The impossible regularization of the Nambu Jona-Lasinio model with vector interactions

We show that the procedure of regularizing the real part of the euclidean action, while leaving the imaginary part unregularized, leads to a non-analytic and highly singular functional of the fields. It is customary to work with an imaginary time component of the vector field, in order to avoid regularization of the anomalous processes. We show that this procedure is flawed by the fact that a stationary point of the action occurs for a real, not imaginary, time component of the vector field. Furthermore the action in the vicinity of the stationary point is singular. The regularized action is thus not suitable for an evaluation of the partition function using a saddle point method. We discuss proposed solutions to this problem, as well as other regularizations. They all lead to practical problems.Comment: 13 pages in Latex, available from [email protected]

Proteoglycans and osteolysis.

Osteolysis is a complex mechanism resulting from an exacerbated activity of osteoclasts associated or not with a dysregulation of osteoblast metabolism leading to bone loss. This bone defect is not compensated by bone apposition or by apposition of bone matrix with poor mechanical quality. Osteolytic process is regulated by mechanical constraints, by polypeptides including cytokines and hormones, and by extracellular matrix components such as proteoglycans (PGs) and glycosaminoglycans (GAGs). Several studies revealed that GAGs may influence osteoclastogenesis, but data are very controversial: some studies showed a repressive effect of GAGs on osteoclastic differentiation, whereas others described a stimulatory effect. The controversy also affects osteoblasts which appear sometimes inhibited by polysaccharides and sometimes stimulated by these compounds. Furthermore, long-term treatment with heparin leads to the development of osteoporosis fueling the controversy. After a brief description of the principal osteoclastogenesis assays, the present chapter summarizes the main data published on the effect of PGs/GAGs on bone cells and their functional incidence on osteolysis

The Genetic Signatures of Noncoding RNAs

The majority of the genome in animals and plants is transcribed in a developmentally regulated manner to produce large numbers of non–protein-coding RNAs (ncRNAs), whose incidence increases with developmental complexity. There is growing evidence that these transcripts are functional, particularly in the regulation of epigenetic processes, leading to the suggestion that they compose a hitherto hidden layer of genomic programming in humans and other complex organisms. However, to date, very few have been identified in genetic screens. Here I show that this is explicable by an historic emphasis, both phenotypically and technically, on mutations in protein-coding sequences, and by presumptions about the nature of regulatory mutations. Most variations in regulatory sequences produce relatively subtle phenotypic changes, in contrast to mutations in protein-coding sequences that frequently cause catastrophic component failure. Until recently, most mapping projects have focused on protein-coding sequences, and the limited number of identified regulatory mutations have been interpreted as affecting conventional cis-acting promoter and enhancer elements, although these regions are often themselves transcribed. Moreover, ncRNA-directed regulatory circuits underpin most, if not all, complex genetic phenomena in eukaryotes, including RNA interference-related processes such as transcriptional and post-transcriptional gene silencing, position effect variegation, hybrid dysgenesis, chromosome dosage compensation, parental imprinting and allelic exclusion, paramutation, and possibly transvection and transinduction. The next frontier is the identification and functional characterization of the myriad sequence variations that influence quantitative traits, disease susceptibility, and other complex characteristics, which are being shown by genome-wide association studies to lie mostly in noncoding, presumably regulatory, regions. There is every possibility that many of these variations will alter the interactions between regulatory RNAs and their targets, a prospect that should be borne in mind in future functional analyses

L’ostéopétrose, de la souris à l’homme

Les ostéoclastes sont des acteurs essentiels du remodelage osseux, et des anomalies de leur différenciation ou de leur activité conduisent à l’apparition de maladies osseuses, dont des défauts de résorption osseuse qui se traduisent par l’apparition d’une ostéopétrose. Différents modèles murins développant une ostéopétrose secondaire à l’apparition de mutations spontanées ou à l’invalidation de gènes ont permis de décrypter, au moins en partie, les mécanismes impliqués dans la différenciation et l’activité des ostéoclastes. Chez l’être humain, en revanche, seules des anomalies d’activité de l’ostéoclaste ont été décrites. Trois modèles murins, les souris oc/oc, gl/gl et Clcn7-/-, présentent un phénotype proche de celui de patients atteints d’ostéopétrose maligne infantile, la forme d’ostéopétrose la plus sévère chez l’homme. Des mutations dans les gènes TCIRG1, GL et CLCN7 ont donc été recherchées chez des patients ostéopétrotiques, et retrouvées majoritairement dans l’ostéopétrose maligne infantile et dans l’ostéopétrose de type II. Une telle correspondance phénotypique et génétique fait de ces trois mutants de souris des modèles particulièrement adaptés à l’étude de l’ostéopétrose humaine.The osteoclast is the main effector of bone resorption. Failure in osteoclast differentiation or function leads to osteopetrosis, a bone disease characterized by an impaired bone resorption. Analysis of mouse models developing osteopetrosis as a consequence of naturally occuring mutations or gene knockouts allowed to establish the osteoclast differentiation pathway. Among these models, the oc/oc, the gl/gl and the Clcn7–/– mice present a phenotype similar to the one displayed by patients with infantile malignant osteopetrosis, the most severe form of osteopetrosis in human. Analysis of these models led to the identification of different mutations in the corresponding human genes TCIRG1, GL and CLCN7, in osteopetrotic patients. Mutations in the TCIRG1 gene seem the most frequent cause of malignant osteopetrosis and mutations in the CLCN7 gene seem the most frequent cause of type II osteopetrosis. Therefore, these three mouse models appear to be particularly well suited for the study of the osteoclast function in order to provide new insights in the therapy of osteopetrosis

Characterization of a novel bipotent hematopoietic progenitor population in normal and osteopetrotic mice.

Several reports indicate that osteoclasts and B-lymphocytes share a common progenitor. This study focuses on the characterization of this bipotent progenitor from the bone marrow of the osteopetrotic oc/oc mouse, where the bipotent progenitor population is amplified, and of normal mice. INTRODUCTION: Osteoclasts have a myelomonocytic origin, but they can also arise in vitro from pro-B-cells, suggesting that a subset of normal pro-B-cells is uncommitted and may reorient into the myeloid lineage representing a B-lymphoid/osteoclastic progenitor. The aim of this study was to characterize this progenitor population. MATERIALS AND METHODS: The osteopetrotic oc/oc mouse was used as a choice model because it displays an increased number of both osteoclasts and pro-B-cells in the bone marrow. Our results have been confirmed in normal littermates. Bone marrow cells from these animals were analyzed by flow cytometry. After sorting, the cells were cultured under different conditions to assess their differentiation capacity. RESULTS: Pro-B-cells from oc/oc and normal mice include an unusual biphenotypic population expressing markers from the B-lymphoid (CD19, CD43, CD5) and the myeloid (F4/80) lineages. This population also expresses progenitor markers (CD34 and Flt3) and is uncommitted. After sorting from the oc/oc bone marrow, this population is able to differentiate in vitro into osteoclast-like cells in the presence of RANKL and macrophage colony-stimulating factor (M-CSF), into dendritic-like cells in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4, and TNFalpha, and into immature B-cells when seeded onto ST2 cells in the presence of IL-7. CONCLUSION: Our results show the existence of a novel bipotent biphenotypic hematopoietic progenitor population present in the bone marrow that has retained the capacity to differentiate into myeloid and B-lymphoid cells

Interleukin-7 partially rescues B-lymphopoiesis in osteopetrotic oc/oc mice through the engagement of B220+ CD11b+ progenitors.

OBJECTIVE: We recently identified in the mouse bone marrow a B-lymphoid/myeloid B220+ CD11b+ progenitor population. This population is accumulated in the osteopetrotic oc/oc mouse, which suggests that it could be controlled by bone marrow factors whose expression varies in this pathologic bone environment. Among the possible factors, interleukin (IL)-7 is involved in the control of B lymphopoiesis and osteoclastogenesis. Therefore, we hypothesized that IL-7 could regulate the accumulation of the B220+ CD11b+ population in oc/oc mice. METHODS: B220+ CD11b+ cells sorted from oc/oc mice were treated with IL-7 and their phenotype was analyzed by flow cytometry and real-time reverse transcriptase polymerase chain reaction (RT-PCR). In vivo, IL-7 was injected in oc/oc mice, and B220+ CD11b+ and B cells, as well as B-cell proliferation and apoptosis, were analyzed by flow cytometry. The expression of B lymphopoiesis and myelopoiesis markers was analyzed by real-time RT-PCR. RESULTS: In vitro, IL-7 induced the differentiation of B220+ CD11b+ cells into B lymphocytes through the induction of Pax5 and the inhibition of myeloid markers. In vivo, IL-7 injections in oc/oc mice induced a decrease of the B220+ CD11b+ population and the partial restoration of B-cell population, which was reduced in oc/oc mice. In parallel, upon IL-7 injections, Pax5 expression was induced in B220+ cells and B-cell apoptosis was reduced. CONCLUSIONS: Our results demonstrate that IL-7 injection can partially rescue B lymphopoiesis in oc/oc mice through the engagement of the B220+ CD11b+ population in the B-lymphoid pathway. Therefore, IL-7 delivery could represent a new therapeutic perspective to circumvent the lymphopenia observed in infantile malignant osteopetrosis patients

Establishment and characterization of new osteoclast progenitor cell lines derived from osteopetrotic and wild type mice.

Malignant infantile osteopetrosis is a rare and lethal disease characterized by the absence of bone resorption due to inactive osteoclasts (OCLs). Among the murine models of osteopetrosis, the Tcirg1oc/oc mouse is the most resembling to the human pathology. In the majority of patients as in Tcirg1oc/oc mouse, the gene involved is the Tcirg1 gene, encoding the a3 subunit of the vacuolar proton pump. However, to date, no osteoclastic cell lines from osteopetrotic mice are available to facilitate the study of either OCL differentiation in osteopetrosis or the factors involved in the control of Tcirg1 gene expression. Heterozygotes Tcirg1+/oc mice were crossed with p53+/- mice to obtain homozygotes p53-/-Tcirg1oc/oc and p53-/-Tcirg1+/+ animals. The p53-/-Tcirg1oc/oc mice display the same bone and hematological phenotype as the original Tcirg1oc/oc mice. From the bone marrow of these mice, we have derived cell lines named POC-MGoc/oc and POC-MG+/+. These cell lines express standard osteoclastogenic markers and differentiate into OCLs in the presence of RANK-L and M-CSF. Furthermore, both cell lines can be transduced by a lentiviral vector with a high efficiency and without alteration of their OCL differentiation potential. Therefore, these cell lines provide valuable new tools to study the differentiation and function of osteoclasts in normal and resorption defective conditions

Apomorphine-Induced Yawning in Migraine Patients

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Characterization of IL-10-secreting T cells derived from regulatory CD4+CD25+ cells by the TIRC7 surface marker.

Natural CD25(+)CD4(+) regulatory T cells (Treg) are essential for self-tolerance and for the control of T cell-mediated immune pathologies. However, the identification of Tregs in an ongoing immune response or in inflamed tissues remains elusive. Our experiments indicate that TIRC7, T cell immune response cDNA 7, a novel membrane molecule involved in the regulation of T lymphocyte activation, identifies two Treg subsets (CD25(low)TIRC7(+) and CD25(high)TIRC7(-)) that are characterized by the expression of Foxp3 and a suppressive activity in vitro and in vivo. We also showed that the CD25(low)TIRC7(+) subset represents IL-10-secreting Tregs in steady state, which is accumulated intratumorally in a tumor-bearing mice model. Blockade of the effect of IL-10 reversed the suppression imposed by the CD25(low)TIRC7(+) subset. Interestingly, these IL-10-secreting cells derived from the CD25(high)TIRC7(-) subset, both in vitro and in vivo, in response to tumoral Ags. Our present results strongly support the notion that, in the pool of natural Tregs, some cells can recognize foreign Ags and that this recognition is an essential step in their expansion and suppressive activity in vivo