Mechanisms of improved survival from intensive followup in colorectal cancer: a hypothesis

A meta-analysis of six randomised trials demonstrated that intensive followup in colorectal cancer was associated with an absolute reduction in all-cause 5-year mortality of 10% (95% confidence interval (CI): 4–16) – however, only two percent (95% CI: 0–5) was attributable to cure from salvage re-operations. We postulate that other factors, such as increased psychological well-being and/or altered lifestyle, and/or improved treatment of coincidental disease may contribute to the remaining lives saved, and form important future research questions

The Second Transmembrane Domain of P2X7 Contributes to Dilated Pore Formation

Activation of the purinergic receptor P2X7 leads to the cellular permeability of low molecular weight cations. To determine which domains of P2X7 are necessary for this permeability, we exchanged either the C-terminus or portions of the second transmembrane domain (TM2) with those in P2X1 or P2X4. Replacement of the C-terminus of P2X7 with either P2X1 or P2X4 prevented surface expression of the chimeric receptor. Similarly, chimeric P2X7 containing TM2 from P2X1 or P2X4 had reduced surface expression and no permeability to cationic dyes. Exchanging the N-terminal 10 residues or C-terminal 14 residues of the P2X7 TM2 with the corresponding region of P2X1 TM2 partially restored surface expression and limited pore permeability. To further probe TM2 structure, we replaced single residues in P2X7 TM2 with those in P2X1 or P2X4. We identified multiple substitutions that drastically changed pore permeability without altering surface expression. Three substitutions (Q332P, Y336T, and Y343L) individually reduced pore formation as indicated by decreased dye uptake and also reduced membrane blebbing in response to ATP exposure. Three others substitutions, V335T, S342G, and S342A each enhanced dye uptake, membrane blebbing and cell death. Our results demonstrate a critical role for the TM2 domain of P2X7 in receptor function, and provide a structural basis for differences between purinergic receptors. © 2013 Sun et al

SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer

Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2(-/-) mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer

An RxLR effector from phytophthora infestans prevents re-localisation of two plant NAC transcription factors from the endoplasmic reticulum to the nucleus

The plant immune system is activated following the perception of exposed, essential and invariant microbial molecules that are recognised as non-self. A major component of plant immunity is the transcriptional induction of genes involved in a wide array of defence responses. In turn, adapted pathogens deliver effector proteins that act either inside or outside plant cells to manipulate host processes, often through their direct action on plant protein targets. To date, few effectors have been shown to directly manipulate transcriptional regulators of plant defence. Moreover, little is known generally about the modes of action of effectors from filamentous (fungal and oomycete) plant pathogens. We describe an effector, called Pi03192, from the late blight pathogen Phytophthora infestans, which interacts with a pair of host transcription factors at the endoplasmic reticulum (ER) inside plant cells. We show that these transcription factors are released from the ER to enter the nucleus, following pathogen perception, and are important in restricting disease. Pi03192 prevents the plant transcription factors from accumulating in the host nucleus, revealing a novel means of enhancing host susceptibility

Utilization of health services in relation to mental health problems in adolescents: A population based survey

BACKGROUND: Only a minority of adolescents reporting symptoms above case-levels on screenings for mental health seeks and receives help from specialist health services. The objective of this study was to a) examine help-seeking for symptoms of anxiety and depression in relation to symptom load dimensionally, b) identify the level of specialization in mental health among service-providers, and c) identify associations between mental health problems and contact with different types of health services. METHODS: This cross-sectional school-based study (response-rate 88%, n = 11154) is based on Norwegian health surveys among 15 and 16 year olds. RESULTS: We found a dose-response association between symptom-load and help seeking. Only 34% of individuals with mental symptom-load above 99(th )percentile reported help-seeking in the last 12 months. Forty percent of help seekers were in contact with specialists (psychiatrists or psychologists), the remaining were mainly in contact with GPs. Mental health problems increased help seeking to all twelve service providers examined. CONCLUSION: It might not be reasonable to argue that all adolescents with case-level mental health problems are in need of treatment. However, concerning the 99(th )percentile, claiming treatment need is less controversial. Even in the Norwegian context where mental health services are relatively available and free of charge, help-seeking in individuals with the highest symptom-loads is still low. Most help seekers achieved contact with health care providers, half of them at a non specialized level. Our results suggest that adolescents' recognition of mental health problems or intention to seek help for these are the major "filters" restricting treatment

Testing foundations of quantum mechanics with photons

The foundational ideas of quantum mechanics continue to give rise to counterintuitive theories and physical effects that are in conflict with a classical description of Nature. Experiments with light at the single photon level have historically been at the forefront of tests of fundamental quantum theory and new developments in photonics engineering continue to enable new experiments. Here we review recent photonic experiments to test two foundational themes in quantum mechanics: wave-particle duality, central to recent complementarity and delayed-choice experiments; and Bell nonlocality where recent theoretical and technological advances have allowed all controversial loopholes to be separately addressed in different photonics experiments.Comment: 10 pages, 5 figures, published as a Nature Physics Insight review articl

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

The evolutionary roots of creativity: mechanisms and motivations

Funding: MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland). MASTS is funded by the Scottish Funding Council (grant reference HR09011) and contributing institutions.We consider the evolution of cognition and the emergence of creative behaviour, in relation to vocal communication. We address two key questions: (i) what cognitive and/or social mechanisms have evolved that afford aspects of creativity?; (ii) has natural and/or sexual selection favoured human behaviours considered ‘creative’? This entails analysis of ‘creativity’, an imprecise construct: comparable properties in non-humans differ in magnitude and teleology from generally agreed human creativity. We then address two apparent problems: (i) the difference between merely novel productions and ‘creative’ ones; (ii) the emergence of creative behaviour in spite of high cost: does it fit the idea that females choose a male who succeeds in spite of a handicap (costly ornament); or that creative males capable of producing a large and complex song repertoire grew up under favourable conditions; or a demonstration of generally beneficial heightened reasoning capacity; or an opportunity to continually reinforce social bonding through changing communication tropes; or something else? We illustrate and support our argument by reference to whale and bird song; these independently evolved biological signal mechanisms objectively share surface properties with human behaviours generally called ‘creative’. Studying them may elucidate mechanisms underlying human creativity; we outline a research programme to do so.PostprintPeer reviewe