A table of elliptic curves over the cubic field of discriminant -23

Let F be the cubic field of discriminant -23 and O its ring of integers. Let Gamma be the arithmetic group GL_2 (O), and for any ideal n subset O let Gamma_0 (n) be the congruence subgroup of level n. In a previous paper, two of us (PG and DY) computed the cohomology of various Gamma_0 (n), along with the action of the Hecke operators. The goal of that paper was to test the modularity of elliptic curves over F. In the present paper, we complement and extend this prior work in two ways. First, we tabulate more elliptic curves than were found in our prior work by using various heuristics ("old and new" cohomology classes, dimensions of Eisenstein subspaces) to predict the existence of elliptic curves of various conductors, and then by using more sophisticated search techniques (for instance, torsion subgroups, twisting, and the Cremona-Lingham algorithm) to find them. We then compute further invariants of these curves, such as their rank and representatives of all isogeny classes. Our enumeration includes conjecturally the first elliptic curves of ranks 1 and 2 over this field, which occur at levels of norm 719 and 9173 respectively

Local Asymmetry and the Inner Radius of Nodal Domains

Let M be a closed Riemannian manifold of dimension n. Let f be an eigenfunction of the Laplace-Beltrami operator corresponding to an eigenvalue \lambda. We show that the volume of {f>0} inside any ball B whose center lies on {f=0} is > C|B|/\lambda^n. We apply this result to prove that each nodal domain contains a ball of radius > C/\lambda^n.Comment: 12 pages, 1 figure; minor corrections; to appear in Comm. PDE

Spots on a Gnat’s Ass, Good Soldiers, and Sociology Departments: Stan Saxton’s Pragmatist Approach to Sociology

Most academics build their careers and establish reputations in the traditional manner, through research and publications. Certainly, this is not the only way to secure a place in the lore of academia. Some are great teachers who gather a large following of students. Still others get involved in professional organizations. While Stan Saxton had a respectable record of publications, was a masterful teacher, and a marvelous critic, his notable contributions to sociology came through his organizational work as a chair of the Department of Sociology and Anthropology at the University of Dayton. After his tenure as chair, Stan continued to be a visible and moral corporate actor in the university, in professional associations, and in academia. His ability to employ sociological knowledge to organizational processes that worked to the advantage of sociology was truly remarkable. His clear vision based on a strong sense of justice was inspirational. Stan’s success as an organizational player occurred during a period of transition for the University of Dayton. Up to 1977 the university was primarily a teaching institution and parochial in its orientation. When Stan was hired as chairperson in that year, a new administration aimed to make the university a leader in Catholic higher education. Stan’s charge was to bring the Department of Sociology and Anthropology in line with the larger project. He found himself in the right place with the right set of circumstances to realize his vision of a sociology department, a vision that fit the conditions of work and the expectations of a private, Catholic university

Programming Idioms for Transactional Events

Transactional events (TE) are an extension of Concurrent ML (CML), a programming model for synchronous message-passing. Prior work has focused on TE's formal semantics and its implementation. This paper considers programming idioms, particularly those that vary unexpectedly from the corresponding CML idioms. First, we solve a subtle problem with client-server protocols in TE. Second, we argue that CML's wrap and guard primitives do not translate well to TE, and we suggest useful workarounds. Finally, we discuss how to rewrite CML protocols that use abort actions

Non-peptidic antagonists of the CGRP receptor, BIBN4096BS and MK-0974, interact with the calcitonin receptor-like receptor via methionine-42 and RAMP1 via tryptophan-74

The receptor for calcitonin gene-related peptide (CGRP) has been the target for the development of novel small molecule antagonists for the treatment of migraine. Two such antagonists, BIBN4096BS and MK-0974, have shown great promise in clinical trials and hence a deeper understanding of the mechanism of their interaction with the receptor is now required. The structure of the CGRP receptor is unusual since it is comprised of a hetero-oligomeric complex between the calcitonin receptor-like receptor (CRL) and an accessory protein (RAMP1). Both the CLR and RAMP1 components have extracellular domains which interact with each other and together form part of the peptide-binding site. It seems likely that the antagonist binding site will also be located on the extracellular domains and indeed Trp-74 of RAMP1 has been shown to form part of the binding site for BIBN4096BS. However, despite a chimeric study demonstrating the role of the N-terminal domain of CLR in antagonist binding, no specific residues have been identified. Here we carry out a mutagenic screen of the extreme N-terminal domain of CLR (residues 23-63) and identify a mutant, Met-42-Ala, which displays 48-fold lower affinity for BIBN4096BS and almost 900-fold lower affinity for MK-0974. In addition, we confirm that the Trp-74-Lys mutation at human RAMP1 reduces BIBN4096BS affinity by over 300-fold and show for the first time a similar effect for MK-0974 affinity. The data suggest that the non-peptide antagonists occupy a binding site close to the interface of the N-terminal domains of CLR and RAMP1

Creation of a novel peptide with enhanced nuclear localization in prostate and pancreatic cancer cell lines

<p>Abstract</p> <p>Background</p> <p>For improved uptake of oligonucleotide-based therapy, the oligonucleotides often are coupled to peptides that facilitate entry into cells. To this end, novel cell-penetrating peptides (CPPs) were designed for mediating intracellular uptake of oligonucleotide-based therapeutics. The novel peptides were based on taking advantage of the nuclear localization properties of transcription factors in combination with a peptide that would bind putatively to cell surfaces. It was observed that adding a glutamate peptide to the N-terminus of the nuclear localization signal (NLS) of the Oct6 transcription factor resulted in a novel CPP with better uptake and better nuclear colocalization than any other peptide tested.</p> <p>Results</p> <p>Uptake of the novel peptide Glu-Oct6 by cancer cell lines was rapid (in less than 1 hr, more than 60% of DU-145 cells were positive for FITC), complete (by 4 hr, 99% of cells were positive for FITC), concentration-dependent, temperature-dependent, and inhibited by sodium azide (NaN₃). Substitution of Phe, Tyr, or Asn moieties for the glutamate portion of the novel peptide resulted in abrogation of novel CPP uptake; however none of the substituted peptides inhibited uptake of the novel CPP when coincubated with cells. Live-cell imaging and analysis by imaging flow cytometry revealed that the novel CPP accumulated in nuclei. Finally, the novel CPP was coupled to a carboxyfluorescein-labeled synthetic oligonucleotide, to see if the peptide could ferry a therapeutic payload into cells.</p> <p>Conclusions</p> <p>These studies document the creation of a novel CPP consisting of a glutamate peptide coupled to the N-terminus of the Oct6 NLS; the novel CPP exhibited nuclear colocalization as well as uptake by prostate and pancreatic cancer cell lines.</p

Early Th2 inflammation in the upper respiratory mucosa as a predictor of severe COVID-19 and modulation by early treatment with inhaled corticosteroids: A mechanistic analysis

Background: Community-based clinical trials of the inhaled corticosteroid budesonide in early COVID-19 have shown improved patient outcomes. We aimed to understand the inflammatory mechanism of budesonide in the treatment of early COVID-19. Methods: The STOIC trial was a randomised, open label, parallel group, phase 2 clinical intervention trial where patients were randomly assigned (1:1) to receive usual care (as needed antipyretics were only available treatment) or inhaled budesonide at a dose of 800 μg twice a day plus usual care. For this experimental analysis, we investigated the nasal mucosal inflammatory response in patients recruited to the STOIC trial and in a cohort of SARS-CoV-2-negative healthy controls, recruited from a long-term observational data collection study at the University of Oxford. In patients with SARS-CoV-2 who entered the STOIC study, nasal epithelial lining fluid was sampled at day of randomisation (day 0) and at day 14 following randomisation, blood samples were also collected at day 28 after randomisation. Nasal epithelial lining fluid and blood samples were collected from the SARS-CoV-2 negative control cohort. Inflammatory mediators in the nasal epithelial lining fluid and blood were assessed for a range of viral response proteins, and innate and adaptive response markers using Meso Scale Discovery enzyme linked immunoassay panels. These samples were used to investigate the evolution of inflammation in the early COVID-19 disease course and assess the effect of budesonide on inflammation. Findings: 146 participants were recruited in the STOIC trial (n=73 in the usual care group; n=73 in the budesonide group). 140 nasal mucosal samples were available at day 0 (randomisation) and 122 samples at day 14. At day 28, whole blood was collected from 123 participants (62 in the budesonide group and 61 in the usual care group). 20 blood or nasal samples were collected from healthy controls. In early COVID-19 disease, there was an enhanced inflammatory airway response with the induction of an anti-viral and T-helper 1 and 2 (Th1/2) inflammatory response compared with healthy individuals. Individuals with COVID-19 who clinically deteriorated (ie, who met the primary outcome) showed an early blunted respiratory interferon response and pronounced and persistent Th2 inflammation, mediated by CC chemokine ligand (CCL)-24, compared with those with COVID-19 who did not clinically deteriorate. Over time, the natural course of COVID-19 showed persistently high respiratory interferon concentrations and elevated concentrations of the eosinophil chemokine, CCL-11, despite clinical symptom improvement. There was persistent systemic inflammation after 28 days following COVID-19, including elevated concentrations of interleukin (IL)-6, tumour necrosis factor-α, and CCL-11. Budesonide treatment modulated inflammation in the nose and blood and was shown to decrease IL-33 and increase CCL17. The STOIC trial was registered with ClinicalTrials.gov, NCT04416399. Interpretation: An initial blunted interferon response and heightened T-helper 2 inflammatory response in the respiratory tract following SARS-CoV-2 infection could be a biomarker for predicting the development of severe COVID-19 disease. The clinical benefit of inhaled budesonide in early COVID-19 is likely to be as a consequence of its inflammatory modulatory effect, suggesting efficacy by reducing epithelial damage and an improved T-cell response

Geographical drivers and predictable climate-linked dynamics of Lassa fever in Nigeria

Lassa fever is a longstanding public health concern in West Africa. Recent molecular studies have confirmed the fundamental role of the rodent host (Mastomys natalensis) in driving human infections, but control and prevention efforts remain hampered by a limited baseline understanding of the disease’s true incidence, geographical distribution and underlying drivers. Here, we show that Lassa fever occurrence and incidence is influenced by climate, poverty, agriculture and urbanisation factors. However, heterogeneous reporting processes and diagnostic laboratory access also appear to be important drivers of the patchy distribution of observed disease incidence. Using spatiotemporal predictive models we show that including climatic variability added retrospective predictive value over a baseline model (11% decrease in out-of-sample predictive error). However, predictions for 2020 show that a climate-driven model performs similarly overall to the baseline model. Overall, with ongoing improvements in surveillance there may be potential for forecasting Lassa fever incidence to inform health planning