No benefits from warming even for subnival vegetation in the central Himalayas

Global temperature has been increasing at unprecedented rates during the Anthropocene,impacting both natural and human sys-tems [1].Alpine biomes,among the most...     

Countering medical nihilism by reconnecting facts and values

A pessimistic strain of thought is fomenting in the health studies literature regarding the status of medicine. Ioannidis’s (2005) now famous finding that “most published research findings are false” and Stegenga’s (2018) book-length argument for medical nihilism are examples of this. In this paper, we argue that these positions are incorrect insofar as they rest on an untenable account of the nature of facts. Proper attention to fallibilism and the social organization of knowledge, as well as Bayesian probabilities in medical reasoning, prompt us to ask why the cynics expect the results of quantitative studies to be incontrovertibly true in the first place. While we agree with Ioannidis and others’ identified flaws in the medical research enterprise, and encourage rectification, we conclude that medical nihilism is not the natural outcome of the current state of research.     

Why eliminativism?

A central thesis of Steven French's brand of ontic structural realism has always been his eliminativism about objects. Unsurprisingly, this bold and controversial thesis has seen a lot of critical discussion. In his book The Structure of the World—Metaphysics & Representation, French accordingly defends this thesis against a range of challenges. A novel feature of this defense is the use of dependence relations to articulate his eliminativism. In this paper I take a critical look at French's defense of eliminativism and argue that the dependence relations invoked do not eliminate objects.     

Analysts’ Dynamic Decisions: Timeliness versus Accuracy

For analysts there is a tradeoff between the accuracy and the timeliness of their forecasts. Prior literature heavily investigates analyst forecast accuracy. Few papers investigate the importance of timeliness. To our best knowledge, there are no empirical papers to date to investigate the dynamic interplay between these key characteristics. We show that if analysts experience a period of high accuracy relative to their peers, they subsequently focus more on the timeliness of their forecasts in the subsequent period and thus issue their forecasts earlier than they did in the prior period. Copyright © 2016 John Wiley & Sons, Ltd.     

Advances in anti-viral immune defence: revealing the importance of the IFN JAK/STAT pathway

Interferon-alpha (IFN-α) is a potent anti-viral cytokine, critical to the host immune response against viruses. IFN-α is first produced upon viral detection by pathogen recognition receptors. Following its expression, IFN-α embarks upon a complex downstream signalling cascade called the JAK/STAT pathway. This signalling pathway results in the expression of hundreds of effector genes known as interferon stimulated genes (ISGs). These genes are the basis for an elaborate effector mechanism and ultimately, the clearance of viral infection. ISGs mark an elegant mechanism of anti-viral host defence that warrants renewed research focus in our global efforts to treat existing and emerging viruses. By understanding the mechanistic role of individual ISGs we anticipate the discovery of a new “treasure trove” of anti-viral mediators that may pave the way for more effective, targeted and less toxic anti-viral therapies. Therefore, with the aim of highlighting the value of the innate type 1 IFN response in our battle against viral infection, this review outlines both historic and recent advances in understanding the IFN-α JAK/STAT pathway, with a focus on new research discoveries relating to specific ISGs and their potential role in curing existing and future emergent viral infections.     

Immunological properties of oxygen-transport proteins: hemoglobin,hemocyanin and hemerythrin

It is now well documented that peptides with enhanced or alternative functionality (termed cryptides) can be liberated from larger, and sometimes inactive, proteins. A primary example of this phenomenon is the oxygen-transport protein hemoglobin. Aside from respiration, hemoglobin and hemoglobin-derived peptides have been associated with immune modulation, hematopoiesis, signal transduction and microbicidal activities in metazoans. Likewise, the functional equivalents to hemoglobin in invertebrates, namely hemocyanin and hemerythrin, act as potent immune effectors under certain physiological conditions. The purpose of this review is to evaluate the true extent of oxygen-transport protein dynamics in innate immunity, and to impress upon the reader the multi-functionality of these ancient proteins on the basis of their structures. In this context, erythrocyte–pathogen antibiosis and the immune competences of various erythroid cells are compared across diverse taxa.     

Phospholipid flippases attenuate LPS-induced TLR4 signaling by mediating endocytic retrieval of Toll-like receptor 4

P4-ATPases are lipid flippases that catalyze the transport of phospholipids to create membrane phospholipid asymmetry and to initiate the biogenesis of transport vesicles. Here we show, for the first time, that lipid flippases are essential to dampen the inflammatory response and to mediate the endotoxin-induced endocytic retrieval of Toll-like receptor 4 (TLR4) in human macrophages. Depletion of CDC50A, the β-subunit that is crucial for the activity of multiple P4-ATPases, resulted in endotoxin-induced hypersecretion of proinflammatory cytokines, enhanced MAP kinase signaling and constitutive NF-κB activation. In addition, CDC50A-depleted THP-1 macrophages displayed reduced tolerance to endotoxin. Moreover, endotoxin-induced internalization of TLR4 was strongly reduced and coincided with impaired endosomal MyD88-independent signaling. The phenotype of CDC50A-depleted cells was also induced by separate knockdown of two P4-ATPases, namely ATP8B1 and ATP11A. We conclude that lipid flippases are novel elements of the innate immune response that are essential to attenuate the inflammatory response, possibly by mediating endotoxin-induced internalization of TLR4.     

Opposing effects on the cell cycle of T lymphocytes by Fbxo7 via Cdk6 and p27

G₁ phase cell cycle proteins, such as cyclin-dependent kinase 6 (Cdk6) and its activating partners, the D-type cyclins, are important regulators of T-cell development and function. An F-box protein, called F-box only protein 7 (Fbxo7), acts as a cell cycle regulator by enhancing cyclin D-Cdk6 complex formation and stabilising levels of p27, a cyclin-dependent kinase inhibitor. We generated a murine model of reduced Fbxo7 expression to test its physiological role in multiple tissues and found that these mice displayed a pronounced thymic hypoplasia. Further analysis revealed that Fbxo7 differentially affected proliferation and apoptosis of thymocytes at various stages of differentiation in the thymus and also mature T-cell function and proliferation in the periphery. Paradoxically, Fbxo7-deficient immature thymocytes failed to undergo expansion in the thymus due to a lack of Cdk6 activity, while mature T cells showed enhanced proliferative capacity upon T-cell receptor engagement due to reduced p27 levels. Our studies reveal differential cell cycle regulation by Fbxo7 at different stages in T-cell development.     

Henderson‐Trending of Macroeconomic Variables and Forecasting Accuracy

Using a structural time‐series model, the forecasting accuracy of a wide range of macroeconomic variables is investigated. Specifically of importance is whether the Henderson moving‐average procedure distorts the underlying time‐series properties of the data for forecasting purposes. Given the weight of attention in the literature to the seasonal adjustment process used by various statistical agencies, this study hopes to address the dearth of literature on ‘trending’ procedures. Forecasts using both the trended and untrended series are generated. The forecasts are then made comparable by ‘detrending’ the trended forecasts, and comparing both series to the realised values. Forecasting accuracy is measured by a suite of common methods, and a test of significance of difference is applied to the respective root mean square errors. It is found that the Henderson procedure does not lead to deterioration in forecasting accuracy in Australian macroeconomic variables on most occasions, though the conclusions are very different between the one‐step‐ahead and multi‐step‐ahead forecasts. Copyright © 2011 John Wiley & Sons, Ltd.