Frequent pathway mutations of splicing machinery in myelodysplasia

Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent (～45 to ～85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3'-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved in human pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.     

Structural basis for the subunit assembly of the anaphase-promoting complex

The anaphase-promoting complex or cyclosome (APC/C) is an unusually large E3 ubiquitin ligase responsible for regulating defined cell cycle transitions. Information on how its 13 constituent proteins are assembled, and how they interact with co-activators, substrates and regulatory proteins is limited. Here, we describe a recombinant expression system that allows the reconstitution of holo APC/C and its sub-complexes that, when combined with electron microscopy, mass spectrometry and docking of crystallographic and homology-derived coordinates, provides a precise definition of the organization and structure of all essential APC/C subunits, resulting in a pseudo-atomic model for 70% of the APC/C. A lattice-like appearance of the APC/C is generated by multiple repeat motifs of most APC/C subunits. Three conserved tetratricopeptide repeat (TPR) subunits (Cdc16, Cdc23 and Cdc27) share related superhelical homo-dimeric architectures that assemble to generate a quasi-symmetrical structure. Our structure explains how this TPR sub-complex, together with additional scaffolding subunits (Apc1, Apc4 and Apc5), coordinate the juxtaposition of the catalytic and substrate recognition module (Apc2, Apc11 and Apc10 (also known as Doc1)), and TPR-phosphorylation sites, relative to co-activator, regulatory proteins and substrates.     

CD4 and CD8 T lymphocyte interplay in controlling tumor growth

The outstanding clinical success of immune checkpoint blockade has revived the interest in underlying mechanisms of the immune system that are capable of eliminating tumors even in advanced stages. In this scenario, CD4 and CD8 T cell responses are part of the cancer immune cycle and both populations significantly influence the clinical outcome. In general, the immune system has evolved several mechanisms to protect the host against cancer. Each of them has to be undermined or evaded during cancer development to enable tumor outgrowth. In this review, we give an overview of T lymphocyte-driven control of tumor growth and discuss the involved tumor-suppressive mechanisms of the immune system, such as senescence surveillance, cancer immunosurveillance, and cancer immunoediting with respect to recent clinical developments of immunotherapies. The main focus is on the currently existing knowledge about the CD4 and CD8 T lymphocyte interplay that mediates the control of tumor growth.     

How to infer explanations from computer simulations

Computer simulations are involved in numerous branches of modern science, and science would not be the same without them. Yet the question of how they can explain real-world processes remains an issue of considerable debate. In this context, a range of authors have highlighted the inferences back to the world that computer simulations allow us to draw. I will first characterize the precise relation between computer and target of a simulation that allows us to draw such inferences. I then argue that in a range of scientifically interesting cases they are particular abductions and defend this claim by appeal to two case studies.     

Brain-wide neuronal dynamics during motor adaptation in zebrafish

A fundamental question in neuroscience is how entire neural circuits generate behaviour and adapt it to changes in sensory feedback. Here we use two-photon calcium imaging to record the activity of large populations of neurons at the cellular level, throughout the brain of larval zebrafish expressing a genetically encoded calcium sensor, while the paralysed animals interact fictively with a virtual environment and rapidly adapt their motor output to changes in visual feedback. We decompose the network dynamics involved in adaptive locomotion into four types of neuronal response properties, and provide anatomical maps of the corresponding sites. A subset of these signals occurred during behavioural adjustments and are candidates for the functional elements that drive motor learning. Lesions to the inferior olive indicate a specific functional role for olivocerebellar circuitry in adaptive locomotion. This study enables the analysis of brain-wide dynamics at single-cell resolution during behaviour.     

Protective role of phospholipid oxidation products in endotoxin-induced tissue damage

Lipopolysaccharide (LPS), an outer-membrane component of Gram-negative bacteria, interacts with LPS-binding protein and CD14, which present LPS to toll-like receptor 4 (refs 1, 2), which activates inflammatory gene expression through nuclear factor kappa B (NF kappa B) and mitogen-activated protein-kinase signalling. Antibacterial defence involves activation of neutrophils that generate reactive oxygen species capable of killing bacteria; therefore host lipid peroxidation occurs, initiated by enzymes such as NADPH oxidase and myeloperoxidase. Oxidized phospholipids are pro-inflammatory agonists promoting chronic inflammation in atherosclerosis; however, recent data suggest that they can inhibit expression of inflammatory adhesion molecules. Here we show that oxidized phospholipids inhibit LPS-induced but not tumour-necrosis factor-alpha-induced or interleukin-1 beta-induced NF kappa B-mediated upregulation of inflammatory genes, by blocking the interaction of LPS with LPS-binding protein and CD14. Moreover, in LPS-injected mice, oxidized phospholipids inhibited inflammation and protected mice from lethal endotoxin shock. Thus, in severe Gram-negative bacterial infection, endogenously formed oxidized phospholipids may function as a negative feedback to blunt innate immune responses. Furthermore, identified chemical structures capable of inhibiting the effects of endotoxins such as LPS could be used for the development of new drugs for treatment of sepsis.     

The amount of carbon released from peat and forest fires in Indonesia during 1997

Tropical peatlands are one of the largest near-surface reserves of terrestrial organic carbon, and hence their stability has important implications for climate change. In their natural state, lowland tropical peatlands support a luxuriant growth of peat swamp forest overlying peat deposits up to 20 metres thick. Persistent environmental change-in particular, drainage and forest clearing-threatens their stability, and makes them susceptible to fire. This was demonstrated by the occurrence of widespread fires throughout the forested peatlands of Indonesia during the 1997 El Ni?o event. Here, using satellite images of a 2.5 million hectare study area in Central Kalimantan, Borneo, from before and after the 1997 fires, we calculate that 32% (0.79 Mha) of the area had burned, of which peatland accounted for 91.5% (0.73 Mha). Using ground measurements of the burn depth of peat, we estimate that 0.19-0.23 gigatonnes (Gt) of carbon were released to the atmosphere through peat combustion, with a further 0.05 Gt released from burning of the overlying vegetation. Extrapolating these estimates to Indonesia as a whole, we estimate that between 0.81 and 2.57 Gt of carbon were released to the atmosphere in 1997 as a result of burning peat and vegetation in Indonesia. This is equivalent to 13-40% of the mean annual global carbon emissions from fossil fuels, and contributed greatly to the largest annual increase in atmospheric CO(2) concentration detected since records began in 1957 (ref. 1).     

Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment

The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.     

Structural insight into filament formation by mammalian septins

Septins are GTP-binding proteins that assemble into homo- and hetero-oligomers and filaments. Although they have key roles in various cellular processes, little is known concerning the structure of septin subunits or the organization and polarity of septin complexes. Here we present the structures of the human SEPT2 G domain and the heterotrimeric human SEPT2-SEPT6-SEPT7 complex. The structures reveal a universal bipolar polymer building block, composed of an extended G domain, which forms oligomers and filaments by conserved interactions between adjacent nucleotide-binding sites and/or the amino- and carboxy-terminal extensions. Unexpectedly, X-ray crystallography and electron microscopy showed that the predicted coiled coils are not involved in or required for complex and/or filament formation. The asymmetrical heterotrimers associate head-to-head to form a hexameric unit that is nonpolarized along the filament axis but is rotationally asymmetrical. The architecture of septin filaments differs fundamentally from that of other cytoskeletal structures.     

Predicting crypto‐currencies using sparse non‐Gaussian state space models

In this paper we forecast daily returns of crypto‐currencies using a wide variety of different econometric models. To capture salient features commonly observed in financial time series like rapid changes in the conditional variance, non‐normality of the measurement errors and sharply increasing trends, we develop a time‐varying parameter VAR with t‐distributed measurement errors and stochastic volatility. To control for overparametrization, we rely on the Bayesian literature on shrinkage priors, which enables us to shrink coefficients associated with irrelevant predictors and/or perform model specification in a flexible manner. Using around one year of daily data, we perform a real‐time forecasting exercise and investigate whether any of the proposed models is able to outperform the naive random walk benchmark. To assess the economic relevance of the forecasting gains produced by the proposed models we, moreover, run a simple trading exercise.