Opinion: the species problem, can we achieve a universal concept?

One of the so called 'species problems' is that no universal concept exists. There is a tendency among microbiologists to criticize the hitherto devised concept. It is considered by some researchers as being too conservative and not suitable to be compared with those for eukaryotes. However, such problem is not only restricted to prokaryotes, but among other taxonomies comparisons seem to be impossible. As it is argued, the underlying cause to this problem is the reductionistic and monistic use of taxonomy. Analyzing the more than 22 devised concepts it seems possible to achieve a universal species concept. However, this might not be pragmatic. For the time being, a pluralistic sense of the species concept might be accepted, and one will have to recognize that any comparison among different taxonomies will be difficult.     

Estrogen and memory in women: how can we reconcile the findings?

Although several randomized controlled trials (RCTS) of surgically menopausal women have provided evidence that estrogen protects aspects of memory, many cross-sectional and longitudinal studies, including those from the RCT, the Women's Health Initiative Memory Study (WHIMS), have reported inconsistent information with regard to the relationship between estrogen and aspects of cognitive function. Although numerous reasons could be offered to explain these discrepancies in research findings, recent evidence from rodent, nonhuman primate, and human studies consistently suggests that one possibility may be critical to our understanding of the estrogenic effect on memory. Results of these animal and human studies indicate that the initiation of estrogen treatment at the time of menopause, or soon after ovariectomy (OVX), provides a window of opportunity for the preservation of memory in females whereas the administration of the hormone following a considerable delay in time after OVX has little or no beneficial effect on cognition. Considering the evidence that, in several organ systems, heightened disease risks accrue to a longer duration of estrogen deprivation in women, it would seem important to determine whether this is also true for brain structure and function in order to protect the quality of life for the considerable number of women who undergo a surgical menopause before their natural menopause had occurred.     

Examining the developing bone: What do we measure and how do we do it?

The clinical tools available to evaluate bone development in children are often ambiguous, and difficult to interpret. Unfortunately bone densitometry methods (i.e., dual energy X-ray absorptiometry, DXA) which have a relatively straightforward application in adult osteoporosis, are far more difficult to evaluate in the growing skeleton. Even with adequate "adjustment" for bone size or maturity, bone "density" (areal or volumetric) alone often gives an inaccurate assessment of bone strength--especially in children. Ideally, we would like to measure both material and geometric properties of bone to accurately estimate "strength". Mechanically meaningful measures of bone geometry (bone cross-sectional area, cortical thickness) and estimates of bending strength (section modulus, or SSI) are available with non-invasive techniques such as (p)QCT and some DXA software. With new technology it might be possible to also measure bone material properties, which will be especially important in some pediatric disorders. In children, we also need to know something about the loads imposed on a child's bone and consider not only absolute bone strength, but also the strength of bone relative to the physiologic loads. Interpreting bone strength in light of the loads imposed (particularly muscle force) is critical for an accurate diagnosis of the developing bone.     

Global elimination of trachoma: how frequently should we administer mass chemotherapy?

The World Health Organization has recommended repeat mass drug administration as part of their global initiative to eliminate blinding trachoma by the year 2020. The efficacy of repeat treatment will be tested empirically, but the results will not be available for many years, and recommendations for the necessary frequency of treatment are needed immediately. We have developed a mathematical model that uses available epidemiological data from a variety of countries. We recommend, based on our analysis, that in areas where trachoma is moderately prevalent (<35% in children), it should be treated annually, but hyperendemic areas (>50% in children), it should be treated biannually.     

Evidence-based care: 2. Setting guidelines: how should we manage this problem?

There are four steps in determining how to manage a clinical problem. The first is to formulate questions that are answerable; the second is to locate and synthesize the evidence needed to answer the questions; the third is to estimate the expected benefits, harms and costs of each option based on the evidence; and the fourth is to judge the relative value of the expected outcomes to conclude whether the benefits are worth the harms and costs. It is impractical to repeat these steps for every clinical decision. Therefore, implicitly or explicitly, physicians rely on guidelines, "rules" that simplify decision making about complex problems. If the methods used to develop a guideline are not explicit it is difficult or impossible to know how much confidence to place in it. Therefore, for common and important clinical problems, physicians should rely on guidelines that are systematically developed using explicit methods.     

Air travel and venous thrombosis: how much help might aspirin be?

There has been considerable attention focused recently on the risk of deep venous thrombosis (DVT) associated with air travel. Despite the lack of evidence among air travelers, a single dose of aspirin has been widely recommended as a means of preventing such thrombosis. We have calculated the potential benefit of aspirin by applying the data for aspirin in preventing DVT in hip fracture patients to the estimated rates of travel-related DVT. If the rate of travel-related DVT is 20 per 100,000 travelers, then we will have to treat 17,000 people with aspirin to prevent 1 additional DVT.     

Breaching the basement membrane: who, when and how?

The basement membrane (BM), a specialized network of extracellular matrix macromolecules, surrounds epithelial, endothelial, muscle, fat and nerve cells. During development, immune surveillance and disease states ranging from cancer to fibrosis, host cells penetrate the BM by engaging tissue-invasive programs, the identity of which remain largely undefined. Although it is commonly assumed that all cells employ similar mechanisms to cross BM barriers, accumulating evidence indicates that cells might selectively mobilize protease-dependent or -independent invasion programs. New data indicate that protease-dependent transmigration is largely reliant on a group of membrane-anchored metalloenzymes, termed the membrane-type matrix metalloproteinases, which irreversibly remodel BM structure. By contrast, mechanisms that enable protease-independent transmigration remain undefined and potentially involve the reversible disassembly of the BM network. Further characterization of the molecular mechanisms underlying BM transmigration should provide important insights into pathophysiologic tissue remodeling events and also enable the development of novel therapeutics.     

SNARE complexes and neuroexocytosis: how many, how close?

Regulated secretion is an essential process in all eukaryotic cells. The release of molecules contained inside exocytic granules and synaptic vesicles is mediated by the assembly of a SNARE complex formed by the coil-coiling of three proteins: SNAP-25, syntaxin and VAMP/synaptobrevin. It seems that SNARE complexes assemble together in rosette-shaped super-complexes but there is controversy on the actual number (N) of copies of SNARE complexes that are necessary to mediate exocytosis. We discuss attempts to determine the value of N and suggest that N varies with the type of exocytic vesicles. In addition, we propose that the N value in neuroexocytosis can be estimated by the comparative use of different types of botulinum neurotoxins.     

Adolescents with childhood-onset GHD: how do we get them to peak bone mass?

The development of osteoporosis, with its attendant risk of fragility fracture, is in part related to the peak bone mass (PBM) achieved in early adulthood. Adolescence is a critical time for the acquisition of bone mass, with around 40% of skeletal mass being accrued during pubertal maturation. Growth hormone (GH) plays an integral role in the achievement of PBM after completion of linear growth, and several recent studies have suggested that GH replacement should continue in individuals with childhood-onset GHD until PBM has been attained - irrespective of the height achieved. In those with severe GHD after growth and pubertal development are complete, a seamless transition of GH therapy into adult life may be preferable to allowing a gap in GH treatment. The 'window of opportunity' concept for achieving PBM will, nevertheless, continue to be challenged by GHD teenagers who may resent the seamless continuation of GH replacement beyond adolescence. Preparation for this possibility should therefore begin during childhood, with all GHD teenagers being encouraged to remain on GH therapy until at least their mid-20s.     

Tissue transglutaminase, inflammation, and cancer: how intimate is the relationship?

Despite significant advances in surgery and biology, cancer remains a major health problem. It is now well accepted that metastasis and cancer cells’ acquired or inherent resistance to conventional therapies are major roadblocks to successful treatment. Chronic inflammation is an important driving force that provides a favorable platform for cancer’s progression and development and suggests a link between inflammation and metastatic transformation. However, how chronic inflammation contributes to metastatic cell transformation is not well understood. According to the current theory of cancer progression, a small subpopulation of cancer stem cells (CSCs) in tumors is responsible for their metastasis, resistance, and sustenance. Whether CSCs originate from normal stem cells or from dedifferentiation of terminally differentiated cells remains unknown. Recent evidence indicates that stem cells are not unique; malignant or nonmalignant cells can reprogram and de-differentiate to acquire a stemness phenotype. Thus, phenotypic plasticity may exist between stem cells and non-stem cells, and a dynamic equilibrium may exist between the two phenotypes. Moreover, this equilibrium may shift in one direction or another on the basis of contextual signals in the microenvironment that influence the interconversion between stem and non-stem cell compartments. Whether the inflammatory microenvironment influences this interconversion and shifts the dynamic equilibrium towards stem cell compartments remains unknown. We recently found that aberrant tissue transglutaminase (TG2) expression induces the mesenchymal transition (EMT) and stem cell characteristics in epithelial cells. This finding, in conjunction with the observation that inflammatory signals (e.g., TGFβ, TNFα, and NF-κB) which induce EMT, also induce TG2 expression, suggests a possible link between TG2, inflammation, and cancer progression. In this review, we summarize TG2-driven processes in inflammation and their implications in cancer progression.     

Analyzing the activity of large populations of neurons: how tractable is the problem?

Understanding how the brain performs computations requires understanding neuronal firing patterns at successive levels of processing-a daunting and seemingly intractable task. Two recent studies have made dramatic progress on this problem by showing how its dimensionality can be reduced. Using the retina as a model system, they demonstrated that multineuronal firing patterns can be predicted by pairwise interactions.     

Dates from the molecular clock: how wrong can we be?

Large discrepancies have been found in dates of evolutionary events obtained using the molecular clock. Twofold differences have been reported between the dates estimated from molecular data and those from the fossil record; furthermore, different molecular methods can give dates that differ 20-fold. New software attempts to incorporate appropriate allowances for this uncertainty into the calculation of the accuracy of date estimates. Here, we propose that these innovations represent welcome progress towards obtaining reliable dates from the molecular clock, but warn that they are currently unproven, given that the causes and pattern of the discrepancies are the subject of ongoing research. This research implies that many previous studies, even some of those using recently developed methods, might have placed too much confidence in their date estimates, and their conclusions might need to be revised.     

Schistosome monogamy: who,how, and why?

Schistosomes represent a unique animal model for comparative analyses of monogamy. Indeed, schistosomes are classified at the lowest taxonomical level of monogamous species and lack complex social interactions, which could alter our understanding of their unusual mating system. Elements discussed here include the fact that monogamy in schistosomes could be an ancestral state between hermaphroditism and polygyny or polygynandry and the occurrence of mate changes. In addition, hypotheses are proposed to explain monogamy in schistosomes (e.g. female dispersion, the need for paternal care, oviposition site limitation or aggressiveness, and mate guarding). We also propose future experimental and analytical approaches to improve our understanding of the schistosomes' mating system.     

Why and how might genetic and phylogenetic diversity be reflected in the identification of key biodiversity areas?

‘Key biodiversity areas'' are defined as sites contributing significantly to the global persistence of biodiversity. The identification of these sites builds from existing approaches based on measures of species and ecosystem diversity and process. Here, we therefore build from the work of Sgró et al. (2011 Evol. Appl. 4, 326–337. (doi:10.1111/j.1752-4571.2010.00157.x)) to extend a framework for how components of genetic diversity might be considered in the identification of key biodiversity areas. We make three recommendations to inform the ongoing process of consolidating a key biodiversity areas standard: (i) thresholds for the threatened species criterion currently consider a site''s share of a threatened species'' population; expand these to include the proportion of the species'' genetic diversity unique to a site; (ii) expand criterion for ‘threatened species'' to consider ‘threatened taxa’ and (iii) expand the centre of endemism criterion to identify as key biodiversity areas those sites holding a threshold proportion of the compositional or phylogenetic diversity of species (within a taxonomic group) whose restricted ranges collectively define a centre of endemism. We also recommend consideration of occurrence of EDGE species (i.e. threatened phylogenetic diversity) in key biodiversity areas to prioritize species-specific conservation actions among sites.