Discovery and structure–activity relationships of small molecules that block the human immunoglobulin G–human neonatal Fc receptor (hIgG–hFcRn) protein–protein interaction

The neonatal Fc receptor, FcRn, prolongs the half-life of IgG in the serum and represents a potential therapeutic target for the treatment of autoimmune disease. Small molecules that block the protein–protein interactions of human IgG–human FcRn may lower pathogenic autoantibodies and provide effective treatment. A novel class of quinoxalines has been discovered as antagonists of the IgG:FcRn protein–protein interaction through optimization of a hit derived from a virtual ligand-based screen.     

Contrasting ability of deep and shallow rooting rice genotypes to grow through plough pans containing simulated biopores and cracks

Plant and Soil - Cracks and biopores in compacted soil such as plough pans could aid deep rooting, mitigating constraints to seasonal upland use of paddy fields for rice production. This research...     

A simulation approach for power calculation in large cohort studies based on multistate models

Realistic power calculations for large cohort studies and nested case control studies are essential for successfully answering important and complex research questions in epidemiology and clinical medicine. For this, we provide a methodical framework for general realistic power calculations via simulations that we put into practice by means of an R‐based template. We consider staggered recruitment and individual hazard rates, competing risks, interaction effects, and the misclassification of covariates. The study cohort is assembled with respect to given age‐, gender‐, and community distributions. Nested case‐control analyses with a varying number of controls enable comparisons of power with a full cohort analysis. Time‐to‐event generation under competing risks, including delayed study‐entry times, is realized on the basis of a six‐state Markov model. Incidence rates, prevalence of risk factors and prefixed hazard ratios allow for the assignment of age‐dependent transition rates given in the form of Cox models. These provide the basis for a central simulation‐algorithm, which is used for the generation of sample paths of the underlying time‐inhomogeneous Markov processes. With the inclusion of frailty terms into the Cox models the Markov property is specifically biased. An “individual Markov process given frailty” creates some unobserved heterogeneity between individuals. Different left‐truncation‐ and right‐censoring patterns call for the use of Cox models for data analysis. p‐values are recorded over repeated simulation runs to allow for the desired power calculations. For illustration, we consider scenarios with a “testing” character as well as realistic scenarios. This enables the validation of a correct implementation of theoretical concepts and concrete sample size recommendations against an actual epidemiological background, here given with possible substudy designs within the German National Cohort.     

Modeling the Role of Negative Cooperativity in Metabolic Regulation and Homeostasis

A significant proportion of enzymes display cooperativity in binding ligand molecules, and such effects have an important impact on metabolic regulation. This is easiest to understand in the case of positive cooperativity. Sharp responses to changes in metabolite concentrations can allow organisms to better respond to environmental changes and maintain metabolic homeostasis. However, despite the fact that negative cooperativity is almost as common as positive, it has been harder to imagine what advantages it provides. Here we use computational models to explore the utility of negative cooperativity in one particular context: that of an inhibitor binding to an enzyme. We identify several factors which may contribute, and show that acting together they can make negative cooperativity advantageous.     

Radioimmunoassay of low molecular weight human kininogen

A radioimmunoassay for low molecular weight (LMW) human Kininogen has been carried out. The first step was to prepare LMW Kininogen from human plasma. The proposed method allowed to get chemically pure and biologically active LMW Kininogen. This preparation was used to induce antibody. Optimal conditions for labelling and incubation were determined. This method may be applied to the assay of Kininogen in human plasma.     

Effect of feeding boxes on the behavior of stereotyping amur tigers (Panthera tigris altaica) in the Zurich Zoo,Zurich, Switzerland

The stereotyped pacing shown by the two Amur tigers in the Zurich Zoo was hypothesized as being caused by permanently frustrated appetitive foraging behavior. Several electrically controlled feeding boxes were installed and access to each box was possible only twice a day for 15 min at semi‐random times. The boxes had to be opened actively by the tigers. Two trials were carried out: one with solitary confinement, and one with paired confinement. During box feeding, the female's stereotyped pacing was significantly reduced from 16% (solitary confinement, conventional feeding) and 7% (paired confinement, conventional feeding) to 1% (solitary confinement) and less than 0.01% (paired confinement) of the daily observed time. The female's sleeping increased significantly in both solitary and paired confinement. The male only showed a significant reduction in stereotyped pacing behavior when kept with the female (conventional feeding: 10%; box feeding: <0.01% of the daily observed time). On days with a box‐feeding regime in paired confinement, the male spent 25% (83 min) of the observed time with active behavior at the feeding boxes. The results support the hypothesis that permanently frustrated appetitive foraging behavior causes stereotyped pacing in adult tigers. Zoo Biol 21:573–584, 2002. © 2002 Wiley‐Liss, Inc.