Circulating tumour cells: The Good,the Bad and the Ugly

This review is an overview of the current knowledge regarding circulating tumour cells (CTCs), which are potentially the most lethal type of cancer cell, and may be a key component of the metastatic cascade. The clinical utility of CTCs (the "Good"), includes their diagnostic, prognostic, and therapeutic potential. Conversely, their complex biology (the "Bad"), including the existence of CD45+/EpCAM+ CTCs, adds insult to injury regarding their isolation and identification, which in turn hampers their clinical translation. CTCs are capable of forming microemboli composed of both non-discrete phenotypic populations such as mesenchymal CTCs and homotypic and heterotypic clusters which are poised to interact with other cells in the circulation, including immune cells and platelets, which may increase their malignant potential. These microemboli (the "Ugly") represent a prognostically important CTC subset, however, phenotypic EMT/MET gradients bring additional complexities to an already challenging situation.     

The Good,the Bad,and the Ugly: Agonistic Behaviour in Juvenile Crocodilians

We examined agonistic behaviour in seven species of hatchling and juvenile crocodilians held in small groups (N = 4) under similar laboratory conditions. Agonistic interactions occurred in all seven species, typically involved two individuals, were short in duration (5–15 seconds), and occurred between 1600–2200 h in open water. The nature and extent of agonistic interactions, the behaviours displayed, and the level of conspecific tolerance varied among species. Discrete postures, non-contact and contact movements are described. Three of these were species-specific: push downs by C. johnstoni; inflated tail sweeping by C. novaeguineae; and, side head striking combined with tail wagging by C. porosus. The two long-snouted species (C. johnstoni and G. gangeticus) avoided contact involving the head and often raised the head up out of the way during agonistic interactions. Several behaviours not associated with aggression are also described, including snout rubbing, raising the head up high while at rest, and the use of vocalizations. The two most aggressive species (C. porosus, C. novaeguineae) appeared to form dominance hierarchies, whereas the less aggressive species did not. Interspecific differences in agonistic behaviour may reflect evolutionary divergence associated with morphology, ecology, general life history and responses to interspecific conflict in areas where multiple species have co-existed. Understanding species-specific traits in agonistic behaviour and social tolerance has implications for the controlled raising of different species of hatchlings for conservation, management or production purposes.     

The Good,the Bad,and the Ugly of interleukin‐6 signaling

Interleukin‐6 (IL‐6) is a pleiotropic cytokine with complex roles in inflammation and metabolic disease. While typically regarded as a pro‐inflammatory cytokine, multiple studies in the last 20 years have generated conflicting data on the role of IL‐6 in inflammation and metabolism. In a recent study in Nature Immunology, Brüning and collaborators demonstrate that IL‐6 signaling in myeloid cells attenuates obesity‐induced inflammation and insulin resistance by promoting macrophage alternative activation (Mauer et al, 2014 ). This study unveils a new and surprising anti‐inflammatory action of IL‐6 and further highlights the complex actions of this cytokine.     

Recovering microbial genomes from metagenomes in hypersaline environments: The Good,the Bad and the Ugly

Current metagenomic tools allow the recovery of microbial genomes directly from the environment. This can be accomplished by binning metagenomic contigs according to their coverage and tetranucleotide frequency, followed by an estimation of the bin quality. The public availability of bioinformatics tools, together with the decreasing cost of next generation sequencing, are democratizing this powerful approach that is spreading from specialized research groups to the general public. Using metagenomes from hypersaline environments, as well as mock metagenomes composed of Archaea and Bacteria frequently found in these systems, we have analyzed the advantages and difficulties of the binning process in these extreme environments to tackle microbial population diversity. These extreme systems harbor relatively low species diversity but high intraspecific diversity, which can compromise metagenome assembly and therefore the whole binning process. The main goal is to compare the output of the binning process with what is previously known from the analyzed samples, based on years of study using different approaches. Several scenarios have been analyzed in detail: (i) a good quality bin from a species highly abundant in the environment; (ii) an intermediate quality bin with incongruences that can be solved by further analyses and manual curation, and (iii) a low-quality bin to investigate the failure to recover a very abundant microbial genome as well as some possible solutions. The latter can be considered the “great metagenomics anomaly” and is mainly due to assembly problems derived from the microdiversity of naturally co-existing populations in nature.     

The Good,the Bad,and the Ugly: in search of gold standards for assessing functional genetic screen quality

Variable screen quality, off‐target effects, and unclear false discovery rates often hamper large‐scale functional genomic screens in mammalian cells. Hart et al (2014) introduce gold standard reference sets of essential and non‐essential genes, aiming at standardizing the analysis of genome‐wide screens. This work provides a framework to compare both the quality and analysis methods of functional genetic screens.     

Mechanisms of radioresistance and the underlying signaling pathways in colorectal cancer cells

Radiotherapy is one of the most common modalities for the treatment of a wide range of tumors, including colorectal cancer (CRC); however, radioresistance of cancer cells remains a major limitation for this treatment. Following radiotherapy, the activities of various cellular mechanisms and cell signaling pathways are altered, resulting in the development of radioresistance, which leads to therapeutic failure and poor prognosis in patients with cancer. Furthermore, even though several inhibitors have been developed to target tumor resistance, these molecules can induce side effects in nontumor cells due to low specificity and efficiency. However, the role of these mechanisms in CRC has not been extensively studied. This review discusses recent studies regarding the relationship between radioresistance and the alterations in a series of cellular mechanisms and cell signaling pathways that lead to therapeutic failure and tumor recurrence. Our review also presents recent advances in the in vitro/in vivo study models aimed at investigating the radioresistance mechanism in CRC. Furthermore, it provides a relevant biochemical basis in theory, which can be useful to improve radiotherapy sensitivity and prolong patient survival.     

The effect of the anabolic agent,clenbuterol, on overloaded rat skeletal muscle

The dietary administration of clenbuterol to young male rats has been shown to produce a muscle specific hypertrophic growth response. This paper demonstrates that the combined effect of drug treatment and hypertrophic stimulus induced by tenotomy produced an additive effect on muscle growth. This effect was demonstrated in terms of both muscle composition (protein and RNA) and fibre size.     

The Good,the Bad,and the Ugly: The Influence of Skull Reconstructions and Intraspecific Variability in Studies of Cranial Morphometrics in Theropods and Basal Saurischians

Several studies investigating macroevolutionary skull shape variation in fossil reptiles were published recently, often using skull reconstructions taken from the scientific literature. However, this approach could be potentially problematic, because skull reconstructions might differ notably due to incompleteness and/or deformation of the material. Furthermore, the influence of intraspecific variation has usually not been explored in these studies. Both points could influence the results of morphometric analyses by affecting the relative position of species to each other within the morphospace. The aim of the current study is to investigate the variation in morphometric data between skull reconstructions based on the same specimen, and to compare the results to shape variation occurring in skull reconstructions based on different specimens of the same species (intraspecific variation) and skulls of closely related species (intraspecific variation). Based on the current results, shape variation of different skull reconstructions based on the same specimen seems to have generally little influence on the results of a geometric morphometric analysis, although it cannot be excluded that some erroneous reconstructions of poorly preserved specimens might cause problems occasionally. In contrast, for different specimens of the same species the variation is generally higher than between different reconstructions based on the same specimen. For closely related species, at least with similar ecological preferences in respect to the dietary spectrum, the degree of interspecific variation can overlap with that of intraspecific variation, most probably due to similar biomechanical constraints.     

Threshold Concepts and Their Use in Rangeland Management and Restoration: The Good, the Bad, and the Insidious

Ecological thresholds describe abrupt changes in ecological properties in time or space. In rangeland management, thresholds reflect changes in vegetation and soils that are expensive or impossible to reverse. The threshold concept has catalyzed important advances in rangeland management thinking, but it has also introduced two classes of drawbacks. First, the ambiguity of the term "threshold" and the desire for simplicity in its application has led to an overemphasis on classification thresholds, such as vegetation cover values. Uncritical use of classification thresholds may lead to the abandonment of management efforts in land areas that would otherwise benefit from intervention. Second, it is possible that the invocation of thresholds and irreversible degradation may eventually result in the wholesale conversion of land areas that would have been recoverable or served important societal functions, such as biodiversity maintenance, that are not reflected in threshold definitions. I conclude with a recommendation to clarify the nature of thresholds by defining the relationships among pattern, process, and degradation and distinguishing preventive thresholds from restoration thresholds. We must also broaden the attributes used to define states and thresholds.     

In Vivo Experiments Reveal the Good,the Bad and the Ugly Faces of sFlt-1 in Pregnancy

Objective

Soluble fms-like tyrosine kinase (sFlt)-1-e15a, a primate-specific sFlt-1-isoform most abundant in the human placenta in preeclampsia, can induce preeclampsia in mice. This study compared the effects of full-length human (h)sFlt-1-e15a with those of truncated mouse (m)sFlt-1(1-3) used in previous preeclampsia studies on pregnancy outcome and clinical symptoms in preeclampsia.

Methods

Mice were injected with adenoviruses or fiber-mutant adenoviruses overexpressing hsFlt-1-e15a, msFlt-1(1-3) or control GFP under the CMV or CYP19A1 promoters on gestational day 8 (GD8) and GD11. Placentas and pups were delivered by cesarean section, and dams were monitored postpartum. Blood pressure was telemetrically recorded. Urine samples were collected with cystocentesis and examined for albumin/creatinine ratios. Tissue specimens were evaluated for transgene as well as endogenous mFlt-1 and msFlt-1-i13 expression. H&E-, Jones- and PAS-stained kidney sections were histopathologically examined. Placental GFP expression and aortic ring assays were investigated with confocal microscopy.

Results

Mean arterial blood pressure (MAP) was elevated before delivery in hsFlt-1-e15a-treated mice compared to controls (GD18: ΔMAP = 7.8 mmHg, p = 0.009), while ΔMAP was 12.8 mmHg (GD18, p = 0.005) in msFlt-1(1-3)-treated mice. Urine albumin/creatinine ratio was higher in hsFlt-1-e15a-treated mice than in controls (GD18, p = 0.04; PPD8, p = 0.03), and msFlt-1(1-3)-treated mice had marked proteinuria postpartum (PPD8, p = 4×10⁻⁵). Focal glomerular changes were detected in hsFlt-1-e15a and msFlt-1(1-3)-treated mice. Aortic ring microvessel outgrowth was decreased in hsFlt-1-e15a (p = 0.007) and msFlt-1(1-3)-treated (p = 0.02) mice. Full-length msFlt-1-i13 expression was unique for the placenta. In hsFlt-1-e15a-treated mice, the number of pups (p = 0.046), total weight of living pups (p = 0.04) and maternal weights (p = 0.04) were higher than in controls. These differences were not observed in truncated msFlt-1(1-3)-treated mice.

Conclusions

Truncated msFlt-1(1-3) simulated the preeclampsia-promoting effects of full-length hsFlt-1. MsFlt-1(1-3) had strong effect on maternal endothelium but not on placentas and embryos. In contrast, hsFlt-1-e15a induced preeclampsia-like symptoms; however, it also increased litter size. In accord with the predominant placental expression of hsFlt-1-e15a and msFlt-1-i13, full-length sFlt-1 may have a role in the regulation of embryonic development. These observations point to the difference in the biological effects of full-length and truncated sFlt-1 and the changes in the effect of full-length sFlt-1 during pregnancy, and may have important implications in the management of preeclampsia.     

Ovarian Steroids: The Good,the Bad,and the Signals that Raise Them

Ovarian steroid production and subsequent local steroid-mediated signaling are critical for normal ovarian processes, including follicle growth, oocyte maturation, and ovulation. In contrast, elevated steroidogenesis and/or increased steroid signaling in the ovary can lead to profound ovarian pathology, such as polycystic ovarian syndrome, the leading cause of infertility in reproductive age women. Through the use of several in vitro and animal models, great strides have been made toward characterizing the mechanisms regulating local steroid production and action in the ovary. Examples of this progress include insights into luteinizing hormone (LH)- and growth factor-mediated signaling, steroidogenic acute regulatory protein (StAR) activation, and both genomic and nongenomic steroid-mediated signaling in somatic and germ cells, respectively. The following review will address these advances, focusing on how this rapidly expanding knowledge base can be used to better understand female reproduction, and to further improve treatments for common diseases of infertility.     

Human-Spider Entanglements: Understanding and Managing the Good,the Bad,and the Venomous

ABSTRACT

Considering the fear that spiders can generate in humans, examining human-spider interactions in urban settings may at first glance appear odd. However, human-spider interactions, which occur quite frequently in urban settings, do not necessarily have to be negative; they can, in some cases, foster respect and tolerance (sometimes through avoidance). When one considers how global transformations, invasive species, urbanization, and adaptation will impact human-spider interactions, a review of the literature pertaining to these encounters is timely. We begin this discussion by describing spiders and providing an overview of some of their positive and negative impacts. Challenges regarding species identification and envenoming are also discussed. After the role of biological, psychological, and social aspects in human-spider interactions are re-examined, we provide future options aimed at organizing broad-scale public programs for five specific target groups: 1) the general public, 2) health professionals, 3) educators, 4) naturalists, and 5) researchers. In the conclusion, we provide potential management and educational strategies aimed at increasing our knowledge and tolerance of these animals in urban settings.     

Telomerase activity in human germline and embryonic tissues and cells

Telomerase is a ribonucleoprotein that synthesizes telomere repeats onto chromosome ends and is involved in maintaining telomere length in germline tissues and in immortal and cancer cells. In the present study, the temporal regulation of expression of telomerase activity was examined in human germline and somatic tissues and cells during development. Telomerase activity was detected in fetal, newborn, and adult testes and ovaries, but not in mature spermatozoa or oocytes. Blastocysts expressed high levels of telomerase activity as did most human somatic tissues at 16–20 weeks of development with the exception of human brain tissue. This activity could no longer be detected in the somatic tissues examined from the neonatal period onward. Neither placenta nor cultured fetal amniocytes contained detectable telomerase activity. Fetal tissues explanted into primary cell culture showed a dramatic decline in telomerase activity which became undetectable after the first passage in vitro. Elucidation of the regulatory pathways involved in the repression of telomerase activity during development may lead to the ability to manipulate telomerase levels and explore the consequences both for cellular aging and for the survival of cancer cells. © 1996 Wiley-Liss, Inc.     

Etiology of Developmental Disorders: Good Science, Bad Science, and Pseudoscience

Developmental disorders originate in infancy or early childhood, are associated with presumed or observed organic abnormalities, and have serious long-term physical and/or psychological sequelae. Of particular interest here are two such disorders, mental retardation and autism. Purported causes range from genetics, early prenatal and/or postnatal exposure to toxins (including heavy metals), and recently, vaccinations. Single factors have often been claimed to be the cause of a developmental disorder, without regard to possible exacerbating or alleviating roles of other factors, including socioeconomic status. Unfortunately, professional and popular literature on both claimed causes and effective treatments has often been characterized by research and theorizing that is seriously flawed (bad science) or actively misrepresented (pseudoscience). The present paper critically reviews selected research on a few controversial issues concerning developmental disorders, particular mental retardation and autism, and emphasizes the role of low socioeconomic status.     

The Good,the Bad,and the Tiny: A Simple,Mechanistic-Probabilistic Model of Virus-Nutrient Colimitation in Microbes

For phytoplankton and other microbes, nutrient receptors are often the passages through which viruses invade. This presents a bottom-up vs. top-down, co-limitation scenario; how do these would-be-hosts balance minimizing viral susceptibility with maximizing uptake of limiting nutrient(s)? This question has been addressed in the biological literature on evolutionary timescales for populations, but a shorter timescale, mechanistic perspective is lacking, and marine viral literature suggests the strong influence of additional factors, e.g. host size; while the literature on both nutrient uptake and host-virus interactions is expansive, their intersection, of ubiquitous relevance to marine environments, is understudied. I present a simple, mechanistic model from first principles to analyze the effect of this co-limitation scenario on individual growth, which suggests that in environments with high risk of viral invasion or spatial/temporal heterogeneity, an individual host’s growth rate may be optimized with respect to receptor coverage, producing top-down selective pressure on short timescales. The model has general applicability, is suggestive of hypotheses for empirical exploration, and can be extended to theoretical studies of more complex behaviors and systems.