Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality: An Individual-Level Pooled Analysis of 30 Cohort Studies

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance–weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88–0.99), 0.78 (0.70–0.85), and 0.88 (0.79–0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88–1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86–0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention

<i>GRIN2A</i>-related disorders:genotype and functional consequence predict phenotype

Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10-6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/- cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders

Formalizing the minimalist program

The objective of this thesis is to provide a formalization of a minimalist description of a small fragment of Dutch. The fragment that is described is outlined in Section 3.4. Although the Minimalist Program is still in development precise definitions of the theory in its current stage of the development will be of use for linguists working inside and outside the Minimalist Program. As a first attempt to formalization two small implementations in Prolog were made. These implementations are described in Chapter 2. The first implementation, which is outlined in Section 2.1, gives a survey of the two structure-building operations Merge and Move. This implementation reveals that the two structure-building operations the Minimalist Program presupposes actually both consist of more disjunctively specifed sub-cases. The structure-building operation Merge has three sub-cases: tree insertion in the complement position, tree insertion in the specifier position, and lexical insertion in the head position. The structure-building operation Move has two sub-cases: head movement and to-specifier movement. Furthermore a new definition of the Move operation is given. This definition states that the moved element in a Move operation has to be contained in the complement domain of the head of the target tree, not in the target tree as the original denition says. From this new definition we can derive that movement to the complement position is impossible. An element (tree) cannot be moved to a position that contains the tree from which the moved element must originate. The second implementation, which is outlined in Section 2.2, is a head-corner parser for a fragment of the Minimalist Program. I argue that because of the nature of the structure-building operations of the Minimalist Program head-corner parsing is a suitable parsing technique for the Minimalist Program. The idea of head-corners from head-corner parsing resembles closely the idea of target trees from the Minimalist Program, as we see in Subsection 2.2.2. In the Chapters 4 through 9 the actual formalization of the minimalist description of the fragment of Dutch is given. The formalization is written in the formal-specification language AFSL. Afterwards, the entire formalization was validated by implementing it in Prolog. The formalization is declaratively stated, not derivationally as the Minimalist Program itself: it describes which trees are correct according to the Minimalist Program. In Chapter 4 I give a description of trees. By considering minimalist trees as some kind of directed graphs, we can omit indices. The function ConnectionTarget represents connections between nodes. It is used instead of indices to indicate movements within trees. In Chapter 5 minimalist ideas on features are formalized. I argue that the notion ‘feature structure’ be introduced in order to be able to treat the features of a node as a unit, although feature structures are not applied in the Minimalist Program. Furthermore I introduce some new features, among which the features [object], [subject], [compcat] and [speccat]. The first two features are used to refer to the object and the subject features of the verb. Since a verb must agree with both its subject and its object (if it is a transitive verb), we need a way to separate the subject agreement features from the object agreement features of the verb. Furthermore, the verb assigns case to the object. This case feature is also, as the agreement feature, a part of the value of the [object] feature. The features [compcat] and [speccat] are introduced to be able to implement subcategorization. The feature [compcat] indicates the category of the complement of a given head, while the feature [speccat] indicates the category of the specifier of a given head. Subcategorization receives no explicit mention in the Minimalist Program, but it turns out to be vital for the formalization. It is important that there is a way to represent what kind of complement or specifier a given head may select, because otherwise the formalization would for instance allow transitive verbs to behave like intransitive verbs, by not forcing transitive verbs to select both a subject and an object. This is especially essential in Zwart’s version (and Chomsky’s 1995 version) since in this version the derivation is not guided by the features of the lexical heads in a sentence. In Chomsky’s 1993 version all lexical heads need to check all their formal features. Therefore the object features of the verb will require the verb to select an object to check against. Furthermore, subcategorization proved to be essential for the word order of sentences. In Chapter 5 I also give an exact definition of the notion ‘feature checking’. I argue that the features of a lexical constituent can only be checked against the features of a functional constituent if the feature structure belonging to the lexical constituent contains at least as many feature-value pairs as the feature structure belonging to the functional head. In Chapter 6 I describe the way the lexicon is treated in the Minimalist Program. In Zwart’s version of the Minimalist Program there are two lexicons. The first lexicon, which I call the prelexicon, is consulted when a lexical item enters the derivation. The second lexicon, which I call the postlexicon, is consulted after the derivation (at PF) to obtain the phonological features of a lexical item. I argue that the lexicon which is consulted at the beginning of the derivation may not contain underspecified feature structures because of the nature of the feature checking operation. Checking is only possible if a certain feature is present in a given functional head as well as in the lexical constituent that checks its features against it. Hence, we cannot indicate that any possible value for a given feature name can be chosen by not representing it at all (under-specification). X-Theory is described in Chapter 7. In the X-rules that are specified in the formalization only bar-levels play a role, while in the original X-rules of the Minimalist Program category features also play a role (for instance: X ! X, YP (where X and Y represent categories)). In the formalization, feature percolation, including the percolation of the category feature, is taken care of separately. Feature percolation is based on the X-rules, since features percolate up from the head with bar-level zero to higher bar-levels. The positions of specifiers, complements, heads and adjuncts are explicitly defined in the X-module. This module seems to be the right location to represent this type of knowledge since in the literature X-rules often implicitly define notions such as ‘specifier’ and ‘complement’. Furthermore I argue that the two-level X-Theory as applied in Zwart’s version and Chomsky’s 1995 version of the Minimalist Programs is problematic. X-Theory and the theory of movement (or chains in our case) are mutually dependent. In the new version of X-Theory heads do not always need to project, but without projection we cannot maintain the notions ‘complement domain’ and ‘checking domain’. In Chapter 8 I show that it is not problematic to treat head movement in a representational way by considering traces to be copies (contra Rizzi [Riz90] and Brody [Bro95]). Furthermore I argue that a [determiner] feature is needed to distinguish the treatment of pronouns and interrogative words on the one hand from nouns on the other hand with respect to the selection of determiners. The former group requires an ‘empty’ D (i.e. a D with no phonological content), while nouns, except for the plural forms, require a D with lexical content. In Chapter 9 the interfaces (LF and PF) of the Minimalist Program are described. The main result of the formalization of the interfaces is the discovery that an additional lexicon, which contains templates for all types of sentences covered by the formalization, is needed for Zwart’s version of the Minimalist Program. Since LF in Zwart’s framework is reached when all functional heads in a tree checked all their features, I needed something to make sure that an LF-tree always contains the required functional projections. Otherwise an LF-tree consisting of only a VP could be approved of by the formalization. In Chomsky’s 1993 framework, lexical heads needed to check all their features before LF, and to check their features they require functional heads. Suggestions for future research The formalization described in this work shows that a more formal approach to minimalist ideas leads to clearer definitions and sometimes to the discovery of inconsistencies and incompleteness. Therefore I think it can be interesting and useful to develop tools with which linguists, for instance, can compare several solutions to the same problem or can test the result of a change in a definition. The formalization described here could be used as a basis for a parser that could serve as such a tool. Furthermore, research on the comparison of aspects of the Minimalist Program with other linguistic theories might be of interest. The formalization presented here could help with such a comparison. For example, the formalization lead to the conclusion that under-specification in the lexicon is not allowed in the Minimalist Program because of the nature of feature checking, although under-specification is common in feature-based theories such as HPSG.