Hannah Research Foundation

Large Language Models (LLMs) are commonly criticized for not understanding language. However, many critiques focus on cognitive abilities that, in humans, are distinct from language processing. Here, we instead study a kind of understanding tightly linked to language: inferring who did what to whom (thematic roles) in a sentence. Does the central training objective of LLMs-word prediction-result in sentence representations that capture thematic roles? In two experiments, we characterized sentence representations in four LLMs. In contrast to human similarity judgments, in LLMs the overall representational similarity of sentence pairs reflected syntactic similarity but not whether their agent and patient assignments were identical vs. reversed. Furthermore, we found little evidence that thematic role information was available in any subset of hidden units. However, some attention heads robustly captured thematic roles, independently of syntax. Therefore, LLMs can extract thematic roles but, relative to humans, this information influences their representations more weakly.

Introduction: Direct oral anticoagulants (DOACs) are increasingly used as alternatives to warfarin for secondary prevention in ischemic stroke patients with atrial fibrillation. Despite demonstrated efficacy in clinical trials, there are few real-world experiences of DOACs vs. warfarin in community practice. Methods: We analyzed ischemic stroke survivors with atrial fibrillation discharged from the Get With The Guidelines Stroke hospitals between 2011-2014 and linked to Medicare claims for longitudinal outcomes through 2015. A propensity score overlap weighting method was used to compare DOACs vs. warfarin. The primary outcomes were major adverse cardiovascular events (MACE) and home time, a patient-centered outcome reflecting desire of “being alive at home, without recurrent stroke, or being hospitalized for complications.” Results: Among 11,662 stroke survivors (median age 80), 4,041 (34.7%) were discharged on DOACs (dabigatran, rivaroxaban, or apixaban) and 7,621 on warfarin. Except for NIHSS (median 4 [IQR 1-9] vs. 5 [2-11]), baseline demographics, medical history, and clinical characteristics were similar between two cohorts. Compared with warfarin, patients discharged on DOACs were less likely to experience MACE (33.95% vs. 40.36% per year, adjusted hazard ratio 0.89, 99% CI 0.83-0.96) and had more days at home (mean 287 vs. 263 days during the first year post discharge, adjusted difference 15.6 days, 99% CI 9.0-22.1) ( Table ). Additionally, there were fewer deaths, all-cause readmissions, cardiovascular readmissions, hemorrhagic strokes, and bleeding hospitalizations in DOAC-treated patients, although no significant differences in fatal bleeding, ischemic stroke readmission, systemic embolism, pneumonia, or sepsis (two negative outcome controls) between the two cohorts. Conclusions: In ischemic stroke survivors with atrial fibrillation, DOACs were associated with improved long-term clinical outcomes compared with warfarin.

Neuroinflammation is important in the pathophysiology of neurodegenerative diseases such as Alzheimer’s disease or vascular cognitive impairment but the role of cerebrovascular inflammation in initiating or modulating neuroinflammation is poorly defined. We aim to determine if endothelial cell inflammation, triggered by medin (a common amyloid protein that accumulates in aging vessels and induces NFκB-mediated EC inflammation) or palmitic acid (PA, the most common saturated fatty acid in Western diet) enhances astrocyte inflammatory response using a novel 3D microscale microfluidic vascular brain-organ-on-a-chip (VBOC). Methods: Human astrocytes on 6-well plates were exposed (20 hrs) to vehicle, medin (5 μM) or media from human umbilical vein endothelial cell (ECs) that were treated with vehicle or medin (20 hrs; n=4 each), and proinflammatory cytokine IL-8 protein was measured by ELISA. VBOCs (Fig. B) engineered to mimic physiologic diffusion conditions were fabricated and the central region (green, 500 μm width) was seeded with astrocytes and 2 outer regions (red) seeded either with (+ECs) or without ECs (No ECs). VBOCs were treated (20 hours, n=3 each) with vehicle, medin or PA (150 μM) and IL-8 protein was measured from astrocyte media. Results: See Fig. Astrocytes showed higher IL-8 when exposed to media from ECs treated with medin when compared to direct medin exposure (Fig. A). Astrocyte activation (GFAP staining) was more prominent in astrocytes exposed to medin in presence of ECs and IL-8 was increased only in astrocytes exposed to medin in presence of ECs (Fig. C-D). Conclusions: Medin-induced astrocyte inflammatory activation is enhanced by presence or action of endothelial cells. This initial prototype VBOC is a useful model to study the paracrine cross-talk between vascular and neuroinflammation which could provide mechanistic insights on the interrelationships among vascular aging, cerebrovascular and neurodegenerative diseases.

The major physiological function of milk is the transport of amino acids, carbohydrates, lipids and minerals to mammalian offspring. Caseins, the major milk proteins, are secreted in the form of a micelle consisting of protein and calcium-phosphate.We have analysed the role of the milk protein α-casein by inactivating the corresponding gene in mice. Absence of α-casein protein significantly curtails secretion of other milk proteins and calcium-phosphate, suggesting a role for α-casein in the establishment of casein micelles. In contrast, secretion of albumin, which is not synthesized in the mammary epithelium, into milk is not reduced. The absence of α-casein also significantly inhibits transcription of the other casein genes. α-Casein deficiency severely delays pup growth during lactation and results in a life-long body size reduction compared to control animals, but has only transient effects on physical and behavioural development of the pups. The data support a critical role for α-casein in casein micelle assembly. The results also confirm lactation as a critical window of metabolic programming and suggest milk protein concentration as a decisive factor in determining adult body weight.