Description of the resolution hierarchy of the global coupled HadGEM3-GC3.1 model as used in CMIP6 HighResMIP experiments

CMIP6 HighResMIP is a new experimental design for global climate model simulations that aims to assess the impact of model horizontal resolution on climate simulation fidelity. We describe a hierarchy of global coupled model resolutions based on the HadGEM3-GC3.1 model that range from an atmosphere-ocean resolution of 130 km-1° to 25 km-1/12°, all using the same forcings and initial conditions. In order to make such high resolution simulations possible, the experiments have a short 30 year spinup, followed by at least century-long simulations with both constant forcing (to assess drift and the focus of this work), and historic forcing. We assess the change in model biases as a function of both atmosphere and ocean resolution, together with the effectiveness and robustness of this new experimental design. We find reductions in the biases in top of atmosphere radiation components and cloud forcing. There are significant reductions in some common surface climate model biases as resolution is increased, particularly in the Atlantic for sea surface temperature and precipitation, primarily driven by increased ocean resolution. There is also a reduction in drift from the initial conditions both at the surface and in the deeper ocean at higher resolution. Using an eddy-present and eddy-rich ocean resolution enhances the strength of the North Atlantic ocean circulation (boundary currents, overturning circulation and heat transports), while an eddy-present ocean resolution has a considerably reduced Antarctic Circumpolar Current strength. All models have a reasonable representation of El Nino – Southern Oscillation. In general the biases present after 30 years of simulations do not change character markedly over longer timescales, justifying the experimental design

High affinity binding of pyrethroids to the � subunit of brain sodium channels

SUMMARY Na ϩ channels are the primary molecular targets of the pyrethroid insecticides. Na ϩ channels consisting of only a type IIA ␣ subunit expressed in Chinese hamster ovary cells responded to pyrethroid treatment in a normal manner: a sustained Na ϩ current was induced progressively after each depolarizing pulse in a train of stimuli, and this Na ϩ current decayed slowly on repolarization. These modified Na ϩ channels could be reactivated at much more negative membrane potentials (V 0.5 ϭ Ϫ139 mV) than unmodified Na ϩ channels (V 0.5 ϭ Ϫ28 mV). These results indicate that pyrethroids can modify the functional properties of the Na ϩ channel ␣ subunit expressed alone by blocking their inactivation, shifting their voltage dependence of activation, and slowing their deactivation. To demonstrate directly the specific interaction of pyrethroids with the ␣ subunit of voltage-gated Na ϩ channels, a radioactive photosensitive derivative, [ 3 H]RU58487, was used in binding and photolabeling studies. In the presence of a low concentration of the nonionic detergent Triton X-100, specific pyrethroid binding to Na ϩ channels in rat brain membrane preparations could be measured and reached 75% of total binding under optimal conditions. Binding approached equilibrium within 1 hr at 4°, dissociated with a half-time of ϳ10 min, and had K D values of ϳ58 -300 nM for three representative pyrethroids. Specific pyrethroid binding was enhanced by ϳ40% in the presence of 100 nM ␣-scorpion toxin, but no allosteric enhancement was observed in the presence of toxins acting at other Na ϩ channel receptor sites. Extensive membrane washing increased specific binding to 89%. Photolabeling with [ 3 H]RU58487 under these optimal binding conditions revealed a radiolabeled band with an apparent molecular mass of 240 kDa corresponding to the Na ϩ channel ␣ subunit. Anti-peptide antibodies recognizing sequences within the ␣ subunit were able to specifically immunoprecipitate the covalently modified channel. Together, these results demonstrate that the pyrethroids can modify the properties of cells expressing only the ␣ subunit of Na ϩ channels and can bind specifically to a receptor site on the ␣ subunit

Update of the Search for the Neutrinoless Decay τ→μγ\tau\to \mu\gamma

We present an update of the search for the lepton family number violating decay $\tau \to \mu\gamma$ using a complete CLEO II data sample of 12.6 million $\tau^+\tau^-$ pairs. No evidence of a signal has been found and the corresponding upper limit is \BR(\tau \to \mu\gamma) < 1.0 \times 10^{-6} at 90% CL, significantly smaller than previous limits. All quoted results are preliminary.Comment: 9 pages postscript, also available through http://w4.lns.cornell.edu/public/CLN

Diversity in collaborative research communities: a multicultural, multidisciplinary thesis writing group in public health

Writing groups for doctoral students are generally agreed to provide valuable learning spaces for Ph.D. candidates. Here an academic developer and the eight members of a writing group formed in a Discipline of Public Health provide an account of their experiences of collaborating in a multicultural, multidisciplinary thesis writing group. We consider the benefits of belonging to such a group for Ph.D. students who are operating in a research climate in which disciplinary boundaries are blurring and where an increasing number of doctoral projects are interdisciplinary in nature; in which both academic staff and students come from enormously diverse cultural and language backgrounds; and in which teamwork, networking and collaboration are prized but not always proactively facilitated. We argue that doctoral writing groups comprising students from diverse cultural and disciplinary backgrounds can be of significant value for postgraduates who wish to collaborate on their own academic development to improve their research writing and communication skills; at the same time, such collaborative work effectively builds an inclusive, dynamic research community.Cally Guerin, Vicki Xafis, Diana V. Doda, Marianne H. Gillam, Allison J. Larg, Helene Luckner, Nasreen Jahan, Aris Widayati and Chuangzhou X

Effect of Neutralizing Monoclonal Antibody Treatment on Early Trajectories of Virologic and Immunologic Biomarkers in Patients Hospitalized With COVID-19

BACKGROUND: Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood. METHODS: Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and D-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models. RESULTS: Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma N-Ag compared with placebo (95% confidence interval, 12%-27%; P \u3c .001), and a steeper rate of decline through the first 5 days (P \u3c .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale. CONCLUSIONS: Our study suggests that nmAb has an antiviral effect assessed by plasma N-Ag among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed. CLINICAL TRIALS REGISTRATION: NCT04501978

Gene expression profiling for molecular distinction and characterization of laser captured primary lung cancers

<p>Abstract</p> <p>Methods</p> <p>We examined gene expression profiles of tumor cells from 29 untreated patients with lung cancer (10 adenocarcinomas (AC), 10 squamous cell carcinomas (SCC), and 9 small cell lung cancer (SCLC)) in comparison to 5 samples of normal lung tissue (NT). The European and American methodological quality guidelines for microarray experiments were followed, including the stipulated use of laser capture microdissection for separation and purification of the lung cancer tumor cells from surrounding tissue.</p> <p>Results</p> <p>Based on differentially expressed genes, different lung cancer samples could be distinguished from each other and from normal lung tissue using hierarchical clustering. Comparing AC, SCC and SCLC with NT, we found 205, 335 and 404 genes, respectively, that were at least 2-fold differentially expressed (estimated false discovery rate: < 2.6%). Different lung cancer subtypes had distinct molecular phenotypes, which also reflected their biological characteristics. Differentially expressed genes in human lung tumors which may be of relevance in the respective lung cancer subtypes were corroborated by quantitative real-time PCR.</p> <p>Genetic programming (GP) was performed to construct a classifier for distinguishing between AC, SCC, SCLC, and NT. Forty genes, that could be used to correctly classify the tumor or NT samples, have been identified. In addition, all samples from an independent test set of 13 further tumors (AC or SCC) were also correctly classified.</p> <p>Conclusion</p> <p>The data from this research identified potential candidate genes which could be used as the basis for the development of diagnostic tools and lung tumor type-specific targeted therapies.</p

The Peripheral Binding of 14-3-3γ to Membranes Involves Isoform-Specific Histidine Residues

Mammalian 14-3-3 protein scaffolds include seven conserved isoforms that bind numerous phosphorylated protein partners and regulate many cellular processes. Some 14-3-3-isoforms, notably γ, have elevated affinity for membranes, which might contribute to modulate the subcellular localization of the partners and substantiate the importance of investigating molecular mechanisms of membrane interaction. By applying surface plasmon resonance we here show that the binding to phospholipid bilayers is stimulated when 14-3-3γ is complexed with its partner, a peptide corresponding to the Ser19-phosphorylated N-terminal region of tyrosine hydroxylase. Moreover, membrane interaction is dependent on salts of kosmotropic ions, which also stabilize 14-3-3γ. Electrostatic analysis of available crystal structures of γ and of the non-membrane-binding ζ-isoform, complemented with molecular dynamics simulations, indicate that the electrostatic potential distribution of phosphopeptide-bound 14-3-3γ is optimal for interaction with the membrane through amphipathic helices at the N-terminal dimerization region. In addition, His158, and especially His195, both specific to 14-3-3γ and located at the convex lateral side, appeared to be pivotal for the ligand induced membrane interaction, as corroborated by site-directed mutagenesis. The participation of these histidine residues might be associated to their increased protonation upon membrane binding. Overall, these results reveal membrane-targeting motifs and give insights on mechanisms that furnish the 14-3-3γ scaffold with the capacity for tuned shuffling from soluble to membrane-bound states.This work was supported by grants from the Norwegian Cancer Society (to ØH), Junta de Andalucía, grant CVI-02483 (to JMSR), The Research Council of Norway (grant 185181 to A.M.), the Western Norway Health Authorities (grant 911618 to A.M.) and The Kristian Gerhard Jebsen Foundation (to AM)

Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial

BACKGROUND: Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. METHODS: In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. FINDINGS: From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). INTERPRETATION: When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. FUNDING: US National Institutes of Health