Single-cell analysis tools for drug discovery and development

The genetic, functional or compositional heterogeneity of healthy and diseased tissues presents major challenges in drug discovery and development. Such heterogeneity hinders the design of accurate disease models and can confound the interpretation of biomarker levels and of patient responses to specific therapies. The complex nature of virtually all tissues has motivated the development of tools for single-cell genomic, transcriptomic and multiplex proteomic analyses. Here, we review these tools and assess their advantages and limitations. Emerging applications of single cell analysis tools in drug discovery and development, particularly in the field of oncology, are discussed

Reexamining age, race, site, and thermometer type as variables affecting temperature measurement in adults – A comparison study

BACKGROUND: As a result of the recent international vigilance regarding disease assessment, accurate measurement of body temperature has become increasingly important. Yet, trusted low-tech, portable mercury glass thermometers are no longer available. Thus, comparing accuracy of mercury-free thermometers with mercury devices is essential. Study purposes were 1) to examine age, race, site as variables affecting temperature measurement in adults, and 2) to compare clinical accuracy of low-tech Galinstan-in-glass device to mercury-in-glass at oral, axillary, groin, and rectal sites in adults. METHODS: Setting 176 bed accredited healthcare facility, rural northwest US Participants Convenience sample (N = 120) of hospitalized persons ≥ 18 years old. Instruments Temperatures (°F) measured at oral, skin (simultaneous), immediately followed by rectal sites with four each mercury-glass (BD) and Galinstan-glass (Geratherm) thermometers; 10 minute dwell times. RESULTS: Participants averaged 61.6 years (SD 17.9), 188 pounds (SD 55.3); 61% female; race: 85% White, 8.3% Native Am., 4.2% Hispanic, 1.7 % Asian, 0.8% Black. For both mercury and Galinstan-glass thermometers, within-subject temperature readings were highest rectally; followed by oral, then skin sites. Galinstan assessments demonstrated rectal sites 0.91°F > oral and ≅ 1.3°F > skin sites. Devices strongly correlated between and across sites. Site difference scores between devices showed greatest variability at skin sites; least at rectal site. 95% confidence intervals of difference scores by site (°F): oral (0.142 – 0.265), axilla (0.167 – 0.339), groin (0.037 – 0.321), and rectal (-0.111 – 0.111). Race correlated with age, temperature readings each site and device. CONCLUSION: Temperature readings varied by age, race. Mercury readings correlated with Galinstan thermometer readings at all sites. Site mean differences between devices were considered clinically insignificant. Still considered the gold standard, mercury-glass thermometers may no longer be available worldwide. Therefore, mercury-free, environmentally safe low-tech Galinstan-in-glass may be an appropriate replacement. This is especially important as we face new, internationally transmitted diseases

Fortune Favours the Bold: An Agent-Based Model Reveals Adaptive Advantages of Overconfidence in War

Overconfidence has long been considered a cause of war. Like other decision-making biases, overconfidence seems detrimental because it increases the frequency and costs of fighting. However, evolutionary biologists have proposed that overconfidence may also confer adaptive advantages: increasing ambition, resolve, persistence, bluffing opponents, and winning net payoffs from risky opportunities despite occasional failures. We report the results of an agent-based model of inter-state conflict, which allows us to evaluate the performance of different strategies in competition with each other. Counter-intuitively, we find that overconfident states predominate in the population at the expense of unbiased or underconfident states. Overconfident states win because: (1) they are more likely to accumulate resources from frequent attempts at conquest; (2) they are more likely to gang up on weak states, forcing victims to split their defences; and (3) when the decision threshold for attacking requires an overwhelming asymmetry of power, unbiased and underconfident states shirk many conflicts they are actually likely to win. These “adaptive advantages” of overconfidence may, via selection effects, learning, or evolved psychology, have spread and become entrenched among modern states, organizations and decision-makers. This would help to explain the frequent association of overconfidence and war, even if it no longer brings benefits today

Bile signalling promotes chronic respiratory infections and antibiotic tolerance

Despite aggressive antimicrobial therapy, many respiratory pathogens persist in the lung, underpinning the chronic inflammation and eventual lung decline that are characteristic of respiratory disease. Recently, bile acid aspiration has emerged as a major comorbidity associated with a range of lung diseases, shaping the lung microbiome and promoting colonisation by Pseudomonas aeruginosa in Cystic Fibrosis (CF) patients. In order to uncover the molecular mechanism through which bile modulates the respiratory microbiome, a combination of global transcriptomic and phenotypic analyses of the P. aeruginosa response to bile was undertaken. Bile responsive pathways responsible for virulence, adaptive metabolism, and redox control were identified, with macrolide and polymyxin antibiotic tolerance increased significantly in the presence of bile. Bile acids, and chenodeoxycholic acid (CDCA) in particular, elicited chronic biofilm behaviour in P. aeruginosa, while induction of the pro-inflammatory cytokine Interleukin-6 (IL-6) in lung epithelial cells by CDCA was Farnesoid X Receptor (FXR) dependent. Microbiome analysis of paediatric CF sputum samples demonstrated increased colonisation by P. aeruginosa and other Proteobacterial pathogens in bile aspirating compared to non-aspirating patients. Together, these data suggest that bile acid signalling is a leading trigger for the development of chronic phenotypes underlying the pathophysiology of chronic respiratory disease