A Flexible Link Function for Discrete-Time Duration Models

This paper proposes a discrete-time hazard regression approach based on the relation between hazard rate models and excess over threshold models, which are frequently encountered in extreme value modelling. The proposed duration model employs a flexible link function and incorporates the grouped-duration analogue of the well-known Cox proportional hazards model and the proportional odds model as special cases. The theoretical setup of the model is motivated, and simulation results are reported to suggest that it performs well. The simulation results and an empirical analysis of US import durations also show that the choice of link function in discrete hazard models has important implications for the estimation results, and that severe biases in the results can be avoided when using a flexible link function as proposed in this study

Enhanced granular medium-based tube press hardening

Active and passive control strategies of internal pressure for hot forming of tubes and profiles with granular media are described. Force transmission and plastic deformation of granular medium is experimentally investigated. Friction between tube, granular medium and die as also the external stress field are shown to be essential for the process understanding. Wrinkling, thinning and insufficient forming of the tube establishes the process window for the active pressure process. By improving the punch geometry and controlling tribological conditions, the process limits are extended. Examples for the passive pressure process reveal new opportunities for hot forming of tubes and profiles.Comment: 4 pages, 11 figure

Sensitive screening of synthetic cannabinoids using liquid chromatography quadrupole time-of-flight mass spectrometry after solid phase extraction

Analysis of synthetic cannabinoids still poses a challenge for many institutions due to the number of available substances and the constantly changing drug market. Both new and well-known substances keep appearing and disappearing on the market, making it hard to adapt analytical methods in a timely manner. In this study, we developed a qualitative screening approach for synthetic cannabinoids and their metabolites by means of liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Samples were measured in data-dependent auto-MS/MS mode and identified by fragment spectra, retention time and accurate mass. Two established solid phase extractions were compared using fortified serum and urine samples. Mixes of 199 synthetic cannabinoids and 110 metabolites were used in 1- and 10-ng/ml concentrations. Up to 93% of synthetic cannabinoids and 74% of metabolites were detected in fortified 1-ng/ml samples. From February 2018 to October 2020, we analyzed 1492 cases, of which 73 cases were positive for synthetic cannabinoids or metabolites. 5F-MDMB-PICA, 4F-MDMB-BINACA, MDMB-4en-PINACA, and 4F-MDMB-BICA were most frequently detected. Hydrolysis metabolites were detected in many blood samples, providing a longer detection window. Quantification was conducted via liquid chromatography triple quadrupole mass spectrometry after liquid–liquid extraction. Concentrations were mostly close to 1 ng/ml in blood samples. LC-QTOF-MS was able to detect substances above trace quantities (< 0.1 ng/ml) in most cases, therefore fulfilling its purpose as a sensitive general screening approach. Expansion of the screening library was uncomplicated and enables future additions for up to thousands of targets

Recombinant human interleukin-12 is the second example of a C-mannosylated protein

The β-chain of human interleukin 12 (IL-12) contains at position 319-322, the sequence Trp-x-x-Trp. In human RNase 2 this is the recognition motif for a new, recently discovered posttranslational modification, i.e., the C-glycosidic attachment of a mannosyl residue to the side chain of tryptophan. Analysis of C-terminal peptides of recombinant IL-12 (rHuIL-12) by mass spectrometry and NMR spectroscopy revealed that Trp-319β is (partially) C-mannosylated. This finding was extended by in vitro mannosylation experiments, using a synthetic peptide derived from the same region of the protein as an acceptor. Furthermore, human B-lymphoblastoid cells, which secrete IL-12, were found to contain an enzyme that carries out the C-mannosylation reaction. This shows that nonrecombinant IL-12 is potentially C-mannosylated as well. This is only the second report on a C-mannosylated protein. However, the occurrence of the C-mannosyltransferase activity in a variety of cells and tissues, and the presence of the recognition motif in many proteins indicate that more C-mannosylated proteins may be foun

SEMIFAR Models, with Applications to Commodities, Exchange Rates and the Volatility of Stock Market Indices

The distinction between stationarity, difference stationarity, deterministic trends as well as between short- and long-range dependence has a major impact on statistical conclusions, such as confidence intervals for population quantities or point and interval forecasts. In this paper, recent results on so-called SEMIFAR models introduced by Beran(1999) are summarized and their potential usefulness for economic time series analysis is illustrated by analyzing several commodities, exchange rates, the volatility of stock market indices and some simulated series. SEMIFAR models provide a unified approach that allows for simultaneous modelling of and distinction between deterministic trends, difference stationarity and stationarity with short- and long-range dependence. An iterative data-driven algorithm combines MLE and kernel estimation. Predictions combine stochastic prediction of the random part with functional extrapolation of the deterministic part

TRIPLE DIVIDENDS OF WATER CONSUMPTION CHARGES IN SOUTH AFRICA

The South African government is exploring ways to address water scarcity problems by introducing a water resource management charge on the quantity of water used in sectors such as irrigated agriculture, mining and forestry. It is expected that a more efficient water allocation, lower use and a positive impact on poverty can be achieved. This paper reports on the validity of these claims by applying a computable general equilibrium model to analyse the triple dividend of water consumption charges in South Africa: reduced water use, more rapid economic growth, and a more equal income distribution. It is shown that the appropriate, budget-neutral combination of water charges, particularly on irrigated agriculture and coal mining, and reduced indirect taxes, particularly on food, would yield triple dividends.water scarcity, water charges, triple dividend, poverty alleviation, computable general equilibrium model

Antibody sequence-based prediction of pH gradient elution in multimodal chromatography

Multimodal chromatography has emerged as a promising technique for antibody purification, owing to its ca- pacity to selectively capture and separate target molecules. However, the optimization of chromatography pa- rameters remains a challenge due to the intricate nature of protein-ligand interactions. To tackle this issue, efficient predictive tools are essential for the development and optimization of multimodal chromatography processes. In this study, we introduce a methodology that predicts the elution behavior of antibodies in multi- modal chromatography based on their amino acid sequences. We analyzed a total of 64 full-length antibodies, including IgG1, IgG4, and IgG-like multispecific formats, which were eluted using linear pH gradients from pH 9.0 to 4.0 on the anionic mixed-mode resin Capto adhere. Homology models were constructed, and 1312 antibody-specific physicochemical descriptors were calculated for each molecule. Our analysis identified six key structural features of the multimodal antibody interaction, which were correlated with the elution behavior, emphasizing the antibody variable region. The results show that our methodology can predict pH gradient elution for a diverse range of antibodies and antibody formats, with a test set R2 of 0.898. The developed model can inform process development by predicting initial conditions for multimodal elution, thereby reducing trial and error during process optimization. Furthermore, the model holds the potential to enable an in silico manu- facturability assessment by screening target antibodies that adhere to standardized purification conditions. In conclusion, this study highlights the feasibility of using structure-based prediction to enhance antibody purifi- cation in the biopharmaceutical industry. This approach can lead to more efficient and cost-effective process development while increasing process understanding

Immune-deficient mouse models for analysis of human stem cells

The field of murine models of xenotransplantation has grown immensely over the past two decades. The explosive growth in this field is in part due to the fact that good in vitro methods do not exist yet to allow examination of human stem cell homing into the bone marrow compartment versus other tissues, long-term survival of human stem cells, or differentiation into tissues outside of the hematopoietic system. Since these important aspects of human stem cell biology can be examined in vivo using immune-deficient mice, the number of different strains and models is constantly increasing. The current review discusses the merits and drawbacks of each immune-deficient mouse xenograft system as it stands to date and reviews how each immune-deficient mouse model has been used to further our knowledge of human hematopoietic stem cell biology