The synthesis and characterization of polypeptide-adriamycin conjugates and its complexes with adriamycin. Part I

Poly(α-l-glutamic acid) (PGA) was grafted with amino acid and oligopeptide spacers up to 5 amino acids with the use of N,N'-carbonyldiimidazole and 2,3-dihydro-1,2-benz-isothiazole-3-on-1, 1-dioxide (saccharin) as an additive, and these polypeptides were characterized. The antitumor antibiotic adriamycin was covalently coupled via an amide bond onto PGA and onto the grafted polymers with the use of N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ); these conjugates were characterized. The conjugates containing Gly—Gly—l-Leu spacer arms did yield free adriamycin upon digestion with papain. Adriamycin gave fairly stable complexes with PGA—adriamycin and branched poly peptide—adriamycin conjugates; these complexes were characterized

Conditional Spectral Analysis of Replicated Multiple Time Series with Application to Nocturnal Physiology

This article considers the problem of analyzing associations between power spectra of multiple time series and cross-sectional outcomes when data are observed from multiple subjects. The motivating application comes from sleep medicine, where researchers are able to non-invasively record physiological time series signals during sleep. The frequency patterns of these signals, which can be quantified through the power spectrum, contain interpretable information about biological processes. An important problem in sleep research is drawing connections between power spectra of time series signals and clinical characteristics; these connections are key to understanding biological pathways through which sleep affects, and can be treated to improve, health. Such analyses are challenging as they must overcome the complicated structure of a power spectrum from multiple time series as a complex positive-definite matrix-valued function. This article proposes a new approach to such analyses based on a tensor-product spline model of Cholesky components of outcome-dependent power spectra. The approach flexibly models power spectra as nonparametric functions of frequency and outcome while preserving geometric constraints. Formulated in a fully Bayesian framework, a Whittle likelihood based Markov chain Monte Carlo (MCMC) algorithm is developed for automated model fitting and for conducting inference on associations between outcomes and spectral measures. The method is used to analyze data from a study of sleep in older adults and uncovers new insights into how stress and arousal are connected to the amount of time one spends in bed

Endogenous Technological Change in Energy Systems Models: Synthesis of Experience with ERIS, MARKAL, and MESSAGE

Technological change is widely recognised as a key factor in economic progress, as it enhances the productivity of factor inputs. In recent years also the notion has developed that targeted technological development is a main means to reconcile economic ambitions with ecological considerations. This raises the issue that assessments of future trajectories of for example en-ergy systems should take into account context-specific technological progress. Rather than tak-ing characteristics of existing and emerging technologies as a given, their development should be a function of dedicated Research, Development and Demonstration (RD&D) and market de-ployment under varying external conditions. Endogenous technological learning has recently shown to be a very promising new feature in energy system models. A learning, or experience curve, describes the specific (investment) cost as a function of the cumulative capacity for a given technology. It reflects the fact that tech-nologies may experience declining costs as a result of its increasing adoption into the society due to the accumulation of knowledge through, among others, processes of learning-by-doing and learning-by-using. This report synthesises the results and findings from experiments with endogenous technologi-cal learning, as reported separately within the EU TEEM project. These experiments have been carried out by three TEEM partners using three models: ERIS (PSI), MARKAL (ECN and PSI), and MESSAGE (IIASA). The main objectives of this synthesis are: to derive common methodo-logical insights; to indicate and assess benefits of the new feature, but also its limitations and issues to solve; and to recommend further research to solve the main issues. This synthesis shows that all model applications are examples of successful first experiments to incorporate the learning-by-doing concept in energy system models. Incorporating the learning-by-doing concept makes an important difference. The experiments demonstrate and quantify the benefits of investing early in emerging technologies that are not competitive at the moment of their deployment. They also show that the long-term impact of policy instruments, such as CO2 taxes or emission limits and RD&D instruments, on technological development can be assessed adequately with models including technology learning. Adopting the concept of endogenous learning, several types of RD&D interventions can be addressed that aim at accelerating the market penetration of new technologies. The directions into which such interventions might lead have been illustrated in some of the experiments. However, quantitative relationships between R&D policy and learning data parameters are still unknow

A Symmetric Integrator for non-integrable Hamiltonian Relativistic Systems

By combining a standard symmetric, symplectic integrator with a new step size controller, we provide an integration scheme that is symmetric, reversible and conserves the values of the constants of motion. This new scheme is appropriate for long term numerical integrations of geodesic orbits in spacetime backgrounds, whose corresponding Hamiltonian system is non-integrable, and, in general, for any non-integrable Hamiltonian system whose kinetic part depends on the position variables. We show by numerical examples that the new integrator is faster and more accurate i) than the standard symplectic integration schemes with or without standard adaptive step size controllers and ii) than an adaptive step Runge-Kutta scheme.Comment: 12 pages, 8 figures, 3 table

Sister species diverge in modality-specific courtship signal form and function

Understanding the relative importance of different sources of selection (e.g., the environment, social/sexual selection) on the divergence or convergence of reproductive communication can shed light on the origin, maintenance, or even disappearance of species boundaries. Using a multistep approach, we tested the hypothesis that two presumed sister species of wolf spider with overlapping ranges and microhabitat use, yet differing degrees of sexual dimorphism, have diverged in their reliance on modality- specific courtship signaling. We predicted that male Schizocosa crassipalpata (no ornamentation) rely predominantly on diet-dependent vibratory signaling for mating success. In contrast, we predicted that male S. bilineata (black foreleg brushes) rely on diet-dependent visual signaling. We first tested and corroborated the sister-species relationship between S. crassipalpata and S. bilineata using phylogenomic scale data. Next, we tested for species-specific, diet-dependent vibratory and visual signaling by manipulating subadult diet and subsequently quantifying adult morphology and mature male courtship signals. As predicted, vibratory signal form was diet-dependent in S. crassipalpata, while visual ornamentation (brush area) was diet-dependent in S. bilineata. We then compared the species-specific reliance on vibratory and visual signaling by recording mating across artificially manipulated signaling environments (presence/absence of each modality in a 2 × 2 full factorial design). In accordance with our diet dependence results for S. crassipalpata, the presence of vibratory signaling was important for mating success. In contrast, the light and vibratory environment interacted to influence mating success in S. bilineata, with vibratory signaling being important only in the absence of light. We found no differences in overall activity patterns. Given that these species overlap in much of their range and microhabitat use, we suggest that competition for signaling space may have led to the divergence and differential use of sensory modalities between these sister species

Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement

Objectives: Janus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety. Methods: Existing data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration. Results: The Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale. Conclusion: The consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management

Endogenous orienting modulates the Simon effect: critical factors in experimental design

Responses are faster when the side of stimulus and response correspond than when they do not correspond, even if stimulus location is irrelevant to the task at hand: the correspondence, spatial compatibility effect, or Simon effect. Generally, it is assumed that an automatically generated spatial code is responsible for this effect, but the precise mechanism underlying the formation of this code is still under dispute. Two major alternatives have been proposed: the referential-coding account, which can be subdivided into a static version and an attention-centered version, and the attention-shift account. These accounts hold clear-cut predictions for attentional cuing experiments. The former would assume a Simon effect irrespective of attentional cuing in its static version, whereas the attention-centered version of the referential-coding account and the attention-shift account would predict a decreased Simon effect on validly as opposed to invalidly cued trials. However, results from previous studies are equivocal to the effects of attentional cuing on the Simon effect. We argue here that attentional cueing reliably modulates the Simon effect if some crucial experimental conditions, mostly relevant for optimizing attentional allocation, are met. Furthermore, we propose that the Simon effect may be better understood within the perspective of supra-modal spatial attention, thereby providing an explanation for observed discrepancies in the literature