Antibiotic resistance-the need for global solutions.

The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.

A dimensionless number for understanding the evolutionary dynamics of antigenically variable RNA viruses.

Antigenically variable RNA viruses are significant contributors to the burden of infectious disease worldwide. One reason for their ubiquity is their ability to escape herd immunity through rapid antigenic evolution and thereby to reinfect previously infected hosts. However, the ways in which these viruses evolve antigenically are highly diverse. Some have only limited diversity in the long-run, with every emergence of a new antigenic variant coupled with a replacement of the older variant. Other viruses rapidly accumulate antigenic diversity over time. Others still exhibit dynamics that can be considered evolutionary intermediates between these two extremes. Here, we present a theoretical framework that aims to understand these differences in evolutionary patterns by considering a virus's epidemiological dynamics in a given host population. Our framework, based on a dimensionless number, probabilistically anticipates patterns of viral antigenic diversification and thereby quantifies a virus's evolutionary potential. It is therefore similar in spirit to the basic reproduction number, the well-known dimensionless number which quantifies a pathogen's reproductive potential. We further outline how our theoretical framework can be applied to empirical viral systems, using influenza A/H3N2 as a case study. We end with predictions of our framework and work that remains to be done to further integrate viral evolutionary dynamics with disease ecology.

Evolution of networks and sequences in eukaryotic cell cycle control.

The molecular networks regulating the G1-S transition in budding yeast and mammals are strikingly similar in network structure. However, many of the individual proteins performing similar network roles appear to have unrelated amino acid sequences, suggesting either extremely rapid sequence evolution, or true polyphyly of proteins carrying out identical network roles. A yeast/mammal comparison suggests that network topology, and its associated dynamic properties, rather than regulatory proteins themselves may be the most important elements conserved through evolution. However, recent deep phylogenetic studies show that fungal and animal lineages are relatively closely related in the opisthokont branch of eukaryotes. The presence in plants of cell cycle regulators such as Rb, E2F and cyclins A and D, that appear lost in yeast, suggests cell cycle control in the last common ancestor of the eukaryotes was implemented with this set of regulatory proteins. Forward genetics in non-opisthokonts, such as plants or their green algal relatives, will provide direct information on cell cycle control in these organisms, and may elucidate the potentially more complex cell cycle control network of the last common eukaryotic ancestor.

Baby on board: olfactory cues indicate pregnancy and fetal sex in a non-human primate.

Olfactory cues play an integral, albeit underappreciated, role in mediating vertebrate social and reproductive behaviour. These cues fluctuate with the signaller's hormonal condition, coincident with and informative about relevant aspects of its reproductive state, such as pubertal onset, change in season and, in females, timing of ovulation. Although pregnancy dramatically alters a female's endocrine profiles, which can be further influenced by fetal sex, the relationship between gestation and olfactory cues is poorly understood. We therefore examined the effects of pregnancy and fetal sex on volatile genital secretions in the ring-tailed lemur (Lemur catta), a strepsirrhine primate possessing complex olfactory mechanisms of reproductive signalling. While pregnant, dams altered and dampened their expression of volatile chemicals, with compound richness being particularly reduced in dams bearing sons. These changes were comparable in magnitude with other, published chemical differences among lemurs that are salient to conspecifics. Such olfactory 'signatures' of pregnancy may help guide social interactions, potentially promoting mother-infant recognition, reducing intragroup conflict or counteracting behavioural mechanisms of paternity confusion; cues that also advertise fetal sex may additionally facilitate differential sex allocation.

Olfactory conditioning facilitates diet transition in human infants.

We evaluated whether Pavlovian conditioning methods could be used to increase the ingestion of non-preferred solutions by formula-fed human infants. In baseline measures, 5-7 month old infants sucked less frequently and consumed less water than regular formula. During a 3-day olfactory conditioning period, parents placed a small scented disk, the conditioned stimulus, on the rim of their infants' formula bottle at every feeding. Following this training, infants' responses to water were tested when their water bottles had a disk scented with the training odor, a novel odor, or no odor. Infants tested with the training odor sucked more frequently and consumed significantly more water than they had at baseline. Infants tested with no odor or a novel odor consumed water at or below baseline levels. These data demonstrate that olfactory conditioning can be used to enhance ingestion in infants and suggest that such methods may be useful for infants experiencing difficulty when making transitions from one diet to another.

Mainland size variation informs predictive models of exceptional insular body size change in rodents.

The tendency for island populations of mammalian taxa to diverge in body size from their mainland counterparts consistently in particular directions is both impressive for its regularity and, especially among rodents, troublesome for its exceptions. However, previous studies have largely ignored mainland body size variation, treating size differences of any magnitude as equally noteworthy. Here, we use distributions of mainland population body sizes to identify island populations as 'extremely' big or small, and we compare traits of extreme populations and their islands with those of island populations more typical in body size. We find that although insular rodents vary in the directions of body size change, 'extreme' populations tend towards gigantism. With classification tree methods, we develop a predictive model, which points to resource limitations as major drivers in the few cases of insular dwarfism. Highly successful in classifying our dataset, our model also successfully predicts change in untested cases.

The impact of host immune status on the within-host and population dynamics of antigenic immune escape.

Antigenically evolving pathogens such as influenza viruses are difficult to control owing to their ability to evade host immunity by producing immune escape variants. Experimental studies have repeatedly demonstrated that viral immune escape variants emerge more often from immunized hosts than from naive hosts. This empirical relationship between host immune status and within-host immune escape is not fully understood theoretically, nor has its impact on antigenic evolution at the population level been evaluated. Here, we show that this relationship can be understood as a trade-off between the probability that a new antigenic variant is produced and the level of viraemia it reaches within a host. Scaling up this intra-host level trade-off to a simple population level model, we obtain a distribution for variant persistence times that is consistent with influenza A/H3N2 antigenic variant data. At the within-host level, our results show that target cell limitation, or a functional equivalent, provides a parsimonious explanation for how host immune status drives the generation of immune escape mutants. At the population level, our analysis also offers an alternative explanation for the observed tempo of antigenic evolution, namely that the production rate of immune escape variants is driven by the accumulation of herd immunity. Overall, our results suggest that disease control strategies should be further assessed by considering the impact that increased immunity--through vaccination--has on the production of new antigenic variants.

Considering the role of social dynamics and positional behavior in gestural communication research.

While the hominin fossil record cannot inform us on either the presence or extent of social and cognitive abilities that may have paved the way for the emergence of language, studying non-vocal communication among our closest living relatives, the African apes, may provide valuable information about how language originated. Although much has been learned from gestural signaling in non-human primates, we have not yet established how and why gestural repertoires vary across species, what factors influence this variation, and how knowledge of these differences can contribute to an understanding of gestural signaling's contribution to language evolution. In this paper, we review arguments surrounding the theory that language evolved from gestural signaling and suggest some important factors to consider when conducting comparative studies of gestural communication among African apes. Specifically, we propose that social dynamics and positional behavior are critical components that shape the frequency and nature of gestural signaling across species and we argue that an understanding of these factors could shed light on how gestural communication may have been the basis of human language. We outline predictions for the influence of these factors on the frequencies and types of gestures used across the African apes and highlight the importance of including these factors in future gestural communication research with primates.

Different Mechanisms Confer Gradual Control and Memory at Nutrient- and Stress-Regulated Genes in Yeast.

Cells respond to environmental stimuli by fine-tuned regulation of gene expression. Here we investigated the dose-dependent modulation of gene expression at high temporal resolution in response to nutrient and stress signals in yeast. The GAL1 activity in cell populations is modulated in a well-defined range of galactose concentrations, correlating with a dynamic change of histone remodeling and RNA polymerase II (RNAPII) association. This behavior is the result of a heterogeneous induction delay caused by decreasing inducer concentrations across the population. Chromatin remodeling appears to be the basis for the dynamic GAL1 expression, because mutants with impaired histone dynamics show severely truncated dose-response profiles. In contrast, the GRE2 promoter operates like a rapid off/on switch in response to increasing osmotic stress, with almost constant expression rates and exclusively temporal regulation of histone remodeling and RNAPII occupancy. The Gal3 inducer and the Hog1 mitogen-activated protein (MAP) kinase seem to determine the different dose-response strategies at the two promoters. Accordingly, GAL1 becomes highly sensitive and dose independent if previously stimulated because of residual Gal3 levels, whereas GRE2 expression diminishes upon repeated stimulation due to acquired stress resistance. Our analysis reveals important differences in the way dynamic signals create dose-sensitive gene expression outputs.

Stress-induced outer membrane vesicle production by Pseudomonas aeruginosa.

As an opportunistic Gram-negative pathogen, Pseudomonas aeruginosa must be able to adapt and survive changes and stressors in its environment during the course of infection. To aid survival in the hostile host environment, P. aeruginosa has evolved defense mechanisms, including the production of an exopolysaccharide capsule and the secretion of a myriad of degradative proteases and lipases. The production of outer membrane-derived vesicles (OMVs) serves as a secretion mechanism for virulence factors as well as a general bacterial response to envelope-acting stressors. This study investigated the effect of sublethal physiological stressors on OMV production by P. aeruginosa and whether the Pseudomonas quinolone signal (PQS) and the MucD periplasmic protease are critical mechanistic factors in this response. Exposure to some environmental stressors was determined to increase the level of OMV production as well as the activity of AlgU, the sigma factor that controls MucD expression. Overexpression of AlgU was shown to be sufficient to induce OMV production; however, stress-induced OMV production was not dependent on activation of AlgU, since stress caused increased vesiculation in strains lacking algU. We further determined that MucD levels were not an indicator of OMV production under acute stress, and PQS was not required for OMV production under stress or unstressed conditions. Finally, an investigation of the response of P. aeruginosa to oxidative stress revealed that peroxide-induced OMV production requires the presence of B-band but not A-band lipopolysaccharide. Together, these results demonstrate that distinct mechanisms exist for stress-induced OMV production in P. aeruginosa.

Polymorphisms at the microRNA binding-site of the stem cell marker gene CD133 modify susceptibility to and survival of gastric cancer.

CD133 is one of the most common stem cell markers, and functional single nucleotide polymorphisms (SNPs) of CD133 may modulate its gene functions and thus cancer risk and patient survival. We hypothesized that potentially functional CD133 SNPs are associated with gastric cancer (GC) risk and survival. To test this hypothesis, we conducted a case-control study of 371 GC patients and 313 cancer-free controls frequency-matched by age, sex, and ethnicity. We genotyped four selected, potentially functional CD133 SNPs (rs2240688A>C, rs7686732C>G, rs10022537T>A, and rs3130C>T) and used logistic regression analysis for associations of these SNPs with GC risk and Cox hazards regression analysis for survival. We found that compared with the miRNA binding site rs2240688 AA genotype, AC + CC genotypes were associated with significantly increased GC risk (adjusted OR = 1.52, 95% CI = 1.09-2.13); for another miRNA binding site rs3130C>T SNP, the TT genotype was associated with significantly reduced GC risk (adjusted OR = 0.68, 95% CI = 0.48-0.97), compared with CC + CT genotypes. In all patients, the risk rs3130 TT variant genotype was significantly associated with overall survival (OS) (adjusted P(trend) = 0.016 and 0.007 under additive and recessive models, respectively). These findings suggest that these two CD133 miRNA binding site variants, rs2240688 and rs3130, may be potential biomarkers for genetic susceptibility to GC and possible predictors for survival in GC patients but require further validation by larger studies.

Dietary quality and encephalization in platyrrhine primates.

The high energetic costs of building and maintaining large brains are thought to constrain encephalization. The 'expensive-tissue hypothesis' (ETH) proposes that primates (especially humans) overcame this constraint through reduction of another metabolically expensive tissue, the gastrointestinal tract. Small guts characterize animals specializing on easily digestible diets. Thus, the hypothesis may be tested via the relationship between brain size and diet quality. Platyrrhine primates present an interesting test case, as they are more variably encephalized than other extant primate clades (excluding Hominoidea). We find a high degree of phylogenetic signal in the data for diet quality, endocranial volume and body size. Controlling for phylogenetic effects, we find no significant correlation between relative diet quality and relative endocranial volume. Thus, diet quality fails to account for differences in platyrrhine encephalization. One taxon, in particular, Brachyteles, violates predictions made by ETH in having a large brain and low-quality diet. Dietary reconstructions of stem platyrrhines further indicate that a relatively high-quality diet was probably in place prior to increases in encephalization. Therefore, it is unlikely that a shift in diet quality was a primary constraint release for encephalization in platyrrhines and, by extrapolation, humans.

Brain evolution by brain pathway duplication.

Understanding the mechanisms of evolution of brain pathways for complex behaviours is still in its infancy. Making further advances requires a deeper understanding of brain homologies, novelties and analogies. It also requires an understanding of how adaptive genetic modifications lead to restructuring of the brain. Recent advances in genomic and molecular biology techniques applied to brain research have provided exciting insights into how complex behaviours are shaped by selection of novel brain pathways and functions of the nervous system. Here, we review and further develop some insights to a new hypothesis on one mechanism that may contribute to nervous system evolution, in particular by brain pathway duplication. Like gene duplication, we propose that whole brain pathways can duplicate and the duplicated pathway diverge to take on new functions. We suggest that one mechanism of brain pathway duplication could be through gene duplication, although other mechanisms are possible. We focus on brain pathways for vocal learning and spoken language in song-learning birds and humans as example systems. This view presents a new framework for future research in our understanding of brain evolution and novel behavioural traits.

Freezing behaviour facilitates bioelectric crypsis in cuttlefish faced with predation risk.

Cephalopods, and in particular the cuttlefish Sepia officinalis, are common models for studies of camouflage and predator avoidance behaviour. Preventing detection by predators is especially important to this group of animals, most of which are soft-bodied, lack physical defences, and are subject to both visually and non-visually mediated detection. Here, we report a novel cryptic mechanism in S. officinalis in which bioelectric cues are reduced via a behavioural freeze response to a predator stimulus. The reduction of bioelectric fields created by the freeze-simulating stimulus resulted in a possible decrease in shark predation risk by reducing detectability. The freeze response may also facilitate other non-visual cryptic mechanisms to lower predation risk from a wide range of predator types.