Adaptive walks on time-dependent fitness landscapes

The idea of adaptive walks on fitness landscapes as a means of studying evolutionary processes on large time scales is extended to fitness landscapes that are slowly changing over time. The influence of ruggedness and of the amount of static fitness contributions are investigated for model landscapes derived from Kauffman's $NK$ landscapes. Depending on the amount of static fitness contributions in the landscape, the evolutionary dynamics can be divided into a percolating and a non-percolating phase. In the percolating phase, the walker performs a random walk over the regions of the landscape with high fitness.Comment: 7 pages, 6 eps-figures, RevTeX, submitted to Phys. Rev.

Star Architecture as Socio-Material Assemblage

Taking inspiration from new materialism and assemblage, the chapter deals with star architects and iconic buildings as socio-material network effects that do not pre-exist action, but are enacted in practice, in the materiality of design crafting and city building. Star architects are here conceptualized as part of broader assemblages of actors and practices ‘making star architecture’ a reality, and the buildings they design are considered not just as unique and iconic objects, but dis-articulated as complex crafts mobilizing skills, technologies, materials, and forms of knowledge not necessarily ascribable to architecture. Overcoming narrow criticism focusing on the symbolic order of icons as unique creations and alienated repetitions of capitalist development, the chapter’s main aim is to widen the scope of critique by bridging culture and economy, symbolism and practicality, making star architecture available to a broad, fragmented arena of (potential) critics, unevenly equipped with critical tools and differentiated experiences

Toleration, Reasonableness, and Power

This chapter explores Rainer Forst’s justification-centric view of nondomination toleration. This view places an idea of equal respect and a corresponding requirement of reciprocal and general justification at the core of non-domination toleration. After reconstructing this view, this chapter addresses two issues. First, even if this idea of equal respect requires the limits of non-domination toleration to be drawn in a manner that is equally justifiable to all affected people, equal justifiability should not be understood in terms of Forst’s requirement of reciprocal and general acceptability. Second, for the equal justifiability of relevant constraints to ensure non-domination outcomes, discursive equality must be understood in substantive, purchase-sensitive terms. This means that a justification-centric view of non-domination toleration stands or falls with the participation value of what it regards as the standards of justification. This places reasonably contested matters of value at the heart of such views

Microcanonical rates, gap times, and phase space dividing surfaces

The general approach to classical unimolecular reaction rates due to Thiele is revisited in light of recent advances in the phase space formulation of transition state theory for multidimensional systems. We analyze in detail the gap time distribution and associated reactant lifetime distribution for the isomerization reaction HCN $\rightleftharpoons$ CNH. Both algebraic (power law) and exponential decay regimes have been identified. Statistical estimates of the isomerization rate are compared with the numerically determined decay rate. Examination of the decay properties of subsensembles of trajectories that exit the HCN well through either of 2 available symmetry related product channels shows that the complete trajectory ensemble effectively attains the full symmetry of the system phase space on a short timescale $t \lesssim 0.5$ ps, after which the product branching ratio is 1:1, the "statistical" value. At intermediate times, this statistical product ratio is accompanied by nonexponential (nonstatistical) decay. We point out close parallels between the dynamical behavior inferred from the gap time distribution for HCN and nonstatistical behavior recently identified in reactions of some organic molecules.Comment: 44 pages, 9 figure

First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)—a systematic review and individual patient data meta-analysis

Evidence for prognosis and treatment of elderly patient with primary central nervous system is limited. High-dose methotrexate should be applied whenever possible, especially combination with oral alkylating agents is a promising approach. Further combinations with other intravenous drugs do not seem to improve outcome. More prospective trials designed for elderly PCNSL patients are warrante

Linagliptin Improves Insulin Sensitivity and Hepatic Steatosis in Diet-Induced Obesity

Linagliptin (tradjenta™) is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor. DPP-4 inhibition attenuates insulin resistance and improves peripheral glucose utilization in humans. However, the effects of chronic DPP-4 inhibition on insulin sensitivity are not known. The effects of long-term treatment (3–4 weeks) with 3 mg/kg/day or 30 mg/kg/day linagliptin on insulin sensitivity and liver fat content were determined in diet-induced obese C57BL/6 mice. Chow-fed animals served as controls. DPP-4 activity was significantly inhibited (67–89%) by linagliptin (P<0.001). Following an oral glucose tolerance test, blood glucose concentrations (measured as area under the curve) were significantly suppressed after treatment with 3 mg/kg/day (–16.5% to –20.3%; P<0.01) or 30 mg/kg/day (–14.5% to –26.4%; P<0.05) linagliptin (both P<0.01). Liver fat content was significantly reduced by linagliptin in a dose-dependent manner (both doses P<0.001). Diet-induced obese mice treated for 4 weeks with 3 mg/kg/day or 30 mg/kg/day linagliptin had significantly improved glycated hemoglobin compared with vehicle (both P<0.001). Significant dose-dependent improvements in glucose disposal rates were observed during the steady state of the euglycemic–hyperinsulinemic clamp: 27.3 mg/kg/minute and 32.2 mg/kg/minute in the 3 mg/kg/day and 30 mg/kg/day linagliptin groups, respectively; compared with 20.9 mg/kg/minute with vehicle (P<0.001). Hepatic glucose production was significantly suppressed during the clamp: 4.7 mg/kg/minute and 2.1 mg/kg/minute in the 3 mg/kg/day and 30 mg/kg/day linagliptin groups, respectively; compared with 12.5 mg/kg/minute with vehicle (P<0.001). In addition, 30 mg/kg/day linagliptin treatment resulted in a significantly reduced number of macrophages infiltrating adipose tissue (P<0.05). Linagliptin treatment also decreased liver expression of PTP1B, SOCS3, SREBP1c, SCD-1 and FAS (P<0.05). Other tissues like muscle, heart and kidney were not significantly affected by the insulin sensitizing effect of linagliptin. Long-term linagliptin treatment reduced liver fat content in animals with diet-induced hepatic steatosis and insulin resistance, and may account for improved insulin sensitivity

Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a novel drug class for the treatment of diabetes. We aimed at describing the maximal benefits and risks associated with SGLT2-i for patients with type 2 diabetes.Systematic review and meta-analysis.We included double-blinded, randomised controlled trials (RCTs) evaluating SGLT2-i administered in the highest approved therapeutic doses (canagliflozin 300 mg/day, dapagliflozin 10 mg/day, and empagliflozin 25 mg/day) for ≥12 weeks. Comparison groups could receive placebo or oral antidiabetic drugs (OAD) including metformin, sulphonylureas (SU), or dipeptidyl peptidase 4 inhibitors (DPP-4-i). Trials were identified through electronic databases and extensive manual searches. Primary outcomes were glycated haemoglobin A1c (HbA1c) levels, serious adverse events, death, severe hypoglycaemia, ketoacidosis and CVD. Secondary outcomes were fasting plasma glucose, body weight, blood pressure, heart rate, lipids, liver function tests, creatinine and adverse events including infections. The quality of the evidence was assessed using GRADE.Meta-analysis of 34 RCTs with 9,154 patients showed that SGLT2-i reduced HbA1c compared with placebo (mean difference -0.69%, 95% confidence interval -0.75 to -0.62%). We downgraded the evidence to 'low quality' due to variability and evidence of publication bias (P = 0.015). Canagliflozin was associated with the largest reduction in HbA1c (-0.85%, -0.99% to -0.71%). There were no differences between SGLT2-i and placebo for serious adverse events. SGLT2-i increased the risk of urinary and genital tract infections and increased serum creatinine, and exerted beneficial effects on bodyweight, blood pressure, lipids and alanine aminotransferase (moderate to low quality evidence). Analysis of 12 RCTs found a beneficial effect of SGLT2-i on HbA1c compared with OAD (-0.20%, -0.28 to -0.13%; moderate quality evidence).This review includes a large number of patients with type 2 diabetes and found that SGLT2-i reduces HbA1c with a notable increased risk in non-serious adverse events. The analyses may overestimate the intervention benefit due bias

Balancing, Proportionality, and Constitutional Rights

In the theory and practice of constitutional adjudication, proportionality review plays a crucial role. At a theoretical level, it lies at core of the debate on rights adjudication; in judicial practice, it is a widespread decision-making model characterizing the action of constitutional, supra-national and international courts. Despite its circulation and centrality in contemporary legal discourse, proportionality in rights-adjudication is still extremely controversial. It raises normative questions—concerning its justification and limits—and descriptive questions—regarding its nature and distinctive features. The chapter addresses both orders of questions. Part I centres on the justification of proportionality review, the connection between proportionality, balancing and theories of rights and the critical aspects of this connection. Part II identifies and analyses the different forms of proportionality both in review, as a template for rights-adjudication, and of review, as a way of defining the scope and limits of adjudication

The Resonance of Resonance: Critical Theory as a Sociology of World-Relations?

The main purpose of this paper is to examine Hartmut Rosa’s account of “resonance.” To this end, the analysis is divided into four parts. The first part focuses on the concept of resonance, including Rosa’s differentiation between horizontal, diagonal, and vertical “axes of resonance” and their role in the construction of different “world-relations.” The second part centers on the concept of alienation, notably the degree to which it constitutes an integral element of modern life forms and, in a larger sense, of the human condition. The third part grapples with the dialectic of resonance and alienation, shedding light on the assumption that they are antithetical to each other, while contending that their in-depth study provides normative parameters to distinguish between “the good life” and “the bad life.” The final part scrutinizes Rosa’s attempt to defend his outline of a sociological theory of resonance against objections raised by his critics and comprises a point-by-point assessment of his plea for a resonance-focused sociology of world-relations. The paper concludes by suggesting that, notwithstanding its limitations, Rosa’s approach represents one of the most promising developments in twenty-first-century critical theory