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Fine Mapping the Spatial Distribution and Concentration of Unlabeled Drugs within Tissue Micro-Compartments Using Imaging Mass Spectrometry

Readouts that define the physiological distributions of drugs in tissues are an unmet challenge and at best imprecise, but are needed in order to understand both the pharmacokinetic and pharmacodynamic properties associated with efficacy. Here we demonstrate that it is feasible to follow the in vivo transport of unlabeled drugs within specific organ and tissue compartments on a platform that applies MALDI imaging mass spectrometry to tissue sections characterized with high definition histology. We have tracked and quantified the distribution of an inhaled reference compound, tiotropium, within the lungs of dosed rats, using systematic point by point MS and MS/MS sampling at 200 µm intervals. By comparing drug ion distribution patterns in adjacent tissue sections, we observed that within 15 min following exposure, tiotropium parent MS ions (mass-to-charge; m/z 392.1) and fragmented daughter MS/MS ions (m/z 170.1 and 152.1) were dispersed in a concentration gradient (80 fmol-5 pmol) away from the central airways into the lung parenchyma and pleura. These drug levels agreed well with amounts detected in lung compartments by chemical extraction. Moreover, the simultaneous global definition of molecular ion signatures localized within 2-D tissue space provides accurate assignment of ion identities within histological landmarks, providing context to dynamic biological processes occurring at sites of drug presence. Our results highlight an important emerging technology allowing specific high resolution identification of unlabeled drugs at sites of in vivo uptake and retention.     

Epithelioid sarcoma

The first appearance, the 12-year follow-up, and the autopsy of a patient with a strange soft-tissue tumor in the lower leg region are described. Although it was originally taken for a malignant synovial tumor, its peculiar distribution pattern, together with its histologic picture, confirmed the final diagnosis as an epithelioid sarcoma.     

Cell degeneration during early development of hymenopteran olfactory sensilla

The imaginal pore plates of Hymenoptera apocrita so far examined embody five or six envelope cells respectively. In early developmental stages, however, supernumerary envelope cells have been found. The results are discussed in the context of cell death as a developmental phenomenon.     

An Estimation Procedure for the Joint Distribution of Spatial Direction and Thickness of Flat Bodies Using Vertical Sections. Part II: An application in soil micromorphology

In soil micromorphology fissures are considered in vertical sections. To get information about the properties of the soil the joint distribution of spatial direction and width of these fissures is of interest. The fissures are mathematically generalized to flat bodies which are defined as stationary weighted surface processes with the weight “thickness”. In a typical point of the surface process suitable, joint parametric distributions of direction and thickness are assumed. The parameters have to be estimated from measurements on vertical sections which are taken from the soil. On these sections only a visible thickness and a visible angle can be observed. The joint distribution of these variables can be expressed by the joint distribution of spatial direction and thickness with the same parameters and in this indirect way the parameters can be estimated. The paper describes how to randomize the vertical section and how to measure the visible variables on the sections. The Chi-Square method is proposed for the parameter estimation. Further it is discussed how to derive good starting values for the numerical procedure. All this is demonstrated in a simulation study using the Bingham-Mardia distribution for the direction and the lognormal distribution for the thickness including a way to correlate the mean thickness and the direction. Finally an application in soil micromorphology is demonstrated for one soil horizon.     

Cloning and expression of the essential gene for guanylate kinase from yeast.

Guanylate kinase catalyzes the reversible transfer of the terminal phosphoryl group of ATP to the acceptor molecule GMP. Detailed analysis of the in vivo function of this enzyme has been limited by the lack of any genetic data. Using oligonucleotides based on amino acid sequence information of the yeast enzyme, the Saccharomyces cerevisiae gene, GUK1, was isolated and characterized. The gene is present in single copy and maps to chromosome IV. Insertional mutagenesis of the GUK1 locus caused recessive lethality, indicating that this enzyme is necessary for vegetative cell growth. Using inducible expression systems, guanylate kinase was produced in large amounts both in S. cerevisiae and in Escherichia coli.