Notch signaling and diseases: an evolutionary journey from a simple beginning to complex outcomes

Notch signaling pathway regulates a wide variety of cellular processes during development and it also plays a crucial role in human diseases. This important link is firmly established in cancer, since a rare T-ALL-associated genetic lesion has been initially reported to result in deletion of Notch1 ectodomain and constitutive activation of its intracellular region. Interestingly, the cellular response to Notch signaling can be extremely variable depending on the cell type and activation context. Notch signaling triggers signals implicated in promoting carcinogenesis and autoimmune diseases, whereas it can also sustain responses that are critical to suppress carcinogenesis and to negatively regulate immune response. However, Notch signaling induces all these effects via an apparently simple signal transduction pathway, diversified into a complex network along evolution from Drosophila to mammals. Indeed, an explanation of this paradox comes from a number of evidences accumulated during the last few years, which dissected the intrinsic canonical and non-canonical components of the Notch pathway as well as several modulatory extrinsic signaling events. The identification of these signals has shed light onto the mechanisms whereby Notch and other pathways collaborate to induce a particular cellular phenotype. In this article, we review the role of Notch signaling in cells as diverse as T lymphocytes and epithelial cells of the epidermis, with the main focus on understanding the mechanisms of Notch versatility.     

Bread matters: a national initiative to profile the genetic diversity of Australian wheat

The large and complex genome of wheat makes genetic and genomic analysis in this important species both expensive and resource intensive. The application of next-generation sequencing technologies is particularly resource intensive, with at least 17?Gbp of sequence data required to obtain minimal (1×) coverage of the genome. A similar volume of data would represent almost 40× coverage of the rice genome. Progress can be made through the establishment of consortia to produce shared genomic resources. Australian wheat genome researchers, working with Bioplatforms Australia, have collaborated in a national initiative to establish a genetic diversity dataset representing Australian wheat germplasm based on whole genome next-generation sequencing data. Here, we describe the establishment and validation of this resource which can provide a model for broader international initiatives for the analysis of large and complex genomes.     

From sustainability to well-being: Lessons learned from the use of sustainable development indicators at national and EU level

Indicators describing sustainability and, more recently, well-being have raised considerable interest throughout the world. Much conceptual and empirical research exists focusing on the criteria for sustainability and development of indicators, while relatively few studies examine the actual use and influence of indicators. Employing document analysis and interviews of key actors, we explore the use of sustainable development indicators at national and EU level and draw forth lessons relevant for topical discussion of the measurement of human well-being. We apply a conceptual model of three main types of indicator use: instrumental, conceptual, and political. The results indicate that the use of sustainability indicators is mainly confined to the ‘indicator circuit’ formed by indicator-developers themselves and actors obliged to use the indicators. The results suggest that direct instrumental use of indicators shows limited potential, whereas conceptual use is the key for enhanced indicator influence in the long term. Political use of indicators cannot be controlled by the indicator-developers.     

Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID)

Introduction

Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin''s lymphoma in a real-life clinical setting.

Methods

Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.

Results

A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician''s visual analogue scale; mean improvement from baseline of 12.1 mm).

Conclusions

Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.     

Antisense-mediated exon skipping: Taking advantage of a trick from Mother Nature to treat rare genetic diseases

Rare diseases can be caused by genetic mutations that disrupt normal pre-mRNA splicing. Antisense oligonucleotide treatment to the splicing thus has therapeutic potential for many rare diseases. In this review we will focus on the state of the art on exon skipping using antisense oligonucleotides as a potential therapy for rare genetic diseases, outlining how this versatile approach can be exploited to correct for different mutations.     

Predicting reef fish connectivity from biogeographic patterns and larval dispersal modelling to inform the development of marine reserve networks

Developing networks of no-take marine reserves is often hindered by uncertainty in the extent to which local marine populations are connected to one another through larval dispersal and recruitment (connectivity). While patterns of connectivity can be predicted by larval dispersal models and validated by empirical methods, biogeographic approaches have rarely been used to investigate connectivity at spatial scales relevant to reserve networks (10's–100's of km). Here, species assemblage patterns in coral reef fish were used together with an individual-based model of dispersal of reef fish larvae to infer patterns of connectivity in a ∼300 km wide region in the Philippines that included the Bohol Sea and adjacent bodies of water. A dominant current flows through the study region, which may facilitate connectivity among >100 no-take reserves. Connectivity was first investigated by analysing data on the presence/absence of 216 species of reef fish and habitat variables across 61 sites. Hierarchical clustering of sites reflecting species assemblage patterns distinguished a major group of sites in the Bohol Sea (Bray–Curtis similarity >70%) from sites situated in adjacent bodies of water (bays, channels between islands and a local sea). The grouping of sites could be partly explained by a combination of degree of embayment, % cover of sand and % cover of rubble (Spearman rank correlation, ρ_w = 0.42). The individual-based model simulated dispersal of reef fish larvae monthly for three consecutive years in the region. The results of simulations, using a range of pelagic larval durations (15–45 days), were consistent with the species assemblage patterns. Sites in the model that showed strongest potential connectivity corresponded to the majority of sites that comprised the Bohol Sea group suggested by hierarchical clustering. Most sites in the model that exhibited weak connectivity were groups of sites which had fish assemblages that were least similar to those in the Bohol Sea group. Concurrent findings from the two approaches suggest a strong influence of local oceanography and geography on broad spatial patterns of connectivity. The predictions can be used as an initial basis to organise existing reserves to form ecologically meaningful networks. This study showed that species assemblage patterns could be a viable supplementary indicator of connectivity if used together with predictions from a larval dispersal model and if the potential effect of habitat on the structuring of species assemblages is taken into consideration.     

构建森林生态补偿机制的关键问题

构建森林生态补偿机制的关键问题主要有三个方面:利益相关者的界定、补偿金额的确定及补偿方式。目前存在的较大争议是森林生态效益货币化计量结果与实际补偿额度之间有巨大差异,一方面森林经营者认为补偿额远远不能满足投入需求,应以生态效益产出为补偿金额的计算依据;另一方面,森林生态效益的很大部分来自自然投入,不能以货币化的形势简单计量。森林生态补偿的国际案例表明:世界各国因森林资源产权制度不同,其森林生态补偿机制有所差异,私有林偏重于市场补偿机制,公有林则偏重于政府主导的补偿机制。森林生态补偿资金主要来自森林生态系统服务用户付费、政府代表受益方付费及国际组织捐赠;在补偿方式上,以政府投资为主,以用户付费和基于市场的认证授权交易为辅。借鉴国际经验,结合我国森林生态效益补偿现状,森林经营者是生态系统服务供给方是确定的,而森林生态系统服务获取方的确定则非常困难。因此,政府主导和第三方介入应是解决森林生态补偿资金来源和补偿的主要方式,受损方及其受损成本是森林生态补偿金额的计算依据。     

Gone to the Dogs: a Study of Bone Attrition at a Central Australian Campsite

This is a study of bone discard at a contemporary archaeological site. It assesses the accumulation of bones in the face of destruction by scavenging animals. Three per cent by numbers and two per cent by weight of discarded bones survived to be collected in a six month study period. It is suggested that patterns of scattering by scavengers may help in the interpretation of prehistoric sites, and in particular may allow the prediction of attrition of bone by dogs.     

Morphogenetic tissue movement and the establishment of body plan during development from blastocyst to gastrula in the mouse

In many animal species, the early development of the embryo follows a stereotypic pattern of cell cleavage, lineage allocation and generation of tissue asymmetry leading to delineation of the body plan with three primary embryonic axes. The mammalian embryo has been regarded as an exception and primary body axes of the mouse embryo were thought to develop after implantation. However, recent findings have challenged this view. Asymmetry in the fertilised oocyte, as defined by the position of the second polar body and the sperm entry point, can be correlated with the orientation of the animal-vegetal and the embryonic-abembryonic axes in the preimplantation blastocyst. Studies of the pattern of morphogenetic movement of cells and genetic activity in the peri-implantation embryo suggest that the animal-vegetal axis of the blastocyst might presage the orientation of the anterior-posterior axis of the gastrula. This suggests that the asymmetry of the zygote that is established at fertilisation and early cleavage has a lasting impact on the delineation of body axes during embryogenesis.