High-throughput Binding Affinity Calculations at Extreme Scales

Resistance to chemotherapy and molecularly targeted therapies is a major factor in limiting the effectiveness of cancer treatment. In many cases, resistance can be linked to genetic changes in target proteins, either pre-existing or evolutionarily selected during treatment. Key to overcoming this challenge is an understanding of the molecular determinants of drug binding. Using multi-stage pipelines of molecular simulations we can gain insights into the binding free energy and the residence time of a ligand, which can inform both stratified and personal treatment regimes and drug development. To support the scalable, adaptive and automated calculation of the binding free energy on high-performance computing resources, we introduce the High- throughput Binding Affinity Calculator (HTBAC). HTBAC uses a building block approach in order to attain both workflow flexibility and performance. We demonstrate close to perfect weak scaling to hundreds of concurrent multi-stage binding affinity calculation pipelines. This permits a rapid time-to-solution that is essentially invariant of the calculation protocol, size of candidate ligands and number of ensemble simulations. As such, HTBAC advances the state of the art of binding affinity calculations and protocols

Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat

The African naked mole-rat’s ($\textit{Heterocephalus glaber}$) social and subterranean lifestyle generates a hypoxic niche. Under experimental conditions, naked mole-rats tolerate hours of extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain. Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase were identified as molecular signatures of fructose metabolism. Fructose-driven glycolytic respiration in naked mole-rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be harnessed to minimize hypoxic damage in human disease.Work was supported aEuropean Research Council (294678), the Deutsche Forschungsgemeinschaft SFB 665 and Go865/9-1, NSF (grant #0744979 ), NIH (grants HL71626 and HL606

Audited credential delegation - a user-centric identity management solution for computational grid environments

One major problem faced by end-users and administrators of computational grid environments arise in connection with the usability of the security mechanisms usually deployed in these environments, in particular identity management. Many of the existing computational grid environments use Public Key Infrastructure (PKI) and X.509 digital certificates as a corner stone for their security architectures. However, security solutions based on PKI have to be usable to be effective otherwise they will not provide the intended protection. This paper presents the Audited Credential Delegation (ACD), a user-centric security identity management solution that accommodates users and resource providers security requirements including authentication, authorisation and auditing security goals from the design level. The proposed architecture removes any association between users and digital certificates, which is the source of the grid usability problem, while addressing resource providers concerns with regards to accountability. A prototype of this architecture has been implemented in Java and Web Services technologies using the recommendations of the Open Web Application Security consortium (OWASP) for developing secure software. It is currently being tested on TeraGrid, NGS and DEISA grid infrastructures and a detailed usability study is underway

Audited credential delegation: a usable security solution for the virtual physiological human toolkit

We present applications of audited credential delegation (ACD), a usable security solution for authentication, authorization and auditing in distributed virtual physiological human (VPH) project environments that removes the use of digital certificates from end-users' experience. Current security solutions are based on public key infrastructure (PKI). While PKI offers strong security for VPH projects, it suffers from serious usability shortcomings in terms of end-user acquisition and management of credentials which deter scientists from exploiting distributed VPH environments. By contrast, ACD supports the use of local credentials. Currently, a local ACD username–password combination can be used to access grid-based resources while Shibboleth support is underway. Moreover, ACD provides seamless and secure access to shared patient data, tools and infrastructure, thus supporting the provision of personalized medicine for patients, scientists and clinicians participating in e-health projects from a local to the widest international scale

Rapid and Reliable Binding Affinity Prediction of Bromodomain Inhibitors: A Computational Study

Binding free energies of bromodomain inhibitors are calculated with recently formulated approaches, namely ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration with enhanced sampling). A set of compounds is provided by GlaxoSmithKline, which represents a range of chemical functionality and binding affinities. The predicted binding free energies exhibit a good Spearman correlation of 0.78 with the experimental data from the 3-trajectory ESMACS, and an excellent correlation of 0.92 from the TIES approach where applicable. Given access to suitable high end computing resources and a high degree of automation, we can compute individual binding affinities in a few hours with precisions no greater than 0.2 kcal/mol for TIES, and no larger than 0.34 and 1.71 kcal/mol for the 1- and 3-trajectory ESMACS approaches

FabSim: Facilitating computational research through automation on large-scale and distributed e-infrastructures

We present FabSim, a toolkit developed to simplify a range of computational tasks for researchers in diverse disciplines. FabSim is flexible, adaptable, and allows users to perform a wide range of tasks with ease. It also pro- vides a systematic way to automate the use of resourcess, including HPC and distributed resources, and to make tasks easier to repeat by recording contextual information. To demonstrate this, we present three use cases where FabSim has enhanced our research productivity. These include sim- ulating cerebrovascular bloodflow, modelling clay-polymer nanocomposites across multiple scales, and calculating ligand-protein binding affinities

Evening Telegram, 1900-04-19

The Evening Telegram began publication in St. John's on 3 April 1879 and remains in print today under the title The Telegram. It was published daily except Sunday through to 1958, the frequency changing thereafter. -- The total collection has been split into several parts; this portion contains from 1900-1918

Interim analysis of the COSA (COVID-19 patients treated with the Seraph® 100 Microbind® Affinity filter) registry

BACKGROUND: The Seraph(®)100 Microbind Affinity Blood Filter(®) is a hemoperfusion device that is licensed for the reduction of pathogens, including several viruses, in the blood. It received Emergency Use Authorization (EUA) for the treatment of severe coronavirus disease 2019 (COVID-19) by the FDA. Several studies have shown that the blood viral load of SARS-CoV-2 correlates with adverse outcomes and removal of the nucleocapsid of the SARS-CoV-2 virus by the Seraph(®)100 has been recently demonstrated. The aim of this registry was to evaluate safety and efficacy of Seraph(®)100 treatment for COVID-19 patients. METHODS: Twelve hospitals from six countries representing two continents documented patient and treatment characteristics as well as outcome parameters without reimbursement. Additionally, mortality and safety results of the device were reported. One hundred-and-two treatment sessions in 82 patients were documented in the registry. Four patients were excluded from mortality analysis due to incomplete outcome data, which were available in the other 78 patients. RESULTS: Overall, a 30-day mortality rate of 46.2% in the 78 patients with complete follow up was reported. Median treatment time was 5.00 [4.00–13.42] h. and 43.1% of the treatments were performed as hemoperfusion only. Adverse events of the Seraph(®)100 treatment were reported in 8.8% of the 102 treatments and represented premature end of treatment due to circuit failure. Patients that died were treated later in their ICU stay and onset of COVID symptoms. They also had higher ferritin levels. Multivariate Cox regression revealed that delayed Seraph(®)100 treatment after ICU admission (>60 hours) as well as bacterial superinfection were associated with mortality. While average predicted mortality rate according to SOFA score in ICU patients was 56.7% the observed mortality was 50.7%. In non-ICU patients 4C-Score average predicted a mortality rate of 38.0% while the observed mortality rate was 11.1% CONCLUSIONS: The treatment of COVID-19 patients with Seraph(®)100 is well tolerated and the circuit failure rate was lower than previously reported for KRT in COVID-19 patients. Mortality corelated with late initiation of Seraph treatment after ICU admission and bacterial superinfection infection. Compared to predicted mortality according to 4C-Score and SOFA Score, mortality of Seraph(®)100 treated patients reported in the registry was lower