Cyclic Boronates Inhibit All Classes of β-Lactamase

β-Lactamase-mediated resistance is a growing threat to the continued use of β-lactam antibiotics. The use of the β-lactam-based serine-β-lactamase (SBL) inhibitors clavulanic acid, sulbactam, tazobactam, and, more recently, the non-β-lactam inhibitor avibactam has extended the utility of β-lactams against bacterial infections demonstrating resistance via these enzymes. These molecules are, however, ineffective against the metallo-β-lactamases (MBLs), which catalyse their hydrolysis. To date, there are no clinically available metallo-β-lactamase inhibitors. Co-production of MBLs and SBLs in resistant infections is, thus, of major clinical concern. The development of ‘dual-action' inhibitors, targeting both SBLs and MBLs, is of interest, but these are considered difficult to achieve due to the structural and mechanistic differences between the two enzyme classes. We recently reported evidence that cyclic boronates can inhibit both serine- and metallo-β-lactmases. Here we report that cyclic boronates are able to inhibit all four classes of β-lactamase, including the class A extended spectrum β-lactamase, CTX-M-15, the class C enzyme, AmpC from Pseudomonas aeruginosa, and class D OXA enzymes with carbapenem-hydrolysing capabilities. We demonstrate that cyclic boronates can potentiate the use of β-lactams against Gram-negative clinical isolates expressing a variety of β-lactamases. Comparison of a crystal structure of a CTX-M-15:cyclic boronate complex with structures of cyclic boronates complexed with other β-lactamases reveals remarkable conservation of the small molecule binding mode, supporting our proposal that these molecules work by mimicking the common tetrahedral anionic intermediate present in both serine- and metallo-β-lactamase catalysis

Biology and evolutionary games

This chapter surveys some evolutionary games used in biological sciences. These include the Hawk-Dove game, the Prisoner’s Dilemma, Rock–Paper–Scissors, the war of attrition, the Habitat Selection game, predatorprey games, and signalling games

Letter processing and font information during reading: beyond distinctiveness, where vision meets design

Letter identification is a critical front end of the reading process. In general, conceptualizations of the identification process have emphasized arbitrary sets of distinctive features. However, a richer view of letter processing incorporates principles from the field of type design, including an emphasis on uniformities across letters within a font. The importance of uniformities is supported by a small body of research indicating that consistency of font increases letter identification efficiency. We review design concepts and the relevant literature, with the goal of stimulating further thinking about letter processing during reading

Patient attitudes toward using computers to improve health services delivery

BACKGROUND: The aim of this study was to examine the acceptability of point of care computerized prompts to improve health services delivery among a sample of primary care patients. METHODS: Primary data collection. Cross-sectional survey. Patients were surveyed after their visit with a primary care provider. Data were obtained from patients of ten community-based primary care practices in the spring of 2001. RESULTS: Almost all patients reported that they would support using a computer before each visit to prompt their doctor to: "do health screening tests" (92%), "counsel about health behaviors (like diet and exercise)" (92%) and "change treatments for health conditions" (86%). In multivariate testing, the only variable that was associated with acceptability of the point of care computerized prompts was patient's confidence in their ability to answer questions about their health using a computer (beta = 0.39, p = .001). Concerns about data security were expressed by 36.3% of subjects, but were not related to acceptability of the prompts. CONCLUSIONS: Support for using computers to generate point of care prompts to improve quality-oriented processes of care was high in our sample, but may be contingent on patients feeling familiar with their personal medical history

A lionfish (Pterois miles) invasion has begun in the Mediterranean Sea

Until now, few sightings of the alien lionfish Pterois miles have been reported in the Mediterranean and it was questionable whether the species could invade this region like it has in the western Atlantic. Here, we present evidence from divers and fishermen that lionfish have recently increased in abundance and within a year colonised almost the entire south eastern coast of Cyprus, likely due to sea surface warming. At least 23 different fish are reported of which 6 were removed. Groups of lionfish exhibiting mating behaviour have been noted for the first time in the Mediterranean. Managers need this information and should alert stakeholders to the potential ecological and socio-economic impacts that may arise from a lionfish invasion. Actions could involve incentives to engage divers and fishermen in lionfish removal programmes, as these have worked well at shallow depths in the Caribbean. Given that the Suez Canal has recently been widened and deepened, measures will need to be put in place to help prevent further invasion

Why Are There So Few Rickettsia conorii conorii-Infected Rhipicephalus sanguineus Ticks in the Wild?

The bacterium Rickettsia conorii conorii is the etiological agent of Mediterranean spotted fever (MSF), which is a life-threatening infectious disease that is transmitted by Rhipicephalus sanguineus, the brown dog tick. Rh. sanguineus-R. conorii conorii relationships in the wild are still poorly understood one century after the discovery of the disease. In this study, we collected naturally infected ticks from the houses of people afflicted by MSF in Algeria. Colonies of both infected and non-infected ticks were maintained in our laboratory, and we studied the effect of temperature variations on the infected and non-infected ticks. We did not observe any major differences between the biological life cycle of the infected and non-infected ticks held at 25°C. However, a comparatively higher mortality relative to the control group was noticed when R. conorii conorii-infected engorged nymphs and adults were exposed to a low temperature (4°C) or high temperature (37°C) for one month and transferred to 25°C. R. conorii conorii-infected Rh. sanguineus may maintain and serve as reservoirs for the Rickettsia if they are not exposed to cold temperatures. New populations of ticks might become infected with Rickettsiae when feeding on a bacteremic animal reservoir

Quantifying Age-Related Differences in Information Processing Behaviors When Viewing Prescription Drug Labels

Adverse drug events (ADEs) are a significant problem in health care. While effective warnings have the potential to reduce the prevalence of ADEs, little is known about how patients access and use prescription labeling. We investigated the effectiveness of prescription warning labels (PWLs, small, colorful stickers applied at the pharmacy) in conveying warning information to two groups of patients (young adults and those 50+). We evaluated the early stages of information processing by tracking eye movements while participants interacted with prescription vials that had PWLs affixed to them. We later tested participants’ recognition memory for the PWLs. During viewing, participants often failed to attend to the PWLs; this effect was more pronounced for older than younger participants. Older participants also performed worse on the subsequent memory test. However, when memory performance was conditionalized on whether or not the participant had fixated the PWL, these age-related differences in memory were no longer significant, suggesting that the difference in memory performance between groups was attributable to differences in attention rather than differences in memory encoding or recall. This is important because older adults are recognized to be at greater risk for ADEs. These data provide a compelling case that understanding consumers’ attentive behavior is crucial to developing an effective labeling standard for prescription drugs

Quantifying the Multivariate ENSO Index (MEI) coupling to CO2 concentration and to the length of day variations

The El Ni\~no Southern Oscillation (ENSO) is the Earth's strongest climate fluctuation on inter-annual time-scales and has global impacts although originating in the tropical Pacific. Many point indices have been developed to describe ENSO but the Multivariate ENSO Index (MEI) is considered the most representative since it links six different meteorological parameters measured over the tropical Pacific. Extreme values of MEI are correlated to the extreme values of atmospheric CO2 concentration rate variations and negatively correlated to equivalent scale extreme values of the length of day (LOD) rate variation. We evaluate a first order conversion function between MEI and the other two indexes using their annual rate of variation. The quantification of the strength of the coupling herein evaluated provides a quantitative measure to test the accuracy of theoretical model predictions. Our results further confirm the idea that the major local and global Earth-atmosphere system mechanisms are significantly coupled and synchronized to each other at multiple scales.Comment: Theoretical Applied Climatology (2012