Weight filtration on the cohomology of complex analytic spaces

We extend Deligne's weight filtration to the integer cohomology of complex analytic spaces (endowed with an equivalence class of compactifications). In general, the weight filtration that we obtain is not part of a mixed Hodge structure. Our purely geometric proof is based on cubical descent for resolution of singularities and Poincar\'e-Verdier duality. Using similar techniques, we introduce the singularity filtration on the cohomology of compactificable analytic spaces. This is a new and natural analytic invariant which does not depend on the equivalence class of compactifications and is related to the weight filtration.Comment: examples added + minor correction

Trust economics feasibility study

We believe that enterprises and other organisations currently lack sophisticated methods and tools to determine if and how IT changes should be introduced in an organisation, such that objective, measurable goals are met. This is especially true when dealing with security-related IT decisions. We report on a feasibility study, Trust Economics, conducted to demonstrate that such methodology can be developed. Assuming a deep understanding of the IT involved, the main components of our trust economics approach are: (i) assess the economic or financial impact of IT security solutions; (ii) determine how humans interact with or respond to IT security solutions; (iii) based on above, use probabilistic and stochastic modelling tools to analyse the consequences of IT security decisions. In the feasibility study we apply the trust economics methodology to address how enterprises should protect themselves against accidental or malicious misuse of USB memory sticks, an acute problem in many industries

The Mass-to-Light Ratio of Binary Galaxies

We report on the mass-to-light ratio determination based on a newly selected binary galaxy sample, which includes a large number of pairs whose separations exceed a few hundred kpc. The probability distributions of the projected separation and the velocity difference have been calculated considering the contamination of optical pairs, and the mass-to-light ratio has been determined based on the maximum likelihood method. The best estimate of $M/L$ in the B band for 57 pairs is found to be 28 $\sim$ 36 depending on the orbital parameters and the distribution of optical pairs (solar unit, $H_0=50$ km s$^{-1}$ Mpc$^{-1}$). The best estimate of $M/L$ for 30 pure spiral pairs is found to be 12 $\sim$ 16. These results are relatively smaller than those obtained in previous studies, but consistent with each other within the errors. Although the number of pairs with large separation is significantly increased compared to previous samples, $M/L$ does not show any tendency of increase, but found to be almost independent of the separation of pairs beyond 100 kpc. The constancy of $M/L$ beyond 100 kpc may indicate that the typical halo size of spiral galaxies is less than $\sim 100$ kpc.Comment: 18 pages + 8 figures, to appear in ApJ Vol. 516 (May 10

The Discovery of Radio Stars within 10 arcseconds of Sgr A* at 7mm

Very Large Array observations of the Galactic Center at 7 mm have produced an image of the 30 arcseconds surrounding Sgr A* with a resolution of 82x42 milliarcseconds (mas). A comparison with IR images taken simultaneously with the Very Large Telescope (VLT) identifies 41 radio sources with L-band (3.8 microns) stellar counterparts. The well-known young, massive stars in the central Sgr A* cluster (e.g., IRS 16C, IRS 16NE, IRS 16SE2, IRS 16NW, IRS 16SW, AF, AFNW, IRS 34W and IRS 33E) are detected with peak flux densities between 0.2 and 1.3 mJy. The origin of the stellar radio emission in the central cluster is discussed in terms of ionized stellar winds with mass-loss rates in the range 0.8-5x10^{-5} solar mass per year. Radio emission from eight massive stars is used as a tool for registration between the radio and infrared frames with mas precision within a few arcseconds of Sgr A*. This is similar to the established technique of aligning SiO masers and evolved stars except that radio stars lie within a few arcseconds of Sgr A*. Our data show a scatter of ~6.5 mas in the positions of the eight radio sources that appear in both the L-band and 7 mm images. Lastly, we use the radio and IR data to argue that members of IRS 13N are Young Stellar Objects rather than dust clumps, supporting the hypothesis that recent star formation has occurred near Sgr A*.Comment: 15 pages, 3 figures, ApJL (in press

On-the-fly Uniformization of Time-Inhomogeneous Infinite Markov Population Models

This paper presents an on-the-fly uniformization technique for the analysis of time-inhomogeneous Markov population models. This technique is applicable to models with infinite state spaces and unbounded rates, which are, for instance, encountered in the realm of biochemical reaction networks. To deal with the infinite state space, we dynamically maintain a finite subset of the states where most of the probability mass is located. This approach yields an underapproximation of the original, infinite system. We present experimental results to show the applicability of our technique

Functional diversity can facilitate the collapse of an undesirable ecosystem state

Biodiversity may increase ecosystem resilience. However, we have limited understanding if this holds true for ecosystems that respond to gradual environmental change with abrupt shifts to an alternative state. We used a mathematical model of anoxic–oxic regime shifts and explored how trait diversity in three groups of bacteria influences resilience. We found that trait diversity did not always increase resilience: greater diversity in two of the groups increased but in one group decreased resilience of their preferred ecosystem state. We also found that simultaneous trait diversity in multiple groups often led to reduced or erased diversity effects. Overall, our results suggest that higher diversity can increase resilience but can also promote collapse when diversity occurs in a functional group that negatively influences the state it occurs in. We propose this mechanism as a potential management approach to facilitate the recovery of a desired ecosystem state

The influence of bright and dim light on substrate metabolism, energy expenditure and thermoregulation in insulin-resistant individuals depends on time of day

AIMS/HYPOTHESIS: In our modern society, artificial light is available around the clock and most people expose themselves to electrical light and light-emissive screens during the dark period of the natural light/dark cycle. Such suboptimal lighting conditions have been associated with adverse metabolic effects, and redesigning indoor lighting conditions to mimic the natural light/dark cycle more closely holds promise to improve metabolic health. Our objective was to compare metabolic responses to lighting conditions that resemble the natural light/dark cycle in contrast to suboptimal lighting in individuals at risk of developing metabolic diseases. METHODS: Therefore, we here performed a non-blinded, randomised, controlled, crossover trial in which overweight insulin-resistant volunteers (n = 14) were exposed to two 40 h laboratory sessions with different 24 h lighting protocols while staying in a metabolic chamber under real-life conditions. In the Bright day–Dim evening condition, volunteers were exposed to electric bright light (~1250 lx) during the daytime (08:00–18:00 h) and to dim light (~5 lx) during the evening (18:00–23:00 h). Vice versa, in the Dim day–Bright evening condition, volunteers were exposed to dim light during the daytime and bright light during the evening. Randomisation and allocation to light conditions were carried out by sequential numbering. During both lighting protocols, we performed 24 h indirect calorimetry, and continuous core body and skin temperature measurements, and took frequent blood samples. The primary outcome was plasma glucose focusing on the pre- and postprandial periods of the intervention. RESULTS: Spending the day in bright light resulted in a greater increase in postprandial triacylglycerol levels following breakfast, but lower glucose levels preceding the dinner meal at 18:00 h, compared with dim light (5.0 ± 0.2 vs 5.2 ± 0.2 mmol/l, n = 13, p=0.02). Dim day–Bright evening reduced the increase in postprandial glucose after dinner compared with Bright day–Dim evening (incremental AUC: 307 ± 55 vs 394 ± 66 mmol/l × min, n = 13, p=0.009). After the Bright day–Dim evening condition the sleeping metabolic rate was identical compared with the baseline night, whereas it dropped after Dim day–Bright evening. Melatonin secretion in the evening was strongly suppressed for Dim day–Bright evening but not for Bright day–Dim evening. Distal skin temperature for Bright day–Dim evening was lower at 18:00 h (28.8 ± 0.3°C vs 29.9 ± 0.4°C, n = 13, p=0.039) and higher at 23:00 h compared with Dim day–Bright evening (30.1 ± 0.3°C vs 28.8 ± 0.3°C, n = 13, p=0.006). Fasting and postprandial plasma insulin levels and the respiratory exchange ratio were not different between the two lighting protocols at any time. CONCLUSIONS/INTERPRETATION: Together, these findings suggest that the indoor light environment modulates postprandial substrate handling, energy expenditure and thermoregulation of insulin-resistant volunteers in a time-of-day-dependent manner. TRIAL REGISTRATION: ClinicalTrials.gov NCT03829982. FUNDING: We acknowledge the financial support from the Netherlands Cardiovascular Research Initiative: an initiative with support from the Dutch Heart Foundation (CVON2014–02 ENERGISE). GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-021-05643-9

Limited added value of laboratory monitoring in thiopurine maintenance monotherapy in inflammatory bowel disease patients

Background: To timely detect myelotoxicity and hepatotoxicity, laboratory monitoring at 3-month intervals is advised throughout thiopurine maintenance treatment for IBD. However, reported incidence rates of myelotoxicity and hepatotoxicity in maintenance treatment are low. Aim: To assess incidence rates and clinical consequences of myelotoxicity and hepatotoxicity in thiopurine maintenance therapy after at least 1 year of thiopurine treatment. Methods: Retrospective analysis of therapy adjustment for laboratory toxicity in adult IBD patients after 12 consecutive months of azathioprine (AZA) or mercaptopurine monotherapy (ie baseline) between 2000 and 2016. Incidence rates of laboratory toxicity (ie myelotoxicity [leucocyte count <4.0 × 10e9/L, and/or platelet count <150 × 10e9/L] and/or hepatotoxicity (gamma-glutamyltransferase [GGT], alkaline phosphatase [AP], ALT and/or AST above ULN, excluding isolated increased AST/AP]) and associated diagnostic procedures and complications were assessed. Results: In total, 12.391 laboratory assessments were performed on 1132 patients (56% female, AZA 74%) during 3.3 years of median follow-up. Median monitoring frequency was 3.1 assessments/treatment year. Only 83/12.391 (0.7%) assessments resulted in therapy adjustment, dose reduction in 46 patients, cessation in 28 and allopurinol initiation in nine; risk of therapy adjustment was 1.9% per treatment year. Incidence rates of myelotoxicity were 7.1% (5.1% mild/1.8% moderate/0.1% severe) and hepatotoxicity 5.1% (3.8% mild/1.1% moderate/0.2% severe) per treatment year. Treatment-related complications with concurrent laboratory toxicity occurred in 12 patients (1.1%) and would not have been prevented by monitoring. Conclusion: Severe laboratory toxicity is uncommon after 1 year of thiopurine monotherapy at 4-month monitoring intervals. Therapy adjustments are rare after detection of laboratory toxicity. After 1 year of thiopurine monotherapy, laboratory monitoring may be lowered to less than a 4-month interval

Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines

0.05), respectively. P-glycoprotein and MRP1 overexpression possibly caused a cellular stress resulting in increased gemcitabine metabolism and sensitivity, while reversal of collateral gemcitabine sensitivity by verapamil also suggests a direct relation between the presence of membrane efflux pumps and gemcitabine sensitivity

Association between Variations in Cell Cycle Genes and Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a devastating and progressive lung disease. Its aetiology is thought to involve damage to the epithelium and abnormal repair. Alveolar epithelial cells near areas of remodelling show an increased expression of proapoptotic molecules. Therefore, we investigated the role of genes involved in cell cycle control in IPF. Genotypes for five single nucleotide polymorphisms (SNPs) in the tumour protein 53 (TP53) gene and four SNPs in cyclin-dependent kinase inhibitor 1A (CDKN1A), the gene encoding p21, were determined in 77 IPF patients and 353 controls. In peripheral blood mononuclear cells (PBMC) from 16 healthy controls mRNA expression of TP53 and CDKN1A was determined