Author Archives: Bora Zivkovic

Continue reading →

So, let’s see what’s new in PLoS Genetics, PLoS Computational Biology, PLoS Pathogens and PLoS ONE this week. As always, you should rate the articles, post notes and comments and send trackbacks when you blog about the papers. Here are my own picks for the week – you go and look for your own favourites:
Robust Food Anticipatory Activity in BMAL1-Deficient Mice:

Food availability is a potent environmental cue that directs circadian locomotor activity in rodents. Even though nocturnal rodents prefer to forage at night, daytime food anticipatory activity (FAA) is observed prior to short meals presented at a scheduled time of day. Under this restricted feeding regimen, rodents exhibit two distinct bouts of activity, a nocturnal activity rhythm that is entrained to the light-dark cycle and controlled by the master clock in the suprachiasmatic nuclei (SCN) and a daytime bout of activity that is phase-locked to mealtime. FAA also occurs during food deprivation, suggesting that a food-entrainable oscillator (FEO) keeps time in the absence of scheduled feeding. Previous studies have demonstrated that the FEO is anatomically distinct from the SCN and that FAA is observed in mice lacking some circadian genes essential for timekeeping in the SCN. In the current study, we optimized the conditions for examining FAA during restricted feeding and food deprivation in mice lacking functional BMAL1, which is critical for circadian rhythm generation in the SCN. We found that BMAL1-deficient mice displayed FAA during restricted feeding in 12hr light:12hr dark (12L:12D) and 18L:6D lighting cycles, but distinct activity during food deprivation was observed only in 18L:6D. While BMAL1-deficient mice also exhibited robust FAA during restricted feeding in constant darkness, mice were hyperactive during food deprivation so it was not clear that FAA consistently occurred at the time of previously scheduled food availability. Taken together, our findings suggest that optimization of experimental conditions such as photoperiod may be necessary to visualize FAA in genetically modified mice. Furthermore, the expression of FAA may be possible without a circadian oscillator that depends on BMAL1.

The Generation of Forces and Moments during Visual-Evoked Steering Maneuvers in Flying Drosophila:

Sideslip force, longitudinal force, rolling moment, and pitching moment generated by tethered fruit flies, Drosophila melanogaster, were measured during optomotor reactions within an electronic flight simulator. Forces and torques were acquired by optically measuring the angular deflections of the beam to which the flies were tethered using a laser and a photodiode. Our results indicate that fruit flies actively generate both sideslip and roll in response to a lateral focus of expansion (FOE). The polarity of this behavior was such that the animal’s aerodynamic response would carry it away from the expanding pattern, suggesting that it constitutes an avoidance reflex or centering response. Sideslip forces and rolling moments were sinusoidal functions of FOE position, whereas longitudinal force was proportional to the absolute value of the sine of FOE position. Pitching moments remained nearly constant irrespective of stimulus position or strength, with a direction indicating a tonic nose-down pitch under tethered conditions. These experiments expand our understanding of the degrees of freedom that a fruit fly can actually control in flight.

Producer Nutritional Quality Controls Ecosystem Trophic Structure:

Trophic structure, or the distribution of biomass among producers and consumers, determines key ecosystem values, such as the abundance of infectious, harvestable or conservation target species, and the storage and cycling of carbon and nutrients. There has been much debate on what controls ecosystem trophic structure, yet the answer is still elusive. Here we show that the nutritional quality of primary producers controls the trophic structure of ecosystems. By increasing the efficiency of trophic transfer, higher producer nutritional quality results in steeper ecosystem trophic structure, and those changes are more pronounced in terrestrial than in aquatic ecosystems probably due to the more stringent nutritional limitation of terrestrial herbivores. These results explain why ecosystems composed of highly nutritional primary producers feature high consumer productivity, fast energy recycling, and reduced carbon accumulation. Anthropogenic changes in producer nutritional quality, via changes in trophic structure, may alter the values and functions of ecosystems, and those alterations may be more important in terrestrial ecosystems.

Directing Experimental Biology: A Case Study in Mitochondrial Biogenesis:

Genome sequencing has provided us with “parts lists” of genes for many organisms, but many of the biological roles these genes are still unknown. While a great deal of functional genomic data exists, providing information about these genes and their roles, the rate at which these data are leveraged into concrete biological knowledge lags far behind the rate of data generation. Many computational approaches have been developed to generate accurate predictions of gene functions, with the goal of bridging this divide. However, as no large-scale experimental efforts have been based on such approaches, their validity and utility remains unproven. We have performed a study that experimentally evaluates predictions from a combination of three computational function prediction approaches, focusing on mitochondrion-related processes in brewer’s yeast as a model system. By using computational predictions to guide our laboratory investigation, we have greatly accelerated the rate at which proteins can be assigned to biological processes. Further, our results demonstrate that in order to achieve the best results, it is important for computational biologists to consider both the underlying data and the algorithmic foundations of the methods used to predict function. Lastly, we demonstrate that iterating through phases of prediction and validation has quickly and extensively expanded our knowledge of mitochondrial biology.

On the Growth of Scientific Knowledge: Yeast Biology as a Case Study:

It is of great interest to understand the patterns and mechanisms of scientific knowledge growth, but such studies have been hampered by the lack of ideal cases in which the structure of the knowledge is known, the knowledge is quantifiable, and the process of knowledge discovery is well understood and documented. The biological knowledge about a species is in part described by its protein interaction network and genetic interaction network. Here, we conduct a temporal meta-analysis of three decades of discoveries of protein interactions and genetic interactions in baker’s yeast to reveal the tempo and mode of the growth of yeast biology. We show that the growth is exponential over time and that important subjects tend to be studied earlier. However, expansions of different domains of knowledge are highly heterogeneous and episodic such that the temporal turnover of knowledge hubs is much greater than that expected by chance. Familiar subjects are preferentially studied over new subjects, leading to a reduced pace of innovation. While research is increasingly done in teams, the number of discoveries per researcher is greater in smaller teams. These findings reveal collective human behaviors in scientific research and help design better strategies in future knowledge exploration.

Computational Model of the Insect Pheromone Transduction Cascade:

All sensory neurons transduce their natural stimulus, whether a molecule, a photon, or a mechanical force, in an electrical current flowing through their sensory membrane via similar molecular and ionic mechanisms. Olfactory receptor neurons (ORNs), whose stimuli are volatile molecules, are no exception, including one of the best known: the exquisitely sensitive ORNs of male moths that detect the sexual pheromone released by conspecific females. We provide a detailed computational model of the intracellular molecular mechanisms at work in this ORN type. We describe qualitatively and quantitatively how the initial event, the interaction of pheromone molecules with specialized receptors at the ORN surface, is amplified through a sequence of linked biochemical and electrical events into a whole cell response, the receptor potential. We detail the respective roles of the upward activating reactions involving a cascade of ionic channels permeable to cations, chloride and potassium, their control by feedback inactivating mechanisms, and the central regulatory role of calcium. This computational model contributes to an integrated understanding of this signalling pathway, provides testable hypotheses, and suggests new experimental approaches.

Broadband Criticality of Human Brain Network Synchronization:

Systems in a critical state are poised on the cusp of a transition between ordered and random behavior. At this point, they demonstrate complex patterning of fluctuations at all scales of space and time. Criticality is an attractive model for brain dynamics because it optimizes information transfer, storage capacity, and sensitivity to external stimuli in computational models. However, to date there has been little direct experimental evidence for critical dynamics of human brain networks. Here, we considered two measures of functional coupling or phase synchronization between components of a dynamic system: the phase lock interval or duration of synchronization between a specific pair of time series or processes in the system and the lability of global synchronization among all pairs of processes. We confirmed that both synchronization metrics demonstrated scale invariant behaviors in two computational models of critical dynamics as well as in human brain functional systems oscillating at low frequencies (<0.5 Hz, measured using functional MRI) and at higher frequencies (1-125 Hz, measured using magnetoencephalography). We conclude that human brain functional networks demonstrate critical dynamics in all frequency intervals, a phenomenon we have described as broadband criticality.

Continue reading →

There are 11 new articles in PLoS ONE today. As always, you should rate the articles, post notes and comments and send trackbacks when you blog about the papers. You can now also easily place articles on various social services (CiteULike, Connotea, Stumbleupon, Facebook and Digg) with just one click. Here are my own picks for the week – you go and look for your own favourites:
Is the New Primate Genus Rungwecebus a Baboon?:

In 2005, a new primate species from Tanzania, the kipunji, was described and recognized as a member of the mangabey genus Lophocebus. However, molecular investigations based upon a number of papionins, including a limited sample of baboons of mainly unknown geographic origin, identified the kipunji as a sister taxon to Papio and not as a member of Lophocebus. Accordingly, the kipunji was separated into its own monotypic genus, Rungwecebus. We compare available mitochondrial and nuclear sequence data from the voucher specimen of Rungwecebus to other papionin lineages, including a set of geographically proximal (parapatric) baboon samples. Based on mitochondrial sequence data the kipunji clusters with baboon lineages that lie nearest to it geographically, i.e. populations of yellow and chacma baboons from south-eastern Africa, and thus does not represent a sister taxon to Papio. Nuclear data support a Papio+Rungwecebus clade, but it remains questionable whether Rungwecebus represents a sister taxon to Papio, or whether it is nested within the genus as depicted by the mitochondrial phylogeny. Our study clearly supports a close relationship between Rungwecebus and Papio and might indicate that the kipunji is congeneric with baboon species. However, due to its morphological and ecological uniqueness Rungwecebus more likely represents a sister lineage to Papio and experienced later introgressive hybridization. Presumably, male (proto-)kipunjis reproduced with sympatric female baboons. Subsequent backcrossing of the hybrids with kipunjis would have resulted in a population with a nuclear kipunji genome, but which retained the yellow/chacma baboon mitochondrial genome. Since only one kipunji specimen was studied, it remains unclear whether all members of the new genus have been impacted by intergeneric introgression or rather only some populations. Further studies with additional Rungwecebus samples are necessary to elucidate the complete evolutionary history of this newly-described primate genus.

Continue reading →

There are 17 new articles in PLoS ONE today. As always, you should rate the articles, post notes and comments and send trackbacks when you blog about the papers. You can now also easily place articles on various social services (CiteULike, Connotea, Stumbleupon, Facebook and Digg) with just one click. Here are my own picks for the week – you go and look for your own favourites:
Adult-Young Ratio, a Major Factor Regulating Social Behaviour of Young: A Horse Study:

Adults play an important role in regulating the social behaviour of young individuals. However, a few pioneer studies suggest that, more than the mere presence of adults, their proportions in social groups affect the social development of young. Here, we hypothesized that aggression rates and social cohesion were correlated to adult-young ratios. Our biological model was naturally-formed groups of Przewalski horses, Equus f. przewalskii, varying in composition. We investigated the social interactions and spatial relationships of 12 one- and two-year-old Przewalski horses belonging to five families with adult-young ratios (AYR) ranging from 0.67 to 1.33. We found striking variations of aggression rates and spatial relationships related to the adult-young ratio: the lower this ratio, the more the young were aggressive, the more young and adults segregated and the tighter the young bonded to other young. This is the first study demonstrating a correlation between adult-young ratios and aggression rates and social cohesion of young individuals in a naturalistic setting. The increase of aggression and the emergence of social segregation in groups with lower proportions of adults could reflect a related decrease of the influence of adults as regulators of the behaviour of young. This social regulation has both theoretical and practical implications for understanding the modalities of the influence of adults during ontogeny and for recommending optimal settings, as for instance, for schooling or animal group management.

I Feel what You Feel if You Are Similar to Me:

Social interactions are influenced by the perception of others as similar or dissimilar to the self. Such judgements could depend on physical and semantic characteristics, such as membership in an ethnic or political group. In the present study we tested whether social representations of the self and of others could affect the perception of touch. To this aim, we assessed tactile perception on the face when subjects observed a face being touched by fingers. In different conditions we manipulated the identity of the shown face. In a first experiment, Caucasian and Maghrebian participants viewed a face belonging either to their own or to a different ethnic group; in a second experiment, Liberal and Conservative politically active participants viewed faces of politicians belonging to their own or to the opposite political party. The results showed that viewing a touched face most strongly enhanced the perception of touch on the observer’s face when the observed face belonged to his/her own ethnic or political group.

Health and Human Rights Education in U.S. Schools of Medicine and Public Health: Current Status and Future Challenges:

Despite increasing recognition of the importance of human rights in the protection and promotion of health, formal human rights education has been lacking in schools of medicine and public health. Our objectives were: 1) to determine the nature and extent of health and human rights (HHR) education among schools of medicine (SOMs) and public health (SPHs); 2) to identify perceived barriers to implementing HHR curricula; 3) to learn about deans’ interests and attitudes toward HHR education, and; 4) to identify factors associated with offering HHR education. We conducted a cross-sectional survey among deans of all accredited allopathic SOMs and SPHs in the United States and Puerto Rico. Seventy-one percent of U.S. SOMs and SPHs responded. Thirty-seven percent of respondents indicated that their schools offered some form of HHR education. Main barriers to offering HHR education included competition for time, lack of qualified instructors and lack of funding. Among schools not offering HHR education, 35% of deans were interested in offering HHR education. Seventy-six percent of all deans believed that it was very important or important to offer HHR education. Multiple regression analysis revealed that deans’ attitudes were the most important factor associated with offering any HHR education. Findings indicate that though a majority of deans of SOMs and SPHs believe that knowledge about human rights is important in health practice and support the inclusion of HHR studies in their schools, HHR education is lacking at most of their institutions. These results and the growing recognition of the critical interdependence between health and human rights indicate a need for SOMs and SPHs to work towards formal inclusion of HHR studies in their curricula, and that HHR competency requirements be considered to overcome barriers to its inclusion.

Media Reporting of Health Interventions: Signs of Improvement, but Major Problems Persist:

Studies have persistently shown deficiencies in medical reporting by the mainstream media. We have been monitoring the accuracy and comprehensiveness of medical news reporting in Australia since mid 2004. This analysis of more than 1200 stories in the Australian media compares different types of media outlets and examines reporting trends over time. Between March 2004 and June 2008 1230 news stories were rated on a national medical news monitoring web site, Media Doctor Australia. These covered a variety of health interventions ranging from drugs, diagnostic tests and surgery to dietary and complementary therapies. Each story was independently assessed by two reviewers using ten criteria. Scores were expressed as percentages of total assessable items deemed satisfactory according to a coding guide. Analysis of variance was used to compare mean scores and Fishers exact test to compare proportions. Trends over time were analysed using un-weighted linear regression analysis. Broadsheet newspapers had the highest average satisfactory scores: 58% (95% CI 56-60%), compared with tabloid newspapers and online news outlets, 48% (95% CI 44-52) and 48% (95% CI 46-50) respectively. The lowest scores were assigned to stories broadcast by human interest/current affairs television programmes (average score 33% (95% CI 28-38)). While there was a non- significant increase in average scores for all outlets, a significant improvement was seen in the online news media: a rise of 5.1% (95%CI 1.32, 8.97; P 0.009). Statistically significant improvements were seen in coverage of the potential harms of interventions, the availability of treatment or diagnostic options, and accurate quantification of benefits. Although the overall quality of medical reporting in the general media remains poor, this study showed modest improvements in some areas. However, the most striking finding was the continuing very poor coverage of health news by commercial current affairs television programs.

The Influence of Recovery and Training Phases on Body Composition, Peripheral Vascular Function and Immune System of Professional Soccer Players:

Professional soccer players have a lengthy playing season, throughout which high levels of physical stress are maintained. The following recuperation period, before starting the next pre-season training phase, is generally considered short but sufficient to allow a decrease in these stress levels and therefore a reduction in the propensity for injury or musculoskeletal tissue damage. We hypothesised that these physical extremes influence the body composition, blood flow, and endothelial/immune function, but that the recuperation may be insufficient to allow a reduction of tissue stress damage. Ten professional football players were examined at the end of the playing season, at the end of the season intermission, and after the next pre-season endurance training. Peripheral blood flow and body composition were assessed using venous occlusion plethysmography and DEXA scanning respectively. In addition, selected inflammatory and immune parameters were analysed from blood samples. Following the recuperation period a significant decrease of lean body mass from 74.4±4.2 kg to 72.2±3.9 kg was observed, but an increase of fat mass from 10.3±5.6 kg to 11.1±5.4 kg, almost completely reversed the changes seen in the pre-season training phase. Remarkably, both resting and post-ischemic blood flow (7.3±3.4 and 26.0±6.3 ml/100 ml/min) respectively, were strongly reduced during the playing and training stress phases, but both parameters increased to normal levels (9.0±2.7 and 33.9±7.6 ml/100 ml/min) during the season intermission. Recovery was also characterized by rising levels of serum creatinine, granulocytes count, total IL-8, serum nitrate, ferritin, and bilirubin. These data suggest a compensated hypo-perfusion of muscle during the playing season, followed by an intramuscular ischemia/reperfusion syndrome during the recovery phase that is associated with muscle protein turnover and inflammatory endothelial reaction, as demonstrated by iNOS and HO-1 activation, as well as IL-8 release. The data provided from this study suggest that the immune system is not able to function fully during periods of high physical stress. The implications of this study are that recuperation should be carefully monitored in athletes who undergo intensive training over extended periods, but that these parameters may also prove useful for determining an individual’s risk of tissue stress and possibly their susceptibility to progressive tissue damage or injury.

There are 20 new articles in PLoS ONE today. As always, you should rate the articles, post notes and comments and send trackbacks when you blog about the papers. You can now also easily place articles on various social services (CiteULike, Connotea, Stumbleupon, Facebook and Digg) with just one click. Here are my own picks for the week – you go and look for your own favourites:
The Spatial and Temporal Construction of Confidence in the Visual Scene:

Human subjects can report many items of a cluttered field a few hundred milliseconds after stimulus presentation. This memory decays rapidly and after a second only 3 or 4 items can be stored in working memory. Here we compared the dynamics of objective performance with a measure of subjective report and we observed that 1) Objective performance beyond explicit subjective reports (blindsight) was significantly more pronounced within a short temporal interval and within specific locations of the visual field which were robust across sessions 2) High confidence errors (false beliefs) were largely confined to a small spatial window neighboring the cue. The size of this window did not change in time 3) Subjective confidence showed a moderate but consistent decrease with time, independent of all other experimental factors. Our study allowed us to asses quantitatively the temporal and spatial access to an objective response and to subjective reports.

Distinct Regions of Right Temporo-Parietal Junction Are Selective for Theory of Mind and Exogenous Attention:

In functional magnetic resonance imaging (fMRI) studies, a cortical region in the right temporo-parietal junction (RTPJ) is recruited when participants read stories about people’s thoughts (‘Theory of Mind’). Both fMRI and lesion studies suggest that a region near the RTPJ is associated with attentional reorienting in response to an unexpected stimulus. Do Theory of Mind and attentional reorienting recruit a single population of neurons, or are there two neighboring but distinct neural populations in the RTPJ? One recent study compared these activations, and found evidence consistent with a single common region. However, the apparent overlap may have been due to the low resolution of the previous technique. We tested this hypothesis using a high-resolution protocol, within-subjects analyses, and more powerful statistical methods. Strict conjunction analyses revealed that the area of overlap was small and on the periphery of each activation. In addition, a bootstrap analysis identified a reliable 6-10 mm spatial displacement between the peak activations of the two tasks; the same magnitude and direction of displacement was observed in within-subjects comparisons. In all, these results suggest that there are neighboring but distinct regions within the RTPJ implicated in Theory of Mind and orienting attention.

Offline Memory Reprocessing: Involvement of the Brain’s Default Network in Spontaneous Thought Processes:

Spontaneous thought processes (STPs), also called daydreaming or mind-wandering, occur ubiquitously in daily life. However, the functional significance of STPs remains largely unknown. Using functional magnetic resonance imaging (fMRI), we first identified an STPs-network whose activity was positively correlated with the subjects’ tendency of having STPs during a task-free state. The STPs-network was then found to be strongly associated with the default network, which has previously been established as being active during the task-free state. Interestingly, we found that offline reprocessing of previously memorized information further increased the activity of the STPs-network regions, although during a state with less STPs. In addition, we found that the STPs-network kept a dynamic balance between functional integration and functional separation among its component regions to execute offline memory reprocessing in STPs. These findings strengthen a view that offline memory reprocessing and STPs share the brain’s default network, and thus implicate that offline memory reprocessing may be a predetermined function of STPs. This supports the perspective that memory can be consolidated and modified during STPs, and thus gives rise to a dynamic behavior dependent on both previous external and internal experiences.

Continue reading →

The Implications of Multiple Circadian Clock Origins:

In the Beginning…
Genetics has had an awesome impact on our understanding of basic processes like circadian rhythms, which were mysterious before the incredibly successful marriage between genetics and recombinant DNA technology about 30 years ago. Subsequent to the pioneering work of Konopka and Benzer [1], genetic screens and DNA sequencing in multiple systems (including but not limited to humans, mice, Drosophila, Neurospora, plants, and cyanobacteria) identified many circadian genes as well as their protein sequences. Coupled with PCR methods to bootstrap from one system to another (e.g., [2,3]), this strategy also revealed that many clock proteins are shared between systems. For example, mammals and Drosophila use orthologs to construct their clocks [4-6]. Fly proteins include the PAS domain-containing transcription factor heterodimer Clock-Cycle (CLK-CYC [orthologs in mammals: CLK-BMAL1]) and the negative regulator Period (PER [orthologs in mammals: PER1, PER2]). These relationships indicate that a similar, basic clock mechanism was present in a common ancestor, before the separation of insects and mammals more than 500 million years ago. Some argue that the relationship of basic clock mechanism and proteins extends to Neurospora [7,8], which would push back the common ancestor date even further. (I am assuming that horizontal gene transfer is not responsible for the commonalities between systems.)
There is, however, no evidence that this relationship extends across the animal-bacterial kingdom divide; i.e., the key circadian proteins of mammals appear completely unrelated to the key circadian proteins of cyanobacteria. Although negative evidence must be interpreted with great caution (“absence of evidence is not evidence of absence”), there is no relationship evident between the circadian proteins of cyanobacteria and those of mammals [4,9]. As this is not the case for many other classes of proteins, the strong suggestion is that circadian rhythms have arisen at least twice, once in an ancestor of present-day cyanobacteria and then again in an ancestor of animals. (More than two evolutionary origins are also possible, as the different set of plant circadian proteins may indicate a third independent origin; although see below.) As some early version of cyanobacteria are generally credited with the rise of oxygen about 2.4 billion years ago, and multicellular eukaryotes did not appear for another 1.5 billion years or so [10], the evolution of cyanobacterial rhythms was probably well before that of eukaryotic rhythms.
The Importance of Biochemistry
A multiple-origin view of circadian clock origins has implications for how animal clocks keep time; i.e., what are their mechanisms or “quartz crystals”? In other words, progress in one system may have no impact on understanding a second. Relevant also is the fact that genetics is a poor way to define mechanism, in contrast to its irrefutable value in identifying key genes and proteins. These sequences are seductive, as a link between a circadian gene and a transcription factor can be interpreted to indicate an intimate relationship between transcription and timekeeping (e.g., [11]). However, only biochemistry can rigorously define mechanism, and nowhere is the distinction with genetics better illustrated than in the breathtaking reconstruction of a cyanobacterial clock in vitro [12].

Exploring the ‘Global Workspace’ of Consciousness:

As an explanatory principle in biology, vitalism has long been in decline, as one discovery after another revealed that mechanisms provide convincing explanations–hearts are pumps, genes are code–for all manner of life’s phenomena. But even through the 20th century, the mind has been vitalism’s last redoubt, because there has been no simple, satisfactory, mechanistic explanation of the most puzzling aspect of the mind: the nature of conscious awareness. For many years, even asking questions about the inner workings of this mental black box was taboo among some groups of scientists.
But that has all changed. A flood of new discoveries in every area of neuroscience has led to competing models of consciousness, and most importantly, testable hypotheses. A new study by Raphael Gaillard, Lionel Naccache, and colleagues provides support for one such model by showing that conscious, but not nonconscious, visual information is rapidly and widely distributed across the brain, provoking the synchronized brain activity that is the hallmark of conscious processing.

Media Portrayals of Suicide:

In a cohort study in this month’s PLoS Medicine, Nav Kapur (University of Manchester, United Kingdom) and colleagues report that young men (24 years and under) who had left the UK Armed Forces were at higher risk of suicide than either young men in the general population or those still in active service [1]. The risk appeared to be greatest in the first two years after discharge, in those with a short length of service, and in those of lower rank. There was a low rate of contact with mental health specialists in the year before death–just 14% for those under 20 years and 20% for those under 24 years. This study has identified a vulnerable group and highlights the need for targeted intervention to save lives.

Continue reading →