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Arachidonic acid (AA)-derived lipid mediators play pivotal roles in inflammation and its resolution. While glycolysis is a key metabolic pathway determining macrophage polarization, the crosstalk between specific AA metabolites and glycolytic reprogramming remains poorly understood. In this study, we explore whether certain AA metabolites modulate macrophage function through covalent protein modification, with therapeutic implications for myocardial ischemia-reperfusion injury. Unlike conventional specialized pro-resolving mediators (SPMs) that primarily act via receptors, here we identify an endogenous electrophilic AA metabolite, 15-keto-prostaglandin F2α (15KPF), that covalently modifies pyruvate kinase M2 (PKM2) at Cys49. Such interaction enhanced tetramerization, suppressed the axis, redirected energy metabolism from glycolysis to mitochondrial respiration, and promoted pro-resolving M2 macrophage polarization. Mutated (C49S) failed to inhibit STAT3 signaling and blocked the effect of 15KPF on M1 to M2 phenotype switch. Moreover, 15KPF reduced infarct size and preserved myocardial integrity in model. Taken together, covalent 15-keto-PGF2α- conjugation represents a self-regulatory mechanism linking AA metabolism to glycolysis to drive macrophage metabolic-inflammatory reprogramming. This pathway positions 15KPF as a promising therapeutic candidate for inflammatory and metabolic diseases, including ischemia-reperfusion injury, and distinguishes it from synthetic allosteric PKM2 activators such as TEPP-46.

Developmental and epileptic encephalopathies (DEEs) are rare, infantile-onset conditions of genetic etiology, particularly CHD2 and SYNGAP1 variants. While pediatric phenotypes are well described, there is a lack of understanding regarding adult outcomes, which may lead to misdiagnoses and barriers to treatment. This thesis aimed to characterize the clinical features, communication skills and adaptive behavioural abilities of adult patients (18 years and older). We determined that features such as delayed pain processing, sleep disturbances and autism spectrum disorder are prevalent in adult patients with SYNGAP1 and CHD2 variants. We also found that patients are highly reliant on caregivers, and that various factors such as behavioural issues can affect caregiver impressions. Overall, these findings contribute to a more holistic understanding of the natural history of DEEs, guiding the diagnoses of adult patients and informing considerations for improving the quality of life of both patients and their families.

The emergence and seasonal persistence of pathogenic H7N9 influenza viruses in China have raised concerns about the pandemic potential of this strain, which, if realized, would have a substantial effect on global health and economies. H7N9 viruses are able to bind to human sialic acid receptors and are also able to develop resistance to neuraminidase inhibitors without a loss in fitness. It is not clear whether prior exposure to circulating human influenza viruses or influenza vaccination confers immunity to H7N9 strains. Here, we demonstrate that 3 of 83 H3 HA-reactive monoclonal antibodies generated by individuals that had previously undergone influenza A virus vaccination were able to neutralize H7N9 viruses and protect mice against homologous challenge. The H7N9-neutralizing antibodies bound to the HA stalk domain but exhibited a difference in their breadth of reactivity to different H7 influenza subtypes. Mapping viral escape mutations suggested that these antibodies bind at least two different epitopes on the stalk region. Together, these results indicate that these broadly neutralizing antibodies may contribute to the development of therapies against H7N9 strains and may also be effective against pathogenic H7 strains that emerge in the future.

The emergence and seasonal persistence of pathogenic H7N9 influenza viruses in China have raised concerns about the pandemic potential of this strain, which, if realized, would have a substantial effect on global health and economies. H7N9 viruses are able to bind to human sialic acid receptors and are also able to develop resistance to neuraminidase inhibitors without a loss in fitness. It is not clear whether prior exposure to circulating human influenza viruses or influenza vaccination confers immunity to H7N9 strains. Here, we demonstrate that 3 of 83 H3 HA-reactive monoclonal antibodies generated by individuals that had previously undergone influenza A virus vaccination were able to neutralize H7N9 viruses and protect mice against homologous challenge. The H7N9-neutralizing antibodies bound to the HA stalk domain but exhibited a difference in their breadth of reactivity to different H7 influenza subtypes. Mapping viral escape mutations suggested that these antibodies bind at least two different epitopes on the stalk region. Together, these results indicate that these broadly neutralizing antibodies may contribute to the development of therapies against H7N9 strains and may also be effective against pathogenic H7 strains that emerge in the future.

Modeling is an important tool for understanding AMOC on all timescales. Mechanistic studies of modern AMOC variability have been hampered by a lack of consistency between free-running models and the sensitivity of AMOC to resolution and parameterization. Recent work within the framework of the phase two Coordinated Ocean- Reference Experiments (CORE-II) addresses this issue head on, looking at model differences of AMOC mean state and interannual variability. One consistent feature across the models is that AMOC mean transport is related to mixed layer depths and Labrador Sea salt content, whereas interannual variability is primarily associated with Labrador Sea temperature anomalies. This is consistent with the hypothesized importance of salt balance for AMOC variability on geological timescales. The simulated relationships between AMOC and subsurface temperature anomalies in fully coupled climate models reveal subsurface AMOC fingerprints that could be used to reconstruct historical AMOC variations at low frequency.With the lack of long-term AMOC observations, models of ocean state that assimilate observational data have been explored as a way to reconstruct AMOC, but comparisons between models indicate they are quite variable in their AMOC representations. Karspeck et al. (2015) found that historical reconstructions of AMOC in such models are sensitive to the details of the data assimilation procedure. The ocean data assimilation community continues to address these issues through improved models and methods for estimating and representing error information.Two objectives of paleoclimate modeling are 1) to provide mechanistic information for interpretation of paleoclimate observations, and 2) to test the ability of predictive models to simulate Earth's climate under different background forcing states. In a good example of the first objective, Schmittner and Lund (2015) and Menviel et al. (2014) provided key information about the proxy signals expected under freshwater disturbance of AMOC, which were used to support the paleoclimate observations made by Henry et al. (2016). In an example of the second objective, Muglia and Schmittner (2015) analyzed Third Paleoclimate Modeling Intercomparison Project (PMIP3) models of the Last Glacial Maximum (LGM) and found consistently more intense and deeper AMOC transports relative to preindustrial simulations, counter to the paleoclimate consensus of LGM conditions, indicating that some processes are not well represented in the PMIP3 models. One challenge is to find adequate paleo observations against which to test these models. PMIP is now in phase 4 (part of CMIP6), which includes experiments covering five periods in Earth's history: the last millennium, last glacial maximum, last interglacial, and the mid-Pliocene. Newly compiled paleoclimate datasets from the PAGES2k project, more transient simulations, and participation of isotope enabled models planned for CMIP6PMIP4 will enable richer paleo data-model comparisons in the near future.