It was devastating to watch; my first ward as a someday doctor relegated to the corners of medicine, where treatment has yet to catch up with diagnosis.Over the next few weeks, I visited Lisa frequently, watching her grow increasingly tired. One Wednesday, she was particularly alight, and when I asked after her good mood, she said she’d felt her baby moving. But when I asked the team about this hopeful turn, they were sceptical: the ultrasounds hadn’t shown any movement at all.One morning, a classmate who had been on call the night before told me that Lisa’s temperature had risen and her blood pressure had dropped. Her baby had died and she had quickly turned septic. Her 25 weeks of pregnancy culminated in an emergent C-section. In the end, her baby had been doomed for weeks, a victim not of methamphetamine but a prematurely ruptured amniotic sac. As physicians pulled her baby from her, they saw the child had only a single, sad eye placed squarely in the centre of its head.In clinic weeks later, I heard a voice call my name from across the hall. I looked up and saw Lisa standing on a scale with a medical assistant. I walked over, and she spoke animatedly about her time since leaving the hospital, with that same indefatigable cheerfulness I had encountered when we first met. She asked if I had heard what had happened to her child, and I said yes. I accompanied her into her appointment, and listened as the resident went through some compulsory questions and an examination. Her drug history came up once, the resident dutifully asking whether she was still using meth. A cloud passed over Lisa’s face. I realized sadly that she wasn’t privy to the prominent inclusion of her drug history in her daily presentations and discharge summary. Her sunny disposition faltered slightly on a confusion: is this what she was to people now?In a medical system where patients have little agency, Lisa’s story highlights the power that health care providers wield. Lisa was no methamphetamine addict; her one-time drug use was tangential to her medical care. Yet, weeks later, ensconced in the medical record, this history haunted her care. In each medical appointment now, Lisa would explain to a new provider that methamphetamine addiction, for all its horrors, was not her burden to bear. Lisa’s story should remind us that we are patients’ stewards in an opaque system, and our behaviour, even at its most automatic and seemingly inconsequential, can profoundly affect their health care for years to come.The views expressed in this essay are the author’s own and do not reflect the views of any educational body.None.The authors declare no conflict of interest.


Trauma memories – like all memories – are malleable and prone to distortion. Indeed, there is growing evidence – from both field and lab-based studies – to suggest that the memory distortion follows a particular pattern. People tend to remember more trauma than they experienced, and those who do, tend to exhibit more of the “re-experiencing” symptoms associated with post-traumatic stress disorder (PTSD). Our own research suggests that the likely mechanism underlying that distortion is a failure in people’s source monitoring. After a traumatic experience, intentional remembering  and unintentional remembering  can introduce new details that, over time, assimilate into a person’s memory for the event. We believe that understanding the role these factors play in distorting people’s memories for traumatic experiences is both theoretically and practically important, particularly given their potential role in influencing people’s recovery.after a traumatic event – both intentionally, for example, via conversation with others, and unintentionally, for example, via intrusive imagery – with what really occurred during the event. Put another way, we suspect the mechanism underlying memory amplification is a failure in people’s source monitoring that ultimately results in memory distortion ].stortion , 4. In tstortion , 4], theFirst, let us briefly outline the tenets of the SMF , 4. Put For example, traumatic events are highly likely to be rehearsed extensively in an intentional manner: victims will often make a statement to police, be exposed to media footage, and engage in conversations with other friends, family, doctors, or therapists . Each remore susceptible to memory distortion than benign events because they typically provide more avenues for mental imagery, which can make source monitoring more difficult, and thus source monitoring errors more likely to occur  or a sustained stressful experience that might involve multiple trauma types (such as military deployment). One line of research examines the impact of an external source of suggestion, such as suggestive questioning, on peoples’ memories for surprising, traumatic, and public events e.g., , 10–17].–17.10–17to occur , 4.A second line of research with real victims of personal trauma examines how they remember their traumatic experience over time. These studies demonstrate that such victims often come to report being exposed to traumatic events they did not initially report experiencing , 18–25. cruxes  – which were also rated as the most traumatic scenes – and non-cruxes . We found that participants were very good at recognizing what they had and had not seen. However, they also falsely claimed to have seen 26% of the missing clips, or an additional 13.5 s of the event. Moreover, participants were more likely to falsely remember seeing the cruxes, the more traumatic scenes, compared to the non-cruxes.Our research provides a third line of evidence for the existence of traumatic memory distortion and the role mental imagery plays in that distortion. In our research, we have systematically examined the influence of source monitoring errors using a laboratory-based trauma analog. In one study, we showed participants a series of film clips depicting a fatal car accident . Each clDrawing on the SMF, we proposed that there are at least two, possibly related, routes to the pattern of memory distortion we observed, both of which rely on mental imagery , 4. FirsTherefore, in a subsequent study, using the same film, we first drew attention to the gaps at encoding and then attempted to induce different approaches to source monitoring . SpecifiHowever, we included two further conditions – where participants also saw visual static highlighting the missing scenes – to test the impact of different source monitoring strategies. First, we warned some participants before encoding that we had removed some scenes. The purpose of this warning was to encourage a more systematic source monitoring approach – a slower, more deliberate and controlled, style – when these participants came to evaluate what they had and had not seen at test. Indeed, basic memory research demonstrates the effectiveness of similar advanced warnings e.g., , 28]. Ou. Ou28)].Of course, there are significant methodological limitations to keep in mind when evaluating all laboratory-based research on traumatic memory. Although laboratory research can provide critical insights as a result of tightly controlled experimental designs, it is frequently a poor analog for an event that meets the criteria described in the Diagnostic and Statistical Manual of Mental Disorder’s (5th Ed.) Criterion A . For exaNevertheless, we believe that developing a better understanding of source monitoring errors and the role of mental imagery in traumatic memory distortion should be a research priority. How people exposed to trauma remember and misremember aspects of their experiences in ways that influence their recovery is both theoretically and practically important. For example, the touted correlation between the likelihood a person will develop PTSD and the severity of their experienced trauma is largely based on observed correlations between self-reported current symptoms and retrospective reports about the severity of the trauma e.g., , 19]. Th. Th19)].The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


While the strict definition of supramolecular chemistry is “chemistry beyond the molecule”, meaning having a focus on non-covalent interactions, the field is primarily associated with the creation of synthetic receptors and self-assembly. For synthetic ease, the receptors and assemblies routinely possess a high degree of symmetry, which lends them an aspect of aesthetic beauty. Pictures of electron orbitals similarly can be seen as akin to works of art. This similarity was an early draw for me to the fields of supramolecular chemistry and molecular orbital theory, because I grew up in a household filled with art. In addition to art, my childhood was filled with repairing and constructing mechanical entities, such as internal combustion motors, where many components work together to achieve a function. Analogously, the field of supramolecular chemistry creates systems of high complexity that achieve functions or perform tasks. Therefore, in retrospect a career in supramolecular chemistry appears to be simply an extension of childhood hobbies involving art and auto-mechanics. The field of supramolecular chemistry abounds with beautiful and aesthetically pleasing molecules. From Stoddart’s rotaxanes –2, SauvaBesides having an aspect of beauty, supramolecular structures are created to achieve a chemical function or task. These functions range from imparting mechanical changes –13, to aMy father, Samuel Anslyn Jr., was an industrial artist. In World War II and later he worked as an artist rendering exquisitely detailed charcoal sketches, and airbrush mock-ups of airplane and ram-jet parts. Before becoming an art and drafting teacher at a Glendale Community College, he was the art director at Marquardt Corporation . My housGrowing up in a household with a father that was both an artist and a mechanic, it became natural to build plastic and balsawood models as a hobby and to work on motorized vehicles. My neighbor from age 7, Brian Heidsiek, became an industrial designer himself. As children we raced and worked on go-karts. We also created numerous models from scratch, culminating in what were known as a series of “destructos”, i.e., vehicles that were indestructible and saved the world from disasters , inspireThus, after 40 years of hindsight – considering my childhood with an artist/mechanic for a father, and a best friend with whom I built functional models, it is not surprising that my career has focused on the creation of new molecular and supramolecular structures designed to execute a particular function or achieve a certain task. Further, while we all know “beauty is in the eye of the beholder”, many of our group’s chemical structures are exquisite, at least in my own somewhat biased opinion. In fact, even after 27 years as a Professor, I experience a thrill when we get a crystal structure because they invoke an aesthetic response . The comAll organic chemists, and in particular supramolecular chemists, must share an enjoyment in creating new chemical entities of our own inspiration. My passion for organic and organometallic synthesis was first developed when performing undergraduate research at the California State University Northridge (CSUN) under the tutelage of Dr. Edward Rosenberg. At this undergraduate institution my major was pre-med, with all the associated drive and motivation to do well, accompanied with the annoying behavior of such students. For example, my major was chemistry solely because a larger fraction of B.S. chemistry majors were accepted to medical school than other majors. I had never taken a chemistry class in high school, yet it was my declared major. Further, because the counselors advised that undergraduate research was a good exercise to build a curriculum vitae for entrance into medical school, research was one of my pursuits from freshman year throughout my undergraduate career. The project entailed the use of variable-temperature NMR to measure the dynamics of ligand migration in trimetallic osmium clusters –23. Dr. To me, mechanistic puzzles are similar to deciphering how to fix an internal combustion engine; both involving diagnosis of the problem within a large “black box” and fixing it with tools appropriate for the job: valve spring compressors, feeler gauges, socket wrenches, etc. As organic chemists, we propose hypotheses explaining how Mother Nature works, and we have particular experimental tools to test our theories: kinetics, isotope effects, solvent effects, etc. .Reactions with multiple components all working in concert to achieve a function beyond that of the individual parts (known recently as “emergent properties” –26) is lAs described below, the field of differential sensing, in which our group works extensively, takes the responses from a suite of receptors and creates patterns for diagnostic purposes that are beyond what can be achieved by the separate components alone. In fact, we are currently working to push this even further creating multicomponent cascades of reactions yielding a final result that the individual reactions themselves cannot achieve. With the hindsight described in this article, it is clear that my inspiration to pursue such research is driven by similar hobbies from my childhood.From my first introductory organic chemistry class I have had a fascination with electron orbitals. The artistic similarity and aesthetic reaction to molecular orbital theory is obvious. Even if beauty is in the eye of the beholder – can anyone really question that HOMOs and LUMOs  are beauAfter receiving a B.S. in chemistry from CSUN, medical school at the University of Southern California (USC) was the next destination. But, this lasted only about two weeks. In the evenings, my inorganic and organic chemistry textbooks –29 were After a one-year break from schooling, Caltech was my destination, where Dr. Robert Grubbs accepted me into his group. This was one of the most important and impactful decisions of my life. Dr. Grubbs was another inspirational individual with a love of science that permeated through his group. He has an innate instinct of when chemistry will and will not work. Part of my Ph.D. thesis was computational under the direction of Dr. William Goddard, involving molecular orbital theory and the rendering of orbitals. Both Professors taught me various aspects of the art of physical organic chemistry. In addition, Dr. Dennis Dougherty welcomed me to his group meetings, where various topics of supramolecular chemistry were common. Little did either of us suspect we’d co-author a physical organic textbook together about 15 years later .Using the combined experience from Grubbs, Goddard, and Dougherty, physical organic chemistry as applied to biological problems was a main interest, which became the topic of my post-doctoral work with Dr. Ronald Breslow at Columbia University. Breslow has the quickest mind of anyone I’ve ever met and his enthusiasm for his group’s work knows no bounds. When he would enter a laboratory to hear the latest news, it was an explosion of energy. He wanted to hear about everything, even the latest TLC conditions. The atmosphere of his group inspires all members to go as far as possible in academia.1) [2) [3)  –35 and Z1) [2) –38. My o [2) [3) .4) that exploited hydrogen bonding based recognition in chloroform [5) [6) [3) shows how far this field progressed. The use of boronic acids of Shinkai/James (7) [8) [From 1989–1993 achieving tenure was a major goal, and I believed pursuing novel biologically relevant targets using supramolecular chemistry would make a unique and new contribution. Thus, our group created some of the earliest reported monosaccharide receptors (loroform –40. The form [5)  and Thum [5) [6)  at arounames (7) –45 and t (7) [8)  for bindThe synthetic receptors we created were designed to answer basic science questions about enzyme mechanisms ,47, rateAfter achieving tenure, it is natural to reflect “Whew, what now?” In answering such questions, one dominant thought continued to recur – the most influential people on my perception and knowledge of chemistry were Grubbs, Breslow, Rosenberg, Lowry and Richardson, as well as Morrison and Boyd. These later two set of individuals were the authors of my graduate  and undeMuch of our group’s work prior to tenure was addressing mechanistic aspects on the timing of proton transfers in hydrolysis reactions ,54–56. W9 as an RNA hydrolysis catalyst. Structure 10 was building up in a vial as a byproduct of synthesizing 9, and we had no idea what to do with it. That was until one day sitting at my desk drinking a Fresca soda and reading the ingredients, the first of which was sodium citrate, the light bulb went off - Bingo! Compound 10 should definitely bind citrate quite strongly, even in a highly competitive media, due to the fact that all the hydrogen bonding will be strengthened from the additional ion-pairing (10). This hypothesis proved to be correct [10 as an optical sensor for citrate. But, we needed a signaling protocol, and neither 10 nor citrate possess a chromophore. The usual approach would have been to covalently attach a chromophore to the receptor, but we wanted a more general approach, one that would not require additional synthesis. Upon remembering that the Breslow group would follow the displacement of fluorophores bound in the cavity of cyclodextrins to measure Keq values, our idea was to instead exploit the displacement as the sensing modality. Thus, the idea of an indicator-displacement assay (IDA) was born [Several events moved our group’s research toward sensing applications. One was having a synthesis to create  correct . Hence, was born –59. As wwas born –61. IDAswas born .11) [11). In other studies, using a lock and key design approach led to very selective and high affinity receptors for heparin [Our group optimized the citrate receptor design by incorporating a single boronic acid (11)  and meas11) , vodkas 11) , and mos11) . The opt11)  to prese heparin –69 and 2 heparin .Although reading the label of a Fresca soda indeed sparked the idea of pursuing a citrate sensor, the idea of working on sensing had been percolating in my mind for a while. A. P. De Silva was pioneering the use of PET (photoinduced electron transfer) signaling , Seiji Sth century. My ex-colleague, Dr. John McDevitt (now at NYU) told me over lunch about devices known as “electronic noses” [Whereas selectivity has been a goal for many studies using synthetic receptors, in part because Clark Still once noted that synthetic receptors could be as selective as antibodies , a chancc noses” –76, whicc noses” . Our devc noses” –79 and Kc noses” –81, who The field of electronic noses and tongues has a biomimetic origin. Having worked with Breslow as a post-doctoral fellow, who coined the word biomimetic , the ideWe did not have an immediate epiphany that the supramolecular community could have a large impact in this field, but instead this realization came gradually, as studies from the group led to the conclusion that a lack of selectivity could be powerful. Furthermore, it was a reviewer of one of my early grants in this area that made me realize what I had not already recognized; we were, and still are, “making lemonade out of lemons”. In essence, we were taking advantage of the fact that synthetic receptors lack a high level of selectivity.11) would indiscriminately bind tannic acids, which are species that leach from oak barrels as the whisky ages. Using this one receptor to signal all tannic acids, we could create an IDA that correlated with the age of the whisky. In a second similar study, we took advantage of our early fledgling interest in chemometrics (see more below), and showed how an artificial neural network (ANN) could be used to analyze mixtures of cross-reactive receptors with indicators to accurately quantitate concentrations of the very similar analytes malate and tartrate [One of the earliest studies from our group that revealed how a lack of selectivity could be useful involved the age of scotch whisky . We fountartrate . Subsequtartrate –87, as wtartrate .To distinguish the idea of using selective receptors from that of using cross-reactive arrays we coined the term “differential sensing” . The ide12, 13, and 14, respectively (Among the earliest work from our group using the electronic tongue and chemometrics were methods to differentiate ATP, GTP and AMP , phosphoectively . Such acIn the beginning, the supramolecular chemistry community was not receptive to this kind of work. Quite well known chemists, and close friends, had comments such as “you’re going to put us all out of business”, “this is not science”, or “you’ve lost your way”.The electronic tongue created with McDevitt possessed beads placed in micromachined divots on a silicon chip , and solIn our own laboratories the most recent uses of differential sensing have focused upon trying to push the limits of the technique. Three studies were driven by attempting to see how far the idea of using cross-reactive arrays could be pushed for solution-based analysis of complex, and/or subtly different, analytes. Probably the most well-known set of studies from our group are on wines. As with our earlier work, the approach uses a suite of combinatorial peptides as differential receptors. The peptides are biased with a large fraction of the amino acid histidine, are metallated with Cu, Ni, and Zn, and bind indicators to create a series of IDAs that can classify wine varietals, hang time, correlate with the human taste response of astringency , and ideAs has Rotello, we are taking our differential sensing work to the biological arena. Kinases are enzymes that are involved in cellular signaling and regulation. Monitoring their activity has commonly involved the creation of highly selective peptides that respond to only one kinase –109. ThiAmong the most challenging guests that we could envision for supramolecular chemistry to tackle are glycerides. Glycerides often differ only by numbers of methylene groups, positions of double bonds, and stereochemistry of the olefins. It seems impossibly difficult to create a synthetic receptor that could bind selectively trielaidin over trielroselaidin (differing only by double bond position in each fatty acid chain, Where should the field of supramolecular analytical chemistry be moving, and therefore what inspirations are there for our group? Undoubtedly, because it is my first love, my group will continue to study mechanisms of organic reactions, molecular recognition, and photophysical techniques. In each study, we’ll be driven to create imaginative new approaches and complex physical entities of beauty that perform functions and tasks. As discussed above, we’ll continue to create differential sensing arrays for new, ever-expanding applications. However, after the analysis of glycerides, we feel there is no longer a need to see how challenging a class of analytes can be tackled. Instead, it is now necessary to make the methods truly practical for real-life applications.But, far more important than my own group’s work, to survive and thrive, supramolecular analytical chemistry must create results that are widely recognized by the chemical community. Our field has to have broad impact, not only advancing the basic science of molecular recognition and chemical reactivity, but also using this information to influence how other scientists perform their own studies. In this regard, differential sensing must find a “Grand Challenge” that it, and only it, can solve. The first artificial nose companies, Aromascan and Cyrano, have fallen by the wayside, primarily for lack of a real market application. It is true that solution-based differential sensing is likewise struggling for a solid foothold in the economy. In contrast, imaging agents are clearly a frontier. These are the kinds of sensors that Tony Czarnik originally envisioned , and comThe directions that Vincent Rotello is taking the field of differential sensing, toward that of biological applications, is one clear future. We are similarly moving to biological applications with kinase and lipid analysis, and cellular classification. But, even beverage analysis, complex mixture authentication, and drug metabolism, are still important areas for differential sensing applications.In addition, the work of Scott Phillips –113 and In summary, it is clear after a 27-year career in supramolecular chemistry that my group’s work is just a continuation of my childhood. This childhood was driven to emulate my father and have fun with my neighbor Brian. Just as I did during these formative years, my current group strives to make complex systems, with numerous moving parts, to achieve a function. This is similar to creating and fixing internal combustion motors on cars and go-karts, as well as designing and constructing from scratch balsa wood models. My current weekend hobbies are not any different, leading my wife to often observe “you’re replicating your childhood“. Further, while not necessarily designed to be objects of art, the compounds our group creates, and those that the field of supramolecular chemistry generally creates, are indeed beautiful. Even molecular orbital theory creates objects of worthy of artistic notice. This is what initially drew me to the field, and the aesthetic feelings evoked to the complexity of chemical assemblies are still my driving force for the creation of imaginative and novel systems chemistry.If there is a lesson here, it is that one should take advantage of their strengths. Our hobbies as children, and as adults, don’t necessarily need to be significantly different than our careers. They can meld together, and thus work and recreation become one and the same.


Many scientific questions are best approached by sharing data—collected by different groups or across large collaborative networks—into a combined analysis. Unfortunately, some of the most interesting and powerful datasets—like health records, genetic data, and drug discovery data—cannot be freely shared because they contain sensitive information. In many situations, knowing if private datasets overlap determines if it is worthwhile to navigate the institutional, ethical, and legal barriers that govern access to sensitive, private data. We report the first method of publicly measuring the overlap between private datasets that is secure under a malicious model without relying on private protocols or message passing. This method uses a publicly shareable summary of a dataset’s contents, its cryptoset, to estimate its overlap with other datasets. Cryptosets approach “information-theoretic” security, the strongest type of security possible in cryptography, which is not even crackable with infinite computing power. We empirically and theoretically assess both the accuracy of these estimates and the security of the approach, demonstrating that cryptosets are informative, with a stable accuracy, and secure. On one hand, data is powerful and sharing it lets us answer big questions that are unapproachable by other means. On the other hand, there is real danger in sharing it publicly or indiscriminately, so there are institutional barriers governing access to useful data.Integrating and analyzing large amounts of data is proving to be a powerful method for exploring and understanding everything around us . In an ilink entities between repositories , we want there to be a high overlap. When trying to extend data by aggregating entities between several repositories , we want there to be a low overlap. But how can we know the overlap between private datasets before sharing them?Often, especially when human subjects are involved, the value of sharing data depends on the overlap between private datasets. The amount of overlap determines if there is reason to work through institutional, legal, or ethical barriers governing access to private data. Herein lies the problem; we often need to know the overlap between datasets to justify sharing. When trying to Measuring the overlap, the intersection, between private datasets is a well-defined problem in cryptography . SeveralFirst, there are methods that share public IDs for each item in the dataset that retain a one-to-one (or nearly one-to-one) relationship to private IDs that need to be kept secret –6. TheseSecond, there are methods that compute the exact overlap between private datasets without relying on shared public IDs , 10–21. Third, there are methods that rely on a randomized data structure, a Bloom filter, to inexactly estimate the overlap between sets –28. ThesHere, we propose a new solution to the private set intersection problem . Our appinformative about private datasets, enabling computation of their overlap. A noisy estimate of overlap is informative if it is accurate enough to inform good decisions about data sharing. Second, this solution’s accuracy would be stable, estimating accuracy at the same resolution for both small and large datasets with a tunable accuracy. Third, the solution would be secure, making it impossible to determine the membership of a specific entity in a private dataset. Critically, security dictates that overlap estimates cannot be exact, but must be intrinsically noisy. Finally, the solution would be public—neither relying on secret passwords, private hash functions, nor back-and-forth message passing—with summaries publishable in public spaces. These criteria immediately rule out all existing approaches and motivate the design of a better algorithm. In contrast, we will see that cryptosets satisfy all four of these properties; they are informative, stable, secure, and public.It is worth considering the properties of an ideal solution. First, the ideal solution would be Here, we develop a statistical framework for cryptosets from which overlap estimates can be computed, as well the confidence intervals, significance, and statistical power of these estimates. This framework makes clear that cryptoset accuracy is stable, and does not reduce as private datasets grow and their cryptosets saturate. Moreover, we prove that as size of private datasets increase, cryptosets approach information-theoretic security, the strongest type of security possible . In contPatient identifiers. We simulated a population of 250,000 patients to use in simulation studies. A name and a birthday were drawn a random according to the distribution of names and birthdays in US census data  that maps strings uniformly to an integer space of public IDs ranging from 0 to L−1, where L is called the “length” of the cryptoset. L is typically chosen between 500 to 10000, but could be any positive integer. The smaller the length, the more secure the data-structure. The larger the length, the more accurate the overlap estimates.A cryptographic hash function From this definition, the cryptoset is computed from a private dataset with the following algorithm. First, compute the regularized, private identifiers for all items in the set. Second, initialize an array 𝒜 of zeros of length L. Third, for each identifier s, compute its hash i = H(s) to use the public ID for this item. Finally, increment item Ai of 𝒜. The resulting histogram of IDs is the cryptoset which we denoted with a calligraphic letter Estimating overlap with cryptosets. Consider two private datasets, from which cryptosets, 𝒜 and ℬ, of length L, with A = ∑Ai and B = ∑Bi members each are constructed using the same protocol, where i ranges from 0 to L−1 and the subscripted letters are the number of private IDs for each public ID i. We assume that the hash function maps private IDs to public IDs in a manner indistinguishable from a uniform, random process, so the expected counts for elements in each cryptoset are A/L and B/L, respectively. Now, there are three types of counts for every item of the datasets. First, there are counts derived from items only in the first dataset, or A′ counts. Second, there are counts derived from items only in the first dataset, or B′ counts. Third, there are counts derived from items in both datasets, or A∩B counts.A′ and A∩B associated variable. Elements of ℬ are modeled as the sum of a B′ and A∩B associated variable. All three variables are characterized by separate Poisson distributions, with rates A′/L, B′/L and A∩B/L. Therefore, each cryptoset’s elements follow a Poisson distribution with rates, respectively, (A′+A∩B)/L and (B′+A∩B)/L. Consequently, the variances of the cryptosets’ elements areL approximates the number of common items. In other words,ϵ is an error term that has zero mean and non-zero variance. Recognizing that the covariance is the Pearson correlation times A, B] we arrive at the estimate for the “overlap proportion”η is the defined as the ratio between A and BFrom this starting point, we model each element of 𝒜 and ℬ as the sum of two of three independent, random variables. Elements of 𝒜 are modeled as the sum of an Theoretical accuracy of cryptoset overlap estimates. A well-studied statistical framework underlies overlap estimates, because cryptoset comparisons are closely related to the Pearson correlation [ϵ in ϵ is distributed likeL is the length of the cryptoset (the number distinct public IDs possible) and not depend on the magnitude of A or B. Cryptosets compute overlap at a predetermined resolution, no matter how many items are added or removed from them.relation . The keyInformation content of cryptosets. Consider a cryptoset 𝒜 with A items generated with a public protocol. Here, we mathematically analyze the extent to which this cryptoset compromises the privacy of the items it contains. An item’s security is compromised if we can show that it is a member of the private dataset. In the context of patients in a genomic study of a disease, for example, identifying a patient in the cryptoset would give us the private information that this patient has this disease. As we will see, cryptoset are non-informative about the membership of specific items.Ui) with U items. The cryptoset includes all the items from which cryptoset 𝒜 could have drawn items. The size of this cryptoset U is domain specific and much larger than A. For example, we might know that people in a cryptoset are drawn from a specific state, so U would be the population of the state. As a consequence of the statistical properties of the hash function, 𝒰 is expected to be nearly uniform, with an approximately equal number of counts for every public ID.For this analysis, we invoke a “universe” cryptoset 𝒰 =  between the cryptoset 𝒜 and 𝒰 , 39,I that mapsstrings uniformly to an integer space of public IDs ranging from 0 to L−1, where L is called the “length” of the filter. L is highly dependent on the number of items in the dat set, and is typically chosen to be large enough to limit the possibility of the filter becoming saturated.A set of From this definition, the Bloom filter is computed from a private dataset with the following algorithm. First, compute the regularized, private identifiers for all items in the set. Second, initialize an array 𝒜 of zeros of length L. Third, for each identifier s, compute a set of public IDs using all k hashes to use for this item, hi = Hi(s), and set item Ahi of 𝒜 to 1. The resulting bit vector of IDs is the Bloom filter which we denoted with a calligraphic letter This algorithm is very similar to the cryptoset algorithm, but has some key differences. First, Bloom filters use a bit vector instead of a integer vector, only strong a binary flag for each public ID. Second, Bloom filters can use more than one hash function. Third, the optimal length of Bloom filters, unlike cryptosets, depends on the size of the database, and cannot be safely fixed ahead of time.Overlap estimates using Bloom filters. Consider two Bloom filters with an observed number of bits turned on in each filter , a specified number of bits turned on in either fingerprint (a∪b), and using k hash functions. The overlap between the elements represented in the Bloom filters is approximately [a, b, or a∪b equals L. At these singularities, the overlap estimate becomes uncomputable. This condition is met with either filter or the union of the two filter is completely saturated. As dataset size increases, the probability of saturation increases until it becomes a near certainly. So, the chances of an uncomputable overlap increase as dataset size increases.ximately A∩B≈−L/kInformation content of Bloom filters. Consider a Bloom filter with A items, a bits turned on, k hash functions and length L. As with Cryptosets, we can quantify how much information, in bits, a Bloom filter conveys by computing the information gain between the the filter and a fully saturated Bloom filter containing all the items in our universe [universe , 39. AlgIn the following sections we study the accuracy and security of cryptosets for computing overlap between private datasets. These results include both theoretical analysis and empirical studies to demonstrate that cryptosets can securely compute the overlap between private dataset. Finally, we compare Cryptosets to Bloom filters with respect to both accuracy and information gain.A good estimate of the overlap can be computed by measuring the Pearson correlation between elements of a cryptoset, and then multiplying the correlation by the geometric mean of the number of elements in each cryptoset. The derivation of this estimate is in the Methods. It might seem surprising that such a simple formula could yield reasonable estimates of accuracy even as the number of items in a cryptoset grows. Nonetheless, this behavior is exactly what we see in both realistic examples and a large simulation with thousands of overlap estimates.For the first example , we simuFor the second example, we computed the overlap between two chemical libraries . In thisFinally, we systematically studied the overlap estimates across a large range of scenarios. From the patient identifier data, we simulated pairs of private datasets with overlap proportions of 10%, 30%, 50%, and 80%, ranging in size from 10 to 10,000. The correct overlap between each pair was compared to the estimated overlap using cryptosets of length 500, 1000, and 2000 . We see Together, these three assessments demonstrate that cryptosets can estimate overlap between private datasets in realistic scenarios. Moreover, the accuracy of the overlap proportion (the relative error) is independent of dataset size. Finally, the theoretical framework we developed can accurately model the distribution of overlap estimates.The security of cryptosets in public environments relies on an intentional, many-to-one relationship between private and public IDs. Every public ID maps to hundreds or thousands of possible private IDs. Enumerating the private IDs associated with a specific public ID is difficult, and there is no way to tell which ones correspond with those from the private dataset. Cryptosets, in contrast with other effort in this area, do not rely on the secrecy of the public IDs or the hash function and are resistant to this attack. Rather, their security is a consequence of the statistical properties of hash functions.Here, we present an analysis of the security of cryptosets, using information gain as a measure of security risk. Datasets are generated by random sampling, the corresponding cryptosets are constructed for a large range of sample sizes and lengths, and the information gain of these cryptosets is computed . The keyOverlaps between private datasets can be estimated using Bloom filters, but the accuracy of these estimates are unstable with a strong dependence on dataset size . As dataThere is a trade of between estimate error and security risk. As the number of public IDs increase (the length), estimates become more accurate but the data structure shares more information, becoming less secure. Plotting the trade off between error and information gain  is anothBloom filters, therefore, are less stable, less accurate, and less secure than cryptosets. As a practical matter, because of the strong interrelationship between filter length, dataset size, and accuracy, it is not possible to pick a single length by which to represent datasets of very different sizes. This complicates the use of Bloom filters, where cryptosets continue to show strong advantages. For example, cryptoset length can be selected without knowing dataset size, based on choosing desired accuracy for overlap estimates. This single length cryptoset will work the same way for the full range of dataset sizes, from very small to very large. Taken together, this set of issues makes cryptosets preferable in our use cases.We have presented a secure method for computing the overlap between private datasets using cryptosets. Cryptosets appear to be both public and secure, resistant to attack without relying on secret keys or algorithms. At the same time, cryptosets are informative about overlaps between private datasets with a stable, tunable accuracy. Our approach may allow patterns of data sharing that are either impossible or very difficult today. For example, cryptosets of study participants could be published along side genomic studies to enable readers to compute the overlap between, and replication strength of, several studies. A hospital could publish on its website a cryptoset of patients with a rare disease to identify other institutions treating these same patients. A company could publish a cryptoset of its portfolio of compounds to attract collaborators with overlapping lines of research.Cryptosets are very concise, short enough to be pasted into the body of an email. This conciseness is useful. For example, it is seems intuitively clear that sharing a few hundred integers cannot expose the molecule structures in a large chemical library. Similarly, It also seems plausible that data depositions involving patients  could include a cryptoset of study participants to facilitate retrospective meta-analysis.For example, imagine several independent hospitals, outpatient clinics, and pharmacies in the same geographic area. They may want to link some of their medical records together for the purposes of reducing duplicate testing, identifying fraud, detecting drug seeking behavior, or monitoring prescription compliance –46. SharThis sharing-privacy dilemma is not unique to health care delivery; it is evident wherever the risks and benefits of sharing are high, and it is particularly acute in genomic medicine. The desire to share the genomic data of large groups of people is only increasing –50. OnceSimilarily, genomic data is particularly sensitive and important to keep private. First, raw genomic data is essentially impossible to anonymize, especially as sequencing becomes more common . SeveralIn situations like this, where both the benefits and risks of sharing data are high, there will probably always remain distinctions between public and private data. With this distinction comes a need to negotiate institutional barriers to sharing.A key factor that may drive the adoption of this approach is the response of legal departments, institutional review boards, and data repository managers. Cryptosets, with its strong theoretical guarantees, could be treated legally and ethically the same as epidemiological data, like publicly-reported hospital infection rates or monthly number of flu cases. Epidemiological data is review-waived information that can be freely shared because the data does not obvioulsy violate patient privacy. In the same way, cryptosets do not threaten the privacy of individuals. They do enable anyone to compute the overlap between datasets, a very useful function. So it is possible, where this function is important, data repositories could enable and encourage scientists to deposit cryptosets along with their data submissions.For the foreseeable future, the conflict between our desire to share data and our need to protect it will continue. Data sharing is protected by many legal and institutional barriers which can require both time and financial resources to successful navigate. However, sharing private data is increasingly necessary for scientific progress in fields that are dominated by sensitive information. Groups assessing the feasible of integrating their data with other organizations want to be guaranteed that the overlap between their private data sets is large enough to validate their efforts. On the other hand, groups looking to expand their private data stores want to be guaranteed of a low overlap so that they are not spending effort acquiring data that they may already have. Cryptosets are an improvement over existing methods, including Bloom filters, and they may be informative and secure enough to help navigate the legal, institutional and financial barriers to accessing data, and enable collaborations and studies that would not otherwise be possible.