Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

Hedgehog signalling--an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer--may also be an important mediator in human pancreatic carcinoma. Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx-Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.     

Dynamics of Mid-Palaeocene North Atlantic rifting linked with European intra-plate deformations

The process of continental break-up provides a large-scale experiment that can be used to test causal relations between plate tectonics and the dynamics of the Earth's deep mantle. Detailed diagnostic information on the timing and dynamics of such events, which are not resolved by plate kinematic reconstructions, can be obtained from the response of the interior of adjacent continental plates to stress changes generated by plate boundary processes. Here we demonstrate a causal relationship between North Atlantic continental rifting at approximately 62 Myr ago and an abrupt change of the intra-plate deformation style in the adjacent European continent. The rifting involved a left-lateral displacement between the North American-Greenland plate and Eurasia, which initiated the observed pause in the relative convergence of Europe and Africa. The associated stress change in the European continent was significant and explains the sudden termination of a approximately 20-Myr-long contractional intra-plate deformation within Europe, during the late Cretaceous period to the earliest Palaeocene epoch, which was replaced by low-amplitude intra-plate stress-relaxation features. The pre-rupture tectonic stress was large enough to have been responsible for precipitating continental break-up, so there is no need to invoke a thermal mantle plume as a driving mechanism. The model explains the simultaneous timing of several diverse geological events, and shows how the intra-continental stratigraphic record can reveal the timing and dynamics of stress changes, which cannot be resolved by reconstructions based only on plate kinematics.     

A unified mixed-model method for association mapping that accounts for multiple levels of relatedness

As population structure can result in spurious associations, it has constrained the use of association studies in human and plant genetics. Association mapping, however, holds great promise if true signals of functional association can be separated from the vast number of false signals generated by population structure. We have developed a unified mixed-model approach to account for multiple levels of relatedness simultaneously as detected by random genetic markers. We applied this new approach to two samples: a family-based sample of 14 human families, for quantitative gene expression dissection, and a sample of 277 diverse maize inbred lines with complex familial relationships and population structure, for quantitative trait dissection. Our method demonstrates improved control of both type I and type II error rates over other methods. As this new method crosses the boundary between family-based and structured association samples, it provides a powerful complement to currently available methods for association mapping.     

We find them here, we find them there: Functional bacterial amyloid

Protein amyloid is often deposited in connection with neurodegenerative diseases. Such deposits generally possess three principal drawbacks: cytotoxicity, lack of spatial control in their deposition and structural polymorphism. These are typical features of biologically non-optimized systems which have not been exposed to evolutionary pressure. Nevertheless, Nature uses the cross-beta self-organizing principle in many structural contexts where a strong but pliable material is needed. Functional amyloid is found in humans, invertebrates, fungi and, not least, bacteria, in which amyloid may be the rule rather than the exception. Detailed case studies reveal how directed nucleation can use tailor-made proteins optimized to assume a specific amyloid conformation, leading to remarkably robust assemblies. This makes it highly challenging to purify and analyze the products formed in vivo. We contrast pathogenic and in-vitro-formed amyloid with functional amyloid, paying particular reference to bacterial amyloid, and discuss challenges and perspectives in identifying and characterizing this class of protein.     

Macrophage migration inhibitory factor (MIF) modulates trophic signaling through interaction with serine protease HTRA1

Macrophage migration inhibitory factor (MIF), a small conserved protein, is abundant in the immune- and central nervous system (CNS). MIF has several receptors and binding partners that can modulate its action on a cellular level. It is upregulated in neurodegenerative diseases and cancer although its function is far from clear. Here, we report the finding of a new binding partner to MIF, the serine protease HTRA1. This enzyme cleaves several growth factors, extracellular matrix molecules and is implicated in some of the same diseases as MIF. We show that the function of the binding between MIF and HTRA1 is to inhibit the proteolytic activity of HTRA1, modulating the availability of molecules that can change cell growth and differentiation. MIF is therefore the first endogenous inhibitor ever found for HTRA1. It was found that both molecules were present in astrocytes and that the functional binding has the ability to modulate astrocytic activities important in development and disease of the CNS.     

Corporate Social Responsibility as a Messy Problem: Linking Systems and Sensemaking Perspectives

Corporate social responsibility (CSR) has become an essential topic with regard to the relationship between business and the wider society. It is a complex and controversial phenomenon that can best be addressed via systems theory and the sensemaking perspective. This paper proposes a way to link a dialectical systems perspective with communications that includes the sensemaking and dialogic collective approaches, which help to build systems of organised activities that aim to find solutions to complex problems from a holistic perspective. Companies are increasingly aware that if they wish to be successful actors in their business and societal relationships, the traditional sole focus on maximising profit is counterproductive, especially in terms of sustaining their value chains. A holistic approach to CSR and the value chain involves companies integrating their stakeholders along their value chains, especially at the downstream and upstream extremes (their customers and suppliers). This paper illustrates its theoretical perspectives with a case study of JYSK, a multinational company based in Denmark, which demonstrates how the company based its actual management of CSR on its willingness to learn from its own actions and from the actions of others.