Two Sides of the Same Coin: Wnt Signaling in Neurodegeneration and Neuro-Oncology

Wnts function through the activation of at least three intracellular signal transduction pathways, of which the canonical β-catenin mediated pathway is the best understood. Aberrant canonical Wnt signaling has been involved in both neurodegeneration and cancer. An impairment of Wnt signals appears to be associated with aspects of neurodegenerative pathologies while overactivation of Wnt signaling is a common theme in several types of human tumors. Therefore, although therapeutic approaches aimed at modulating Wnt signaling in neurodegenerative and hyperproliferative diseases might impinge on the same molecular mechanisms, different pharmacological outcomes are required. Here we review recent developments on the understanding of the role of Wnt signaling in Alzheimer’s disease and CNS tumors, and identify possible avenues for therapeutic intervention within a complex and multi-faceted signaling pathway.     

Stem Cell Proliferation and Quiescence—Two Sides of the Same Coin

The kinetics of label uptake and dilution in dividing stem cells, e.g., using Bromodeoxyuridine (BrdU) as a labeling substance, are a common way to assess the cellular turnover of all hematopoietic stem cells (HSCs) in vivo. The assumption that HSCs form a homogeneous population of cells which regularly undergo cell division has recently been challenged by new experimental results. For a consistent functional explanation of heterogeneity among HSCs, we propose a concept in which stem cells flexibly and reversibly adapt their cycling state according to systemic needs. Applying a mathematical model analysis, we demonstrate that different experimentally observed label dilution kinetics are consistently explained by the proposed model. The dynamically stabilized equilibrium between quiescent and activated cells leads to a biphasic label dilution kinetic in which an initial and pronounced decline of label retaining cells is attributed to faster turnover of activated cells, whereas a secondary, decelerated decline results from the slow turnover of quiescent cells. These results, which support our previous model prediction of a reversible activation/deactivation of HSCs, are also consistent with recent findings that use GFP-conjugated histones as a label instead of BrdU. Based on our findings we interpret HSC organization as an adaptive and regulated process in which the slow activation of quiescent cells and their possible return into quiescence after division are sufficient to explain the simultaneous occurrence of self-renewal and differentiation. Furthermore, we suggest an experimental strategy which is suited to demonstrate that the repopulation ability among the population of label retaining cells changes during the course of dilution.     

Chlamydia trachomatis Infection and Anti-Hsp60 Immunity: The Two Sides of the Coin

Chlamydia trachomatis (CT) infection is one of the most common causes of reproductive tract diseases and infertility. CT-Hsp60 is synthesized during infection and is released in the bloodstream. As a consequence, immune cells will produce anti-CT-Hsp60 antibodies. Hsp60, a ubiquitous and evolutionarily conserved chaperonin, is normally sequestered inside the cell, particularly into mitochondria. However, upon cell stress, as well as during carcinogenesis, the chaperonin becomes exposed on the cell surface (sf-Hsp60) and/or is secreted from cells into the extracellular space and circulation. Reports in the literature on circulating Hsp and anti-Hsp antibodies are in many cases short on details about Hsp60 concentrations, and about the specificity spectra of the antibodies, their titers, and their true, direct, pathogenetic effects. Thus, more studies are still needed to obtain a definitive picture on these matters. Nevertheless, the information already available indicates that the concurrence of persistent CT infection and appearance of sf-Hsp60 can promote an autoimmune aggression towards stressed cells and the development of diseases such as autoimmune arthritis, multiple sclerosis, atherosclerosis, vasculitis, diabetes, and thyroiditis, among others. At the same time, immunocomplexes composed of anti-CT-Hsp60 antibodies and circulating Hsp60 (both CT and human) may form deposits in several anatomical locations, e.g., at the glomerular basal membrane. The opposite side of the coin is that pre-tumor and tumor cells with sf-Hsp60 can be destroyed with participation of the anti-Hsp60 antibody, thus stopping cancer progression before it is even noticed by the patient or physician.     

Melanocyte‐Specific Immune Response in Melanoma and Vitiligo: Two Faces of the Same Coin?

The appearance of depigmentation during the course of malignant melanoma has been considered a good prognostic sign. Is it only a side‐effect, informative of the immune system's response to the treatment, or does it act as a necessary amplifier of these clinically important anti‐tumor responses? The current review will attempt to tackle this question by reviewing the current literature, as well as by posing some novel hypotheses. Understanding the nature of humoral and cellular immune responses directed against normal melanocytes and their malignant counterparts may lead to the design of improved therapeutic strategies relevant to both vitiligo and melanoma.     

Sufism and Islamic Reform in Egypt: The Battle for Islamic Tradition

Sufism and Islamic Reform in Egypt: The Battle for Islamic Tradition. Julian Johansen. Oxford, England: Clarendon Press, 1996. 323 pp.     

Tradition and Modernity in the Mediterranean: The Wedding as Symbolic Struggle

Tradition and Modernity in the Mediterranean: The Wedding as Symbolic Struggle. Vassos Argyrou. Cambridge: Cambridge University Press, 1996. 210 pp.     

Two Sides of the City: Dog-keeping Practices in Russian Urban Areas

This article examines dog–owner relations and dog ownership in Omsk, Russia. We describe typical dog-keeping practices and reveal how diverse urban environments can influence these practices. A two-stage survey was conducted in 2014 to determine the numbers and management of dogs owned. In total, some 1,583 households at the first stage of the research and 323 households at the second stage were interviewed face-to-face. About 23% of all households in Omsk owned dogs, but this proportion varied markedly for different parts of the city. In the city's single-story area, 71.5% of households had dogs, while in the multi-story area this was only 10.8%. Dog-keeping practices were different in these areas. Significant differences in these practices were shown for almost all aspects: the selection criteria, dog feeding, veterinary treatment, dog walking, the roles of dogs, and owners’ attitudes toward them. Owners living in the single-story area demonstrated a utilitarian or functional approach to their dogs—influencing the sex, size, and the breed of the animal. Dogs often lived outside the house; they were vaccinated and taken to the veterinarian less often than dogs from the multi-story area. The owners in the multi-story area described more affectionate feelings toward their dogs. This is reflected in both the choice and treatment of the animals. We observed a larger proportion of pedigree dogs, a larger proportion of female animals, more vaccinations, and the owners making a variety of purchases for their dogs.     

Functional Equivalence of the Two Sides of the Human Nose in Odor Detection

Repeated measurements of detection thresholds for amyl acetateand acetic acid on different days demonstrated that the rightand left sides of the human nose are functionally equivalentin detecting odors. Chem. Senses 20: 585–587, 1995.     

The Oslerian Tradition and Changing Medical Education: A Reappraisal

Although only 21 of Sir William Osler''s 45 years in academic medicine were spent in US medical schools (1884 to 1905), he played a major role in shaping modern medical education in this country. The integration of scholarship with patient care, together with the science and art of medicine, was central to Osler''s teaching and writing throughout his career. A classic generalist and a charismatic clinical teacher, he taught by example and was as concerned with the ideals of medicine as with its science and knowledge.Many changes have reshaped the content, process and concerns of American medical education since Osler''s time. Subspecialization and balkanization of medical education and practice have become dominant. Many of the important issues in medicine today do not fit neatly into the domain of any of the established specialties or medical organizations. There is now an urgent need to promote generalist attitudes in medicine, and the Oslerian tradition has much to offer in approaching today''s problems in medical education and practice.     

Yeast Communities of Diverse Drosophila Species: Comparison of Two Symbiont Groups in the Same Hosts

The combination of ecological diversity with genetic and experimental tractability makes Drosophila a powerful model for the study of animal-associated microbial communities. Despite the known importance of yeasts in Drosophila physiology, behavior, and fitness, most recent work has focused on Drosophila-bacterial interactions. In order to get a more complete understanding of the Drosophila microbiome, we characterized the yeast communities associated with different Drosophila species collected around the world. We focused on the phylum Ascomycota because it constitutes the vast majority of the Drosophila-associated yeasts. Our sampling strategy allowed us to compare the distribution and structure of the yeast and bacterial communities in the same host populations. We show that yeast communities are dominated by a small number of abundant taxa, that the same yeast lineages are associated with different host species and populations, and that host diet has a greater effect than host species on yeast community composition. These patterns closely parallel those observed in Drosophila bacterial communities. However, we do not detect a significant correlation between the yeast and bacterial communities of the same host populations. Comparative analysis of different symbiont groups provides a more comprehensive picture of host-microbe interactions. Future work on the role of symbiont communities in animal physiology, ecological adaptation, and evolution would benefit from a similarly holistic approach.     

Two Different Prunus SFB Alleles Have the Same Function in the Self-incompatibility Reaction

Many species in the families of Rosaceae, Solanaceae, and Scrophulariaceae exhibit gametophytic self-incompatibility, a phenomenon controlled by two polymorphic genes at the S-locus, style-S (S-RNase) and pollen-S (SFB). Sequences of both genes show high levels of diversity, characteristic of genes involved in recognition of self-incompatibility systems in plants. In this study, S ₂₄ -RNase and SFB ₂₄ alleles were cloned from Prunus armeniaca cv. Chuanzhihong (Chinese apricot). Sequence comparisons of deduced amino acid sequences revealed that the P. armeniaca S ₂₄ -haplotype has different SFB alleles, but shares a single S-RNase allele with P. armeniaca S ₄ -haplotype. Moreover, P. armeniaca S ₂₄ -RNase haplotype has a single and three different alleles with S ₁ -RNase of P. tenella (dwarf almond) and S ₁ -RNase of P. mira (smooth pit peach), respectively. The functionalities of SFB ₂₄ and SFB ₄ have been evaluated by pollen tube growth and controlled field tests of P. tenella and P. mira. Genetic analysis of the two intercrosses showed that progenies segregated 1:1 into two S-genotype classes, which is consistent with the expected ratio for semi-compatibility. These findings imply that the allelic function of the S ₂₄ -haplotype is identical to that of the S ₄ -haplotype in a self-incompatibility reaction. Thus, these two Prunus S-haplotypes are in fact two neutral variants of the same S-haplotype. The evolution of the S-allele is also discussed in terms of both functions and differences between S ₂₄ - and S ₄ -haplotypes in Prunus.     

PIE-FLIM Measurements of Two Different FRET-Based Biosensor Activities in the Same Living Cells

We report the use of pulsed interleaved excitation (PIE)-fluorescence lifetime imaging microscopy (FLIM) to measure the activities of two different biosensor probes simultaneously in single living cells. Many genetically encoded biosensors rely on the measurement of Förster resonance energy transfer (FRET) to detect changes in biosensor conformation that accompany the targeted cell signaling event. One of the most robust ways of quantifying FRET is to measure changes in the fluorescence lifetime of the donor fluorophore using FLIM. The study of complex signaling networks in living cells demands the ability to track more than one of these cellular events at the same time. Here, we demonstrate how PIE-FLIM can separate and quantify the signals from different FRET-based biosensors to simultaneously measure changes in the activity of two cell signaling pathways in the same living cells in tissues. The imaging system described here uses selectable laser wavelengths and synchronized detection gating that can be tailored and optimized for each FRET pair. Proof-of-principle studies showing simultaneous measurement of cytosolic calcium and protein kinase A activity are shown, but the PIE-FLIM approach is broadly applicable to other signaling pathways.