Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease. Design Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries. Participants 194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors. Main outcome measures Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals. Results CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P<10 −34) and were unrelated to other risk factors. Risk ratios for coronary heart disease per additional copy of an allele associated with raised C reactive protein were 0.93 (95% confidence interval 0.87 to 1.00) for rs3093077; 1.00 (0.98 to 1.02) for rs1205; 0.98 (0.96 to 1.00) for rs1130864; and 0.99 (0.94 to 1.03) for rs1800947. In a combined analysis, the risk ratio for coronary heart disease was 1.00 (0.90 to 1.13) per 1 SD higher genetically raised natural log (ln) concentration of C reactive protein. The genetic findings were discordant with the risk ratio observed for coronary heart disease of 1.33 (1.23 to 1.43) per 1 SD higher circulating ln concentration of C reactive protein in prospective studies (P=0.001 for difference). Conclusion Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease.

U1 snRNP plays a critical role in 5ʹ-splice site recognition and is a frequent target of alternative splicing factors. These factors transiently associate with human U1 snRNP and are not amenable for structural studies, while their Saccharomyces cerevisiae (yeast) homologs are stable components of U1 snRNP. Here, we report the cryoEM structure of yeast U1 snRNP at 3.6 Å resolution with atomic models for ten core proteins, nearly all essential domains of its RNA, and five stably associated auxiliary proteins. The foot-shaped yeast U1 snRNP contains a core in the “ball-and-toes” region architecturally similar to the human U1 snRNP. All auxiliary proteins are in the “arch-and-heel” region and connected to the core through the Prp42/Prp39 paralogs. Our demonstration that homodimeric human PrpF39 directly interacts with U1C-CTD, mirroring yeast Prp42/Prp39, supports yeast U1 snRNP as a model for understanding how transiently associated auxiliary proteins recruit human U1 snRNP in alternative splicing.

[1] Significant increases in electron fluxes and energy densities at energies from 200 eV to !1 MeV have been observed during magnetic storms to L values as low as 2. To investigate the processes responsible for these flux increases of ring current electrons, we simulate the guiding-center drift and loss of electrons from the plasma sheet to the inner magnetosphere during storms. We use a dipole field plus a constant southward interplanetary magnetic field as our magnetic field model. Over this magnetic field model we impose corotation, quiescent Stern-Volland, and storm-associated enhancements in the convection electric field. We perform phase-space mapping simulations with imposed initial (theoretical results or Combined Release and Radiation Effects Satellite (CRRES) observations) and boundary (averaged Los Alamos National Laboratory/multiple-particle analyzer or CRRES observations) conditions for hypothetical and real storm events, respectively. Wave-particle interactions are the dominant loss process for ring current electrons. Wave activity outside the plasmapause is enhanced during storms due to the particle injection from the plasma sheet to the inner magnetosphere during active times. Our loss model takes such enhanced losses into account. We compare our simulated electron fluxes with previously reported fluxes observed by Explorer 45 for hypothetical storms and with in situ fluxes from CRRES/low-energy plasma analyzer (LEPA) ($100 eV to $20 keV) and CRRES/medium-energy sensor A (MEA) (153 keV to 1.582 MeV) for two storm events (26 August 1990 and 10 October 1990). We find that direct injection from the plasma sheet by enhanced convection can account for increases in the stormtime ring current electron fluxes from 10 to $50 keV. Our simulations quantitatively reproduce the enhanced low-energy ($10 keV) electron fluxes observed by CRRES/LEPA at equatorial radial distances of $3 to 6.6R E . Our simulated electron fluxes at intermediate energies ($50 keV) overestimate the corresponding fluxes observed by Explorer 45 at L $ 3-5, suggesting that the loss model that we are currently using underestimates the actual electron losses at energies of $50 keV. We find that transport via enhanced convection cannot account for the rapid filling of the slot region at 3-5R E for !100 keV electrons when we apply linearly interpolated Data Acquisition and Processing Program (DMSP) cross-polar-cap potentials in our simple electric field model. However, when we superimpose stormtime fluctuations of the cross-tail potential drop over linearly interpolated DMSP potentials, we find that the fluxes of electrons are enhanced up to energies of $150 keV at L $ 3-5R E during the October 1990 event because radial diffusion of the high-energy electrons during the 22-hour main phase can be significant. However, it still cannot account for the stormtime flux increases of E ! 200 keV at L $ 3-5. This may be in part because the simple electric field model that we are using underestimates the electric field intensity in the slot region. L...

Neurological disorders such as Alzheimer's disease, stroke and epilepsy are currently marred by the lack of effective treatments to prevent neuronal death. Erroneous cell cycle reentry (CCR) is hypothesized to have a causative role in neurodegeneration. We show that forcing S-phase reentry in cultured hippocampal neurons is sufficient to induce neurodegeneration. We found that kainic-acid treatment in vivo induces erroneous CCR and neuronal death through a Notch-dependent mechanism. Ablating Notch signaling in neurons provides neuroprotection against kainic acid-induced neuronal death. We further show that kainic-acid treatment activates Notch signaling, which increases the bioavailability of CyclinD1 through Akt/GSK3β pathway, leading to aberrant CCR via activation of CyclinD1-Rb-E2F1 axis. In addition, pharmacological blockade of this pathway at critical steps is sufficient to confer resistance to kainic acid-induced neurotoxicity in mice. Taken together, our results demonstrate that excitotoxicity leads to neuronal death in a Notch-dependent manner through erroneous CCR.

[1] We use SuperDARN radar measurements of ionospheric plasma flow on the dayside to evaluate the extent to which substorm onset is the result of interplanetary magnetic field (IMF) changes that lead to a reduction in the strength of magnetospheric convection. We also use this data to evaluate the timing of such convection changes relative to the time of onset. By using direct observations of convection, we avoid the uncertainties in previous studies of substorm triggering arising from their use of IMF measurements from locations away from the magnetosphere. We first identified 12 well-defined substorm onsets for which sufficient SuperDARN echo coverage on the dayside was available for our analysis. We find that at least 10 of the onsets were associated with a reduction in the strength of large-scale convection that is imparted to the magnetosphere from the solar wind. This indicates that the majority of substorms with well-defined onsets are associated with such a convection reduction. We also find that the convection reduction imparted to the magnetosphere initiates a few minutes prior to substorm onset. This is the same time relative to onset that based on auroral observations, the nightside magnetosphere undergoes a transition to an unstable configuration. This suggests that the convection reduction is responsible for the transition to instability that leads to the substorm expansion phase. Our results are consistent with the idea that under enhanced magnetospheric convection, energy builds up within the nightside magnetosphere and can reach a stable equilibrium where energy losses balance further energy input. If the energy accumulated on the nightside during a period of enhanced convection exceeds that of the equilibrium configuration after a reduction in the strength of convection, the nightside magnetosphere undergoes a transition to instability when the strength of convection is reduced and the excess energy is released as the substorm expansion phase. These results indicate that the question of how this instability arises and develops after a decrease in convection is a critical outstanding question for understanding the substorm expansion phase.

[1] We evaluate the relative importance of stormtime ring current electrons to protons by calculating the energy content ratio of electrons to protons for typical ring current energies inferred from observations and simulations. We analyze Explorer 45 measurements taken around the minimum Dst(=À171 nT) of the 17 December 1971 storm. We simulate the electron and proton ring current energy content during a hypothetical storm using drift-loss simulations. From the data analysis, we find that electrons with energies of $1 -50 keV and protons with energies of $10-200 keV contribute the most to the corresponding particle energy content. From both observations and simulations, the ring current electrons contribute only $1% as much energy content as ring current protons during quiet times. However, this ratio increases to $8-19% during storm main phase. Thus, the ring current electrons can contribute significantly to the ring current energy content during storms. Citation: Liu, S., M. W. Chen, J. L. Roeder, L. R. Lyons, and M. Schulz (2005), Relative contribution of electrons to the stormtime total ring current energy content, Geophys. Res. Lett., 32, L03110,

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate of 5%. Biomarkers for the early detection of pancreatic cancer are urgently needed. Transforming growth factor-beta1 (TGF-β1) is elevated in the tissues and plasma of patients with PDAC. However, no studies systemically report prognostic significance of plasma TGF-β1 levels in PDAC. In the present study, we assessed the prognostic significance of serum TGF-β levels in patients with PDAC. TGF-β levels were determined in serum from 146 PDAC patients, and 58 patients with benign pancreatic conditions. Regression models were used to correlate TGF-β levels to gender, age, stage, class, and metastasis. Survival analyses were performed using multivariate Cox models. Serum levels of TGF-β1 distinguished PDAC from benign pancreatic conditions (P<0.001) and healthy control subjects (P<0.001). Serum levels of TGF-β also distinguished tumor stage (P=0.002) and lymph node metastasis (P=0.001). High serum levels of TGF-β1 were significantly correlated with reduced patient survival. Multivariate analysis revealed that TGF-β1, lymph node metastasis and tumor stage were independent factors for PDAC survival. Our results indicate that serum TGF-β1 may be used as a potential prognostic marker for PDAC.

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