A new approach to high resolution, high contrast electron microscopy of macromolecular block copolymer assemblies

Determining the structure of macromolecular samples is vital for understanding and adapting their function. Transmission electron microscopy (TEM) is widely used to achieve this, but, owing to the weak electron scattering cross-section of carbon, TEM images of macromolecular samples are generally low contrast and low resolution. Here we implement a fast and practically simple routine to achieve high-contrast imaging of macromolecular samples using exit wave reconstruction (EWR), revealing a new level of structural detail. This is only possible using ultra-low contrast supports such as the graphene oxide (GO) used here and as such represents a novel application of these substrates. We apply EWR on GO membranes to study self-assembled block copolymer structures, distinguishing not only the general morphology or nanostructure, but also evidence for the substructure (i.e. the polymer chains) which gives insight into their formation mechanisms and functional properties

Using Ai-Generated Suggestions From ChatGPT to Optimize Clinical Decision Support

OBJECTIVE: To determine if ChatGPT can generate useful suggestions for improving clinical decision support (CDS) logic and to assess noninferiority compared to human-generated suggestions. METHODS: We supplied summaries of CDS logic to ChatGPT, an artificial intelligence (AI) tool for question answering that uses a large language model, and asked it to generate suggestions. We asked human clinician reviewers to review the AI-generated suggestions as well as human-generated suggestions for improving the same CDS alerts, and rate the suggestions for their usefulness, acceptance, relevance, understanding, workflow, bias, inversion, and redundancy. RESULTS: Five clinicians analyzed 36 AI-generated suggestions and 29 human-generated suggestions for 7 alerts. Of the 20 suggestions that scored highest in the survey, 9 were generated by ChatGPT. The suggestions generated by AI were found to offer unique perspectives and were evaluated as highly understandable and relevant, with moderate usefulness, low acceptance, bias, inversion, redundancy. CONCLUSION: AI-generated suggestions could be an important complementary part of optimizing CDS alerts, can identify potential improvements to alert logic and support their implementation, and may even be able to assist experts in formulating their own suggestions for CDS improvement. ChatGPT shows great potential for using large language models and reinforcement learning from human feedback to improve CDS alert logic and potentially other medical areas involving complex, clinical logic, a key step in the development of an advanced learning health system

The Discovery of a Debris Disk Around the DAV White Dwarf PG 1541+651

To search for circumstellar disks around evolved stars, we targeted roughly 100 DA white dwarfs from the Palomar Green survey with the Peters Automated Infrared Imaging Telescope (PAIRITEL). Here we report the discovery of a debris disk around one of these targets, the pulsating white dwarf PG 1541+651 (KX Draconis, hereafter PG1541). We detect a significant flux excess around PG1541 in the K-band. Follow-up near-infrared spectroscopic observations obtained at the NASA Infrared Telescope Facility (IRTF) and photometric observations with the warm Spitzer Space Telescope confirm the presence of a warm debris disk within 0.13-0.36 Rsun (11-32x the stellar radius) at an inclination angle of 60deg. At Teff = 11880 K, PG1541 is almost a twin of the DAV white dwarf G29-38, which also hosts a debris disk. All previously known dusty white dwarfs are of the DAZ/DBZ spectral type due to accretion of metals from the disk. High-resolution optical spectroscopy is needed to search for metal absorption lines in PG1541 and to constrain the accretion rate from the disk. PG1541 is only 55 pc away from the Sun and the discovery of its disk in our survey demonstrates that our knowledge of the nearby dusty white dwarf population is far from complete.Comment: MNRAS Letters, in pres

Mechanical Relaxation in Glasses and at the Glass Transition

The Gilroy-Phillips model of relaxational jumps in asymmetric double-well potentials, developed for the Arrhenius-type secondary relaxations of the glass phase, is extended to a formal description of the breakdown of the shear modulus at the glass transition, the flow process.Comment: 13 pages, 11 figures, 49 ref

Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.Peer reviewe

Restoring tumour selectivity of the bioreductive prodrug pr-104 by developing an analogue resistant to aerobic metabolism by human aldo-keto reductase 1c3

PR-104 is a phosphate ester pre-prodrug that is converted in vivo to its cognate alcohol, PR-104A, a latent alkylator which forms potent cytotoxins upon bioreduction. Hypoxia selectivity results from one-electron nitro reduction of PR-104A, in which cytochrome P450 oxidoreductase (POR) plays an important role. However, PR-104A also undergoes ‘off-target’ two-electron reduction by human aldo-keto reductase 1C3 (AKR1C3), resulting in activation in oxygenated tissues. AKR1C3 expression in human myeloid progenitor cells probably accounts for the dose-limiting myelotoxicity of PR-104 documented in clinical trials, resulting in human PR-104A plasma exposure levels 3.4- to 9.6-fold lower than can be achieved in murine models. Structure-based design to eliminate AKR1C3 activation thus represents a strategy for restoring the therapeutic window of this class of agent in humans. Here, we identified SN29176, a PR-104A analogue resistant to human AKR1C3 activation. SN29176 retains hypoxia selectivity in vitro with aerobic/hypoxic IC(50) ratios of 9 to 145, remains a substrate for POR and triggers γH2AX induction and cell cycle arrest in a comparable manner to PR-104A. SN35141, the soluble phosphate pre-prodrug of SN29176, exhibited superior hypoxic tumour log cell kill (>4.0) to PR-104 (2.5–3.7) in vivo at doses predicted to be achievable in humans. Orthologues of human AKR1C3 from mouse, rat and dog were incapable of reducing PR-104A, thus identifying an underlying cause for the discrepancy in PR-104 tolerance in pre-clinical models versus humans. In contrast, the macaque AKR1C3 gene orthologue was able to metabolise PR-104A, indicating that this species may be suitable for evaluating the toxicokinetics of PR-104 analogues for clinical development. We confirmed that SN29176 was not a substrate for AKR1C3 orthologues across all four pre-clinical species, demonstrating that this prodrug analogue class is suitable for further development. Based on these findings, a prodrug candidate was subsequently identified for clinical trials

Measurement of the eta-Meson Mass using psi(2S) --> eta J/psi

We measure the mass of the eta meson using psi(2S) --> eta J/psi events acquired with the CLEO-c detector operating at the CESR e+e- collider. Using the four decay modes eta --> gamma gamma, 3pi0, pi+pi-pi0, and pi+pi-gamma, we find M(eta)=547.785 +- 0.017 +- 0.057 MeV, in which the first uncertainty is statistical and the second systematic. This result has an uncertainty comparable to the two most precise previous measurements and is consistent with that of NA48, but is inconsistent at the level of 6.5sigma with the much smaller mass obtained by GEM.Comment: 10 pages postscript,also available through http://www.lns.cornell.edu/public/CLNS/2007/, Submitted to PR

Update of the measurement of the cross section for e^+e^- -> psi(3770) -> hadrons

We have updated our measurement of the cross section for e^+e^- -> psi(3770) -> hadrons, our publication "Measurement of sigma(e^+e^- -> psi(3770) -> hadrons) at E_{c.m.} = 3773 MeV", arXiv:hep-ex/0512038, Phys.Rev.Lett.96, 092002 (2006). Simultaneous with this arXiv update, we have published an erratum in Phys.Rev.Lett.104, 159901 (2010). There, and in this update, we have corrected a mistake in the computation of the error on the difference of the cross sections for e^+e^- -> psi(3770) -> hadrons and e^+e^- -> psi(3770) -> DDbar. We have also used a more recent CLEO measurement of cross section for e^+e^- -> psi(3770) -> DDbar. From this, we obtain an upper limit on the branching fraction for psi(3770) -> non-DDbar of 9% at 90% confidence level.Comment: 3 pages, 0 figures. This is an erratum to Phys.Rev.Lett.96:092002,2006. Added a reference

Suppressed Decays of D_s^+ Mesons to Two Pseudoscalar Mesons

Using data collected near the Ds*+ Ds- peak production energy Ecm = 4170 MeV by the CLEO-c detector, we study the decays of Ds+ mesons to two pseudoscalar mesons. We report on searches for the singly-Cabibbo-suppressed Ds+ decay modes K+ eta, K+ eta', pi+ K0S, K+ pi0, and the isospin-forbidden decay mode Ds+ to pi+ pi0. We normalize with respect to the Cabibbo-favored Ds+ modes pi+ eta, pi+ eta', and K+ K0S, and obtain ratios of branching fractions: Ds+ to K+ eta / Ds+ to pi+ eta = (8.9 +- 1.5 +- 0.4)%, Ds+ to K+ eta' / Ds+ to pi+ eta' = (4.2 +- 1.3 +- 0.3)%, Ds+ to pi+ K0S / Ds+ to K+ K0S = (8.2 +- 0.9 +- 0.2)%, Ds+ to K+ pi0 / Ds+ to K+ K0S = (5.0 +- 1.2 +- 0.6)%, and Ds+ to pi+ pi0 / Ds+ to K+ K0S < 4.1% at 90% CL, where the uncertainties are statistical and systematic, respectively.Comment: 9 pages postscript,also available through http://www.lns.cornell.edu/public/CLNS/2007/, Submitted to PR