Classification of likely functional class for ligand binding sites identified from fragment screening

Fragment screening is used to identify binding sites and leads in drug discovery, but it is often unclear which binding sites are functionally important. Here, data from 37 experiments, and 1309 protein structures binding to 1601 ligands were analysed. A method to group ligands by binding sites is introduced and sites clustered according to profiles of relative solvent accessibility. This identified 293 unique ligand binding sites, grouped into four clusters (C1-4). C1 includes larger, buried, conserved, and population missense-depleted sites, enriched in known functional sites. C4 comprises smaller, accessible, divergent, missense-enriched sites, depleted in functional sites. A site in C1 is 28 times more likely to be functional than one in C4. Seventeen sites, which to the best of our knowledge are novel, in 13 proteins are identified as likely to be functionally important with examples from human tenascin and 5-aminolevulinate synthase highlighted. A multi-layer perceptron, and K-nearest neighbours model are presented to predict cluster labels for ligand binding sites with an accuracy of 96% and 100%, respectively, so allowing functional classification of sites for proteins not in this set. Our findings will be of interest to those studying protein-ligand interactions and developing new drugs or function modulators

Classification of likely functional class for ligand binding sites identified from fragment screening

Fragment screening is used to identify binding sites and leads in drug discovery, but it is often unclear which binding sites are functionally important. Here, data from 37 experiments, and 1309 protein structures binding to 1601 ligands were analysed. A method to group ligands by binding sites is introduced and sites clustered according to profiles of relative solvent accessibility. This identified 293 unique ligand binding sites, grouped into four clusters (C1-4). C1 includes larger, buried, conserved, and population missense-depleted sites, enriched in known functional sites. C4 comprises smaller, accessible, divergent, missense-enriched sites, depleted in functional sites. A site in C1 is 28 times more likely to be functional than one in C4. Seventeen sites, which to the best of our knowledge are novel, in 13 proteins are identified as likely to be functionally important with examples from human tenascin and 5-aminolevulinate synthase highlighted. A multi-layer perceptron, and K-nearest neighbours model are presented to predict cluster labels for ligand binding sites with an accuracy of 96% and 100%, respectively, so allowing functional classification of sites for proteins not in this set. Our findings will be of interest to those studying protein-ligand interactions and developing new drugs or function modulators

Sensemaking through the storm: how postpartum depression shapes personal work–family narratives.

Many women experience psychological and emotional challenges during their transition to becoming a working mother. Postpartum depression (PPD) is one common, salient aspect of motherhood that can serve as a work–life shock event and profoundly shape women’s work and nonwork lives yet has evaded discussion in the organizational sciences. Taking a grounded theory approach, we interviewed 41 women who experienced PPD as well as key informants who provided additional insights about PPD (e.g., an obstetrician, women working for organizations that support postpartum health). Our analysis highlights how being diagnosed with PPD activates a complex sensemaking process in which women process an imposing identity—a concept we introduce to the identity and work–family literatures reflecting an unexpected, undesirable identity that imposes upon existing (e.g., work) and/or provisional identities that may or may not be fully elaborated (e.g., motherhood), ultimately shifting how women think about the intersection of work and family. We also delineate how supports and antisupports (i.e., overt acts dismissive of women’s PPD) shape the aforementioned processes. Combined, our research aims to advance the discussion of PPD within organizational scholarship, rendering significant implications for both theory and practice

Amikacin use and therapeutic drug monitoring in adults : do dose regimens and drug exposures affect either outcome or adverse events? A systematic review

Objectives To identify the amikacin dosage regimens and drug concentrations consistent with good outcomes and to determine the drug exposures related to nephrotoxicity and ototoxicity. Methods A literature review was conducted in Medline, EMBASE and the Cochrane Central Register of Controlled Trials. Full journal articles of randomised controlled trials, controlled clinical trials, interrupted time series trials and controlled before and after studies involving amikacin TDM and dose adjustment were considered for inclusion. Results Seventeen included studies were identified, comprising 1677 participants. Amikacin doses ranged from 11-15 mg/kg/day with thirteen studies using 15 mg/kg/day. Studies were generally designed to compare different aminoglycosides rather than to assess concentration-effect relationships. Only eleven papers presented data on target concentrations, rate of clinical cure and toxicity. Target peak concentrations ranged from 15 – 40 mg/L and target troughs were typically <10 mg/L or <5 mg/L. It was not clear whether these targets were achieved. Measured peaks averaged 28 mg/L for twice daily dosing and 40-45 mg/L for once daily dosing; troughs averaged 5 mg/L and 1-2 mg/L, respectively. Fifteen of the included studies reported rates of nephrotoxicity; auditory and vestibular toxicities were reported in twelve and eight studies. Conclusions This systematic review found little published evidence to support an optimal dosage regimen or TDM targets for amikacin therapy. The use of alternative approaches, such as consensus opinion and a review of current practice, will be required to develop guidelines to maximise therapeutic outcomes and minimise toxicity with amikacin

Exploring the pharmacokinetics of phenoxymethylpenicillin (Penicillin-V) in adults: a healthy volunteer study

This healthy volunteer study aimed to explore Phenoxymethylpenicillin (Penicillin-V) pharmacokinetics (PK) to support the planning of large, dosing studies in adults. Volunteers were dosed with penicillin-V at steady state. Total and unbound penicillin-V serum concentration was determined and a base population PK model were fitted to the data

Consistent Anisotropic Repulsions for Simple Molecules

We extract atom-atom potentials from the effective spherical potentials that suc cessfully model Hugoniot experiments on molecular fluids, e.g., $O_2$ and $N_2$. In the case of $O_2$ the resulting potentials compare very well with the atom-atom potentials used in studies of solid-state propertie s, while for $N_2$ they are considerably softer at short distances. Ground state (T=0K) and room temperatu re calculations performed with the new $N-N$ potential resolve the previous discrepancy between experimental and theoretical results.Comment: RevTeX, 5 figure

Adsorption of para-Hydrogen on Krypton pre-plated graphite

Adsorption of para-Hydrogen on the surface of graphite pre-plated with a single layer of atomic krypton is studied thoretically by means of Path Integral Ground State Monte Carlo simulations. We compute energetics and density profiles of para-hydrogen, and determine the structure of the adsorbed film for various coverages. Results show that there are two thermodynamically stable monolayer phases of para-hydrogen, both solid. One is commensurate with the krypton layer, the other is incommensurate. No evidence is seen of a thermodynamically stable liquid phase, at zero temperature. These results are qualitatively similar to what is seen for for para-hydrogen on bare graphite. Quantum exchanges of hydrogen molecules are suppressed in this system.Comment: 12 pages, 6 figures, to appear in the proceedings of "Advances in Computational Many-Body Physics", Banff, Alberta (Canada), January 13-16 200

Epidural abscess caused by Streptococcus milleri in a pregnant woman

BACKGROUND: Bacteria in the Streptococcus milleri group (S. anginosus, S. constellatus, and S. intermedius) are associated with bacteremia and abscess formation. While most reports of Streptococcus milleri group (SMG) infection occur in patients with underlying medical conditions, SMG infections during pregnancy have been documented. However, SMG infections in pregnant women are associated with either neonatal or maternal puerperal sepsis. Albeit rare, S. milleri spinal-epidural abscess in pregnancy has been reported, always as a complication of spinal-epidural anesthesia. We report a case of spinal-epidural abscess caused by SMG in a young, pregnant woman without an antecedent history of spinal epidural anesthesia and without any underlying risk factors for invasive streptococcal disease. CASE PRESENTATION: A 25 year old pregnant woman developed neurological symptoms consistent with spinal cord compression at 20 weeks gestation. She underwent emergency laminectomy for decompression and was treated with ceftriaxone 2 gm IV daily for 28 days. She was ambulatory at the time of discharge from the inpatient rehabilitation unit with residual lower extremity weakness. CONCLUSION: To our knowledge, this is the first reported case of a Streptococcus milleri epidural abscess in a healthy, pregnant woman with no history of epidural anesthesia or invasive procedures. This report adds to the body of literature on SMG invasive infections. Treatment of SMG spinal-epidural abscess with neurologic manifestations should include prompt and aggressive surgical decompression coupled with targeted anti-infective therapy

Retrospective observational study to assess the clinical management and outcomes of hospitalised patients with complicated urinary tract infection in countries with high prevalence of multidrug resistant Gram-negative bacteria (RESCUING)

INTRODUCTION: The emergence of multidrug resistant (MDR) Gram-negative bacteria (GNB), including carbapenemase-producing strains, has become a major therapeutic challenge. These MDR isolates are often involved in complicated urinary tract infection (cUTI), and are associated with poor clinical outcomes. The study has been designed to gain insight into the epidemiology, clinical management, outcome and healthcare cost of patients with cUTI, especially in countries with high prevalence of MDR GNB. METHODS AND ANALYSIS: This multinational and multicentre observational, retrospective study will identify cases from 1 January 2013 to 31 December 2014 in order to collect data on patients with cUTI as a cause of hospital admission, and patients who develop cUTI during their hospital stay. The primary end point will be treatment failure defined as the presence of any of the following criteria: (1) signs or symptoms of cUTI present at diagnosis that have not improved by days 5–7 with appropriate antibiotic therapy, (2) new cUTI-related symptoms that have developed within 30 days of diagnosis, (3) urine culture taken within 30 days of diagnosis, either during or after completion of therapy, that grows ≥104 colony-forming unit/mL of the original pathogen and (4) death irrespective of cause within 30 days of the cUTI diagnosis. SAMPLE SIZE: 1000 patients afford a power of 0.83 (α=0.05) to detect an absolute difference of 10% in the treatment failure rate between MDR bacteria and other pathogens. This should allow for the introduction of about 20 independent risk factors (or their interaction) in a logistic regression model looking at risk factors for failure. ETHICS AND DISSEMINATION: Approval will be sought from all relevant Research Ethics Committees. Publication of this study will be considered as a joint publication by the participating investigator leads, and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE)