A Dimension-Adaptive Multi-Index Monte Carlo Method Applied to a Model of a Heat Exchanger

We present an adaptive version of the Multi-Index Monte Carlo method, introduced by Haji-Ali, Nobile and Tempone (2016), for simulating PDEs with coefficients that are random fields. A classical technique for sampling from these random fields is the Karhunen-Lo\`eve expansion. Our adaptive algorithm is based on the adaptive algorithm used in sparse grid cubature as introduced by Gerstner and Griebel (2003), and automatically chooses the number of terms needed in this expansion, as well as the required spatial discretizations of the PDE model. We apply the method to a simplified model of a heat exchanger with random insulator material, where the stochastic characteristics are modeled as a lognormal random field, and we show consistent computational savings

Synaptic NMDAR activity suppresses FOXO1 expression via a cis-acting FOXO binding site:FOXO1 is a FOXO target gene

Activation of gene expression by FOXO transcription factors can promote neuronal death in response to loss of trophic support, or oxidative stress. The predominant neuronal FOXOs, FOXO1 and FOXO3, promote the expression of pro-death genes, such as Fas Ligand, Bim and Txnip. Neuroprotective signals initiated by neurotrophins, growth factors or synaptic activity trigger the nuclear export of FOXOs via activation of the PI3K-Akt pathway. One key aspect of FOXO regulation is that once PI3K-Akt activity has returned to baseline, FOXOs return to the nucleus to resume the activation of their target genes. Thus, the FOXO-inhibiting capacity of the PI3K-Akt pathway is thought to be short-lived. However, we show here that synaptic NMDA receptor activity not only triggers FOXO export, but also suppresses the expression of FOXO1. Blockade of PI3K activity prevents both FOXO nuclear export and suppression of FOXO1 expression, raising the possibility that FOXO1 is itself a FOXO target gene. We found that FOXO3, and to a lesser extent FOXO1 transactivates the FOXO1 promoter via a consensus FOXO binding site (GTA AAC AA), and also an upstream sequence resembling a classical FOXO-binding insulin response sequence (CAA AAC AA). Activity-dependent suppression of the FOXO1 promoter is mediated through the proximal GTAAACAA sequence. Similar suppression via this site is observed by activating neuronal IGF-1 receptors by exogenous insulin. Thus, through a feed-forward inhibition mechanism, synaptic activity triggers FOXO export resulting in suppression of FOXO1 expression. These results suggest that FOXO-inactivating signals are likely to result in longer-term inhibition of FOXO target gene expression than previously thought

Effect of alteplase use on outcomes in patients with atrial fibrillation: Analysis of the Initiation of Anticoagulation after Cardioembolic Stroke study

Background Intravenous alteplase improves outcome after acute ischemic stroke without a benefit in 90-day mortality. There are limited data on whether alteplase is associated with reduced mortality in patients with atrial fibrillation (AF)-related ischemic stroke whose mortality rate is relatively high. We sought to determine the association of alteplase with hemorrhagic transformation and mortality in patients with AF. Methods and Results We retrospectively analyzed consecutive patients with acute ischemic stroke between 2015 and 2018 diagnosed with AF included in the IAC (Initiation of Anticoagulation After Cardioembolic Stroke) study, which pooled data from stroke registries at 8 comprehensive stroke centers across the United States. For our primary analysis, we included patients who did not undergo mechanical thrombectomy (MT), and secondary analyses included patients who underwent MT. We used binary logistic regression to determine whether alteplase use was associated with risk of hemorrhagic transformation and 90-day mortality. There were 1889 patients (90.6%) who had 90-day follow-up data available for analyses and were included; 1367 patients (72.4%) did not receive MT, and 522 patients (27.6%) received MT. In our primary analyses we found that alteplase use was independently associated with an increased risk for hemorrhagic transformation (odds ratio [OR], 2.23; 95% CI, 1.57-3.17) but reduced risk of 90-day mortality (OR, 0.58; 95% CI, 0.39-0.87). Among patients undergoing MT, alteplase use was not associated with a significant reduction in 90-day mortality (OR, 0.68; 95% CI, 0.45-1.04). Conclusions Alteplase reduced 90-day mortality of patients with acute ischemic stroke with AF not undergoing MT. Further study is required to assess the efficacy of alteplase in patients with AF undergoing MT

Activation of Nrf2 to optimise immune responses to intracerebral haemorrhage

Haemorrhage into the brain parenchyma can be devastating. This manifests as spontaneous intracerebral haemorrhage (ICH) after head trauma, and in the context of vascular dementia. Randomised controlled trials have not reliably shown that haemostatic treatments aimed at limiting ICH haematoma expansion and surgical approaches to reducing haematoma volume are effective. Consequently, treatments to modulate the pathophysiological responses to ICH, which may cause secondary brain injury, are appealing. Following ICH, microglia and monocyte derived cells are recruited to the peri-haematomal environment where they phagocytose haematoma breakdown products and secrete inflammatory cytokines, which may trigger both protective and harmful responses. The transcription factor Nrf2, is activated by oxidative stress, is highly expressed by central nervous system microglia and macroglia. When active, Nrf2 induces a transcriptional programme characterised by increased expression of antioxidant, haem and heavy metal detoxification and proteostasis genes, as well as suppression of proinflammatory factors. Therefore, Nrf2 activation may facilitate adaptive-protective immune cell responses to ICH by boosting resistance to oxidative stress and heavy metal toxicity, whilst limiting harmful inflammatory signalling, which can contribute to further blood brain barrier dysfunction and cerebral oedema. In this review, we consider the responses of immune cells to ICH and how these might be modulated by Nrf2 activation. Finally, we propose potential therapeutic strategies to harness Nrf2 to improve the outcomes of patients with ICH

Optical imaging and spectroscopy for the study of the human brain: status report

This report is the second part of a comprehensive two-part series aimed at reviewing an extensive and diverse toolkit of novel methods to explore brain health and function. While the first report focused on neurophotonic tools mostly applicable to animal studies, here, we highlight optical spectroscopy and imaging methods relevant to noninvasive human brain studies. We outline current state-of-the-art technologies and software advances, explore the most recent impact of these technologies on neuroscience and clinical applications, identify the areas where innovation is needed, and provide an outlook for the future directions. Keywords: DCS; NIRS; diffuse optics; functional neuroscience; optical imaging; optical spectroscop

Circumpolar thinning of Arctic sea ice following the 2007 record ice extent minimum

September 2007 marked a record minimum in sea ice extent. While there have been many studies published recently describing the minimum and its causes, little is known about how the ice thickness has changed in the run up to, and following, the summer of 2007. Using satellite radar altimetry data, covering the Arctic Ocean up to 81.5 degrees North, we show that the average winter sea ice thickness anomaly, after the melt season of 2007, was 0.26 m below the 2002/2003 to 2007/2008 average. More strikingly, the Western Arctic anomaly was 0.49 m below the six-year mean in the winter of 2007/2008. These results show no evidence of short-term preconditioning through ice thinning between 2002 and 2007 but show that, after the record minimum ice extent in 2007, the average ice thickness was reduced, particularly in the Western Arctic. Citation: Giles, K. A., S. W. Laxon, and A. L. Ridout (2008), Circumpolar thinning of Arctic sea ice following the 2007 record ice extent minimum, Geophys. Res. Lett., 35, L22502, doi: 10.1029/2008GL035710

Activation of Nrf2-Regulated Glutathione Pathway Genes by Ischemic Preconditioning

Prophylactic pharmacological activation of astrocytic gene expression driven by the transcription factor Nrf2 boosts antioxidant defences and protects against neuronal loss in ischemia and other disease models. However, the role of Nrf2 in mediating endogenous neuroprotective responses is less clear. We recently showed that Nrf2 is activated by mild oxidative stress in both rodent and human astrocytes. Moreover, brief exposure to ischemic conditions was found to activate Nrf2 both in vivo and in vitro, and this was found to contribute to neuroprotective ischemic preconditioning. Here we show that transient ischemic conditions in vitro and in vivo cause an increase in the expression of Nrf2 target genes associated with the glutathione pathway, including those involved in glutathione biosynthesis and cystine uptake. Taken together, these studies indicate that astrocytic Nrf2 may represent an important mediator of endogenous neuroprotective preconditioning pathways

Medical education and research environment in Qatar: a new epoch for translational research in the Middle East

Recent advances in medical technology and key discoveries in biomedical research have the potential to improve human health in an unprecedented fashion. As a result, many of the Arab Gulf countries, particularly Qatar are devoting increasing resources toward establishing centers of excellence in biomedical research. However, there are challenges that must be overcome. The low profile of private medical institutions and their negligible endowments in the region are examples of such challenges. Business-type government controlled universities are not the solution for overcoming the challenges facing higher education and research programs in the Middle East

Western Arctic Ocean freshwater storage increased by wind-driven spin-up of the Beaufort Gyre

The Arctic Ocean’s freshwater budget comprises contributions from river runoff, precipitation, evaporation, sea-ice and exchanges with the North Pacific and Atlantic. More than 70,000km3 of freshwater are stored in the upper layer of the Arctic Ocean, leading to low salinities in upper-layer Arctic sea water, separated by a strong halocline from warm, saline water beneath. Spatially and temporally limited observations show that the Arctic Ocean’s freshwater content has increased over the past few decades, predominantly in the west. Models suggest that wind-driven convergence drives freshwater accumulation. Here we use continuous satellite measurements between 1995 and 2010 to show that the dome in sea surface height associated with the western Arctic Beaufort Gyre has been steepening, indicating spin-up of the gyre. We find that the trend in wind field curl—a measure of spatial gradients in the wind that lead to water convergence or divergence—exhibits a corresponding spatial pattern, suggesting that wind-driven convergence controls freshwater variability. We estimate an increase in freshwater storage of 8,000±2,000km3 in the western Arctic Ocean, in line with hydrographic observations, and conclude that a reversal in the wind field could lead to a spin-down of the Beaufort Gyre, and release of this freshwater to the Arctic Ocean