Expression of Distal-less, dachshund, and optomotor blind in Neanthes arenaceodentata (Annelida, Nereididae) does not support homology of appendage-forming mechanisms across the Bilateria

The similarity in the genetic regulation of arthropod and vertebrate appendage formation has been interpreted as the product of a plesiomorphic gene network that was primitively involved in bilaterian appendage development and co-opted to build appendages (in modern phyla) that are not historically related as structures. Data from lophotrochozoans are needed to clarify the pervasiveness of plesiomorphic appendage forming mechanisms. We assayed the expression of three arthropod and vertebrate limb gene orthologs, Distal-less (Dll), dachshund (dac), and optomotor blind (omb), in direct-developing juveniles of the polychaete Neanthes arenaceodentata. Parapodial Dll expression marks premorphogenetic notopodia and neuropodia, becoming restricted to the bases of notopodial cirri and to ventral portions of neuropodia. In outgrowing cephalic appendages, Dll activity is primarily restricted to proximal domains. Dll expression is also prominent in the brain. dac expression occurs in the brain, nerve cord ganglia, a pair of pharyngeal ganglia, presumed interneurons linking a pair of segmental nerves, and in newly differentiating mesoderm. Domains of omb expression include the brain, nerve cord ganglia, one pair of anterior cirri, presumed precursors of dorsal musculature, and the same pharyngeal ganglia and presumed interneurons that express dac. Contrary to their roles in outgrowing arthropod and vertebrate appendages, Dll, dac, and omb lack comparable expression in Neanthes appendages, implying independent evolution of annelid appendage development. We infer that parapodia and arthropodia are not structurally or mechanistically homologous (but their primordia might be), that Dll’s ancestral bilaterian function was in sensory and central nervous system differentiation, and that locomotory appendages possibly evolved from sensory outgrowths

Shh Signaling from the Nucleus Pulposus Is Required for the Postnatal Growth and Differentiation of the Mouse Intervertebral Disc

Intervertebral discs (IVD) are essential components of the vertebral column. They maintain separation, and provide shock absorbing buffers, between adjacent vertebrae, while also allowing movements between them. Each IVD consists of a central semi-liquid nucleus pulposus (NP) surrounded by a multi-layered fibrocartilagenous annulus fibrosus (AF). Although the IVDs grow and differentiate after birth along with the vertebral column, little is known about the mechanism of this. Understanding the signals that control normal IVD growth and differentiation would also provide potential therapies for degenerative disc disease, which is the major cause of lower back pain and affects a large proportion of the population. In this work, we show that during postnatal growth of the mouse, Sonic hedgehog (Shh) signaling from the NP cells controls many aspects of growth and differentiation of both the NP cells themselves and of the surrounding AF, and that it acts, at least partly, by regulating other signaling pathways in the NP and AF. Recent studies have shown that the NP cells arise from the embryonic notochord, which acts as a major signaling center in the embryo. This work shows that this notochord-derived tissue continues to carry out a major signaling function in the postnatal body and that the IVDs are signaling centers, in addition to their already known functions in the mechanics of vertebral column function

Cost-of-Illness Analysis of Type 2 Diabetes Mellitus in Iran

Diabetes is a worldwide high prevalence chronic progressive disease that poses a significant challenge to healthcare systems. The aim of this study is to provide a detailed economic burden of diagnosed type 2 diabetes mellitus (T2DM) and its complications in Iran in 2009 year.This is a prevalence-based cost-of-illness study focusing on quantifying direct health care costs by bottom-up approach. Data on inpatient hospital services, outpatient clinic visits, physician services, drugs, laboratory test, education and non-medical cost were collected from two national registries. The human capital approach was used to calculate indirect costs separately in male and female and also among different age groups.The total national cost of diagnosed T2DM in 2009 is estimated at 3.78 billion USA dollars (USD) including 2.04±0.28 billion direct (medical and non-medical) costs and indirect costs of 1.73 million. Average direct and indirect cost per capita was 842.6±102 and 864.8 USD respectively. Complications (48.9%) and drugs (23.8%) were main components of direct cost. The largest components of medical expenditures attributed to diabetes's complications are cardiovascular disease (42.3% of total Complications cost), nephropathy (23%) and ophthalmic complications (14%). Indirect costs include temporarily disability (335.7 million), permanent disability (452.4 million) and reduced productivity due to premature mortality (950.3 million).T2DM is a costly disease in the Iran healthcare system and consume more than 8.69% of total health expenditure. In addition to these quantified costs, T2DM imposes high intangible costs on society in terms of reduced quality of life. Identification of effective new strategies for the control of diabetes and its complications is a public health priority

Anticancer potential of Thevetia peruviana fruit methanolic extract

Abstract Background: Thevetia peruviana (Pers.) K. Schum or Cascabela peruviana (L.) Lippold (commonly known as ayoyote, codo de fraile, lucky nut, or yellow oleander), native to Mexico and Central America, is a medicinal plant used traditionally to cure diseases like ulcers, scabies, hemorrhoids and dissolve tumors. The purpose of this study was to evaluate the cytotoxic, antiproliferative and apoptotic activity of methanolic extract of T. peruviana fruits on human cancer cell lines. Methods: The cytotoxic activity of T. peruviana methanolic extract was carried out on human breast, colorectal, prostate and lung cancer cell lines and non-tumorigenic control cells (fibroblast and Vero), using the MTT assay. For proliferation and motility, clonogenic and wound-healing assays were performed. Morphological alterations were monitored by trypan blue exclusion, as well as DNA fragmentation and AO/EB double staining was performed to evaluate apoptosis. The extract was separated using flash chromatography, and the resulting fractions were evaluated on colorectal cancer cells for their cytotoxic activity. The active fractions were further analyzed through mass spectrometry. Results: The T. peruviana methanolic extract exhibited cytotoxic activity on four human cancer cell lines: prostate, breast, colorectal and lung, with values of IC50 1.91 ± 0.76, 5.78 ± 2.12, 6.30 ± 4.45 and 12.04 ± 3.43 μg/mL, respectively. The extract caused a significant reduction of cell motility and colony formation on all evaluated cancer cell lines. In addition, morphological examination displayed cell size reduction, membrane blebbing and detachment of cells, compared to non-treated cancer cell lines. The T. peruviana extract induced apoptotic cell death, which was confirmed by DNA fragmentation and AO/EB double staining. Fractions 4 and 5 showed the most effective cytotoxic activity and their MS analysis revealed the presence of the secondary metabolites: thevetiaflavone and cardiac glycosides. Conclusion: T. peruviana extract has potential as natural anti-cancer product with critical effects in the proliferation, motility, and adhesion of human breast and colorectal cancer cells, and apoptosis induction in human prostate and lung cancer cell lines, with minimal effects on non-tumorigenic cell lines. Keywords: Cytotoxic activity, Anti-proliferative activity, Motility, Apoptosis, Human cancer cells, Flavonoid, Cardiac glycoside

Genetics of migraine in the age of genome-wide association studies

Genetic factors importantly contribute to migraine. However, unlike for rare monogenic forms of migraine, approaches to identify genes for common forms of migraine have been of limited success. Candidate gene association studies were often negative and positive results were often not replicated or replication failed. Further, the significance of positive results from linkage studies remains unclear owing to the inability to pinpoint the genes under the peaks that may be involved in migraine. Problems hampering these studies include limited sample sizes, methods of migraine ascertainment, and the heterogeneous clinical phenotype. Three genome-wide association studies are available now and have successfully identified four new genetic variants associated with migraine. One new variant (rs1835740) modulates glutamate homeostasis, thus integrates well with current concepts of neurotransmitter disturbances. This variant may be more specific for severe forms of migraine such as migraine with aura than migraine without aura. Another variant (rs11172113) implicates the lipoprotein receptor LRP1, which may interact with neuronal glutamate receptors, thus also providing a link to the glutamate pathway. In contrast, rs10166942 is in close proximity to TRPM8, which codes for a cold and pain sensor. For the first time this links a gene explicitly implicated in pain related pathways to migraine. The potential function of the fourth variant rs2651899 (PRDM16) in migraine is unclear. All these variants only confer a small to moderate change in risk for migraine, which concurs with migraine being a heterogeneous disorder. Ongoing large international collaborations will likely identify additional gene variants for migraine

Multi-model seascape genomics identifies distinct environmental drivers of selection among sympatric marine species

Background As global change and anthropogenic pressures continue to increase, conservation and management increasingly needs to consider species’ potential to adapt to novel environmental conditions. Therefore, it is imperative to characterise the main selective forces acting on ecosystems, and how these may influence the evolutionary potential of populations and species. Using a multi-model seascape genomics approach, we compare putative environmental drivers of selection in three sympatric southern African marine invertebrates with contrasting ecology and life histories: Cape urchin (Parechinus angulosus), Common shore crab (Cyclograpsus punctatus), and Granular limpet (Scutellastra granularis). Results Using pooled (Pool-seq), restriction-site associated DNA sequencing (RAD-seq), and seven outlier detection methods, we characterise genomic variation between populations along a strong biogeographical gradient. Of the three species, only S. granularis showed significant isolation-by-distance, and isolation-by-environment driven by sea surface temperatures (SST). In contrast, sea surface salinity (SSS) and range in air temperature correlated more strongly with genomic variation in C. punctatus and P. angulosus. Differences were also found in genomic structuring between the three species, with outlier loci contributing to two clusters in the East and West Coasts for S. granularis and P. angulosus, but not for C. punctatus. Conclusion The findings illustrate distinct evolutionary potential across species, suggesting that species-specific habitat requirements and responses to environmental stresses may be better predictors of evolutionary patterns than the strong environmental gradients within the region. We also found large discrepancies between outlier detection methodologies, and thus offer a novel multi-model approach to identifying the principal environmental selection forces acting on species. Overall, this work highlights how adding a comparative approach to seascape genomics (both with multiple models and species) can elucidate the intricate evolutionary responses of ecosystems to global change

Unique establishment of procephalic head segments is supported by the identification of cis-regulatory elements driving segment-specific segment polarity gene expression in Drosophila

Anterior head segmentation is governed by different regulatory mechanisms than those that control trunk segmentation in Drosophila. For segment polarity genes, both initial mode of activation as well as cross-regulatory interactions among them differ from the typical genetic circuitry in the trunk and are unique for each of the procephalic segments. In order to better understand the segment-specific gene network responsible for the procephalic expression of the earliest active segment polarity genes wingless and hedgehog, we started to identify and analyze cis-regulatory DNA elements of these genes. For hedgehog, we could identify a cis-regulatory element, ic-CRE, that mediates expression specifically in the posterior part of the intercalary segment and requires promoter-specific interaction for its function. The intercalary stripe is the last part of the metameric hedgehog expression pattern that appears during embryonic development, which probably reflects the late and distinct establishment of this segment. The identification of a cis-regulatory element that is specific for one head segment supports the mutant-based observation that the expression of segment polarity genes is governed by a unique gene network in each of the procephalic segments. This provides further indication that the anterior-most head segments represent primary segments, which are set up independently, in contrast to the secondary segments of the trunk, which resemble true repetitive units

Environmental factors are stronger predictors of primate species’ distributions than basic biological traits

Understanding the neutral, biological and environmental processes driving species distributions is valuable in informing conservation efforts because it will help us predict how species will respond to changes in environmental conditions. Environmental processes affect species differently according to their biological traits, which determine how they interact with their environment. Therefore, functional, trait-based modelling approaches are considered important for predicting distributions and species responses to change but even for data-rich primate communities our understanding of the relationships between traits and environmental conditions is limited. Here we use a large-scale, high-resolution dataset of African diurnal primate distributions, biological traits and environmental conditions to investigate the role of biological traits and environmental trait filtering in primate distributions. We collected data from published sources for 354 sites, and 14 genera with 57 species across Sub-Saharan Africa. We then combined a three-table ordination method, RLQ, with the Fourth Corner approach to test relationships between environmental variables and biological traits and used a mapping approach to visually assess patterning in primate genus and species’ distributions. We found no significant relationships between any groups of environmental variables and biological traits, despite a clear role of environmental filtering in driving genus and species’ distributions. The most important environmental driver of species distributions was temperature seasonality, followed by rainfall. We conclude that the relative flexibility of many primate genera means that not any one particular set of traits drives their species-environment associations, despite the clear role of such associations in their distribution patterns