Some rare helical Ammonoidea from the lower Aptian (Lower Cretaceous) of the Paris Basin (NE France)

In the present paper, we describe and figure some rare lower Aptian (Lower Cretaceous) helical ammonoids from the Deshayesites deshayesi Zone of the Argiles à Plicatules Formation (Paris Basin, NE France). Those are the only helical ammonoids known in this zone so far. They were only occasionally evoked in literature and this is probably on the basis of the specimens here described that, according to us, the genus Toxoceratoides (Helicancylidae) was wrongly regarded as possessing an early helical spiral part. We demonstrate here that these specimens are not belonging to Toxoceratoides nor Helicancylidae: they are interpreted as ‘abnormally’ helical representatives of the genus Ancyloceras (Ancyloceratidae) or a new taxon of Ancyloceratidae.     

Role of magnesium cations in the yeast orotate phosphoribosyltransferase catalyzed reaction. Mechanism of the inhibition by Cu++ and Ni++ ions

The magnesium chelate of the N(3)H tautomer of orotate, L₃Mg, is the true substrate in the biosynthesis of orotidine 5′-monophosphate (OMP) catalyzed by yeast orotate phosphoribosyltransferase (OPRTase, E.C. 2.4.210) with a Michaelis constant K_m^L₃Mg equal to 12(2) μM. It is postulated that Mg⁺⁺ cations activate the transport of orotate to the active site by neutralizing the orotate charges; the ligand N(3)H is then exchanged between the incoming cation and the cation bound to the enzyme, thus ensuring the stabilization of the appropriate isomeric structure of orotate. This scheme, together with kinetic and thermodynamic data on orotate complexation by Mg⁺⁺ and Ca⁺⁺, accounts for the role of Ca⁺⁺ cations that neither activate nor inhibit OMP synthesis.Cu⁺⁺ and Ni⁺⁺ inhibiting properties arise from the formation of inert complexes of orotate. Ni⁺⁺ complexes have a poor affinity for the protein, whereas Cu⁺⁺ complexes have a Michaelis constant similar to that of the L₃Mg active species. The inertness of these complexes is tentatively understood in terms of low phosphoribosyl transfer rates as postulated from the kinetic study of the protonation of the complexes in water.     

Deux nouvelles espèces de brachiopodes rhynchonelliformes de l’Albien stratotypique (Bassin de Paris) – mise au point

Two new Rhynchonellide brachiopods from the Albian stratotype region (Paris Basin) (Dipoloceas cristatum zone), analyzed according to their external morphology and internal characters completed by the observation of their corresponding microstructure, are set apart from a cluster of specimens previously recognized as Rhynchonella sulcata d’Orbigny. They correspond to Lamellaerhynchia carronensis n. sp. (Cyclothyrididae) and Burrirhynchia albiensis n. sp. (Tetrarhynchiidae) brought up and described in this context, in respect to the demand of the amended article 8.6 of the International Code of Zoological Nomenclature. This article concerns works published after 1999 which does not make use of printing edition. Therefore, these two species previously figured by Gaspard (2010a, paper version) then described and figured by Gaspard (2010b) in a joint CD-ROM of the collective edition entitled “Stratotype Albien”, will be definitively available in this printing version.     

云南可食的革菌属真菌的分类研究

“干巴菌”因别具清香的佳美食味而与竹荪、虫草、鸡、松茸等同属于云南珍贵的野生食用菌。每年夏秋，鲜干巴菌类在市场上深受欢迎。干巴菌分布于滇中的昆明、安宁、富民、禄丰等，滇西的丽江、保山、昌宁等地。常生于松林、油杉林等针叶松林下。     

Cloning and Functional Characterization of a Squalene Synthase from Paris polyphylla var. yunnanensis

Paris polyphylla Smith var. yunnanensis (Franch.) Hand. – Mazz. is a precious traditional Chinese medicine, and steroidal saponins are its major bioactive constituents possessing extensive biological activities. Squalene synthase (SQS) catalyzes the first dedicated step converting two molecular of farnesyl diphosphate (FDP) into squalene, a key intermediate in the biosynthetic pathway of steroidal saponins. In this study, a squalene synthase gene (PpSQS1) was cloned and functionally characterized from P. polyphylla var. yunnanensis, representing the first identified SQS from the genus Paris. The open reading frame of PpSQS1 is 1239 bp, which encodes a protein of 412 amino acids showing high similarity to those of other plant SQSs. Expression of PpSQS1 in Escherichia coli resulted in production of soluble recombinant proteins. Gas chromatography-mass spectrometry analysis showed that the purified recombinant PpSQS1 protein could produce squalene using FDP as a substrate in the in vitro enzymatic assay. qRT-PCR analysis indicated that PpSQS1 was highly expressed in rhizomes, consistent with the dominant accumulation of steroidal saponins there, suggesting that PpSQS1 is likely involved in the biosynthesis of steroidal saponins in the plant. The findings lay a foundation for further investigation on the biosynthesis and regulation of steroidal saponins, and also provide an alternative gene for manipulation of steroid production using synthetic biology.     

Discontinuous Schedule of Bevacizumab in Colorectal Cancer Induces Accelerated Tumor Growth and Phenotypic Changes

Antiangiogenics administration in colorectal cancer patients seemed promising therapeutic approach. Inspite of early encouraging results, it however gave only modest clinical benefits. When AAG was administered with discontinuous schedule, the disease showed acceleration in certain cases. Though resistance to AAG has been extensively studied, it is not documented for discontinuous schedules. To simulate clinical situations, we subjected a patient-derived CRC subcutaneous xenograft in mice to three different protocols: 1) AAG (bevacizumab) treatment for 30 days (group A) (group B was the control), 2) bevacizumab treatment for 50 days (group C) and bevacizumab for 30 days and 20 without treatment (group D), and 3) bevacizumab treatment for 70 days (group E) and 70 days treatment with a drug-break period between day 30 and 50 (group F). The tumor growth was monitored, and at sacrifice, the vascularity of tumors was measured and the proangiogenic factors quantified. Tumor phenotype was studied by quantifying cancer stem cells. Interrupting bevacizumab during treatment accelerated tumor growth and revascularization. A significant increase of proangiogenic factors was observed when therapy was stopped. On withdrawal of bevacizumab, as also after the drug-break period, the plasmatic VEGF increased significantly. Similarly, a notable increase of CSCs after the withdrawal and drug-break period of bevacizumab was observed (P<.01). The present study indicates that bevacizumab treatment needs to be maintained because discontinuous schedules tend to trigger tumor regrowth, and increase tumor resistance and CSC heterogeneity.     

The ‘experimental stable’ of the BCG vaccine: safety, efficacy, proof, and standards, 1921–1933

The anti-tuberculosis BCG (Bacille Calmette-Guérin) vaccine was conceived and developed between 1905 and 1921 at Pasteur Institutes in France. Between 1921 and A. Calmette’s death in 1933, the vaccine went through a first period of national and international production and distribution for its use in humans. In France these activities were exclusively carried out by Calmette and his collaborators at the Pasteur Institute in Paris. Initially improvised production in a small room in the cellar gave way in 1931 to the construction of the spacious and magnificent ‘New laboratories for research on tuberculosis and the preparation of the BCG’ within the premises of the Pasteur Institute. Presentation and image-building of the vaccine in France insisted on the fact that the BCG was not a commercial specialty but distributed free of charge. The technical monopoly of its production nevertheless lay with the Paris Pasteur Institute and standardization of scientific proof of safety, efficacy and stability was dominated by that Institute in France. In contrast, the international production and distribution of the vaccine was entrusted and transferred, free of charge, to trustworthy laboratories outside France. Multiplication of producers and users led to an increased need for standardization. For this process the analysis distinguishes between the standardization of scientific proof concerning safety, efficacy and stability of the vaccine and standardization of its medical uses. Whereas standardization was rather successful in the inter-war period in France, the international efforts remained rather unsuccessful. Only after world war II under Scandinavian leadership and in the context of mass vaccination programs supported by the WHO and UNICEF was the international standardization effectively implemented and succeeded at least to some extend.     

The IL-23/IL-17 pathway in human chronic inflammatory diseases – new insight from genetics and targeted therapies

Chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, spondyloarthritis and psoriasis cause significant morbidity and are a considerable burden for the patients in terms of pain, impaired function and diminished quality of life, as well as for society, because of the associated high health-care costs, and loss of productivity. Our limited understanding of the pathogenic mechanisms involved in these diseases currently hinders early diagnosis and the development of more specific and effective therapies.The past years have been marked by considerable progress in our insight of the genetic basis of many diseases. In particular, genome-wide association studies (GWAS) performed with thousands of patients have provided detailed information about the genetic variants associated with a large number of chronic inflammatory diseases. These studies have brought to the forefront many genes linked to signaling pathways that were not previously known to be involved in pathogenesis, pointing to new directions in the study of disease mechanisms. GWAS also provided fundamental evidence for a key role of the immune system in the pathogenesis of these diseases, because many of the identified loci map to genes involved in different immune processes. However, the mechanisms by which disease-associated genetic variants act on disease development and the targeted cell populations remain poorly understood. The challenge of the post-GWAS era is to understand how these variants affect pathogenesis, to allow translation of genetic data into better diagnostics and innovative treatment strategies.Here, we review recent results that document the importance of the IL-23/IL-17 pathway for the pathogenesis of several chronic inflammatory diseases and summarize data that demonstrate how therapeutic targeting of this pathway can benefit affected patients.