Convergence of synaptic pathophysiology in the Hippocampus of Fmr1-/y and Syngap1+/- Mice

The genetic causes of intellectual disability (ID) and autism spectrum disorder (ASD) are frequently associated with mutations in genes that encode synaptic proteins. A recent screen of ID patients has revealed that approximately 4% of individuals carry spontaneous autosomal-dominant de novo mutations in the SYNGAP1 gene. This gene encodes the synaptic GTPase activating protein (SYNGAP) a known regulator of Ras signalling. Investigations into the pathological consequences of Syngap1 haploinsufficiency (Syngap+/−) in mice have reported abnormalities in behaviour, synaptic plasticity and dendritic spine development. These are analogous to findings from the mouse model of fragile X syndrome (FXS; Fmr1-/y), the most common inherited form of ID. One of the prominent phenotypes reported in the mouse model of FXS is that a form of hippocampal long-term depression (LTD) mediated by the activation of Group 1 (Gp1) metabotropic glutamate (mGlu) receptors is enhanced and independent of new protein synthesis (Huber et al. 2002; Nosyreva et al. 2006). The cause of these synaptic plasticity deficits together with other cognitive abnormalities observed in FXS are thought to arise, in part, from excessive protein synthesis, the consequence of altered mGlu5 receptor signalling via the Ras-ERK1/2 signalling pathway. Enhanced protein synthesis rates in Fmr1-/y mice can be corrected by either inhibiting mGlu5 receptors or reducing Ras and subsequent ERK1/2 activity (Osterweil et al. 2013). In this thesis mGluR-dependent LTD was examined at Schaffer collateral/commissural inputs to CA1 pyramidal neurones in hippocampal slices obtained from Fmr1-/y, Syngap+/− and Fmr1-/ySyngap+/− double mutant mice. Extracellular field recordings reveal that acute application of the Gp1 mGluR agonist dihydroxyphenylglycine (DHPG) induces a form of mGluR-dependent LTD that is enhanced and independent of new protein synthesis in CA1 of Fmr1-/y mice. In Syngap+/− mice, the magnitude of mGluR-dependent LTD is also significantly increased relative to WT littermates and insensitive to protein synthesis inhibitors. Furthermore, in the Fmr1-/ySyngap+/− double mutant, Syngap haploinsufficiency occludes the increase in mGluR-dependent LTD caused by the loss of FMRP. In addition, metabolic labelling studies reveal basal protein synthesis rates to be modestly enhanced in the hippocampus of Fmr1-/y mice compared to WT mice. Importantly this phenotype translates to the rat model of FXS. In Syngap+/- hippocampal slices, basal protein synthesis rates are also significantly elevated compared to WT counterparts. Interestingly, elevated basal protein synthesis rates in Syngap+/- mice could be corrected in the hippocampus by similarly pharmacological strategies employed in Fmr1-/y mice. The comparable neuropathophysiology we observe between Syngap+/− and Fmr1-/y mice suggests that SYNGAP and fragile X mental retardation protein (FMRP) may converge on similar biochemical pathways raising the intriguing possibility that therapeutic strategies used in the treatment of FXS may also be of benefit in treating individuals with ID caused by mutations in SYNGAP1

Real-time, model-based magnetic field correction for moving, wearable MEG

Most neuroimaging techniques require the participant to remain still for reliable recordings to be made. Optically pumped magnetometer (OPM) based magnetoencephalography (OP-MEG) however, is a neuroimaging technique which can be used to measure neural signals during large participant movement (approximately 1 m) within a magnetically shielded room (MSR) (Boto et al., 2018; Seymour et al., 2021). Nevertheless, environmental magnetic fields vary both spatially and temporally and OPMs can only operate within a limited magnetic field range, which constrains participant movement. Here we implement real-time updates to electromagnetic coils mounted on-board of the OPMs, to cancel out the changing background magnetic fields. The coil currents were chosen based on a continually updating harmonic model of the background magnetic field, effectively implementing homogeneous field correction (HFC) in real-time (Tierney et al., 2021). During a stationary, empty room recording, we show an improvement in very low frequency noise of 24 dB. In an auditory paradigm, during participant movement of up to 2 m within a magnetically shielded room, introduction of the real-time correction more than doubled the proportion of trials in which no sensor saturated recorded outside of a 50 cm radius from the optimally-shielded centre of the room. The main advantage of such model-based (rather than direct) feedback is that it could allow one to correct field components along unmeasured OPM axes, potentially mitigating sensor gain and calibration issues (Borna et al., 2022)

Global Drivers on Southern Ocean Ecosystems: Changing Physical Environments and Anthropogenic Pressures in an Earth System

Copyright © 2020 Morley, Abele, Barnes, Cárdenas, Cotté, Gutt, Henley, Höfer, Hughes, Martin, Moffat, Raphael, Stammerjohn, Suckling, Tulloch, Waller and Constable. The manuscript assesses the current and expected future global drivers of Southern Ocean (SO) ecosystems. Atmospheric ozone depletion over the Antarctic since the 1970s, has been a key driver, resulting in springtime cooling of the stratosphere and intensification of the polar vortex, increasing the frequency of positive phases of the Southern Annular Mode (SAM). This increases warm air-flow over the East Pacific sector (Western Antarctic Peninsula) and cold air flow over the West Pacific sector. SAM as well as El Niño Southern Oscillation events also affect the Amundsen Sea Low leading to either positive or negative sea ice anomalies in the west and east Pacific sectors, respectively. The strengthening of westerly winds is also linked to shoaling of deep warmer water onto the continental shelves, particularly in the East Pacific and Atlantic sectors. Air and ocean warming has led to changes in the cryosphere, with glacial and ice sheet melting in both sectors, opening up new ice free areas to biological productivity, but increasing seafloor disturbance by icebergs. The increased melting is correlated with a salinity decrease particularly in the surface 100 m. Such processes could increase the availability of iron, which is currently limiting primary production over much of the SO. Increasing CO2 is one of the most important SO anthropogenic drivers and is likely to affect marine ecosystems in the coming decades. While levels of many pollutants are lower than elsewhere, persistent organic pollutants (POPs) and plastics have been detected in the SO, with concentrations likely enhanced by migratory species. With increased marine traffic and weakening of ocean barriers the risk of the establishment of non-indigenous species is increased. The continued recovery of the ozone hole creates uncertainty over the reversal in sea ice trends, especially in the light of the abrupt transition from record high to record low Antarctic sea ice extent since spring 2016. The current rate of change in physical and anthropogenic drivers is certain to impact the Marine Ecosystem Assessment of the Southern Ocean (MEASO) region in the near future and will have a wide range of impacts across the marine ecosystem

The Energetics of Molecular Adaptation in Transcriptional Regulation

Mutation is a critical mechanism by which evolution explores the functional landscape of proteins. Despite our ability to experimentally inflict mutations at will, it remains difficult to link sequence-level perturbations to systems-level responses. Here, we present a framework centered on measuring changes in the free energy of the system to link individual mutations in an allosteric transcriptional repressor to the parameters which govern its response. We find the energetic effects of the mutations can be categorized into several classes which have characteristic curves as a function of the inducer concentration. We experimentally test these diagnostic predictions using the well-characterized LacI repressor of Escherichia coli, probing several mutations in the DNA binding and inducer binding domains. We find that the change in gene expression due to a point mutation can be captured by modifying only a subset of the model parameters that describe the respective domain of the wild-type protein. These parameters appear to be insulated, with mutations in the DNA binding domain altering only the DNA affinity and those in the inducer binding domain altering only the allosteric parameters. Changing these subsets of parameters tunes the free energy of the system in a way that is concordant with theoretical expectations. Finally, we show that the induction profiles and resulting free energies associated with pairwise double mutants can be predicted with quantitative accuracy given knowledge of the single mutants, providing an avenue for identifying and quantifying epistatic interactions

Predictive shifts in free energy couple mutations to their phenotypic consequences

Mutation is a critical mechanism by which evolution explores the functional landscape of proteins. Despite our ability to experimentally inflict mutations at will, it remains difficult to link sequence-level perturbations to systems-level responses. Here, we present a framework centered on measuring changes in the free energy of the system to link individual mutations in an allosteric transcriptional repressor to the parameters which govern its response. We find that the energetic effects of the mutations can be categorized into several classes which have characteristic curves as a function of the inducer concentration. We experimentally test these diagnostic predictions using the well-characterized LacI repressor of Escherichia coli, probing several mutations in the DNA binding and inducer binding domains. We find that the change in gene expression due to a point mutation can be captured by modifying only the model parameters that describe the respective domain of the wild-type protein. These parameters appear to be insulated, with mutations in the DNA binding domain altering only the DNA affinity and those in the inducer binding domain altering only the allosteric parameters. Changing these subsets of parameters tunes the free energy of the system in a way that is concordant with theoretical expectations. Finally, we show that the induction profiles and resulting free energies associated with pairwise double mutants can be predicted with quantitative accuracy given knowledge of the single mutants, providing an avenue for identifying and quantifying epistatic interactions

Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma

Measurement of the Lifetime Difference Between B_s Mass Eigenstates

We present measurements of the lifetimes and polarization amplitudes for B_s --> J/psi phi and B_d --> J/psi K*0 decays. Lifetimes of the heavy (H) and light (L) mass eigenstates in the B_s system are separately measured for the first time by determining the relative contributions of amplitudes with definite CP as a function of the decay time. Using 203 +/- 15 B_s decays, we obtain tau_L = (1.05 +{0.16}/-{0.13} +/- 0.02) ps and tau_H = (2.07 +{0.58}/-{0.46} +/- 0.03) ps. Expressed in terms of the difference DeltaGamma_s and average Gamma_s, of the decay rates of the two eigenstates, the results are DeltaGamma_s/Gamma_s = (65 +{25}/-{33} +/- 1)%, and DeltaGamma_s = (0.47 +{0.19}/-{0.24} +/- 0.01) inverse ps.Comment: 8 pages, 3 figures, 2 tables; as published in Physical Review Letters on 16 March 2005; revisions are for length and typesetting only, no changes in results or conclusion