Modular, higher order cardinality analysis in theory and practice

Since the mid '80s, compiler writers for functional languages (especially lazy ones) have been writing papers about identifying and exploiting thunks and lambdas that are used only once. However, it has proved difficult to achieve both power and simplicity in practice. In this paper, we describe a new, modular analysis for a higher order language, which is both simple and effective. We prove the analysis sound with respect to a standard call-by-need semantics, and present measurements of its use in a full-scale, state-of-the-art optimising compiler. The analysis finds many single-entry thunks and one-shot lambdas and enables a number of program optimisations. This paper extends our preceding conference publication (Sergey et al. 2014 Proceedings of the 41st Annual ACM SIGPLAN-SIGACT Symposium on Principles of Programming Languages (POPL 2014). ACM, pp. 335–348) with proofs, expanded report on evaluation and a detailed examination of the factors causing the loss of precision in the analysis

Realizing availability-oriented business models in the capital goods industry

The validation results of a concept for the development of availability-oriented business models are addressed. The developed concept contains five steps by means of primarily design thinking methods. For the validation, the developed concept is applied at Lenze, a German innovative manufacturer of drive and automation solutions for materials handling, handling technology, packaging industry, robotics and automotive industry. Therefore, a use case is defined, business models, extended value networks, persona analyses and customer journey are elaborated. The results show the applicability of the concept for the development of availability-oriented business models for the capital goods industry. © 2018 The Authors. Published by Elsevier B.V

Evidence for an elevated aspartate pKa in the active site of human aromatase

Aromatase (CYP19A1), the enzyme that converts androgens to estrogens, is of significant mechanistic and therapeutic interest. Crystal structures and computational studies of this enzyme shed light on the critical role of Asp(309) in substrate binding and catalysis. These studies predicted an elevated pK(a) for Asp(309) and proposed that protonation of this residue was required for function. In this study, UV-visible absorption, circular dichroism, resonance Raman spectroscopy, and enzyme kinetics were used to study the impact of pH on aromatase structure and androstenedione binding. Spectroscopic studies demonstrate that androstenedione binding is pH-dependent, whereas, in contrast, the D309N mutant retains its ability to bind to androstenedione across the entire pH range studied. Neither pH nor mutation perturbed the secondary structure or heme environment. The origin of the observed pH dependence was further narrowed to the protonation equilibria of Asp(309) with a parallel set of spectroscopic studies using exemestane and anastrozole. Because exemestane interacts with Asp(309) based on its co-crystal structure with the enzyme, its binding is pH-dependent. Aromatase binding to anastrozole is pH-independent, consistent with the hypothesis that this ligand exploits a distinct set of interactions in the active site. In summary, we assign the apparent pK(a) of 8.2 observed for androstenedione binding to the side chain of Asp(309). To our knowledge, this work represents the first experimental assignment of a pK(a) value to a residue in a cytochrome P450. This value is in agreement with theoretical calculations (7.7–8.1) despite the reliance of the computational methods on the conformational snapshots provided by crystal structures

Apolipoprotein B is a novel marker for early tau pathology in Alzheimer's disease

INTRODUCTION: We examine the role of brain apolipoprotein B (apoB) as a putative marker of early tau pathology and cognitive decline. METHODS: Cerebrospinal fluid (CSF) samples from cognitively normal and Alzheimer's disease (AD) participants were collected to measure protein levels of apoB and AD biomarkers amyloid beta (Aβ), t-tau and p-tau, as well as synaptic markers GAP43, SYNAPTOTAGMIN-1, synaptosome associated protein 25 (SNAP-25), and NEUROGRANIN. CSF apoB levels were contrasted with positron emission tomography (PET) scan measures of Aβ (18F-NAV4694) and Tau (flortaucipir) along with cognitive assessment alterations over 6 to 8 years. RESULTS: CSF apoB levels were elevated in AD participants and correlated with t-tau, p-tau, and the four synaptic markers in pre-symptomatic individuals. In the latter, CSF apoB levels correlated with PET flortaucipir-binding in entorhinal, parahippocampal, and fusiform regions. Baseline CSF apoB levels were associated with longitudinal visuospatial cognitive decline. DISCUSSION: CSF apoB markedly associates with early tau dysregulation in asymptomatic subjects and identifies at-risk individuals predisposed to develop visuospatial cognitive decline over time

Dementia in Swedish Twins: Predicting Incident Cases

Thirty same-sex twin pairs were identified in which both members were assessed at baseline and one twin subsequently developed dementia, at least 3 years subsequent to the baseline measurement, while the partner remained cognitively intact for at least three additional years. Eighteen of the 30 cases were diagnosed with Alzheimer’s disease. Baseline assessments, conducted when twins’ average age was 70.6 (SD = 6.8), included a mailed questionnaire and in-person testing. Which twin would develop dementia was predicted by less favorable lipid values (higher apoB, ratio of apoB to apoA1, and total cholesterol), poorer grip strength, and—to a lesser extent—higher emotionality on the EAS Temperament Scale. Given the long preclinical period that characterizes Alzheimer’s disease, these findings may suggest late life risk factors for dementia, or may reflect changes that are part of preclinical disease

Study of cosolvent-induced α-chymotrypsin fibrillogenesis: Does protein surface hydrophobicity trigger early stages of aggregation reaction?

The misfolding of specific proteins is often associated with their assembly into fibrillar aggregates, commonly termed amyloid fibrils. Despite the many efforts expended to characterize amyloid formation in vitro, there is no deep knowledge about the environment (in which aggregation occurs) as well as mechanism of this type of protein aggregation. Alpha-chymotrypsin was recently driven toward amyloid aggregation by the addition of intermediate concentrations of trifluoroethanol. In the present study, approaches such as turbidimetric, thermodynamic, intrinsic fluorescence and quenching studies as well as chemical modification have been successfully used to elucidate the underlying role of hydrophobic interactions (involved in early stages of amyloid formation) in α-chymotrypsin-based experimental system. © 2009 Springer Science+Business Media, LLC

Challenges in QCD matter physics --The scientific programme of the Compressed Baryonic Matter experiment at FAIR

Substantial experimental and theoretical efforts worldwide are devoted to explore the phase diagram of strongly interacting matter. At LHC and top RHIC energies, QCD matter is studied at very high temperatures and nearly vanishing net-baryon densities. There is evidence that a Quark-Gluon-Plasma (QGP) was created at experiments at RHIC and LHC. The transition from the QGP back to the hadron gas is found to be a smooth cross over. For larger net-baryon densities and lower temperatures, it is expected that the QCD phase diagram exhibits a rich structure, such as a first-order phase transition between hadronic and partonic matter which terminates in a critical point, or exotic phases like quarkyonic matter. The discovery of these landmarks would be a breakthrough in our understanding of the strong interaction and is therefore in the focus of various high-energy heavy-ion research programs. The Compressed Baryonic Matter (CBM) experiment at FAIR will play a unique role in the exploration of the QCD phase diagram in the region of high net-baryon densities, because it is designed to run at unprecedented interaction rates. High-rate operation is the key prerequisite for high-precision measurements of multi-differential observables and of rare diagnostic probes which are sensitive to the dense phase of the nuclear fireball. The goal of the CBM experiment at SIS100 (sNN= 2.7--4.9 GeV) is to discover fundamental properties of QCD matter: the phase structure at large baryon-chemical potentials (μB> 500 MeV), effects of chiral symmetry, and the equation of state at high density as it is expected to occur in the core of neutron stars. In this article, we review the motivation for and the physics programme of CBM, including activities before the start of data taking in 2024, in the context of the worldwide efforts to explore high-density QCD matter

Is telomere length socially patterned? Evidence from the West of Scotland Twenty-07 study

Lower socioeconomic status (SES) is strongly associated with an increased risk of morbidity and premature mortality, but it is not known if the same is true for telomere length, a marker often used to assess biological ageing. The West of Scotland Twenty-07 Study was used to investigate this and consists of three cohorts aged approximately 35 (N = 775), 55 (N = 866) and 75 years (N = 544) at the time of telomere length measurement. Four sets of measurements of SES were investigated: those collected contemporaneously with telomere length assessment, educational markers, SES in childhood and SES over the preceding twenty years. We found mixed evidence for an association between SES and telomere length. In 35-year-olds, many of the education and childhood SES measures were associated with telomere length, i.e. those in poorer circumstances had shorter telomeres, as was intergenerational social mobility, but not accumulated disadvantage. A crude estimate showed that, at the same chronological age, social renters, for example, were nine years (biologically) older than home owners. No consistent associations were apparent in those aged 55 or 75. There is evidence of an association between SES and telomere length, but only in younger adults and most strongly using education and childhood SES measures. These results may reflect that childhood is a sensitive period for telomere attrition. The cohort differences are possibly the result of survival bias suppressing the SES-telomere association; cohort effects with regard different experiences of SES; or telomere possibly being a less effective marker of biological ageing at older ages

Pressure-Induced Dimerization and Collapse of Antiferromagnetism in the Kitaev Material α-Li2IrO3

We present magnetization measurements carried out on polycrystalline and single-crystalline samples of α-Li2IrO3 under hydrostatic pressures up to 2 GPa and establish the temperature-pressure phase diagram of this material. The Néel temperature (TN) of α-Li2IrO3 is slightly enhanced upon compression with dTN/dp = 1.5 K/GPa. Above 1.2 GPa, α-Li2IrO3 undergoes a first-order phase transition toward a nonmagnetic dimerized phase, with no traces of the magnetic phase observed above 1.8 GPa at low temperatures. The critical pressure of the structural dimerization is strongly temperature dependent. This temperature dependence is well reproduced on the ab initio level by taking into account lower phonon entropy in the nonmagnetic phase. We further show that the initial increase in TN of the magnetic phase is due to a weakening of the Kitaev interaction K along with the enhancement of the Heisenberg term J and off-diagonal anisotropy Γ. Our study reveals a common thread in the interplay of magnetism and dimerization in pressured Kitaev materials. © 2022 American Physical Society.This work was funded by the German Research Foundation (DFG) via Project No. 107745057 (TRR80) and via the Sino-German Cooperation Group on Emergent Correlated Matter. D.P. acknowledges financial support by the Russian Science Foundation, Grant No. 21-72-10136

Elevated Ratio of Urinary Metabolites of Thromboxane and Prostacyclin Is Associated with Adverse Cardiovascular Events in ADAPT

Results from prevention trials, including the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), have fueled discussion about the cardiovascular (CV) risks associated with non-steroidal anti-inflammatory drugs (NSAIDs). We tested the hypotheses that (i) adverse CV events reported among ADAPT participants (aged 70 years and older) are associated with increased ratio of urine 11-dehydrothromboxane B2 (Tx-M) to 2′3-donor–6-keto-PGF1 (PGI-M) attributable to NSAID treatments; (ii) coincident use of aspirin (ASA) would attenuate NSAID-induced changes in Tx-M/PGI-M ratio; and (iii) use of NSAIDs and/or ASA would not alter urine or plasma concentrations of F2-isoprostanes (IsoPs), in vivo biomarkers of free radical damage. We quantified urine Tx-M and PGI-M, and urine and plasma F2-IsoPs from 315 ADAPT participants using stable isotope dilution assays with gas chromatography/mass spectrometry, and analyzed these data by randomized drug assignment and self-report compliance as well as ASA use. Adverse CV events were significantly associated with higher urine Tx-M/PGI-M ratio, which seemed to derive mainly from lowered PGI-M. Participants taking ASA alone had reduced urine Tx-M/PGI-M compared to no ASA or NSAID; however, participants taking NSAIDs plus ASA did not have reduced urine Tx-M/PGI-M ratio compared to NSAIDs alone. Neither NSAID nor ASA use altered plasma or urine F2-IsoPs. These data suggest a possible mechanism for the increased risk of CV events reported in ADAPT participants assigned to NSAIDs, and suggest that the changes in the Tx-M/PGI-M ratio was not substantively mitigated by coincident use of ASA in individuals 70 years or older