Identification of kinase modulators as host-directed therapeutics against intracellular methicillin-resistant Staphylococcus aureus

The increasing prevalence of antimicrobial-resistant Staphylococcus aureus strains, especially methicillin-resistant S. aureus (MRSA), poses a threat to successful antibiotic treatment. Unsuccessful attempts to develop a vaccine and rising resistance to last-resort antibiotics urge the need for alternative treatments. Host-directed therapy (HDT) targeting critical intracellular stages of S. aureus emerges as a promising alternative, potentially acting synergistically with antibiotics and reducing the risk of de novo drug resistance. We assessed 201 ATP-competitive kinase inhibitors from Published Kinase Inhibitor Sets (PKIS1 and PKIS2) against intracellular MRSA. Seventeen hit compounds were identified, of which the two most effective and well-tolerated hit compounds (i.e., GW633459A and GW296115X) were selected for further analysis. The compounds did not affect planktonic bacterial cultures, while they were active in a range of human cell lines of cervical, skin, lung, breast and monocyte origin, confirming their host-directed mechanisms. GW633459A, structurally related to lapatinib, exhibited an HDT effect on intracellular MRSA independently of its known human epidermal growth factor receptor (EGFR)/(HER) kinase family targets. GW296115X activated adenosine monophosphate-activated protein kinase (AMPK), thereby enhancing bacterial degradation via autophagy. Finally, GW296115X not only reduced MRSA growth in human cells but also improved the survival rates of MRSA-infected zebrafish embryos, highlighting its potential as HDT

Effects of Nitrogen Nutrition on the Growth, Yield and Reflectance Characteristics of Corn Canopies

An experiment was conducted in which spectral and agronomic measurements were collected from corn (Zea mays L.) canopies under four nitrogen treatment levels (0, 67, 134, and 202 kg/ha) at the Purdue Agronomy Farm, W. Lafayette, IN, on 11 dates during 1978 and 12 dates during 1979. Spectral measurements over the 0.4 to 2.4 µm wavelength region were acquired with a spectroradiometer and used to compute reflectance factor. Agronomic data collected included biomass, leaf area index, plant height, crop development stage, and percent soil cover. Data were analyzed to determine: (1) the relationship between the spectral responses of canopies and their agronomic characteristics and (2) the spectral separability of the four treatments. Red reflectance was increased, while the near infrared reflectance was decreased for canopies under nitrogen deprivation. Spectral differences between treatments were seen throughout each growing season. The near infrared/red reflectance ratio increased spectral treatment differences over those shown by single band reflectance measure. The spectra of the four nitrogen treatments were significantly different on August dates; however, early and late in the season only two spectral classes were resolved. Of the spectral variables examined, the near infrared/red reflectance ration most effectively separated the treatments. Differences in spectral response between treatments were attributed to varying soil cover, leaf area index, and leaf pigmentation values, all of which changed with N treatment. The results further confirm the potential of remote sensing for monitoring the growth and condition of crops

Improvement and renewal of healthcare processes : results of an empirical research project

Professionals in healthcare organizations, who generally produce high-quality work, commonly operate in isolation or locally. However, due to developments in society and legislation, healthcare organizations are forced to integrate healthcare activities, and achieve integral quality management, instead of suboptimal, local quality management. Eindhoven University of Technology set up a study in 11 Dutch healthcare organizations in the area of interface management. The study was performed in general and mental hospitals, and clinics for care and treatment of drug addicts. The research projects aimed to develop methods to achieve an improvement or a renewal of healthcare processes. Special attention was paid to the interfaces between departments and individual parts of the healthcare process. In this paper an outline is given of both the improvement and the renewal approach, results of three of the 11 case studies are presented (as an example) and the improvement and the renewal approach are compared with respect to healthcare processes. Author Keywords: Healthcare processes; Improvement; Industrial engineering view; Renewal Index Terms: health care quality; health care personne