We interpret the wait-and-see strategy as a decision to maintain unchanged the firm's commitments to its business network relationships. To explain why firms choose a wait-and-see strategy, we ...propose an extension to the relationship commitment decisions aspect of the Uppsala internationalization process (IP) Model. With this development, we explain that the wait-and-see strategy can result from a change in the levels of risk assumed in the firm and not only from the decision to adjust the risk that the firm encounters by changing commitments to its network relationships. This development enhances the ability of the IP model to accommodate contextual influences on relationship commitment decisions and to explain a more complete suite of internationalization trajectories. Extending the theoretical core of the IP model further confirms its efficacy, its application to international strategy, and its potential to be developed as a general process model of strategic change.
Edge effects, abiotic and biotic changes associated with habitat boundaries, are key drivers of community change in fragmented landscapes. Their influence is heavily modulated by matrix composition. ...With over half of the world’s tropical forests predicted to become forest edge by the end of the century, it is paramount that conservationists gain a better understanding of how tropical biota is impacted by edge gradients. Bats comprise a large fraction of tropical mammalian fauna and are demonstrably sensitive to habitat modification. Yet, knowledge about how bat assemblages are affected by edge effects remains scarce. Capitalizing on a whole-ecosystem manipulation in the Central Amazon, the aims of this study were to i) assess the consequences of edge effects for twelve aerial insectivorous bat species across the interface of primary and secondary forest, and ii) investigate if the activity levels of these species differed between the understory and canopy and if they were modulated by distance from the edge. Acoustic surveys were conducted along four 2-km transects, each traversing equal parts of primary and ca. 30-year-old secondary forest. Five models were used to assess the changes in the relative activity of forest specialists (three species), flexible forest foragers (three species), and edge foragers (six species). Modelling results revealed limited evidence of edge effects, except for forest specialists in the understory. No significant differences in activity were found between the secondary or primary forest but almost all species exhibited pronounced vertical stratification. Previously defined bat guilds appear to hold here as our study highlights that forest bats are more edge-sensitive than edge foraging bats. The absence of pronounced edge effects and the comparable activity levels between primary and old secondary forests indicates that old secondary forest can help ameliorate the consequences of fragmentation on tropical aerial insectivorous bats.
Current human pluripotent stem cells lack the transcription factor circuitry that governs the ground state of mouse embryonic stem cells (ESC). Here, we report that short-term expression of two ...components, NANOG and KLF2, is sufficient to ignite other elements of the network and reset the human pluripotent state. Inhibition of ERK and protein kinase C sustains a transgene-independent rewired state. Reset cells self-renew continuously without ERK signaling, are phenotypically stable, and are karyotypically intact. They differentiate in vitro and form teratomas in vivo. Metabolism is reprogrammed with activation of mitochondrial respiration as in ESC. DNA methylation is dramatically reduced and transcriptome state is globally realigned across multiple cell lines. Depletion of ground-state transcription factors, TFCP2L1 or KLF4, has marginal impact on conventional human pluripotent stem cells but collapses the reset state. These findings demonstrate feasibility of installing and propagating functional control circuitry for ground-state pluripotency in human cells.
Epigenetic resetting of human pluripotency Guo, Ge; von Meyenn, Ferdinand; Rostovskaya, Maria ...
Development (Cambridge),
08/2017, Letnik:
144, Številka:
15
Journal Article
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Much attention has focussed on the conversion of human pluripotent stem cells (PSCs) to a more naïve developmental status. Here we provide a method for resetting via transient histone deacetylase ...inhibition. The protocol is effective across multiple PSC lines and can proceed without karyotype change. Reset cells can be expanded without feeders with a doubling time of around 24 h. WNT inhibition stabilises the resetting process. The transcriptome of reset cells diverges markedly from that of primed PSCs and shares features with human inner cell mass (ICM). Reset cells activate expression of primate-specific transposable elements. DNA methylation is globally reduced to a level equivalent to that in the ICM and is non-random, with gain of methylation at specific loci. Methylation imprints are mostly lost, however. Reset cells can be re-primed to undergo tri-lineage differentiation and germline specification. In female reset cells, appearance of biallelic X-linked gene transcription indicates reactivation of the silenced X chromosome. On reconversion to primed status,
-induced silencing restores monoallelic gene expression. The facile and robust conversion routine with accompanying data resources will enable widespread utilisation, interrogation, and refinement of candidate naïve cells.
The spin states of single electrons in gate-defined quantum dots satisfy crucial requirements for a practical quantum computer. These include extremely long coherence times, high-fidelity quantum ...operation, and the ability to shuttle electrons as a mechanism for on-chip flying qubits. To increase the number of qubits to the thousands or millions of qubits needed for practical quantum information, we present an architecture based on shared control and a scalable number of lines. Crucially, the control lines define the qubit grid, such that no local components are required. Our design enables qubit coupling beyond nearest neighbors, providing prospects for nonplanar quantum error correction protocols. Fabrication is based on a three-layer design to define qubit and tunnel barrier gates. We show that a double stripline on top of the structure can drive high-fidelity single-qubit rotations. Self-aligned inhomogeneous magnetic fields induced by direct currents through superconducting gates enable qubit addressability and readout. Qubit coupling is based on the exchange interaction, and we show that parallel two-qubit gates can be performed at the detuning-noise insensitive point. While the architecture requires a high level of uniformity in the materials and critical dimensions to enable shared control, it stands out for its simplicity and provides prospects for large-scale quantum computation in the near future.
The Science and Technology of Particle Accelerators provides an accessible introduction to the field, and is suitable for advanced undergraduates, graduate students, and academics, as well as ...professionals in national laboratories and facilities, industry, and medicine who are designing or using particle accelerators. Providing integrated coverage of accelerator science and technology, this book presents the fundamental concepts alongside detailed engineering discussions and extensive practical guidance, including many numerical examples. For each topic, the authors provide a description of the physical principles, a guide to the practical application of those principles, and a discussion of how to design the components that allow the application to be realised. Features: Written by an interdisciplinary and highly respected team of physicists and engineers from the Cockcroft Institute of Accelerator Science and Technology in the UK Accessible style, with many numerical examples Contains an extensive set of problems, with fully worked solutions available Rob Appleby is an academic member of staff at the University of Manchester, and Chief Examiner in the Department of Physics and Astronomy. Graeme Burt is an academic member of staff at the University of Lancaster, and previous Director of Education at the Cockcroft Institute. James Clarke is head of Science Division in the Accelerator Science and Technology Centre at STFC Daresbury Laboratory. Hywel Owen is an academic member of staff at the University of Manchester, and Director of Education at the Cockcroft Institute. All authors are researchers within the Cockcroft Institute of Accelerator Science and Technology and have extensive experience in the design and construction of particle accelerators, including particle colliders, synchrotron radiation sources, free electron lasers, and medical and industrial accelerator systems.
Reducing rates of depressive symptoms in older adults is a public health priority. Men's Sheds are a community organisation that may protect against depressive symptoms in older men. It is currently ...unclear how social anxiety and behavioural activation may relate to depressive symptoms for Men's Shed members. We employed a cross-sectional design to explore whether the relationships between social anxiety, behavioural activation and depressive symptoms were contingent upon Shed social network quality in a sample of 164 Men's Shed members. Conditional effects analysis found social anxiety (B = -0.08, p < 0.01) and behavioural activation's (B = 0.02, p < 0.001) relationships with depression to be contingent on Shed social network quality. Additionally, we found evidence for a conditional effect of social anxiety on the relationship between behavioural activation and depression (B = -0.03, p < 0.01) such that this relationship was stronger for those with higher levels of social anxiety. Our findings suggest that a strong social network within a Men's Shed weakens the association between social anxiety and depression, that the relationship between behavioural activation and depression is stronger in those with poorer Shed social networks, and that the relationship between behavioural activation and depression may be stronger for those with higher levels of social anxiety. We suggest that our findings contribute to increasing quantitative support for the mental health benefits of Men's Shed membership, highlight the potential importance of Shed social network quality and explore how social anxiety may affect the mental health outcomes for members.
International experience, the experience that firms accrue from operating internationally, is a key concept in explaining firm internationalization. This paper reviews the conceptualization of ...international experience in the international business literature. It highlights how prior research has identified three dimensions of the international experience construct (length, scope and diversity), thereby demonstrating that international experience should be treated as a multidimensional construct. In addition, intensity is presented as a fourth and novel dimension of international experience. The importance of this multidimensional conceptualization is highlighted in an explanation of why the international diversification and international experience constructs are not synonymous. In light of the importance of international experience in explaining firm internationalization, the authors explore how the source of the firm's international experience will determine the limits to its application in foreign markets. In particular, the authors distinguish between location‐bound international experience and non‐location‐bound international experience as sources of firm‐specific advantages (FSAs). The FSAs that the firm develops from its experience with equity and non‐equity entry modes are presented as examples of specific FSAs developed within the firm's bundle of FSAs concerning internationalization. The paper concludes with some implications of the conceptualization of international experience for several issues of international business research as well as providing managerial implications.
Discourse Constraints for Document Compression Clarke, James; Lapata, Mirella
Computational linguistics - Association for Computational Linguistics,
09/2010, Letnik:
36, Številka:
3
Journal Article
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Sentence compression holds promise for many applications ranging from summarization to subtitle generation. The task is typically performed on isolated sentences without taking the surrounding ...context into account, even though most applications would operate over entire documents. In this article we present a discourse-informed model which is capable of producing document compressions that are coherent and informative. Our model is inspired by theories of local coherence and formulated within the framework of integer linear programming. Experimental results show significant improvements over a state-of-the-art discourse agnostic approach.
Dolutegravir (DTG; S/GSK1349572) is a potent HIV-1 integrase inhibitor with a distinct resistance profile and a once-daily dose regimen that does not require pharmacokinetic boosting. This work ...investigated the in vitro drug transport and metabolism of DTG and assessed the potential for clinical drug-drug interactions. DTG is a substrate for the efflux transporters P-glycoprotein (Pgp) and human breast cancer resistance protein (BCRP). Its high intrinsic membrane permeability limits the impact these transporters have on DTG's intestinal absorption. UDP-glucuronosyltransferase (UGT) 1A1 is the main enzyme responsible for the metabolism of DTG in vivo, with cytochrome P450 (P450) 3A4 being a notable pathway and UGT1A3 and UGT1A9 being only minor pathways. DTG demonstrated little or no inhibition (IC(50) values > 30 μM) in vitro of the transporters Pgp, BCRP, multidrug resistance protein 2, organic anion transporting polypeptide 1B1/3, organic cation transporter (OCT) 1, or the drug metabolizing enzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, UGT1A1, or 2B7. Further, DTG did not induce CYP1A2, 2B6, or 3A4 mRNA in vitro using human hepatocytes. DTG does inhibit the renal OCT2 (IC(50) = 1.9 μM) transporter, which provides a mechanistic basis for the mild increases in serum creatinine observed in clinical studies. These in vitro studies demonstrate a low propensity for DTG to be a perpetrator of clinical drug interactions and provide a basis for predicting when other drugs could result in a drug interaction with DTG.
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