Numb regulates cell–cell adhesion and polarity in response to tyrosine kinase signalling

Epithelial-mesenchymal transition (EMT), which can be caused by aberrant tyrosine kinase signalling, marks epithelial tumour progression and metastasis, yet the underlying molecular mechanism is not fully understood. Here, we report that Numb interacts with E-cadherin (E-cad) through its phosphotyrosine-binding domain (PTB) and thereby regulates the localization of E-cad to the lateral domain of epithelial cell–cell junction. Moreover, Numb engages the polarity complex Par3–aPKC–Par6 by binding to Par3 in polarized Madin-Darby canine kidney cells. Intriguingly, after Src activation or hepatocyte growth factor (HGF) treatment, Numb decouples from E-cad and Par3 and associates preferably with aPKC–Par6. Binding of Numb to aPKC is necessary for sequestering the latter in the cytosol during HGF-induced EMT. Knockdown of Numb by small hairpin RNA caused a basolateral-to-apicolateral translocation of E-cad and β-catenin accompanied by elevated actin polymerization, accumulation of Par3 and aPKC in the nucleus, an enhanced sensitivity to HGF-induced cell scattering, a decrease in cell–cell adhesion, and an increase in cell migration. Our work identifies Numb as an important regulator of epithelial polarity and cell–cell adhesion and a sensor of HGF signalling or Src activity during EMT

Easily retrievable objects among the NEO population

Asteroids and comets are of strategic importance for science in an effort to understand the formation, evolution and composition of the Solar System. Near-Earth Objects (NEOs) are of particular interest because of their accessibility from Earth, but also because of their speculated wealth of material resources. The exploitation of these resources has long been discussed as a means to lower the cost of future space endeavours. In this paper, we consider the currently known NEO population and define a family of so-called Easily Retrievable Objects (EROs), objects that can be transported from accessible heliocentric orbits into the Earth’s neighbourhood at affordable costs. The asteroid retrieval transfers are sought from the continuum of low energy transfers enabled by the dynamics of invariant manifolds; specifically, the retrieval transfers target planar, vertical Lyapunov and halo orbit families associated with the collinear equilibrium points of the Sun-Earth Circular Restricted Three Body problem. The judicious use of these dynamical features provides the best opportunity to find extremely low energy Earth transfers for asteroid material. A catalogue of asteroid retrieval candidates is then presented. Despite the highly incomplete census of very small asteroids, the ERO catalogue can already be populated with 12 different objects retrievable with less than 500 m/s of Δv. Moreover, the approach proposed represents a robust search and ranking methodology for future retrieval candidates that can be automatically applied to the growing survey of NEOs

Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair.

Repair of double strand DNA breaks (DSBs) can result in gene disruption or gene modification via homology directed repair (HDR) from donor DNA. Altering cellular responses to DSBs may rebalance editing outcomes towards HDR and away from other repair outcomes. Here, we utilize a pooled CRISPR screen to define host cell involvement in HDR between a Cas9 DSB and a plasmid double stranded donor DNA (dsDonor). We find that the Fanconi Anemia (FA) pathway is required for dsDonor HDR and that other genes act to repress HDR. Small molecule inhibition of one of these repressors, CDC7, by XL413 and other inhibitors increases the efficiency of HDR by up to 3.5 fold in many contexts, including primary T cells. XL413 stimulates HDR during a reversible slowing of S-phase that is unexplored for Cas9-induced HDR. We anticipate that XL413 and other such rationally developed inhibitors will be useful tools for gene modification

Isolation of human monoclonal autoantibodies derived from pancreatic lymph node and peripheral blood B cells of islet autoantibody-positive patients

Aims/hypothesis Autoantibodies against pancreatic islets and infections by enteroviruses are associated with type 1 diabetes, but the specificity of immune responses within the type 1 diabetic pancreas is poorly characterised. We investigated whether pancreatic lymph nodes could provide a source of antigen-specific B cells for analysis of immune responses within the (pre)diabetic pancreas. Methods Human IgG antibodies were cloned from single B lymphocytes sorted from pancreatic lymph node cells of three organ donors positive for islet autoantibodies, and from the peripheral blood of a patient with type 1 diabetes. Antibodies to insulinoma-associated antigen 2 (IA-2), GAD65, zinc trans- porter 8 (ZnT8) and Coxsackie B virus proteins were assayed by immunoprecipitation and by immunofluorescence on pan- creatic sections. Results Human IgG antibodies (863) were successfully cloned and produced from 4,092 single B cells from lymph nodes and peripheral blood. Reactivity to the protein tyrosine phosphatase domain of the IA-2 autoantigen was detected in two cloned antibodies: one derived from a pancreatic lymph node and one from peripheral blood. Epitopes for these two antibodies were similar to each other and to those for circulat- ing antibodies in type 1 diabetes. The remaining 861 antibod- ies were negative for reactivity to IA-2, GAD65 or ZnT8 by both assays tested. Reactivity to a Coxsackie viral protein 2 was detected in one antibody derived from a peripheral blood B cell, but not from lymph nodes. Conclusions/interpretation We show evidence for the infre- quent presence of autoantigen-specific IgG+ B lymphocytes in the pancreatic-draining lymph nodes of islet autoantibody- positive individuals

Autonomous control for miniaturized mobile robots in unknown pipe networks

Despite recent advances in robotic technology, sewer pipe inspection is still limited to conventional approaches that use cable-tethered robots. Such commercially available tethered robots lack autonomy, and their operation must be manually controlled via their tethered cables. Consequently, they can only travel to a certain distance in pipe, cannot access small-diameter pipes, and their deployment incurs high costs for highly skilled operators. In this paper, we introduce a miniaturised mobile robot for pipe inspection. We present an autonomous control strategy for this robot that is effective, stable, and requires only low-computational resources. The robots used here can access pipes as small as 75 mm in diameter. Due to their small size, low carrying capacity, and limited battery supply, our robots can only carry simple sensors, a small processor, and miniature wheel-legs for locomotion. Yet, our control method is able to compensate for these limitations. We demonstrate fully autonomous robot mobility in a sewer pipe network, without any visual aid or power-hungry image processing. The control algorithm allows the robot to correctly recognise each local network configuration, and to make appropriate decisions accordingly. The control strategy was tested using the physical micro robot in a laboratory pipe network. In both simulation and experiment, the robot autonomously and exhaustively explored an unknown pipe network without missing any pipe section while avoiding obstacles. This is a significant advance towards fully autonomous inspection robot systems for sewer pipe networks

Multimodal freight transportation: sustainability challenges

Due to globalization in trade, the development of multimodal cargo shipments and the related transport needs have created a range of challenges. Interestingly, sustainability of multimodal freight transportation is still subject to minor consideration, on the grounds that economic interests are frequently positioned much higher than social or environmental objectives. This proposed research plan is needed to assess whether and to what extent the multimodal freight system is achieving the results in the sustainability dimensions: economic, social and environmental. Thus, it will carry out a critical appraisal of the multimodal freight transportation sector to provide an up-to-date knowledge on the sustainability challenges and the potential solutions through doctoral research. This paper structured to present a review of existing literature on freight transportation and multimodal freight transport highlighting the sustainability concerns with multimodal freight transport systems. It also highlights the gaps in knowledge with a justification on the need to address these gaps for the system to function optimally. It also covers the methodology that would be applied and the sources of data that would be reviewed to ensure the aim and objectives are clearly addressed. The paper concludes by discussing the significance of the expected findings in the light of sustainability in multimodal freight transport to the academia, policy makers and the freight transportation industry

A global perspective on marine photosynthetic picoeukaryote community structure

A central goal in ecology is to understand the factors affecting the temporal dynamics and spatial distribution of microorganisms and the underlying processes causing differences in community structure and composition. However, little is known in this respect for photosynthetic picoeukaryotes (PPEs), algae that are now recognised as major players in marine CO2 fixation. Here, we analysed dot blot hybridisation and cloning–sequencing data, using the plastid-encoded 16S rRNA gene, from seven research cruises that encompassed all four ocean biomes. We provide insights into global abundance, α- and β-diversity distribution and the environmental factors shaping PPE community structure and composition. At the class level, the most commonly encountered PPEs were Prymnesiophyceae and Chrysophyceae. These taxa displayed complementary distribution patterns, with peak abundances of Prymnesiophyceae and Chrysophyceae in waters of high (25:1) or low (12:1) nitrogen:phosphorus (N:P) ratio, respectively. Significant differences in phylogenetic composition of PPEs were demonstrated for higher taxonomic levels between ocean basins, using Unifrac analyses of clone library sequence data. Differences in composition were generally greater between basins (interbasins) than within a basin (intrabasin). These differences were primarily linked to taxonomic variation in the composition of Prymnesiophyceae and Prasinophyceae whereas Chrysophyceae were phylogenetically similar in all libraries. These data provide better knowledge of PPE community structure across the world ocean and are crucial in assessing their evolution and contribution to CO2 fixation, especially in the context of global climate change

Why alternative teenagers self-harm: exploring the link between non-suicidal self-injury, attempted suicide and adolescent identity

Background: The term ‘self-harm’ encompasses both attempted suicide and non-suicidal self-injury (NSSI). Specific adolescent subpopulations such as ethnic or sexual minorities, and more controversially, those who identify as ‘Alternative’ (Goth, Emo) have been proposed as being more likely to self-harm, while other groups such as ‘Jocks’ are linked with protective coping behaviours (for example exercise). NSSI has autonomic (it reduces negative emotions) and social (it communicates distress or facilitates group ‘bonding’) functions. This study explores the links between such aspects of self-harm, primarily NSSI, and youth subculture.<p></p> Methods: An anonymous survey was carried out of 452 15 year old German school students. Measures included: identification with different youth cultures, i.e. Alternative (Goth, Emo, Punk), Nerd (academic) or Jock (athletic); social background, e.g. socioeconomic status; and experience of victimisation. Self-harm (suicide and NSSI) was assessed using Self-harm Behavior Questionnaire and the Functional Assessment of Self-Mutilation (FASM).<p></p> Results: An “Alternative” identity was directly (r ≈ 0.3) and a “Jock” identity inversely (r ≈ -0.1) correlated with self-harm. “Alternative” teenagers self-injured more frequently (NSSI 45.5% vs. 18.8%), repeatedly self-injured, and were 4–8 times more likely to attempt suicide (even after adjusting for social background) than their non-Alternative peers. They were also more likely to self-injure for autonomic, communicative and social reasons than other adolescents.<p></p> Conclusions: About half of ‘Alternative’ adolescents’ self-injure, primarily to regulate emotions and communicate distress. However, a minority self-injure to reinforce their group identity, i.e. ‘To feel more a part of a group’

Rethinking the patient: using Burden of Treatment Theory to understand the changing dynamics of illness

<b>Background</b> In this article we outline Burden of Treatment Theory, a new model of the relationship between sick people, their social networks, and healthcare services. Health services face the challenge of growing populations with long-term and life-limiting conditions, they have responded to this by delegating to sick people and their networks routine work aimed at managing symptoms, and at retarding - and sometimes preventing - disease progression. This is the new proactive work of patient-hood for which patients are increasingly accountable: founded on ideas about self-care, self-empowerment, and self-actualization, and on new technologies and treatment modalities which can be shifted from the clinic into the community. These place new demands on sick people, which they may experience as burdens of treatment.<p></p> <b>Discussion</b> As the burdens accumulate some patients are overwhelmed, and the consequences are likely to be poor healthcare outcomes for individual patients, increasing strain on caregivers, and rising demand and costs of healthcare services. In the face of these challenges we need to better understand the resources that patients draw upon as they respond to the demands of both burdens of illness and burdens of treatment, and the ways that resources interact with healthcare utilization.<p></p> <b>Summary</b> Burden of Treatment Theory is oriented to understanding how capacity for action interacts with the work that stems from healthcare. Burden of Treatment Theory is a structural model that focuses on the work that patients and their networks do. It thus helps us understand variations in healthcare utilization and adherence in different healthcare settings and clinical contexts