Finite-size effects in the self-organized critical forest-fire model

We study finite-size effects in the self-organized critical forest-fire model by numerically evaluating the tree density and the fire size distribution. The results show that this model does not display the finite-size scaling seen in conventional critical systems. Rather, the system is composed of relatively homogeneous patches of different tree densities, leading to two qualitatively different types of fires: those that span an entire patch and those that don't. As the system size becomes smaller, the system contains less patches, and finally becomes homogeneous, with large density fluctuations in time.Comment: 10 pages, 11 figure

Sorafenib inhibits therapeutic induction of necroptosis in acute leukemia cells

Induction of necroptosis has emerged as an alternative approach to trigger programmed cell death, in particular in apoptosis-resistant cancer cells. Recent evidence suggests that kinase inhibitors targeting oncogenic B-RAF can also affect Receptor-interacting serine/threonine-protein kinase (RIP) 1 and RIP3. Sorafenib, a multi-targeting kinase inhibitor with activity against B-RAF, is used for the treatment of acute leukemia. In the present study, we therefore investigated whether Sorafenib interferes with therapeutic induction of necroptosis in acute leukemia. Here, we report that Sorafenib inhibits necroptotic signaling and cell death in two models of necroptosis in acute leukemia. Sorafenib significantly reduces Second mitochondria-derived activator of caspases (Smac) mimetic-induced necroptosis in apoptosis-resistant acute myeloid leukemia (AML) cells as well as Smac mimetic/Tumor Necrosis Factor (TNF)alpha-induced necroptosis in FADD-deficient acute lymphoblastic leukemia (ALL) cells. Sub- to low micromolar concentrations of Sorafenib corresponding to its plasma levels reported in cancer patients are sufficient to inhibit necroptosis, emphasizing the clinical relevance of our findings. Furthermore, Sorafenib blocks Smac mimetic-mediated phosphorylation of mixed-lineage kinase domain-like protein (MLKL) that marks its activation, indicating that Sorafenib targets components upstream of MLKL such as RIP1 and RIP3. Intriguingly, Sorafenib reduces the Smac mimetic/TNF alpha-stimulated interaction of RIP1 with RIP3 and MLKL, demonstrating that it interferes with the assembly of the necrosome complex. Importantly, Sorafenib significantly protects primary, patient-derived AML blasts from Smac mimetic-induced necroptosis. By demonstrating that Sorafenib limits the anti-leukemic activity of necroptosisinducing drugs in acute leukemia cells, our study has important implications for the use of Sorafenib in the treatment of acute leukemia

Effectiveness and Tolerability of Tapentadol Prolonged Release Compared With Prior Opioid Therapy for the Management of Severe, Chronic Osteoarthritis Pain

BACKGROUND: Tapentadol prolonged release (PR; 100–250 mg twice daily) has been efficacious and well tolerated for managing moderate-to-severe, chronic osteoarthritis hip or knee pain in phase 3 studies with washout of previous analgesic treatment. OBJECTIVE: The objective of this study was to evaluate the effectiveness and tolerability of tapentadol PR (50–250 mg twice daily) after direct rotation from World Health Organization (WHO) step III opioids in patients with severe osteoarthritis knee pain who previously responded to WHO step III therapy but showed poor tolerability. METHODS: This open-label, phase 3b study (NCT00982280) was conducted from October 2009 through June 2010 (prematurely terminated due to slow recruitment and study drug shortages) in clinical care settings in Europe and Australia. The study population included patients with severe, chronic osteoarthritis knee pain who had taken WHO step III opioids daily for ≥2 weeks before screening, responded to therapy (average pain intensity [11-point numerical rating scale-3 (NRS-3)] ≤5 at screening), and reported opioid-related adverse effects as their reason for changing analgesics. Patients switched directly from WHO step III therapy to tapentadol. Patients received oral tapentadol PR (50–250 mg twice daily) during 5-week titration and 7-week maintenance periods. Oral tapentadol immediate release (IR) was permitted (≤twice/day, ≥4 h apart) for acute pain episodes due to index pain or withdrawal symptoms following discontinuation of previous opioids (combined dose of tapentadol [PR and IR] ≤500 mg/day). This study was planned to evaluate conversion to tapentadol PR, based on responder rate 1 (percentage of patients with same/less pain [NRS-3] versus Week −1) at Week 6 (primary endpoint), adverse events (AEs), and discontinuation rates. Equianalgesic ratios were calculated for tapentadol prior to WHO step III opioids (PR and PR plus IR formulations). RESULTS: Of 82 patients enrolled, 63 received study medication. In the per-protocol population, responder rate 1 at Week 6 (last observation carried forward) was 94.3 % (50/53; P < 0.0001 vs. the null hypothesis rate [<60 %]). Mean (standard deviation) pain intensity scores were 4.7 (0.66) at baseline, 2.5 (1.46) at Week 6, and 1.8 (1.41) at Week 12 in the main analysis population (change from baseline at Weeks 6 and 12, P < 0.0001). Tapentadol to transdermal buprenorphine equianalgesic ratios (PR [n = 48], 262.9:1; PR plus IR [n = 48], 281.1:1) and tapentadol to oral oxycodone equianalgesic ratios (PR [n = 4], 4.3:1; PR plus IR [n = 6], 4.6:1) were calculated for the main analysis population. In the safety population, prevalence of AEs reported as associated with prior opioids at Week −1 (reasons for rotation) and related to tapentadol treatment at Week 12 decreased over time; the most common were nausea (46.0 vs. 24.1 %) and constipation (31.7 vs. 7.4 %). Overall, 14.3 % of patients discontinued the study early; reasons included AEs (9.5 %), lack of efficacy (3.2 %), and withdrawal of consent (1.6 %). CONCLUSIONS: Significant improvements in effectiveness were observed for tapentadol PR (50–250 mg twice daily) versus WHO step III opioids in patients with severe, chronic osteoarthritis knee pain who previously responded to WHO step III therapy. Equianalgesic ratios were calculated for tapentadol to transdermal buprenorphine and oral oxycodone and were in line with observations from previous phase 3 studies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40261-013-0102-0) contains supplementary material, which is available to authorized users

Floral evidence for high summer temperatures in southern Scandinavia during 15-11 cal ka BP

The global climate transition from the Lateglacial to the Early Holocene is dominated by a rapid warming trend driven by an increase in orbital summer insolation over high northern latitudes and related feedbacks. The warming trend was interrupted by several abrupt shifts between colder (stadial) and warmer (interstadial) climate states following instabilities of the Atlantic Meridional Overturning Circulation (AMOC) in response to rapidly melting ice sheets. The sequence of abrupt shifts between extreme climate states had profound impacts on ecosystems which make it challenging to reliably quantify state variables like July temperatures within a non-analogue climate envelope. For Europe, there is increasing albeit inconclusive evidence for higher stadial summer temperatures than initially thought. Here we present a comprehensive floral compilation of plant macrofossils from lake sediment cores of 15 sites from S-Scandinavia covering the period similar to 15 to 11 ka BP. We find evidence for a continued presence of plant species indicating high July temperatures throughout the last deglaciation. The presence of hemiboreal plants in close vicinity to the southern margin of the Fennoscandian Ice Sheet implies a strong thermal summer forcing for the rapid ice sheet melt. Consistent with some recent studies, we do not find evidence for a general stadial summer cooling, which indicates that other reasons than summer temperatures caused drastic setbacks in proxy signals possibly driven by extreme winter cooling and/or shorter warm seasons. (C) 2020 The Authors. Published by Elsevier Ltd.Peer reviewe

Biochemistry of the erythrocyte Rh polypeptides: a review

The clinically important Rh blood group system is complex, consisting of multiple distinct antigens. Despite clinical recognition for over 50 years, the Rh blood group antigens have remained poorly understood on a molecular level until the recent identification and characterization of the "Rh polypeptides," the core structural proteins of the Rh antigens. This group of erythrocyte membrane proteins of molecular weight 30,000-35,000 daltons was first recognized by employing Rh-specific antibodies to immunoprecipitate radiolabeled components of erythrocyte membranes. By using antibodies specific for the Rh D, c, and E antigens, a series of highly related non-identical proteins were immunoprecipitated, indicating that the Rh antigens are composed of multiple related proteins. The Rh polypeptides have been purified and characterized, and they were found to have several unusual biochemical characteristics. The Rh polypeptides penetrate the membrane bilayer; they are linked to the underlying membrane skeleton; they are covalently fatty acid acylated with palmitate. While the Rh antigenic reactivity is unique to human erythrocytes, the Rh polypeptides have been isolated from erythrocytes of diverse species and are thought to be fundamental components of all mammalian erythrocyte membranes. The functional role of the Rh polypeptides remains undefined, but a role in the organization of membrane phospholipid is suspected

The self-organized critical forest-fire model on large scales

We discuss the scaling behavior of the self-organized critical forest-fire model on large length scales. As indicated in earlier publications, the forest-fire model does not show conventional critical scaling, but has two qualitatively different types of fires that superimpose to give the effective exponents typically measured in simulations. We show that this explains not only why the exponent characterizing the fire-size distribution changes with increasing correlation length, but allows also to predict its asymptotic value. We support our arguments by computer simulations of a coarse-grained model, by scaling arguments and by analyzing states that are created artificially by superimposing the two types of fires.Comment: 26 pages, 7 figure

Workshop Proceeding of the 2nd Workshop on Green (Responsible, Ethical and Social) IT and IS – the Corporate Perspective (GRES-IT/IS)

For the 2nd Workshop on Green (Responsible, Ethical and Social) IT and IS – the Corporate Perspective (GRES-IT/IS), extended abstracts from various fields of the information systems research community have been submitted. We received 36 extended abstracts and were happy to invite seven of them for presentation.Series: Working Papers on Information Systems, Information Business and Operation

Warm summers during the Younger Dryas cold reversal

The Younger Dryas (YD) cold reversal interrupts the warming climate of the deglaciation with global climatic impacts. The sudden cooling is typically linked to an abrupt slowdown of the Atlantic Meridional Overturning Circulation (AMOC) in response to meltwater discharges from ice sheets. However, inconsistencies regarding the YD-response of European summer temperatures have cast doubt whether the concept provides a sufficient explanation. Here we present results from a high-resolution global climate simulation together with a new July temperature compilation based on plant indicator species and show that European summers remain warm during the YD. Our climate simulation provides robust physical evidence that atmospheric blocking of cold westerly winds over Fennoscandia is a key mechanism counteracting the cooling impact of an AMOC-slowdown during summer. Despite the persistence of short warm summers, the YD is dominated by a shift to a continental climate with extreme winter to spring cooling and short growing seasons.Peer reviewe

Evaluation of the informed consent process for male circumcision scale-up in Zambia

This report evaluates the informed consent process for male circumcision conducted through the Male Circumcision Partnership for Zambia, led by Population Services International (Society for Family Health, Zambia), in partnership with Jhpiego, Marie Stopes International, and the Population Council. The objectives of the study were to assess male circumcision clients\u27 comprehension of the informed consent process, examine social norms and practices regarding informed consent for adolescents, compare clients\u27 expectations and experiences, and make additional recommendations for improving the informed consent process