Why is big Pharma getting out of antibacterial drug discovery?

Since the advent of the antibiotic era in the late 1940s drug discovery and development has evolved into an expensive, time consuming, cumbersome and bureaucratic process involving multiple interest groups such as pharmaceutical manufacturers, governmental regulatory authorities, patent officers, academic and clinical researchers and trial lawyers. It would seem that the least involved among the interest groups are the consumers of health care themselves. Politicians and the public alike complain loudly about drug prices although fewer and fewer new therapies are being developed. The cost and complexities of drug discovery and development have shifted the investment equation away from the development of drugs targeting short course therapies for acute diseases and towards long-term treatment of chronic conditions. Coupled with the failure of large investments into target-based approaches to produce novel antibacterial agents, companies large and small have exited from this field despite a growing clinical need.     

A review of the effectiveness of vaccine potency control testing

The use of potency control testing is a valuable tool for testing the actual relative strength of manufactured assembly lots of vaccine. Biological-based manufacturing methods are inherently variable and potency testing is a tool to ensure lot-to-lot consistency of commercial vaccines. A strong historical link to clinical efficacy has been established where correlation to efficacy and adequate test validation have been achieved. The link to immunogenicity and efficacy has traditionally been strongest with attenuated vaccines and toxoids. Control potency test failure does predict that a serial or batch of vaccine would most likely provide insufficient immunogenicity in typical field applications. Because of the complexity of pathogenic processes and associated immune responses, potency tests may not always directly predict the effectiveness of a vaccine. Thus, vaccines that pass control potency testing may not always provide adequate efficacy. This is particularly true of adjuvanted, inactivated vaccines. In the development of vaccine formulations and control tests for vaccines, the nature of the desired protective immune responses to the targeted pathogen (when known) should be considered. These considerations could provide better alternatives in the assays chosen as correlates of immunity and may more accurately predict efficacy and assure batch-to-batch consistency. Also, the effects of the dose and duration of antigen exposure as well as the nature of antigen presentation and generation of extrinsic cytokines could be characterised and correlated to vaccine potency as additional indicators of vaccine efficacy.     

Developmental changes in the response of murine cerebellar granule cells to nitric oxide

Nitric oxide is a diffusible messenger that plays a multitude of roles within the nervous system including modulation of cell viability. However, its role in regulating neuronal survival during a defined period of neurodevelopment has never been investigated. We discovered that expression of the messenger RNA for both neuronal and endothelial nitric oxide synthase increased in the early postnatal period in the cerebellum in vivo, whilst the expression of inducible nitric oxide synthase remained constant throughout this time in development. Whilst scavenging of nitric oxide was deleterious to the survival of early postnatal cerebellar granule neurons in vitro, this effect was lost in cultures derived at increasing postnatal ages. Conversely, sensitivity to exogenous nitric oxide increased with advancing postnatal age. Thus, we have shown that as postnatal development proceeds, cerebellar granule cells alter their in vitro survival responses to both nitric oxide inhibition and donation, revealing that the nitric oxide's effects on developing neurons vary with the stage of development studied. These findings have important consequences for our understanding of the role of nitric oxide during neuronal development.     

Thermal effects in stretching of Go-like models of titin and secondary structures

The effect of temperature on mechanical unfolding of proteins is studied using a Go-like model with a realistic contact map and Lennard-Jones contact interactions. The behavior of the I27 domain of titin and its serial repeats is contrasted to that of simple secondary structures. In all cases, thermal fluctuations accelerate the unraveling process, decreasing the unfolding force nearly linearly at low temperatures. However, differences in bonding geometry lead to different sensitivity to temperature and different changes in the unfolding pattern. Due to its special native-state geometry, titin is much more thermally and elastically stable than the secondary structures. At low temperatures, serial repeats of titin show a parallel unfolding of all domains to an intermediate state, followed by serial unfolding of the domains. At high temperatures, all domains unfold simultaneously, and the unfolding distance decreases monotonically with the contact order, that is, the sequence distance between the amino acids that form the native contact.     

Do intraspecific life history patterns follow interspecific predictions? A test using latitudinal variation in ringed seals

Mammals adapted to unpredictable and low-energy environments often evolve a “bet-hedging” life history strategy characterized by less costly reproductive outputs over a longer and slower-growing life. In contrast, species adapted to more predictable (i.e., low variation) and higher energy environments may evolve greater fecundity over a shorter and faster-growing life. We tested whether this known interspecific pattern also occurs within a species. We compared life history traits of the ringed seal (Pusa hispida) in the Canadian High Arctic to those closer to the southern limit of the species' circumpolar distribution. We found that northern seals grew slower than southern seals (Brody growth coefficient), achieved a greater asymptotic body weight (82 and 69 kg vs. 74 and 54 kg female and male, respectively), reached sexual maturity later (6.1 years vs. 4.5 years), had lower fecundity (1.8 years vs. 1.3 years interbirth interval), longer average lifespan (5 years vs. 3 years median age), and greater movements (1,269 vs. 681 km). Mating systems also likely differed with northern seals showing morphological evidence of a promiscuous mating system with potential sperm competition as indicated by greater relative testes size. The northern region was also characterized by more unpredictable environmental timing of seasonal events, such as spring sea ice breakup. Life history variation between the intraspecific groups of seals appears to agree with interspecific patterns and provides a better understanding of how species' life history parameters shift in concert with environmental conditions.     

Traits associated with naturalization in <Emphasis Type=Italic>Anolis</Emphasis> lizards: comparison of morphological,distributional, anthropogenic,and phylogenetic models

The worldwide spread of invasive species affects native biodiversity and causes economic loss, but also allows better understanding of historical biogeographic patterns. Prediction of likely invaders facilitates economic and conservation decisions and gives insight into characteristics that have allowed natural colonization over evolutionary time. However, it is not clear what types of characters best predict naturalization or even whether naturalization is predictable at all. Squamate reptiles have been understudied subjects for invasion biology. Lizards of the genus Anolis have been highly successful colonizers both recently and over evolutionary time. Nineteen of the approximately 350 described species of Anolis have established naturalized populations. We constructed models of naturalization using morphological, distributional, anthropogenic, and phylogenetic characters and compared these single character class models to each other and to a composite model incorporating all four classes. We show that (1) each class of variables significantly predicts invasion, (2) a composite model significantly outperforms each of the submodels, and (3) the final composite model displays extraordinary ability to objectively identify naturalized species of Anolis.