How close are we to a predictive science of the biosphere?

In just 20 years, the field of biosphere-atmosphere interactions has gone from a nascent discipline to a central area of modern climate change research. The development of terrestrial biosphere models that predict the responses of ecosystems to climate and increasing CO2 levels has highlighted several mechanisms by which changes in ecosystem composition and function might alter regional and global climate. However, results from empirical studies suggest that ecosystem responses can differ markedly from the predictions of terrestrial biosphere models. As I discuss here, the challenge now is to connect terrestrial biosphere models to empirical ecosystem measurements. Only by systematically evaluating the predictions of terrestrial biosphere models against suites of ecosystem observations and experiments measurements will a true predictive science of the biosphere be achieved.     

How to prove the existence of metabolons?

Sequential enzymes in biosynthetic pathways are organized in metabolons. It is challenging to provide experimental evidence for the existence of metabolons as biosynthetic pathways are composed of highly dynamic protein–protein interactions. Many different methods are being applied, each with strengths and weaknesses. We will present and evaluate several techniques that have been applied in providing evidence for the orchestration of the biosynthetic pathways of cyanogenic glucosides and glucosinolates in metabolons. These evolutionarily related pathways have ER-localized cytochromes P450 that are proposed to function as anchoring site for assembly of the enzymes into metabolons. Additionally, we have included commonly used techniques, even though they have not been used (yet) on these two pathways. In the review, special attention will be given to less-exploited fluorescence-based methods such as FCS and FLIM. Ultimately, understanding the orchestration of biosynthetic pathways may contribute to successful engineering in heterologous hosts.     

How is a seita fitted to the body?

A seita is a carrier frame for backpacking used in Nishiki-cho, Yamaguchi Prefecture, Japan. In this mountainous district, people make their living by agriculture and forestry and carry everything on their backs with seita. In this study, we investigated the relationships between the sizes of a body and the dimensions of a seita. This survey was conducted on 30 subjects (mean +/- SD; 68.1 +/- 9.0 years old) at three mountain villages. We measured some anthropometric sizes and seita dimensions and found that the correlation between height and sum of shoulder-lumbar-nuki distance (back length of a seita) and shoulder strap length is significant. In additional surveys, we took photographs with some markers on iliocristale, trochanterion, and so on, when the subjects carried seita in two load conditions. The photographs indicate that the load-supporting points in 16 of 23 subjects were between the iliocristale and trochanterion (i.e., on the sacrum). It is important to note that nobody showed that point above the iliocristale (i.e., on the lumbar vertebra). These data lead to the conclusion that when people in Nishik-icho carry loads with seita, they support loads not on the lumbar vertebrae but on the sacrum, and that they adjust the perimeter consisting of the back part and shoulder strap of the seita.     

Scientific discovery as a combinatorial optimisation problem: How best to navigate the landscape of possible experiments?

A considerable number of areas of bioscience, including gene and drug discovery, metabolic engineering for the biotechnological improvement of organisms, and the processes of natural and directed evolution, are best viewed in terms of a 'landscape' representing a large search space of possible solutions or experiments populated by a considerably smaller number of actual solutions that then emerge. This is what makes these problems 'hard', but as such these are to be seen as combinatorial optimisation problems that are best attacked by heuristic methods known from that field. Such landscapes, which may also represent or include multiple objectives, are effectively modelled in silico, with modern active learning algorithms such as those based on Darwinian evolution providing guidance, using existing knowledge, as to what is the 'best' experiment to do next. An awareness, and the application, of these methods can thereby enhance the scientific discovery process considerably. This analysis fits comfortably with an emerging epistemology that sees scientific reasoning, the search for solutions, and scientific discovery as Bayesian processes.     

How to use the paradigm of ischemic preconditioning to protect the heart?

Ischemic preconditioning affords the most powerful protection to a heart submitted to a prolonged ischemia-reperfusion. During the past decade, a huge amount of work allowed to better understand the features of this protective effect as well as the molecular mechanisms. Ischemic preconditioning reduces infarct size and improves functional recovery; its effects on arrhythmias remain debated. Triggering of the protection involves cell surface receptors that activate pro-survival pathways including protein kinase C, PI3-kinase, possibly Akt and ERK1/2, whose downstream targets remain to be determined. Much attention has been recently focused on the role of mitochondrial K(+)ATP channels and the permeability transition pore that seem to play a major role in the progression toward irreversible cellular injury. Based on these experimental studies attempts have been made to transfer preconditioning from bench to bedside. Human experimental models of ischemic preconditioning have been set up, including cardiac surgery, coronary angioplasty or treadmill exercise, to perform pathophysiological studies. Yet, protecting the heart of CAD (coronary artery disease) patients requires a pharmacological approach. The IONA trial has been an example of the clinical utility of preconditioning. It helped to demonstrate that chronic administration of nicorandil, a K(+)ATP opener that mimics ischemic preconditioning in experimental preparations, improves the cardiovascular prognosis in CAD patients. Recent experimental studies appear further encouraging. It appears that "postconditioning" the heart (i.e. performing brief episodes of ischemia-reperfusion at the time of reperfusion) is as protective as preconditioning. In other words, a therapeutic intervention performed as late as at the time of reflow can still significantly limit infarct size. Further work is needed to determine whether this may be transferred to the clinical practice.     

How to determine the susceptibility of Meligethes aeneus to neonicotinoids?

Three different bioassays were used to determine the susceptibility to the neonicotinoid Biscaya^® of oilseed rape pollen beetles collected from fields in Bavaria. The one in which the test substance was applied to the inner wall of glass tubes is recommended for future studies on pollen beetles because it is not dependent on the availability of plant material and provides precise information on the amount of insecticide required per unit area.     

Proline Substitution of Dimer Interface β-strand Residues as a Strategy for?the Design of Functional Monomeric Proteins

Proteins that exist in monomer-dimer equilibrium can be found in all organisms ranging from bacteria to humans; this facilitates fine-tuning of activities from signaling to catalysis. However, studying the structural basis of monomer function that naturally exists in monomer-dimer equilibrium is challenging, and most studies to date on designing monomers have focused on disrupting packing or electrostatic interactions that stabilize the dimer interface. In this study, we show that disrupting backbone H-bonding interactions by substituting dimer interface β-strand residues with proline (Pro) results in fully folded and functional monomers, by exploiting proline’s unique feature, the lack of a backbone amide proton. In interleukin-8, we substituted Pro for each of the three residues that form H-bonds across the dimer interface β-strands. We characterized the structures, dynamics, stability, dimerization state, and activity using NMR, molecular dynamics simulations, fluorescence, and functional assays. Our studies show that a single Pro substitution at the middle of the dimer interface β-strand is sufficient to generate a fully functional monomer. Interestingly, double Pro substitutions, compared to single Pro substitution, resulted in higher stability without compromising native monomer fold or function. We propose that Pro substitution of interface β-strand residues is a viable strategy for generating functional monomers of dimeric, and potentially tetrameric and higher-order oligomeric proteins.     

How random is the toss of a coin?

Background

The toss of a coin has been a method used to determine random outcomes for centuries. It is still used in some research studies as a method of randomization, although it has largely been discredited as a valid randomization method. We sought to provide evidence that the toss of a coin can be manipulated.

Methods

We performed a prospective experiment involving otolaryngology residents in Vancouver, Canada. The main outcome was the proportion of “heads” coin tosses achieved (out of 300 attempts) by each participant. Each of the participants attempted to flip the coin so as to achieve a heads result.

Results

All participants achieved more heads than tails results, with 7 of the 13 participants having significantly more heads results (p ≤ 0.05). The highest proportion of heads achieved was 0.68 (95% confidence interval 0.62–0.73, p < 0.001).

Interpretation

Certain people are able to successfully manipulate the toss of a coin. This throws into doubt the validity of using a coin toss to determine a chance result.The toss or flip of a coin to randomly assign a decision traditionally involves throwing a coin into the air and seeing which side lands facing up. This method may be used to resolve a dispute, see who goes first in a game or determine which type of treatment a patient receives in a clinical trial. There are only 2 possible outcomes, “heads” or “tails,” although, in theory, landing on an edge is possible. (Research suggests that when the coin is allowed to fall onto a hard surface, the chance of this happening is in the order of 1 in 6000 tosses.¹)When a coin is flipped into the air, it is supposedly made to rotate about an axis parallel to its flat surfaces. The coin is initially placed on a bent forefinger, and the thumb is released from under the coin surface, where it has been held under tension. The thumbnail strikes the part of the coin unsupported by the index finger, sending it rotating upward. All this is done with an upward movement of the hand and forearm. The coin may be allowed to fall to the floor or other surface or it may be caught by the “tosser” and sometimes turned onto the back of the opposite hand and then revealed. The catching method should not matter, provided it is consistent for each toss. The opponent often calls the toss when the coin is airborne, although in the case of randomization for clinical trials, this is unnecessary because one is simply looking for an outcome.Open in a separate windowThe appeal of the coin toss that it is a simple, seemingly unbiased, method of deciding between 2 options. Although the outcome of a coin toss should be at even odds, the outcome may well not be. Historically, the toss of a coin before a duel reputedly decided which person had his back to the sun — an obvious advantage when taking aim! In medical trials, a simple statistical manipulation can have a dramatic effect on the treatment a patient receives. Our hypothesis is that with minimal training, the outcome of the toss can be weighted heavily to the call of the tosser, thus abolishing the 50:50 chance result that is expected and allowing for manipulation of an apparently random event.     

How Large is the Probability for the Estimate of a Variance Component to be Negative?

For a balanced one-way classification, where the normally distributed observations obey a random model y_ij=μ+b_i+c_ij with two variance components var (b_i) = δ and var (c_ij) = δ, the probability is given that the analysis of variance estimate of δ will be negative. This probability depends on δ/δ and the degrees of freedom in the ANOVA table. Tables for this probability are given. If the normally distributed observations obey an intra-class correlation model, the probability that the Mean Square between groups is smaller than the Mean Square within groups can also be evaluated from the given tables.     

How long does it take to equilibrate the unfolded state of a protein?

How long does it take to equilibrate the unfolded state of a protein? The answer to this question has important implications for our understanding of why many small proteins fold with two state kinetics. When the equilibration within the unfolded state U is much faster than the folding, the folding kinetics will be two state even if there are many folding pathways with different barriers. Yet the mean first passage times (MFPTs) between different regions of the unfolded state can be much longer than the folding time. This seems to imply that the equilibration within U is much slower than the folding. In this communication we resolve this paradox. We present a formula for estimating the time to equilibrate the unfolded state of a protein. We also present a formula for the MFPT to any state within U, which is proportional to the average lifetime of that state divided by the state population. This relation is valid when the equilibration within U is very fast as compared with folding as it often is for small proteins. To illustrate the concepts, we apply the formulas to estimate the time to equilibrate the unfolded state of Trp-cage and MFPTs within the unfolded state based on a Markov State Model using an ultra-long 208 microsecond trajectory of the miniprotein to parameterize the model. The time to equilibrate the unfolded state of Trp-cage is ∼100 ns while the typical MFPTs within U are tens of microseconds or longer.     

The peregrination of Alcide d’Orbigny's Foraminifera Collection at the Museum of Natural History,Paris: From the creation of a Palaeontology chair to the advent of Micropalaeontology

Alcide d’Orbigny made his mark in the history of French Palaeontology by becoming, in 1853, the first holder of the chair of Palaeontology at the Museum of Natural History, Paris. His work on foraminifera made him one of the pioneers of Micropalaeontology. Today, his original collection of foraminifera, bought by the Museum after his death, represents one of the most prestigious collections of the institution. However, for more than a century, it had been relegated to the reserves and to the good will of a few enthusiasts, while the priority of research study was given to the large vertebrate fossils. It survived the conflicts that affected the Palaeontology department, and was moved in response to construction works, wars and natural accidents such as the great flood of 1910. These different events, combined with inappropriate storage conditions, probably caused the fragility of the specimens. In order to better understand this phenomenon, known as Byne's decay, research has been undertaken to reconstruct the various storage points of the collection from its acquisition to the present day. This article aims to demonstrate the close link between the Foraminifera Collection and the history of the chair of Palaeontology, through evidence drawn from the archives of the Palaeontology laboratory and the Museum of Natural History.     

How to lift a model for individual behaviour to the population level?

The quick answer to the title question is: by bookkeeping; introduce as p(opulation)-state a measure telling how the individuals are distributed over their common i(ndividual)-state space, and track how the various i-processes change this measure. Unfortunately, this answer leads to a mathematical theory that is technically complicated as well as immature. Alternatively, one may describe a population in terms of the history of the population birth rate together with the history of any environmental variables affecting i-state changes, reproduction and survival. Thus, a population model leads to delay equations. This delay formulation corresponds to a restriction of the p-dynamics to a forward invariant attracting set, so that no information is lost that is relevant for long-term dynamics. For such equations there exists a well-developed theory. In particular, numerical bifurcation tools work essentially the same as for ordinary differential equations. However, the available tools still need considerable adaptation before they can be practically applied to the dynamic energy budget (DEB) model. For the time being we recommend simplifying the i-dynamics before embarking on a systematic mathematical exploration of the associated p-behaviour. The long-term aim is to extend the tools, with the DEB model as a relevant goal post.