Information and Efficiency in the Nervous System—A Synthesis

In systems biology, questions concerning the molecular and cellular makeup of an organism are of utmost importance, especially when trying to understand how unreliable components—like genetic circuits, biochemical cascades, and ion channels, among others—enable reliable and adaptive behaviour. The repertoire and speed of biological computations are limited by thermodynamic or metabolic constraints: an example can be found in neurons, where fluctuations in biophysical states limit the information they can encode—with almost 20–60% of the total energy allocated for the brain used for signalling purposes, either via action potentials or by synaptic transmission. Here, we consider the imperatives for neurons to optimise computational and metabolic efficiency, wherein benefits and costs trade-off against each other in the context of self-organised and adaptive behaviour. In particular, we try to link information theoretic (variational) and thermodynamic (Helmholtz) free-energy formulations of neuronal processing and show how they are related in a fundamental way through a complexity minimisation lemma.     

Proportionality: A Valid Alternative to Correlation for Relative Data

In the life sciences, many measurement methods yield only the relative abundances of different components in a sample. With such relative—or compositional—data, differential expression needs careful interpretation, and correlation—a statistical workhorse for analyzing pairwise relationships—is an inappropriate measure of association. Using yeast gene expression data we show how correlation can be misleading and present proportionality as a valid alternative for relative data. We show how the strength of proportionality between two variables can be meaningfully and interpretably described by a new statistic ϕ which can be used instead of correlation as the basis of familiar analyses and visualisation methods, including co-expression networks and clustered heatmaps. While the main aim of this study is to present proportionality as a means to analyse relative data, it also raises intriguing questions about the molecular mechanisms underlying the proportional regulation of a range of yeast genes.     

Brachial Neuralgia and the Carpal Tunnel Syndrome

The carpal tunnel syndrome can cause severe pain and disability, both of which are avoidable if the condition is diagnosed and treated early in its course. Two sets of circumstances—delay in the correct diagnosis and recurrence of symptoms after an apparently successful operation—may give rise to problems in these aspects of management and delay recovery.     

Nutritional biology: a neglected basic discipline of nutritional science

On the basis of a scientific-philosophical analysis, this paper tries to show that the approaches in current nutritional science—including its subdisciplines which focus on molecular aspects—are predominantly application-oriented. This becomes particularly evident through a number of conceptual problems characterized by the triad of ‘dearth of theoretical foundation,’ ‘particularist research questions,’ and ‘reductionist understanding of nutrition.’ The thesis presented here is that an interpretive framework based on nutritional biology is able to shed constructive light on the fundamental problems of nutritional science. In this context, the establishment of ‘nutritional biology’ as a basic discipline in research and education would be a first step toward recognizing the phenomenon of ‘nutrition’ as an oecic process as a special case of an organism–environment interaction. Modern nutritional science should be substantively grounded on ecological—and therefore systems biology as well as organismic—principles. The aim of nutritional biology, then, should be to develop near-universal ‘law statements’ in nutritional science—a task which presents a major challenge for the current science system.     

Use of artificial genomes in assessing methods for atypical gene detection

Parametric methods for identifying laterally transferred genes exploit the directional mutational biases unique to each genome. Yet the development of new, more robust methods—as well as the evaluation and proper implementation of existing methods—relies on an arbitrary assessment of performance using real genomes, where the evolutionary histories of genes are not known. We have used the framework of a generalized hidden Markov model to create artificial genomes modeled after genuine genomes. To model a genome, “core” genes—those displaying patterns of mutational biases shared among large numbers of genes—are identified by a novel gene clustering approach based on the Akaike information criterion. Gene models derived from multiple “core” gene clusters are used to generate an artificial genome that models the properties of a genuine genome. Chimeric artificial genomes—representing those having experienced lateral gene transfer—were created by combining genes from multiple artificial genomes, and the performance of the parametric methods for identifying “atypical” genes was assessed directly. We found that a hidden Markov model that included multiple gene models, each trained on sets of genes representing the range of genotypic variability within a genome, could produce artificial genomes that mimicked the properties of genuine genomes. Moreover, different methods for detecting foreign genes performed differently—i.e., they had different sets of strengths and weaknesses—when identifying atypical genes within chimeric artificial genomes.     

Fifteen compelling open questions in plant cell biology

As scientists, we are at least as excited about the open questions—the things we do not know—as the discoveries. Here, we asked 15 experts to describe the most compelling open questions in plant cell biology. These are their questions: How are organelle identity, domains, and boundaries maintained under the continuous flux of vesicle trafficking and membrane remodeling? Is the plant cortical microtubule cytoskeleton a mechanosensory apparatus? How are the cellular pathways of cell wall synthesis, assembly, modification, and integrity sensing linked in plants? Why do plasmodesmata open and close? Is there retrograde signaling from vacuoles to the nucleus? How do root cells accommodate fungal endosymbionts? What is the role of cell edges in plant morphogenesis? How is the cell division site determined? What are the emergent effects of polyploidy on the biology of the cell, and how are any such “rules” conditioned by cell type? Can mechanical forces trigger new cell fates in plants? How does a single differentiated somatic cell reprogram and gain pluripotency? How does polarity develop de-novo in isolated plant cells? What is the spectrum of cellular functions for membraneless organelles and intrinsically disordered proteins? How do plants deal with internal noise? How does order emerge in cells and propagate to organs and organisms from complex dynamical processes? We hope you find the discussions of these questions thought provoking and inspiring.

We asked 15 experts to address what they consider to be the most compelling open questions in plant cell biology and these are their questions.     

Relatedness influences signal reliability in evolving robots

Communication is an indispensable component of animal societies, yet many open questions remain regarding the factors affecting the evolution and reliability of signalling systems. A potentially important factor is the level of genetic relatedness between signallers and receivers. To quantitatively explore the role of relatedness in the evolution of reliable signals, we conducted artificial evolution over 500 generations in a system of foraging robots that can emit and perceive light signals. By devising a quantitative measure of signal reliability, and comparing independently evolving populations differing in within-group relatedness, we show a strong positive correlation between relatedness and reliability. Unrelated robots produced unreliable signals, whereas highly related robots produced signals that reliably indicated the location of the food source and thereby increased performance. Comparisons across populations also revealed that the frequency for signal production—which is often used as a proxy of signal reliability in empirical studies on animal communication—is a poor predictor of signal reliability and, accordingly, is not consistently correlated with group performance. This has important implications for our understanding of signal evolution and the empirical tools that are used to investigate communication.     

VOMITING AS A SYMPTOM OF SERIOUS DISEASE IN INFANTS AND CHILDREN

Vomiting or its lesser stages—anorexia, nausea—is a prime symptom of the most serious surgically curable diseases of childhood.In the newborn, when vomitus is green, abdomen scaphoid, and erect roentgen view shows air-fluid levels in stomach and duodenum with gas beyond, partial duodenal obstruction is present and midgut volvulus with malrotation is likely enough to justify immediate exploration.In infancy, vomiting is a clear sign of intussusception when associated with intermittent colicky pain, palpable mass and “currant-jelly” feces. These symptoms are not always present, and if there is blood in the feces, barium enema study must follow. In further doubt, exploration may be justified.In childhood, a common early symptom of appendicitis is vomiting accompanied by pain without any complete remission. Constipation is frequent but diarrhea may occur and contribute to an impression of gastroenteritis. Complete and repeated physical examination, with a history of the above symptoms, should lead to correct diagnosis.     

The Role of Percutaneous Lung Biopsy in the Workup of a Solitary Pulmonary Nodule

As the technique of percutaneous lung biopsy continues to evolve, it offers an increasingly accurate method of establishing the malignancy or benignity of a solitary pulmonary nodule. There are relatively few contraindications to the procedure, and the complications—primarily pneumothorax and hemoptysis—generally resolve without therapy. Transthoracic needle aspiration has an important role in the workup for a “coin lesion.” Other elements of the diagnostic workup—particularly the history, a chest roentgenogram, computed tomography, sputum cytology, and transbronchial brush biopsy—may either add to or substitute for a transthoracic needle aspiration biopsy. An algorithm can be used to guide the diagnostic approach to a solitary pulmonary nodule.     

FATIGUE FRACTURES IN TRACK ATHLETES

Pain in a foot or in the lower leg, not related to specific injury, in a track athlete who does a great deal of running, is the first symptom of fatigue fracture. X-ray films taken at the time pain begins may show no abnormality. Films taken a month or more later may show formation of callus, and perhaps a fracture line, at the point of pain.Usually no treatment beyond cessation of running for two months or more is needed.Since the incidence is highest in middle-distance runners who train intensively—quartermilers in particular—and may be related to the hardness of the running track, limiting running to alternate days and doing part of it on grass may help in prevention.     

A helping hand: How vinculin contributes to cell-matrix and cell-cell force transfer

Vinculin helps cells regulate and respond to mechanical forces. It is a scaffolding protein that tightly regulates its interactions with potential binding partners within adhesive structures—including focal adhesions that link the cell to the extracellular matrix and adherens junctions that link cells to each other—that physically connect the force-generating actin cytoskeleton (CSK) with the extracellular environment. This tight control of binding partner interaction—mediated by vinculin''s autoinhibitory head–tail interaction—allows vinculin to rapidly interact and detach in response to changes in the dynamic forces applied through the cell. In doing so, vinculin modulates the structural composition of focal adhesions and the cell''s ability to generate traction forces and adhesion strength. Recent evidence suggests that vinculin plays a similar role in regulating the fate and function of cell–cell junctions, further underscoring the importance of this protein. Using our lab''s recent work as a starting point, this commentary explores several outstanding questions regarding the nature of vinculin activation and its function within focal adhesions and adherens junctions.     

Clarifying the Use of Aggregated Exposures in Multilevel Models: Self-Included vs. Self-Excluded Measures

Background

Multilevel analyses are ideally suited to assess the effects of ecological (higher level) and individual (lower level) exposure variables simultaneously. In applying such analyses to measures of ecologies in epidemiological studies, individual variables are usually aggregated into the higher level unit. Typically, the aggregated measure includes responses of every individual belonging to that group (i.e. it constitutes a self-included measure). More recently, researchers have developed an aggregate measure which excludes the response of the individual to whom the aggregate measure is linked (i.e. a self-excluded measure). In this study, we clarify the substantive and technical properties of these two measures when they are used as exposures in multilevel models.

Methods

Although the differences between the two aggregated measures are mathematically subtle, distinguishing between them is important in terms of the specific scientific questions to be addressed. We then show how these measures can be used in two distinct types of multilevel models—self-included model and self-excluded model—and interpret the parameters in each model by imposing hypothetical interventions. The concept is tested on empirical data of workplace social capital and employees'' systolic blood pressure.

Results

Researchers assume group-level interventions when using a self-included model, and individual-level interventions when using a self-excluded model. Analytical re-parameterizations of these two models highlight their differences in parameter interpretation. Cluster-mean centered self-included models enable researchers to decompose the collective effect into its within- and between-group components. The benefit of cluster-mean centering procedure is further discussed in terms of hypothetical interventions.

Conclusions

When investigating the potential roles of aggregated variables, researchers should carefully explore which type of model—self-included or self-excluded—is suitable for a given situation, particularly when group sizes are relatively small.     

Placebo Trends across the Border: US versus Canada

Background

Physicians around the world report to using placebos in a variety of situations and with varying degrees of frequency. Inconsistent methodologies, however, complicate interpretation and prevent direct comparisons across studies. While US- and Canada-based physicians share similar professional standards, Canada harbours a less-litigious universal healthcare model with no formal placebo-related policy—factors that may impact how physicians view and use placebos.

Methods

To compare American and Canadian data, we circulated an online survey to academic physicians practicing in Canada, collected anonymous responses, and extracted those of internists and rheumatologists for comparison to US data obtained through parallel methodologies.

Results

Whereas our data show overall concordance across the border—from definitions to ethical limitations and therapeutic potential—differences between American- and Canadian-based placebo practices merit acknowledgement. For example, compared to 45%-80% among US-based respondents, only 23±7% of Canada-based respondents reported using placebos in clinical practice. However, 79±7% of Canada-respondents—a figure comparable to US data—professed to prescribing at least one form of treatment without proven or expected efficacy. Placebo interventions including unwarranted vitamins and herbal supplements (impure placebos) as well as sugar pills and saline injections (pure placebos) appear more common in Canada, where more doctors described placebos as “placebos” (rather than “medications”) and used them as a “diagnostic” tool (rather than a means of placating patient demands for treatment).

Interpretation

Cross-border variation in the use of clinical placebos appears minor despite substantial differences in health care delivery system, malpractice climate, and placebo-related policy. The prevalence of impure placebos in both Canadian and US clinics raises ethical and practical questions currently unaddressed by policy and warranting investigation.     

Uncovering the different scales in deer–forest interactions

Deer are regarded to be a keystone species as they play a crucial role in the way an ecosystem functions. Most deer–forest interaction studies apply a single scale — process of analyzing ecological interactions by only taking into account one dependent variable — to understand how deer browsing behavior shapes different forest components, but they overlook the fact that forests respond to multiple scales simultaneously. This research evaluates the effect of browsing by wild deer on temperate and boreal forests at different scales by synthesizing seminal papers, specifically (a) what are the effects of deer population density in forest regeneration? (b) What are the effects of deer when forests present diverging spatial characteristics? (c) What are the effects on vegetation at different temporal scales? and (d) What are the hierarchical effects of deer when considering other trophic levels? Additionally, a framework based on modern technology is proposed to answer the multiscale research questions previously identified. When analyzing deer–forest interactions at different scales, the strongest relationships occur at the extremes. For example: when deer assemblage occurs in low or high density and is composed of a mix of small and large species. As forests on poor soils remain restrained in size, isolated and chronically browsed. When forests harbor incomplete trophic levels, the effects spill over to lower trophic levels. To better understand the complexities in deer–forest interactions, researchers should combine technology‐based instruments like fixed sensors and drones with field‐tested methods such observational studies and experiments to tackle multiscale research questions.     

NEWER HORMONAL PREPARATIONS

A review of the present status of various hormonal substances is presented. The pituitary preparations include various growth hormones (human and beef), still used only experimentally, thyrotropic hormone, used mainly for testing thyroid function, corticotropin—widely used—and gonadotropic hormone.Thyroid, thyroxin and triiodothyronine preparations are considered, with USP thyroid still being most useful. Glucagon may be of some use in terminating hypoglycemia — tolbutamide is now used in many older diabetic persons. New adrenal cortical steroids are still appearing and show variation in effects; cortisone or hydrocortisone remain relatively inexpensive. Many combinations are available.The newest addition to available male hormone preparations is fluoxymesterone which is anabolic in smaller dosage than the older forms.Several new long acting preparations of androgens, estrogens and progesterone are available, and many ingenious combinations are presented.     

Effect of Mating Structure on Variation in Linkage Disequilibrium

Measurement of linkage disequilibrium involves two sampling processes. First, there is the sampling of gametes in the population to form successive generations, and this generates disequilibrium dependent on the effective population size (N_e) and the mating structure. Second, there is sampling of a finite number (n) of individuals to estimate the population disequilibrium.——Two-locus descent measures are used to describe the mating system and are transformed to disequilibrium moments at the final sampling. Approximate eigenvectors for the transition matrix of descent measures are used to obtain formulae for the variance of the observed disequilibria as a function of N_e, mating structure, n, and linkage or recombination parameter.——The variance of disequilibrium is the same for monoecious populations with or without random selfing and for dioecious populations with random pairing for each progeny. With monogamy, the variance is slightly higher, the proportional difference being greater for unlinked loci.     

Awareness during Caesarean Section under General Anaesthesia

Investigation of a series of 150 obstetric patients, the majority undergoing caesarean section, showed the expected figure of 2% with factual recall. There was, however, a 17·3% occurrence of unpleasant recall—associated in 10 cases (6·6% of the total) with recall of pain. There was a negative correlation between the giving of a narcotic within six hours of the operation and the occurrence of unpleasant recall. Several other aetiological factors—age, parity, preoperative emotional tension, ventilation, nitrous oxide wash-out with oxygen, and nitrous oxide concentration—were investigated and no relation was found between them and unpleasant recall. It is suggested, therefore, that premedication still has an important function in light anaesthesia, using muscle relaxants, to prevent any form of unpleasant operative awareness.     

Involvement of autophagy and mitochondrial dynamics in determining the fate and effects of irreparable mitochondrial DNA damage

Mitochondrial DNA (mtDNA) is different in many ways from nuclear DNA. A key difference is that certain types of DNA damage are not repaired in the mitochondrial genome. What, then, is the fate of such damage? What are the effects? Both questions are important from a health perspective because irreparable mtDNA damage is caused by many common environmental stressors including ultraviolet C radiation (UVC). We found that UVC-induced mtDNA damage is removed slowly in the nematode Caenorhabditis elegans via a mechanism dependent on mitochondrial fusion, fission, and autophagy. However, knockdown or knockout of genes involved in these processes—many of which have homologs involved in human mitochondrial diseases—had very different effects on the organismal response to UVC. Reduced mitochondrial fission and autophagy caused no or small effects, while reduced mitochondrial fusion had dramatic effects.     

Whole Body Skeletal Scintiphotography in the Detection of Occult Metastatic Breast Carcinomas

Whole body skeletal scintiphotography was carried out in a series of 111 breast cancer patients. The results of scintiphotography were compared with the results of roentgenography and with the diagnostic usefulness of serum alkaline phosphatase levels and the presence or absence of bone pain. In 27 percent of cases, lesions were first identified with the scintiphotos. When lesions were present on both scintiphotos and roentgenograms, involvement generally appeared greater on the scintiphotos. Two false negative studies were recorded. Sixty-seven percent of patients with early metastasis—that is, those with positive scintiphotos and negative roentgenograms—were asymptomatic. Serum alkaline phosphatase levels were normal in 38 percent of those with early skeletal involvement. Skeletal scintiphotography is superior to other commonly employed techniques used to assess bone metastasis in breast carcinoma.     

Comparative genomics of cyclic-di-GMP signalling in bacteria: post-translational regulation and catalytic activity

Cyclic-di-GMP is a bacterial second messenger that controls the switch between motile and sessile states. It is synthesized by proteins containing the enzymatic GGDEF domain and degraded by the EAL domain. Many bacterial genomes encode several copies of proteins containing these domains, raising questions on how the activities of parallel c-di-GMP signalling systems are segregated to avoid potentially deleterious cross-talk. Moreover, many ‘hybrid’ proteins contain both GGDEF and EAL domains; the relationship between the two apparently opposing enzymatic activities has been termed a ‘biochemical conundrum’. Here, we present a computational analysis of 11 248 GGDEF- and EAL-containing proteins in 867 prokaryotic genomes to address these two outstanding questions. Over half of these proteins contain a signal for cell-surface localization, and a majority accommodate a signal-sensing partner domain; these indicate widespread prevalence of post-translational regulation that may segregate the activities of proteins that are co-expressed. By examining the conservation of amino acid residues in the GGDEF and EAL catalytic sites, we show that there are predominantly two types of hybrid proteins. In the first, both sites are intact; an additional regulatory partner domain, present in most of these proteins, might determine the balance between the two enzymatic activities. In the second type, only the EAL catalytic site is intact; these—unlike EAL-only proteins—generally contain a signal-sensing partner domain, suggesting distinct modes of regulation for EAL activity under different sequence contexts. Finally, we discuss the role of proteins that have lost GGDEF and EAL catalytic sites as potential c-di-GMP-binding effectors. Our findings will serve as a genomic framework for interpreting ongoing molecular investigations of these proteins.