Network Centrality and Delegated Investment Performance

We document a positive relation between network centrality and risk-adjusted performance in a delegated investment management setting. More connected managers take more portfolio risk and receive higher investor flows, consistent with these managers improving their ability to exploit investment opportunities through their network connections. Greater network connections are shown to be particularly important in reducing the diseconomies-of-scale for large managers who are well-connected. We also use the exogenous merger of two investment consultants, which creates a sudden change in the network connections of the managers they oversee, to provide evidence that a greater number of connections translates into better portfolio performance

Sensitivity of the Atlantic meridional overturning circulation to South Atlantic freshwater anomalies

The sensitivity of the Atlantic Meridional Overturning Circulation (AMOC) to changes in basin integrated net evaporation is highly dependent on the zonal salinity contrast at the southern border of the Atlantic. Biases in the freshwater budget strongly affect the stability of the AMOC in numerical models. The impact of these biases is investigated, by adding local anomaly patterns in the South Atlantic to the freshwater fluxes at the surface. These anomalies impact the freshwater and salt transport by the different components of the ocean circulation, in particular the basin-scale salt-advection feedback, completely changing the response of the AMOC to arbitrary perturbations. It is found that an appropriate dipole anomaly pattern at the southern border of the Atlantic Ocean can collapse the AMOC entirely even without a further hosing. The results suggest a new view on the stability of the AMOC, controlled by processes in the South Atlantic. <br/

Integrated analysis of Xist upregulation and gene silencing at the onset of random X-chromosome inactivation at high temporal and allelic resolution

To ensure dosage compensation between the sexes, one randomly chosen X chromosome is silenced in each female cell in the process of X-chromosome inactivation (XCI). XCI is initiated during early development through upregulation of the long non-coding RNA Xist, which mediateschromosome-wide gene silencing. Cell differentiation, Xist upregulation and silencing are thought tobe coupled at multiple levels to ensure inactivation of exactly one out of two X chromosomes. Here we perform an integrated analysis of all three processes through allele-specific single-cellRNA-sequencing. Specifically, we assess the onset of random XCI with high temporal resolution indifferentiating mouse embryonic stem cells, and develop dedicated analysis approaches. By exploitingthe inter-cellular heterogeneity of XCI onset, we identify Nanog downregulation as its main trigger and discover additional putative Xist regulators. Moreover, we confirm several predictions of thestochastic model of XCI where monoallelic silencing is thought to be ensured through negativefeedback regulation. Finally, we show that genetic variation modulates the XCI process at multiplelevels, providing a potential explanation for the long-known Xce effect, which leads to preferentialinactivation of a specific X chromosome in inter-strain crosses. We thus draw a detailed picture of thedifferent levels of regulation that govern the initiation of XCI. The experimental and computationalstrategies we have developed here will allow us to profile random XCI in more physiological contexts,including primary human cells in vivo

New procedures for testing whether stock price processes are martingales

We propose procedures for testing whether stock price processes are martingales based on limit order type betting strategies. We first show that the null hypothesis of martingale property of a stock price process can be tested based on the capital process of a betting strategy. In particular with high frequency Markov type strategies we find that martingale null hypotheses are rejected for many stock price processes

Alternative splicing coupled mRNA decay shapes the temperature‐dependent transcriptome

Mammalian body temperature oscillates with the time of the dayand is altered in diverse pathological conditions. We recently iden-tified a body temperature-sensitive thermometer-like kinase,which alters SR protein phosphorylation and thereby globallycontrols alternative splicing (AS). AS can generate unproductivevariants which are recognized and degraded by diverse mRNAdecay pathways—including nonsense-mediated decay (NMD). Herewe show extensive coupling of body temperature-controlled AS tomRNA decay, leading to global control of temperature-dependentgene expression (GE). Temperature-controlled, decay-inducingsplicing events are evolutionarily conserved and pervasively foundwithin RNA-binding proteins, including most SR proteins. AS-coupledpoison exon inclusion is essential for rhythmic GE of SR proteins andhas a global role in establishing temperature-dependent rhythmicGE profiles, both in mammals under circadian body temperaturecycles and in plants in response to ambient temperature changes.Together, these data identify body temperature-driven AS-coupledmRNA decay as an evolutionary ancient, core clock-independentmechanism to generate rhythmic GE

Transcriptomic and proteomic insight into the effects of a defined European mistletoe extract in Ewing sarcoma cells reveals cellular stress responses

Background The hydrophobic triterpenes, oleanolic and betulinic acid as well as the hydrophilic mistletoe lectins and viscotoxins possess anticancer properties. They do all occur in combination in European mistletoe (Viscum album L.). Commercial Viscum album L. extracts are aqueous, excluding the insoluble triterpenes. We have previously shown that mistletoe lectins and triterpene acids are effective against Ewing sarcoma in vitro, ex vivo and in vivo. Methods We recreated a total mistletoe effect (viscumTT) by combining an aqueous extract (viscum) and a triterpene extract (TT) solubilised with cyclodextrins and analysed the effects of viscumTT and the single extracts on TC-71 Ewing sarcoma cells in vitro by transcriptomic and proteomic profiling. Results Treatment with the extracts strongly impacted Ewing sarcoma cell gene and protein expression. Apoptosis-associated and stress-activated genes were upregulated, proteasomal protein abundance enhanced and ribosomal and spliceosomal proteins downregulated. The mechanism of action of viscum, TT and viscumTT in TC-71 and MHH-ES-1 cells suggests the involvement of the unfolded protein response. While viscum and viscumTT extract treatment indicate response to oxidative stress and activation of stress-mediated MAPK signalling, TT extract treatment suggests the involvement of TLR signalling and autophagy. Conclusions Since the combinatory extract viscumTT exerts highly effective pro-apoptotic effects on Ewing sarcoma cells in vitro, this phytopolychemotherapy could be a promising adjuvant therapeutic option for paediatric patients with Ewing sarcoma

An In-Silico Study on Integrated Mechanisms of Mechano-Electric Coupling in Ischaemic Arrhythmogenesis

Heterogeneous mechanical dyskinesis during acute myocardial ischaemia is thought to contribute to arrhythmogenic alterations to cardiac electrophysiology. Various forms of mechano-electric coupling (MEC) mechanisms have been suggested to contribute to these changes, with two primary mechanisms being: (1) myofilament-dependent calcium release events, and (2) the activation of stretch-activated currents (SACs). In this computational investigation, we assessed the collective impact of these processes on mechanically-induced alternans that create an arrhythmogenic substrate during acute ischaemia. To appraise the potential involvement of MEC in ischaemia-induced arrhythmias, we developed a coupled model of ventricular myocyte electrophysiology and contraction including SACs and stretch-dependent calcium buffering and release. The model, reflecting observed electrophysiological changes during ischaemia, was exposed to a series of stretch protocols that replicated both physiological and pathological mechanical conditions. Pathologically realistic myofiber stretch variations revealed calcium sensitivity changes dependent on myofilament, leading to alterations in cytosolic calcium concentrations. Under calcium overload conditions, these changes resulted in electrical alternans. The study implies that strain impacts cellular electrophysiology through myofilament calcium release and SAC opening in ventricular mechano-electrical models, parameterised to available data. This supports experimental evidence suggesting that both calcium-driven instability via MEC and SAC-induced effects contribute to electrical alternans in acute ischaemia.Comment: 20 pages; 8 figures; original pape