Effective SAT-based Solutions for Generating Functional Sequences Maximizing the Sustained Switching Activity in a Pipelined Processor

During device testing, one of the aspects to be considered is the minimization of the switching activity of the circuit under test in order to steer clear of introducing problems due to device overheating. Nevertheless, there are also certain scenarios during which the maximization of switching activity of the circuit under test (CUT) or of certain parts of it could be proven beneficial e.g., during Burn-In (BI), where internal stress is often produced by applying suitable stimuli. This can be done in a functional manner based on Software-based Self-Test in order to avoid possible damages to the CUT and/or any kind of yield loss. However, the generation of suitable test programs for this task represents a non-trivial task. In this paper we consider a scenario where the circuitry to be stressed is a pipelined processor. We present a methodology, based on formal techniques, able to automatically generate the best functional stress stimuli, i.e., a short and repeatable sequence of assembly instructions, which is guaranteed to induce the maximum switching activity within a given target processor module over a pre-defined time period. For the purposes of our experiments we used the OpenRISC 1200. The gathered experimental results demonstrate the effectiveness of the developed method. In particular, we show that the time for generating the best instruction sequence is limited in most cases, while the generated sequence can always achieve a significantly higher sustained toggling activity than any other solution

The DWD climate predictions website: Towards a seamless outlook based on subseasonal, seasonal and decadal predictions

The climate predictions website of the Deutscher Wetterdienst (DWD, https://www.dwd.de/climatepredictions) presents a consistent operational outlook for the coming weeks, months and years, focusing on the needs of German users. At global scale, subseasonal predictions from the European Centre of Medium-Range Weather Forecasts as well as seasonal and decadal predictions from the DWD are used. Statistical downscaling is applied to achieve high resolution over Germany. Lead-time dependent bias correction is performed on all time scales. Additionally, decadal predictions are recalibrated. The website offers ensemble mean and probabilistic predictions for temperature and precipitation combined with their skill (mean squared error skill score, ranked probability skill score). Two levels of complexity are offered: basic climate predictions display simple, regionally averaged information for Germany, German regions and cities as maps, time series and tables. The skill is presented as traffic light. Expert climate predictions show complex, gridded predictions for Germany (at high resolution), Europe and the world as maps and time series. The skill is displayed as the size of dots. Their color is related to the signal in the prediction. The website was developed in cooperation with users from different sectors via surveys, workshops and meetings to guarantee its understandability and usability. The users realize the potential of climate predictions, but some need advice in using probabilistic predictions and skill. Future activities will include the further development of predictions to improve skill (multi-model ensembles, teleconnections), the introduction of additional products (data provision, extremes) and the further clarification of the information (interactivity, video clips)

Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism

<p>Abstract</p> <p>Background</p> <p>Septic encephalopathy is a severe brain dysfunction caused by systemic inflammation in the absence of direct brain infection. Changes in cerebral blood flow, release of inflammatory molecules and metabolic alterations contribute to neuronal dysfunction and cell death.</p> <p>Methods</p> <p>To investigate the relation of electrophysiological, metabolic and morphological changes caused by SE, we simultaneously assessed systemic circulation, regional cerebral blood flow and cortical electroencephalography in rats exposed to bacterial lipopolysaccharide. Additionally, cerebral glucose uptake, astro- and microglial activation as well as changes of inflammatory gene transcription were examined by small animal PET using [18F]FDG, immunohistochemistry, and real time PCR.</p> <p>Results</p> <p>While the systemic hemodynamic did not change significantly, regional cerebral blood flow was decreased in the cortex paralleled by a decrease of alpha activity of the electroencephalography. Cerebral glucose uptake was reduced in all analyzed neocortical areas, but preserved in the caudate nucleus, the hippocampus and the thalamus. Sepsis enhanced the transcription of several pro- and anti-inflammatory cytokines and chemokines including tumor necrosis factor alpha, interleukin-1 beta, transforming growth factor beta, and monocot chemoattractant protein 1 in the cerebrum. Regional analysis of different brain regions revealed an increase in ED1-positive microglia in the cortex, while total and neuronal cell counts decreased in the cortex and the hippocampus.</p> <p>Conclusion</p> <p>Together, the present study highlights the complexity of sepsis induced early impairment of neuronal metabolism and activity. Since our model uses techniques that determine parameters relevant to the clinical setting, it might be a useful tool to develop brain specific therapeutic strategies for human septic encephalopathy.</p

High-Resolution Decadal Drought Predictions for German Water Boards: A Case Study for the Wupper Catchment

Water boards in Germany require decadal predictions to develop optimized management and adaptation strategies, especially within the claims of flood protection and water distribution management. Specifically, the Wupper catchment water board in western Germany is interested in decadal predictions of drought indices, which are correlated to dam water levels. For the management of small catchments, they need multi-year means and multi-year seasonal means of the hydrological seasons for forecast years 1–3 at high spatial resolution. Thus, the MPI-ESM-LR global decadal prediction system with 16 ensemble members at 200 km resolution was statistically downscaled with EPISODES to ~11 km in Germany. Simulated precipitation was recalibrated, correcting model errors and adjusting the ensemble spread. We tested different recalibration settings to optimize the skill. The 3-year mean and 3-year seasonal mean SPI (Standardized Precipitation Index), indicating excess or deficit of precipitation, was calculated. We evaluated the prediction skill with HYRAS observations, applying skill scores and correlation coefficients, and tested the significance of the skill at a 95% level via 1,000 bootstraps. We found that the high-resolution statistical downscaling is able to preserve the skill of the global decadal predictions and that the recalibration can clearly improve the precipitation skill in Germany. Multi-year annual and August–October mean SPI predictions are promising for several regions in Germany. Additionally, there is potential for skill improvement with increasing ensemble size for all temporal aggregations, except for November–January. A user-oriented product sheet was developed and published on the Copernicus Climate Change Service website (https://climate.copernicus.eu/decadal-predictions-infrastructure). It provides 3-year mean probabilistic SPI predictions for the Wupper catchment and north-western Germany. For 2021–2023, a high probability of negative SPI (dry conditions) is predicted in most of the area. The decadal prediction skill is higher than using the observed climatology as reference prediction in several parts of the area. This case study was developed in cooperation with the Wupper catchment water board and discussed with further German water managers: The skill of high-resolution decadal drought predictions is considered to be promising to fulfill their needs. The product sheet is understandable, well-structured and can be applied to their working routines

Alteration of NF-κB activity leads to mitochondrial apoptosis after infection with pathological prion protein

Nuclear factor kappa B (NF-κB) is a key regulator of the immune response, but in almost the same manner it is involved in induction of inflammation, proliferation and regulation of apoptosis. In the central nervous system activated NF-κB plays a neuroprotective role. While in some neurodegenerative disorders the role of NF-κB is well characterized, there is poor knowledge on the role of NF-κB in prion disease. We found binding but no transcriptional activity of the transcription factor in vitro. Characterizing the mechanism of cell death after infection with pathological prion protein increased caspase-9 and caspase-3 activity was detected and the lack of NF-κB activity resulted in the inability to activate target genes that usually play an important role in neuroprotection. Additionally, we investigated the role of NF-κB after prion infection of Nfkb1–/–, Nfkb2–/– and Bcl3–/– mice and central nervous system-specific p65-deleted mice revealing an accelerated prion disease in NF-κB2- and Bcl-3-deficient mice, which is in line with a reduced neuroprotective activity in prion infection. Based on our findings, we propose a model whereby the alteration of NF-κB activity at the early stages of infection with pathological prion protein leads to neuronal cell death mediated by mitochondrial apoptosis

c-Rel is dispensable for the differentiation and functional maturation of M cells in the follicle-associated epithelium

AbstractM cells reside within the follicle-associated epithelium (FAE) overlying the gut-associated lymphoid tissues. These unique phagocytic epithelial cells enable the mucosal immune system to sample antigens within the lumen of the intestine. The differentiation of M cells from uncommitted precursors in the FAE is dependent on the production of receptor activator of nuclear factor-κB ligand (RANKL) by subepithelial stromal cells. The ligation of a variety of cell surface receptors activates the nuclear factor-κB (NF-κB) family of transcription factors which in-turn induce the transcription of multiple target genes. RANKL-stimulation can stimulate the nuclear translocation of the NF-κB subunit c-Rel. We therefore used c-Rel-deficient mice to determine whether the differentiation and functional maturation of M cells in the Peyer’s patches was dependent on c-Rel. Our data show that c-Rel-deficiency does not influence the expression of RANKL or RANK in Peyer’s patches, or the induction of M-cell differentiation in the FAE. RANKL-stimulation in the differentiating M cells induces the expression of SpiB which is essential for their subsequent maturation. However, SpiB expression in the FAE was also unaffected in the absence of c-Rel. As a consequence, the functional maturation of M cells was not impaired in the Peyer’s patches of c-Rel-deficient mice. Although our data showed that the specific expression of CCL20 and ubiquitin D in the FAE was not impeded in the absence of c-Rel, the expression of ubiquitin D was dramatically reduced in the B cell-follicles of c-Rel-deficient mice. Coincident with this, we also observed that the status of follicular dendritic cells in the B cell-follicles was dramatically reduced in Peyer’s patches from c-Rel-deficient mice. Taken together, our data show that c-Rel is dispensable for the RANKL-mediated differentiation and functional maturation of M cells

IKKα controls ATG16L1 degradation to prevent ER stress during inflammation

Inhibition of the IκB kinase complex (IKK) has been implicated in the therapy of several chronic inflammatory diseases including inflammatory bowel diseases. In this study, using mice with an inactivatable IKKα kinase (IkkαAA/AA), we show that loss of IKKα function markedly impairs epithelial regeneration in a model of acute colitis. Mechanistically, this is caused by compromised secretion of cytoprotective IL-18 from IKKα-mutant intestinal epithelial cells because of elevated caspase 12 activation during an enhanced unfolded protein response (UPR). Induction of the UPR is linked to decreased ATG16L1 stabilization in IkkαAA/AA mice. We demonstrate that both TNF-R and nucleotide-binding oligomerization domain stimulation promote ATG16L1 stabilization via IKKα-dependent phosphorylation of ATG16L1 at Ser278. Thus, we propose IKKα as a central mediator sensing both cytokine and microbial stimulation to suppress endoplasmic reticulum stress, thereby assuring antiinflammatory function during acute intestinal inflammation

Recent applications and potential of near-term (interannual to decadal) climate predictions

Following efforts from leading centres for climate forecasting, sustained routine operational near-term climate predictions (NTCP) are now produced that bridge the gap between seasonal forecasts and climate change projections offering the prospect of seamless climate services. Though NTCP is a new area of climate science and active research is taking place to increase understanding of the processes and mechanisms required to produce skillful predictions, this significant technical achievement combines advances in initialisation with ensemble prediction of future climate up to a decade ahead. With a growing NTCP database, the predictability of the evolving externally-forced and internally-generated components of the climate system can now be quantified. Decision-makers in key sectors of the economy can now begin to assess the utility of these products for informing climate risk and for planning adaptation and resilience strategies up to a decade into the future. Here, case studies are presented from finance and economics, water management, agriculture and fisheries management demonstrating the emerging utility and potential of operational NTCP to inform strategic planning across a broad range of applications in key sectors of the global economy

Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury

AbstractWarm and cold hepatic ischemia followed by reperfusion leads to necrotic cell death (oncosis), which often occurs within minutes of reperfusion. Recent studies also suggest a large component of apoptosis after ischemia/reperfusion. Here, we review the mechanisms underlying adenosine triphosphate depletion—dependent oncotic necrosis and caspase-dependent apoptosis, with emphasis on shared features and pathways. Although apoptosis causes internucleosomal DNA degradation that can be detected by terminal deoxynucleotidyl transferase—mediated deoxyuridine triphosphate nick-end labeling and related assays, DNA degradation also occurs after oncotic necrosis and leads to pervasive terminal deoxynucleotidyl transferase—mediated deoxyuridine triphosphate nick-end labeling staining far in excess of that for apoptosis. Similarly, although apoptosis can occur in a physiological setting without inflammation, in pathophysiological settings apoptosis frequently induces inflammation because of the onset of secondary necrosis and stimulation of cytokine and chemokine formation. In liver, the mitochondrial permeability transition represents a shared pathway that leads to both oncotic necrosis and apoptosis. When the mitochondrial permeability transition causes severe adenosine triphosphate depletion, plasma membrane failure and necrosis ensue. If adenosine triphosphate is preserved, at least in part, cytochrome c release after the mitochondrial permeability transition activates caspase-dependent apoptosis. Mitochondrial permeability transition-dependent cell death illustrates the concept of necrapoptosis, whereby common pathways lead to both necrosis and apoptosis. In conclusion, oncotic necrosis and apoptosis can share features and mechanisms, which sometimes makes discrimination between the 2 forms of cell death difficult. However, elucidation of critical cell death pathways under clinically relevant conditions will show potentially important therapeutic intervention strategies in hepatic ischemia/reperfusion injury